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GuLF STUDY
Version 20.0 (07/19/2013)
GuLF STUDY:
Gulf Long-Term Follow-Up Study
Dale P. Sandler, Ph.D.
Principal Investigator
Chief, Epidemiology Branch
Division of Intramural Research
National Institute of Environmental Health Sciences
Richard K. Kwok, Ph.D.
Lead Associate Investigator
Epidemiology Branch
Division of Intramural Research
National Institute of Environmental Health Sciences
Lawrence S. Engel, Ph.D.
Associate Investigator
Department of Epidemiology
Gillings School of Global Public Health
University of North Carolina at Chapel Hill
and
Epidemiology Branch
Division of Intramural Research
National Institute of Environmental Health Sciences
Christine Parks, Ph.D.
Associate Investigator
Epidemiology Branch
Division of Intramural Research
National Institute of Environmental Health Sciences
Stephanie J. London, M.D., Dr.P.H.
Associate Investigator
Epidemiology Branch
Division of Intramural Research
National Institute of Environmental Health Sciences
Aubrey K. Miller, M.D., M.P.H.
Associate Investigator
Office of the Director
National Institute of Environmental Health Sciences
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National Institute of Environmental Health Sciences (NIEHS)
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Aaron Blair, Ph.D.
Consultant
Occupational and Environmental Epidemiology Branch
National Cancer Institute
Mark Stenzel
Consultant
Exposure Assessment Applications, LLC.
Patricia A. Stewart, Ph.D.
Consultant
Stewart Exposure Assessments, LLC.
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Table of Contents
Table of Contents................................................................................................ 3
List of Acronyms................................................................................................. 7
Protocol Summary .............................................................................................. 9
Précis ................................................................................................................. 10
Schematic of Study Design .............................................................................. 12
Background Information and Scientific Rationale ......................................... 12
1
Study Objectives .................................................................................... 15
1.1
Primary Objective ................................................................................. 16
1.2
Secondary Objectives ........................................................................... 16
1.3
Sub-study Objectives ............................................................................ 16
2
Study Design .......................................................................................... 17
2.1
Description of the Study Design ........................................................... 17
2.1.1
Study Population ........................................................................... 17
2.1.2
Study Cohort and Sub-cohorts ...................................................... 18
2.1.3
Exposure Reconstruction .............................................................. 20
2.2
Eligibility Criteria ................................................................................... 23
2.2.1
Rationale for including only workers or those who were trained .... 23
2.2.2
Rationale for Exclusions ................................................................ 24
2.3
Recruitment .......................................................................................... 25
2.3.1
Recruitment Database ................................................................... 25
2.4
Community and Scientific Outreach ..................................................... 26
2.4.1
Meetings with potentially affected groups ...................................... 26
2.4.2
Community Advisory Group........................................................... 29
2.4.3
Communicating the Study to the Community ................................ 29
2.4.4
Scientific Outreach ........................................................................ 31
2.5
Enrollment Procedures and Enrollment Questionnaire ......................... 31
2.6
Tracing.................................................................................................. 33
2.7
Procedures for Enrolling Cohort Members............................................ 33
2.7.1
Recruitment and Retention ............................................................ 33
2.7.2
Recruitment/Retention Strategies and Approach .......................... 34
2.8
Recruitment of Special Populations ...................................................... 35
2.8.1
Special Issues in Recruiting Vietnamese Participants ................... 35
2.8.2
Special Issues in Recruiting Creole-Speaking Persons ................. 36
2.8.3
Special Issues in Recruiting Women ............................................. 37
2.8.4
Special Issues in Persons with Reactive Airways Disease ............ 37
2.8.5
Other Special Populations ............................................................. 37
2.9
Home Visit ............................................................................................ 37
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2.9.1
Advance Study Packet .................................................................. 38
2.9.2
In-Home Visit ................................................................................. 38
2.9.3
Baseline Questionnaire ................................................................. 40
2.9.4
Anthropometric/Physiological Measures........................................ 41
2.9.5
Collection of Biological Samples ................................................... 43
2.9.6
Home Environment Sampling ........................................................ 45
2.9.7
In-Home Biospecimen Processing and Shipment ......................... 46
2.10 Reports to Participants, Health Care Referrals and Incident Reports ... 46
2.10.1 Overview ....................................................................................... 46
2.10.2 Home Visits or Participant Evaluations at other Locations ............ 47
2.10.3 Home Visit/Evaluation Measurements & Testing ........................... 48
2.10.4 Follow-up Actions for Abnormal Findings ...................................... 48
2.10.5 Abnormal Findings Form ............................................................... 54
2.10.6 Follow-up Reports & Information ................................................... 54
2.11 Laboratory Biospecimen Processing and Storage ................................ 55
2.11.1 Central Laboratory Processing ...................................................... 55
2.11.2 Study Sample Long-Term Storage at the NIEHS Repository ........ 56
2.11.3 Analyses (including future studies) ................................................ 57
2.12 Supplemental Add-on Studies .............................................................. 58
2.13 Follow-Up of Cohorts ............................................................................ 58
2.13.1 Telephone Questionnaires ............................................................ 58
2.13.2 Biomedical Surveillance Sub-cohort Follow-up (Year 1 and 3)...... 58
2.13.3 Annual Morbidity and Mortality Outcomes (Year 2 and later) ........ 59
2.13.4 Follow-up in Years 6-10................................................................. 59
2.14 Retention Strategies ............................................................................. 59
2.14.1 Annual Update of Contact Information........................................... 59
2.14.2 Newsletters and Other Mailings ..................................................... 60
2.14.3 Study Website ............................................................................... 60
2.14.4 Social Media .................................................................................. 60
2.14.5 Community Partnerships and Outreach......................................... 61
2.15 Remuneration ....................................................................................... 61
2.16 Study Timeline ...................................................................................... 62
3
Evaluation of Benefits and Risks.......................................................... 64
3.1
Potential Benefits .................................................................................. 64
3.2
Potential Risks ...................................................................................... 64
4
Adverse Event Reporting ...................................................................... 65
5
Study Oversight ..................................................................................... 66
6
Statistical Analysis Methods ................................................................. 67
Treatment of Exposure Status and Health Outcomes .......................... 67
Statistical Methods to Address Study Objectives .................................. 68
Interim and Safety Analyses ................................................................. 70
Laboratory QA/QC Analyses ................................................................ 70
6.1
6.2
6.3
6.4
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6.5
Sample Size Considerations and Power............................................... 70
6.5.1
Estimated sizes of worker (exposed) and non-worker (unexposed)
groups ........................................................................................... 70
6.5.2
Sample Power ............................................................................... 72
7
Analysis Plan .......................................................................................... 74
7.1
Primary Endpoints ................................................................................ 75
8
Training, Quality Control, and Quality Assurance .............................. 77
8.1
Staff Recruitment and Enrollment Process ........................................... 77
8.1.1
Telephone Interviewers ................................................................. 77
8.1.2
Home Visit Personnel .................................................................... 78
8.1.3
Monitoring of Recruitment and Field Activities ............................... 79
8.1.4
Personal Safety ............................................................................. 79
8.1.5
Mandatory Reporting Requirements .............................................. 80
8.1.6
Identifying and Dealing with Mental Health Issues, Domestic
Violence, and Acute Physical Illness ............................................. 80
8.1.7
Reporting Individual Results to the Participants ............................ 82
8.2
Data Quality Control ............................................................................. 83
8.2.1
Data Collection Quality Control ..................................................... 83
8.2.2
Data Storage ................................................................................. 83
8.2.3
Data Management & Communications .......................................... 84
8.3
Laboratory Procedures ......................................................................... 85
8.3.1
Laboratory Data Quality Control .................................................... 85
8.3.2
Quality Control Specimen Collection ............................................. 85
8.4
Run-in Period........................................................................................ 86
9
Human Subjects Protections ................................................................ 86
Institutional Review Board .................................................................... 86
Informed Consent Process ................................................................... 86
Participant Confidentiality ..................................................................... 87
Study Discontinuation ........................................................................... 88
9.1
9.2
9.3
9.4
10
Data Handling and Record Keeping ..................................................... 88
10.1 Data Capture Methods.......................................................................... 88
10.2 Data Management Responsibilities ...................................................... 89
10.3 Data Access and Sharing ..................................................................... 90
10.3.1 Access to Biospecimens and Use of Cohort for Add-on Studies ... 91
10.4 Study Records Retention ...................................................................... 91
Appendix A:
Scientific References............................................................... 92
Addendum 1: Current Environmental Exposures in GuLF STUDY
Participants Exposure Monitoring Addendum .................................... 99
Addendum 2: Pilot Study to Estimate Contact Rates for GuLF Follow-up
Interviews.............................................................................................. 115
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Addendum 3: GuLF STUDY Biomedical Surveillance Clinical
Examination .......................................................................................... 117
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List of Acronyms
ACD
AE
AAPOR
AIHA
ASTHO
ATS
ATSDR
BFR
BISCO
BP
BPA
BPM
BPSOS
BRFSS
CAG
CAI
CAPI
CATI
CBC
CDC
CLSI
CNS
CPL
CS
DMS
DNA
EPA
EPL
ERS
FDA
FEV1
FMV
FVC
GCF
GCP
GIS
GPS
HVA
HVAC
IL-18
IOM
IRB
Acid/Citrate/Dextrose
Adverse event
American Association for Public Opinion Research
American Industrial Hygiene Association
Association of State and Territorial Healthcare Officials
American Thoracic Society
Agency for Toxic Substances and Disease Registry
Brominated flame retardant
Bayou Interfaith Shared Community Organizing
British Petroleum
Bisphenol A
Beats Per Minute
Boat People SOS
Behavioral Risk Factor Surveillance System
Community Advisory Group
Computer-Assisted Interview
Computer-Assisted Personal Interview
Computer-Assisted Telephone Interview
Complete blood count
Centers for Disease Control and Prevention
Clinical Laboratory Standard Institute
Central Nervous System
Central processing lab
Clinical specialist
Data management system
Deoxyribonucleic acid
Environmental Protection Agency
Environmental Pathology Laboratories
European Respiratory Society
Food and Drug Administration
Forced Expiratory Volume in First Second
First morning void
Forced Vital Capacity
Gulf Coast Fund
Good Clinical Practices
Geographic Information System
Global Positioning System
Home Visit Agent
Heating, ventilating, and air conditioning
Interleukin-18 (IL-18)
Institutes of Medicine
Institutional Review Board
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JEM
KIM-1
LFT
LN2
MQVN CDC
MVV
NAGs
NDI
NGAL
NGO
NHANES
NIEHS
NIH
NIOSH
NOAA
NSDUH
NTP
OSHA
PAH
PEC
PFT
PTSD
QEESI
RBC
RFP
RNA
VOC
WBC
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Job-exposure matrix
Kidney injury molecule-1
Liver function test
Liquid Nitrogen
Mary Queen of Vietnam Community Development Corporation
Maximum Voluntary Ventilation
N-acetyl-beta-D-glucosaminidase
National Death Index
Neutrophil gelatinase-associated lipocalin
Non-governmental organization
National Health and Nutrition Examination Survey
National Institute of Environmental Health Sciences
National Institutes of Health
National Institute of Occupational Safety and Health
National Oceanic and Atmospheric Administration
National Survey on Drug Use and Health
National Toxicology Program
Occupational Safety and Health Administration
Polycyclic aromatic hydrocarbon
Petroleum Education Council
Pulmonary Function Testing
Post traumatic stress syndrome
Quick Environment Exposure Sensitivity Inventory
Red blood cells
Request for proposal
Ribonucleic Acid
Volatile organic compound
White blood cells
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Protocol Summary
Full Title:
Gulf Long-Term Follow-Up Study
Short Title:
GuLF STUDY
Conducted by:
NIEHS and SRA (NIEHS Epidemiology Branch
Clinical Research Contractor)
Principal Investigator:
Dale Sandler, Ph.D.
Division of Intramural Research
Epidemiology Branch
National Institute of Environmental Health Sciences
Sample Size:
55,000
Study Population:
Workers and volunteers engaged or potentially
engaged in oil spill clean-up operations in the Gulf of
Mexico
Accrual Period:
3/2011 – 03/2013
Study Design:
Closed prospective cohort
Study Duration:
10 years initially, with the possibility of extending the
follow-up period
Primary Objective:
To investigate potential short- and long-term health
effects associated with oil spill clean-up
activities/exposures surrounding the Deepwater
Horizon disaster
Secondary Objectives:
To investigate biomarkers of potentially adverse
biological effect in relation to oil spill clean-up
activities/exposures
To create a resource for additional collaborative
research on focused hypotheses or subgroups
To create a resource to better understand the short
and long-term human health effects of oil and oil
dispersants in the environment
Primary Endpoints:
Respiratory, genotoxic, hematologic, neurologic,
immunologic, and mental health
Secondary Endpoints:
Cancer, reproductive, cardiovascular, hepatic, and
renal effects
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Précis
The Gulf Long-term Follow-up Study (GuLF STUDY) will investigate potential short- and
long-term health effects associated with the clean-up activities following the Deepwater
Horizon disaster in the Gulf of Mexico on April 20, 2010. Crude oil, burning oil, and the
dispersants used during clean-up efforts contain a range of known and suspected toxins.
Over 100,000 persons have completed safety training in preparation for participation in
clean-up activities related to the spill. While many of these individuals participated in
active clean-up efforts, others did not. Exposures among persons involved in clean-up
range from negligible to potentially significant, especially for workers involved in tasks
associated with direct exposure to crude or burning oil, or to chemical dispersants.
However, prediction of adverse health effects is not possible because the long-term
human health consequences of oil spills are largely unknown due to the dearth of
research in this area. The potential health effects associated with the levels of exposure
experienced by clean-up workers are largely unstudied. Heat and stress experienced by
these workers may also have adverse long-term health effects. In addition to the oil
itself, the widespread economic and lifestyle disruption caused by the oil spill may
contribute to mental health problems among this population.
The over-arching hypotheses of this study are:
1. Exposure to constituents of oil, dispersants, and oil-dispersant mixtures, and to
spill-related stress by workers engaged in clean-up of the Deepwater Horizon oil
spill are associated with adverse health effects, particularly respiratory,
neurological, hematologic, and psychological or mental health.
2. There are exposure-response relationships between the above exposures and
health effects.
3. Biomarkers of potentially adverse biologic effects are associated with the above
exposures.
Based on what is known about individuals involved in clean-up efforts, the cohort will
consist primarily of English-, Spanish-, or Vietnamese-speaking adults who performed
oil-spill clean-up-related work (“exposed”) and similar persons who did not engage in
clean-up-related work (“unexposed” controls). Accommodations for enrolling
participants speaking other languages will be developed through community
collaborations as appropriate. Workers will be sampled from across job/potential
exposure groups. A total of approximately 55,000 persons are expected to be enrolled
into the cohort. A random sample of the full cohort, stratified by category of job/potential
exposure (including N~6,000 with no oil-spill work to serve as controls) and oversampled
for workers with higher potential exposures, will be enrolled into an Active Follow-up
Sub-cohort (N~20,000). A random sample of the Active Follow-up Sub-cohort, also
stratified by category of job/potential exposure and oversampled for workers with higher
potential exposures, will be enrolled into a Biomedical Surveillance Sub-cohort
(N~5,000). Participants will be interviewed about their clean-up-related tasks,
demographic and socioeconomic factors, occupational and health histories,
psychosocial factors, and physical and mental health. Members of the Active Follow-up
Sub-cohort will also be asked to provide biological samples (blood, urine, hair, toenail
clippings, and possibly saliva) and environmental samples (house dust) and will have
basic clinical measurements (height, weight, waist and hip circumference, blood
pressure, urinary glucose levels, FEV1 and FVC as a measure of pulmonary function)
taken during home visits at baseline. The Biomedical Surveillance Sub-cohort will
participate in a more comprehensive clinical assessment after the initial home visit,
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including more comprehensive pulmonary function testing, neurological testing, and
collection of additional biological and environmental samples. The specific tests to be
performed and clinical protocols will be developed in collaboration with extramural
investigators selected through a request for proposals (RFP). When developed, the
protocol for this portion of the study will be submitted separately to the Institutional
Review Board as a study amendment.
Exposures will be estimated using detailed job-exposure matrices developed from data
from monitoring performed by different agencies and organizations during the crisis, as
well as information on recommended or actual use of personal protection, information
obtained by interview, and the available scientific literature. It should be noted that, in the
absence of individual or group monitoring data for most workers, estimates of exposure,
whether based on job activities or on more refined job-exposure matrices, will indicate
the degree of potential exposure (i.e., exposure opportunity) rather than known
exposure. We will investigate acute health effects via self-report from the enrollment
interview among all cohort members and also via clinical measures and biological
samples from Active Follow-up Sub-cohort members. All cohort members will be
followed for development of a range of health outcomes through record linkage (cancer,
mortality) and if feasible, through linkage with electronic medical records that may
become available during the course of follow-up. Health outcomes among the Active
Follow-up Sub-cohort will also be identified through self-report via periodic follow-up
interviews. Additional outcome information will be obtained on the Biomedical
Surveillance Sub-cohort from periodic follow-up clinical evaluations (e.g., spirometry,
neurological testing) and analysis of follow-up biospecimens (e.g., immunologic
parameters, liver function, renal function, DNA damage). Follow-up of the entire cohort
is initially planned for 10 years, with extended follow-up possible depending upon
scientific and public health needs and the availability of funds.
Recruitment of subjects should begin in March 2011, with the telephone interviews
expected to be completed within 12-24 months and the baseline home visits within 18-26
months. For the home visits, we will initially target workers residing in the four most
affected Gulf States (LA, MS, AL, and FL), although we may expand to other states if
further information about the geographic distribution of workers and their potential
exposures warrants additional follow-up in these states. We will work closely with a
Community Advisory Board to develop community support for this study and appropriate
communications and study materials.
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Schematic of Study Design
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Background Information and Scientific Rationale
There has been little research of the long-term health effects from oil spills despite the
fact that between 1970 and 2009, there were 356 spills of more than 700 tons from oil
tankers, with approximately 38 of these spills affecting coastal populations [International
Tanker Owners Pollution Federation Limited (ITOPF) 2009, Aguilera, et al. 2010]. The
Deepwater Horizon disaster, with its release of approximately 5 million barrels (~680,000
tons) of crude oil into the Gulf of Mexico, is far larger than any of these tanker spills.
Given the magnitude of this spill and the scope of the potential exposures – at least
55,000 workers involved in clean-up efforts and countless residents of the affected areas
– study of the human health effects of this spill is urgently needed to monitor Gulf cleanup workers and to understand the adverse consequences of oil spills in general.
Crude oil is a complex mixture containing a range of known and suspected toxins,
including volatile organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs),
hydrogen sulfide, and heavy metals. VOCs, particularly benzene, have been linked to
lymphohematopoietic malignancies [Savitz and Andrews 1997, Hayes, et al. 2001,
Glass, et al. 2003, Steinmaus, et al. 2008, Baan, et al. 2009] and kidney dysfunction
[Chang, et al. 2010]. They can also cause central nervous system (CNS) depression,
respiratory irritation, and immune system alterations [Kirkeleit, et al. 2006, Gillis, et al.
2007, Lee, et al. 2007, Cho 2008]. Naphthalene, which causes olfactory
neuroblastomas, nasal tumors, and lung tumors in rodents, is listed as possibly
carcinogenic to humans (Group 2B) by IARC [IARC 2002]. Polycyclic aromatic
hydrocarbons (PAHs) include known carcinogens and may alter reproductive and
immune functions [Agency for Toxic Substances and Disease Registry (ATSDR) 1995].
Hydrogen sulfide can cause acute and chronic CNS effects such as headaches, poor
attention span, poor memory, and poor motor function [Agency for Toxic Substances
and Disease Registry (ATSDR) 2006]. Heavy metals found in crude oil, including
arsenic, cadmium, chromium, manganese, copper, nickel, vanadium, and lead, have a
range of adverse health effects, including neurotoxicity and carcinogenicity, renal and
immunotoxicity [ATSDR 1999, 2004, 2005, 2007a, 2007b, 2008a, 2008b, 2009, Hazen,
et al. 2010, Camilli, et al. 2010, Botello, et al. 1997].
Burning oil produces particulates, which have adverse cardiac and respiratory effects,
and may generate dioxins because of incomplete combustion in the presence of chlorine
in the sea water (Howard 2010).
The dispersants used to break up the oil contain a number of respiratory irritants,
including 2-butoxyethanol, propylene glycol, and sulfonic acid salts. Heat and stress
experienced by the clean-up workers may also have adverse health effects. In addition
to exposures from the oil itself, the widespread economic disruption caused by the oil
spill may also contribute to mental health problems in a population with potentially
increased vulnerability due to prior exposures to trauma, financial strain and social
stressors arising from other recent disasters [Galea, et al. 2008]. Such stressors may
also adversely impact physical health.
The few studies that have evaluated the human health consequences of oil spills have
primarily focused on acute physical effects and psychological sequelae. These studies
have examined the Exxon Valdez (Alaska, 1989), Braer (Shetland Islands, UK, 1993),
Sea Empress (Wales, UK, 1996), Nakhodka (Oki Islands, Japan, 1997), Erika (Brittany,
France, 1999), Prestige (Galicia, Spain, 2002) and Tasman Spirit (Karachi, Pakistan,
2003) oil tanker spills. Most of these studies were cross-sectional. A number of the
studies reported respiratory symptoms, including cough and shortness of breath
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[Carrasco, et al. 2006, Janjua, et al. 2006, Meo, et al. 2009, Sim, et al. 2010]. In a followup study among clean-up workers of the Prestige oil spill, Zock et al [2007] observed
that lower respiratory tract symptoms persisted 1 to 2 years after exposure had ended
(although the excess risk decreased with increasing time from last exposure) and that
the symptoms showed exposure-response patterns in relation to number of exposed
days, exposed hours per day, and number of activities. Meo et al [2008, 2009] reported
a reduction in forced vital capacity (FVC), forced expiratory volume in first second
(FEV1), and forced expiratory flow and maximum voluntary ventilation (MVV), including
exposure-response trends, in a small study of workers involved in the clean-up of the
Tasman Spirit oil spill. Other commonly reported symptoms in these studies include itchy
eyes, nausea/vomiting, dizziness, and headaches [Campbell, et al. 1993, Lyons, et al.
1999, Morita, et al. 1999, Carrasco, et al. 2006, Janjua, et al. 2006, Meo, et al. 2009,
Sim, et al. 2010], and skin irritation/dermatitis [Campbell, et al. 1993, Janjua, et al. 2006,
Sim, et al. 2010]. It is worth noting that, among Prestige oil spill clean-up workers, proper
safety training was associated with greater use of protective equipment and a lower
frequency of health problems [Carrasco, et al. 2006], which indicates that training can be
effective in prevention.
In addition to health effects induced by chemical and physical exposures, physical and
mental health may be adversely affected through pathways involving physiological and
psychological responses to acute and chronic stressors related to the disaster. Adverse
psychological consequences have frequently been linked to previous oil spills. Excess
prevalence of generalized anxiety disorder, posttraumatic stress disorder (PTSD), and
depressive symptoms were observed among communities affected by the Exxon Valdez
oil spill approximately one year after the spill occurred [Palinkas, et al. 1993]. Similar
patterns of higher anxiety and depression scores and worse mental health were
observed among communities near the Sea Empress spill [Lyons, et al. 1999]. The
Braer spill was associated with increased somatic symptoms, anxiety, and insomnia, but
not personal dysfunction or severe depression [Campbell, et al. 1994]. Worse mental
health scores were related to proximity to the Prestige spill [Sabucedo, et al. 2010].
In studying stress-related effects, it will be important to consider measures of mental
health and biological response to evaluate both subjective and objective outcomes. In a
community-based study of residents living near a petrochemical complex, perceived
health was related to perceived risks due to chemical exposures, while inflammatory
cytokine levels were related to objective proximity to the complex [Peek, et al. 2009]. In
the same community, interviews after a petrochemical accident revealed significant
decreases in perceived physical and mental health associated with multiple covariates,
including lower education, distance and impact of the disaster [Peek, et al. 2008].
Susceptibility to the adverse effects of disasters may be increased by a variety of
factors, including extent of exposure, female gender, middle age, ethnicity or minority
status, pre-existing mental and physical health, economic and psychosocial resources
[Norris, et al. 2002]. Consequently, the stress-related effects of the Deepwater Horizon
Disaster may be amplified in a population still recovering from the impact of other recent
disasters and in vulnerable subpopulations [King and Steinmann 2007, Galea, et al.
2008]. Research in the affected region also needs to take into account the unique
history and potential vulnerability of migrants, ethnic or cultural minorities in the study
population, e.g., Vietnamese [Palinkas, et al. 1992, Do, et al. 2009, Norris, et al. 2009].
Studies of genotoxicity and endocrine toxicity also point to potential adverse effects
among oil spill clean-up workers. All but one of these studies were conducted among
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clean-up workers involved in the Prestige incident. Findings include significantly higher
DNA damage, as measured by the comet assay, but not cytogenetic damage, as
measured by the micronucleus test, among exposed individuals compared to controls,
which was related to duration of exposure [Laffon, et al. 2006, Perez-Cadahia, et al.
2006]. Clean-up workers were also found to have significantly elevated blood levels of
aluminum, nickel, and lead, but decreased levels of zinc [Perez-Cadahia, et al. 2008]. In
addition, exposed workers had significant decreases in blood prolactin and cortisol levels
[Perez-Cadahia, et al. 2007]. A recently published study of the Prestige cohort
[Rodriguez-Trigo, et al. 2010] found an increased risk of structural chromosomal
alterations in circulating lymphocytes among exposed workers two years after the spill.
These results are consistent with studies showing increased DNA damage in relation to
low level exposure to benzene [Bagryantseva, et al. , Maffei, et al. 2005, Chen, et al.
2008, Fracasso, et al. 2010] and PAHs [Bagryantseva, et al. , Novotna, et al. 2007,
Gamboa, et al. 2008]. On the other hand, a study of persons affected by the Braer spill
[Cole, et al. 1997] found no evidence of genotoxicity through either DNA adducts in
peripheral blood mononuclear cells or mutations at the HPRT locus in T lymphocytes.
Studies of upstream petrochemical workers, who are likely to have many exposures
similar to that of oil spill clean-up workers, have reported excesses of leukemia, multiple
myeloma, melanoma, and esophageal adenocarcinoma [Schnatter, et al. 1992, Kirkeleit,
et al. 2008]. While such rare outcomes may take years to develop, immediate and
lasting changes may be seen in intermediate biomarkers indicating toxic effects and
potential for future disease risk. The immune system may represent a particularly
sensitive and accessible system for determining physiological impact of oil spill
exposures. For example, the hematotoxic and immunotoxic effects of benzene
exposure have been well-described, occurring even at relatively low levels of exposure
[Lan, et al. 2004]. These effects, indicated by downward shifts in leukocyte and red
blood cell counts, may also be more apparent in susceptible subgroups defined by
genetic variation in inflammatory, apoptotic, or metabolizing pathways [Lan, et al. 2005,
Kim, et al. 2007, Lan, et al. 2009, Zhang, et al. 2010]. Benzene’s toxicity to
hematopoietic progenitor cells may also impart long-term effects on the immune system
leading to premature immunosenescence. This idea is supported by the finding that
higher personal benzene exposures in traffic officers were associated with significantly
shorter leukocyte DNA telomere length [Hoxha, et al. 2009], a marker of immune aging
that has been related to risk of multiple chronic disease outcomes and mortality. Other
intermediate markers related to chronic disease risk include inflammatory cytokines,
antibodies indicating reduced immunity to latent viral infections, or auto-antibodies,
though limited information exists on these measures in past studies of oil spill or
petrochemical workers.
1
Study Objectives
This research effort is designed to investigate potential short- and long-term health
effects among workers engaged in clean-up activities surrounding the Deepwater
Horizon oil spill. Given the very limited health effects research conducted to date on oil
spill clean-up workers, the GuLF STUDY is designed not to study a few narrow a priori
hypotheses, but rather to allow the investigation of a wide range of potential adverse
health effects, including physical, psychological, and biological effects. The long-term
goal of this study is not only to identify adverse health outcomes related to clean-up
activities among the Deepwater Horizon responders, but also to assemble information
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that can be used for prevention and intervention of adverse health outcomes in any
future similar disasters.
The over-arching hypotheses of this study are:
1. Exposure to constituents of oil, dispersants, and oil-dispersant mixtures, and to
spill-related stress by workers engaged in clean-up of the Deepwater Horizon oil
spill are associated with adverse health effects, particularly respiratory,
neurological, hematologic, and psychological or mental health.
2. There are exposure-response relationships between the above exposures and
health effects.
3. Biomarkers of potentially adverse biologic effects are associated with the above
exposures.
1.1
Primary Objective
The primary objective of the GuLF STUDY is to assess a wide range of potential shortand long-term human health effects associated with clean-up and disposal activities
surrounding the Deepwater Horizon oil spill in the Gulf of Mexico. Health areas of
interest include, but are not limited to, respiratory, cardiovascular, hematologic,
dermatologic, neurologic, cancer, reproductive, mental health, substance abuse,
immunologic, hepatic, and renal effects.
1.2
Secondary Objectives
A key aspect of assessing these health effects will be to investigate biomarkers of
potentially adverse biological effect, including DNA damage, aberrant epigenetic profiles,
and alterations in gene expression, some of which have been observed in previous
studies of oil spill clean-up workers.
Additionally, secondary objectives of the study are to: 1) create a resource for additional
collaborative research on specific scientific hypotheses or on subgroups of interest. We
will work with external scientists to facilitate nested sub-studies within the existing cohort
to examine outcomes and exposure subgroups of interest; and 2) create a resource to
better understand the short and long-term human health effects of oil and oil dispersants
in the environment.
1.3
Sub-study Objectives
At this time, one sub-study, the Biomedical Surveillance Sub-cohort, is planned as an
integral part of the study proposal although the specific tests to be carried out and the
implementation details are not yet designed. The detailed protocol (s) for this Subcohort will be developed in collaboration with extramural partners and will be separately
peer-reviewed. Objectives of the Biomedical Surveillance Sub-cohort will include
investigating immediate and ongoing physiological and clinical parameters in a group of
highly exposed workers and a smaller number of unexposed workers. Establishing this
exposure-enriched group that contains more detailed information on adverse outcomes
and repeated biological measures will provide an important resource for longitudinal
studies and enable nested comparisons with measures obtained on the larger cohort.
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Study Design
2.1
Description of the Study Design
The GuLF STUDY has been designed to allow investigation of potential short- and longterm health effects associated with the oil spill clean-up work and to create a resource
for collaborative research on specific scientific hypotheses or subgroups. It is an
observational prospective cohort study that will create opportunities for both analyses of
the full cohort as well as numerous nested analyses. The design will enable investigators
to efficiently address specific hypotheses generated from previous studies of oil spill
exposures and, importantly for an exposure that has not been studied in relation to longterm health outcomes, allow them more generally to identify new symptoms and
conditions that may occur in excess among the exposed participants and determine the
extent to which any physical and mental health conditions persist. The data and the
biological and environmental samples that will be collected will allow examination of a
wide range of health areas of interest, including respiratory, cardiovascular, hematologic,
dermatologic, neurologic, cancer, reproductive, mental health, immunologic, hepatic, and
renal. The study is planned to be at least 10 years in duration, although it is anticipated
that the study may continue for 20 years or more, through record linkage, at a minimum.
Prospective studies typically have a long-term design because some diseases of
interest, such as cancer, generally have long latency periods, e.g., 15-20 years or more.
Consequently, we will consider extending this study, based on what we learn during the
initial study period, scientific and public health needs, and on the availability of funds.
2.1.1
Study Population
To capture a representative sample of the clean-up workers and controls, we will target
individuals across the various categories of job/potential exposure from the Petroleum
Education Council (PEC), National Institute of Occupational Safety and Health (NIOSH),
or other worker/volunteer rosters, security badging and access lists, and other
administrative lists maintained by BP contractors such as The Response Group (TRG)
Swift, and Foresight Vantage (among others). These individuals are potential
participants because they are believed to have engaged in clean-up work or participated
in worker training modules in anticipation of such work. We will exclude individuals such
as journalists who did not engage in clean-up activities but were required to undergo
safety training to gain access to worker staging areas (and, therefore, may appear on
the PEC list). These individuals will be determined from either the training lists (i.e.,
individuals who indicated that they intended to work for less than one week) or via
screening questions during the enrollment telephone interview. We will use data from
our planned mini-pilot (at the beginning of field work) to determine the feasibility of also
efficiently identifying and excluding individuals such as caterers and administrative/office
staff who engaged in clean-up related activities, but not clean-up activities per se;
however, this issue is complex and requires data that will become available only after we
go into the field. We define potentially exposed subjects as individuals who completed
at least one day of oil-spill clean-up-related work, either paid or volunteer. We define
unexposed subjects as eligible individuals who either 1) completed safety training in
anticipation of performing clean-up work but did not do so or 2) engaged only in clean-up
activities such as administration, oversight, and logistics that involved no exposure to
spill-related oil, oil byproducts, or dispersants. Selection for the Active Follow-up Subcohort will cover all levels of potential exposure but will oversample workers with the
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highest potential exposures to oil, oil byproducts and dispersants. We will conduct
interviews in English, Spanish, and Vietnamese. Special accommodation will be made
for those speaking other languages (e.g. Haitian Creole, Louisianan Creole, etc.), if
feasible and warranted by the number of workers speaking these languages. PEC
training was conducted in English, Spanish, and Vietnamese only so we do not
anticipate a large number of those speaking other languages. However, should this
change based on data from the PEC list or input from community groups, we will submit
an amendment to the IRB with appropriate translated documents for approval.
2.1.2
Study Cohort and Sub-cohorts
After administering a screening enrollment questionnaire to each potential cohort
member, we will use a two-stage sampling design to randomly sample individuals across
categories of job/potential exposure for invitation to participate in the Active Follow-up
Sub-cohort (N~20,000), which will be nested within the full cohort (N~55,000). We will
also randomly sample individuals within the Active Follow-up Sub-cohort across
categories of job/potential exposure for inclusion in the Biomedical Surveillance Subcohort (“tagging” N~6,250 with the expectation of obtaining agreement from N~5,000).
This nested design represents an efficient and cost-effective way to include most of the
clean-up workers in a prospective study and also to obtain comprehensive and detailed
clinical and biologic information on a scientifically appropriate sample of the total group
while maintaining statistical integrity through the use of the two-stage random sampling
design. The study effort, participant commitment, and potential knowledge gain
increases from passively followed members of the full cohort to members of the Active
Follow-up Sub-cohort to members of the Biomedical Surveillance Sub-cohort. For each
sub-cohort, we will oversample from job categories that had higher potential exposures
and/or were smaller to ensure adequate representation of higher potential exposures
and of all tasks performed.
Workers will primarily be identified from a combined list of workers who completed a
voluntary NIOSH Roster form and additional workers identified through the PEC list and
other lists that may become available of persons who may have been involved in cleanup activities (see Section 2.3.1 for a description of the lists of potential subjects.)
The Active Follow-up Sub-cohort will contain ~15,000 workers (“exposed”) from across
all job categories and ~5,000 controls (“unexposed”). While these groups are selected
on the basis of their potential exposure to oil or dispersants used in clean-up, both
groups will contain individuals who are “exposed” and not exposed to the stresses
associated with having lost their source of income due to the oil spill or living with
economic or social uncertainty due to their residential proximity to the spill. This subcohort will be largely restricted to persons residing in one of the four Gulf States primarily
engaged in clean-up activities (LA, MS, AL, and FL), prioritizing workers closest to the
spill area. Based on data on approximately 44,000 workers from the NIOSH roster, all
but 8% of workers were from these four states. Eligibility may later be expanded to
include other states based on information on the geographic distribution of workers that
we will receive from the PEC list and other worker lists. We will recruit workers from
other states only if it is determined, upon receipt of the potential subject lists that a large
number of workers with potential high exposures came from a given state. For logistical
reasons, we will not recruit controls from outside of the four most affected Gulf States.
Federal workers (e.g. Coast Guard, Occupational Safety and Health Administration
(OSHA), Fish and Wildlife Service (FWS), National Oceanic and Atmospheric
Administration (NOAA), Environmental Protection Agency (EPA), and others) residing
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outside of the four Gulf States and other workers who reside outside of the Gulf States
are eligible to be included if they had potentially high exposures because of specific
clean-up tasks performed. A Federal control group, within the larger sub-cohort control
group, will be based on the large number of Federal responders whose participation in
the clean-up was limited to roles such as administration, oversight, and logistics that
provided no potential exposure to spill-related oil, oil byproducts, or dispersants. We will
oversample certain categories of job/potential exposure of particular interest (e.g., those
with potential direct exposure to fresh crude or burning oil or to chemical dispersants).
Because there is a lack of centralized data concerning the distribution of categories of
work/potential exposure and we are likely to determine this distribution only when the
enrollment interviews are underway, we will periodically evaluate and revise as
appropriate our sampling probabilities. These probabilities will take into account the
distribution of jobs/potential exposures and statistical power. Participants in the Active
Follow-up Sub-cohort will 1) be administered detailed interviews, 2) provide biological
samples (blood, urine, hair, toe nail clippings, and possibly saliva) and environmental
samples (house dust), and 3) have basic clinical measurements taken at enrollment, and
4) will be administered two follow-up interviews. In contrast, passively followed members
of the full cohort will be administered only a brief telephone interview at enrollment.
Disease and mortality during follow-up will be obtained via linkage with cancer registries
and State vital statistics records.
The controls will preferentially be drawn from the PEC/NIOSH lists, which include some
individuals who were trained in anticipation of being hired for clean-up work but were
never hired. At some time during the peak work weeks, employers were advised that
heat related health issues might be especially problematic for obese workers or those
with high blood pressure. Although pre-employment screening may have been advised,
it is uncertain whether or not it was systematically carried out, and if done, may have
been contractor specific. Therefore, because some potential workers may have been
turned away due to health concerns, potential controls will be asked why they did not
participate in clean-up activities. Those indicating they did not qualify for medical
reasons will be excluded as will those who completed training to facilitate receipt of a
badge to enter the area, with no intention of performing any clean-up related tasks.
We estimate that there will be sufficient potential workers with minimal exposure for
internal comparison to serve as controls. However, if it turns out that our estimates are
incorrect and we need to consider other mechanisms to enroll a comparison group, we
will consider other approaches such as direct media or asking participants to tell their
friends and colleagues about the study and have their friends and colleagues contact the
study directly.
Because some workers from the four Gulf States will come from areas away from the
affected communities and because controls from the affected communities may have
experienced some spill-related exposures, including stress and social disruption, we will
establish two control groups. Persons from the lists described in Section 3.3.1 who are
determined to have not engaged in clean-up activities and are eligible for this study will
be placed in either a “local” control group or a “non-local” control group. The “local”
control group will consist of controls residing within the affected communities. Their
inclusions in analyses of the health effects of chemical exposures will account for the
stress and other psychosocial factors experienced by clean-up workers residing in the
affected communities. The “non-local” control group will consist of individuals residing
within the affected states, but outside of the affected communities. These individuals will
serve as a control group in evaluation of spill-related stress and other societal effects
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that may affect both exposed clean-up workers and unexposed controls residing in the
affected communities. Based on residence information from the 44,000 persons in the
NIOSH roster, 77% of the workers were “local” (i.e. lived in a coastal county in one of the
four states). Consequently, we will oversample “non-local” trainee controls to provide
sufficient statistical power for analyses involving this group. A third control group will
consist of the large number of Federal responders whose participation in the clean-up
was limited to roles such as administration, oversight, and logistics that entailed no
exposure to spill-related oil, oil byproducts, or dispersants.
