Options and Recommendations for Further Study of the AFHS Data Assets
This final chapter of the report draws on the material presented previously to draw conclusions and recommendations regarding the disposition of the medical records, other study data, and laboratory specimens collected in the course of the Air Force Health Study (AFHS) after its currently scheduled termination date. The charge to the committee set forth a set of interrelated questions to be addressed in relation to future research using the AFHS data assets: in brief, whether—and if so in what form—the study should be extended, whether the data assets should be made available for independent research, and whether—and if so, in what form—independent oversight of these activities should be provided. The committee was also asked to evaluate the potential value and relevance of further research, and its potential cost. Assessing the potential value and relevance of future research is integral to the question of whether there is scientific merit to retaining and maintaining the data assets—this was addressed in Chapter 5. The remaining issues are dealt with here.
In answering these questions, the committee took a broad view of what constituted extension of the AFHS. It thus considered a number of options for the future of the AFHS data assets, including rendering the assets to the National Archives, dissemination of the existing assets by a research entity, continuation of data collection through publicly available sources or from the study subjects, and the extension of the AFHS in its current form.
DISPOSITION OF THE AFHS NONELECTRONIC DATA ASSETS
Hard Copy Records
The AFHS’s collection of hard copy originals of cycle physical exam reports and completed questionnaires; the subject’ medical, military administrative, and vital status records; research reference materials; and copies of the study’s reports and papers take up ~5,350 cubic feet of records storage systems space (AFHS, 2005b). All have been scanned and the images1 stored in electronic files in Portable Document Format (PDF).
The two primary considerations in evaluating the disposition of the hard copy records are compliance with the Federal Records Act and retention for further research purposes. These are addressed below.
Compliance with Records Retention Requirements
The U.S. Air Force (USAF) has regulations (termed instructions) defining records management responsibilities (USAF, 2003) and the proper disposition of records (USAF, 1994). The latter document directs that no records be disposed of “without the specific authority of the Archivist of the United States” (§ 1.1.1) and indicates that “valuable research records” are generally sent to the Archive’s Washington National Records Center for evaluation and either transfer to permanent storage or destruction (§ 188.8.131.52).
A threshold issue is thus whether any of the resources of the AFHS are subject to the requirements of the Federal Records Act, which requires agencies to “make and preserve records containing adequate and proper documentation of the … decisions, procedures, and essential transactions of the agency … designed to furnish the information necessary to protect the legal and financial rights of the Government and of persons directly affected by the agency’s activities” (44 USC § 3101). As defined by the Act, records include the following:
All books, papers, maps, photographs, machine-readable materials, or other documentary materials, regardless of physical form or characteristics, made or received by an agency of the United States Government under Federal law or in connection with the transaction of public business and preserved or appropriate for preservation by that agency or its legitimate successor as evidence of the organization, functions, policies, decisions, procedures, operations, or other activities of the Government or because of the informational value of data in them. (44 USC § 3301)
Using this definition, the biologic specimens collected during the AFHS are not subject to the Act and can be handled pursuant to the recommendations of-
fered later in this chapter. Because the findings of the AFHS have been a basis for certain disability determinations,2 an argument can be made that the data and supporting documentary materials created during the study (the medical records) are covered by the Act.
If these resources are records within the statutory definition, the National Archivist must determine whether they “have sufficient administrative, legal, research, or other value to warrant their continued preservation by the Government” (44 USC § 3303a). If not, and the vast majority of materials are not judged worthy of retention, the Archivist may dispose of them following notice in the Federal Register and opportunity to comment. Separately, the AFHS must meet other applicable Department of Defense (DOD) and USAF records retention and disposal requirements.
In the event that the Archivist concludes that the data and supporting documentary materials are records that should be retained, either the original hard copy documents or the PDF copies could be stored (NARA, 2006). Documents stored in the National Archives3 are subject to the requirements of the Federal Privacy Act of 1974, discussed below, as well as all the protections that were provided in the research protocol (36 CFR § 1228.274).
