Longitudinal prospective studies that follow a population for an extended period (a decade or more) are the gold standard of observational epidemiologic studies. Such studies are uncommon though, because of the great expense and time needed to conduct them. Rarer still are well-designed cohort studies that include the collection and storage of biospecimens for use in current and future analyses. The Nurses’ Health Study (Colditz et al., 1997), the Framingham Heart Study (Oppenheimer, 2005, 2010), and the Atherosclerosis Risk in Communities Study (1989) are examples of such efforts that had been designed to study a particular health outcome (cancer for the former and heart disease for the two latter studies) but which have produced broader research findings as well. The design, data and biospecimen collection, and continued use of the assets assembled in these studies are considered to be exemplars of epidemiologic research.
One member of this select group—little known outside the veterans health research community—is the Air Force Health Study (AFHS): a longitudinal, prospective epidemiologic study of more than 2,700 men followed for approximately 20 years. This cohort participated in up to six intensive physical examinations with high rates of compliance. In addition to a complete record of the clinical measurements and observations at these exams, serum and other biological samples were obtained and preserved. Extensive questionnaires addressing health, lifestyle, and socioeconomic status were administered during each exam, and other information was obtained about the men’s employment and potential sources of environmental exposures. While the team responsible for collecting these assets was disbanded at the end of the study, the data and the biospecimens were preserved and—at the direction of Congress—made generally available for research 3 years ago.
Because the AFHS has only recently been accessible to the scientific community (outside of the Air Force study personnel and a few limited collaborations) for research, the vast majority of its potential is yet to be realized.
In 2007, after the original study—which examined whether U.S. Air Force personnel involved in Operation Ranch Hand, the program responsible for herbicide spraying in Vietnam, experienced adverse health effects from their service—was completed and its final report published, Congress directed that the AFHS data and biospecimens be transferred to the custody of the Institute of Medicine (IOM). The IOM was directed to undertake a program of research using the assets to better understand the determinants of health and promote wellness in veterans and the general population. As a first step, the IOM contacted the participants and obtained consent for their data and biospecimens to be used in a broad range of future research, including topics not directly related to the aims of the original study. The IOM also developed and implemented procedures by which investigators could obtain access to the data and biospecimens. As part of the law that required the AFHS assets be made available for research through the IOM, Congress requested that the IOM advise them on the feasibility and advisability of maintaining the biospecimens and data and conducting additional research on them.
A number of peer-reviewed papers have been published and numerous reports and presentations made from analyses that used AFHS data or biospecimens, both during the study and following the end of new data collection. Findings from the AFHS have been used for many purposes to date—prominently, to improve the pharmacokinetic modeling of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and refine half-life estimates of TCDD in exposed populations (Michalek et al., 1996; Warner et al., 2005; Wolfe et al., 1994).1 Other IOM committees have used findings from the AFHS to help inform conclusions regarding the health effects associated with exposure to herbicides and TCDD (IOM, 1996, 2000). However, the importance and applicability of the AFHS data and biospecimens extend far beyond research related to the study’s original purpose (IOM, 2006).
Upon completion of the AFHS by a team of researchers under the direction of the Air Force, Congress passed three laws with sections relating to the disposition of its data and biospecimens. Appendix B contains the text of these sections, which are summarized below.
Section 602 of Public Law 108-183, the Veterans Benefits Act of 2003, directed the Secretary of Veterans Affairs to contract with the National Academy of Sciences to address several questions regarding the appropriate disposition of
1 TCDD was an unintended byproduct of the synthesis of trichlorophenoxyacetic acid (2,3,5-T), a herbicide used for tactical defoliation during the Vietnam conflict. 2,3,5-T was also commonly used as an agricultural herbicide until the late 1960s.
the AFHS. Subsequently, in response to a request by the Secretary of Veterans Affairs, the IOM of the National Academy of Sciences established the Committee on the Disposition of the Air Force Health Study, which issued a detailed report that recommended that the AFHS data and biospecimens be maintained and used to foster new research and identified several possible appropriate custodians of such assets (IOM, 2006).