Passively followed members of the full cohort will be those individuals who completed an
enrollment interview but were not included in the Active Follow-up Sub-cohort because
1) they did not reside in one of the targeted Gulf States, 2) they were not randomly
sampled for inclusion in the Active Follow-up Sub-cohort, or 3), they were unable or
unwilling to participate in active follow-up but are willing to be tracked over time.
Outcomes follow-up will be obtained via linkage with State cancer registries and vital
statistics databases.
The Biomedical Surveillance Sub-cohort will be an intensively evaluated subgroup
nested within the Active Follow-up Sub-cohort. It will be sampled from across the
categories of job/potential exposure and from controls, with oversampling of workers
with the highest potential exposures. Potential members of this sub-cohort will be
identified during the enrollment interview, based on their reported clean-up activities. To
achieve our target of ~5,000 members in this sub-cohort, we will identify ~6,250 potential
members during the enrollment interview, assuming that ~80% will ultimately agree to
participate in the further procedures required of the Biomedical Surveillance Sub-cohort
(given that they already agreed to participate in the Active Follow-up Sub-cohort and will
receive the benefit of more detailed health monitoring during the study) when they are
re-contacted later by extramural collaborators. This sub-cohort will undergo the same
baseline and follow-up procedures as the rest of the Active Follow-up Sub-cohort, but
will additionally participate in multiple follow-up visits involving health assessments that
include spirometry with bronchodilator challenge and neurological testing and collection
of repeat biological and environmental samples. This sub-cohort will undergo more
intensive biomonitoring than the rest of the Active Follow-up Sub-cohort, including
having their complete blood counts (CBCs), white blood cell (WBC) differentials and
more comprehensive urinalysis measured at baseline. [Note: These tests will be
performed for all 6,250 identified as potentially eligible for the Biomedical Surveillance
Sub-cohort as they must be performed on fresh samples. Similarly, lymphocytes will be
extracted and cryopreserved for the larger sample of potential participants.]
Protocols for the additional clinical examinations will be developed and implemented in
collaboration with local university partners identified through a request for proposals
(RFP) and, therefore, will not be discussed further in this protocol. These will undergo
separate scientific and Institutional Review Board (IRB) review. Consideration will be
given to focusing on the more highly exposed Gulf States (e.g. Louisiana and Alabama)
to facilitate comprehensive health examinations. We anticipate a standardized core
protocol with room for unique investigator initiated options to address additional
hypotheses.
2.1.3
Exposure Reconstruction
Although monitoring data will be available on some individuals for some exposures, most
participants in the study cohorts will lack such measurements. Because it is critical to
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have some indication of quantitative levels of exposure, it will be necessary to construct
exposure indicators from the available individual and environmental monitoring data,
characteristics of clean-up tasks, work locations, and times that these events occurred.
Given the absence of individual or area/group monitoring data for most workers, it is
important to note that estimates of exposure, whether dichotomous
(exposed/unexposed) or semi-quantitative (e.g., none, low, medium, high), will reflect
potential exposure rather than known exposure and references in this protocol to
exposures, except where indicated otherwise, should be interpreted as such. We will
validate the self-reported clean-up activities with security badge and payroll records to
the extent possible using available data. Moreover, we will work with survey
methodologists to ensure valid data collection. Investigators who are experts in industrial
hygiene exposure assessment will assemble exposure data and construct job-exposure
matrices for the exposures of interest using monitoring data from multiple sources.
These monitoring data, including individual measurements for some workers, area
measurements, and Health Hazard Evaluations, were collected during clean-up activities
and monitoring by OSHA, NIOSH, NOAA, EPA, Fish and Wildlife Service, US Geologic
Survey, the Coast Guard, and British Petroleum (BP). An interagency meeting was
convened on August 19 in Washington, DC to discuss these issues and identify sources
of data that could be used to reconstruct worker exposures across all tasks. An example
of these environmental monitoring data is provided in Appendix U. This spreadsheet was
first created by EPA as a way to identify data streams and later expanded to identify any
sampling within the Deepwater Horizon Response that may be redundant or
complementary. It will serve as a useful springboard from which to start cataloging the
available environmental data and will aid in the exposure assessment process.
In addition, available chemical analysis data of oil from the well, the dispersants used,
samples of weathered oil, and weather data from the period of the spill clean-up will be
considered in relation to exposure opportunities. This information will be assembled for
the exposure panel and may be used in exposure estimation and reconstruction. By
linking this exposure information with self-reported activity data, exposures will be
estimated for all included workers, including those from Federal agencies/institutions.
We will also use environmental samples (house dust), if available and appropriate, and
questionnaire data to identify relevant occupational and non-occupational exposures.
Lastly, we will evaluate existing exposure measurements on beach clean-up workers
and consider collection of additional biomonitoring data for this large subgroup if cleanup efforts are still underway at the time of cohort enrollment. A detailed protocol of
exposure assessment procedures will be developed by the study investigators in close
collaboration with the panel of experts described above.
We will work closely with academic and federal partners such as OSHA and NIOSH to
convene a panel of experts to systematically work through these exposure assessment
issues and develop a scientifically sound method for assigning exposures to the study
participants. This expert panel will develop a Job-Exposure Matrix (JEM) based on the
varied work tasks of cleanup workers and volunteers. Different dichotomous and ordinal
ranking metrics may need to be developed for the different chemicals and exposure
pathways that may be associated with different health effects. For example, a single
metric will probably not capture important differences in PAH exposure from particle
inhalation among oil burn workers versus dermal PAH exposure of absorbent boom
operators. The exposure metrics will not only need to consider differential exposures
based on job task, but will also need to consider the duration of exposures (e.g., hours
per day, total days of work).
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One of the challenges of this research is that most workers and controls will have
exposures to many of the chemicals of interest that are unrelated to the oil spill. Most
persons are exposed to benzene in ambient air (usually at very low levels) and to PAHs
from inhalation, dietary ingestion, and house dust. Such exposures are particularly
common among residents along the Gulf coast in Louisiana. There are also a number of
consumer products that contain 2-butoxyethanol or propylene glycol, two dispersant
ingredients of potential interest. Some workers and controls could have significant
occupational (non-spill related) exposures to some of these chemicals. In most cases,
these types of “background” exposures are likely to have similar distributions among the
worker and control populations. However, the study will need to carefully consider and
collect information to characterize these exposures. For example:
•
Commercial boat operators who participated in cleanup activities could
potentially receive higher long-term exposures to fuel oil and engine exhaust,
with many of the same chemical constituents as found in the spilled oil,
compared to a control group that did not include active boat operators.
•
Workers may come from Gulf coast locations affected by point sources of
petrochemical pollution not experienced by control living inland or in other states.
•
Workers hired directly by BP or its long-term contractors may have had other oil
industry jobs.
•
Workers hired early on may include those with prior training in hazard
remediation and may have been involved in cleanup from other smaller spills.
This potential confounding will be addressed through questionnaire data (occupational
and other relevant activities/exposures), GIS mapping as appropriate, and analysis of
biological and environmental samples. The expert panel will need to address these and
other challenges that face this critical component of the study.
While we have already consulted individually with other researchers who have examined
health effects associated with past oil spills, we are exploring the possibility of convening
an exposure assessment workshop of all of these study investigators to explore lessons
learned and to discuss findings to ensure that the GuLF STUDY is conducted to the
state-of-the-science.
It is important to note that many scientifically rigorous epidemiologic studies have
successfully used qualitative or semi-quantitative data derived from job-exposure
matrices to investigate exposure-disease associations [Coble, et al., 2009, Allen, et al.,
2006, Baris, et al., 2004, Kromhout, et al., 1995, Laakkonen, et al., 2008, Young, et al.,
2004, Richardson, et al., 2008, Lee, et al., 2003, Elci, et al., 2003]. This representative
sample of studies linked job titles and usual job activities to available monitoring data to
create job-exposure matrices that were used to estimate exposures in the study
population. Indeed, the epidemiologic investigations surrounding the Prestige oil spill
response in Spain utilized self-reported exposure information to assess health outcomes
that otherwise might have been missed [Suarez, et al. 2005, Carrasco, et al. 2006, Zock,
et al., 2007], Such studies have yielded scientifically valuable information and
demonstrate the important role that qualitative and semi-quantitative exposure data
and/or job-exposure matrices can play in epidemiologic research.
Although the development and evaluation of job-exposure matrices for the present
worker population would ideally have been done prior to beginning subject recruitment,
this was not a feasible option for this study, as is typically the case for studies
responding to disasters. A large amount of monitoring data has already been collected,
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is currently being aggregated, and will be available to us. Our main concern to this point
has been to design a scientifically rigorous study that we can get into the field as quickly
as possible and 1) capture the self-reported activities, dates, times, locations, etc. of
clean-up work that these workers engaged in before their memories fade and 2) enroll
these workers into the study before they move, change phone numbers, or otherwise
become lost to follow-up.
2.2
Eligibility Criteria
We anticipate screening as many as 90,000 individuals in order to recruit approximately
55,000 volunteers primarily from the four most affected Gulf States* (LA, MS, AL, and
FL) into the cohort, which will include a randomly sampled Active Follow-up Sub-cohort
of approximately 24,000 individuals nested within it. Eligibility criteria for the cohort
include:
•
21 years of age or older
•
Fall into one of two oil-related exposure categories:
•
Potentially exposed subjects must have completed at least one day of oil-spill
clean-up-related work (other than safety training), either paid or volunteer.
•
Unexposed subjects will be individuals who were not directly involved in oil spill
clean-up activities, but who worked near the oil spill or completed some oil spill
worker training.
Invitation to enroll in the Active Follow-up Sub-cohort will be made based primarily on
level of potential exposure as well as state of residence. Sampling probabilities will vary
across categories of job/potential exposure, with probabilities of up to 100% for persons
who report having engaged in oil clean-up related activities that are suspected of having
high exposures (e.g. working at the source, skimming, incineration, booming (specifically
retrieval of contaminated boom), wildlife clean-up, etc.). Available funding imposes an
upper limit on the size of the Active Follow-up Sub-cohort, but the number of workers in
different categories of job/potential exposure is currently unknown (and will likely remain
unknown until interviewing commences). Consequently, sampling probabilities will be reevaluated and adjusted periodically as study enrollment proceeds in order to realize the
study objectives and achieve the target size of the Active Follow-up Sub-cohort.
Because of 1) the small proportion of non-Federal clean-up workers from outside of the
four most affected Gulf States (< 8%, based on current data) and 2) the substantial
logistical challenges of including these workers in the Active Follow-up Sub-cohort, we
will include these individuals in the Active Follow-up Sub-cohort only if we determine that
an appreciable number of them engaged in clean-up activities with high potential
exposure. Otherwise, these individuals will be enrolled into the passive follow-up portion
of the cohort. This strategy is the same as that employed for the Federal workers in this
cohort.
2.2.1
Rationale for including only workers or those who
were trained
Morbidity and mortality rates from the general population include individuals who are
often too sick to work. Thus, those who are hired, or trained to be hired, are generally
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healthier than those who aren’t trained because relatively healthy individuals are more
likely to gain employment and remain employed – a phenomenon known as the “healthy
worker effect.” The healthy worker effect is particularly relevant in the selection of
unexposed controls. In order to obtain comparable controls for workers engaged in oil
spill clean-up activities, we would need to find individuals who otherwise would have
been able to work (i.e., were healthy enough to work), but weren’t hired to do so, thus
limiting their exposure. We plan to recruit from a master list that incorporates training
and badging information (e.g., the NIOSH roster, PEC training lists, Coast Guard
deployment logs, etc.) to identify workers who were trained to participate but may or may
not have been engaged in clean-up activities (“exposed” and “unexposed,” respectively).
Since everyone in the spill area was required to have a badge, and completion of a basic
training module was required to receive a badge, volunteers should have also completed
one or more training modules before engaging in clean-up activities. Others who worked
but were not trained through the PEC will also be eligible. This includes workers whose
training was separately administered through Parish organizations and individuals who
might not have completed required training modules for language or other reasons (e.g.
crew on Vessels of Opportunity whose captains, only, received formal worker training).
While exposed and unexposed individuals will be recruited during the same enrollment
period, if we aren’t able to find suitable non-exposed individuals from this master list, we
will seek matched controls in the community through references provided by the
participants themselves, individuals from the BP claims databases, or other community
selection techniques such as random digit dialing. This may involve more time than
identification of controls from the clean-up training lists. We have planned for these
activities to occur in the later months of recruitment so that we can focus on enrolling
exposed workers first.
We will actively enroll any individual, 21 years or older who is on a worker or volunteer
list describing any potential contact with oil and dispersants, regardless of their gender,
racial and ethnic background, or pregnancy status. Approximately 19% of the 44,000
workers enumerated by NIOSH were women. Although we do not anticipate a large
pregnant population, there may be individuals who were not aware that they were
pregnant or who otherwise engaged in clean-up related activities despite knowing that
they were pregnant and who may be recruited into the study.
2.2.2
Rationale for Exclusions
Participant selection and rationale for eligibility criteria have been described in detail in
Section 2.2 - Eligibility Criteria. Enrollment is open to adults of all racial and ethnic
background. Children will not be enrolled because they were not allowed to participate in
clean-up activities. Study activities present minimal risk to pregnant women. Therefore,
pregnant women will be allowed to enroll in the study, and women who become
pregnant during the study will not be withdrawn.
Those who were deemed medically ineligible to participate in clean-up activities because
of pre-existing conditions are excluded because they won’t be representative of those
individuals who were engaged in clean-up activities.
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Recruitment
2.3.1
Recruitment Database
The cohort will be recruited over a 12-24 month period, starting in March 2011 with the
baseline home visits completed within 26 months and will initially be followed annually
for at least 10 years. (We anticipate that the cohort will be followed for up to 20 years to
extract the maximum information from a study with a prospective design). Potential
participants will be identified from the existing NIOSH Voluntary Worker Roster
(N~55,000) which is being shared with the National Institute of Environmental Health
Sciences (NIEHS) through a Data Transfer Agreement. The NIOSH roster is believed to
contain a majority of the workers who engaged in clean-up activities, but is known to
have left out workers who were on the job early, workers trained through special
arrangements or certified as having been trained prior to the spill, and other potentially
important worker groups. We have reached an agreement with BP for access to the
larger Petroleum Education Council (PEC) list of individuals who completed one or more
safety training modules (N≈110,000) and will seek similar agreement to obtain other
known lists of individuals involved in clean-up activities (e.g., parish responder lists, BP
contractor payroll, and lists of Federal workers and contractors deployed to, or otherwise
engaged in, on-site clean-up activities in, the Gulf, including the Coast Guard, OSHA,
NIOSH, NOAA, EPA, Fish and Wildlife Service, US Geologic Survey, National Guard,
etc.). Because the NIOSH roster was developed in connection with worker training, it is
expected that most, if not all, names from the roster will be included on the PEC list.
Some, but not necessarily all, of those identified through Federal worker lists will also
appear on the PEC list. Some workers trained through Parish organizations and crew
members on Vessels of Opportunity are not expected to be found on the PEC list. Thus
as many as 130,000 may be enumerated through all lists combined. The PEC list may
include some duplicate names as a few workers were required to complete additional
training modules at a later date as workplace hazards were identified. Some of these
lists, such as those of employees of Federal agencies/institutions, will contain mostly, if
not entirely, persons involved in clean-up operations; other lists, such as the PEC list,
will include a substantial proportion of persons who did not participate in clean-up (but
may have taken the safety training in anticipation of doing so) and can be identified only
at the time of the telephone interview. We will work as quickly and efficiently as possible
with collaborating partners and other federal agencies in obtaining access to these lists.
Time is of the essence because we wish to interview clean-up workers and collect
biologic and environmental samples during clean-up activities or as shortly thereafter as
possible. This is necessary because biologic indicators of exposure dissipate with time
and individual’s recall of their activities also diminishes. In addition, it is important to
enroll subjects into the study before they move, change phone numbers, or otherwise
become lost to follow-up. Getting into the field as soon as possible is also essential to
maintain the goodwill of the affected communities, which will profoundly affect the
enthusiasm, support, and cooperation they show towards this study.
These databases will be merged into a master recruitment file to identify and remove
duplicates. We expect a total of about 130,000 names from the PEC list and other
worker lists combined, which we are assuming will be reduced to about 90,000 after
eliminating duplicate names and, if possible, those who completed training only to obtain
access to the spill site, with no intention of engaging in clean-up work (e.g. reporters,
government visitors, etc.). Where possible, we will infer potential exposure through the
training the individuals obtained, their reported or anticipated activities (collected on the
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NIOSH roster), and/or location in which they reported for work. However, we may not be
able to definitively confirm oil spill clean-up related activities until we interview the
participant and ascertain the types of activities that they performed. Thus, initial
exposure characterization will involve a two-stage process where a participant is flagged
for potentially being exposed/non-exposed which may later be modified based on
information from the telephone enrollment questionnaire will include a series of
questions which will ascertain exposure. Exposure classification for enrollment purposes
into the Active Follow-up Sub-cohort will be based on the participant’s answers to these
exposure questions. We will try to identify and prioritize enrollment of individuals with
likely exposures so that we can better characterize their exposures, but given the
limitation of not knowing a participant’s true exposure status prior to their interview, we
will most likely be enrolling exposed participants and unexposed controls at a
comparable rate.
2.4
Community and Scientific Outreach
The goal of the community outreach efforts is to fully apprise the community of study
activities, to ensure community collaboration and support in all aspects of the study
including design, implementation, evaluation, translation, and to disseminate findings
and results. Close and ongoing community engagement is expected to enhance the
scientific validity of the study, make it more broadly relevant from a public health
perspective, and expand its benefits to the affected communities.
2.4.1
Meetings with potentially affected groups
We have already established contacts and are continuing to solicit new contacts with
several community organizations, representative worker organizations, advocacy
groups, and state and local government representatives to identify the primary health
issues of concern locally and to discuss study implementation issues across the four
state area.
We have conducted a series of meetings with state and local health department
representatives as well as with the NGOs that span the various advocacy and
occupational groups representing the workers involved in clean-up throughout the Gulf.
We met with groups in Mississippi and Alabama during the week of September 12, 2010;
Florida the week of September 19, 2010; and Louisiana during the week of October 3,
2010. Other meetings are ongoing.
The groups we have contacted span cultural, religious, occupational, and state and local
government sectors and are continuously updated as more information and contacts are
made (current as of 10/22/2010). These groups serve as important links into the
community and can act as an informal Community Advisory Board for study protocol
issues and concerns for study investigators until a more formal Board can be
established. The groups listed below the groups that we have identified and established
contact with:
•
Advocates for Environmental
Human Rights
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•
Alabama State Health
Department
•
Alliance Institute
National Institute of Environmental Health Sciences (NIEHS)
•
Asian Americans for Change,
Mississippi
•
Bayou Grace Community
Services
•
Bayou Interfaith Shared
Community Organizing (BISCO)
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•
Louisiana Shrimp Association
•
Mary Queen of Vietnam
Community Development
Corporation (MQVN CDC)
•
Mississippi Center for Justice
•
Mississippi Commission on
Volunteer Service
•
Boat People SOS (BPSOS)
•
Coastal Family Health Center
•
•
Commercial Fisherman of
America
Mississippi Gulf Coast
Community College
•
Mobile BayKeeper
•
Deep South Center for
Environmental Justice
•
Moving Forward Gulf Coast, Inc.
•
Parish Presidents
•
Gulf Coast Fund for Community
Renewal and Ecological Health
(GCF)
•
South Bay Communities
Alliance, Inc.
•
Gulf Restoration Network
•
SeaGrant Programs in LA, MS
and AL
•
Interfaith Disaster Network
•
St. Bernard Project
•
Isle de Jean Charles Band of the
Biloxi Chitimacha
•
Steps Coalition
•
Local chambers of commerce
•
The Village/El Pueblo
•
Louisiana Bayoukeeper
•
Tri-Coastal Community Outreach
•
Louisiana Bucket Brigade
•
Turkey Creek Community
Initiatives
•
Louisiana Department of Health
and Hospitals, Region 1
•
United Commercial Fisherman
Association of Louisiana
•
Louisiana Department of Health
and Hospitals, Region 3
•
United Houma Nation
•
Louisiana Disaster Recovery
Foundation, Oil Spill Recovery
Policy & Advocacy Initiative
•
Vietnamese American Young
Leaders Association of New
Orleans
•
Louisiana Justice Institute
•
Vietnamese Martyr's Church
•
Louisiana Oystermen
Association
•
Zion Travelers Cooperative
Center
The meetings conducted to date with state and local health department and community
group representatives have already led to several improvements in questionnaire
development and study design. For example, the questionnaire has been revised to:
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•
•
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Better define labor categories;
Better characterize definitions of exposure;
Improve the ability with which the workers can recall key dates in their work
history; and
Include questions about the symptoms that are of the greatest concern to the
workers so that prevalence rates can be reported to the community.
•
Additionally, these meetings have allowed us to expand the resources included in the
health referral network and enabled us to better tailor messages to participants about the
study’s purpose and the importance of their participation. They have also provided us
with a better understanding of the barriers in recruitment and enrollment and how to use
community-based strategies to avoid these barriers.
As we further extend community outreach efforts, we will identify Community Outreach
Coordinators to organize and implement outreach activities in each of the Gulf States
who will:
•
•
•
Help to build strong relationships with NGOs representing the worker and
volunteer populations across the four Gulf Coast States.
Augment an advertising campaign (as described in Section 3.4.3) with grassroots promotional activities including local media placement (church bulletins,
community newspapers, etc) and community presentations.
Assist in recruitment of special populations as needed.
In addition to the continuing efforts with public health and community group
representatives, we have been conducting outreach in the following ways:
Webinars. NIEHS hosted a 90-minute webinar with local researchers, community
organizations and others interested in the GuLF STUDY on August 17, 2010 and a twohour Webinar on September 15, 2010. The purpose of the webinars was to announce
publicly the plans for the GuLF STUDY and obtain feedback on study design and
implementation from interested stakeholders. Prior to the webinar, NIEHS distributed a
draft GuLF STUDY Concept document and a Key Points document. Each webinar was
well attended by over 100 participants and we have received multiple offers from
community organizations to provide assistance for the study. Suggestions made during
and after the webinar have been incorporated into the study design. Additional webinars
are planned at future dates to be determined to continue information exchange and
dialog.
Phone briefing. As a follow-up to the first webinar and next step in the community
outreach efforts, we will invite key stakeholder groups, such as from the list above to a
follow-up phone briefing. The purpose of the phone briefing is to meet individually with
each stakeholder group to review the study aims and implementation, answer any
question or concerns about the study, establish a dialog with stakeholders, and begin
discussions on the primary health issues of concern for their constituents. Approximately
10-15 phone briefings will be conducted each lasting up to 30 minutes. At the end of the
call, we will document any action items and discuss plans for future meetings in person.
In-person meetings. As a follow-up to the phone briefings, we will travel to the four Gulf
States to meet in person with the community stakeholder groups. During the in-person
sessions, we will request to meet both with organizational leadership in addition to their
constituents. The purpose of these meetings is to further build strong community ties
and gather information to finalize the study design. Due to the short timeline to study
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launch we will immediately conduct informal discussions with leadership and listening
sessions with their constituents. The topics of these discussions are expected to broadly
include possible barriers to study implementation, resolutions to those barriers and the
best methods to communicate with study participants and publicize the study.
HRSA and State Health Department meetings. Meetings were conducted with State and
local Health Department representatives beginning the second week in September,
2010, including a combined meeting of leadership from Health Service Regions covering
the Gulf States on September 9-10, 2010. These meetings were intended to inform
state and local leadership about study plans and to obtain input into study design and
implementation. A specific focus of these meetings was to develop strategies for
community based health and mental health referrals for participants identified as
needing follow-up medical care (e.g. for follow-up of elevated blood pressure, or
glucosuria) or identified as having unmet mental health or social service needs. While
the GuLF STUDY is not designed to provide medical care to its participants, we will work
closely with local health officials to provide the appropriate referral information to
participants identified as having unmet medical and/or mental health needs.
Dockside Chats. Study staff joined the Unified Command in several Dockside chats with
workers during the week of August 22, 2010. These informal sessions provided insight
into some of the health and community concerns of workers from the affected region.
2.4.2
Community Advisory Group
A Community Advisory Group will be created to provide continued advice on the study
and outreach efforts. The group will consist of up to 15 members representing
communities as well as organizations representing worker groups from all four states as
well as various occupational groups and is expected to engage in the following activities:
•
Facilitate dialogue between community members and the study team
•
Identify effective communication strategies and vehicles tailored to the communities’
needs
•
Assist in the dissemination of study related information locally and regionally
•
Host community neighborhood meetings
•
Proactively identify issues of concern with study implementation and options for
resolutions
•
Retain participants in the study over time
A Community Advisory Group chair will be carefully selected from among its members
and will work in close collaboration with the study investigators. The Community
Advisory Group will meet regularly throughout the entire study duration. Meetings are
expected to occur more frequently during study planning and initiation and then less
frequently in the out years of the study.
2.4.3
Communicating the Study to the Community
Communication of the study activities to oil spill clean-up workers and affected
communities is essential. Many of these efforts will involve communications through
community leaders directly to their constituents, some will involve targeted outreach by
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the study and NIEHS, and other efforts will involve media-based outreach. Typically, it
takes multiple points of contact to build study credibility and motivate an individual to
participate in a health study, particularly a longitudinal health study. Although we will be
working from a known population of oil spill clean-up workers, media-based efforts will
afford the study legitimacy in an environment fraught with competing Katrina-focused
studies, distrust of the government, and scientific complexity. Additionally, media-based
outreach in conjunction with more direct-to-worker outreach will allow for the ability to
reach a larger number of individuals in a very short time frame. The Community Advisory
Group will be crucial in designing this process and enhancing its effectiveness.
Brochure. A study brochure (Appendix G) will be developed in English, Spanish and
Vietnamese. The purpose of the brochure is to introduce the study and provide contact
information though the hotline and website. The brochure will be sent with the lead letter
inviting study participants during enrollment but may also serve a variety of other
purposes for community outreach.
Hotline. We will establish a toll free hotline for the study. During enrollment, the hotline
will be used for workers to return a call to participate in the study. A call center
representative will answer the hotline during call center hours of operation, i.e. from 9
AM to 9 PM, Monday through Saturday and from 12 noon to 6 PM on Sundays. It will roll
to an answering machine after hours with all calls to potential participants returned the
following day. Call center hours will be determined based on input from the community
groups as to what would be acceptable.
Internet. We will maintain a website to provide information about the study. The website
will be updated regularly with details on recruitment efforts, study findings, and links to
other organizations and information resources. Additionally, we will seek to have each of
our community partners have a link on their website to the study website. We will also
explore the possibility of using Web 2.0 resources such as Facebook and Twitter if we
can be assured that participant confidentiality can be maintained and there are sufficient
numbers of individuals within our study population and community who would be using
these sites.
Advertising. Additional forms of media-based advertising will be determined in
collaboration with key stakeholder groups. Based on preliminary conversations with
various community groups, we anticipate utilizing media-based advertising to both
increase awareness and credibility of the study as well as motivate participation. Radio
may provide a good medium for communicating the study to certain segments of the
population while outdoor advertising may appeal better to other segments. Whenever
feasible, we will capitalize on opportunities to collaborate with community partners on
radio or TV show interviews, local newspaper articles, and other media as a form of
generating awareness and credibility for the study. Media outlets that have been
suggested by community members thus far include:
•
•
•
Radio stations: Q93, 98.5, 102.9, 106.7 (New Orleans, LA)
Newspapers: Sun Herald, Mobile Press Register
Television: WLOX, WDSU, WGNO
As a first step in developing a media campaign, we will enlist the support of a public
relations/communications firm with an understanding of the various communities along
the Gulf Coast in the post-Katrina era and experience using print, electronic and
broadcast media to recruit for public health studies. To develop culturally competent
materials, this firm will develop key messages for different segments of the worker and
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volunteer populations and a communications plan to disseminate these messages.
Prototype materials will be submitted for IRB review once they are developed along with
details regarding the implementation of the communications campaign when the plan is
determined at a later date.
Text Messaging. An additional recruitment tool may include the use of text messaging.
We will pilot test a “Make the Call” campaign targeting ~250 individuals who have not
responded to recruitment mailings or calls. The plan complies with federal regulations
regarding text messaging solicitation in that participants must first opt-in to receive future
text messages. After an initial opt-in text, participants will receive no further texts unless
they choose to opt-in. Participants who opt-in will receive a series of text messages at a
rate of one per week that encourage participants to call the study hotline to enroll. If the
pilot effort is successful in increasing enrollment, we will extend the effort to others who
have been difficult to reach.
2.4.4
Scientific Outreach
The Webinars specifically targeted members of the scientific community, including
researchers from local universities, NIEHS grantees, and researchers with past
experience studying communities involved in other environmental disasters such as the
World Trade Center cohort. The study concept was reviewed by the National Institutes of
Health (NIH) Institutes and Centers Directors at a regularly scheduled meeting. An early
draft of the protocol outline was reviewed at a meeting August 12, 2010 with NIOSH and
CDC. The proposal was discussed August 19, 2010 at a meeting of multiple federal
agencies involved in some aspect of the Oil Spill response. Suggestions received during
those meetings have been incorporated into the current protocol draft. The proposed
study builds on ideas generated during a scientific meeting hosted by the Institute of
Medicine (IOM) on June 22, 2010. In addition to undergoing scientific peer-review prior
to submission of the study for NIEHS IRB review, the study received additional review by
an IOM panel at a meeting held in Tampa, FL on September 22, 2010. Additionally,
presentations of the study design have been (and will continue to be) made to a number
of Federal panels and committees (e.g., Association of State and Territorial Healthcare
Officials (ASTHO) and National Association of County and City Health Officials
(NACCHO)). The IOM is expected to provide ongoing scientific oversight. Oversight will
also be provided (see below) by a Scientific Advisory Board appointed by the Chair of
the NIEHS Board of Scientific Counselors, operating as a subcommittee of that Board.
2.5
Enrollment Procedures and Enrollment
Questionnaire
Initial contact with participants will be through a mailing which includes: 1) a one-page
lead letter (Appendix F); 2) a study brochure (Appendix G); and 3) a privacy statement.
The study brochure will briefly outline the study purpose, study benefits, study
sponsorship, contractor name, what will be asked of the participant, compensation if they
participate, confidentiality assurance, importance of their participation, and contact
information (contact names, toll-free telephone number, and web site address) if they
would like more information. Both the lead letter and the study brochure will contain
instructions together with the toll-free telephone number for opting out of being contacted
about participating in the study. Every attempt will be made to have the lead letter have
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the same message in English and either Spanish or Vietnamese, using both the front
and back of the page. The lead letter will introduce the enclosed four-color, tri-fold study
brochure which will contain instructional graphics and more details of the study. The
lead letter and brochure will both point to the website address for additional information.
The telephone contact schedule will be coordinated with the lead letter mailing by
parsing the sample into batches and working the mailing and then calling one a batch at
a time. Mailing of letters to each batch of names will precede calling by at least two
weeks to allow the letter and brochure to be delivered and the potential participant to opt
out of the study. The letter envelopes will request USPS to forward mail and to provide
us with an address update. Mail returned as undeliverable and with address update
notifications will be flagged for tracing.
At least two weeks after the lead letter mailings, the associated telephone numbers will
be released to telephone interviewers to commence screening and enrollment dialing
and interviewing. Interviewers will discover unusable telephone numbers – fast busy,
disconnected, no one by that name, etc. Telephone numbers with outcome codes
indicating they are unusable will be flagged for tracing. The telephone number
management system will apply calling algorithm rules to each telephone number based
on the pattern of interim outcome codes assigned by the interviewers at each dialing
(e.g., no more than two calls per day), varied times of day and weekend, weekend only,
once-a-day only, wait for a cool down period (initial refusal), scheduled call-backs, soft
appointments, etc. The telephone number management system will enforce these rules
when delivering telephone numbers to the interviewers. Calls will be conducted from 9
AM to 9 PM (local), Monday through Saturday, and 12 PM to 6 PM (local) on Sunday, if
acceptable to the community.
The interviewing staff will include a group of interviewers who are bilingual in English
and either Spanish or Vietnamese. We will attempt to identify the primary language of
each potential participant in advance of assigning calls to interviewers by considering
surname and other information that may be available in the master recruitment dataset
(e.g. variable indicating primary language in the NIOSH roster data). Potential
participants will be assigned to an interviewer who is fluent in their primary language and
English. In some cases, the call assignment process may fail to overcome language
barriers between the interviewer and the participant, and the interviewer may be forced
to abort the call. If the call is aborted, the interviewer will make notes about the call and
attempt to classify the primary language of the potential participant so that the call can
be reassigned to the appropriate interviewer.
The entire screening and enrollment telephone call will take approximately 30 minutes to
complete. Should the respondent be selected for active follow-up and agree to
participate, their contact information and scheduling information will be transmitted to
one of 14 regionally distributed clinical field supervisors who will assign the respondent
to the most geographically proximate Home Visit Agents (HVA) under their supervision.
Alternative strategies may be employed to enroll potential participants without phone
numbers or who cannot be reached by telephone, especially those from populations of
special interest such as Vietnamese fishermen involved in the Vessels of Opportunity
Program. We will work with community partners to bring such workers to community
centers where they may be interviewed by phone or in person or arrange for home visits
to complete the enrollment questionnaire (please see section 2.8 for additional details).
In the rare instance of data system technical difficulties that results in interview
interruption and in-process data not being saved, the participant will be recontacted and
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asked to restart the questionnaire. If they agree, we will provide remuneration in the
amount of a $10 gift card.
2.6
Tracing
Tracing will be conducted if we are unable to contact the participant by telephone or
reach them through the contact person they named on the NIOSH roster data.
Participants who cannot be initially reached with roster information will be flagged and
submitted for tracing in monthly batches. Fortunately, we have cell phone numbers (at
least for those listed on the NIOSH roster) which should significantly improve our ability
to contact participants. However, we are aware that participants may follow regional
practices found post Katrina and use “disposable” cell phones only for the time needed.
We have projected the need to conduct tracing for as much as 15 percent of the sample
and expect that we subsequently will be unsuccessful in tracing 5 percent of this group.
Recruitment and tracing efforts will be carried about by different staff members so that
the time required for tracing does not disrupt the recruitment process.
Rigorous locating operations will be instituted to reach study participants based on the
contact information obtained through the automated batch tracing databases, such as
Lexis Nexis Accurint, Telematch, Pension Benefit Information, National Change of
Address, and Trans-union as well as InfoUSA and Experian.
2.7
Procedures for Enrolling Cohort Members
Participants will be randomly sampled across categories of job/potential exposure
reported during the enrollment interview, with oversampling of categories with higher
potential exposures, for invitation to participate in the Active Follow-up Sub-cohort.
Additionally, controls will be randomly sampled for invitation to participate in the Active
Follow-up Sub-cohort.
Persons who are not randomly selected for inclusion in the Active Follow-up Sub-cohort
or who decline to participate in the Active Follow-up Sub-cohort will be enrolled as
passively followed members of the full cohort. They will have given verbal consent for
completing the telephone interview, providing annual updates on contact information,
and having their health and vital status tracked via electronic data. They will include
individuals across the range of exposures, including controls. Because this group will
include persons not selected into the Active Follow-up Sub-cohort, it will likely be
disproportionately weighted towards workers with lower potential exposures to oil-spill
related chemicals.
2.7.1
Recruitment and Retention
Effective recruitment is critical to the success of this study yet the nature of the study
population, protocol, and the long follow-up period present inherent challenges to
recruiting and retention. A multi-faceted approach to participant recruitment and
retention will take into account best practices in the participant recruitment literature as
well as proven methods utilized in past studies conducted in similar populations.
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Participation rates in health studies and surveys have been declining for the last several
decades. This general trend serves as backdrop to several specific challenges inherent
to this study.
One significant challenge in recruiting and retaining participants will be to address the
unique circumstances faced by Gulf Coast families both prior and subsequent to the
Deepwater Horizon Oil Spill. Many of the affected communities were already under
economic stress because of Hurricane Katrina and the recent recession, which makes it
difficult to engage them in research even under the best circumstances. Gulf Coast
families are experiencing further environmental, financial, and health-related impacts
since the disaster. Recruitment and retention strategies must take into account these
day-to-day circumstances and other obligations such as employment, childcare, etc. to
mitigate known barriers to participation.
A related challenge will lie in gaining credibility and cooperation from a population that
may be wary of research studies conducted by outsiders, particularly government-based
studies. It will be important to demonstrate an understanding of the circumstances these
individuals face. Recruitment strategies are needed that position the team to capitalize
on community outreach efforts as well as efforts to brand the study as something other
than “just another government study.” As with all studies, potential participants may be
reluctant or unable to spend the time or experience the inconvenience involved in study
participation. Recruitment strategies are needed to overcome these sources of
reluctance and present the study as beneficial.
After participants are enrolled in the study, maintaining their continued participation over
the full follow-up period is critical. Participants will relocate, experience family disruptions
such as divorce, death or illness, undergo economic changes, and realize logistical
difficulties. Strategies are needed that motivate continued participation and alleviate
logistical constraints.
For all of these reasons, this study will develop a comprehensive recruiting and retention
plan designed to maximize participation for the entire duration of the study with
assistance from the Scientific and Community Advisory Committees, while using study
resources efficiently. Although monetary incentives may be necessary, an array of other
strategies will be applied to cultivate a sense of loyalty, commitment, and appreciation
among study participants and oil-spill communities to the study. We will work closely with
state and local officials and local community groups to tailor an approach that will
resonate with the local community and foster participation in the study.
2.7.2
Recruitment/Retention Strategies and Approach
Importance. Recruitment interviewers will be trained to convey an appropriate sense of
the importance of the research among both exposed and unexposed individuals. This
importance relates not only to the oil spill, but also, more generally, to all of the health,
environmental, and psychological impacts (e.g., displacement, stress, exposures)
associated with disasters, ultimately to support a better understanding of how to respond
to such disasters. This will be reinforced throughout the study with communications from
health officials and study investigators.
Direct Benefit. The main benefit is pride in having participated in an important public
health research effort for their communities. Participants will receive some results from
the medical testing. Recruitment approaches will be designed to minimize any potential
gap in perceived study benefit between the exposed and unexposed.
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Study Identification and Branding. The study will be presented publicly in a manner
that appropriately conveys its importance both to participants and to other audiences.
The study website will include information for the public as well as a place for
participants to learn more about the study, receive important study information, and
allow for the opportunity to email study investigators to schedule visits and update
contact information. Scientific publications and results will be posted on the website.
News items and press releases will announce and publicize the study while reflecting
local interest group and health department participation. Participants will also receive
annual newsletters to keep them informed about the progress of the study.
