The Air Force Health Study Assets Research Program (2015)

Summary

Longitudinal prospective studies that follow a population for 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 Framingham Heart Study and Atherosclerosis Risk in Communities Study are two examples of such research efforts that were designed to examine a particular health outcome but used to produce 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 clinical measurements and observations collected 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 participants’ employment, families and offspring, and potential sources of environmental exposures.

The U.S. Congress, which played a role in the initiation of the study in 1979, passed three laws with sections relating to the disposition of its assets (data and biospecimens). Section 602 of Public Law 108-183 directed the Secretary of Veterans Affairs to contract with the National Academy of Sciences’ Institute

of Medicine (IOM) to address several questions regarding the appropriate management of the AFHS assets at the conclusion of the study. The committee formed to answer them concluded that the AFHS data and biospecimens appeared to be of high quality and well preserved. It recommended that these assets be maintained and used to foster new research that addressed a broader range of questions than the original study and that took advantage of advances in science and technology to learn more from the collected assets. However, it also noted that obstacles existed to making the assets available to outside investigators; in particular, deficiencies in their documentation and organization. The committee identified several possible appropriate custodians for the data and biospecimens, and recommended that a mechanism of independent oversight on all future research using the AFHS assets be implemented to ensure that the work conducted on them was of high scientific quality and conformed to legal requirements and ethical standards for the handling of the participants’ information (IOM, 2006).

Following on the findings, conclusions, and recommendations from the 2006 IOM report, Congress passed Public Law 109-364, Section 714 of which directed the U.S. 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—at the completion of the study in September 2007. Before the assets could be transferred to MFUA, the surviving members of the cohort were asked to consent to the transfer of their data and biospecimens to the custody of the IOM and more than 90% gave this permission.

Two years after MFUA became the custodian of the AFHS assets, Congress passed Public Law 110-389, Section 803 which 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 research program aimed at “understanding the determinants of health, and promoting wellness,” specifically in veterans but also for the broader U.S. population. The law also directed that up to $250,000 per year be used for pilot funds to be made available when appropriate to support investigations using the AFHS assets. At the end of that effort, Congress directed that a report be submitted to them that considered the feasibility and advisability of conducting additional research on the AFHS data and biospecimens. This report responds to that congressional directive.

THE COMMITTEES’ TASKS

The IOM undertook two related efforts to carry out the tasks identified in 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. Second, to conform to institutional requirements, a

consensus committee composed of the same membership was created to write the report regarding the feasibility and advisability of conducting additional research on the AFHS data and biospecimens called for in the legislation.

The advisory committee operationalized its responsibilities by developing and implementing protocols for

• reviewing the content of prospective research proposals;
• determining whether a proposal met the criteria for scientific merit;
• overseeing the dissemination and use of the biospecimens, including deciding whether and which specimens should be made available and how much material should be provided; and
• awarding pilot funding to investigators who applied for support.

The statement of task for the consensus committee—the body responsible for this report—is shown in Box S-1. Its work comprised a summary of the activities carried out since the IOM assumed custodianship of the AFHS assets, a critical analysis of the lessons learned in administering these assets, and a survey of the experiences of the investigators who received data or specimens to solicit feedback on the process. 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 believed to be feasible and possible for a research program managing and using the AFHS assets and its realized experience.

THE AIR FORCE HEALTH STUDY

The original purpose of the AFHS was to determine whether Air Force personnel who had participated in the Operation Ranch Hand program of wartime herbicide spraying in Vietnam had experienced adverse health outcomes as a result of their service. Personnel who were involved in the operation—commonly referred to as the Ranch Hands—and who were living when the study began were identified and individually matched on age, race, and military occupation to comparison subjects who were stationed in and flew cargo operations elsewhere in Southeast Asia during the Vietnam conflict, had not been exposed to tactical herbicides, and were assumed to be similar in training profiles, socioeconomic factors, and lifestyles.

The AFHS program was conducted over 27 years (1979–2006). Clinical measurements and observations were made, extensive health questionnaires were administered, and biological samples were obtained from the participants at each of six exams, or cycles: at baseline (1982) and then in years 3, 5, 10, 15, and 20 of the study. Data collected during physical examinations comprised indices of health status that encompassed general health and endpoints by major organ system. More than 200 clinical laboratory tests and measures were conducted and evaluated, and more than 60 of these were measured at all six cycles. Other information was obtained from personal medical records and from the participants’ families. Box S-2 summarizes the major types of information collected.