Based in part on the findings, conclusions, and recommendations in the 2006 IOM report, Congress passed Public Law 109-364, section 714 of which directed the Air Force to transfer custodianship of the AFHS’s data and biospecimens to the Medical Follow-Up Agency (MFUA)—a unit within the IOM responsible for data-intensive epidemiologic studies—when the study formally concluded in September 2007. The Air Force was instructed to seek permission from the surviving members of the cohort for this transfer. This activity took place over the Spring and Summer of 2007, and more than 90% of the cohort members consented to the move.
Two years after Congress directed the IOM to become the custodian of the AFHS assets, Congress passed Public Law 110-389, of which section 803 directed the Department of Veterans Affairs (VA) to provide funding to MFUA to maintain and manage the AFHS assets and to make them “available as a resource for future research for the benefit of veterans and their families, and for other humanitarian purposes.” MFUA was authorized to administer a program of research on the assets aimed at “understanding the determinants of health, and promoting wellness, in veterans.” The law also directed that up to $250,000 per year of pilot funds be made available when appropriate to support investigations using the AFHS assets. At the end of the effort, Congress directed that a report be submitted to them that assessed the feasibility and advisability of conducting additional research on the AFHS data and biospecimens.
The IOM undertook two related efforts to carry out the tasks identified in section 803 of Public Law 110-389. First, in its role as custodian of the AFHS data and biospecimens, it established an advisory committee to facilitate new research using the AFHS assets and to review proposals from researchers who requested access to the data and biospecimens. Its statement of task is shown in Box 1-1. This activity is detailed in Chapter 3.
The advisory committee operationalized its statement of task by developing and implementing protocols for
- reviewing the content of prospective research proposals;
- assessing whether proposals merited access to the AFHS assets;
- governing the management and use of the biospecimens, including deciding whether and which biospecimens should be made available and how much material should be provided; and
Statement of Task—Advisory Committee
The U.S. Congress asked the Institute of Medicine to assume responsibility for managing a robust set of research assets that were produced in the course of the Air Force Health Study (also known as the Ranch Hand study), which operated from 1979 until 2006. Materials include extensive information on the health and socioeconomic status of the cohort, and serum, whole blood, adipose tissue, semen, and urine samples collected during six cycles of examinations. In its capacity as custodian of this material, the IOM will work with a committee of scientific advisors to foster the use of these data and specimens in new studies that will provide insight into factors affecting the health of veterans and the population at large, and to review research proposals.
- determining whether to award pilot funding to investigators who requested support.
Second, in 2014, to conform to institutional requirements, a consensus committee composed of the same membership was created to write a report regarding the feasibility and advisability of conducting additional research on the AFHS data and biospecimens as called for in the legislation. Its statement of task is shown in Box 1-2. While the consensus committee was not asked to evaluate the data and biospecimens dissemination program it does offer lessons learned from the program as part of its examination of the feasibility and advisability of maintaining the biospecimens.
The consensus committee held eight biweekly meetings via conference call from August through December 2014 and conducted a 1-day in-person meeting in Washington, DC, to examine the issues under its purview. It used information acquired by the advisory committee in its deliberations, including
- results of searches of relevant scientific literature on topics related to the AFHS data or biospecimens;
- annual updates from investigators in open sessions of committee meetings, during which the committee had the opportunity to question them; and
- input from interested parties, including representatives of the Ranch Hand Vietnam Association,2 who presented information from the perspective
2 The Ranch Hand Vietnam Association is an organization composed of members of the AFHS cohort.
Statement of Task—Consensus Committee
A June 28, 2011, contract between the National Academies and the Department of Veterans Affairs entitled Air Force Health Study (AFHS) Assets Research Program—which operationalizes directives contained in Public Law 110-389, section 803 (Maintenance, Management, and Availability for Research of Assets of Air Force Health Study)—directs the IOM to “provide the final report to Congress at the end of the final period of performance outlining the feasibility and advisability of maintaining the biospecimens based on interest generated from the general scientific community and results of pilot projects and other research projects using the AFHS assets.” An ad hoc committee will conduct a study and prepare a report in response to this charge. The final period of performance ends on June 30, 2015.
of AFHS participants; and VA, which attended the open sessions and addressed the committee.