2.8
Recruitment of Special Populations
Based on data from the NIOSH roster and from reports from the field, we are currently
planning to recruit Vietnamese, Spanish, and English speaking participants. Speakers of
other languages may be targeted later through special accommodations such as
facilitated interviews by a relative or community representative speaking one of these
languages or through RFPs (and funded via subcontracts), as described below.
Although they may represent a small fraction of the worker population, it may be
important to include the Vietnamese and other unique ethnic subpopulations in the Gulf
region who may have participated in oil spill clean-up. Based on initial feedback from
the community, a multi-modal approach may be needed to ensure sufficient participation
amongst these groups that may have had elevated exposure through the Vessels of
Opportunity program and other clean-up related activities. Our planned multi-modal
recruitment approach would consist of the standard recruitment package of a mailed
recruitment letter and study brochure, but also additional community meetings to explain
the purpose of the study, opportunities to enroll in-person and/or at a centralized
recruitment facility, and other techniques to be developed in conjunction with input from
community representatives and state and local health officials. These groups will be
included in our pilot effort to provide adequate feedback to the rest of the study.
2.8.1
Special Issues in Recruiting Vietnamese Participants
To address issues around literacy, outreach, and access to the Vietnamese population
specifically, we will identify and work with NGOs having connections to, and
understanding of, this community. For example, in analysis of data from the NIOSH
roster and anecdotal reports from persons in the field it appears that Vietnamese
workers are substantially underrepresented on the NIOSH roster and may be similarly
underrepresented on the PEC list relative to the general population. This may be due to
language / literacy barriers that resulted in Vietnamese workers not receiving the worker
training or completing the NIOSH roster. To help identify these workers and suitable
controls, and to overcome language and cultural barriers to their participation in this
study, we will work closely with community groups, enlisted via RFPs (and funded via
subcontracts to the study contractor), that are integrated in the Vietnamese
community/communities. These groups include Asian Americans for Change, Boat
People SOS, Mary Queen of Vietnam Community Development Corporation,
Vietnamese American Young Leaders Association of New Orleans, and Vietnamese
Martyr's Church. Many of these community groups, along with Parish governments in
Louisiana, have maintained separate lists of clean-up workers from their communities.
We will meet with these community groups to explain the purpose of the study, the
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importance of participation of Vietnamese clean-up workers, the study methods, what
will be expected of the participants, and how these groups can help us, and we will
attempt to address their concerns.
For groups that agree to assist us in recruitment, we will work with their staff to develop
strategies and resources that are both culturally and scientifically appropriate for
promoting the study and identifying potential study participants. These groups will be
asked not to recruit study participants per se, but rather to assist in developing interest
and support for the study so that study staff can then approach potential participants in a
methodologically rigorous manner. They may be asked to produce and provide to study
investigators regularly updated lists of persons who they know or believe to have
participated in oil spill clean-up activities, including names, telephone numbers,
addresses, and other appropriate contact information (especially for any persons without
telephones). They will be requested to provide some basic demographic information and
reason for refusal for any workers who indicate that they are unwilling or unable to
participate in this study. They will also be asked to provide similar lists of Vietnamese
controls who are comparable to the clean-up workers they identify, based on criteria that
they will develop together with study investigators. However, it may prove necessary to
carry out a parallel supervised process to enroll this group, allowing subcontractors to
conduct in-person screening interviews rather than telephone interviews. In that case,
we will work with community groups to implement enrollment and data collection directly
but provide sufficient oversight to ensure protocol standardization.
To minimize bias in subject selection and data collection, we will attempt to conduct all
telephone interviews and in-home visits by study staff in Vietnamese. We will work with
community group staff to approach persons who do not have telephones or other
individuals recommended by the community group staff who could serve as liaisons. For
persons for whom telephone interviews are not appropriate or possible, interviews will be
conducted in-person, either at the subject’s home or at another suitable location. While
we will make every effort to provide Vietnamese-speaking phlebotomists/interviewers, it
may be necessary in some cases to provide a trained Vietnamese translator with
English-speaking phlebotomists/interviewers. In order to ensure full enumeration of the
potential cohort, participants and those who decline to participate will be asked to
provide names and contact information of any other Vietnamese clean-up workers they
may know. In order to facilitate engagement, commitment, and valid data collection
within this community, we will take the necessary steps to maintain as much
transparency as possible including inviting community stakeholder groups to the
interviewer training sessions and inviting them to assist in developing the training
materials to ensure cultural competency among the study staff. We will review these
procedures on an ongoing basis and modify them as needed to achieve the dual goals
of enumerating as fully as possible the workers and suitable controls in this community,
and recruiting and interviewing them in a scientifically rigorous manner.
2.8.2
Special Issues in Recruiting Creole-Speaking Persons
Anecdotal reports indicate that Creole-speaking persons in the Gulf have also been
involved in clean-up activities. These persons are likely to be substantially
underrepresented on the NIOSH, PEC, and other worker training lists because most of
these trainings have been conducted only in English, Spanish, and Vietnamese. We
have no information on how many such workers there were nor on what types of cleanup activities did they engage in. To fill in these critical information gaps, we will issue
RFPs to local community groups to help us enumerate these population(s) that may be
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under-represented in other worker lists. If we determine through these means that there
are sufficient numbers of potentially exposed workers in this population, we will work
with community stakeholder groups to promote the study and help recruit the workers
and appropriate controls from this population in a similar manner to that described above
for the Vietnamese.
2.8.3
Special Issues in Recruiting Women
Women will be recruited into the cohort by the same eligibility and selection criteria as
men. However, some additional sex-specific questions, focusing on menopausal status,
reproductive history, and pregnancy status, will be included in the enrollment
questionnaire. Potential sub-studies of women will be considered later, based on the
number of women, their exposure profiles, and the numbers of outcomes of interest.
2.8.4
Special Issues in Persons with Reactive Airways
Disease
We may consider focused sub-studies among persons identified with, or suspected to
have, reactive airways disease at enrollment. The timing and nature of these sub-studies
will depend on the number of such persons identified during enrollment and will be
described in more detail at a later date.
2.8.5
Other Special Populations
Other subgroups may be identified for add-on studies of focused hypotheses related to
specific exposures or health outcomes. These studies may be initiated by us or by
extramural collaborators. Participants will be informed that such add-on studies may be
possible and that separate informed consent to participate will be obtained.
2.9
Home Visit
Participants selected for the Active Follow-up Sub-cohort will be scheduled for an inhome visit by a field staff member (i.e., a home visit agent or HVA). We will ensure that
Home Visit Assistants (HVAs) hired for this study have the necessary education,
qualifications and experience to conduct the required home visit activities, or we will
provide additional training as needed. We currently plan to hire qualified staff of Certified
Medical Assistants (CMAs) who can do both phlebotomy and interviewing. During our
initial contact with the participant, we will note their ethnic status and, if they are selected
for participation in the Active Follow-up sub-cohort, do our best to match them with a
field interviewer of the same ethnicity, though this may not always be possible.
Whenever possible, the staff will be hired from within the local communities so they
should be familiar with local norms.
Home visits will be scheduled seven days a week between the hours of 8 AM and 9 PM
local time. Sunday visits will not be scheduled in communities for which this is
considered socially unacceptable. We anticipate that the home visit will take 2-3 hours
to complete. By going to participants’ homes to complete data collection for the Active
sub-cohort rather than requiring that they make their own arrangements for specimen
collection or visit a central location, we minimize their burden for study participation while
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maximizing the likelihood that we will be able to collect the desired study data,
biospecimens, and environmental samples.
During the home visit, the HVA will administer informed consent (Appendix D). Should
the participant be unable to read, the HVA will read the informed consent verbatim to the
participant in front of a witness to ensure the participant understands all aspects of the
study. The HVA will return the signed consent document to the study office by overnight
carrier. Present plans are for biospecimens and environmental samples to be sent by
priority overnight carrier to the central processing laboratory (CPL) for additional
processing and storage. Because commercial carriers do not operate on Sundays, we
are investigating use of specialty couriers that can make these off-hour pick-ups and
deliveries, but typically at a premium price. We are currently exploring options for
batching Sunday collections or having samples delivered to a central site for shipping to
minimize specialty courier costs.
In field studies, occasionally crucial samples are lost or accidentally destroyed after
collection. Some reasons for this include (but are not limited to):
•
•
•
•
Specimens are damaged during or after the visit due to breakage or equipment
failure;
Specimens are lost or delayed by overnight carriers during shipment;
Specimens are damaged or lost/mislabeled during processing in the Central
Processing Laboratory;
Or for other not yet anticipated reasons.
In the rare instances when such losses occur, study staff, with the concurrence of study
managers, will ask the participant if they are willing to provide replacement samples. If
they agree, we will provide a further token of appreciation in the amount of a $20 gift
card.
2.9.1
Advance Study Packet
In advance of the home visits, we will assemble and mail to each participant a home visit
kit containing the following materials needed to conduct the visit:
•
•
•
•
•
•
•
Appointment cover letter (Appendix R);
Home visit preparation instruction sheet (Appendix S and Appendix T);
FAQs (Appendix H);
Informed consent form for the participant to review in advance (Appendix D);
Informed consent quick reference guide (Appendix E)
Urine collection container and lid along with detailed instructions for collecting a
first morning void (FMV);
ID labels for participant -specific documents and specimens/samples.
The HVA will bring all other materials needed for the home visit.
2.9.2
In-Home Visit
At the beginning of the visit, the HVA will obtain informed consent prior to conducting
any study procedures. Additional details concerning the informed consent procedure can
be found in Section 10.2. After consent is obtained, the HVA will ask if the participant
wants abnormal test results for clinical and laboratory assessments conducted at the
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time of baseline visit reported to their health care provider and obtain contact information
for that provider. The HVA will collect physiologic and anthropometric measures;
biological specimens (e.g., blood, hair, toenail, and urine); environmental samples (e.g.
house dust); and administer a baseline questionnaire. The HVA will also determine and
record the latitude and longitude of the home using a handheld Global Positioning
System (GPS) device; this information will be used in later Geographic Information
System (GIS)-based studies to determine residential proximity to sites of potentially
relevant environmental exposures, such as petroleum refineries and toxic waste dumps
and incinerators. If a subject is interviewed away from the home, their residential
address will be collected (along with nearest cross-street and landmarks) so that it can
be more accurately geocoded using existing software geocoding tools; this will also be
done for previous addresses as indicated in the subjects residential history. Table 1
provides an overview and approximate timeline of the home visit activities.
Table 1.
Home Visit Overview
Activity
Estimated
Time
Notes
Interview is assigned to HVA, and HVA
calls participant to schedule in-home visit
N/A
Scheduled at least 3-5 days
in advance. Provide toll free
number and website to
reschedule if necessary
Mail Home Visit Kit
N/A
Packet arrives 3-5 days in
advance of scheduled home
visit
First morning void urine collection*
N/A
Collected by the participant
using urine collection kit
provided
Arrival, greeting and set-up
5 minutes
Informed consent
15 minutes
Review and obtain informed
consent
Anthropometric / Physiologic measures
collection
20 minutes
Ht, Wt, BP, Waist and Hip
Circumference, Spirometry
Biological specimen collection and
labeling
20 minutes
Hair, Blood , Toenail
Clippings
Questionnaire measures collection
60 minutes
Environmental sample collection and
labeling
10 minutes
+
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Activity
Estimated
Time
Biological specimen processing and
labeling
10 minutes
†
Urine dipstick analysis for glucosuria and
writing of report
5 minutes
Debriefing of blood pressure, pulmonary
function, urinary glucose and BMI results
report to the participant
10 minutes
Clean-up and packing
10 minutes
Departure
Total time:
2 hours,
45 minutes
Post-visit processing
Notes
Shipping and data back-up
* If first morning void collection has not been obtained when the study staff arrive, the HVA will
request that the participant provide a random or “spot” urine during the home visit instead.
†
Blood will be allowed to clot for at least 30 minutes while the baseline questionnaire is being
administered to the study participant and will be centrifuged for 15 minutes following the
questionnaire administration (and during the environmental sample collection) in order to
minimize the biospecimen processing time and overall time spent in the home during this visit.
+If toenail specimens cannot be collected during the visit, the participant will receive toenail
collection instructions and a prepaid self-addressed envelope to ship the toenails separately.
2.9.3
Baseline Questionnaire
The baseline questionnaire elicits information not included in the enrollment
questionnaire, including more detailed information on residential and occupational
history, personal and family medical history, alcohol and tobacco consumption, mental
health and anxiety, and recent eating and drinking and use of medications.
Before designing the questionnaires, study investigators referred to questionnaires used
by other data collection efforts occurring in the Gulf States, regionally, and nationally in
order to facilitate regional and national comparisons and potential cross-study analyses.
National studies such as the National Health and Nutrition Examination Survey
(NHANES), Behavioral Risk Factor Surveillance System (BRFSS), and National Survey
on Drug Use and Health (NSDUH) were used. We also referred to measures provided in
the PhenX Toolkit in developing some sections of the questionnaire. We substituted
sections from other questionnaires when we found something that appeared to work
better or to better capture our study interests.
Detailed information on oil spill clean-up related activities in the enrollment telephone
questionnaire completed by all participants; Questions collected at baseline during the
home visit include: residential history; personal and family medical history; occupational
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history; reproductive history; history of military service; demographic and socioeconomic
factors; alcohol consumption; mental health status; a neurocognitive screener; and other
information, including hobbies, sleep patterns, tobacco use and environmental tobacco
smoke exposure, and consumption of seafood from the Gulf of Mexico. Occupational
histories will enable us to identify, and infer relevant exposures from, occupations such
as employment in the petrochemical industry and commercial fishing. Separate
questionnaire modules will be developed and administered to subgroups reporting prior
employment in the petrochemical industry and prior experience in hazard remediation,
including other oil spills or other substances such as lead or asbestos. Residential
histories, together with Geographic Information Systems, will help us to infer potentially
relevant environmental exposures from sites such as petroleum refineries and toxic
waste dumps and incinerators. Additionally, hobbies and use and storage location of
gasoline can be important indicators of non-occupational exposures. This exposure
information will be incorporated into analyses of health outcomes related to the clean-up
work. Information on history of military service will identify persons who may have prespill serum samples and medical data available through the Department of Defense
Serum Repository and health care system and identify workers with potentially
confounding military exposures. Although the interview asks for identifying information
from the participant to facilitate follow-up and future linkage with external databases for
GIS-based studies, the computer-assisted interview will be programmed to create a
separate data file for identifying information in order to maintain a secure data system.
In developing our questions on environmental and occupational exposures, we first
considered the chemicals that have been identified in the crude oil and also in the
dispersants as identified by the National Toxicology Program (NTP). By linking to various
national databases, we will be able to identify the potential toxicity of these agents. We
also considered the frequency with which participants were engaged in oil-spill clean-up
related activities and their past occupational and recreational exposures to these agents.
2.9.4
Anthropometric/Physiological Measures
The HVA will weigh (kg) participants and measure height (m), hip and waist
circumference (cm), and take the participant’s heart rate and blood pressure. Height (m)
and weight (kg) will be measured using a metal tape measure and digital scale using
standard methods from the NHANES IV national survey. All measurements will be taken
three times. If a person is unable to stand, we will measure waist circumference and
sitting height using the crown to rump method with a cloth tape measure, but we will not
measure their weight. Instead, we will collect their self-reported weight). We will use a
cloth tape measure to collect waist circumference. We will provide participants with a
report of their anthropometric measures during the field visit. To reduce the amount of
equipment needed and facilitate training and scheduling, we plan to perform pulmonary
function testing during the home visit on members of the Active Follow-up Sub-cohort
who live within the immediately affected areas, which represents approximately 75% of
the members of this cohort.
2.9.4.1 Heart Rate and Blood Pressure Measurement
Three blood pressure and heart rate measurements will be collected by trained study
staff. Heart rate will always be measured prior to respiratory testing. Blood pressure will
be measured three times using standard clinical oscillometric (not mercury-based)
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equipment and these results will be provided to the participant at the home visit along
with information regarding what these blood pressure results mean using a form similar
to that being used in the NIEHS Sister Study. Seated heart rate and blood pressure will
be taken three times in rapid succession after a 5 minute rest period and the second and
third readings will generally be used to calculate average values for analysis and
reporting.
2.9.4.2 Pulmonary Function Testing
Pulmonary function testing (PFT) will consist of spirometry data collection. All PFT will
be conducted using American Thoracic Society/European Respiratory Society
(ATS/ERS) guidelines [Pellegrino, et al. 2005].
The PFT will be performed using a portable, ultrasound transit-time based spirometer
(EasyOn; NDD Medical Technologies, Chelmsford MA, USA, or a comparable model). A
full Forced Vital Capacity maneuver will be used. We will obtain three ATS acceptable
forced expiratory maneuvers out of a maximum of eight attempts. All spirometry
examinations will be done with the person seated and wearing a disposable nose clip.
We will use new individually packaged, disposable mouthpieces for each subject and a
new spacer for each subject.
Combined with the symptom and medical history information, this objective measure of
respiratory status will allow for an assessment of obstructive lung disease. By detecting
these small changes in pulmonary function in the population as a whole, we will be able
to make comparisons to other environmental exposures including air pollution and
environmental tobacco smoke in order to assess the potential severity of their disease.
To the extent possible, we will ask participants to withhold their asthma inhalers on the
day of the examination (a commonly used protocol). For those participants unwilling or
unable to withhold medications, we will document this during the home visit. For all
participants, we will record the timing and dosage of all asthma medications over the
preceding seven days.
To ensure quality results, we will conduct formal training and recertification on all field
procedures. The HVA will be required to take a NIOSH-approved spirometry course,
which is a well recognized training among medical professionals. In addition, all HVAs
will complete the online exam and submit 10 practice tests administered by a certified
spirometry expert. All spirometers will undergo standard quality checks before use in the
field. To ensure high quality control and HVA feedback, we will use reviewing software
similar to the one recently developed specifically for the EasyOn spirometer by
Hankinson Consulting, Inc (Athens, GA). An expert in pulmonary function quality control
will review all tracings on a weekly basis and override any software-provided readings if
needed. The quality scores and other results will be electronically forwarded to field
coordinators who will feed the quality information to the HVAs. If an unexpected number
of unacceptable tracings occur, the HVA in question will be retrained.
Participants who answer yes to any of the following questions will not undergo
spirometry during the visit:
• In the past three months, have you had any surgery to your chest or abdomen?
• In the past three months, have you had a heart attack or stroke?
• In the past three months, have you had a detached retina or have you had eye
surgery?
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• In the past three months, have you been hospitalized for any other heart problem?
• Are you pregnant?
• Are you currently taking medication for tuberculosis?
Our exclusion questions include those used in BOLD [Buist, et al. 2007] and PLATINO
[Menezes, et al. 2005], multinational studies that enrolled over 14,000 adults over age
40 years for pre and post bronchodilator spirometry with only trained technicians. No
adverse events occurred in either the BOLD or PLATINO studies. These exclusions are
considered very conservative and these questions are not generally asked before
spirometry is done in clinical practice. Note that exclusions for having a resting heart
rate > 120 bpm is included.
Figure 1. Example of EasyOn Spirometer and Disposable Mouthpiece
2.9.4.3 Glucosuria Testing
During the in-home visit, a small amount of the urine collected from each participant
(described in section 2.9.5 below) will be transferred to a sterile cup. A commercially
available dipstick will then be used by the trained study staff to measure the urinary
glucose level. The result will be provided to the participant at the home visit, along with
information regarding the meaning of the result, using the form in Appendix L.
2.9.5
Collection of Biological Samples
Biological specimens will be collected from participants in their homes by a trained HVA.
The HVA will draw blood, retrieve urine specimens, and direct the participant to collect
hair and nail samples. The following specimens will be collected:
•
Blood samples: The HVA will collect 52.5 mL of venous blood into eight
Vacutainer tubes:
o Lavender Top EDTA Tubes: Three purple-topped tubes will be collected:
One 10 mL and one 6 mL tube will provide plasma, buffy coat, and red
blood cells (RBCs) for future analyses.
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•
•
•
One 2 mL tube will either be 1) analyzed for CBC with WBC differentials
upon arrival in the central laboratory for persons tagged to be recruited for
the Biomedical Surveillance Sub-cohort (N=6,250) or 2) aliquotted and
stored as whole blood for future analyses for the rest of the Active Followup Sub-cohort.
o Royal Blue Top EDTA Tube: One 6 mL trace metals tube will frozen for future
selected measurement of antimony, arsenic, cadmium, calcium, chromium,
copper, iron, lead, magnesium, manganese, mercury, selenium, and/or zinc
(i.e., all of the metals for which these trace metal tubes have been validated).
o Red Top Serum Tube: Two 10 mL tubes with no additives will provide serum
and clots, which will be frozen for future analyses.
o Yellow Top ACD-B Tube: One 6 mL tube with Acid/Citrate/Dextrose Solution
B tube will be collected from each participant for future analyses. How the
specimen is processed will depend on whether the participant is a member of
the Biomedical Surveillance Sub-cohort, as described below.
o PAXgene RNA Tube: One 2.5 mL PAXgene blood RNA tube will provide
stabilized whole blood for mRNA isolation for future analyses.
In the rare event that a partial blood tube is collected due to a temporary
interruption of the blood collection procedure, we will retain the partially filled
tube.
Urine: Each participant will be asked to collect a first morning void (FMV) urine
sample on the day of the scheduled visit in the collection container from the
Home Visit Kit. If an FMV was not collected, the HVA will ask the participant to
provide a “spot” urine. A small amount of the specimen will be transferred to a
sterile cup during the home visit and used to measure glucose levels with a
commercially available dipstick. Another portion will used for a more complete
basic chemistry urinalysis (by dipstick) upon arrival in the central laboratory to
measure protein, glucose, and several other parameters among persons tagged
to be part of the Biomedical Surveillance Sub-cohort. The remainder of the urine
sample will be processed in the Central Processing Laboratory for storage as
described in Section 2.11 and as illustrated in Appendix C2.
Toenails: The HVA will ask each participant to collect toenail clippings from each
toe unless they have a medical or physical condition (e.g., diabetes) that would
prohibit collection. Toenail clippings will be stored as described in Section 2.11
for future analysis of metals. Participants will be advised in advance of the visit
not to clip their toenails before the visit. If toenail specimens cannot be collected
during the visit, the participant will receive toenail collection instructions and a
prepaid self-addressed envelope to ship the toenails separately.
Hair: Each participant will be ask to collect a small hair sample as close to their
scalp as possible. Hair will be clipped to indicate which end is closest to the scalp
and stored as described in Section 2.11 for future analysis of metals and cortisol.
Substantial volumes of biospecimens will be required for quality assurance and quality
control (QA/QC), cross-sectional surveys, and assay validation over time, but will not
directly contribute to addressing the specific aims of this study. To meet this need, we
will collect an additional 40 mL urine and four additional tubes of blood, consisting of one
10 mL lavender top, one 6 mL royal blue top, one 10 mL red top, and one 6 mL yellow
top (i.e., an additional 32 mL blood) from a 3% random sample of the Biomedical
Surveillance Sub-cohort (N=150) and a ~0.7% random sample of the remaining Active
Follow-up Sub-cohort (N=150). The extra urine needed (40 mL) will be taken from the
sample already collected because participants collect urine in a larger cup and
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examiners typically pour out excess urine after filling the transport tubes. We will attempt
to collect additional QA/QC samples from the group of 150 Biomedical Surveillance Subcohort participants at each subsequent visit in order to have serial samples that will be
essential for certain assays.
In total, we will collect these additional QA/QC samples from 300 individuals. These
samples will be processed and banked in the same manner as the main study samples.
These specimens will be critical when serial samples or samples known to be from the
source population are required. For these randomly selected individuals (n=300), an
addendum to the consent document detailing this additional biospecimen collection will
be administered and they will be remunerated with an extra $10 for these additional
samples.
Saliva: All study participants who are unwilling or unable to provide a blood sample
during the home visit will subsequently be mailed an Oragene OG-250 DNA SelfCollection kit, together with instructions for using and returning the kit, and a stamped,
self-addressed padded envelope for returning the kit to the central processing lab (CPL).
The CPL will store these samples as described in Section 2.11 and as illustrated in
Appendix C.2.
2.9.6
Home Environment Sampling
The HVA will be trained to collect the following home environmental samples according
to detailed sample collection protocols. These samples will provide valuable information
about the home environment and enable researchers to better characterize and control
for confounding based on residential exposures as opposed to exposure related to
clean-up activities.
Household Dust: The HVA will collect a household dust sample using the
alcohol wipe collection protocol from the Sister Study. This protocol calls for
swiping areas in several rooms that are typically ignored in dusting, such as
above door or window frames or the tops of bookshelves. In two Louisiana
Parishes, the HVA will also collect a vacuum dust sample collected following the
National Children’s Study protocol. The HVA will bring a study-provided vacuum
cleaner to collect the dust sample. A standardized area will be vacuumed, with
dust collected into a special collection device inserted into the vacuum cleaner
hose. Collection of both wipe and vacuum samples will allow us to compare
levels of specific exposures in dust and wipes and will serve as a pilot study for
assessing the confounding impact of molds, dust mites, and other endotoxins
and allergens on pulmonary function. The dust sample will be shipped to the CPL
along with the biospecimens for further processing and storage as described in
Section 2.11 and illustrated in Appendix C.Collecting household dust samples will
enable a snapshot view of exposure to potential environmental confounders such
as heavy metals, persistent organic pollutants, and (where vacuum samples are
collected) endotoxins.
The Biomedical Surveillance Sub-cohort may afford further opportunity to
validate the suitability of our proposed approach for rank-ordering exposure
levels looking at potential confounders such as persistent organic pollutant levels
using alcohol wipes and vacuum samples. We will explore the feasibility of other
methods to assess household exposures, including a dipstick test of nitrates in
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water, and a semi-permeable membrane being developed at the EPA for the
detection of volatile compounds.
2.9.7
In-Home Biospecimen Processing and Shipment
After blood collection, the HVA will allow the blood in the serum tubes to clot for 30
minutes before centrifuging the tubes in the participant’s home and separating the serum
and clot, which will be retained. At the same time, the HVA will centrifuge the 10 mL and
6 mL EDTA tubes, separating and retaining the plasma and the packed cells/buffy coat.
The HVA will then package all of the biospecimens and environmental samples for
shipment to the CPL. The ACD-B tube and the 2 mL lavender top EDTA tube will be
shipped at ambient temperature. The remaining specimens and environmental samples
will be shipped cool but not frozen, accompanied by a frozen cold pack. These materials
will be shipped by priority overnight service to the central processing laboratory. All
biological samples will be shipped according to local, state, and federal requirements
governing shipment of biological specimens. In the event that specimens or samples are
lost or damaged during shipment, the participant will be offered the opportunity to have
specimens recollected, with a small compensation.
2.10
Reports to Participants, Health Care Referrals and
Incident Reports
2.10.1
Overview
All HVA personnel will be CMAs with up-to-date CPR certifications. HVAs will receive
additional training prior to beginning the study regarding the evaluation and testing
procedures, form completion, handling of emergency situations, personal safety, signs of
abusive behavior, and appropriate referral strategies for the locality. Prior to any home
visits participants will receive information about the study including a brochure (see
Appendix N) that lists healthcare providers in their area that can provide health care
services, including any that can assist with free or reduced-cost services.
During each home visit, or participant encounter, the HVA will measure BMI, blood
pressure, urinary glucose, and spirometry. With the exception of spirometry, which
requires a specially trained reader to properly interpret the test results, the HVA will
inform participants of their test results at the time of evaluation, as well as any needed
actions for identified abnormalities. The HVA will also observe participant behavior in
case of any urgent physical or mental health behaviors requiring emergency
intervention. Urgent observations or test findings (such as hypertensive crisis, acute
mental or physical distress, abusive behavior, etc.) identified at the time of the home visit
will be handled immediately as discussed below (Section 2.10.6.1, Follow-up of
Urgent/Emergency Situations During In-person Encounter).
In addition to providing the participant with a written summary of test results and
recommended actions (Appendix L and M), the HVA will perform the following actions:
1) Complete an Incident Report for any acute medical, mental health, or social
problems (Appendix J, Baseline Questionnaire, Section N) and report the
incident to their RM and the Coordinating Center to inform them of this action.
The Project Manager will then immediately notify the NIEHS Principal
Investigator of what transpired.
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2) Enter the results of evaluations and their interpretations provided to participants,
and actions taken about abnormal results into the CAPI system (Appendix J,
Baseline Questionnaire, Section N).
3) Provide referrals for medical and mental health care, as needed, and document
referrals (see sample referral handout in Appendix N).
Additionally, all participants will receive a follow-up letter and report within 1 month of the
visit that reiterate the evaluation results (i.e. BMI, blood pressure, urinary glucose, and
spirometry) and recommended actions (Section 2.10.6, Follow-up Reports and
Information and Appendix P and Q). The participant’s health care provider will also
receive a copy of the report within one month of the encounter, if any significant
abnormalities are detected and provided that the participant has indicated that they have
a health care provider, consented to sharing this information with their provider, and
have given their provider’s name and contact information (Appendix O). For individuals
in the Biomedical Surveillance Sub-cohort, CBC results and interpretations will be
included in the report that accompanies the follow-up letter. Urgent findings identified by
the laboratory will be phoned to individuals by the HVA or Call Center within one week of
receipt from the laboratory (Section 2.10.6.3, Reporting of CBC Laboratory Tests).
2.10.2
2.10.2.1
Home Visits or Participant Evaluations at other
Locations
Participant Mental and Physical Condition Observations
HVA agents will respond to mental health issues, domestic violence situations, and
acute medical problems according to the procedures described in Section 8.1.6,
Identifying and Dealing with Mental Health Issues, Domestic Violence, and Acute
Physical Illness.
2.10.2.2
Other Social Behavior Observations
During the encounter, the HVA will observe the household and be alert for unusual
situations suggesting the existence of reportable (varies by state) social or abusive
behaviors. If anyone in the home environment is in immediate danger, the HVA will end
the visit and, once in a safe location, will call 911, complete an incident report, and report
the event to study supervisors by phone. Should a HVA witness signs that lead to
suspicion of child, spouse or elder abuse while in the participant’s home, the HVA will
generate an incident report in the CAPI system at the conclusion of the visit and report
the incident by phone, as discussed above. Such situations will not be discussed with
the participant, except in instances where it appears that the study participant is the
victim of abuse. In those cases, the HVA will discreetly ask if the participant would like to
be put in touch with someone who might be of assistance.
2.10.2.3
Incident Report Form
An incident report form will be completed by the HVA for all acute medical, mental
health, and social problems that are observed during encounters with participants
(Appendix J, Baseline Questionnaire, Section N). This report will be accessible in the
CAPI system on the HVA’s laptop, and it will include workflow features that prompt the
HVA to take appropriate action based on evaluation findings, observed behaviors, or
noted circumstances. The CAPI system will also be programmed with automated data
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checks that alert Coordinating Center staff to problems that require immediate attention
and follow-up, such as telephone follow-up to a participant who required a 911 response
for a hypertensive crisis. The principal investigator will be responsible for reporting to the
IRB all acute medical, mental health, and social problems that are observed during
encounters with participants that result in a call to 911 or social services as well as any
adverse events that result from study interventions or protocol violations, as specified in
the section 4. Due to the unique nature of the study population which is under
substantial stress due to job losses associated with the oil spill and major hurricanes and
is medically underserved, it is expected that the majority of emergency contacts will be
unrelated to the study per se, but due to the fact that we are screening for medical
conditions among individuals without access to care and have an opportunity to observe
individual and family behaviors because we will spend several hours in a participants’
home.
2.10.3
Home Visit/Evaluation Measurements & Testing
Participant evaluations will include several measures and tests for which the results can
be conveyed during the time of the HVA encounter providing potential health benefits for
early recognition of disease, as well as enhanced opportunities for health education and
utilization of health care resources. HVAs will be trained to provide participants with
appropriate and standard feedback about their individual blood pressure and BMI
measurements, and urine glucose results before departing the participant’s home. HVAs
will be trained to record all observations and in-home test results in the data
management application as well as on participant Test Result Forms that provide the
participant with a basic interpretation of the various measurements and test results.
HVAs will also be trained to strictly follow scripts when conveying results to participants.
The participant Test Result Forms will include scripts that provide recommended actions
for participants to take depending on the measured values for each test. For each test
result, we provide standard recommendations depending on the result value (see Test
Results Forms in Appendix L).
As the HVA performs the various measurements and tests during the visit, the results
will be recorded into the data management system and also transcribed onto pre-printed
test result forms for each test. The HVA will provide these forms filled-in with the
measured results to each participant and go over the results with the participants and
any suggested follow-up actions. If any of these results are abnormal, the relevant test
result form indicates what actions the participant should take and how soon. With the
possible exception of extremely elevated blood pressure, most abnormal findings will
lead to a recommendation to contact their health care provider or other community
healthcare providers for additional evaluation within a specified time interval.
2.10.4
2.10.4.1
Follow-up Actions for Abnormal Findings
Medical Referral Guidelines
During the home visit or encounters at other locations, participants will receive handouts
that provide results of their evaluations, interpretation of findings, recommended action
based on findings, and health care referrals for any abnormal results (if needed). These
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results will be also summarized in a follow-up mailing to participants one month after the
visit. The letter will thank participants for their participation in the study, introduce the
summary report of findings and recommended actions, and remind them of study
activities in the coming years. The handouts and summary report will provide information
on BMI, blood pressure, urinary glucose, and pulmonary function test results. The CBC
results for the Biomedical Surveillance Sub-cohort will also be included in the summary
report, along with recommended actions. The CBC analysis will be done in a Clinical
Laboratory Improvement Amendments (CLIA) certified laboratory (as will any future
clinical tests that may be reported back to participants). The urine glucose screening
test performed in-home has a CLIA waiver (FDA 2010).
During the consent process, participants will be asked if they would like the study to
send abnormal evaluation findings to their health care provider and whether they would
like a referral for health care, if they do not have a health care provider but need to see
one based on evaluation findings.
If the participant asks that evaluation results be sent to their health care provider, the
HVA will collect the name and contact information for the health care provider and record
the information in the CAPI system. Within a month of the visit, the results of evaluations
and advice regarding health care referrals will be shared with the participant’s health
care provider, if any abnormal evaluation findings were detected. Any evaluation finding
that does not fall within the normal ranges will result in a letter to the health care
provider. The health care provider will receive a cover letter that briefly describes the
study and the reason the results are being sent, as well as a copy of the summary report
that all participants will receive by mail. If the participant does not have a health care
provider, the HVA will provide information about local health care resources, if
warranted, based on abnormal evaluation findings. Participants who receive a referral
will be instructed to present the health care provider with the results handouts at the time
of the referral visit.
The advice that participants receive about medical referrals will be based on level of
urgency of their findings. For example, the referral levels for hypertension are based
upon recently published guidelines from the American Heart Association (AHA) for blood
pressure. We tended to select the more conservative guidelines when there were
several choices, given the fact that the community under study includes many without
access to care and the fact that our study will be highly visible and we want to err on the
side of caution. Nonetheless, levels of urgency can vary across practitioners and
communities; setting levels too low may unnecessarily over-burden area medical care
systems, while setting them too high may put participants at risk. The frequency of
referral for care will be monitored as will the outcomes for referrals deemed urgent. If it
is determined that we are making too many unnecessary referrals or that these
guidelines are inconsistent with local practice, we will consider other less conservative
standards. Any proposed changes would be brought back to the IRB for evaluation.
Participant referrals or follow-up instructions will be categorized into one of the five
classifications below, based upon their test results or findings (see Table 2 below).
1. Emergency: The HVA is instructed to immediately offer to assist the participant or
family members in contacting emergency medical services or their treating physician. If
the participant declines this immediate assistance, the HVA will continue with the
minimal risk components of the visit, omitting the blood collection and spirometry
components at that time. If it is later determined that the emergency situation has
resolved, we will attempt to perform these remaining components after confirming at that
time that the emergency situation is indeed resolved.
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2. Urgent: The Urgent referral category is divided into two levels depending upon the
urgency of the results or findings.
Level 1: the participant is asked to follow-up with their health care provider in 72
hours.
Level 2: the participant is asked follow-up with their health care provider in one
week or two week intervals depending on the urgency of the results. HVA or Call
Center staff will follow-up with all “Urgent” referral category participants by phone
to assess their disposition.
3. Check-Up: The participant is asked to follow-up with their health care provider within
one to two months.
4. Routine Care: The participant is advised to seek guidance from health care providers
to learn about healthy lifestyle choices to help prevent disease.
5. No Referral: Results are within the normal range.
Alert Levels for Laboratory Results & Spirometry Interpretations:
CBC Abnormalities:
Alert levels for abnormalities associated with the CBC components that are reported to
the participant (i.e., white blood cell count, hemoglobin concentration, hematocrit
percentage or platelet count) will trigger “Urgent” referrals. Within one week of Alert
Level findings being reported by the laboratory, participants will be notified by phone and
advised to follow-up with a health care provider in either 72 hours for Alert Level 1
findings or one-to-two weeks for Alert Level 2 findings (as indicated in Table 2). The
chosen laboratory urgent referral action levels were based upon values used for the
Jackson Heart Study of African-American males and females ages 35-84 living in the
Jackson, Mississippi area and reference values used by our central diagnostic
laboratory. The Alert Level 1referrals for total white blood cell count (≤ 1.1 x 103 / µL),
hemoglobin (≤ 6.1 g/dL) and hematocrit (≤18.1%) lead to a recommendation for
participant follow-up in 72 hours. These thresholds are based upon the “panic levels”
from our central diagnostic laboratory.
Spirometry Abnormalities:
Alert Level for post-exam spirometry interpretations will be reported to participants by
phone within one week of receipt from the central laboratory. Participants will be advised
to follow-up with a health care provider within one week (as indicated in Table 2). The
spirometry alert level for an urgent referral utilizes the lower limits of normal (LLN) which
is an index derived from population data based on race, age, sex, and height. The LLN
is designed to be the 5th percentile for the index (FEV1, FVC, & Fev1/FVC) of interest
(Roberts 2006). The use of FEV1 < 50% results in a “severe classification” regardless of
obstructive or restrictive conditions and is consistent with ATS guidelines, assuming a
valid and interpretable test (Pellegrino 2005). Given the nature of worker cohorts we do
not expect to see very many participants in the severe category
Table 2.
Medical Care Referral Guidelines
Evaluation
Findings
Referral
Comments
Blood Pressure
SBP > 180 or
Urgent*. Seek care as soon
as possible if confirmed as
HVA to offer to contact 911 or
help assist with referral as
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Findings
Referral
Comments
DBP ≥ 110
a chronic condition.
indicated. HVA / Call Center to
follow up with participant by
phone ASAP.
*Based on AHA 2010
guidelines
SBP 160 to 179 or
Check-up. See health care
provider within one month.
Results provided to participant
during encounter and mailed to
participant within one month.
Check-up. See health care
provider within two months.
Results provided to participant
during encounter and mailed to
participant within one month.
DBP 80 to 89
Routine. Those with slightly
high BP advised to discuss
need for any additional
evaluations of lifestyle
changes with HCP.