While the study was completed in 2006, the extensive health data linked to several types of longitudinally collected biologic specimens—some 91,000 serum, whole blood, urine, semen, and adipose tissue specimens—remain a resource for additional research. The AFHS assets are exceptional in the sheer multitude and range of types of information available for each participant.

TRANSFER, PREPARATION, AND MANAGEMENT OF THE AFHS ASSETS

Following passage of Public Laws 109-364 and 110-389, it took approximately 3 years for a final agreement to be reached and for funding to be in place for administration of the new AFHS Assets Research Program through the IOM. More than 123,000 electronic files were transferred to MFUA. These comprise text files, images of X-rays and electrocardiograms, analysis and translation files (Statistical Analysis System databases and programs, Fortran programs, Excel spreadsheets), and PDFs of questionnaires, physical exam forms, reports, and other paper records. Because the IOM does not have the physical plant needed to maintain a biospecimens collection, MFUA reached an agreement and contracted with the Air Force Research Laboratory (AFRL) at Wright-Patterson Air Force Base in Dayton, Ohio, to house the biospecimens.

Although 2,758 individuals participated in at least one exam cycle, not all gave consent to have their data and biospecimens transferred to the IOM or to be used in future research. Materials from the 2,488 participants who allowed the custody change were transferred. Subsequently, the IOM sought permission from the participants to allow use of their materials in future research, and 2,210 gave their consent.

The electronic data transferred to the IOM were not standardized between cycles or in a database format. The first year of MFUA’s management of the data was, therefore, dedicated to documenting, reading in, verifying, and integrating the disparate files, and otherwise preparing them for use by outside investigators as well as obtaining the consent of the cohort. Further, an updated database of the biospecimens needed to be created to document accessions of them. This was a unique and challenging undertaking. To the committee’s knowledge, such a large transfer of both data and biospecimens and the need to recreate such an extensive database with little documentation and no formal consultants from the original project staff had never been accomplished before. Because of this, there were no examples for the IOM staff or the advisory committee to base such work on and not all issues could be anticipated when the program first began. Questions regarding the actual quality and usability of the data and biospecimens needed to be addressed before research using the AFHS assets could be realized.

While these activities were under way, the advisory committee charged with administrative oversight of the research program and fostering the use of the AFHS data and biospecimens in new research established a process for solicit-

ing and reviewing research proposals. The first request for proposals (RFP) was announced on April 30, 2012. International and U.S. researchers from academic institutions, industry, and government organizations were eligible to apply for access to the AFHS assets. The application process consisted of two steps: a letter of intent and a full proposal. Proposals were required to be hypothesis-driven studies, not merely data mining endeavors. The RFP was publicized on the AFHS project page of the IOM website and initially sent to researchers and organizations that were familiar with the AFHS or had an interest in research related to herbicide exposure.

Since MFUA became the custodian of the AFHS assets, more than 80 inquiries from researchers have been received. As of February 1, 2015, 26 letters of intent were submitted by investigators, 24 of whom were invited to submit full proposals. Of the 24 proposal invitations, 19 complete proposals were submitted to the committee for review. Of the 19 proposals reviewed by the committee, 13 proposals were approved; 6 studies required access to the data only, and 7 studies used both data and biospecimens.

NEW RESEARCH USING THE AFHS ASSETS

The first proposals were approved in 2012, and while it is premature to expect publications so soon into the program, the committee was able to review preliminary results from approved studies in the feasibility stage, and one investigator published two papers describing his results. The research proposals reviewed and approved for use of the AFHS biospecimens and data span a wide range of scientific and biomedical research topics (see Table S-1).

Awareness of the AFHS resource and its potential value beyond herbicide-exposure research has been disseminated throughout the research community, as evidenced by a steady increase in the diversity and number of proposals received. Research topics that have emerged among the submitted and approved proposals include aging, neurologic diseases, and cancer research, demonstrating that AFHS data and biospecimens remain relevant for important biomedical and public health research projects. Moreover, the biospecimens have been well-preserved and viable, and given the current storage conditions, should remain so for many years to come. The extensive data and biospecimens collected over the extended period of the AFHS makes it invaluable for examining potential etiological factors relating to rare diseases, diseases and conditions that have a long latency periods, or for examining biomarkers associated with the natural history of slowly progressive disorders. For example, diagnostic data can be combined with DNA analysis from whole blood, semen, or adipose tissue samples to investigate genetic markers of disease predisposition or prognosis.