Committing the records to the National Archives would not preclude using them for research in the future. The Archivist can—again, subject to Privacy Act requirements—make the PDFs, other electronic files, and the hard copy documents available to researchers at one of their facilities or via the World Wide Web. Alternatively, the Archivist can place the materials with another entity within or outside the federal government (44 USC § 2107(3)). The Federal Records Act does not preclude additional copies of the dataset being placed with, used by, or managed by other entities.
Retention for Further Research Purposes
The committee believes the major obstacles to retaining the AFHS hard copy records are the costs to securely store and manage the paper and the possibility that these records may be improperly disclosed to third persons. The committee has not explicitly estimated costs for hard copy records storage, as this varies considerably by location. Further, assuming that the scanned images are of acceptable quality and that sufficient electronic backup procedures will be established to ensure the integrity of these electronic records, the committee does not
believe that it is necessary to retain hard copy records in order to conduct further research on the AFHS cohort. Modern privacy concerns suggest secure destruction of unnecessary medical records held by government bodies.
Recommendations Regarding the AFHS Hard Copy Records
Given the legal, regulatory, and logistic considerations discussed above, the committee recommends the following:
All of the hard copy originals of AFHS documents that have been saved in electronic form should be destroyed unless the National Archivist concludes that these records must be maintained or they are subject to other records retention requirements. No matter what decision is made by the National Archives regarding the retention of the records produced during the AFHS, a separate complete set of electronic copies of these records should be kept for possible placement with another custodian.
These recommendations are predicated on the assumption that the electronic images (PDFs) accurately represent the hard copy records. The committee was informed that the PDF files were subjected to quality control checks for readability, and that special attention was given to poor quality originals4 to try to enhance the scanned images (J. Robinson, Air Force Health Study, personal communication, January 10, 2006).
Facilitating Future Use of Other Nonelectronic Assets
The committee’s interim letter report (IOM, 2005a) offered several recommendations for organizing and documenting the serum, whole blood, urine, and semen specimens collected by the AFHS that would facilitate their future use. These recommendations are reiterated in Chapter 4 of this report.
There are three other components of the AFHS data collection that are neither in traditional paper nor electronic form: the electrocardiogram (ECG) strips, X-ray films, and Super-VHS (SVHS) video tapes collected during the cycle exams. If there is to be further study of the AFHS data assets, then the committee believes that consideration should be given to taking additional steps to render these assets in a form and format that facilitates their use in the future.
ECG Strips and X-Ray Images
As Chapter 3 notes, 12-lead, scalar, resting ECGs were obtained from subjects during all six physical exam cycles. The ECGs were evaluated and informa-
tion regarding various parameters5 and evidence and type of prior myocardial infarction were coded and placed into the electronic database. There are also over 15,000 X rays, primarily chest films captured during Cycles 2–6.
Chest X rays are objective evidence of lung pathology (at least by one measure), and ECGs serve the analogous function for cardiovascular pathology. Both of these could be important endpoints for herbicide or dioxin exposure, and both are likely to show findings well in advance of symptoms or medical diagnoses. Because these measures are largely standardized, in the sense that chest X rays and ECGs are taken in more or less the same way for everyone and have been for decades, they provide a potentially valuable resource defining preclinical health endpoints that may relate to subjects’ exposures. The serial nature of these data provides critical time-point information and allows for the analysis of changes over the 20 years in which data were taken. It also lessens concerns about confounding from intercurrent disease that might affect one cycle of measurements. The X-ray films and ECGs are thus valuable components of the database.