Results provided to participant
during encounter and mailed to
participant within one month.
SBP < 120 AND
No Referral.
Results provided to participant
during encounter and mailed to
participant within one month.
HR > 120 bpm
Check-up. See health care
provider as soon as
possible.
Results provided to participant
during encounter and mailed to
participant within one month.
101 ≤ HR ≤ 120 bpm
Check-up. See health care
provider within one month.
Results provided to participant
during encounter and mailed to
participant within one month.
40 ≤ HR ≤ 59 bpm
Check-up. See health care
provider within one month.
Results provided to participant
during encounter and mailed to
participant within one month.
HR < 40 bpm
Check-up. See health care
provider as soon as
possible.
Results provided to participant
during encounter and mailed to
participant within one month.
Glucose > trace OR
Urgent. See health care
provider within one week.
Results provided to participant
during encounter and mailed to
participant within one month.
DBP 100 to 109
SBP 140 to 159 or
DBP 90 to 99
SBP 120 to 139 or
DPB < 80
Resting Heart Rate
Urine Glucose
Trace glucose with specific
symptoms* of diabetes.
HVA / Call Center to follow up
with participant by phone within
two weeks of encounter.
*frequent urination & thirst
Negative glucose with
symptoms of diabetes OR
Of Potential Concern. See
health care provider within
one month
Results provided to participant
during encounter and mailed to
participant within one month.
Glucose negative, no
symptoms* of diabetes,
Normal. No Referral.
Results provided to participant
during encounter and mailed to
participant within one month.
Obese (≥ 30)
Routine. If overweight or
Results provided to participant
Trace glucose with no
symptoms* of diabetes
BMI
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Findings
Referral
Comments
Overweight (25 to 29.9)
underweight, discuss
results and potential
lifestyle changes with
health care provider.
during encounter and mailed to
participant within one month.
Urgent Referral. See health
care provider within one
week.
Participant advised to see HCP
within one week of receiving
phone call.
HVA / Call Center contacts
participant by phone within
one week of receiving
spirometry evaluation
Results mailed to participant
within one month.
Check-up. See health care
provider within one month.
Results mailed to participant
within one month.
FEV 1 , FVC, and
FEV1/FVC all above lower
limits of normal
No Referral.
Results mailed to participant
within one month.
CBC
ALERT LEVEL 1*
Urgent Referral.
Total White Blood
Cell Count
All: ≤ 1.1 x 10
HVA / Call Center contacts
participant by phone within
one week of receiving
results.
Participant advised to see HCP
within 72 hours of receiving
phone call for alert level 1.
Normal (18.6 to 24.9)
Underweight (< 18.5)
Spirometry
ALERT LEVEL
Either FEV 1 , FVC, or
FEV1/FVC below lower
limits of normal AND
FEV 1 , < 50% predicted
Either FEV 1 , FVC, or
FEV1/FVC below lower
limits of normal AND
FEV 1 , ≥ 50% predicted
3
Letter with results mailed to
participant within one month of
receipt from lab.
Results between alert level
and normal reference
range
Check-up. See health care
provider within two months.
Letter with results mailed to
participant within one month of
receipt from lab.
Within lab normal reference
range
No Referral.
Letter with results mailed to
participant within one month of
receipt from lab.
CBC
ALERT LEVEL 1*
Urgent Referral.
Hemoglobin
All: ≤ 6.1
HVA / Call Center contacts
participant by phone within
one week of receiving
results.
Participant advised to see HCP
within 72 hours of receiving
phone call for alert level 1.
ALERT LEVEL 2
Males: > 6.1 to 12 OR >20
Participant advised to see HCP
within two weeks of receiving
phone call for alert level 2.
Letter with results mailed to
participant within one month of
receipt from lab.
Females: > 6.1 to 10 OR
>17
Results between alert level
and normal reference
range
Check-up. See health care
provider within two months.
Letter with results mailed to
participant within one month of
receipt from lab.
Within lab normal reference
range
No Referral.
Letter with results mailed to
participant within one month of
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Referral
Comments
receipt from lab.
CBC
ALERT LEVEL 1*
Urgent Referral.
Hematocrit
All: ≤ 18.1
HVA / Call Center contacts
participant by phone within
one week of receiving
results.
ALERT LEVEL 2
Males > 18.1 to 35 OR >53
Platelets
Participant advised to see HCP
within two weeks of receiving
phone call for alert level 2.
Letter with results mailed to
participant within one month of
receipt from lab.
Females > 18.1 to 30 OR
>50
CBC
Participant advised to see HCP
within 72 hours of receiving
phone call for alert level 1.
Results between alert level
and normal reference
range
Check-up. See health care
provider within two months.
Letter with results mailed to
participant within one month of
receipt from lab.
Within lab normal reference
range
No Referral.
Letter with results mailed to
participant within one month of
receipt from lab.
ALERT LEVEL
Urgent Referral.
Participant advised to see HCP
within two weeks of receiving
phone call.
3
3
<50 x 10 OR >500 x 10
HVA / Call Center contacts
participant by phone within
one week of receiving
results.
Letter with results mailed to
participant within one month of
receipt from lab.
Results between alert level
and normal reference
range
Check-up. See health care
provider within two months.
Letter with results mailed to
participant within one month of
receipt from lab.
Within lab normal reference
range
No Referral.
Letter with results mailed to
participant within one month of
receipt from lab.
* Alert Level 1 for total white blood cell count, hemoglobin, and hematocrit are based on central
diagnostic laboratory reference values.
Note: Other alert levels are based on a combination of central diagnostic laboratory reference
values and alert values used for the Jackson Heart Study
If the participant has abnormal test results, the HVA will suggest appropriate follow-up
with their healthcare provider. If the participant does not have a healthcare provider, they
will receive referrals for medical and mental health care providers, as needed, including
those providers that can assist with free or reduced-cost services (see Appendix N for
example of Healthcare Provider Resource Information).
For example, Louisiana State Health officials in District 1 have indicated that they are
willing and able to help individuals identify and access healthcare providers in their
community, if needed, and a growing list of community clinics are available to see
participants at little or no cost. Such referral information is being developed on an
ongoing basis, in close coordination with state and local health departments, non-
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governmental organizations, and the local communities to help ensure appropriate
medical and mental healthcare referrals. It is anticipated that such information will
continue to evolve and require frequent updating. In order to ensure that this task is
being explicitly addressed, Study Coordinators located in the Gulf States will work with
health officials and communities in this matter.
Additionally, we are working with state and local public health officials to identify any
additional public health information and resources related to weight control,
hypertension, diabetes, and other conditions that the HVAs can provide to the study
participants for educational and public health benefit.
2.10.5
Abnormal Findings Form
The HVA will document all evaluation findings in the CAPI system while they are
conducting the visit. This CAPI module that collects evaluation findings will contain
workflow features that prompt the HVA on how to proceed when abnormal findings are
obtained. The HVA will review the actions and check the appropriate items on the
checklist for cues as to subsequent steps to be taken depending on the findings or
situation (Appendix J, Baseline Questionnaire, Section N). Once this information has
been uploaded to the central database, selected responses will trigger further actions for
the HVA and Coordinating Center staff, such as follow-up phone calls, follow-up letters,
and assistance with referrals.
2.10.6
2.10.6.1
Encounter
Follow-up Reports & Information
Follow-up of Urgent/Emergency Situations During In-person
If the HVA contacts 911 for an emergency situation, the HVA or Study Center
representatives may immediately follow-up, or as soon as possible with respect to the
situation, with the participant or their spouse to express our concern, check on their
current condition and determine future interest and ability to participate in the study.
2.10.6.2
Follow-up Letters to Summarize Evaluation Findings and Encourage
Recommended Actions
Within one month of the home visit, we will mail the participant a follow-up letter with a
summary of their evaluation results (see Appendix P and Q). This letter will also contain
information reiterating their results and recommended actions.
2.10.6.3
Reporting of CBC Laboratory Tests
For individuals in the Biomedical Surveillance Sub-cohort, selected components of the
CBC results and interpretations will be included in the report that accompanies the
follow-up letter. Urgent findings identified by the laboratory will be phoned to individuals
by the HVAs or Call Center within one week of receipt from the laboratory. HVAs or Call
Center staff will also follow-up with participants within two weeks of sharing the results
by phone to see if they need additional assistance scheduling an appointment with a
health care provider. The date of all follow-up mailings will be recorded in the data
system, any returned mailings will be noted, and those that cannot be reached by mail
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will be contacted by phone, if possible. Results of follow-up phone calls, including dates
and times of calls, responses, advice, and referrals given to participants will also be
entered into the data system.
2.10.6.4
Reporting of Spirometry Results to Participants
For participants that complete spirometry evaluations, interpretations of their results will
be included in the report that accompanies the follow-up letter. Alert Findings identified
during evaluation of their measurements will be phoned to individuals by the HVAs or
Call Center within one week of receipt from trained pulmonary study reviewers. Urgent
Referrals for participants to see their HCPs within one week will have HVAs or Call
Center staff follow-up with participants within two weeks of sharing the results by phone
to see if they need additional assistance scheduling an appointment with a health care
provider. The date of all follow-up mailings will be recorded in the data system, any
returned mailings will be noted, and those that cannot be reached by mail will be
contacted by phone, if possible. Results of follow-up phone calls, including dates and
times of calls, responses, advice, and referrals given to participants will also be entered
into the data system.
2.10.6.5
Results Reporting to Physicians
If any of the participants’ evaluation findings are abnormal and the participant has a
health care provider and consents to sharing evaluation findings, we will mail the health
care provider a cover letter explaining the study and a copy of the summary of results
and recommended actions that was sent to the participant. This report will be sent to the
health care provider within one month of the home visit along with relevant contextual
information such as normal value ranges (see Appendix O) so that the physician can
provide the appropriate care to their patients.
2.11
Laboratory Biospecimen Processing and Storage
Once the biospecimens have arrived in the Central Processing Laboratory they will
undergo additional processing to separate out the various components (serum, plasma,
cell fractions) and aliquoting of samples into small volumes for cryostorage, before being
transferred to the long-term storage facility.
2.11.1
Central Laboratory Processing
Active Follow-up Sub-cohort Sample Processing: The ACD tube will be
cryopreserved with 10% DMSO and aliquotted into cryovials, which will be subjected to
programmed cryopreservation and stored in LN2. The Trace Metal and PAXgene
samples will be frozen in their original tubes at -20°C. The serum and plasma will be
aliquotted into cryovials and stored in LN2. The RBCs/buffy coat (from the 10 mL and 6
mL EDTA tubes) will be aliquotted into cryovials and stored in LN2. The 2 mL EDTA tube
will be aliquotted as whole blood into cryovials and stored at -80°C or LN2. The urine
and saliva samples will be aliquotted and stored at -80°C or LN2. The blood clots will be
aliquotted and stored at -80°C or LN2. The hair samples and dust wipes will be stored at
-20°C. Toenail samples will be stored with desiccant, under controlled ambient
temperature and humidity.
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Biomedical Surveillance Sub-cohort Sample Processing: Samples from persons
tagged as eligible for inclusion in this sub-cohort will be processed in the same manner
as those of the rest of the Active Follow-up Sub-cohort except that, promptly upon
receipt at the central processing laboratory, 1) A portion of the urine sample will be sent
to a diagnostic testing laboratory to undergo a more comprehensive dipstick urinalysis,
2) The 2 mL EDTA tube will be analyzed by the diagnostic laboratory for CBC with WBC
differential, and 3) The ACD-B tube will undergo discontinuous density gradient
centrifugation in the CPL to isolate the lymphocytes, which will be mixed with 10%
DMSO, aliquotted, and subjected to programmed freezing and storage in LN2.
The CPL will prepare the accumulated samples for transport in bulk for archive storage
at the NIEHS Repository. All samples will be transferred to the NIEHS Repository for
storage in liquid nitrogen or -20°C/-80°C mechanical freezers, as appropriate for each
sample, within one week of receipt.
2.11.2
Study Sample Long-Term Storage at the NIEHS
Repository
Environmental Pathology Laboratories (EPL) is the contractor that operates the NIEHS
Repository. EPL is located in Keystone Park, in close proximity to the NIEHS campus in
the Research Triangle Park in North Carolina.
The EPL Repository is a state of the art storage facility which integrates structural,
mechanical, electrical, HVAC, liquid nitrogen (LN2), and backup and monitoring systems
to maintain ideal storage temperatures. These systems ensure specimen integrity and
long-term preservation while supporting the safe and efficient storage of frozen
specimens.
EPL’s Repository houses a wide variety of biological and environmental samples and
provides storage space for frozen, refrigerated, and room temperature specimens and
associated data. The 17,000 square foot facility provides space for ultra-low temperature
mechanical and liquid nitrogen freezers, data and specimen storage, and a processing
laboratory. Nearly 10,500 square feet of space is dedicated to frozen storage, with a
capacity of approximately 185 ultra-low temperature mechanical and liquid nitrogen
freezers depending on the types of specimens to be stored. Additionally, the facility has
three -20°C walk-in freezers totaling 675 square feet of space. Currently, EPL has over
3.5 million frozen specimens stored in archival storage.
EPL has over 25 years experience managing and operating archives and repository
storage facilities for government and commercial clients. EPL provides qualified
professional and technical personnel, materials, equipment and facilities for the receipt
and long term, secure storage of samples, packaging of the samples for shipment,
processing requests for samples and for aliquoting and labeling new samples, as well as
distributing requested data and specimens.
Aliquots of a given type will be divided across liquid nitrogen and -20°C/-80°C
mechanical freezers, as appropriate for each sample, to maximize integrity of the
samples during long-term storage and to reduce risk of complete loss due to freezer
failure.
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Analyses (including future studies)
Subjects targeted for the Biomedical Surveillance Sub-cohort (exposed and unexposed
participants) will have their CBC and WBC differentials measured in the 2 mL lavender
top tube promptly upon receipt of the tube by the diagnostic testing laboratory. This will
allow assessment of these measures among many, if not all, workers with the highest
expected benzene exposure (e.g., from exposure to crude oil or burning oil). These sets
of samples will be flagged prior to shipping and the lab will be separately notified of
these samples. The 2 mL lavender top tubes from all other subjects will be processed in
the same manner as the other lavender top tubes. Future analyses performed on
incoming fresh blood specimens in the sub-cohort may also include flow-cytometry to
determine changes to specific cell populations, such as CD4 or CD8, CD17, and
regulatory T-cells.
Subjects targeted for the Biomedical Surveillance Sub-cohort also will have a portion of
their urine samples used for a basic chemistry urinalysis (Multistix Pro 10LS reagent
strips) to measure protein, creatinine, blood, leukocytes, nitrite, glucose, ketone, pH, and
specific gravity immediately upon receipt of the urine samples at the central laboratory.
All other samples will be processed and banked for future analyses.
Future analyses, to be conducted among targeted subsets of the cohort, may include
assessment of DNA damage via assays such as the alkaline comet assay and the
micronucleus test on the cryopreserved lymphocytes [Chang, et al. 2006, Zijno, et al.
2007]; global hypomethylation and average telomere length in DNA from buffy coat; liver
function tests (LFT) on serum; total immunoglobulins, autoantibodies, and inflammatory
markers in the serum; antibodies indicating loss of latency of chronic infections such as
Epstein-Barr virus and herpes viruses; gene expression related to exposure to benzene
and other VOCs using the sample in the PAXgene tube; N-acetyl-beta-Dglucosaminidase (NAGs), beta-2 microglobulin, microalbuminuria, neutrophil gelatinaseassociated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1),
liver-type fatty acid binding protein in the urine to assess kidney injury; polymorphisms in
genes encoding metabolizing enzymes for benzene, other VOCs, and PAHs. The
specific assays and markers listed here are intended only to give an indication of the
types of test that we may want to perform later and that are being performed now in
similar contexts. In order to take best advantage of rapidly emerging technologies, we
will determine – and justify – the specific approaches to use around the time that we are
ready to undertake such analyses. We have developed our biospecimen collection,
processing, and storage protocols to allow as wide a range of analyses as can be
anticipated, including those not yet developed.
Exposure markers measured in stored specimens may include arsenic, cadmium,
chromium, copper, lead, manganese, mercury, and zinc, in the whole blood (royal blue
top tubes, which have been validated for these metals), to be based on toxicological
analyses by other agencies of the oil from this spill; more distant exposure to metals in
the toe nail clippings; cortisol and more distant exposure to metals in the hair; cortisol
and urinary catecholamines in urine specimens.
If any workers are still engaged in clean-up or terminated clean-up within 30 days of
enrollment in the cohort, we may also examine more transient markers of exposure,
including urinary levels of benzene, toluene, mandelic acid, trans-muconic acid, hippuric
acid; and hemoglobin-PAH adducts.
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Supplemental Add-on Studies
Supplemental questionnaires may be developed and administered to address other
unique exposure scenarios experienced by subsets of workers. For example, a short
supplementary questionnaire module will be administered to up to 200 participants who
were exposed to ammonia during an accidental release in August 2010 at a refrigeration
facility adjacent to an oil spill clean-up site in Theodore, AL. An Exposure Monitoring
Addendum has also been added to the main GuLF STUDY to address ongoing concerns
among Gulf state residents about potentially higher levels of exposure to oil-spill related
chemicals and implications for current and future health (See Addendum 1). Participants
may receive additional remuneration depending on the level of effort associated with
each sub-study.
2.13
Follow-Up of Cohorts
2.13.1
Telephone Questionnaires
Follow-up telephone questionnaires will be administered to a subgroup of participants
periodically to assess changes in health status and factors that could confound
associations between exposures and outcomes. The initial follow-up interview will take
place approximately 2 years after the start of enrollment and will be completed in
approximately one year. Interviews will be conducted with participants in the Active
Follow-up Sub-cohort who have completed the home visit examination (N=~11,000) and
a random sample of the remainder of the Full Cohort (N=~9,000) to achieve a target
sample size of 20,000.
Prior to the interview, participants will be mailed an invitational letter encouraging them
to complete the follow-up questionnaire. Participants will then be contacted by trained
interviewers who will administer the questionnaire using computer assisted telephone
interviewing software. The interview will take approximately 30 minutes to complete.
Additional mailings may be sent to participants who are hard to reach or who initially
decline to participate in the interview to reinforce the importance of their participation.
We also plan to invite ~4,600 individuals from Alabama, Florida, Louisiana, and
Mississippi who completed home visits to complete an additional mental health
questionnaire module at the time of their first follow-up telephone interview and again 6,
12, and 24 months later. We hope to collect data for all four waves of mental health
follow-up with at least 2,000 participants. We are inviting 4,600 participants to complete
the mental health module to account for expected difficulties reaching participants by
phone and expected attrition over time. Due to ongoing concerns about the mental
health impacts of the disaster, we plan to enrich the sample with participants who
showed signs of potential mental health issues at baseline (N~3,600) and randomly
sample a “healthy” comparison group (N~1,000) from the remaining Active Sub-cohort.
2.13.2
Biomedical Surveillance Sub-cohort Follow-up (Year 1
and 3)
Participants selected for the Biomedical Surveillance Sub-cohort will undergo more
extensive testing and follow-up. These exams will be administered through an external
contract or contracts run in collaboration with extramural collaborators. Detailed
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neurobehavioral, neurocognitive, and peripheral neuropathy measures will be collected.
More thorough respiratory function testing, including bronchodilator challenge, will be
performed. Additional tests and follow-up questionnaires and protocols will be
determined with the extramural collaborators and necessary approvals will be obtained
through the respective organizations.
2.13.3
Annual Morbidity and Mortality Outcomes (Year 2 and
later)
Routine surveillance of GuLF study participants will be conducted beginning in Year 2.
Follow-up will include linkage with State Cancer Registries and state vital statistics as
well as linkage with the National Death Index (NDI). We will explore the feasibility of
other passive monitoring for changes in health via linkage with other routinely collected
surveillance data and electronic medical records that may become available.
2.13.4
Follow-up in Years 6-10
Routine surveillance of all GuLF study participants, using the NDI, potentially available
electronic medical records, and state cancer registries (among others), will be conducted
to investigate any morbidity and mortality associated with clean-up related activities.
Telephone interviews may be administered to all Active Follow-up Sub-cohort
participants in Years 6-7 and 9-10, using questionnaires similar to those used in Years 3
and 4 (see 2.12.1 above), but possibly including additional questions based on the
results of follow-up to date.
2.14
Retention Strategies
The strategies outlined in this section are intended to maximize retention, and in some
cases recruitment, efforts. These strategies will capitalize on the community outreach
and engagement efforts as a core activity of the study design and implementation
activities and build on the trust and rapport between the local members of the research
team, the target communities and public health leadership across all four states.
A key to high response rates and long-term participation is not to simply contact
participants when data are needed but rather to maintain contact in small ways and
provide useful information including study results back to participants on a regular basis.
We will provide regular feedback about study progress and group results as well as
make sure we show our appreciation to the participants for their tremendous
commitment to this study. We will also meet regularly as a study team to review
progress made on retention efforts and obtain direct feedback to follow-up where
necessary.
2.14.1
Annual Update of Contact Information
In order to minimize loss to follow-up, we will send participants emails and letters
requesting that they update their contact information through an application on the study
website or by contacting the study hotline. Update requests will be sent to participants
once they have completed the telephone interview and will be included with all
subsequent study mailings for use as needed. The study website will feature an “update
contact information” page to securely register changes in contact information through an
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encrypted server. Thank you letters following the initial visit will include a GuLF STUDY
magnet that reminds participants to “keep in touch” and includes pertinent contact
information.
In addition, efforts will be made to update contact information annually. Participants will
be asked to complete contact information updates annually, whether or not they have
had any changes in their contact information. Any mailings that have been “returned to
sender” will undergo tracing to identify updated address information. Individuals lost to
follow-up will be traced using traditional methods such as internet and other phone-book
searches, credit bureaus, and the Social Security Death Index.
2.14.2
Newsletters and Other Mailings
Similar to the study website, annual newsletters will provide information on study
progress and findings. Additionally, we will send birthday cards or holiday cards every
year to enrolled participants along with small incentives/tokens of appreciation such as
pens, notepads, calendars, and magnets with the study logo on them to maintain contact
and long-term study interest.
2.14.3
Study Website
We will maintain a website to provide information about the study. The website will be
updated regularly with details on recruitment efforts, study findings, and links to other
organizations and information resources. Additionally, we will seek to have each of our
community partners have a link on their website to the study website. As feasible, the
website may contain details on upcoming or ongoing health research studies of oil spill
workers. In order to support retention efforts, study participants will also be able to
provide study investigators updates to their contact information via a secured web form
on the website.
2.14.4
Social Media
Segments of the oil clean-up worker population are active social media users partly due
to long trips away from home. Social media such as Facebook can be used to reach
these workers to build study credibility, provide more frequent updates, and prompt
participation in the out years of the study. However, as we expect web access to be
quite incomplete, this approach is not expected to be effective across the cohort. As
part of our outreach and retention efforts, we will explore the use of Web 2.0 resources
(e.g. Facebook, Twitter, etc.) to encourage awareness and credibility and facilitate
follow-up. We will explore the possibility of establishing a presence on a site such as
Facebook and maintain study updates as well as other information related to the spill.
We envision that study participants can opt to be emailed when updates are provided to
the social media site or may even chose to be a “friend” of the site. Additionally, we
envision that we will be able to reach out to community organizations and invite them to
be a “friend” of the site. Because the social media landscape will undoubtedly change
during the study duration, we will continue to monitor for opportunities to utilize this
technology for maintaining contact and encouraging retention in study activities.
However, we must be assured that participant confidentiality will be maintained and that
a significant proportion of participants are actively participating in these media to justify
the feasibility of creating and maintaining these resources. We will seek IRB approval
for all social media advertising activities. The addition of the use of social media must be
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reviewed and approved by the IRB in accordance with NIH policy prior to implementation
and we will consult with a computer specialist regarding security issues prior to opening
any account.
2.14.5
Community Partnerships and Outreach
As described in Section 2.4 - Community Outreach, we will utilize linkages with the
communities in all four states to augment recruitment efforts. Similarly, we will utilize
community partnerships and relationships with other organizations to support retention
efforts. First, we will continue to convene the Community Advisory Group (CAG) on at
least a semi-annual basis throughout the life of the project. Subcommittees of the CAG
may be created where necessary to address retention activities and other challenging
situations regarding the cohort. We will rely on the leaders within each community to
recommend retention strategies best utilized with their constituents. As we continue to
develop relationships with communities, we will incorporate these strategies and revise
the plans for study retention.
2.15
Remuneration
In addition to non-monetary incentives such as refrigerator magnets, chip clips,
stationery, and pens, participants in the Active Follow-up Sub-cohort will receive
remuneration for their time and effort in the form of pre-paid gift cards or phone cards. A
monetary incentive will be offered to participants at the baseline home visit. Gift cards
with a $50 value will be given to participants immediately upon completion. Participants
will be asked to acknowledge their receipt of their gift card by completing a form
(Appendix V), which will be returned by the HVA to the study office with other study
materials. If the Participant also completed the Ammonia Release Survey or provided
an additional Quality Control Sample for the study, they will be given an additional gift
cards (see Table 3 below), receipt of which will also be acknowledged on this form. The
amount of remuneration for each study event is summarized in the table below.
Table 3.
Remuneration for Completion of Study Events
Study Event
Active Follow-up
Sub-cohort
Passively followed
members of full cohort
Baseline Home Visit
$50
N/A
Duplicate Biospecimen Collection at
Baseline Home Visit*
$10*
N/A
Ammonia Release Survey**
$20
$20
N/A
Exposure Monitoring Supplement***
$10 or $30
Total
$50 - $110
$20
* Only for the N=300 randomly selected individuals participating in the QA/QC
biospecimen collection.
** Only for the individuals eligible for the ATSDR Sub-study.
*** Participants in the Exposure Monitoring Addendum receive $10 for providing an extra
blood sample or $30 if also asked to wear a personal air monitoring device.
Additional incentives for recruitment and participation such as drawings for prizes,
sporting event tickets or gift cards, and recruitment events featuring food bank
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distributions, community health fairs, or other community events will be explored based
on feedback from the community and assessment during the run-in phase of the study.
We will confer with the appropriate scientific, community, institutional and ethical
advisory boards to determine the appropriateness of these additional incentives.
Participants who complete the home visit will be entered into a drawing for a $500.00 gift
card. Drawings will be held after every 5,000th participant completes the home visit and
three winners will be selected at each drawing. The odds of winning are about 1 in 1650.
Similarly, participants who complete the Follow-up Telephone Questionnaire will be
entered into a drawing for a $500.00 gift card. One drawing will be held after every 500th
participant completes the interview. The odds of winning are about 1 in 500. Early
responders who complete the Follow-up Telephone Questionnaire within three weeks of
the release of their invitational mailing will be entered in an additional drawing for a
$500.00 gift card. One drawing will be held after every 500th early responder completes
the interview. The odds of winning are about 1 in 500. There is no cost associated with
entering the drawings or accepting the gift cards.
Participants selected to complete the SAMHSA Extended Mental Health Questionnaire
questions during their Follow-up Telephone Questionnaire will receive a $10.00 gift card
for their additional time and effort following each interview ($10.00 per interview; $40.00
total).
A separate remuneration schedule will be developed for the more comprehensive
activities of the Biomedical Surveillance Sub-cohort.
2.16
Study Timeline
The GuLF STUDY investigators will engage community and scientific leaders during the
study design process for input and refinement. A timeline of study activities is presented
in Table 4.
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Table 4.
Study timeline
Study Design
and Scientific
Input
Community
Outreach
Study Start
Subject
Recruitment
Enrollment
Questionnaires
Home Visits
Biomedical
Surveillance
Sub-Cohort
Follow-up
Newsletter &
Annual Update
Active Subcohort Followup
Q3
2010
Q4
Q1
2011
Q2
Q3
Q4
Q1
2012
Q2
Q3
Q4
Q1
2013
Q2
Q3
Q4
Q1
2014
Q2
Q3
Q4
Q1
2015
Q2
Q3
Q4
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Evaluation of Benefits and Risks
3.1
Potential Benefits
All study participants may benefit from positive feelings associated with participating in a
study of the health effects of the oil spill that may be of value to their community. In
addition the knowledge gained from this study may have a significant impact on future
public health responses to similar disasters. It is also possible that participants may
benefit directly from public health responses that are based on early findings from this
study.
Participants in the Active Follow-up Sub-cohort may benefit from receiving results of
medical evaluations and health care referrals that they may not otherwise receive (see
Section 3.10. - Reports to Participants and Health Care Referrals).
3.2
Potential Risks
The questionnaires and procedures in this observational study present minimal risks to
study participants. The questionnaires are based on instruments that are widely used in
epidemiological studies. Adverse events associated with study procedures are expected
to be uncommon and limited to mild and transient discomforts. In order to minimize risks
to participants, all study procedures will be conducted by qualified, experienced, and
well-trained field staff.
The main risk in questionnaire administration involves questions about sensitive health
topics or personal experiences that may be traumatic. Participants will be told that they
can skip any questions that make them feel uncomfortable or end the interview at any
time. Participants will also be warned of the possibility of loss of privacy should their deidentified data distributed through controlled access procedures (see section 11.2a) be
linked back to them in ways that cannot be foreseen at present.
Pulmonary function testing is considered safe. The primary risk, which is exceedingly
rare, is fainting in older participants with impaired lung function. We minimize the chance
that this rare event will occur first through our very conservative exclusions for
pulmonary function testing – any heart attack or hospitalization for other heart problem
or stroke in the past 3 months. Pregnant women will not undergo pulmonary function
testing until at least 3 months post-partum. To further minimize risk of fainting,
pulmonary function testing is done in a seated position, and study staff will be trained to
look for signs of dizziness or other problems and to stop the maneuver if necessary. The
risk of infection is all but eliminated by using disposable mouthpieces (spirettes). These
disposable mouthpieces have the additional protection of having a built-in bacterial filter.
In the PLATINO [Menezes, et al. 2005] and BOLD [Buist, et al. 2007] studies, home
visits were conducted on 14,000 adults over age 40 by trained technicians only, without
physicians present, and no adverse events were associated with in-home spirometry.
There may be some minor discomfort associated with blood collection, including
temporary pain, bruising, or swelling at the phlebotomy site. Fainting during blood
collection is exceeding rare.
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There is also a remote risk of accidental disclosure of study information. Measures that
will be taken to guard against accidental disclosures include maintaining complete
confidentiality of the questionnaires and laboratory samples, use of secure data
systems, and staff training (see Section 10.3 – Participant Confidentiality). Participants
will also be warned of the possibility of loss of privacy should their de-identified data
distributed through controlled access procedures be linked back to them in ways that
cannot be foreseen at present.
4
Adverse Event Reporting
Adverse events associated with this study procedures are expected to occur very
infrequently. Most of the potential risks associated with study procedures (see Section
3.2) is limited to mild, transient discomforts of no clinical significance. Only clinically
significant adverse events will be reported to the IRB. Examples of clinically significant
adverse events include:
•
fainting during spirometry or blood collection
•
respiratory distress induced by spirometry that requires medical attention
•
prolonged bleeding, hematoma formation, or infection associated with blood
collection that requires medical attention
Field staff will be trained to detect and respond to clinically significant adverse events.
They will also be expected to report clinically significant adverse events to the
Coordinating Center immediately. Because some adverse event may not emerge until
after the visit, participants will be instructed to call the study hotline if they experience a
new or worsening health problem that could be due to a study procedure. The principal
investigator will be responsible for reporting all clinically significant adverse events
related to study procedures to the IRB within 72 hours of receiving notification that an
event occurred.
A clinically significant adverse event related to study procedures will be reported as a
serious adverse event if it is life threatening, causes persistent or significant disability,
leads to death, or requires medical or surgical intervention to prevent one of these
outcomes.
As described in Section 2.10.2, HVAs may encounter participants who report or display
symptoms of acute, pre-existing medical or mental health conditions that are not related
to participation in the study. HVAs may also observe unusual situations in the home that
may suggest the existence of reportable social or abusive behaviors. In addition, the
results of study procedures, such as blood pressure measurement, may indicate the
need for immediate medical attention for previously undiagnosed or poorly controlled
illnesses (see Section 2.10.4.1). Telephone interviewers may also encounter participants
who report or display symptoms that are consistent with acute medical, mental health, or
social problems. Any pre-existing health problem or social situation that requires a call to
911, local authorities, or social services will be reported to the IRB as an adverse event
at the time of continuing review. The report will include information on the outcome of the
actions taken in response to the event. We expect these events to occur in less than 1%
of telephone interviews and home visits.
The investigator will report unanticipated problems to the IRB within 72 hours of
identifying such an occurrence. Unanticipated problems are defined as any incident,
experience, or outcome that meets all of the following criteria:
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•
unexpected in terms of nature, severity, or frequency given (a) the research
procedures that are in protocol and informed consent and (b) the characteristics
of the subject population being studied;
•
related or possibly related to participation in the research;
•
suggests that the research places subjects or others at a greater risk of harm
(including physical, psychological, economic, or social harm) than was previously
known or recognized.
5
Study Oversight
The Principal Investigator will monitor and evaluate the progress of the study, including
periodic assessments of data quality and timeliness, participant recruitment,
administration of informed consent, accrual and retention, participant risk versus benefit,
performance of contractors and other factors that can affect study outcome. This
monitoring will also consider factors external to the study when interpreting the data,
such as scientific or therapeutic developments that may have an impact on the safety of
the participants or the ethics of the study.
The study team, all of whom will contribute to study oversight, has the experience
necessary to provide this oversight. We list the investigators and their roles and
responsibilities
•
Dale Sandler, Ph.D. Principal Investigator NIEHS (Protocol development and
overall oversight and responsibility for all parts of the study)
•
Richard Kwok, Ph.D., Lead Associate Investigator, NIEHS (Protocol development
and oversight over the day-to-day operations of the study, exposure assessment
and coordination for all parts of the study)
•
Lawrence Engel, Ph.D., Associate Investigator, University of North Carolina at
Chapel Hill and NIEHS (Protocol and questionnaire development, and oversight
over the neurologic and biologic areas of the study)
•
Stephanie London, M.D., Dr.P.H., Associate Investigator, NIEHS (Oversight over
the respiratory areas of the study)
•
Aubrey Miller, M.D., M.P.H. Associate Investigator, NIEHS (Oversight over the
medical and medical alert / referral areas of the study)
•
Christine Parks, Ph.D., Associate Investigator, NIEHS (Oversight over the
immunologic areas of the study)
•
Aaron Blair, Ph.D., Consultant, NCI (Consultation on overall study
implementation and design and exposure reconstruction)
•
Mark Stenzel, Consultant, Exposure Assessment Applications, LLC.
(Consultation on exposure assessment and industrial hygiene)
•
Patricia A. Stewart, Ph.D., Consultant, Stewart Exposure Assessments, LLC.
(Consultation on exposure assessment and industrial hygiene, development of
exposure metrics for study participants)
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SRA International (SRA), a provider of professional research services company, will
provide support for this study through an existing contract with the NIEHS. SRA will
oversee the day-to-day activities of the study with oversight from the NIEHS
investigators. SRA will be responsible for recruiting and enrolling participants,
conducting home visits, managing study data, providing laboratory processing services,
and completing follow-up telephone interviews. All SRA staff and any SRA subcontractor
staff will have the proper education, experience, and training required for their role in the
study. Staff members who interact with participants or have access to study data will be
trained in human subjects research protections, the study protocol, and study
procedures relevant to their role. They will also be required to sign confidentiality
agreements. SRA’s telephone interviewers are hired and payrolled through staffing
agencies, consistent with standard industry practices, but are trained and managed
directly by SRA. The responsibilities of SRA’s key subcontractors and collaborators are
described below.
•
ClinForce, a medical research staffing agency, will identify, hire, and payroll
home visit agents and regional field managers. SRA will be responsible for
training, equipping, and managing the work of all field staff.
•
Social and Scientific Systems, Inc. (SSS), a provider of professional research
services, will provide central laboratory processing services through a
subcontract with SRA.
•
Experimental Pathology Laboratories (EPL) will provide biorepository services
under an existing contract with the NIEHS.
•
Stewart Exposure Assessment, LLC will provide assessments to characterize
possible worker exposure to a number of chemical and physical agents
associated with crude oil, dispersants, and other chemicals arising from the spill
or used in the clean-up work.
A GuLF STUDY Scientific Advisory Board will be established as a subcommittee of the
NIEHS Board of Scientific Counselors to provide additional oversight. This Board will
include one or more members of the Board of Scientific Counselors, scientific experts,
community representatives and Federal agency representatives. A separate Community
Advisory Board, consisting of representatives of key study populations in the affected
states, also will be established. Through funding made possible by a Gift to the NIH, the
NIH has arranged to have the Institute of Medicine review the initial plans for the study
and monitor study progress. The IOM held its first meeting focused on the GuLF
STUDY on September 22, 2010. It is expected that the IOM will meet twice a year for
several years, and then annually to review study progress and findings. An Interagency
working group made up of representatives from each Federal Agency involved in some
aspect of the oil spill response met on August 19, and is also expected to meet regularly
to provide study oversight.
6 Statistical Analysis Methods
6.1
Treatment of Exposure Status and Health Outcomes
Estimates of quantitative levels for specific exposures will be developed to the extent
possible by the industrial hygiene team. Exposure status (e.g. any contact with crude oil,
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dispersants, or relevant crude oil specific chemicals, e.g., benzene, heavy metals, etc.)
will also be defined dichotomously as “exposed” or “unexposed” based on the definitions
given above for the study population and an activity-based exposure reconstruction
(Sections 3.1.1 and 3.1.3). Similarly, health outcomes will be examined quantitatively
where appropriate (e.g., FEV1/FVC, CBC measures), and will also be defined as
“present” or “not present” based on the existence of specific endpoints within each
disease area of interest (respiratory, cardiovascular, hematologic, dermatologic,
neurologic, cancer, reproductive, mental health, immunologic, renal, liver).
We expect that very few workers engaged in clean-up related tasks, but not in clean-up
per se, such as those providing only administrative, logistical, or personnel support, will
be enrolled in the cohort because of the initial screening. However, any such workers
found to be enrolled in the cohort will be placed in an “unexposed worker” category and
excluded from most analyses because their exposure profile will be fundamentally
different from that of the other clean-up workers and they are likely to differ in important,
potentially unmeasured, respects (e.g., physical activity, socioeconomic status, health
care access or quality) from the other clean-up workers. We will revisit this approach
after examining results from the mini-pilot to determine whether this should be
incorporated into the full study.
6.2
Statistical Methods to Address Study Objectives
The objectives of this study are to evaluate and characterize relationships between
exposures to oil, oil byproducts and/or chemical dispersants, and stress associated with
the disaster and short- and long-term health effects. General analysis methods to
address these objectives are as follows:
•
Descriptive analyses will be conducted as a precursor to other investigations.
Rates and proportions will be estimated and bivariate relationships will be explored
using cross tabulations. 95% confidence intervals (CIs) will be estimated where
appropriate.
•
Acute- and Short-term Outcomes: Acute- and short-term health effects that may
have been incurred during or immediately following exposure will primarily be
assessed during baseline data collection and in the immediate follow-up time-period.