The committee solicited comments from the principal investigators of approved research studies after they had received all of their requested data or biospecimen samples. Investigators were asked to give specific examples of how

TABLE S-1 Studies Approved for Use of the AFHS Data or Biospecimens Since 2012^a,b

^a This list represents studies approved as of February 1, 2015.

^b The date that a proposal was approved and the date the study was able to start varied depending on the type and extensiveness of the requested assets. For example, studies that requested more biospecimens (for example, more than 100) took longer to process than those requesting fewer samples.

^c Denotes studies that were awarded pilot funding.

the AFHS assets were valuable for their research and any suggestions they could provide to make the AFHS assets research program more beneficial. Questions were related to the overall application process, quality and completeness of the data received, quality and usefulness of the biospecimens, and future plans regarding the results and additional uses of the AFHS assets. The responses were supportive of both the AFHS assets as well as the application process. Investigators who received and used data stated that it was generally complete. While at least half of the investigators’ studies were still in progress when they provided feedback to the committee, they were confident that the quality of the data, both provided and generated, would allow them to draw reliable conclusions. For the studies that used the biospecimens, all of the investigators that had received biospecimens reported that the samples were in good condition, and they were able to perform the proposed assays successfully. Both DNA and microRNA were isolated successfully from the biospecimens.

CONSIDERATIONS FOR CUSTODIANS OR STEWARDS OF THE AFHS ASSETS

MFUA’s experience as custodian has yielded a number of lessons learned that need to be considered and accounted for to ensure continued successful use of the AFHS data and biospecimens for new and innovative research, no matter who exercises future responsibility for the assets. These include storage (including data security), data curation, and privacy protection; laws, rules, and policies related to asset management and dissemination; and sustained funding to support these activities. Both data and biospecimens require continued management based on best practices that will also serve to make these assets more accessible and useful to the broader research community.

Data must be stored in a manner that maintains its physical and logical integrity and allows it to be easily retrievable. Data curation refers to the active management of data required to maintain it long term for preservation and reuse. Proper data documentation, quality, and accessibility are key to enhancing and enabling use internally as well as by the broader scientific community. Because of the longitudinal nature of the AFHS and the diverse manners by which data were often collected, recorded, and documented, as well as the different statistical methods used to analyze and account for missing data and loss to follow-up, the structure of the data is complex. In addition to continued storage and data curation, the biospecimens also require continued management to ensure their viability and value for use in future research.

The extensive data collected on the AFHS participants and the linkage of that data to the biospecimens provides an extremely rich research resource. However, while those data are being made available for a broad array of research, it is critical to maintain appropriate safeguards to protect participants’ privacy and confidentiality. The safeguards in place encompass not only data already available

but should extend to additional data that may be generated in the future from the biospecimens or from studies that seek to collect new information on cohort participants. Balancing access to the AFHS data and biospecimens while safeguarding the privacy of the AFHS participants is essential to maintaining a successful research program. The policy of the IOM advisory committee has been to limit the information released to approved researchers to only that information required for the specific research question of interest. Variables that may lead to the identification of a participant are suppressed. The committee finds that the practices used by the IOM for maintaining privacy protection of the cohort participants are appropriate and comply with legal requirements and ethical and social norms and expectations including respecting the individuals who have voluntarily provided biospecimen samples, meeting public expectations, and supporting the efficient functioning and transparent practices of the biorepository.

The current AFHS research program should be viewed as a pilot effort. To truly realize the potential of the AFHS data and biospecimens as a research asset like the Framingham Heart Study, the Atherosclerosis Risk in Communities Study, and other longitudinal epidemiologic studies will require a more sustained and possibly greater investment of money and personnel as detailed below.

FUTURE DIRECTIONS

A number of steps have been taken to prepare the data and biospecimens for use in research since the IOM began its AFHS Assets Research Program. However, the time period for evaluating the use of the data and biospecimens for other purposes has been short, and owing to the level and length of funding this pilot effort could not have the impact of a more established research program.

The longitudinal nature of the AFHS—with its extended follow-up, high rates of retention, and repeat biological samples—provides a valuable opportunity for research beyond the original aims of the study. Unused biospecimens and already-collected medical records can be used to conduct research studies in a far faster and more cost-effective manner than those that require investigators to identify and assemble such materials from scratch. Potential new areas for the AFHS assets include study of the determinants of incidence or natural history of common conditions (for example, hypertension, diabetes, or obesity) as well as the correlates of health in aging.

As the research program moves forward, short- and long-term metrics will need to be developed to evaluate its reach, value, and success. Different metrics may be appropriate for the data and biospecimens.

FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS

The committee’s findings fall into two overarching categories: the scientific value of the AFHS data and biospecimens and the lessons learned in managing ac-

cess to the assets. These and the conclusions that flow from them are summarized in Box S-3 and explicated in Chapter 5.

When the Disposition of the Air Force Health Study report was published, it was presumed that a successful research program could be implemented, but there

was no way of knowing whether it would work as that committee had envisioned. That presumption has now been confirmed and the once-speculative potential of the program has been largely realized. The assets have generated continuous interest from researchers, as evidence by the more than 80 inquiries and requests between 2012 and 2014, something that is especially encouraging considering that it has not been possible to actively promote their availability until recently. Therefore, the committee concluded that it is possible to manage the AFHS assets and perform high-quality scientific research with them. Furthermore, it is feasible and advisable to maintain the AFHS data and biospecimens and make them available for continued use in research. However, while the committee is pleased that a broad spectrum of investigators is carrying out a variety of studies using the AFHS assets, it believes that the full potential of the assets has not come close to being realized.

The committee concludes that sustaining access to the AFHS biospecimens and data benefits the veterans community and the public at large, who will gain from the information derived from studies of the assets. It is too soon to know whether and which studies of the assets will yield information that will promote health and wellness in veterans or in the greater population, but the research performed to date has the potential to contribute to the current body of medical knowledge, especially the results of studies that are examining potential biomarkers of disease. This area of research has greatly advanced in recent years, allowing for studies that were not possible when the original AFHS was conducted. The combination of longitudinally collected data and biospecimens is well suited to biomarker research, which could advance the science of disease diagnosis and treatment.

Despite the fact that the AFHS is among the few long-term, prospective, epidemiologic studies that included longitudinally collected biospecimens, it has only recently been accessible to the broad scientific community for research. Therefore, there has been limited awareness and use of the assets for novel research. Publication of the results of currently ongoing research should help to address this problem, but a more concerted effort to raise the assets’ visibility is also needed. Any attempts to expand the number of researchers, though, will have to be accompanied by plans for how to fulfill requests for the assets and fund that work.

The congressionally directed transfer of the AFHS assets to the custodianship of the IOM has resulted in promising research that is yielding further benefits from the government’s approximately $143 million investment in the original study. Many of the data files have now been transformed and documented in a manner that facilitates research by outside investigators, and sustaining access to them along with the biospecimens will advance knowledge regarding the determinants of health and wellness.

The value of the AFHS assets lies in their combination of longitudinal epidemiologic data and associated biospecimens and would be greatly diminished

if the participants’ serum, whole blood, urine, semen, and adipose tissue samples are not maintained in addition to their health data and other personal information. Both resources should thus be preserved, and the funding to maintain the resources must include support for both if the assets are to remain valuable for research.

Based on these findings and conclusions,

This must be done in a manner that continues to preserve the privacy of study participants and the security of their data.

The committee identified two options regarding the continued maintenance and management of the AFHS assets:

1. Retain custody of the assets within the IOM’s MFUA, either maintaining the current management structure—where MFUA curates the assets—or forming a partnership between the IOM and another organization to manage and distribute the data to researchers (as is presently done with the biospecimens); or
2. Transfer custody of the AFHS data and biospecimens to another organization.

The Disposition of the Air Force Health Study report identified several characteristics of a good custodian for the AFHS assets. Those characteristics included a demonstrated ability to properly house, secure, and manage both very large and complex data and the accompanying biospecimens (IOM, 2006). The committee finds that the IOM has met each of these criteria and has maintained and managed the AFHS assets in accordance with best practices.

MFUA has much experience in storing, administering, and disseminating epidemiologic data, and maintaining the current structure of the assets management program is a viable option. However, joining forces with an organization that administers databases or funds research as its primary mission may allow for better promotion and dissemination of the AFHS data and biospecimens for new and original research than could be accomplished by the IOM alone. This is not meant to cast doubt on the ability of the IOM to manage this program, but instead to suggest a possible alternative approach that combines the strengths of the IOM in scientific review with the institutional capabilities of a dedicated data archive. In this scenario, MFUA would retain custodianship and partner with an organization that has the infrastructure for storing, curating, and maintaining the electronic data, and experience in promoting the use of large datasets. Such a partnership would be similar to the one currently in place for the storage and maintenance of the biospecimens between the IOM and AFRL. Under such an arrangement, the IOM would retain custody of the assets and approve the type and amount of

information given to researchers through an advisory committee. The partnering organization would physically hold the assets; have responsibility for cleaning and applying quality control, managing, and maintaining them; and preparing and distributing data (and biospecimen samples) to researchers as directed by the IOM. Affiliating with a clearinghouse for data and biospecimens could significantly raise the visibility of the AFHS assets and spur their greater use.