As part of its approach to its task, the consensus committee developed and administered a survey to investigators who received data or biospecimens to solicit feedback on the process, completeness of the data, and quality of the biospecimens. The committee also used the findings and recommendations of the Disposition of the Air Force Health Study report as a guide for assessing what was then believed to be feasible and possible for a research program managing and using the AFHS assets and to compare with its now realized experience.
The remainder of this report is organized into four chapters plus supporting appendices. Chapter 2 provides background information on the design and scope of the original AFHS, the types of extensive detailed data and biospecimens collected, and the usefulness of the AFHS assets, especially its biospecimens, for continued research. Chapter 3 describes the research effort under the IOM’s custodianship, including examples of new research using both the electronic data and the biospecimens. The impact and value of the research to date and the AFHS assets’ continued application to future research are also discussed. It also presents an overview of some of the practical challenges to managing the vast number and type of assets, such as their transfer, cleaning, processing, storage, and maintenance, and summarizes the proposal process created and used by the
advisory committee to evaluate proposals for access to the AFHS assets. Chapter 4 examines the future of the research program including potential options to increase the availability and use of the AFHS assets while taking into account some of the associated legal requirements and ethical and social norms and expectations. Chapter 5 summarizes the committee’s findings, conclusions, and recommendation regarding the disposition of the AFHS data and biospecimens, specifically the feasibility and advisability of their continued maintenance and use in new research. Appendix A provides short biographies of each committee member. Appendix B contains excerpts of the public laws regarding the National Academy of Sciences and the AFHS. Appendix C provides abstracts of all research approved by the advisory committee as of February 1, 2015.
Atherosclerosis Risk in Communities Investigators. 1989. The Atherosclerosis Risk in Communities (ARIC) Study: Design and objectives. American Journal of Epidemiology 129(4):687-702.
Colditz, G. A., J. E. Manson, and S. E. Hankinson. 1997. The Nurses’ Health Study: 20-year contribution to the understanding of health among women. Journal of Women’s Health 6(1):49-62.
IOM (Institute of Medicine). 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press.
IOM. 2000. Veterans and Agent Orange: Herbicide/dioxin exposure and type 2 diabetes. Washington, DC: National Academy Press.
IOM. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press.
Michalek, J. E., J. L. Pirkle, S. P. Caudill, R. C. Tripathi, D. G. Patterson, and L. L. Needham. 1996. Pharmacokinetics of TCDD in veterans of Operation Ranch Hand: 10-year follow-up. Journal of Toxicology and Environmental Health 47:209-220.
Oppenheimer, G. M. 2005. Becoming the Framingham Study 1947–1950. American Journal of Public Health 95(4):602-610.
Oppenheimer, G. M. 2010. Framingham Heart Study: The first 20 years. Progress in Cardiovascular Disease 53(1):55-61.
Warner, M., B. Eskenazi, D. G. Patterson, G. Clark, W. E. Turner, L. Bonsignore, P. Mocarelli, and P. M. Gerthoux. 2005. Dioxin-like TEQ of women from the Seveso, Italy, area by ID-HRGC/HRMS and CALUX. Journal of Exposure Analysis and Environmental Epidemiology 15(4):310-318.
Wolfe, W. H., J. E. Michalek, J. C. Miner, J. L. Pirkle, S. P. Caudill, D. G. Patterson, Jr., and L. L. Needham. 1994. Determinants of TCDD half-life in veterans of Operation Ranch Hand. Journal of Toxicology and Environmental Health 41(4):481-488.