Relationships between exposures and these outcomes will be investigated at the
most basic level by fitting regression models: logistic regression models for
dichotomous outcomes to estimate odds ratios (ORs) and 95% confidence intervals
(CIs) for each exposure and least squares regression for continuous outcomes to
estimate betas and standard errors (SEs) for each exposure. Relevant demographic
variables (e.g., sex, age, race, socioeconomic status indicators) and other exposures
will be included in the regression models as covariates and effect modifiers. More
refined analyses will incorporate specific characterizations of exposure, such as type
of work performed, location, nature, and duration of exposure, protective equipment
used, and ultimately a quantitative index of exposures developed by a panel of
industrial hygienists and other exposure experts to reflect the risk factors of interest.
Outcomes that will be evaluated include respiratory symptoms, nausea, headaches,
dermatitis, depressive symptoms, anxiety, FEV1/FVC, CBC components, WBC
differentials, DNA damage, etc.
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Long-term Outcomes: Long-term health effects that may be incurred in the years
following the exposure will be assessed at regular intervals through follow-up by
interview or linkage with disease/mortality registries. Relationships between
exposures and dichotomous health outcomes will be investigated by fitting binomial
repeated measures models to each outcome, using standard statistical software
such as SAS Proc GENMOD and Proc MIXED. Exposure effects will be assessed
via ORs for each observation period. Non-dichotomous outcome measures will be
investigated using generalized linear models; appropriate transformations will be
used to satisfy model assumptions. Relevant demographic variables (e.g., sex, age,
race, SES indicators) and other exposures (including ongoing, repeated
environmental variables where available) will be included in the repeated measures
models as covariates. These outcomes will include cancer, neurological
(neurocognitive, neurobehavioral, neurophysiological) deficits, cardiovascular injury,
reproductive effects, persistence of early effects, among others.
Various refinements to these basic methods as well as these additional analyses will
also be pursued:
•
Confounding and Effect Modification: Potential confounders and effect modifiers
will be introduced into the models to determine the extent to which they might
influence any effect. A potential confounder will be retained in the model if its
inclusion changes the estimated effect of an exposure or the length of its 95%
confidence interval by 10% or more. Stratified analyses will also be used, as
appropriate. Information on many of these factors will be obtained by interview, but
others may come from analysis of biologic specimens. In addition, we will perform
sensitivity analyses to assess the impact of unmeasured confounders, classification
errors (for both exposures and outcomes), and selection bias on estimates of
exposure-disease association. This will be done in part using probabilistic methods
to quantify the likely effects of misclassification of dichotomous measures [Fox, et al.
2005, Chu, et al. 2006] and polytomous measures [Arah, et al. 2008].
•
Repeated measures: Repeated measurements on individual components of longterm health outcomes (examples: reported numbers of days experiencing asthma
symptoms, FEV1/FVC) will be investigated for association with exposure through
repeated measures mixed-effect models, while introducing appropriate effect
modifiers. In particular, pulmonary function measures provide objective data that
complement less objective self-reported symptom data, but are typically quite
variable. Results from other studies suggest that, at a given time point, we can
expect to detect differences in FEV1 as low as 5% between subgroups of about 250
participants per group with 80% power. Analyses to compare larger subgroups,
compare groups across multiple time points, detect changes over time, or investigate
the FEV1/FVC ratio all involve more stable measures or comparisons and so will
exhibit greater statistical power.
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Non-reversing binary prospective outcomes, such as incident diagnoses, will also be
modeled using Cox proportional hazards models.
6.3
Interim and Safety Analyses
Adverse events associated with study procedures such as blood draws and pulmonary
function testing are expected to be uncommon and limited to mild and transient
discomforts. Such events will be monitored through interim reports. Interim reports will
also be used to monitor parameters that characterize the conduct of the study, such as
pace of recruitment, completeness of scheduled activities, time lags associated with data
entry and laboratory testing, as well as QC reports for issues such as inter-observer
variability and inter- and intra-laboratory variability. Study statisticians will develop these
and other reports. No early stopping rules are in place for this study since there is no
treatment and no anticipated risk to participants. Analyses of short-term health outcomes
will be conducted after completion of baseline visits. Other interim analyses may be
conducted in a blinded fashion so as not to influence investigators or study staff with
respect to the conduct or completion of the study.
6.4
Laboratory QA/QC Analyses
Laboratory QA/QC data will be reviewed for evidence of excessive variability and for
trends indicating shifts in process control. Data from blind QC samples submitted to
laboratories will be analyzed and within-pair coefficients of variation (CV) for internal
(within laboratory) consistency samples will be calculated. Inter-laboratory reliability will
be investigated by analysis of results of laboratory same-sample analyses. The
duplicate blood and urine samples collected from randomly selected individuals in the
study (mentioned in Section 2.9.5) will provide specimens for these QA/QC efforts.
These individual and pooled samples will be used for quality control purposes such as
assessing long-term storage effects and assay batch variability.
6.5
Sample Size Considerations and Power
6.5.1
Estimated sizes of worker (exposed) and non-worker
(unexposed) groups
Based on currently available information, we anticipate that when we merge the PEC list,
the NIOSH list, the lists of workers from Federal agencies that may be included in this
study (e.g., Coast Guard, Fish and Wildlife Service, US Geologic Survey), and other
worker lists, and then remove duplicates, persons who provided no contact information,
and persons who indicated that they intended to work on clean-up for less than one
week (< 0.2% of the early NIOSH roster, but possibly a larger number; likely to be
persons with no intention of engaging in clean-up work), the merged list will contain
approximately 90,000 names. Based on early NIOSH information, approximately 92% of
these persons will be from one of the four most affected Gulf States. Restriction of the
workers, for logistical reasons, to persons from the four Gulf States and to those workers
from outside of those states who experienced certain high exposures such as to
benzene, burning oil, and dispersants will produce a list of approximately 86,000
persons. It is expected that after loss to follow-up, non-response, and refusal, about
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55,000 eligible persons (a 60-65% participation rate) will complete the enrollment
questionnaire. These 55,000 persons will comprise the full cohort. Among this group, we
estimate that about 43,000 (80%) will have engaged in clean-up activities while the
remaining 12,000 (~20%) did not. These 12,000 unexposed persons will include up to
several thousand Federal responders who engaged only in response activities such as
administrative, oversight, or logistical support that did not involve any contact with spillrelated oil, oil byproducts, or dispersants.
There are sufficient eligible persons to recruit 15,000 workers and 5,000 controls into the
Active Follow-up Sub-cohort, assuming a 40% participation rate (after applying
sampling probabilities and assuming an 80% response rate for those who have gotten
this far) among persons who have already enrolled in the full cohort by participating in
the telephone interview. The size of the Active Follow-up Sub-cohort has been capped at
20,000 in light of available funding and statistical power considerations; the base
population is large enough that this target is achievable even with a modestly lower
participation rate. Based on current information, we estimate that about 26% of the
eligible controls are from outside the immediately affected communities. By
oversampling these non-local controls, we expect to recruit approximately 1,500 nonlocal controls and 3,500 local controls, with both groups including Federal controls as
described above.
The expected participation rates provided above are reasonable, given anecdotal reports
from collaborating federal agencies, media reports, and feedback from community
groups and focus groups of clean-up workers that indicate widespread concern about
potential health effects from the oil spill among clean-up workers and members of the
affected communities. Furthermore, it is possible that the eventual cumulative total of
workers will be greater than is currently estimated. We will know the real total only after
we have obtained worker lists from other agencies and local communities engaged in
clean-up and crossed the lists to identify unique additional workers who did not complete
PEC training. In any case, power calculations indicate that even if actual participation
rates turn out to be as much as 20% lower than those indicated above, this study will still
be sufficiently powered to achieve its specified aims, with an increase in minimum
detectable ORs or differences of less than 10-15%.
The rest of the full cohort (N~35,000) will comprise individuals to be passively followed
who either were not randomly sampled to be part of the Active Follow-up Sub-cohort or
who refused to be part of the Active Follow-up Sub-cohort (but participated in the
enrollment telephone interview). This represents about 28,000 workers and about 7,000
controls.
Thus, the total size of the full cohort is anticipated to be approximately 55,000 persons
(43,000 workers and 12,000 controls), consisting of 20,000 members of the Active
Follow-up Sub-cohort (15,000 workers and 5,000 controls [3,500 local and 1,500 nonlocal, including Federal]) and 35,000 passively followed members of the full cohort
(28,000 workers and 7,000 controls).
Based on other prospective observational studies, we anticipate 90% follow-up and
participation in telephone interviews after enrollment for the Active Follow-up Sub-cohort.
Thus, completed follow-up interviews are expected for approximately 13,500 workers
and 4,500 controls in Years 3-4.
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Sample Power
This study is designed not around a few narrow a priori hypotheses, but rather to allow
the investigation of a wide range of potential adverse health effects. The study size and
the number of individuals who experienced a given exposure – and the consequent
statistical power – have largely been determined by the number of individuals involved in
the clean-up operations and their distribution by task/exposure. While this study will have
limited power to examine certain rarer exposures or outcomes in the near future, this is
the largest study to date of oil spill clean-up workers and it is important that we address,
to the extent feasible, the wide range of public health concerns. It is a prospective study
and as time passes, if the exposure continues to exert an impact on some health
outcomes, power will increase.
Table 3 presents minimum detectable odds ratios across a range of proportions of
exposure among the workers and of health outcome among the controls. Estimates are
shown separately for analyses of the full cohort and of the Active Follow-up Sub-cohort,
including all controls or including only the non-local controls. Estimates are also shown
for analyses of the Biomedical Surveillance Sub-cohort. All estimates are based on a
two-sided test with α=5% and power=80%. As the table shows, this study has excellent
power to detect small risks, except when exposure or outcome is rare. For example, in
an analysis of the full cohort, if 10% of the workers received a given exposure (e.g., high
exposure to VOCs) and the incidence or prevalence of disease is 1%, this study would
have sufficient power to detect an OR of at least 1.56 when using all 12,000 controls and
1.86 when using only the 2,500 non-local controls. In an analysis restricted to the Active
Follow-up Sub-cohort, with proportion of exposure of 10% and disease
incidence/prevalence of 10%, the minimum detectable OR would be only 1.30 when
using the full control group (N=5,000) and 1.38 for the non-local control group (N=1,500).
The Biomedical Surveillance Sub-cohort, with 4,500 workers and 500 controls, provides
adequate statistical power to detect odds ratios of at least 1.59 when 25% of workers
received a given exposure and the incidence or prevalence of disease is 10%. For
perspective, estimated relative risks of lower respiratory tract symptoms observed
among clean-up workers in previous oil spills ranged from 1.5 to 3.6 [Janjua, et al. 2006,
Zock, et al. 2007, Meo, et al. 2009, Sim, et al. 2010]. Thus GuLF STUDY is sufficiently
powered to observe such prevalence or relative risks for these outcomes.
Table 3. Minimum detectable odds ratios for a range of proportions of exposure among
the workers and for all controls vs. non-local controls, based on a two-sided test with
α=5% and power=80%
Size of
control group
(i.e., all vs.
non-local)
Proportion (N) of workers exposed to a given agent
5%
10%
25%
50%
75%
100%
N=21,500
N=32,250
N=43,000
1.35
1.72
1.33
1.71
1.32
1.70
Full cohort: 43,000 workers, 12,000 controls:
N=2,150
N=4,300
N=10,750
Proportion of controls with outcome=1%
12,000a
1.74
1.56
1.41
b
2,500
2.02
1.86
1.76
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Proportion of controls with outcome=10%
12,000a
2,500b
1.23
1.30
1.17
1.25
1.13
1.22
1.11
1.21
1.10
1.21
1.10
1.21
1.08
1.14
1.07
1.14
1.07
1.14
1.07
1.13
N=7,500
N=11,250
N=15,000
Proportion of controls with outcome=1%
5,000a
2.33
1.98
1.71
b
1,500
2.66
2.34
2.11
1.59
2.02
1.55
1.99
1.53
1.97
Proportion of controls with outcome=10%
5,000a
1.40
1.30
1.21
b
1,500
1.47
1.38
1.31
1.18
1.29
1.17
1.28
1.16
1.28
Proportion of controls with outcome=30%
5,000a
1.26
1.19
1.14
1,500b
1.31
1.25
1.20
1.12
1.19
1.11
1.18
1.11
1.18
Proportion of controls with outcome=30%
12,000a
2,500b
1.15
1.19
1.11
1.16
Active Follow-up Sub-cohort: 15,000 workers, 5,000 controls:
N=750
N=1,500
N=3,750
Biomedical Surveillance Sub-cohort: 4,500 workers, 500 controls:
N=225
N=450
N=1,125
N=2,250
N=3,375
N=4,500
3.32
3.11
3.04
3.00
Proportion of controls with outcome=10%
500a
1.92
1.73
1.59
1.54
1.53
1.52
Proportion of controls with outcome=30%
500a
1.60
1.47
1.38
1.35
1.33
1.33
Proportion of controls with outcome=1%
500a
a
b
4.62
3.86
All controls in cohort/sub-cohort
Non-local controls in cohort/sub-cohort
Minimum detectable differences for continuous outcomes are presented in Table 4.
Differences are expressed in standard deviations (SDs) and are based on a two-sided
test with α=5% and power=80%. Results are shown separately for analyses of the full
cohort and of the Active Follow-up Sub-cohort including all controls or including only the
non-local controls. In addition, estimates are shown for analyses of the Biomedical
Surveillance Sub-cohort. This table demonstrates that the present study has sufficient
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power to detect small differences in continuous outcomes. For example, in an analysis of
the full cohort that examines an exposure of 10% prevalence, we will be able to detect
minimum differences of less than 0.050 SD for the full cohort and 0.070 SD for the nonlocal cohort. A similar analysis in the Active Follow-up Sub-cohort will be able to detect
minimum differences of less than 0.082 SD when using all 5,000 controls and 0.102
when using the 1,500 non-local controls. Such an analysis in the Biomedical
Surveillance Sub-cohort will have sufficient power to detect a minimum difference of
0.182 SD. For perspective, in a study of volunteers involved in the Prestige oil spill
clean-up and unexposed controls [Laffon, et al. 2006], results of the comet assay in
peripheral blood leukocytes showed differences between the two groups of
approximately 4.3 SD in comet tail length. A study of health effects related to the
Tasman Spirit oil spill found a difference of about 0.6 SD in symptom scores between
coastal residents affected by the spill and persons living away from the site of the spill
[Janjua, et al. 2006]. The present study is very well powered to detect such effects.
Table 4. Minimum detectable differences, in standard deviations, for continuous
outcomes for a range of proportions of exposure among the workers and for all controls
vs. non-local controls, based on a two-sided test with α=5% and power=80%
Size of
control group
(full vs. nonlocal)
Proportion of workers exposed to a given agent
5%
10%
25%
50%
75%
100%
N=21,500
0.032
0.059
N=32,250
0.030
0.058
N=43,000
0.029
0.058
N=11,250
0.048
0.077
N=15,000
0.046
0.076
Full cohort: 43,000 workers, 12,000 controls:
a
12,000
2,500b
N=2,150
0.066
0.082
N=4,300
0.050
0.070
N=10,750
0.037
0.062
Active Follow-up Sub-cohort: 15,000 workers, 5,000 controls:
5,000a
1,500b
N=750
0.110
0.125
N=1,500
0.082
0.102
N=3,750
0.061
0.086
N=7,500
0.051
0.079
Biomedical Surveillance Sub-cohort: 4,500 workers, 500 controls:
500a
a
b
N=225
0.217
N=450
0.182
N=1,125
0.151
N=2,250
0.139
N=3,375
0.134
N=4,500
0.132
All controls in cohort/sub-cohort
Non-local controls in cohort/sub-cohort
Finally, power calculations indicate that even if participation rates turn out to be as much
as 20% lower than expected, the minimum detectable ORs or differences will increase
by less than 10-15%.
7
Analysis Plan
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Primary Endpoints
Given the very limited health effects research conducted to date on oil spill clean-up
workers, the GuLF STUDY is designed not around a particular a priori hypothesis, but
rather to allow investigation of a wide range of potential adverse health effects, including
physical, psychological, and biological effects. These include both short-term and longterm effects focused on, but not limited to, the following areas: respiratory,
cardiovascular, hematologic, dermatologic, neurologic, cancer, reproductive, mental
health, immunologic, hepatic, and renal. A priori outcomes of greatest interest based on
previous studies are respiratory effects, neurological dysfunction, and genotoxic and
hematologic effects.
Questionnaire-based exposure information will be examined in relation to outcomes in
both prospective and cross-sectional analyses in the full cohort or sub-cohorts. Because
many biological and environmental assays are expensive and samples are limited, we
also plan to carry out nested case-control or case-cohort studies within the cohort.
Many of the primary exposure measures will be from job-exposure matrices (JEMs),
which will be developed by the investigators using time-specific task and exposure data
from a range of sources. These will be semi-quantitative (e.g., 5-point scale). They will
be treated in statistical analyses as ordinal values or, depending on distribution or
scientific considerations, collapsed into fewer categories (e.g., high vs. low).
Endpoints will be identified through several means. First, we will use the self-reported
health information provided in the enrollment interview(s) to define case groups or to
assign quantitative or semi-quantitative health categories for a given outcome or
constellation of outcomes, as appropriate. Self-reported health histories from this
interview will be used to identify outcomes with an onset or increase in severity after the
subject began clean-up work (i.e., not a pre-existing condition). Some self-reported
health information may be validated in sub-studies through subsequent information
provided, with participant permission, by the subject’s doctor, the subject’s medical
record, and/or the subject him/herself. Second, we will have clinic information such as
the FEV1/FVC results collected at enrollment from all subjects who live within the
immediately affected areas and the urinary glucose results obtained at enrollment from
all subjects.
We will examine results of a Complete Blood Count (CBC) with white blood cell
differentials among members of the Biomedical Surveillance Sub-cohort. Endpoints will
include total WBCs, individual WBC components, red cell measures, and platelets.
White blood cell and platelet counts have been found to be significantly reduced among
workers with low exposure to benzene, with reduced hemoglobin concentration among
workers with higher exposure to benzene [Lan, et al. 2004]. To explore potential effects
of metals, particulates, and stress, we will examine measures of the acute phase
response (C-reactive protein), inflammatory cytokines, as well as anti-nuclear and
thyroid antibodies. We will also examine results of the urinalysis (for protein, creatinine,
blood, leukocytes, nitrite, glucose, ketone, pH, and specific gravity) among members of
the Biomedical Surveillance Sub-cohort.
In subsets of the Active Follow-up Sub-cohort or the Biomedical Surveillance Sub-cohort
defined by higher or lower stress exposure and in vulnerable sub-populations, we will
also examine antibodies to latent viral infections as indicators of sub-clinical depressed
immunity. Antibodies to latent infections have been studied frequently in relation to the
physiological impact of stress, and may vary according to socioeconomic factors [Aiello,
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et al. 2009, Dowd and Aiello 2009]. We will also examine stress-associated
immunosenescence as indicated by average leukocyte telomere length and stress
biomarkers [Epel, et al. 2004, Parks, et al. 2009], which along with viral antibodies may
be related to a variety of chronic disease outcomes. Such tests may be performed using
baseline samples or, for the Biomedical Surveillance Sub-cohort, samples collected at
subsequent visits may be utilized.
For a subset of subjects representing high and low exposures to agents known or
suspected to be nephrotoxic, including volatile organic compounds and heavy metals,
and also unexposed subjects, we will examine urinary markers of kidney injury, including
N-acetyl-beta-D-glucosaminidase (NAGs), beta-2 microglobulin, microalbuminuria,
neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury
molecule-1 (KIM-1), and liver-type fatty acid binding protein.
We will similarly conduct liver function tests using sera from a subset of subjects having
either high or low exposures to agents known or suspected to alter liver function,
including volatile organic compounds, PAHs, and heavy metals, and also unexposed
subjects.
For a subset of subjects representing high and low exposures to agents known or
suspected to be genotoxic, including volatile organic compounds, heavy metals, PAHs,
and hydrogen sulfide, and also unexposed subjects, we will examine results of DNA
damage assays, The specific assays will be determined, based on the current state of
the art around the time that we are ready to undertake these analyses, as described
above in section 3.11.3. They may include the comet assay and the micronucleus test.
Comet assay measures will include the tail moment, defined as the product of the
percentage of DNA in the comet tail and the tail length, and the tail intensity, defined as
the percentage of DNA in the tail. Micronucleus test measures will consist of the
frequency of micronuclei and the frequency of binucleated micronucleated cells.
During follow-up of the cohort, we will identify incident outcomes or changing severity of
those outcomes via self-reported health status in follow-up interviews, via linkage with
cancer and vital status registries, and via testing of follow-up biospecimens. Our
analyses will consider onset or changes in severity relative to both enrollment health
status and health history, as appropriate. For some subjects, such as Coast Guard
members, we may be able to obtain additional information from electronic medical
records.
Continuous outcome measures such as FEV1/FVC will be treated as continuous and/or
categorized according to appropriate cutpoints in statistical analyses. They will be logtransformed as needed.
Initial analyses will be largely descriptive, including examination of distributions of jobs,
exposures, demographic and lifestyle factors, health history, and recent health outcomes
at enrollment. We will quantify and examine patterns of missing data and outliers. We
will perform data cleaning as appropriate. To the extent possible, we will explore
potential bias in subject selection and reporting.
We will next conduct cross-sectional analyses, consisting primarily of comparisons of
prevalence or extent of a given outcome by clean-up task or estimated exposure to a
given factor (from the JEM). These will be performed using least squares regression for
continuous outcomes or logistic regression for dichotomous outcomes, adjusted for
confounders as appropriate. We will explore possible modifiers of effect such as race,
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sex, baseline health characteristics, lifestyle factors, and access to health care by also
conducting stratified analyses by these factors, as appropriate and as numbers permit.
When follow-up data become available, we will also be able to perform prospective
analyses linking clean-up activities/exposures to incident outcomes using Cox
proportional hazards regression. We will use logistic regression for nested case-control
analyses. Extent of change of outcomes will be assessed using least squares
regression. Confounding and effect modification will be addressed as described above.
Clinical protocols for a number of outcomes, including respiratory and neurologic effects,
will be developed and carried out in collaboration with local university partners identified
through a request for proposals (RFP). Therefore, analysis of these outcomes will be
addressed in a later protocol.
8
Training, Quality Control, and Quality Assurance
8.1
Staff Recruitment and Enrollment Process
8.1.1
Telephone Interviewers
Locating and screening tasks will be conducted by approximately 50 trained telephone
interviewers working part time over different shifts. Interview staff will be given training
on good practices in interviewing—locating, gaining cooperation, overcoming barriers to
participation and correctly coding outcomes, and American Association for Public
Opinion Research (AAPOR) code of ethics which includes training on confidentiality and
non-disclosure, and other training in human subjects research. Trainees also receive
interactive cultural competence training. Administrative aspects of the computer-assisted
telephone interviewing (CATI) system and time record keeping are practiced.
The training program will be tailored to meet the specific needs of this study, including a
discussion of successful approaches for conducting interviews with people facing the
continuing life disruptions following Hurricanes Rita/Katrina and now the BP oil spill.
Interviewers will learn the best methods for refusal avoidance and conversion
techniques, and will receive extensive hands-on training with the Computer-Assisted
Interviewing (CAI) questionnaire. They will also learn the most effective ways to explain
the importance of participating in the study, and how to best answer questions about the
study’s purpose and process. Interviewers will be trained to make respondents aware of
other sources of information about the study, such as the study website. Training will
include sensitivity exercises designed to ensure that interviewers show unconditional
positive regard for participants. Interviewers will be trained to use positive rather than
patronizing language, use structured probes, check for respondent fatigue, and offer
encouragement without leading the respondent to respond in a specific way. The training
will focus on the three general challenges in interviews—communication, stamina, and
cognitive challenges—and specific recommendations for overcoming these challenges.
Each training topic will be reinforced with group discussion and interaction, trainer
demonstrations, and classroom practice and discussion. Role-playing and practice will
be used.
Confidentiality safeguards will be maintained throughout the data collection period. All
study personnel will be trained in their responsibilities under HIPAA to protect the
confidentiality and privacy of each participant’s personal health information. The training
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will also describe the civil and criminal penalties if an interviewer violates a participant’s
right to privacy. All interviewing staff will be required to sign a Confidentiality Agreement
and an Affidavit of Nondisclosure as part of their training on protecting the privacy and
rights of respondents. Training will also include identification of social and mental health
issues in need of intervention and appropriate protocols for seeking outside support or
making community referrals.
Individual Telephone Interviewer performance will be monitored by Telephone
Supervisors using Computer Assisted Telephone Interviewing (CATI) and telephony
technology that permits silent monitoring of voice together with key-stroke by key-stroke
monitoring within the CATI instrument. The supervisors will systematically select
interviewers for monitoring and will formally evaluate performance providing praise or
corrective feedback, as appropriate. Evaluations are maintained in individual
interviewer performance files and are regularly reviewed by the call center manager for
purposes of performance recognition, performance improvement coaching or dismissal.
The call center manager will frequently review recruitment and enrollment statistics in
the study database to ensure that participants are being enrolled consistent with the
distribution of the various study populations of interest in the selected sampling frame.
Weekly reports will summarize recruitment statistics which also will be discussed at
weekly project meetings. If it appears that too many or not enough of given subgroups
are being enrolled, study staff, investigators will meet SRA’s statistical and
programming staff to consider adjusting the calling cue to rebalance the recruitment calls
as appropriate. SRA’s Director of Survey Activities will closely monitor day-to-day call
center activities to ensure that call center staff is closely adhering to recruitment and
enrollment quality and productivity goals.
8.1.2
Home Visit Personnel
Home visits will be conducted by as many as 60-80 home visit agents (HVA) and 8-12
Regional Managers (RM). In this study, it will be important to retain HVAs with particular
aptitude, skill, and sensitivity in working with persons having experienced natural
disaster, life disruption, and probable dislocation.
Training for home visit data collection will start with a Regional Manager training
sessions that precede the HVA training. This RM training will focus on data collection
procedures, management of HVAs, the importance of data quality and cost containment,
and reporting. Following the RM training, training sessions will be held for the HVAs. The
field data collection trainings will be conducted both in person and over the internet. The
training sessions will consist of large-group exercises, demonstrations, round-robin and
dyad mock interviews, and question-and-answer sessions. HVAs will be trained and
tested on their mastery of the ethics and protection of human subjects in research,
establishing rapport, setting visit dates, obtaining informed consent, and administering
questionnaires. They will also be trained in the clinical portion of the study protocol and
tested specifically on the clinical protocol components to include setup, preparation and
shipping of biological samples. The training will also include practice session. The HVA
will practice the complete baseline protocol under the close supervision of the field
supervisors and trainers.
Periodically, RMs will accompany the HVA for follow-up assessment of performance.
Deviations from protocol evidenced in the receipt of data or specimens will be reported
to project management staff at SRA and the RM will follow-up with corrective training or
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dismissal of the HVA as appropriate. The investigators and the NIEHS IRB will be
informed of all deviations.
Field activities will be closely monitored by SRA’s Director of Laboratory Services and
the Home Visit Coordinator who will monitor field operations and the Storage
Coordinator, who will monitor activities of the central processing laboratory, the testing
laboratory and archiving of specimens at the NIEHS Repository, managed by
Experimental Pathology Laboratories.
The Home Visit Coordinator will monitor home visit activities to ensure that these are
proceeding according to schedule. The Home Visit Coordinator will interact with the
RMs on a frequent/near daily basis to ensure that HVAs are receiving home visit
assignments and that they are receiving the necessary home visit supplies to complete
the visits in a timely manner. The Storage Coordinator will also ensure that HVAs are
processing and shipping the collected study specimens immediately upon completion of
the visits and closely monitor arrival of collected study specimens at the CPL and will
ensure that these are being processed according to the study protocol. The Storage
Coordinator will also ensure that processed samples are being routinely transferred to
the NIEHS Repository under appropriate transport conditions. The Storage Coordinator
will also work closely with the Repository Staff to ensure that study samples are entered
into storage and that final storage locations (e.g., freezer, shelf/rack/box/column/row) are
sent to SRA for import into the study database.
8.1.3
Monitoring of Recruitment and Field Activities
Recruitment, retention and field operations are a challenge in most studies. SRA will
generate routine reports for the investigators that summarize recruitment, enrollment,
and retention rates, as well as outcomes of operation processes. Frequent reviews of
study status reports will allow the investigators and SRA to identify problems early and
make adjustment to keep enrollment and study operations on track. Examples of the
types of reports that SRA will generate include:
•
Call center reports that monitor telephone questionnaire outcomes, such as call
rescheduling (soft refusal) rates, duration of interviews, and points of break-off for
incomplete interviews.
•
Enrollment reports that present contact and participation rates for the telephone
enrollment questionnaire both overall and for different demographic subgroups.
•
Home visit reports that monitor outcomes of field activities, such time required to
schedule appointments, no-show and reschedule rates, missed procedure rates,
and duration of visits.
8.1.4
Personal Safety
During our training sessions for HVAs, we will emphasize the importance of safety
during in-home visits and awareness of local laws and regulations. For example, we will
instruct the HVAs to stay on main thoroughfares and well-lighted routes as much as
possible when traveling and give them the option of terminating a visit if there are safety
concerns. The police and sheriff’s departments will be informed of the project’s
presence in their county/parish. Each HVA will be issued a cell phone that they can use
to make emergency calls during travel to or from subjects’ homes as well as during the
visit. SRA is also making provisions for HVAs to request an escort for home visits in
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neighborhoods where there may be safety concerns or for home visits during evening
hours or to remote locations.
Regional managers will—if not already familiar with their assigned area of operation—
consult with local law enforcement officials to determine what, if any, “trouble spots” may
exist in their area. When participants who live in these areas are scheduled for home
visits, the Regional Managers will share this information with the HVAs so that escorting
arrangements can be made and extra travel precautions can be made as necessary. In
addition, we will work with local health departments and other community groups to find
alternate locations in which to conduct interviews if safety is a major concern.
After training, each HVA will have a fundamental and operational knowledge of the
following principles:
•
•
•
•
•
•
Come prepared for the neighborhood, based on the informal information
gathered from the scheduling call, a preview of the neighborhood, and
information from your supervisor,
Always be aware of your environment
Leave the house and reschedule if you think it is necessary for your safety,
When concerned about an area or participant, keep your supervisor aware of
when you are to arrive and when you expect to leave,
Call your supervisor when you do leave.
Emergency telephone numbers are programmed for speed dial into each HVA’s
cell phone
8.1.5
Mandatory Reporting Requirements
In addition to personal safety training, the HVAs will be trained to detect signs of turmoil
and abuse in the homes. Should a HVA witness signs of child, spouse or elder abuse
while in the participant’s home, the HVA will immediately generate an incident report and
transmit this to their Regional Manager and to the Coordinating Center. The
Coordinating Center will immediately contact the NIEHS Project Officer and after
appropriate consultation will report the situation to local authorities in accordance with
applicable laws.
8.1.6
Identifying and Dealing with Mental Health Issues,
Domestic Violence, and Acute Physical Illness
Study staff may encounter participants who are experiencing mental health issues,
domestic violence, or acute physical illness when they interact with participants over the
phone (i.e. on the study hotline or during telephone interviews) or during home visits.
Staff will be trained to handle these situations according to standardized procedures that
are adapted from approaches developed by the CDC and SAMSHA. In brief, the general
approach involves study staff assessing the level of risk and taking appropriate action to
prevent harm to the participant or others.
8.1.6.1 Mental Health Issues
Due to the economic, social and potential health impacts of the oil spill, staff may
encounter potential recruits and study participants who are experiencing mild to severe
psychosocial distress. Call center and field staff will be trained to remain neutral when
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asking questions or responding to issues related to physical or mental health conditions
and socioeconomic status and to reply with sensitivity. In most situations, mild
distresses can be effectively addressed with an empathetic and respectful listening,
allowing study activities to continue as planned. When these approaches fail, study staff
will offer to provide health care referrals and to continue study activities at a later date.
Staff will also be trained to respond to more serious signs of mental health distress, such
as suicidal or homicidal thoughts, that require additional interventions. Those who
express such thoughts will be assessed for signs of acute distress and asked if they
have plans, intentions, and means to act on their thoughts. Based on these assessment
findings, study staff will take appropriate action, as summarized in Table 5 below.
Table 5. Action Plan for Responding to Suicidal and Homicidal Thoughts
Individual
at Risk
Imminent
Danger*
Self
No
Action
• Continue study activities, depending on level of emotional distress
• Offer a health care referral
• Offer to “hotlink” to National Suicide Prevention Hotline
Self
Yes
• End study activities
• Offer to “hotlink” to National Suicide Prevention Hotline
• Call 911, if referral to hotline is declined
• Escalate to study managers and investigators
Other
No
• Continue study activities, depending on level of emotional distress
• Offer a health care referral
Other
Yes
• End study activities
• Call 911
• Escalate to study managers and investigators
* Homicidal or suicidal thoughts combined with plans, intention, or means to act on thoughts.
8.1.6.2
Domestic Violence
Study staff may encounter domestic violence situations when interacting with
participants over the phone or during home visits. In cases where telephone interactions
result in direct evidence (e.g. pleas for help) or indirect signs (e.g. screams, guns shots)
of domestic violence, study staff will offer to call 911. If the phone call ends abruptly,
study staff will initiate a call to 911. Field staff will be trained to immediately leave the
home setting if domestic violence situations arise and to call 911 as soon as they are in
a safe location. Study managers and investigators will be informed of these incidents
immediately after 911 is notified of the situation.
8.1.6.3 Acute Physical Illness
Study staff will be trained to contact 911 when they encounter potential recruits and
study participants who are displaying signs and symptoms of acute physical illness. In
addition, field staff will be certified and trained to provide basic first aid and life support, if
needed, and will help participants and families access emergency care.
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8.1.6.4 Escalation and Documentation
Study supervisors and managers will be immediately notified of all cases involving active
suicidal or homicidal thoughts (i.e. thoughts combined with intentions, plans, or means),
domestic violence situations, and acute medical emergencies. Upon notification, study
managers will notify study investigators and seek advice for any cases that fall outside
the standardized response procedures. Study staff will be responsible for completing
incident reports to document these situations.
8.1.7
Reporting Individual Results to the Participants
HVAs will be trained to provide participants with appropriate and standard feedback
about their individual blood pressure, heart rate and BMI measurements, preliminary
pulmonary function test observations, and urine glucose results before departing the
participant’s home. HVAs will be trained to record all observations and in-home test
results in the data management application as well as on participant Test Result Forms
that provide the participant with a basic interpretation of the various measurements and
test results. HVAs will also be trained to strictly follow scripts when conveying results to
participants. The participant Test Result Forms will include scripts that provide
recommended actions for participants to take depending on the measured values for
each test. For each test result, we provide standard recommendations depending on the
result value (see also section 2.11 and the Test Results Forms in Appendix X).
“Normal” results or expected test values will be relayed as such and the participant will
be told that no additional actions are necessary. If test results or measures are slightly
or moderately elevated or abnormal, the HVA will instruct the participant that he or
she should consult with their healthcare provider at an interval defined by the test in
question to discuss the significance of these results. If test results or measures are
markedly elevated or abnormal, the HVA will instruct the participant to seek medical
evaluation as soon as possible. HVAs will be trained not to offer any medical advice or
to discuss study results in more detail or to engage in general discussions with the
participant about any health-related issues.
HVAs will ask the participant if they would like information on healthcare facilities in their
local area that can provide medical treatment or care. If they receive an affirmative
response, the HVA will use the GuLF STUDY Resource Guide to provide a list of local
providers. If the participant declines, the HVA will re-emphasize to the participant that
there are local providers available and that they can contact the study helpline at any
point to receive information about resources that are available to them.
The HVA will note in the CAPI system which resource contacts were provided to the
participant as well as what follow-up recommendations were given. When these data
are uploaded to the network, the system will auto-generate reports of participants who
should receive follow-up calls to assess whether the participant contacted their
healthcare provider or one of the healthcare/mental health resources provided by the
HVA (or interviewer).Once specimens from participants who are members of the
Biomedical Surveillance Sub-cohort have been transported to and processed by the
Central Processing Laboratory, additional test results such as the complete blood count
with white blood cell differential and a complete urinalysis will be performed by the
diagnostic laboratory and the results will be entered into the study database.
Additionally, pulmonologist interpretations of the pulmonary function test results will also
be captured in the study database. The data management system will then generate a
test result letter and an enclosure with a complete summary of all test findings along with
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their interpretations and recommendations for follow-up that will be sent to the
participant.
In rare event that the central diagnostic lab identifies clinically significant abnormalities
that are not included in results letters for participants, we will contact the participant by
phone, present the findings, and encourage the participant to follow-up with their health
care provider. We will also mail the participant a copy of the laboratory report with a
cover letter encouraging them to see their health care provider. In the event that the
participant does not have a health care provider, we will offer a referral to a local clinic
that provides care for free or at a reduced cost.
8.2
Data Quality Control
8.2.1
Data Collection Quality Control
At the core of our data collection efforts, we will use a commercially available survey
platform. The platform has the following features:
A flexible interface for loading complex sample data initiates and drives study
recruitment activities.
A Computer-Assisted Telephone Interview (CATI) component that guides project
personnel through the interview process to determine eligibility. This component
provides complex branching and algorithm support to collect data, make eligibility
determinations, schedule future contact and direct the management of the new recruit’s
case to regional field supervisors. The CATI system allows data managers to monitor the
recruitment process and all call center operations and success metrics. All CATI data
are updated and managed in the central data management system. A notification system
text-messages all receiving field representatives and managers when new cases are
assigned to them.
A CAPI component running on field laptop computers to administer study questionnaires
and capture clinical evaluations. The CAPI component guides field personnel through a
questionnaire that has complex and conditional branching as well as rostering. The CAPI
system provides real-time data validation, ensuring data are valid when captured and the
immediate correction of data after an error is detected.
A central management tool ensures that all CAPI and CATI data are collected into a
single repository and manages the aggregation of laptop interview data. Field
representatives connect to the communications portal (described below) using secure
internet technology, and automatically upload collected interview data and download
preparatory data for forthcoming interviews. CATI user data are managed via the same
software tool that reads and writes data directly to the database.
8.2.2
Data Storage
All study data are housed in a single SQL Server data repository stored in the secure
data center. This single database ensures that all system users are accessing the same
database; allows for greater control via role-based access privileges; provides a robust
architecture to support backup, security, and disaster recovery; and provides the
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flexibility needed to change the data input mechanisms that could change during a
potentially very long study.
8.2.3
Data Management & Communications
The communications portal provides a single access point for all study data, reports,
status updates and communications. The communications portal provides the ability to
record, track, and analyze information associated with all types of case management
activities such as scheduling, field interviews, tracking, and data acquisition. Project field
personnel and other authorized project personnel connect to the communications portal
over the Internet, go through an authorization process to establish an SSL connection,
and have access to a variety of functions that support their work. These functions
include the ability to:
•
Upload and download interview data
•
Update interview schedules; view upcoming workloads for self or field staff (for
supervisors)
•
View data completeness reports including status of lab data
•
Receive updates from project management including updated modules, with training
provided
•
Transmit laboratory data, receive validations
•
Report and track errors or technical support needs and follow them to closure
•
Receive warnings about overdue lab data transfers
•
Update participant profile information if within user rights
•
Keep track of project personnel; review training completeness reports and training
records
•
Monitor call center performance
Field representatives or managers connect to the Data Management System (DMS)
using laptops with real-time, whole-disk encryption. Data will be transferred from the
laptop to the DMS over the Internet or using smart phone tethering technology to gain
Internet access. The DMS is integrated with email, enabling key events to trigger emails
accessible via smart phones, ensuring that our distributed workforce is as current with
information as possible. Regular data transmissions are required of all field personnel
and phone email messaging prompt field staff to establish a data upload session if
overdue.