The committee does not have any recommendations concerning partnering organizations, but it can offer some examples for consideration should this option be pursued. The National Institute on Aging sponsors the Chicago Core for Biomarkers in Population-Based Aging Research, which—among other activities—maintains a directory of longitudinal studies that include biomarker and personal health data that are made available to investigators. The National Heart, Lung, and Blood Institute’s Biologic Specimen and Data Repositories Information Coordinating Center serves a similar function for studies that hold assets relevant to the institute’s mission. And the Inter-university Consortium for Political and Social Research “stores, curates, and provides access to scientific data so others can reuse the data and validate research findings” (ICPSR, 2014). The organization’s vast collection of databases, which are primarily focused on health (including aging) and social science issues, includes some that address health questions and a small number with associated biospecimens. All are made available to interested investigators according to the rules set out by the data depositor. A thorough evaluation of partnering options would require discussions with candidate organizations to determine their willingness and capacity to take on curation of the AFHS data and a determination of the logistics and costs of preparing them for the relocation—tasks that are beyond the scope of this committee.

If Congress chooses to designate an alternate custodian to manage the AFHS data and biospecimens and to administer a research program, such a decision should be carefully considered and based on thorough comparison of the attributes and characteristics between the IOM and alternatives it evaluates. Many issues would have to be resolved before such a transfer could take place. A new custodian would need to exercise the same commitment to protecting the confidentiality of the assets as has been practiced to date; and to adhere to best practices, legal and regulatory requirements for the storage, maintenance, and dissemination of data and biospecimens. The cohort would have to consent to having responsibility for their study materials transferred to a new custodian, which based on previous experience would likely result in a further diminution of the cohort. Loss of additional cohort members will reduce the value of these assets for use in additional research because the sample size may not be adequate for many types of studies. Additionally, if the AFHS assets were transferred to a different custodian, their availability for continued use in research would likely suffer a setback because the new custodian would have to set up a new research program or integrate the AFHS into an existing one. It is unclear in what format the data would be transferred and whether the custodian would choose to create a new database using the original

text files or would try to incorporate the work MFUA has done (if the systems are compatible). Finally, a new custodian would need to find an appropriate and secure location to house the freezers in which the biospecimens are stored, form a relationship with AFRL, or transfer them to a different ultralow temperature storage facility. Funding would need to be provided to support the staff needed to prepare assets for the transfer and assure that it was successfully completed.

No matter who serves as custodian of the AFHS assets, a multiyear commitment to funding this organization is highly desirable as this would permit the long-term planning and sustaining of the infrastructure needed to conduct an effective assets dissemination program.

To derive the maximum value from research conducted on the assets, steps should be taken to make sure the knowledge developed from them is widely disseminated through peer-reviewed publications and other professional venues and integrated into the database for subsequent use by other investigators. Data use agreements with investigators should continue to require that newly developed data be returned to the custodian, with a reasonable amount of time allotted for publications to first be generated. After these data are integrated, their availability should be promoted. When investigators establish that the biospecimens are amenable to analysis by particular assays, this information should be made generally available so other potential researchers can factor it into their plans.

Finally, the committee believes it important to increase the breadth of scientific disciplines that are aware of and use the AFHS assets. These data and biospecimens have been and continue to be used to make important contributions to the understanding of the toxicologic mechanisms and health impacts of exposure to herbicides and their contaminants. However, there are many additional opportunities to learn from these assets beyond the purpose of their initial collection or to use technology and science that had yet to be developed when the original study ended. Given the rapid development of new analysis techniques and instrument technologies; assay methods with improved analytical sensitivity and specificity; and an abundance of existing proteomic, metabolomic, and genetic methods that can be applied to specimens and data from the AFHS, the potential value and utility of the AFHS specimens is far greater than what was originally imagined at the beginning of the study. It will be up to the custodian to identify new areas of research and to find ways to reach the people who conduct it so they can start taking advantage of this rare and valuable resource.

REFERENCES

ICPSR (Inter-university Consortium for Political and Social Research). 2014. Elements of a public access plan for scientific data. ICSPR data management and curation. http://www.icpsr.umich.edu/icpsrweb/content/datamanagement/ostp.html (accessed September 22, 2014).

IOM (Institute of Medicine). 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press.