The major obstacles to retaining these materials are the costs to index and store them and the possibility that these records may be inappropriately disclosed to third persons. Means exist for converting paper ECGs to digital format (Badilini et al., 2005; Moody, 2005) but the technologies are not widespread, and the committee cannot offer any observations on their utility or costs. The X-ray films could be housed in a repository, but the committee believes it makes more sense to convert them to digital format: this will allow them to be more compactly stored and more easily made available for research purposes. Conversion is a mature and widely available technology, and the committee estimates that the labor and materials cost to digitize the X-ray films is on the order of $35,000.6 The cost of proper disposal of the original films may be mitigated through silver recovery.
The committee thus recommends that:
All electrocardiogram strips collected in the course of the AFHS should be retained; their documentation should be reviewed and, if needed, supplemented to ensure easy retrieval.
All X-ray films collected in the course of the AFHS should be digitized with acceptable quality control, this resource properly documented, and thereafter the original films be disposed of according to standard practices. The digitized records should be retained and handled in accor-
dance with the recommendations for the disposition of the AFHS data assets.
SVHS Video Tapes
There are 3,074 Super-VHS (SVHS) format video tapes in the AFHS data collection, comprising high-resolution images of subjects’ teeth taken during the Cycle 4 and 5 exams. The tapes were made as part of a National Institute of Dental and Craniofacial Research (NIDCR) adjunct to the study examining the association between exposure to elemental mercury via dental amalgams and measures of neurologic function (Kingman et al., 2005).
The major obstacles to retaining these records are, again, the costs to index and store them and the possibility that any personal information on the tapes might be disclosed to third persons. The committee does not have any suggestions for future research employing the videos but understands that such material, in combination with other data on the subjects, can be useful in oral epidemiology studies.
As this data asset was gathered under a contract with NIDCR and would be of primary interest to the oral epidemiology community, the committee suggests that the NIDCR be consulted on whether the tapes can be usefully exploited by the research community. If the decision is made to retain them, then their usefulness will depend on their linkage to the rest of the AFHS data assets, and it thus makes sense for them to be a part of the collection. In this circumstance, the SVHS tapes—which are in a little-used and largely-obsolete format—should be digitized and written to a medium such as DVD for ease of long-term storage. The cost of this would be ~$50,000, based on $15/tape for the conversion. Additional costs would be incurred in documenting and indexing the materials.
The committee therefore recommends that:
The AFHS should consult with the National Institute of Dental and Craniofacial Research on whether the video tapes of subjects’ teeth collected in the course of the study have future research value. If the tapes have value for future research, they should be digitized with appropriate quality control, written to an acceptable long-term storage medium, properly documented, and thereafter the original tapes be disposed of according to standard practices. The digitized records, if created, should be retained and handled in accordance with the recommendations for the disposition of the AFHS data assets.
Concluding Remarks Concerning the AFHS Nonelectronic Data Assets
In summary, the committee believes that the (nonbiologic) data assets of the AFHS that are not already in electronic form should be converted to this form
where a mature technology exists to do so and where the assets have future research value. Federal regulations addressing the preparation of electronic records for transmittal to the National Archives (36 C.F.R. § 1228.270) contain specific information about file formats and media that are appropriate for long-term storage. These assets must be stored in a manner that ensures their integrity and security, and protects the privacy of study subjects.
ALTERNATIVES FOR THE FUTURE OF THE AFHS DATA ASSETS
This section addresses two closely interrelated issues: the alternatives for administering the AFHS data assets and the parameters of future research using those assets. Five alternatives were identified for administering the assets after the currently scheduled termination date of the study in September 2006. The committee’s conclusions on the preferred means for carrying out future research on the assets and the scope of that work—including potential future data gathering—are in turn driven by their consideration of these alternatives.
Alternatives for Administering the AFHS Data Assets
Render the Data Assets to the National Archives for Evaluation and Possible Retention
As noted above, federal law and USAF regulations require that the National Archives make a determination of whether it will retain the data collected in the course of the AFHS. Rendering the assets to the Archives is thus the default option.