The communication portal is key to the success of this project as it provides the most
timely, accurate information and delivers it to project staff in real-time. For example, it is
crucial that supervisors monitor recruitment and enrollment trends, and compare these
results against various call center operations to improve overall recruitment success
rates. Furthermore, enrollment success measures are compared based on time of day,
call center operators, source of telephone number, and ordinal number of call attempts
in order to identify trends that suggest necessary modifications.
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Laboratory Procedures
8.3.1
Laboratory Data Quality Control
The study laboratories that will be selected to analyze the study specimens will be
evaluated in part based upon their existing performance measures to assure the quality
of their testing results. This includes (1) internal and external quality control and
proficiency testing programs, (2) testing methodologies vis à vis industry standards such
as those published by the Clinical Laboratory Standard Institute (CLSI) and the
American Industrial Hygiene Association (AIHA), (3) assay standardization to ensure the
desired analytical range and sensitivity/specificity, and (4) methodology validation and
analytical instrument performance using CLSI standard GP-31A and others, and preand post-analytical processes such as specimen receipt and accessioning, sample
aliquoting and batching, treatment of out-of-range results, reporting, and electronic data
transfer.
A continuing performance review on both external and internal quality control programs
will be conducted prior to commencing study data collection. Once home visits have
begun and biospecimens and environmental specimens are submitted for analyses, test
reproducibility and accuracy will be monitored as follows:
•
Assay Variability/Reproducibility: Intra-assay (measurement) variability will be
assessed through replicate assays conducted on the same day and in the same run.
Inter-assay variability will be assessed through replicate assays conducted on
different days in different runs.
•
Testing Accuracy: Assessing the accuracy of test results presumes that there are
available “gold standards” for each analyte of interest. While it is possible to
quantitatively determine the amount of some analytes present (generally chemical
compounds such as cotinine, lead, BFRs, and phthalates), definitively quantifying
biological analytes such as IgE allergens, endotoxins, mold, and fungi, or volatile
analytes such as formaldehyde and VOCs is more problematic and assay
dependent. Biospecimen controls, environmental controls, and split specimens will
be implemented for this purpose.
Laboratory testing quality will also be monitored by requiring submission of regular QC
results as well as periodic proficiency testing program results. Modifications to testing
procedures or sample processing/ extraction procedures will be avoided or minimized to
the extent possible.
8.3.2
Quality Control Specimen Collection
To preserve valuable study subject materials, we will collect biospecimens and
environmental samples from up to 200 randomly selected anonymous donors to use for
quality control. These will be used to create samples that can be inserted blindly for
quality control when laboratories process or analyze GuLF STUDY samples, to assess
drift over time in laboratory analyses, and to provide a sample source for assay
development and testing. These samples will be in addition to the quality control
samples that will be collected from a random subset of cohort members and that are
essential for analyses requiring serial samples or known representativeness of the study
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cohort. The volunteers providing these samples will be selected to be roughly similar to
the clean-up worker population. Each person will provide blood, urine, saliva, hair and
nail clippings, and household dust samples. Blood will be stored as serum, plasma, and
blood clots in cryovials in vapor phase liquid nitrogen. Urine will be stored in cryovials in
vapor phase liquid nitrogen. Dust wipes and hair samples will be stored at -20°C. Toenail
samples will be stored with desiccant under controlled ambient temperature and
humidity. We will collect these samples from anonymous donors under a separate
protocol.
8.4
Run-in Period
Study personnel, procedures and forms will need to be tested in order to determine
whether planned data collection efforts will yield valid and reliable results in the most
time and cost efficient manner. We plan to conduct a 4-5 week run-in period of the study.
We aim to recruit N~2,000 participants during the run-in period and schedule as many
in-home visits as possible during this time. This will establish a vanguard group of
participants to allow us to test the questionnaires and, as the participants move through
the phases of the study, the protocols to ensure that the GuLF STUDY data collection
efforts will work as planned. We will evaluate the data from the field as it becomes
available and any necessary alterations in the study protocol that will need to be made
can be identified and adjudicated accordingly based on the results of this vanguard
group. The IRB will be notified of any necessary changes to the protocol.
9
Human Subjects Protections
9.1
Institutional Review Board
The investigator will submit the protocol, informed consent form, questionnaires,
proposed recruitment materials, and other materials for participants to the NIEHS IRB for
review and approval. Subjects will not be enrolled until the submission has been
approved in writing by the IRB chair. Once the protocol is approved, the principal
investigator will be responsible for obtaining IRB approval during annual Continuing
Review for the duration of the study.
The principal investigator will submit and obtain approval from the IRB for all
amendments to the protocol, informed consent form, and other study documentation
referenced above. Amendments will not be implemented without prior IRB approval,
except where necessary to eliminate immediate hazards to participants. The principal
investigator will report adverse events, protocol deviations, inadvertent loss or disclosure
of data, and loss of samples in accordance with IRB policies.
9.2
Informed Consent Process
Informed consent is an ongoing, interactive process that is initiated when the discussion
regarding study participation begins and continues throughout the study. The consent
process will begin with a lead letter and study brochure that provides an overview of the
study and what it means to participate. During the telephone enrollment call, recruiters
will explain the reason for the call, reference the lead letter and brochure that were sent
by mail in advance of the call, introduce the study, and seek verbal consent for the initial
screening and enrollment process. Participants will be informed that they will receive an
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annual Newsletter for the duration of the study and be asked to provide periodic contact
information updates. The elements of passive follow-up via linkage with Cancer
Registries, Vital Statistics and other data sources will be described and verbal consent
will be obtained. They will also be informed about data sharing policies and that they
may be contacted for potential participation in related studies but that they would have
an opportunity to consent or not consent at that time.
Those who are eligible for participation in the Active Follow-up Sub-cohort will receive
additional information about the study and will be invited to schedule a home visit. Field
staff will obtain written informed consent from participants prior to conducting any study
activities during the home visit. In order to ensure that participants make an informed
decision about enrollment, field staff will review the study’s purpose, procedures, risks,
and benefits, as well as the rights of research participants. Explicit consent will be
sought for sharing individual-level data with qualified researchers committing to maintain
participant confidentiality and comply with their consent provisions, similar to NIH
policies for data sharing in genome-wide association studies
(http://grants.nih.gov/grants/gwas/).
Field staff will allow the participant ample time to review the consent, ask questions, and
obtain clarifications regarding the study prior to agreeing to enrollment. After voluntarily
agreeing to take part in the study, participants will be asked to sign and date a current
IRB-approved informed consent form. Field staff will return the signed consent to SRA
for storage in the central study file. A copy of the consent form will be provided to the
subject along with a summary of the key points in the consent document and a study
FAQ document – a series of answers to questions participants may have about aspects
of the study.
The consent form will contain contact information (i.e., toll-free phone number) for study
staff that will be available to answer questions that may arise after the visit. Questions
about study participation will also be addressed at the time of follow-up interviews.
Passively followed participants will receive an enrollment packet after the enrollment call
is completed. The packet will contain information that describes the study and provides
contact information for study staff, including the toll-free study phone number and
address for the study website. They will receive a description of what they agreed to
during the telephone call and will be provided with information on how to withdraw from
the study if they have changed their mind about long-term passive participation.
Participants who are invited to complete the Follow-up Telephone Questionnaires will
receive an advance mailing that provides an overview of the additional telephone
interviews. The telephone interviewer will review the purpose of the interview and the
participant will provide verbal consent prior to answering any questions.
All participants will receive an annual newsletter that contains updates about study
progress and findings (see Section 3.L.ii – Newsletters).
9.3
Participant Confidentiality
All study personnel will be required to complete on-line training in the protection of
human research subjects. The investigators and study staff will strictly maintain
participant confidentiality. This confidentiality will be extended to cover questionnaire
data, clinical assessments, biological samples, and environmental samples.
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All study-related information will be stored securely. All study datasets, laboratory
specimens, and administrative forms will be identified by a coded number in order to
maintain participant confidentiality. All records that contain names or other personal
identifiers will be stored separately from study records identified by code number. All
databases will be secured behind firewalls with password-protected access systems.
Worksheets, lists, logbooks, appointment books, and any other documents that link
participant ID numbers to other identifying information will be stored in a separate,
locked file in an area with limited access.
A Federal Certificate of Confidentiality will be obtained for this study. The Certificate will
help protect against disclosures of study-related information by Federal, State or local
civil, criminal, administrative, legislative, or other proceedings, although it will not
guarantee that data cannot be released. Participants will be informed about the
certificate during the informed consent process.
9.4
Study Discontinuation
Participants may voluntarily withdraw from the study for any reason at any time.
Participants will be informed that unless explicit written instructions are received,
investigators will continue to use data and samples collected up to the point of
withdrawal although no new information will be collected from them. Study staff will
effectively destroy all known remaining biologic and environmental samples by
anonymizing the samples using a newly assigned ID number and report what was done
to both the subject and to the IRB. This decision will not affect the subject’s participation
in this protocol or any other protocols at NIH. Anonymizing the samples will effectively
terminate any association the samples have with the study participant, fulfilling their
request, while simultaneously providing samples that can be used for laboratory QA/QC
procedures. However, should the subject specifically request it, we will physically
destroy all remaining samples.
Study staff will seek feedback from the participant to determine reasons for
discontinuation and to identify any barriers that can be addressed to keep the participant
in the study. The reasons for all discontinuations will be recorded in the data collection
system and routinely monitored by the investigators. Common barriers to ongoing
participation may be addressed by changes in retention strategies or study design.
10
Data Handling and Record Keeping
10.1
Data Capture Methods
The core of the data capture system will rely on an industry standard field data collection
system, using standard technologies. The system platform must allow for:
•
A flexible interface for loading complex sample data initiates and drives study
recruitment activities.
•
A Computer-Assisted Telephone Interview (CATI) component that guides project
personnel through the interview process to determine eligibility. This component
provides complex branching and algorithm support to collect data, make eligibility
determinations, schedule future contact and direct the management of the new
recruit’s case to regional field supervisors. The CATI system allows data managers
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to monitor the recruitment process and all call center operations and success
metrics. All CATI data are updated and managed in the central data management
system. A notification system alerts all receiving field representatives and managers
when new cases are assigned to them.
•
A Computer-Assisted Personal Interview (CAPI) component running on field laptop
computers to administer study questionnaires and capture clinical evaluations. The
CAPI component guides field personnel through a questionnaire that has complex
and conditional branching as well as rostering. The CAPI system provides real-time
data validation, ensuring data are valid when captured and the immediate correction
of data after an error is detected. SRA will prepare all CAPI systems, ship them to
kickoff training, train personnel to use the system, and support the laptop PCs and
CAPI applications via a toll-free and email helpdesk function.
•
A central management tool that ensures that all CAPI and CATI data are collected
into a single repository. The centralized data management and aggregation tool will
manage the matriculation of data from field interview data platforms to the
centralized data repository. Field representatives will connect to the communications
portal (described below) using internet SSL technology, and automatically upload
collected interview data and download preparatory data for forthcoming interviews.
10.2
Data Management Responsibilities
The captured data will be stored in a comprehensive data management system (DMS)
that centralizes study information into an integrated solution. From the time that
participants become part of the potential sample to the time they are complete, all
project data are managed and tracked in the DMS. Project personnel will have an
appropriate “view” into the data using role-based access control. The DMS will support
the full scope of study data management activities, including management of study
sampling; collection of field and laboratory data; management of participant activities
(case management); reporting of all data collection efforts and status; and preparation of
analysis datasets.
The heart of the DMS will be the database server. The database server will be
configured for 24/7 operation, and provide the capability of offsite backups.
The DMS also includes a communications portal which provides a single access point
for all study data, reports, status updates and communications. The communications
portal serves as the gateway between users and the data repository. The portal enables
the ability to record, track, and analyze information associated with all types of case
management activities such as scheduling, field interviews, tracking, and data
acquisition. Project field personnel and other authorized project personnel connect to the
communications portal over the Internet, go through an authorization process to
establish an SSL connection, and have access to a variety of functions that support their
work. These functions include the ability to:
•
Upload and download interview data
•
Update interview schedules; view upcoming workloads for self or field staff (for
supervisors)
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•
View data completeness reports including status of lab data and abstracted medical
records
•
Receive updates from project management including updated modules, with training
provided
•
Transmit laboratory data, receive validations
•
Report and track errors or technical support needs and follow them to closure
•
Receive warnings about overdue lab data transfers
•
Update participant profile information if within user rights
•
Track project personnel; review training completeness reports and training records
•
Monitor call center performance
Field representatives or managers connect to the DMS using laptops over the Internet or
using smart phone tethering technology to gain Internet access. The DMS is integrated
with email, enabling key events to trigger emails accessible via smart phones, ensuring
that our distributed workforce is as current with information as possible. Regular data
transmissions are required of all field personnel, and field staff are prompted to establish
a data upload session if overdue.
The communication portal is key to the success of this project as it provides the most
timely, accurate information and delivers it to project staff in real-time. For example, it is
crucial that supervisors monitor recruitment and enrollment trends, and compare these
results against various call center operations to improve overall recruitment success
rates. Furthermore, enrollment success measures are compared based on time of day,
call center operators, source of telephone number, and ordinal number of call attempts
in order to identify trends that suggest necessary modifications.
10.3
Data Access and Sharing
Given the public health importance of research on the health effects of the Deepwater
Horizon disaster and its aftermath, results from the GuLF STUDY will be made available
for research use by any interested and qualified investigator or organization, within the
limits of providing appropriate protection of research participants and compliance with
their informed consent. Policies for data access will build on NIH established policies for
controlled access to individual-level data in genome-wide association studies, as
described at http://grants.nih.gov/grants/gwas/ and open-access data sharing policies
developed for other NIH sponsored longitudinal studies. Researchers interested in
obtaining controlled-access GuLF data will agree to keep the data secure, use the data
only for the approved research purposes, and not to attempt to identify individual study
participants. In recognition of the rights and intellectual contributions of the GuLF
investigators to publish data within a reasonable timeframe, outside researchers will also
agree to observe a twelve month moratorium on submitting abstracts and publications
using the data. Data and documentation will be made publicly available soon after
collection along with information on all data that have been or will be collected. Typically
(e.g. as currently practiced on dbGaP, protocols, descriptions of data and files, and
counts of responses are available online. Summary descriptive tables may also be
posted. In order to prevent accidental disclosure of individual participant data, de-
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identified datasets are separately provided to qualified requesters; individual level data
are not posted online. Access to the data will be granted by an NIH Data Access
Committee which will ensure that these conditions are met initially and monitor
subsequent compliance during the study.
10.3.1
Access to Biospecimens and Use of Cohort for Addon Studies
Additionally, other investigators (both at NIH and outside) may wish to study the stored
biologic and/or environmental samples or propose add-on studies that generate new
data and/or involve direct participant contact. In that case, NIEHS IRB approval must be
sought prior to any sharing of samples. Any clinical information shared about the
sample would similarly require prior NIEHS IRB approval. Procedures and guidelines for
proposing new assays or add-on studies will be established and posted. An
independent committee will be established to review proposals for scientific merit,
feasibility, and impact on the study cohort.
10.4
Study Records Retention
All study records will be retained indefinitely. Study records that will be retained include
IRB approvals and correspondence, signed informed consent forms, tracking logs,
contact information update forms, and other study documentation that may be developed
during the course of the study. To protect against accidental or premature destruction of
these documents, the records will be maintained in a secure, locked storage areas that
are only accessible to study staff.
All study data will be housed in a single data repository. This single database ensures
that all system users are accessing the same database; allows for greater control via
role-based access privileges; provides a robust architecture to support backup, security,
and disaster recovery; and provides the flexibility needed to change the data input
mechanisms that could change during a potentially long study.
Any loss or unanticipated destruction of samples or data (for example, due to freezer
malfunction) that meets the NIH Intramural Protocol Violation definition or results in a
violation that compromises the scientific integrity of the data collected for the study; will
be reported to the NIEHS IRB.
At the completion of the protocol (termination), samples and data will either be
destroyed, or after IRB approval, transferred to another existing protocol where they will
be maintained in a repository as applicable.
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Appendix A:
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Addendum 1: Current Environmental Exposures in
GuLF STUDY Participants Exposure Monitoring
Addendum
I.
Overview
The Exposure Monitoring (EM) Addendum is designed to address ongoing concerns
among Gulf state residents about potentially higher levels of exposure to oil-spill related
chemicals and implications for current and future health. Since the half-life in blood of
relevant volatile organic compounds (VOCs) is short (12-24 hours), reports of high levels
of chemicals such as benzene, toluene, ethylbenzene, and xylene (BTEX) in blood from
Gulf area residents should be due to ongoing environmental, lifestyle, and occupational
exposures rather than to the oil spill per se. Yet concern that these reportedly high levels
are a direct result of exposure to the oil spill persist, fanned by periodic reports in the
media. It is important to determine both the factors that contribute to these potentially
higher levels of oil spill chemicals and to explore any relationship between chemical
levels and symptom reporting. This information will aid in future interpretation of the
larger GuLF STUDY data. The EM Addendum will take advantage of the ongoing GuLF
STUDY to cost-effectively collect the needed samples and data to assess current levels of
oil-related chemicals and metabolites in blood and identify potential sources and
consequences of exposure. The EM Addendum will:
1. Describe current exposure levels in GuLF STUDY participants who are residents
in the four states most affected by the Deepwater Horizon disaster – Alabama,
Florida, Louisiana, and Mississippi.
•
•
Compare current exposure levels with data from a national sample of US
adults
Assess current exposure levels of GuLF STUDY participants in relation to
proximity to the Gulf of Mexico, taking into account behavioral and other
determinants of exposure
2. Identify factors associated with current exposure levels of GuLF STUDY
participants, including potential determinants of exposure and any associations
between current exposure levels and health measures.
3. Evaluate correlations between current personal air monitoring data and biological
measures for a subset of participants in the EM Addendum.
Measured blood VOC levels will be evaluated in relation to behaviors, environmental and
occupational exposures, lifestyle, and oil-spill clean-up experiences as ascertained in the
GuLF STUDY baseline questionnaires and additional surveys specific to the EM
Addendum. The association between measured levels of biological and environmental
exposures and self-reported symptoms and health conditions will be evaluated to address
questions of concern to GuLF STUDY communities.
The EM Addendum will take advantage of the operational efficiencies of the ongoing
GuLF STUDY by sampling from the GuLF STUDY population - oil-spill clean-up
workers and volunteers who reside in communities affected by the April 2010 Gulf of
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Mexico oil spill and have already agreed to a home visit for the GuLF STUDY. GuLF
STUDY participants who reside in Alabama, Florida, Louisiana, and Mississippi will be
recruited for biomonitoring and, for a subset of EM Addendum participants, 24-hour
personal air monitoring. The EM Addendum will take advantage of ongoing home visits
for the GuLF STUDY to enroll participants and collect biological samples and personal
monitoring data. Participants will be identified at either the completion of the GuLF
STUDY telephone interview or afterwards if the telephone interview is completed and
they are selected for a home visit. Those individuals who have completed the telephone
interview and are selected for a home visit will receive a recruitment call asking them to
complete the EM Addendum during their scheduled home visit.
Approximately 1,000 participants will provide additional blood samples and answer some
additional questions during their normal GuLF STUDY home visit. Of those ~1,000
participants, approximately 200 will be asked to also participate in the personal
monitoring portion of the EM Addendum which will require participants to wear a
personal air monitoring badge for 24-hours prior to the GuLF STUDY home visit.
II.
Background
The Deepwater Horizon disaster resulted in the release of over 4.9 million barrels
of crude oil into the Gulf of Mexico. During the course of the oil-spill clean-up
response, over 150,000 workers and volunteers participated in oil-spill clean-up
activities. Community groups have expressed ongoing concerns about exposures
and health outcomes they believe to be associated with components of oil and
dispersants used to clean-up the oil spill [1]. Reported symptoms among clean-up
workers and volunteers included headaches, coughing, dizziness, nausea,
exhaustion, and heat stress symptoms [2]. Such symptoms continue to be reported
by GuLF STUDY participants, with the frequency of symptoms higher in Gulf
than non-Gulf communities (unpublished GuLF STUDY data).
Of particular concern among residents and clean-up workers have been oil-related
chemicals such as heavy metals and VOCs. VOCs are aromatic hydrocarbons that
occur naturally in crude oil and evaporate quickly (<24 hours) after oil reaches the
water surface. VOCs were examined in the Gulf oil plume at 1.5 km depth in June
2010 [3]. Although benzene, toluene, ethylbenzene, and xylenes (BTEX) made up
a significant portion of the oil plume, most airborne breathing zone measurements
of BTEX collected between April 2010 and October 2010 indicated that BTEX
concentrations did not exceed Occupational Exposure Limits during the Gulf
cleanup activities [4]. Additionally, heavy metals found in crude oil, including
cadmium, chromium, manganese, copper, nickel, and lead, have a range of
adverse health effects, including neurotoxicity and carcinogenicity, renal and
immunotoxicity[5-12]. However, even at the time of the oil spill, exposures were
reported to be very low due to weathering and other properties of the oil.
Nonetheless, there is still a high level of community concern about these
exposures and resulting health effects.
In other studies, significant associations have been reported between selected
VOCs in air (benzene, chloroform, 1,4-dichlorobenzene, ethylbenzene, methyl
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tert-butyl ether, tetrachloroethane, toluene, m-/p-xylene, and o-xylene) and VOCs
in blood [13]. The half-life of VOCs in blood is 24-hours in adults with no
ongoing occupational exposure, and blood levels in the U.S. population range
from parts per trillion to parts per billion with concentrations elevated among
smokers [14-17]. Occupational studies have demonstrated positive associations
between personal exposure to VOCs and blood VOC concentrations. In a study of
VOC exposure among Mexico City workers, passive VOC monitors were used to
assess personal exposures during a work shift and blood samples were drawn
immediately after the work shift [18]. Significant associations were observed
between job category, personal monitoring VOC concentrations, and blood VOC
concentrations. Outside of the occupational setting, environmental exposures to
VOCs are predominantly due to emissions from industrial sources, mobile
sources, landfill sites, personal time-activity patterns, and building characteristics
[19, 20].
Exposures resulting from the Deepwater Horizon Disaster were generally reported
to be low for most communities, with the majority of area and breathing zone
measurements below the limits of detection in assays designed to measure
occupational threshold-level exposures. Government and industry measurement
data are mistrusted by some community members, with concern that tests were
insufficiently sensitive or not focused to detect exposures related to the spill.
Although current levels cannot plausibly be linked to exposures that took place at
the time of the spill, case reports of residents and workers with elevated levels of
BTEX chemicals in blood continue to appear in the media and to draw attention at
community meetings related to the oil spill. Residents of the Gulf region may
have ongoing opportunities to be exposed to oil and oil-related constituents
through their occupation (e.g. working with degreasers and cleaning agents),
recreational and lifestyle behaviors (e.g. smoking), or by residing near industrial
facilities. The Exposure Monitoring Addendum will systematically characterize
current exposures to oil-related constituents in a sample of approximately 1,000
GuLF STUDY participants.
III.
Objectives
The Exposure Monitoring (EM) Addendum aims to investigate exposure to
selected metals and volatile organic compounds (VOCs, including benzene,
toluene, ethylbenzene, and xylenes) among a subset of GuLF STUDY
participants. The following are the objectives of the EM Addendum:
1. To characterize current environmental exposures among participants during the
course of their normal daily activities.
2. To describe associations of behavioral, residential, and socioeconomic
characteristics with measured levels of heavy metals and VOCs among
participants.
3. To explore associations between EM Supplement measured exposures and health
outcomes reported in the GuLF STUDY questionnaires.
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Population
Participants will be recruited for the EM Addendum from among those
completing the GuLF STUDY telephone interview and agreeing to the home visit.
For those individuals who have already completed the telephone questionnaire but
not the home visit, we will place recruitment calls to invite them to complete the
EM Addendum in addition to their home visit. The goal is to have 1,000
participants complete the EM Addendum, including providing the additional
blood samples and answering the extra questionnaire items. Due to operational
challenges and participant preferences, we anticipate that some participants will
provide either the blood samples or the questionnaire data, but not both. In these
incomplete cases, we plan to keep the data or samples that are obtained. Thus, we
will invite approximately 1,200 GuLF STUDY participants to achieve a sample
size of approximately1,000 fully compliant cases for the EM Addendum.
We will recruit participants from Alabama, Florida, Louisiana, and Mississippi
(from any home-visit eligible GuLF STUDY county or parish) prospectively at
completion of the telephone interview as well as from among those who have
already completed the telephone interview but have not yet completed their home
visit.
We plan to enroll a sample that includes participants across a range of distances
from the Gulf of Mexico (Gulf and Adjacent counties, as defined in the GuLF
STUDY protocol, and the rest of the state) and that includes sufficient numbers of
women and nonsmokers for analysis. Based on data from the first 2,500 home
visit participants, 75% reside in Gulf counties or parishes, 8% in adjacent
counties, and 17% are from more distant locations. Since the bulk of the concern
about ongoing exposures is concentrated in the Gulf counties, this distribution of
participants will allow us to address local concerns as well as to include sufficient
numbers of non-Gulf county participants to have a natural comparison group of
persons less proximate to the Gulf of Mexico.
Both active and passive exposure to tobacco smoke are strongly associated with
increased levels of metals and VOCs in blood. Approximately 38% of GuLF
STUDY participants who have agreed to a Home Visit are current smokers (active
smokers). Non-active smokers will be over-sampled in order to examine the
potential contributions of non-tobacco sources to personal exposures. Although
we now collect information on passive smoking during the telephone interview,
until late February 2012, this information was collected only from those
completing a home visit. Table 1, therefore, shows information on active and
passive smoking for individuals who completed the home visit as of May 15,
2012. Approximately 35% of GuLF STUDY participants who are not active
smokers report they are currently exposed to tobacco smoke in their home.
When selecting participants for the EM Addendum, we will apply sampling
weights so that at least 80% of the participants are not active smokers. Thus
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based on current rates of passive exposure, we expect that 20 percent will be
active smokers and 28% will be passive smokers (0.8*.35) for a total of 48% with
smoke exposure and 52% unexposed.
Table 1. Active and Passive Smoking Status among GuLF STUDY participants
Passive Smokers
Currently Exposed to Tobacco Smoke in the Home
Yes
No
Total
Active
N
%
N
%
N
%
Smokers
Currently
Yes
966
63.8%
549
36.2%
1515
100%
Smoke
No
858
34.9%
1600
65.1%
2458
100%
Currently about 20% of those eligible for a home visit are women. We will also
apply sampling weights in order to target a sample that is at least 30% women.
A. Selection of Participants for EM Addendum (Phase I)
Beginning with participants who agree or tentatively agree to a home visit (about
83% of GuLF STUDY participants), we will invite 1,200 (300 per state) to
provide the additional samples for the EM Addendum to achieve a final sample
size of approximately 1,000 participants with complete data and samples (83%
participation). This accounts for the loss of participants between agreement and
final completion (currently 15%) and allows for some additional losses due to
inability to obtain the extra blood samples or secondary refusals.
B. Selection of Participants for Personal Environmental Monitoring (Phase II)
A subset of participants will be randomly selected and asked to wear a personal
environmental sampler to collect corresponding information on BTEX and other
VOC’s for cross comparisons with blood measures and comparison with external
environmental data (Phase II). There will be no environmental monitoring of
metals. Allowing for a combined rate of 80% for response and compliance (e.g.,
using the badge correctly), we will invite approximately 250 participants to wear
the exposure monitor in order to achieve a final sample of approximately 200
compliant participants, including badge and questionnaire data and blood
samples. Participants in this phase of the EM Addendum will be selected from
among EM participants in just two states (Louisiana and Alabama) to maximize
the number of participants per state.
Because the exposure opportunities may differ for men and women and because
there are fewer women than men in the GuLF STUDY overall, we will also
oversample women for this phase of the EM Addendum. We anticipate
approximately 250 participants per state in the full EM Addendum, among whom
75 are expected to be women, and an expected 80% response/compliance rate.
For the personal environmental monitoring portion of the EM Addendum, we
will attempt to account for drop outs and no shows by recruiting approximately
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63 women per state (84% of those available) for a target sample of 100 women
and 100 men total (50 each per state).
Participants selected for personal monitoring will be sent an environmental
monitoring kit via commercial overnight courier 2-3 days before the scheduled
home visit. Each monitoring kit will include a personal VOC monitor and
customized pictorial and written instructions for personal monitor use during the
24 hours prior to the home visit. Two days before the scheduled home visit, the
HVA will place a reminder phone call to the participant to confirm receipt of the
monitoring kit, review EM Addendum instructions, and answer any questions
that the EM Addendum participant may have. There will be a second call made
approximately 24 hours before the GuLF STUDY Home Visit to remind the
participant and confirm that they are able to deploy and wear the VOC monitor.
During the normal Gulf STUDY Home Visit, the HVA will collect the additional
blood samples from the EM Addendum participants and collect additional
information about exposure opportunities in the past 24 hours (behavioral,
dietary, occupational and environmental). Information on current exposures
collected for the EM Addendum will addendum data collected from the GuLF
STUDY to characterize the current environmental exposures among participants
during the course of normal daily activities. The HVA will also retrieve the VOC
monitor from those selected for the monitoring phase of the EM Addendum and
review compliance with regard to wearing the monitor.
C. Informed Consent
Verbal consent will be obtained from potential EM Addendum participants
during the GuLF STUDY baseline enrollment telephone questionnaire or from a
follow-up recruitment call for those recruited from the home visit back-log. The
Home Visit Agent (HVA) will schedule a GuLF STUDY Home Visit after
obtaining verbal consent from EM Addendum participants. Written informed
consent for the EM Addendum will be obtained by the HVA during the normal
GuLF STUDY Home Visit.
D. Remuneration
EM Addendum participants who contribute only the additional blood samples for
the EM Addendum will receive an additional $10 for their EM Addendum
participation ($60 total, including the normal GuLF STUDY remuneration).
Participants who also complete personal air monitoring will receive an extra $30
for their EM Addendum-related efforts ($80 total, including the normal GuLF
STUDY remuneration).
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Figure 1. Overview of Exposure Monitoring Addendum
Phase I
Phase II
●
●
Baseline Enrollment Telephone Questionnaire
EM Addendum recruitment and consent
Personal Air Monitoring Setup
Personal monitoring equipment mailed to EM
Addendum participant
●
Personal monitoring reminder phone calls
●
Home Visit
●
Collect personal monitoring equipment
Collect blood samples
●
●
Administer EM Addendum forms
●
●
Administer parent GuLF STUDY questionnaires
●
●
$10
$30
Additional Remuneration
V.
Data Collection
During the Gulf STUDY Home Visit, the HVA will collect the additional blood samples
from EM Addendum participants in addition to information about exposure opportunities
in the past 24 hours.
A. Addendumal Residential, Lifestyle, and Behavioral Data
The HVA will collect additional information from EM Addendum participants
to help identify potential sources of heavy metals and VOCs that may
contribute to personal exposures. The HVA will query participants about
residential, dietary, and occupational characteristics and personal behaviors.
Three forms will be used to collect additional information about EM
Addendum participants, residential characteristics, and recent activities:
i.
ii.
The Residence Exposure Form includes questions about building
characteristics, residential exposures, ventilation, and water use
(Appendix
W_I - Form is adapted from the CDC NHANES 2007-2008
questionnaires and the EPA DEARS surveys).
The Twenty-Four Hour Activities Form includes questions about
selected activities during the previous 24 hours (Appendix W_II Form is adapted from the CDC NHANES 2007-2008
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questionnaires and the EPA DEARS surveys) to aid in
interpretation of blood sample results and identify factors
contributing to measured exposure levels.
The Current Occupation Addendum includes questions about
current employment in specific industries, commuting practices,
and occupational exposures (Appendix W_III - Addendum is
adapted from the CDC NHANES 2007-2008 questionnaires and
the EPA DEARS surveys).
B. Local Ambient Source Mapping
GuLF STUDY investigators will use geographic information system (GIS)
technology to map potential area and mobile sources within 300m of the each
participant’s residence. These GIS analyses will be used to characterize a
participants’ potential exposure to the following data sources:
i.
ii.
The Toxics Release Inventory (TRI) database, compiled annually by
EPA, contains county-level emissions data on all manufacturing facilities
(with ≥ 10 full-time employees) that process > 25,000 lb in aggregate or
use > 10,000 lb of any one of 600+ TRI chemicals [21]. The TRI
database includes chemical data by industry, facility address, on-site
disposals, and off-site disposals.
Facility data from state and county agencies, including information on
the address and/or GPS coordinates of local facilities that may emit
VOCs.
C. Biomonitoring
The Division of Laboratory Sciences, National Center for Environmental
Health (NCEH), Centers for Disease Control and Prevention will provide
biomonitoring technical assistance and oversight. NCEH laboratories will
provide supplies and instructions for collecting blood samples and analyze
samples for selected heavy metals and VOCs. NCEH will also help to
interpret analytical results and provide a comparison data set (The National
Health and Nutrition Examination Survey, NHANES). All records associated
with biological samples will be labeled with a coded identification number
that contains no personal identifiers
During the GuLF STUDY Home Visit, the HVA will collect an additional
13mL of blood for metals (3mL) and VOCs (10 mL) analyses. After sample
collection, the HVA will ship the samples to the central GuLF STUDY
processing laboratory for temporary storage before shipment in batches to the
testing laboratory for VOC and metals analysis. Samples will be analyzed for
selected VOCs (including but not limited to benzene, toluene, ethylbenzene,
and xylenes) and metals (including but not limited to cadmium, lead,
manganese, mercury, and selenium). Participants in the EM addendum will
not be asked to provide blood or other samples for quality assurance purposes
in the main study.
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D. Personal Air Monitoring
A qualified lab will provide technical assistance and oversight for
environmental VOC monitoring. Environmental monitoring kits will include
a passive air sampler and customized pictorial and written instructions on
proper sampler deployment and use. Passive sampling badges for
measurements of VOCs (Assay Technology 521 Organic Vapor Monitor or
similar type badge) will be used to collect 24-hour air samples of BTEX and
possibly other VOCs. Passive diffusive samplers are inexpensive personal
monitors that are easy to use, small and unobtrusive, and studies have shown
that the performance of passive air sampling is comparable to canister-based
methods [22]. Environmental monitoring kits and all records associated with
environmental samples will be labeled with a coded identification number that
contains no personal identifiers.
During the reminder phone calls, the HVA will instruct EM Addendum
participants on personal monitoring equipment use and compliance. Briefly,
each participant will be instructed to carry the VOC sampler on their person
for the 24 hour time period prior to the GuLF STUDY Home Visit. The
participants will be instructed that while sleeping, showering, or bathing, the
sampler should be removed and placed in a location that represents their
breathing zone. Participants will be instructed to place the sampler in a dry
location if they engage in other activities with a high likelihood of the
participant/sampler getting wet. However, because some of the workers may
be fishermen or boat captains and we want do not want to exclude exposures
during those activities, they will be advised on approaches to keep the detector
dry and be asked to remove the VOC monitor as needed to avoid submersion
under water. If the participant is unable to wear the VOC monitor during the
sampling period because of the potential for underwater submersion or
employer objection, the duration of time without the monitor will be noted in
the Twenty-Four Hour Activities Form (Appendix W_II, Question 29).
Participants who deploy the monitor but are unable to wear it because of
circumstances such as employer objection or underwater submersion will still
receive the additional $30 remuneration, regardless of duration of monitor use
as long as it was deployed. Participants who do not deploy the monitor at all
will not receive remuneration for wearing a monitor. After 24 hours of
sampling, the HVA will collect and package the samplers for FedEx shipment
to the analysis laboratory.
VI.
Data Analysis
Descriptive analyses, stratified by gender, state of residence and smoking status,
will be conducted to describe the EM Addendum population in terms of
demographic, smoking, behavioral, residential, and socioeconomic characteristics.
Descriptive analyses will include frequencies for categorical variables and means
for continuous variables. Correlations between environmental and biological
exposure measurements will be evaluated.
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Multivariable analyses will include multiple linear regression to explore
demographic, behavioral, residential, socioeconomic, and self-reported Gulf
clean-up characteristics as predictors of personal exposure concentrations.
Multiple logistic regression analyses will be performed to explore associations
between measured exposure levels and health outcomes.
VII.
Statistical Power
Power calculations were based on reported mean concentrations and standard
deviations from existing literature. Geometric means and selected percentiles of
blood concentrations for the U.S. population are presented in Tables 3-5 [23, 24].
Table 3. Volatile Organic Compounds in Blood – Less-than-daily Smokers
(ng/mL)
Selected percentiles
(95% conf. interval)
Geometric Mean
(95% conf. interval)
Benzene
2,5-Dimethylfuran
Ethylbenzene
Toluene
o-Xylene
m- p-Xylene
Sample Size
50th
95th
<0.024
<0.024
0.063
Neg. Control
Neg. Control
(0.051-0.070)
<0.011
<0.011
<0.011
Neg. Control
Neg. Control
Neg. Control
0.028
0.028
0.071
(0.026-0.031)
(0.026-0.031)
(0.056-0.083)
0.082
0.076
0.330
(0.071-0.096)
(0.065-0.091)
(0.240-0.520)
<0.021
<0.021
0.081
Neg. Control
Neg. Control
(0.066-0.083)
0.122
0.120
0.280
(0.109-0.137)
(0.097-0.130)
(0.240-0.330)
859
880
827
854
877
861
Table 4. Volatile Organic Compounds in Blood – Daily Smokers (ng/mL)
Selected percentiles
Geometric Mean
(95% conf. interval)
(95% conf. interval)
50th
Benzene
2,5-Dimethylfuran
Ethylbenzene
Toluene
o-Xylene
Sample Size
95th
0.138
0.140
0.450
(0.126-0.151)
(0.120-0.150)
(0.380-0.510)
0.074
0.076
0.260
(0.067-0.082)
(0.067-0.088)
(0.210-0.280)
0.068
0.065
0.160
(0.064-0.072)
(0.061-0.069)
(0.012-0.018)
0.327
0.330
0.940
(0.294-0.364)
(0.290-0.370)
(0.690-1.300)
0.048
0.044
0.090
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(0.045-0.051)
(0.035-0.052)
(0.083-0.099)
0.212
0.220
0.460
(0.197-0.228)
(0.200-0.230)
(0.400-0.500)
287
Power was calculated using the POWER procedure in SAS (Version 9.2, SAS
Institute, Cary, NC). All power analyses assumed alpha = 0.05. Under a sample
size of 1000 allocated equally between comparison groups, the EM Addendum
will have sufficient power to detect a 21% difference in geometric mean blood
lead concentrations (Table 6). Under a 1:2 between-group sample size allocation,
a 22% difference will be detectable.
Table 6. Detectable between-group ratio of geometric mean blood lead
concentration, based on 80% power for a two-sided test, at significance level
0.05
Total Sample Size
100
Detectable Ratio of Geometric Means
1:1 Allocation1
1:2 Allocation2
1.82
1.89
500
1.31
1.33
1000
1.21
1.22
1500
1.17
1.18
2000
1.15
1.15
1
Equal sample sizes in each comparison group, as anticipated for comparisons based on smoking status
groups.
2
Sample size allocation of one-third-to-two-thirds, as anticipated for comparisons based on current exposure
or occupational groups.
VIII.
Reporting of Results
At the conclusion of the EM Addendum, NIEHS will provide confidential reports
to each EM Addendum participant that will summarize results. Reports will be
developed in collaboration with the CDC and be vetted with community leaders
and health departments as well as the IRB before being distributed. The EM
Addendum report will include a cover letter that describes overall results along
with individualized reports of biological and environmental sampling results. The
EM Addendum report will provide findings in the context of study, regional, and
national results. For biological sampling results, results will be compared to levels
reported in CDC’s National Report on Human Exposure to Environmental
Chemicals, a population-based assessment of exposure to environmental
chemicals in blood and urine. Environmental sampling results will be compared to
national recommended standards.
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During the consent process, participants will be asked if they would like the GuLF
STUDY to send their blood and environmental monitoring results (if available) from the
EM Addendum to their health care provider. The GuLF STUDY already includes options
for referral to low or no cost health care. State-specific results will be shared with state
and local health department officials and with other community leaders. Community
meetings will be held to present results and discuss resulting concerns.
IX.
Timeline
HVA training is currently scheduled to begin in July 2012 and pilot testing of the
EM procedures will occur shortly thereafter followed by the full EM Addendum
enrollment to coincide with the GuLF STUDY recruitment and home visit
schedule until the EM Addendum enrollment goals have been attained. Figure 2
indicates the approximate times for the primary EM Addendum tasks:
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Figure 2. EM Addendum Timeline (June 2012 – June 2013)*
Jun
Jul
HVA training
●
Pilot testing
●
Participant
recruitment
Equipment setup
and Home visits
Laboratory
analyses
●
Aug
Sep
Oct
Nov
Dec
Jan
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
Feb
Apr
May
Jun
●
●
●
●
●
●
Data analysis
Mar
Dissemination of
individual test
results to
participants
Preparation of
reports and
manuscripts
* Note: The EM Addendum timeline may be extended to coincide with the end of enrollment and
study visits for the GuLF STUDY so that we can maximize the enrollment into the EM Addendum.
X.
Exposure Monitoring Addendum Appendices
Appendix W_I.
Residence Exposure Form
Appendix W_II. Twenty-Four Hour Activities Form
Appendix W_III. Current Occupation Addendum
Appendix W_IV. TraceAir Monitor Instructions
Appendix W_V. Additional Scripts
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References
1.
Jamail, D. Environmental Protection Agency? Residents of the US Gulf Coast say their
pleas for help and transparency continue to be ignored by regulators. 2010 December 6,
2010 October 11, 2011]; Available from:
http://english.aljazeera.net/indepth/2010/12/2010125113825735197.html.
2.
King, B.S. and J.D. Gibbons. Health Hazard Evaluation of Deepwater Horizon Response
Workers. 2011 October 7, 2011]; Available from:
http://www.cdc.gov/niosh/hhe/reports/pdfs/2010-0115-0129-3138.pdf.
3.
Reddy, C., et al., Composition and fate of gas and oil released to the water column
during the Deepwater Horizon oil spill. Proceedings of the National Academy of
Sciences, July 18, 2011.
4.
Avens, H.J., et al., Analysis and Modeling of Airborne BTEX Concentrations from the
Deepwater Horizon Oil Spill. Environmental Science & Technology, 2011. 45(17): p.
7372-7379.
5.
Agency for Toxic Substances and Disease Registry (ATSDR), Toxicological profile for
Copper, 2004, U.S. Department of Health and Human Services, Public Health Service:
Atlanta, GA.
6.
Agency for Toxic Substances and Disease Registry (ATSDR), Toxicological profile for
Nickel, 2005, U.S. Department of Health and Human Services, Public Health Service:
Atlanta, GA.
7.
Agency for Toxic Substances and Disease Registry (ATSDR), Toxicological profile for
Lead, 2007, U.S. Department of Health and Human Services, Public Health Service:
Atlanta, GA.
8.
Agency for Toxic Substances and Disease Registry (ATSDR), Toxicological profile for
Cadmium (Draft for public comment), 2008a, U.S. Department of Health and Human
Services, Public Health Service: Atlanta, GA.
9.
Agency for Toxic Substances and Disease Registry (ATSDR), Toxicological profile for
Chromium (Draft for public comment), 2008b, U.S. Department of Health and Human
Services, Public Health Service: Atlanta, GA.
10.
Hazen, T.C., et al., Deep-Sea Oil Plume Enriches Indigenous Oil-Degrading Bacteria.
Science, 2010. 330(6001): p. 204-208.
11.
Camilli, R., et al., Tracking Hydrocarbon Plume Transport and Biodegradation at
Deepwater Horizon. Science, 2010. 330(6001): p. 201-204.
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12.
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Botello, A.V., S. Villanueva, and G. Diaz, Petroleum pollution in the Gulf of Mexico and
Caribbean Sea. Reviews of environmental contamination and toxicology, 1997. 153: p.
91-118.
13.
Lin, Y.S., P.P. Egeghy, and S.M. Rappaport, Relationships between levels of volatile
organic compounds in air and blood from the general population. Journal of Exposure
Science and Environmental Epidemiology, 2008. 18(4): p. 421-429.
14.
Ashley, D.L., et al., Blood concentrations of volatile organic compounds in a
nonoccupationally exposed US population and in groups with suspected exposure.
Clinical Chemistry, 1994. 40(7B): p. 1401-1404.
15.
Ashley, D.L. and J.D. Prah, Time dependence of blood concentrations during and after
exposure to a mixture of volatile organic compounds. Archives of Environmental Health,
1997. 52(1): p. 26-33.
16.
Perbellini, L., et al., Analysis of benzene, toluene, ethylbenzene and m-xylene in
biological samples from the general population. Journal of Chromatography B-Analytical
Technologies in the Biomedical and Life Sciences, 2002. 778(1-2): p. 199-210.
17.
Su, F.-C., B. Mukherjee, and S. Batterman, Trends of VOC exposures among a nationally
representative sample: Analysis of the NHANES 1988 through 2004 data sets.
Atmospheric Environment, 2011. 45(28): p. 4858-4867.
18.
Romieu, I., et al., Environmental exposure to volatile organic compounds among workers
in Mexico city as assessed by personal monitors and blood concentrations.
Environmental Health Perspectives, 1999. 107(7): p. 511-515.
19.
Weisel, C.P., et al., Relationship of Indoor, Outdoor and Personal Air (RIOPA) Study:
Study design, methods and quality assurance/control results. Journal of Exposure
Analysis and Environmental Epidemiology, 2005. 15(2): p. 123-137.
20.
Williams, R., et al., The design and field implementation of the Detroit Exposure and
Aerosol Research Study. Journal of Exposure Science and Environmental Epidemiology,
2009. 19(7): p. 643-659.
21.
Dolinoy, D.C. and M.L. Miranda, GIS modeling of air toxics releases from TRI-reporting
and non-TRI-reporting facilities: Impacts for environmental justice. Environmental
Health Perspectives, 2004. 112(17): p. 1717-1724.
22.
Pratt, G.C., et al., A field comparison of volatile organic compound measurements using
passive organic vapor monitors and stainless steel canisters. Environmental Science &
Technology, 2005. 39(9): p. 3261-3268.
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23.
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Centers for Disease Control and Prevention, Fourth National Report on Human Exposure
to Environmental Chemicals 2009, 2009.
24.
Chambers, D., et al., Impact of cigarette smoking on Volatile Organic Compound (VOC)
blood levels in the U.S. Population: NHANES 2003-2004. Environment International,
2011. 37(8): p. 1321-1328.
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Addendum 2: Pilot Study to Estimate Contact Rates for
GuLF Follow-up Interviews
Purpose:
Test a variety of approaches to collecting updated contact information to estimate contact rates
for follow-up telephone interviews under different pre-notification scenarios
Eligible Participants:
Random sample of participants in the first wave of annual re-contact; select a sample large
enough to test conditions below
Approaches:
Approach
1
2
3
4
1
2
E-mail 1
Yes
Yes
No
No
E-mail 2
No
Yes
No
No
3
Letter
Yes
No
Yes
No
4
Phone
Yes
Yes
Yes
Yes
1
Email – send once and use text planned for mail re-contact effort
2
Email – send a follow-up email once, approximately 1 week after sending Email 1 and use text
planned for mail re-contact effort
3
Letter – send once and use letter planned for main re-contact effort
4
Phone – call participants to request phone, address, email updates, and secondary contact
information; use current data system for main re-contact effort for data collection; call all numbers
on file for each participant using current calling rules and call disposition codes
Note: All participant contact information will be submitted to a locating service for batch tracing;
however, contact information obtained through locating efforts will only be used for participants
who do not respond to the initial contact approach
Sample Size and Related Design Considerations:
The table illustrates the proportion of successful recontacts using email or telephone (method B)
that can be detected with at least 80% power, based upon different sample sizes (N, in each of
four arms) and different underlying recontact rates (method A). As shown in the last line of the
table which reflects a worst-case underlying rate of 0.5, with a sample size of N=1,000 per arm,
or 4,000 total, we can detect a 5% difference in the recontact rate.
Proportion of successful recontacts
N per
group
Recontacted
using method A
Recontacted
using method B
Power
achieved
250
0.3
0.398
0.803
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Proportion of successful recontacts
N per
group
Recontacted
using method A
Recontacted
using method B
Power
achieved
500
0.3
0.368
0.801
750
0.3
0.355
0.809
1000
0.3
0.347
0.817
250
0.4
0.500
0.801
500
0.4
0.470
0.809
750
0.4
0.457
0.810
1000
0.4
0.449
0.806
250
0.5
0.598
0.801
500
0.5
0.570
0.804
750
0.5
0.557
0.803
1000
0.5
0.549
0.814
Note that the sample size analysis is based on Fisher’s Exact Test in a 2x2 factorial design in
which we have two factors: Letter and Email, as in Approaches 1-4 above (noting that Phone is
present in all approaches). Thus the test for a "Letter" vs "No Letter" effect involves a test of
combined approaches 1 & 3 (method B) vs approaches 2 & 4 (method A). Similarly a test for the
"Email" effect involves 1 & 2 (method B) vs 3 & 4 (method A). We assume a two-sided test and,
to account for multiple testing, we use a Bonferroni adjustment and conduct each test at
significance level 0.05/2=0.025. For sample size purposes we do not seek sufficient power to
support a formal test of interaction which would require significantly higher numbers.
The pilot sample will be drawn across multiple waves of recontacting in order to assure inclusion
of a diverse population of workers, some of which are only minimally represented in early study
waves (e.g., Coast Guard, workers from TRG file, rig workers). We will also oversample active
cohort participants with a target of 50% representation, so as to support more precise estimates
from which to project likely follow-up interview participation rates. It is also possible that the pilot
sample might somewhat exceed the target sample size of 4,000 if needed to accommodate
operational constraints.
Approximately 500 participants who are eligible for the Biomedical Surveillance Subcohort clinical
exams may be invited to participate in an additional pilot study to examine factors that may
influence participation in the exam. These additional questions will be administered after their
contact information is confirmed or updated. The questionnaire will take approximately 5-10
minutes to complete.
Operational Plans:
In-bound calls in response to emails and letters – handle as we would in the main re-contact
effort and end additional follow-up for those in approach 1, 2, and 3 at the time the update is
completed
Time between emails, letters and phone calls – one week between each form of contact
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Addendum 3: GuLF STUDY Biomedical Surveillance
Clinical Examination
1. Study Objectives & Background
A. Objectives
The Deepwater Horizon (DWH) disaster resulted in the release of over 4.9 million barrels
of crude oil into the Gulf of Mexico [1]. In the ensuing oil-spill clean-up response,
150,000 workers and volunteers participated in in some aspect of oil-spill clean-up.
Community groups across the Gulf region have expressed ongoing concerns about oilspill exposures and health outcomes they believe to be associated with components of oil
and dispersants used in the DWH clean-up efforts [2]. Reported symptoms among cleanup workers and volunteers at the time of the spill included headaches, cough, dizziness,
nausea, exhaustion, and heat stress [3]; media reports and preliminary data collected as
part of ongoing studies of the health of workers and community members suggest that
such symptoms continue to be reported.
The potential long-term health effects of participation in this and other clean-up efforts
are largely unknown. The few previous studies examining health consequences of oil
spills have reported respiratory, neurological, hematologic, and psychological or mental
health related outcomes (see “Background” section below). Workers involved in the
DWH oil spill have not only been exposed to the constituents of the oil but also to
dispersants and oil & dispersant mixtures as well as to extended uncertainty and
unemployment due to the long-term nature of the spill and its impact on the region. Thus
they offer a unique opportunity to further understand exposure-response relationships and
mental health outcomes associated with oil spills in general and this event, specifically.
In response to concerns about potential health impact of the Deepwater Horizon oil spill,
a cohort of nearly 33,000 persons involved in some aspect of oil spill clean-up has been
surveyed regarding clean-up experiences and current health. A subgroup of 11,200
participants from Gulf states have completed brief clinical examinations at home during
which lung function and blood pressure were measured and biological samples (blood,
urine, toenails, hair) and environmental samples (dust wipes) were collected. The GuLF
STUDY Biomedical Surveillance Clinical Examination (BSCE) which will be carried
out among a subset of GuLF STUDY participants is designed to more thoroughly
investigate the following questions related to potential health effects of this
environmental disaster.
1. Are worker exposures to constituents of oil, dispersants, and oil & dispersant
mixtures associated with adverse effects on respiratory and neurological
function?
2. Are worker exposures or experiences related to the DWH oil spill resulting in
measurable and sustained psychological or mental health related outcomes?
3. Are there biomarkers of potentially adverse biologic effects associated with oil
spill-related exposures?
The proposed BSCE extends the work of the GuLF STUDY among a subgroup of
participants who completed home visits (Active Surveillance Follow-up Cohort) by
undertaking more intensive clinical testing and mental health evaluations (hereafter
referred to as “clinical examinations”). These additional clinical examinations will allow
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for a much more in-depth understanding of pulmonary, neurological, and mental health
outcomes that may be associated with the DWH oil spill exposures and experiences.
B. Background
The Deepwater Horizon disaster resulted in the release of over 4.9 million barrels of
crude oil into the Gulf of Mexico [1]. In the ensuing oil-spill clean-up response, over
150,000 workers and volunteers participated in some aspect of oil-spill clean-up,
including just completing safety training in hopes of being hired. The potential long-term
health effects of participation in this and other clean-up efforts are largely unknown. The
few studies that have evaluated the human health consequences of oil spills have
primarily focused on acute physical effects and psychological sequelae.
Previous Oil Spill Health Studies
Prior studies have examined the Exxon Valdez (Alaska, 1989), Braer (Shetland Islands,
UK, 1993), Sea Empress (Wales, UK, 1996), Nakhodka (Oki Islands, Japan, 1997), Erika
(Brittany, France, 1999), Prestige (Galicia, Spain, 2002) and Tasman Spirit (Karachi,
Pakistan, 2003) oil tanker spills [4]. Most of these studies were cross-sectional, though
two spills (the Prestige and Heibei Spirit oil spill in Korea) have been the focus of small
follow-up studies after several years. Several studies reported respiratory symptoms,
including cough and shortness of breath [5-8]. In a follow-up study among clean-up
workers from the Prestige oil spill, Zock et al. [9] observed that lower respiratory tract
symptoms persisted up to 2 years after exposure had ended, although the excess risk
decreased with increasing time from last exposure. Some symptoms showed exposureresponse patterns in relation to number of exposed days, exposed hours per day, and
number of activities. Elevated levels of 8-isoprostane, vascular endothelial growth factor,
and basic fibroblast growth factor in the exhaled breath condensate (EBC) were found
among workers involved in the Prestige oil spill clean-up, with evidence of increasing
levels with increasing intensity of exposure to the clean-up two years after the oil spill
[10]. Among those exposed to the oil, evidence of increased non-specific bronchial
responsiveness and increased levels of 8-isoprostance and growth factors in EBC
persisted five years after the oil spill [11]. Studies of other petroleum-exposed groups
have also observed adverse health effects associated with petroleum exposures including
increased respiratory symptoms, increased exhaled nitric oxide, and decreased
FEV1/FVC [12]. Meo et al. reported a reduction in forced vital capacity (FVC), forced
expiratory volume in first second (FEV1), and forced expiratory flow and maximum
voluntary ventilation (MVV), including exposure-response trends, in a small study of
workers involved in the clean-up of the Tasman Spirit oil spill [13, 14]. Other commonly
reported symptoms from previous oil spill studies include itchy eyes, nausea/vomiting,
dizziness, headaches [5, 6, 8, 14-17], and skin irritation/dermatitis [6, 8, 15].
Other Hydrocarbon Exposure Health Studies
Neurotoxic effects of hydrocarbon and hydrocarbon constituents have been observed in
both occupational groups and laboratory studies on human volunteers [18-22]. These
include significant effects on intellectual capacity, psychomotor and visuomotor function,
immediate and delayed memory, and increased proportionate mortality ratio for mental
and psychoneurotic conditions [22-24]. In laboratory studies on human volunteers,
inhalation exposure to xylene at 90 ppm caused deleterious effects on reaction time,
manual dexterity, body balance, and memory span [25, 26]. Toluene exposure at 100
ppm was associated with altered short term memory, visual memory, locomotion, poorer
manual dexterity performance, and mood [27, 28]. In addition, the Agency for Toxic
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Substances and Disease Registry has identified several heavy metals found in crude oil as
neurotoxic in humans or in animal models [29-35]. These findings suggest effects on the
central nervous system functioning in the absence of clinical disease diagnosis.
Mental Health Studies
In addition to health effects induced by chemical and physical exposures, physical and
mental health may be adversely affected through pathways involving physiological and
psychological responses to acute and chronic stressors related to the disaster. Adverse
psychological consequences have frequently been linked to previous oil spills. Excess
prevalence of generalized anxiety disorder, post-traumatic stress disorder (PTSD), and
depressive symptoms were observed among communities affected by the Exxon Valdez
oil spill approximately one year after the spill occurred [36]. Similar patterns of higher
anxiety and depression scores and worse mental health were observed among
communities near the Sea Empress spill [16]. The Braer spill was associated with
increased somatic symptoms, anxiety, and insomnia, but not personal dysfunction or
severe depression [37]. Worse mental health scores were related to closer proximity to
the Prestige spill [38].
2. Study Overview
Approximately 6,000 cohort members from Louisiana, Mississippi, Alabama, and Florida
will be invited to take part in the clinical examinations. We will invite all cohort members
who were previously identified as a potential participant in the Biomedical Surveillance
Sub-cohort during the baseline phase of the study (and for whom additional baseline
laboratory tests were performed) to participate in a clinic visit. We will augment this
sample with additional cohort members who live within driving distance of one of two
clinics in New Orleans, Louisiana and Mobile, Alabama who additionally meet selection
criteria related to potential for, cleanup-related exposures, mental health distress, or
baseline pulmonary function findings (see below). The clinical examinations will be
performed in controlled clinical settings under the direction of health professionals from
the University of South Alabama (USA) and Louisiana State University (LSU) Health
Sciences Center. The clinic exams and procedures are described below, but briefly these
research exams will include anthropometric measurements, biological sample collection,
neurobehavioral evaluations, pulmonary function testing, and mental health
questionnaires. The exams are for research purposes only and are not intended as delivery
of primary or specialty health care services. Referral networks such as those developed
for Phase 1 of the GuLF SUDY will be developed/augmented to help those participants
who wish to pursue clinical follow-up find appropriate services. The exam is expected to
take between 3.75 and 4.0 hours and participants will be compensated for their time and
travel costs as described below.
Study Oversight
The Principal Investigator will monitor and evaluate progress of the study, including
periodic assessment of accrual, administration of informed consent, data quality and
timeliness of data collection, participant risk versus benefit, performance of contractors
and other factors that can affect study outcome. This monitoring will also consider factors
external to the study, such as scientific findings that may have an impact on the safety of
the participants or the ethics of the study.
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SRA International (SRA), a company that provides professional research services and
supports the overall GuLF STUDY, will serve as the coordinating center for BSCE phase
of the study through an existing contract with the NIEHS. SRA will coordinate with the
clinical collaborators at USA and LSU to oversee the day-to-day activities of the clinical
examinations with additional oversight from the NIEHS investigators. SRA will be
responsible for data management, laboratory sample management, and the performance
of subcontractors who support ancillary research activities.
In accordance with NIEHS requirements, an independent study monitor will visit the
coordinating center and each clinical site at least once a year to ensure compliance with
the protocol, NIEHS research policies, and federal regulations for the protection of
human subjects. During the visits, the monitor will review informed consent forms,
central and local study files, data management procedures, and laboratory sample storage
conditions. The monitor will document findings in a formal monitoring report that will be
shared with the NIEHS Office of Human Subjects Protection, the Principal Investigator,
the coordinating center, and the clinical site directors. The coordinating center and
clinical sites will be responsible for responding to and resolving any issues identified in
the report.
The clinical examinations will be carried out by collaborators at the University of South
Alabama and Louisiana State University Health Sciences Center. Clinical directors at
each site will be responsible for overseeing day-to-day activities at their sites.
The study team, all of whom will contribute to study oversight, has the experience
necessary to provide this oversight. We list the roles and responsibilities of the
investigators and key collaborators below.
• Dale Sandler, Ph.D., Principal Investigator, NIEHS (Protocol development and overall
oversight and responsibility for all parts of the study)
• Richard Kwok, Ph.D., Lead Associate Investigator, NIEHS (Protocol development
and oversight over the day-to-day operations of the study and coordination for all parts
of the study)
• Lawrence Engel, Ph.D., Associate Investigator, University of North Carolina at
Chapel Hill and NIEHS (Protocol and questionnaire development, and oversight over
the neurologic and biologic areas of the study)
• Aubrey Miller, M.D., M.P.H., Associate Investigator, NIEHS (Oversight over the
medical and medical alert / referral areas of the study)
• Stephanie London, M.D., Dr.P.H., Associate Investigator, NIEHS (Consultation on
the respiratory areas of the study)
• Robert L. Jensen, Ph.D., Consultant, University of Utah (Consultation on pulmonary
function testing quality control and interpretation)
• Christine Parks, Ph.D., Associate Investigator, NIEHS (Consultation on the
immunologic areas of the study)
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• Aaron Blair, Ph.D., Consultant, NCI (Consultation on overall study implementation
and design)
• David A. Welsh, MD., Associate Investigator, Louisiana State University (Louisiana
Clinical Site Director)
• Errol D. Crook, M.D., Associate Investigator, University of Southern Alabama
(Alabama Clinical Site Director)
• David Abramson, Consultant, Columbia University (Consultation on mental health
assessment)
• Fredric Gerr, M.D., Consultant, University of Iowa (Consultation and oversight over
the neurobehavioral and neurological areas of the study)
• Diane Rohlman, M.A., Ph.D., Consultant, University of Iowa (Consultation and
oversight over the neurobehavioral and neurological areas of the study)
The GuLF STUDY Scientific Advisory Board, a subcommittee of the NIEHS Board of
Scientific Counselors, will provide additional oversight. The board is comprised of
scientific experts, community representatives, and federal agency representatives. A
separate Community Advisory Board, consisting of representatives of key study
populations in the affected states, has also been established.
3. Training, Certification, and Quality Control
Study staff members will have the necessary education, qualifications and experience to
conduct study activities. Staff members who interact with participants or have access to
study data will be trained in human subjects research protections, the study protocol, and
study procedures relevant to their role. All will be required to sign confidentiality
agreements. Staff will be required to complete web-based, self-study, and centralized inperson training programs specific to their roles in the project. The study coordinating
center (SRA) will provide study-specific training to all clinical site staff in collaboration
with the study PIs, clinical site directors, and expert consultants.
Study manuals and job aids will be developed to ensure the standardized administration/
implementation of procedures. Staff members will be required to pass proficiency testing
and receive certification prior to conducting study procedures. Study coordinators at each
site will conduct periodic quality control assessments of staff performance using
standardized quality control checklist and will provide feedback to staff. Study managers
at the coordinating center will monitor accrual and weekly procedural completion data,
review site coordinator QC assessment forms quarterly, and conduct site monitoring
visits as part of the overall quality control process. Data managers at the coordinating
center will also generate data QC reports that will allow the study investigators and
coordinating center staff to identify problems missing, inconsistent, implausible data so
that any problems with data quality can identify and corrected in a timely manner.
Corrective actions for unsatisfactory performance will include coaching, retraining, or
termination.
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4. Eligibility and Selection of Participants
Approximately 6,000 cohort members will be identified for invitation to take part in the
clinical examination, with about 4,000 expected to complete the examination (anticipated
participation rate ~67%).
All cohort members who were tagged for inclusion in the Biomedical Surveillance Subcohort on the basis of residence in gulf counties/parishes in Alabama and Louisiana and
predicted exposure level (based in industrial hygienist evaluation of exposure potential
for specific jobs and tasks) and completed the baseline home visit will be eligible to
complete an exam (N ~ 4,000). In addition to completing the home visit, persons who had
been selected for this Sub-cohort had Complete Blood Count (CBC) evaluation at
baseline and lymphocytes were extracted and cryopreserved for later functional assays.
We will augment the sample with N~2,000 persons who completed a Home Visit but
were not initially tagged for inclusion in the Biomedical Surveillance Sub-cohort but live
within about 60 miles (i.e. less than a one hour drive) of the two clinic sites, provided
they meet one of three criteria: 1) they scored poorly on one or more standardized scales
of mental distress (e.g., depression, anxiety, PTSD); 2) they scored in the medical alert
range or had a failed test of pulmonary function; or 3) they had higher likelihood of
exposure to oil or dispersants based on their job tasks, location, and timing.
Table 1 provides characteristics of cohort members who are eligible to take part in the
clinical examinations from both the “tagged” Biomedical Surveillance Subcohort and the
Supplemental participants.
Based on response rates after the first few months of clinic operation and experience
gained with recruiting participants living far from the clinic sites, we may modify the
criteria for selecting supplemental participants (e.g., by expanding or contracting the
distance requirement) for the clinic exam – with the goal of completing 4,000 exams.
For reasons of logistics, cost, and procedure standardization, we will have only two main
clinical sites, one in Mobile, AL and the other in New Orleans, LA. However, reluctance
of cohort members to travel long distance to get to a clinical site may lower participation
rates. We will provide reimbursement for travel expenses, lodging and meals, as needed,
to accommodate participants who live further away from the two main clinical sites in
Mobile, AL and New Orleans, LA.
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Table 1. Characteristics of Eligible Cohort Members
Biomedical
Surveillance
“Tagged”
Supplemental
Sub-cohort
Participants
Total
Mental Health
Poor Score on Mental Health Scales
689
589
1278
Medium-High or High
2103
1179
3282
Other Markers of Unusual Exposure
453
213
666
Combined Medium-High or High
Exposure or Marker of Unusual Exposure
2116
1186
3302
Poor Lung Function
806
706
1512
Poor Quality PFT
793
705
1498
Yes to Any of 3 Overall Categories
2896
2195
5091
No to Any of the Overall Categories
638
--
638
Estimated Exposure Levels
Lung Function
5. Visit Scheduling
Eligible cohort members will receive a letter from the GuLF STUDY PI and the director
of the clinical site closest to their home inviting them to participate in the clinical exam.
The letter will be on GuLF STUDY letterhead and will contain the logos of both the
GuLF STUDY and the clinical site closest to the subject’s home. This letter will explain
the purpose and components of the exam, and how to contact the study center to schedule
the exam. Study center staff will contact eligible cohort members who do not respond to
the letter within one week. Study center staff will schedule visits with contacted eligible
cohort members who agree to participate.
Study staff will flag eligible cohort members who cannot be reached with existing
primary and secondary contact information. The study coordinating center will send their
names and other personally identifiable information (when available) to a commercial
tracing service. All information exchanges will be encrypted using standard computer
security and encryption protocols. If the commercial tracing service returns contact
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information, the coordinating center will attempt to contact the eligible cohort member. If
contact is made and the eligible cohort member is willing to schedule the exam, the
coordinating center will schedule the appointment at a date and time convenient for the
cohort member. If updated contact information is not obtained, the coordinating center
may deploy field staff to visit the eligible cohort member’s last known address to obtain
updated contact information and to schedule the visit. For eligible cohort members who
cannot be reached by these methods, the coordinating center may also send emails and
letters to their last known email or mailing address to encourage participation, and may
telephone the alternate contacts provided by participants when they enrolled or last
updated their contact information to confirm or update contact information.
A confirmation letter will be sent to the selected participant 4 to 5 days in advance of the
scheduled visit along with preparatory materials, which include pre-visit instructions, a
list of answers to frequently asked questions, a one-page summary of key information in
the consent form, and directions to the clinical site. The study center will serve as the first
point of contact for selected participants for questions about the exam and for
cancellations and rescheduling.
In order to promote the clinical examinations more generally, we will engage eligible
cohort members and their local communities through our community advisory group
(CAG), the study website, social media (e.g. Facebook, Twitter).
6. Components of the Clinical Examination
Table 2 below summarizes the components of the clinical exam and the time required to
complete each component. During the run-in period of the study, we will administer all
of the components listed, although, as per the overall study design, some components will
be performed on a subset of participants. Should the administration time of the clinical
exam substantially exceed our estimates and/or prove unacceptable to participants during
the run-in period or afterward, we will modify the administration of each exam to reduce
burden. The two most time-consuming exam components are the neurobehavioral testing
and pulmonary testing. If it is deemed necessary to substantially shorten the exam time,
we may decide to include only the pulmonary testing (Exhaled Nitric Oxide, Exhaled
Breath Condensate, and Pulmonary Function Testing) or the neurobehavioral testing, but
not both. An alternative we might also consider is to also include the much briefer
assessment of pulmonary function that was performed during the home visit, for those
participants selected for the neurobehavioral testing arm. Should this modification be
necessary, we will use a stratified random sampling method to assign individuals to either
the “pulmonary” or the “neurobehavioral” group, with participants demonstrating poor
pulmonary measures during their home visit being assigned to the “pulmonary” group.
Those with “normal” pulmonary measures during their home visit will be randomly
assigned to either the “pulmonary” group or the “neurobehavioral” group. Should we
determine that this stratification is necessary, we estimate that it will shorten the clinical
exam by approximately 45-50 minutes. Additional details about the clinical exam are
provided in the sections that follow.
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Table 2. Clinical Visit Overview
Activity
Visit Scheduling
Time
N/A
Notes
•
•
•
•
Initiation mailing
Scheduling calls
Pre-visit procedural eligibility
assessment
Confirmation letter and visit
preparation materials mailed
Arrival and Greeting
5 min.
•
Greetings and introduction to study
staff
Informed Consent
10 min.
•
Review and obtain informed consent
Anthropometric Measures
10 min.
•
Height, Weight, Waist and Hip
Circumference
Physiological Measures
5 min.
•
Resting Blood Pressure and Heart
Rate
Biological Specimen Collection
15 min.
•
Hair, Blood, Toenail Clippings*,
Saliva, and Urine Collection
Finger stick for Hemoglobin A1c
Provide training and materials for
serial saliva samples (for a subset)
•
•
Clinic Visit Questionnaire
15 min.
•
Clinic Visit Questionnaire
Neurobehavioral Tests
50 min.
•
•
•
•
•
•
•
•
Symbol-Digit
Finger Tapping
Simple Reaction Test
Continuous Performance
Trailmaking
Digit Span
Match to Sample
Progressive Ratio
Peripheral Nervous System
Tests
25 min.
•
•
•
•
•
•
•
•
Standing Balance
Standing Steadiness
Vibrotactile Threshold Testing
Visual Acuity
Visual Contrast Sensitivity
Handgrip Strength
Walking Speed
Long Distance Walk (400m)
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Notes
**
15 min.
•
•
Exhaled Nitric Oxide
Exhaled Breath Condensate (for a
subset)
Pulmonary Function Testing***
30 min.
•
Pre/post-bronchodilator spirometry
Mental Health Assessment
40 min.
•
Questionnaire administration and
referral, if needed
N/A
•
Process, aliquot, label, and
temporarily store specimens
10 min.
•
•
Handout provided with clinically
relevant findings and
recommendations for seeking
additional care, if indicated
Referral provided, if needed
5 min.
•
Remuneration
N/A
•
Samples packed and shipped in
batches by clinical staff
eNO and EBC
Biological Specimen Processing
Report of Findings
Check-Out and Remuneration
Clean-up and Specimen
Shipping
Total time
3hrs. 55 min.
* If toenail specimens cannot be collected during the visit, the participant will receive toenail collection instructions
and a prepaid self-addressed envelope to return toenail samples to the central processing laboratory.
** If selected
*** Pulmonary measures will be collected in the order of eNO, EBC and spirometry because spirometry may affect
eNO and EBC measurements. [39]
6.1 Informed Consent
Informed consent will be obtained before any visit activities are conducted. A one-page
consent form summary will be used to guide the informed consent process. Clinic staff
will allow the participant ample time to review the consent, ask questions, and obtain
clarifications prior to agreeing to enrollment. After voluntarily agreeing to take part in the
study, participants will be asked to sign and date a current IRB-approved version of the
informed consent form. The consent form will contain contact information for clinical
site staff, the study center, and the NIEHS IRB in the event that questions or concerns
emerge after the visit. A copy of the signed consent form will be provided to the
participant. The original copy of the consent will be stored at clinical sites until the
conclusion of the study, at which time they will be shipped to the coordinating center for
long-term storage. Random review of consent forms will be included in the study’s
clinical monitoring plan.
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6.2 Anthropometric Measures
Clinic staff will take three measurements of weight (kg), height (cm) and hip and waist
circumference (cm). Height will be measured with a wall-mounted stadiometer, and
weight will be measured with digital scales. Height and weight (converted from metric to
English) will be used to calculate BMI for participant reports. Hip and waist
circumference will be measured with a vinyl measuring tape. The measuring tape will be
inspected daily for defects / stretching and will be replaced as needed should any defects
be identified.
6.3
Heart Rate and Blood Pressure Measurement
Clinic staff will take three measurements of resting heart rate and blood pressure using
standard clinical oscillometric equipment after the participant has rested in a seated
position for at least five minutes. The second and third readings will be used to calculate
average values for reporting results to participants.
6.4
Biological Samples
Clinic staff will collect a variety of biological samples, including blood, urine, hair,
toenail clippings, and saliva, as described in the sections below. All samples will be
processed as described below until shipment to the central processing laboratory for any
final processing and transfer to the biorepository for long-term storage. The participant
will not be asked to fast before the biologic samples are taken. A recent community based
cross-sectional analysis has shown that measuring blood lipid levels when a participant
has not fasted will yield acceptable results. [40]
Blood samples (54.5 mL in seven vacutainer tubes)
• Lavender Top EDTA Tubes: Two 10 mL lavender-top tubes will be collected to
provide plasma and packed cells for future analyses. These specimens will be
aliquotted into cryovials and frozen at -80 ºC.
• Royal Blue Top EDTA Tube: One 6 mL trace metals tube will be obtained and
the blood will be stored in the original (unopened) collection container. These
specimens will be frozen at -20 °C for future selected measurement of antimony,
arsenic, cadmium, calcium, chromium, copper, iron, lead, magnesium, manganese,
mercury, selenium, and/or zinc (i.e., all of the metals for which these trace metal
tubes have been validated).
• Red Top Serum Tubes: Two 10 mL red top tubes, with no additives and no
separator gel, will be collected. After clotting, the serum and clots will be separated
by centrifugation and both will be frozen at -80 °C.
• Yellow Top ACD-B Tube: One 6 mL tube with Acid/Citrate/Dextrose Solution B
tube will be collected for future analyses.
• PAXgene RNA Tube: One 2.5 mL PAXgene blood RNA tube will be collected
to obtain stabilized whole blood for mRNA isolation for future analyses. Sample will
be stored in its original tube at -20 °C.
• One finger stick capillary blood sample (~250 μL) will be collected for the
measurement of Hemoglobin A1c and a standard lipid panel (Total Cholesterol, HDL
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Cholesterol, LDL Cholesterol, and Triglyceride)and analyzed at the clinical sites
using a CLIA-waived point of care testing device.
• In the rare event that a partial blood tube is collected due to a temporary
interruption of the blood collection procedure, we will retain the partially filled tube.
• In the event that a participant has poor venous access, clinic staff will attempt to
draw blood up to three times if the participant agrees.
Exhaled Breath Condensate (EBC)
To reduce the burden on study staff while still obtaining a representative sample of
participants, a stratified random sample of ~700 participants at LSU will be asked to
provide EBC based on PFT results at baseline. As described below, this sample size will
be sufficient for proposed statistical analyses. We will select:
•
200 participants with FVC, FEV1, or FEV1 / FVC below the lower limit of
normal and FEV1 % predicted at <50%
•
200 participants with FVC, FEV 1 , or FEV 1 / FVC below the lower limit of
normal and FEV 1 % predicted at ≥ 50%
•
200 participants with normal baseline PFT measurements
•
100 participants with poor quality pulmonary function tests
To avoid contamination of the sample, the participant will be asked to rinse his/her mouth
with sterile water prior to the procedure and to wear a nose clip during the procedure, and
clinical staff will wear nitrile-free gloves while collecting, handling, and processing
samples. Clinical staff will instruct participants to breathe into a commercially available
EBC collector (RTube, Respiratory Research Inc., Charlottesville, VA) a handheld, selfcontained, single-use device. The device consists of a mouthpiece connected to a oneway valve that directs exhaled breath through a condenser tube cooled by a chiller sleeve
and an insulated safety cover. Gaseous phase liquid and aerosols in exhaled breath
condense into liquid form on the inside surface of the chilled condenser tube and can be
extracted using a plunger device supplied by the manufacturer.
For collections, the aluminum chiller sleeve will be cooled at -80º C until immediately
before the collection. Once the chiller sleeve and safety cover are placed around the
RTube, subjects will breathe tidally through the mouthpiece for 10 minutes. Staff will
wear special gloves while handling the sleeve to prevent injury. Participants will be
encouraged to expectorate any accumulated saliva into a separate sample container.
EBC will be extracted from the device using a supplied plunger per manufacturer’s
instructions, with expected volumes of 100-200 µl/min, or 1-2 ml of condensate per
collection. EBC will be divided into 500 µl aliquots and stored at -80º C, then shipped on
dry ice to a central laboratory for storage and analysis.
Urine Samples
Participants will be asked to provide a random (“spot”) urine sample in a sterile container
using the mid-stream catch technique. The sample will be analyzed by local clinical site
labs using a commercially available dipstick with ten parameters (glucose, bilirubin,
ketone, specific gravity, occult blood, pH, protein, urobilinogen, nitrite, leukocyte
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esterase). Up to 50mL of the remaining urine sample will be aliquotted for long-term
storage and future analyses.