In this alternative, any further research on the assets would be dependent on the Archives deciding to preserve the data and make them available to the public—the latter decision subject to applicable privacy and other laws. It could choose to make the data accessible as it has for other epidemiologic datasets in its collection such as the Hill Air Force Base Study Files (NARA, 2000) which includes electronically encoded information on the health status of persons whose job at the base exposed them to hazardous substances and potential diseases (Blair et al., 1998). The Archives also holds data from the Vietnam Experience Study (VES), another study that included a medical examination, laboratory tests, and a psychologic evaluation of a cohort of Vietnam veterans. However, the Archives website indicates, without further explanation, that the VES records cannot be released (NARA, 2005).
Privacy considerations might lead to a decision to restrict access to the AFHS data for an extended time period—possibly 75 years or more—intended to ensure that all study subjects are deceased before information on them is made public. Work on any publicly available materials would need to be done without any research support to investigators as the Archives does not provide this service.
The Archives does not maintain biospecimens. A 2001 GAO congressional briefing (GAO, 2001) mentioned that the AFHS was considering transmitting biospecimens to the Armed Forces Institute of Pathology (AFIP), but it is not known whether this option was actively pursued or whether the AFIP would have an interest in the samples.7 The National Archives sometimes chooses to manage materials through disposal by donation, in which case they would be passed on to one or more entities that would assume responsibility for them. The data assets would then presumably be handled in accordance with one of the alternatives below.
This option is separate from the others discussed in this section because it would involve no action on the part of the Congress and no additional funding. The National Archives already has the mission to evaluate—and where appropriate to preserve and make publicly available—documents and materials created in the course of business conducted by the United States federal government. It does not, however, have exclusive rights to the data. No matter what the Archives decides, copies of the data can be made available through other channels.
Identify or Establish a Research Entity for Dissemination of Existing Data Assets
This alternative would require a research entity with the funding and mission to carry out responsible management of the assets. Management responsibilities would include the ability to securely store materials, to conduct or manage the appropriate review of requests for data access, and ensure that subjects’ privacy was maintained. It could also include aiding investigators in understanding and exploiting the assets, collaborating with outside investigators, and preparing custom data sets for analysis by those researchers.
Specimens could be disposed of, maintained by the research entity, or stored by a separate entity. It should be noted, however, that the specimens have little value without the detailed medical and questionnaire data collected. Access and linkage to subjects’ data are thus necessary components to the retention of the specimens.
Identify or Establish a Research Entity to Continue Passive Data Collection on AFHS Subjects
Under this alternative, the activities described above would be expanded to include the collection of data on the AFHS morbidity or mortality cohort through publicly available sources such as the National Death Index. Such work could
take place under one or both of two circumstances. It could be part of an explicit research project conducted by the entity holding the existing data assets. Alternatively or additionally, one-time studies could be pursued by outside investigators.
If the entity holding the data assets were to carry out this work, there would be the need for a specific research plan with a data manager or principal investigator and some assurance of research funding for the period covered by the plan. An outside investigator could carry out the same work, although there would be no assurance that data would be collected systematically or consistently over time.
Identify or Establish a Research Entity to Maintain Contact with the AFHS Subjects and Conduct or Facilitate Further Active Data Collection
This alternative would extend the passive data collection option above to also encompass active following of and contact with AFHS cohort participants. Active administration of an epidemiologic cohort entails far more effort and cost than the previously identified options. It would require regular communication with study subjects to ensure that contact information remained current and to ensure that they were vested members of the research team.
Active data collection could take many forms, including questionnaires seeking self-reported health or sociodemographic data, or ascertaining vital status from all or parts of the cohort; as well as conducting limited physical examinations of subjects. New tests results could be obtained and medical imagery or specimens could be collected. Data gathering could be accomplished through outside investigator initiatives or through an explicit research plan carried out by the entity responsible for holding the assets.