Toenails
During the examination, clinic staff will ask participants to collect toenail clippings from
each toe, unless participant has a medical or physical condition (e.g., poorly controlled
diabetes) that would contraindicate collection. Sites will temporarily store toenail
clippings at ambient temperature prior to shipping samples for long-term storage and
future analysis. Clinic staff will advise participants in advance of their scheduled clinic
visit not to clip their toenails before the visit. If toenail specimens cannot be collected, the
clinic staff will provide the participant with toenail collection instructions and a prepaid
self-addressed envelope to ship the toenails to the CPL at a later date.
Hair
Clinic staff will collect a small nape hair sample as close to the participant’s scalp as
possible. Clinic staff will clip and mark hair samples to indicate which end was closest to
the scalp. The clinics will temporarily store collected hair samples at ambient
temperature with a desiccant prior to shipping samples for long-term storage and future
analysis. A hair sample will be collected only if it is at least 1 cm long.
Saliva
A sample of ~1,000 participants who live within 30 miles of the University of South
Alabama will be asked to provide serial saliva samples for the measurement of salivary
cortisol, following an in-home sample collection protocol used successfully in other
studies [41]. To maximize analytic power among women, who represent approximately
20% of the cohort, we will invite all female clinical exam participants who live within 30
miles of the University of South Alabama to participate in the saliva collection
component. We will randomly sample male clinical exam participants who live within 30
miles of the University of South Alabama to achieve a total of approximately 1,000
participants in the saliva collection component. Participants will be asked to produce five
samples on two different days during a one-week period following their exam. The
samples will be collected to allow for measurement of diurnal patterns in cortisol levels:
1) upon waking, 2) about 45 minutes after waking, 3) 4 hours after waking, 4) 10 hours
after waking, and 5) before bed time.
To ensure the participants understand the collection process, clinical site staff will train
participants to collect samples at the time of their exams and ask participants to produce
one sample as part of the training. The practice sample will be discarded, as it is unlikely,
given the clinical exam setting, to be representative of their usual cortisol levels. Clinical
site staff will also provide participants with a collection kit that includes instructions,
collection containers, return shipping materials, and a collection log. The collection log
will capture the days and times of sample collection, as well as information about factors
that may influence cortisol levels. Participants will be instructed to refrigerate samples
from the time of collection until shipment. Clinical site staff will contact participants 3-4
days after their exam to remind them to collect the samples and return them in the selfaddressed, stamped mailer. Study staff will make another reminder call if samples are
not received within 8 days of their exam. No further reminder calls will be made. After
the samples are collected, they will be temporarily stored at the clinical site and shipped
to the testing laboratory (Salimetrics) in batch.
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Quality Control (QC) Samples
We anticipate that future researchers will require substantial volumes of biospecimens for
quality control and assay validation purposes, but that the results of these procedures will
not directly contribute to addressing the specific aims of this study. These specimens will
be critical when serial samples or samples known to be from the source population are
required.
To meet this need, we will collect an additional 40 mL urine and four additional tubes of
blood, consisting of one 10 mL lavender top, one 6 mL royal blue top, one 10 mL red top,
and one 6 mL yellow top (i.e., an additional 32 mL blood) from a total of 200
participants. We will request these QC samples of all participants who provided QC
samples at baseline (maximum of 200). We will supplement these with a random sample
of other clinical exam participants to achieve a total sample size of 200. The extra QC
urine (40 mL) will be taken from the sample already collected because participants
provide samples in a large cup that contains more sample than needed for long-term
storage. Site staff will aliquot the urine and blood QC samples in the same manner as
their corresponding study samples (above) and ship them with the study samples to the
CPL for long-term cryo-storage.
6.5
Clinic Visit Questionnaire
Clinical staff will administer a 15-minute questionnaire to participants using Computer
Assisted Personal Interview software (CAPI) to screen for exclusion criteria for exam
components. These include factors such as recent chest surgery, which is an exclusion
criterion for the pulmonary function testing, and need for walking aids or assistive
devices, which is an exclusion criterion for the long distance corridor walk. We will also
collect information on factors that may impact performance on the neurobehavioral or
peripheral nervous system tests, on pulmonary function testing, or that might affect
biological specimens. These factors are not exclusion criteria, but will be considered as
potential confounders or to use for sub-selection for sensitivity analyses, as appropriate,
when analyzing the results of the clinical tests.
6.6
Neurobehavioral Examination
We will use the Behavioral Assessment and Research System (BARS) to measure
neurobehavioral function. The purpose of the examination is to determine whether
exposures to oil and oil dispersants are associated with brain or nervous system
dysfunction. Individual components of the neurobehavioral exam are summarized in
Table 3 and described in detail below.
We selected BARS for testing in this study because it was specifically designed for use in
populations with limited levels of educational attainment and minimal experience using
computers. The same design features that were implemented to improve ease of test
administration – step-by-step spoken and written instructions, practice exercises, and a
simple 9-button keyboard – have the added benefit of reducing staffing effort for
examiners and variability in test administration. Our examiners will be trained and
monitored by Fred Gerr and Diane Rohlman, collaborators at the University of Iowa who
are experts in the field of neurobehavioral assessment and supported by the central study
coordinator.
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Table 3. Components of the Neurobehavioral Exam
Test
Function
Measurements
Symbol-Digit
Complex function/Information
Processing Speed
• Latency to complete the matrices
Finger Tapping
Response speed, coordination
• Number of taps completed in a fixed
time
Simple Reaction Time
Response speed
• Response latency or reaction time
Continuous Performance
Sustained attention
• Reaction time
• Errors
• Number of hits
• Errors of omission
• Errors of commission
Digit Span
Attention, memory
• Longest span forward and backward
Match-to-Sample
Visual memory
• Number correct
• Correct response latency
Progressive Ratio
Motivation
• Number of ratios completed
• Longest ratios completed
Trail Making
Visual search, scanning, speed
of processing, mental
flexibility and executive
functions
• Amount of time required to complete
each part of the task
6.6.1 Symbol Digit
The symbol digit test, an assessment of complex scanning and visual tracking, is one of
the most widely used and sensitive measures of neurotoxicity. The test presents nine
symbols that are paired with a number between one and nine. The symbol-digit pairs are
arranged in a 2 x 9 table at the top of the screen. A similar table at the bottom of the
screen contains the symbols but not the digits. The subject is instructed to type the
missing numbers that correspond with symbols in the bottom table as quickly as possible.
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6.6.2 Tapping
The tapping test measures response speed and coordination. The subject is instructed to
tap as rapidly as possible with the right hand, the left hand and alternating hands over a
20 second period. Taps increase the height of a dark bar to suggest progress to the
subject.
6.6.3 Simple Reaction Time
The simple reaction time test measures response speed. The subject is instructed to
respond by pressing a response button as quickly as possible after seeing a stimulus on
the screen or when a response button becomes backlighted. Fifty trials are presented and
the latency for each button press is recorded.
6.6.4 Continuous Performance
The continuous performance test measures sustained visual attention. A series of stimuli
are presented one at a time and in an unpredictable order for approximately 5 minutes.
Subjects are instructed to press a response button as quickly as possible after a cue-target
(plus sign followed by a circle) is presented. Three hundred stimuli are presented; 20% of
them are target stimuli.
6.6.5 Digit Span
The digit span test measures attention and memory. A series of numbers between one and
nine is presented sequentially on the computer screen. The participant is instructed to
reproduce the sequence of numbers by pressing the numbered response buttons in either
the same or reverse order in which they were presented. The number of digits increases,
starting from three numbers, until a failure criterion is met.
6.6.6 Match to Sample
The match to sample test measures visual memory. A 10 × 10 matrix of blocks is
followed by three choices, among which one is the same as the sample stimulus. Subjects
are asked to select the sample stimulus.
6.6.7 Progressive Ratio
The progressive ratio test measures motivation. Subjects are instructed to press a button
multiple times and receive a “reinforcer” (smiley face) for completing the task. The
criterion for earning a reinforcer increases with each successive trial. The total number of
button presses or taps in two minutes is recorded.
6.6.8 Trail Making
The trail making test is a paper and pencil test that measures multiple domains, including
visual search, scanning, speed of processing, mental flexibility and executive functions.
The test consists of two tasks. In Task A, subjects are asked to draw lines sequentially
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connecting 25 encircled numbers distributed on a sheet of paper. Task B is similar to ask
Task A, except the subject must alternate between numbers and letters (e.g., 1, A, 2, B, 3,
C).
6.6.9 Peripheral Nerve Testing
Direct assessment of physical performance has become standard practice in
epidemiologic observational studies of health and disease processes. The most
commonly used assessments were initially designed to differentiate function in older
adults [42, 43], but modifications in administration and scoring[44] can improve the
utility of these assessments to discriminate meaningful differences and change in
functional capacity in most middle-age persons, as well. Although the measurement
ceiling of these tests may be low for young and some middle-age adults (i.e., they can
easily achieve the maximum possible performance on all tests), they provide useful
comparative measures to other study populations such as the NIA-sponsored Baltimore
Longitudinal Study of Aging (BLSA).[45] Furthermore, repeat assessment following
standardized procedures over subsequent visits can aid in identifying the approximate
point at which meaningful loss of functional capacity begins to emerge. The following
protocol constitutes a modification of the physical performance battery originally used in
the Established Populations for Epidemiologic Studies of the Elderly (EPESE)[43] and
Women’s Health and Aging Study (WHAS), developed for and used in the Health, Aging
and Body Composition (Health ABC) study. [44]
6.6.10 Standing Balance Test
Measurement of postural stability allows for assessment of the integrated function of
several components of the nervous system, including the vestibular apparatus,
cerebellum, and proprioceptive system. Loss of functional integrity of any of these
systems secondary to disease or toxic exposure may affect postural stability.
We will measure: side-by-side, semi- and full-tandem and single leg stands, each held for
30 seconds, if possible. Capacity to hold each stand for 10 seconds will be recorded to
retain comparability with the EPESE battery.
6.6.11 Standing Steadiness (Postural Stability)
The Advanced Mechanical Technology, Inc. (AMTI) force platform assesses postural
stability by measuring the forces applied to the platform through the subject’s feet. The
device uses strain gauges in the metal platform and a computer interface to record the
forces applied to it. The signals from these strain gauges are amplified, digitized, and
stored in the computer. From these forces, a times series of locations of the subject’s
center of pressure can be collected. The path of these center of pressure locations is
plotted on the computer screen and the length and velocity of the sway path over a
standard time period (e.g., 60 seconds) is recorded. Other summary measures such as the
average deviation in the lateral and anterior-posterior directions can also be calculated.
We will repeat the test two times with the subject’s eyes open and two times with eyes
closed. A complete test session requires approximately 8 minutes.
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6.6.12 Vibrotactile Threshold Testing
The measurement of cutaneous vibrotactile threshold is used to diagnose peripheral
neuropathy. Cutaneous vibratory stimuli are carried on large myelinated sensory nerve
fibers. These fibers are believed to be more sensitive to both diffuse and focal insult than
are small myelinated and unmyelinated fibers carrying other sensory information such as
pain or temperature. Thus, large fiber function abnormalities can be an early indicator of
peripheral neurological disease in an individual at risk. Many occupational and
environmental hazards, including heavy metals and organic solvents, can affect these
fibers. Testing large fiber function may allow for early detection of neurotoxicity due to
these and other agents.
The Vibratron II is a simple and widely used electromechanical vibrometer consisting of
a controller unit and two identical transducer units that cause plastic posts protruding
from their housings to vibrate at a frequency of 120 Hz. The intensity (amplitude) of the
Vibration is controlled by the OUTPUT knob on the face of the controller unit. The
amplitude is provided in "Vibration Units" on a digital display on the face of the
controller. The Vibratron is a manually operated device and does not require computer
interface for operation. It is relatively physically robust and readily portable. Data will
be manually entered into the data system by the tester. Set-up requires about 5 minutes.
Each threshold requires about two minutes to obtain. We will obtain five threshold values
(three descending and two ascending values) for each great toe, requiring a total of about
10 minutes. The vibration threshold for each toe is the median value obtained from
values 2-5 (value 1 is discarded).
6.6.13 Visual Acuity
Visual Acuity is the measurement of clarity or sharpness of vision. We will use the
standard Snellen chart to determine visual acuity with and without current correction (if
applicable) at 20 feet.
6.6.14 Visual Contrast Sensitivity
Visual contrast sensitivity will be evaluated with the Functional Assessment of Contrast
Sensitivity test using a standard testing instrument, the Optec 1000 (Optec, Inc. USA).
Circular stimuli consisting of alternating light and dark bars will be presented. Nine
stimuli of decreasing contrast will be presented at each of 5 spatial frequencies, i.e., 1.5,
3, 6, 12, and 18 cycles per degree. The index of the weakest contrast correctly identified
(i.e., threshold) will be recorded for each spatial frequency.
6.6.15 Handgrip Strength
Measurement of grip strength provides information about the functional integrity of the
voluntary motor system from the brain’s motor cortex to the peripheral skeletal muscles.
Impulses for voluntary contraction of skeletal muscles are carried on large, myelinated
nerve fibers with cell bodies located in the anterior horn of the spinal cord. In
occupational and environmental health settings, the most common disorder affecting grip
strength is distal sensory-motor axonopathy.
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Grip strength and pinch strength will be assessed with the Jamar dynamometer. It is a
self-contained mechanical/hydraulic device that records on a dial the maximum force
exerted by the subject's "power" or whole-hand grip. It is equipped with a "tell-tale" that
retains the maximum excursion of the force indicator needle. It is commonly used by
physical medicine and rehabilitation specialists for evaluation of patients with motor
abnormalities.
The device is manually operated. It requires no set-up and is relatively robust, but may be
damaged or lose calibration if dropped. We will perform one set of three grip strength
measures of the dominant hand followed by one set of three grip strength measures of the
non-dominant hand. The mean of the three measures for each hand are the summary
metrics for the handgrip measure. A full set of grip strength measurements requires
approximately 2 minutes.
6.6.16 Walking Speed
Timed walks are similar to the short walk tests used in many epidemiological and clinical
studies. We will assess functional mobility and gait with a 6-meter walk test. The
participant will be asked to perform a series of 3 walks on a 6 meter course two times.
For the first, they will be asked to walk at their normal walking pace. For the second, they
will be asked to walk as quickly as possible. For the third, they will be asked to walk
while keeping their feet within two lines that are 20 cm apart. This test has been
successfully used in the Baltimore Longitudinal Study of Aging.
6.6.17 Long Distance Corridor Walk (LDCW)
Insufficient cardiovascular fitness may be a major mechanism through which different
behaviors and diseases contribute to functional decline; a key landmark on the pathway
from independence to disability. As substantial decline in exercise tolerance may precede
recognition of mobility-related difficulty, particularly in sedentary individuals, low
exercise tolerance may be an early indicator of impending functional limitation.
The LDCW, a walking-based test of exercise tolerance and fitness level, developed for
use in the Health ABC study, was designed to minimize shortcomings associated with
self-paced walking tests. [46] The participant is asked to walk four hundred meters at
their normal pace and the time to accomplish this task is recorded. Four hundred meters
is the approximate distance an average healthy older adult can cover in 6 minutes and is
comparable to the reference distance (1/4 mile) of a commonly used self-report measure
of mobility-related difficulty. [46] Participants are told that they will be timed but are
advised to walk at a normal, comfortable pace.
6.7
Fractional Exhaled Nitric Oxide (FeNO)
eNO will be measured according to ATS/ERS standards, using a Sievers analyser (NOA2080i ) a with chemoluminsecent sensor. Clinical staff will conduct measurements with
the participant in a seated position. The participant will place the mouth piece in their
mouth, inhale for two to three seconds to total lung capacity, then exhale immediately at
a constant flow rate (50mL/s) for ten seconds. The participant will be allowed to perform
up to 8 maneuvers in order to achieve two measurements that agree within 5%. If the
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participant cannot perform two reproducible 10-second maneuvers, two 6-second
maneuvers will be considered acceptable. Both EBC (on a subset of participants) and
FeNO will be collected immediately prior to the pulmonary function testing
6.8
Pulmonary Function Testing
Pre and post-bronchodilator pulmonary function testing (PFT) will be conducted
according to ATS/ERS guidelines [48]. Bronchodilation will be achieved through the
administration of 2 metered doses of albuterol (90 µg per actuation, 2 puffs) through a
500-mL spacer, with one minute between puffs. Post-bronchodilator spirometry will take
place 10-15 minutes after bronchodilator administration.
PFT will be performed using a portable, ultrasound transit-time based spirometer
(EasyOn; NDD Medical Technologies, Chelmsford MA, USA, or a comparable model).
A full Forced Vital Capacity maneuver will be conducted. We will obtain three ATS
acceptable forced expiratory maneuvers out of a maximum of eight attempts before and
after bronchodilator administration. Spirometry will be conducted with the participant
seated and wearing a disposable nose clip. We will use new individually packaged,
disposable mouthpieces for each subject and a new spacer for each subject. All
spirometers will undergo standard quality control checks each day they are used.
To the extent possible, we will ask participants to not use their asthma inhalers on the day
of the examination. We will record the timing and dosage of all asthma medications over
the preceding seven days.
Participants who answer yes to any of the following questions will not undergo
spirometry during the visit:
•
In the past three months, have you had any surgery to your chest or abdomen?
•
In the past three months, have you had a heart attack or stroke?
•
In the past three months, have you had a detached retina or have you had eye
surgery?
•
In the past three months, have you been hospitalized for any other heart problem?
•
Are you pregnant?
•
Are you currently taking medication for tuberculosis?
In addition, participant with a blood pressure > 180 mmHg systolic or > 110 mmHg
diastolic, or with a heart rate > 100 or < 40 beats per minute will not be tested.
Our exclusion questions include those used in BOLD [49] and PLATINO [50],
multinational studies that enrolled over 14,000 adults over age 40 years for pre and post
bronchodilator spirometry with only trained technicians. No adverse events occurred in
either the BOLD or PLATINO studies. These exclusions are considered very
conservative and these questions are not generally asked before spirometry is done in
clinical practice.
Study staff conducting PFT will be required to take a web-based, NIOSH-approved
spirometry course prior and to attend an in-person training session. Following training,
staff will be required to submit 10 practice tests that are judged as acceptable by a PFT
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expert in order to receive certification of proficiency. During the run-in phase, our PFT
expert will review PFTs on a weekly basis and will send findings to clinical site directors,
along with suggested corrective actions. Clinical site directors or another staff member
experienced in PFT will work with study staff to improve performance. If necessary,
additional training and practice sessions will be provided by the coordinating center in
conjunction with the study PFT expert consultant. After the run-in phase, we plan to
over-read all tests with poor quality scores and a random sample of 10% of passing
scores, if more than 90% of tests during the run-in were high quality. If quality scores are
lower than expected during the run-in, we will re-train staff and continue to over-read all
tests until 90% of scores meet quality standard and stabilize at that level of quality.
6.9
Mental Health Assessment
The clinical exam will include a more comprehensive assessment of mental health status,
mental health needs, and resiliency than the telephone interview. This assessment allows
for a more focused examination of complex interactions between mental and physical
health status and will also cover domains that cannot be well-covered in a telephone
interview, such as suicidal ideation and substance abuse. The assessment will repeat
certain measures included in the telephone interview and will obtain information on
participants’ access and utilization of local mental health services. Participants will be
administered the Center for Epidemiological Studies Depression Scale (CES-D), which
measures current depressive symptoms, with an emphasis on depressed mood, and the
Positive and Negative Affect Scales (PANAS) which, as its name suggests, measures
levels of both positive and negative affect. Participants will be asked to complete the
PANAS scale in reference to the past week. We will also administer instruments based on
the Connor-Davidson Resiliency Scale, the Traumatic Life Events Questionnaire, and the
Financial Events Scale, which have previously been used in studies of the general
population. This mental health assessment will be conducted at the end of the clinical
exam.
Staff may encounter study participants during the clinic visit who are experiencing mild
to severe psychosocial distress and will be trained to remain neutral when asking
questions or responding to issues related to mental health conditions and to reply with
sensitivity. In most situations, mild distress can be effectively addressed with an
empathetic and respectful listening, allowing study activities to continue as planned.
While the purpose of the exam is not to provide mental health diagnosis, counseling or
care, every attempt will be made to connect participants in need with mental health
services available in their community (lists of such services have been compiled (and will
be updated as needed) with the assistance of other State and Federal Agencies and has
been actively used throughout the GuLF STUDY. We will use a standardized checklist to
systematically assess mental health distress that is based on a model SAMHSA has used
in other studies and that we used in the baseline enrollment phase of the GuLF STUDY.
Follow-up calls will be placed to all participants who receive a mental health referral to
available mental health services in their area to determine if services were obtained and to
provide additional information regarding health services, if necessary.
Staff will also be trained to respond to more serious signs of mental health distress, such
as suicidal or homicidal thoughts, that require additional interventions. Participants who
express such thoughts will be assessed for signs of acute distress and asked if they have
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plans, intentions, and means to act on their thoughts. Based on these assessment findings,
study staff will take appropriate action, as summarized in Table 4 below.
Table 4. Action Plan for Responding to Suicidal and Homicidal Thoughts
Individual at
Risk
Imminent
Danger*
Self
No
Action
•
•
Self
Yes
•
•
•
•
Other
No
•
•
Other
Yes
•
•
•
•
Continue study activities, depending on level of
emotional distress
Offer a mental health care referral and follow-up
call for all referrals
End study activities
Refer to emergency care at local community
services if available, or through national Hotline
Escalate to study managers and investigators
Follow-up call for all referrals
Continue study activities, depending on level of
emotional distress
Offer a health care referral and follow-up call for
all referrals
End study activities
Call 911
Escalate to study managers and investigators
Follow-up call for all referrals
* Homicidal or suicidal thoughts combined with plans, intention, or means to act on
thoughts.
6.10 Biospecimen Processing and Shipment
After blood collection, clinic staff will allow the blood in the serum tubes to clot for 30
minutes before promptly centrifuging the tubes in the clinic and separating the serum and
clot, which will be retained. At the same time, the clinic staff will centrifuge the 10 mL
EDTA tubes, separating and retaining the plasma and the packed cell volume.
The ACD-B tubes will be mixed with DMSO (10% v/v DMSO) and aliquotted into 1 mL
cryovials. These cryovials will then be subjected to controlled freezing at a rate of ~1.0°C/min to -80°C using Biocision CoolCell LX alcohol-free cell freezing containers
(BioCision, Larkspur, CA) with a -80°C freezer. These samples will be kept at ambient
temperature until processing. Sample processing will be completed and cooling begun
within 2 hours of collection.
Following collection and processing, including aliquotting into cryovials, all specimens
will be labeled and temporarily stored at clinical sites until they can be shipped via
priority over-night service to the central processing lab (Social and Scientific Systems).
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The serum, blood clot, plasma, packed cells, and cryopreserved whole blood (from ACDB tubes) aliquots will be stored at -80°C. The trace metal samples and PAXgene RNA
samples will be frozen in their original tubes at -20°C. The urine aliquots will be stored at
-80°C. Toenail clippings and hair samples will be stored with desiccant, under controlled
ambient temperature and humidity.
Samples stored on-site at -80°C will be shipped on dry ice, while those stored on-site at 20°C will be shipped in a container maintaining a temperature of approximately -20°C.
Other samples will be shipped at ambient temperature. Samples will be shipped weekly,
on a Monday or Tuesday, minimizing possibility of weekend or holiday arrivals. All
biological samples will be shipped according to local, state, and federal requirements
governing shipment of biological specimens.
After samples are received and registered in the NIEHS Biospecimen Inventory System
at the central processing lab, they will be held in short-term storage under the same
conditions as above until they are shipped to the NIEHS biorepository. At the
biorepository, the serum, plasma, packed red cells, and cryopreserved whole blood
aliquots will be stored in LN2. The blood clots will be stored at -80°C. The trace metal
tubes and PAXgene RNA tubes will be stored at -20°C. The urine aliquots will be split
between LN2 and -80°C. Toenail and hair samples will be stored with desiccant, under
controlled ambient temperature and humidity.
6.11 Remuneration
Participants who complete the Biomedical Surveillance Sub-cohort clinic visit will
receive $100 for their time and effort. Participants who complete the saliva collection and
return their samples will receive an additional $20. Participants will also receive
reimbursement for travel costs based on the table below. A reimbursement for lodging
and meals will be provided, if needed, to participants who travel long distances (e.g. 100
miles), and whose scheduled appointment requires early morning or late evening travel.
Table 6. Travel Reimbursement
Approximate Distance from the Clinic
7
Amount
≤ 30 miles
$25
31 miles – 60 miles
$50
≥ 61 miles
$75
Reports to Participants and Health Care Referrals
During each clinical exam visit, clinical staff will measure height and weight to calculate
BMI, blood pressure, spirometry, and hemoglobin A1c and lipid levels. The participant
will receive handouts with the results of these tests/measurements, standardized clinical
interpretations, and advice for seeking care. In addition to providing the participant with
results handouts and recommended actions (see Table 7), participants who do not have a
primary care provider or who cannot afford to pay for care will be referred to a local
clinic that provides care for services based on a sliding scale.
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Table 7. Recommendations for Action based on Medical Findings
Evaluation
Findings
Recommended Actions
Blood Pressure
SBP > 180 or
Seek care as soon as possible as this is a potentially an
emergency health condition
DBP ≥ 110
*Based on AHA 2010 guidelines
SBP 160 to 179 or
See health care provider within one month.
DBP 100 to 109
SBP 140 to 159 or
See health care provider within two months.
DBP 90 to 99
SBP 120 to 139 or
DBP 80 to 89
SBP < 120 AND
Those with slightly high BP advised to discuss need for
any additional evaluations of lifestyle changes with HCP.
No recommendation.
DPB < 80
Resting Heart Rate
BMI
HR > 120 bpm
See health care provider as soon as possible.
101 ≤ HR ≤ 120 bpm
See health care provider within one month.
40 ≤ HR ≤ 59 bpm
See health care provider within one month.
HR < 40 bpm
See health care provider as soon as possible.
60 ≤ HR ≤ 100
No recommendation.
Obese (≥ 30)
If overweight or underweight, discuss results and potential
lifestyle changes with health care provider.
Overweight (25 to 29.9)
Normal (18.6 to 24.9)
Underweight (< 18.5)
Spirometry
Hemoglobin A1c
Either FEV 1 , FVC, or
FEV1/FVC below lower
limits of normal AND
FEV 1 , < 50% predicted
See health care provider within one week.
Either FEV 1 , FVC, or
FEV1/FVC below lower
limits of normal AND
FEV 1 , ≥ 50% predicted
See health care provider within one month.
FEV 1 , FVC, and
FEV1/FVC all above
lower limits of normal
No recommendation.
> 5.7%
See health care provider within one month.
≤ 5.7%
No recommendation.
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Evaluation
Findings
Recommended Actions
Total Cholesterol
< 200 mg/dL
No recommendation
200 – 239 mg/dL
Those with borderline high Total Cholesterol levels
advised to discuss need for any additional evaluations of
lifestyle changes with HCP.
≥ 240 mg/dL
See health care provider as soon as possible.
Less than 40 mg/dL
(for men)
Less than 50 mg/dL
(for women)
Those with low HDL Cholesterol levels advised to discuss
need for any additional evaluations of lifestyle changes
with HCP.
≥ 60 mg/dL
No recommendation
<130 mg/dL
No recommendation
130 – 159 mg/dL
Those with borderline high LDL Cholesterol levels
advised to discuss need for any additional evaluations of
lifestyle changes with HCP.
160 – 189 mg/dL
See health care provider within one week.
≥ 190 mg/dL
See health care provider as soon as possible.
< 150 mg/dL
No recommendation
150 – 199 mg/dL
Those with borderline high Triglyceride levels advised to
discuss need for any additional evaluations of lifestyle
changes with HCP.
200 – 499 mg/dL
See health care provider within one week.
≥ 500 mg/dL
See health care provider as soon as possible.
HDL Cholesterol
LDL Cholesterol
Triglyceride
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Data Collection
Study computers with whole-disk encryption will be issued to clinical sites, as required
by the security plan in effect for the GuLF STUDY. A clinical data management and
scheduling system will be utilized to standardized data collection and centralize the
storage of study data. The system will be accessible only to project team members at the
coordinating center and clinical sites, via an encrypted, secure connection to GuLF
STUDY central servers (VPN or Secure-Socket-Layer). Thus, no project data will be
archived on remote computers for long-term storage. Study data recorded on the
neurobehavioral and PFT computers will be uploaded weekly and stored in a secured,
password protected database at the study coordinating center. The system has user access
rights designed to ensure site personnel have access only to participants assigned to their
site, and cannot see data collected elsewhere. Any ancillary data collected using 3rd
party software (e.g. pulmonary function data) will not contain personally identifying
information when possible. All clinical data management systems will be programmed in
order to minimize the risk of errors. For example, real-time data validation and
consistency checks will be performed as data is being collected, in order to preserve the
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integrity of the data. Study computers will be returned to the central office at the closure
of clinical data collection efforts.
9
Record Retention
Paper documents will be kept in locked filing cabinets, to which only authorized
personnel and study staff will have access. Electronically stored information and
materials will be on password protected access systems, computers and devices with
various safeguards (i.e. firewalls) put in place to address privacy and security concerns.
All records that contain names or other personal identifiers will be stored separately from
study records identified by code number. Worksheets, lists, logbooks, appointment
books, and any other documents that link participant ID numbers to other identifying
information will be stored in a separate, locked file in an area with limited access. At the
end of enrollment, consent forms and all other study related materials will be transferred
to the coordinating center for long term storage.
10
Data Analysis
Descriptive analyses, stratified by gender, state of residence and smoking status, will be
conducted to characterize the demographic, lifestyle, behavioral, residential, and
socioeconomic profiles of participants. We will also investigate these factors in relation
to the nature and extent of subjects’ participation in the oil spill clean-up effort. In
addition, to assess selection bias, we will compare these profiles among those invited to
participate in the exam compared to those who actually participated. Descriptive
analyses will include frequencies for categorical variables and means for continuous
variables.
We will use least squares regression and logistic regression to examine self-reported and
measured outcomes in relation to cleanup-related activities and exposures, as well as
demographic, lifestyle, and other factors. Measured outcomes include measures of
neurobehavioral function, peripheral nerve function, pulmonary function, and mental
health. Statistical methods will be appropriate to the outcomes. For example, in addition
to using least squares regression to investigate the association between selected factors
and continuous outcome measures, we will employ, when appropriate, logistic regression
to examine these factors in relation to outcomes categorized according to clinical criteria.
11
Statistical Power
Consistent with the overall aims of the GuLF STUDY, the clinical exam is designed to
allow us to measure the effects of varying levels of exposures to oil and oil dispersants
across a wide range of physical and mental health outcomes. As demonstrated in Table 5,
we are powered to detect relatively small differences in the prevalence of outcomes
between exposed and unexposed participants when the frequency of the outcome is not
rare among the unexposed. Similarly, as shown in Table 6, we also have power to detect
small differences in continuous outcomes. Even if participation is as much as 25% lower
than expected, our power calculations (not shown) indicate that the minimum detectable
ORs or mean differences will increase by less than 10-15%.
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For subgroup analyses, power will be adequate (80%) to detect moderate odds ratios
(OR) when the proportion not exposed with the outcome is not rare and the prevalence of
exposure is between 25 and 75 percent. For example, assuming an N of 700 for the EBC
analyses, when the proportion of those unexposed with the outcome is at least 10 percent
and the prevalence of exposure is between 25 and 75% there will be adequate power to
detect an OR between 1.6 and 2.1. When the prevalence of the outcome is lower among
the unexposed and/or the proportion with the exposure is less than 10% or greater than
75%, larger ORs will be needed to attain adequate power.
Table 5. Minimum detectable odds ratios (OR) for a range of proportions of exposure and
outcome frequencies, based on a two-sided test with alpha=5%, power=80%, and N =
4,000
Frequency of
outcome
among
unexposed
Proportion of cohort exposed to a given agent
5%
10%
25%
50%
75%
90%
200
400
1,000
2,000
3,000
3,600
1%
3.72
2.88
2.26
2.12
2.39
3.34
5%
2.11
1.78
1.52
1.46
1.55
1.85
10%
1.79
1.55
1.37
1.32
1.38
1.59
30%
1.53
1.37
1.24
1.21
1.25
1.37
Table 6. Minimum detectable mean differences for a range of proportions of exposure,
based on a two-sided test with alpha=5%, standard deviation=1, power=80%, and N =
4,000
12
Proportion of cohort exposed
to a given agent
Mean
Difference
5% or 95%
0.203
10% or 90%
0.148
25% or 75%
0.102
50%
0.089
Institutional Review Board
The investigator and clinical site directors will submit the protocol, informed consent
form, questionnaires, and other materials for participants to the NIEHS IRB and local site
IRBs for review and approval. Clinical exams will not commence until the submission
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has been approved in writing by all IRBs. Once the protocol is approved, the principal
investigator and clinical site directors will be responsible for obtaining IRB approval
during annual Continuing Review for the duration of the study. Amendments will not be
implemented without prior IRB approval, except where necessary to eliminate immediate
hazards to participants. The principal investigator will report adverse events, protocol
deviations, inadvertent loss or disclosure of data, and loss of samples in accordance with
the policies of all IRBs.
13
Evaluation of Risks and Benefits
13.1 Potential Benefits
Study participants may benefit from the positive feelings associated with participating in
a study of the health effects of the oil spill that may be of value to their community. In
addition, the knowledge gained from this study may have a significant impact on future
public health responses to similar disasters. It is also possible that participants may
benefit directly from public health responses that are based on early findings from this
study. Finally, participants may benefit from receiving results of medical evaluations and
health care referrals that they may not otherwise receive.
13.2 Potential Risks
The questionnaires and study procedures associated with the clinical exam study present
minimal risks to study participants. Adverse events associated with study procedures are
expected to be uncommon and limited to mild and transient discomforts. In order to
minimize risks to participants, all study procedures will be conducted by qualified,
experienced, and well-trained research staff.
The questionnaires are based on instruments that are widely used in epidemiological
studies and administered in the baseline enrollment effort. The main risk in questionnaire
administration involves questions about sensitive health topics or personal experiences
that may be traumatic. Participants will be told that they can skip any questions that make
them feel uncomfortable or end the interview at any time. Questions related to mental
health and distress and drug abuse may be more stressful than other questions, but as
described above, staff will be appropriately trained and systems have been put in place to
deal with any issues that may arise. Participants will also be warned of the possibility of
loss of privacy should their de-identified data distributed through controlled access
procedures be linked back to them in ways that cannot be foreseen at present.
Pulmonary function testing is considered safe. The primary risk, which is exceedingly
rare, is fainting in older participants with impaired lung function. We minimize the
chance that this rare event will occur by using very conservative exclusions for
pulmonary function testing. To further minimize risk of fainting, pulmonary function
testing is done in a seated position, and study staff will be trained to look for signs of
dizziness or other problems and to stop the maneuver if necessary. We will also exclude
participants from testing who have extremely high blood pressure or rapid pulse rates.
The risk of infection is all but eliminated by using disposable mouthpieces (spirettes).
These disposable mouthpieces have the additional protection of having a built-in bacterial
filter.
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The only other health risk is associated with the use of albuterol, a bronchodilator, which
may cause some jitteriness and increased heart rate. In order to minimize these risks, this
study calls for the use of only two puffs of albuterol, rather than the four-puff dose that is
more routinely recommended for testing airway reactivity. This is felt to be a very safe
dosage, even if a person has recently used their own inhaler for quick relief of symptoms
in the few hours preceding the testing [51].
EBC collection is also very safe. The risk of infection will be very low because each
participant will use a different mouthpiece and collection device. Cooling sleeves will be
cleaned between participants, further reducing the low risk of infection.
There may be some minor discomfort associated with blood collection, including
temporary pain, bruising, or swelling at the phlebotomy site. Fainting during blood
collection is exceedingly rare.
14
Adverse Event Reporting
Adverse events that are related to clinical procedures and that require clinical intervention
are expected to be very uncommon and occur in less than 1% of the study population.
Any clinically- significant, procedural-related adverse events requiring medical attention
will be reported to the IRBs during the annual continuing review.
Study staff may encounter participants who report or display symptoms of acute, preexisting medical or mental health conditions that are not related to participation in the
study. The results of study procedures, such as blood pressure measurement, may indicate
the need for immediate medical attention for poorly controlled or previously undiagnosed
illness. Clinic personnel may also observe signs that suggest the existence of reportable
social or abusive behaviors or encounter participants who are experiencing mental health
distress, suicidal ideation, or homicidal thoughts. Any pre-existing health problem,
mental health distress, or social situation that requires a call to 911, local authorities, or
social services will also be reported to the NIHES IRB and local site IRBs as an adverse
event at the time of continuing review. The report will include information on the
outcome of the actions taken in response to the event.
A clinically significant adverse event related to study procedures will be reported as a
serious adverse event if it is life threatening, causes persistent or significant disability,
leads to death, or requires medical or surgical intervention to prevent one of these
outcomes. The principal investigator will be responsible for reporting all clinically
significant serious adverse events related to study procedures to the NIEHS and clinical
site IRBs within 24 hours of receiving notification that an event occurred.
Unanticipated problems are defined as any incident, experience, or outcome that meets all
of the following criteria:
•
unexpected in terms of nature, severity, or frequency given (a) the research
procedures that are in protocol and informed consent and (b) the characteristics of the
subject population being studied;
•
related or possibly related to participation in the research;
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suggests that the research places subjects or others at a greater risk of harm
(including physical, psychological, economic, or social harm) than was previously
known or recognized
Unanticipated problems will be reported to the NIEHS and local site IRBs within 24
hours of the time they are reported to the principal investigator.
15
Timeline
We plan to initiate clinical examinations in September 2013. The initiation phase will
begin with a run-in period to assess the feasibility of operational plans. The run-in will
last for approximately four months and will be followed by ramp-up in visit rates that
will allow us to complete all exams within approximately18 months of start-up (March
2016).
During the four month run-in phase, we will pilot test all aspects of the study, as currently
planned, including study procedures, data collection systems, and operational plans. In
addition, we will monitor participation rates, implementation of procedures, and overall
timing of the clinic visit. We also aim to gain a more accurate reflection of how distance
and remuneration impact cohort members’ willingness to be involved, as well as overall
participant motivation to complete the exam. We will seek IRB approval for any protocol
changes that need to be made based on our experience during the run-in phase.
We plan to ramp up the study up in January 2014 to ensure that all visits are completed
over the next 12-14 months. Depending on when we obtain final IRB approval from all
participating sites, we will adjust the launch and ramp-up dates as necessary. However,
we anticipate that the run-in phase and study ramp-up will take 4 months and 12-14
months respectively. We will implement any necessary changes during the ramp-up
phase in response to our experience during the run-phase. We may ramp up the study
sooner, if we find that operational activities stabilize more quickly than current
anticipated.
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| File Type | application/pdf |
| File Title | TITLE |
| Author | bridgeh |
| File Modified | 2014-01-27 |
| File Created | 2013-10-08 |