Extend the AFHS
Extension of the AFHS would entail a decision by Congress to provide funds to continue the administration of periodic, extensive data and biospecimen gathering through cohort-wide physical examinations and questionnaires. Support for a dedicated staff to maintain contact with the cohort and manage and analyze these data assets would also be required. This alternative could be accomplished with the existing AFHS infrastructure or by assigning responsibility and funding to some other entity.
Parameters of Future Research on the AFHS Data Assets
Means of Carrying out Future Research on the Data Assets
There are two means of carrying out any of the research options listed above: through the work of a dedicated research staff, as the AFHS is currently conducted; or via a custodian that makes the assets available to independent research-
ers. The committee believes that the second of these options is more desirable because it taps the creativity, expertise, and motivation of the entire research community to pursue promising applications. This custodian should not act as a passive repository of the data but should play an active role in fostering its use. Such activities should at minimum include collaboration with outside researchers to ensure the assets are used effectively and with proper respect for the participants. Depending on the scope of future research, the custodian’s responsibilities could also include the preparation of restricted datasets or managing interactions between researchers and the study subjects for the collection of new data. Work done on behalf of outside investigators should be compensated, of course—a cost that these parties can factor into their requests for research support. In addition to facilitating the work of others, the persons responsible for managing the assets may also seek funding for their own research on them.
Scope of Future Research on the Data Assets
Developing a future research agenda or setting research priorities for the AFHS data assets is beyond the charge of the committee. However, it is possible to talk about the scope of such work in general terms.
In Chapter 5, the committee indicated that while AFHS analyses focused on the effects of herbicide or dioxin exposure, data were collected on a wide range of potential influences on disease and health status, and that a number of outcomes not addressed in the AFHS reports could potentially be studied with them. Given the nature of the cohort, all studies of the data assets are arguably studies of veterans’ health. It may, thus, be more appropriate to view the range of studies possible with the data as a function of how closely they conform to the original intent of the AFHS. Potential studies could be classified, for example, by whether they address the health consequences of wartime exposure to herbicides or dioxin, service in Vietnam, service in the military during the Vietnam era, aging in males, or general health and well-being. A less specific construction might define the Cycle 6 consent form term military health and add a category for all other studies.
Depending on the objective of the specific investigation, the AFHS’s division of the cohort into Ranch Hand and comparison subjects might or might not be relevant—research might combine the two or only use one of the subcohorts. Other studies might need to identify a different comparison cohort because all of the subjects were in-theater veterans. Researchers conducting work under one of these rubrics would, of course, need to factor the relevant limitations of the cohort.
The committee believes that the issues of military and veterans’ health should be paramount in future research but that other applications are also appropriate. Taking a broader view of applications for AFHS data assets will allow the study to generate results that could potentially inform a greater range of VA compensation and health delivery issues—not just those related to wartime exposure to
herbicides. It may also allow a better understanding of health issues that can best be explored in a population for whom detailed longitudinal data are available. Other studies using cohorts of veterans have taken this broader view and done so in a manner that respects the study participants. The Normative Aging Study, for example, has recently addressed the relationship between lead exposure and changes in cognition (Weisskopf et al., 2004) and the effects of air pollution on heart rate variability (Park et al., 2005) while the Vietnam Era Twins (VET) Registry database has been used to examine the genetic and dietary influences on nephrolithiasis (Goldfarb et al., 2005) and the links between depression symptoms, hypertension, and heart disease (Scherrer et al., 2003).
The decision on the scope of future research is ultimately in the hands of the participants who contributed the data—their informed consents will define the span of the work. It is important, then, that the consent request clearly communicate the options and what research might flow from them—a topic that is addressed below.
Future Data Gathering
The AFHS’s current collection of data and specimens is rich and could be a source for studies for several years. However, there are also options for supplementing the collection. One of these is for the custodian to collect or facilitate the collection of data from publicly available sources. Chapter 5 and Appendix D discuss the possibility of expanding the study’s period of analysis through a mortality follow-up of the cohorts using the National Death Index and other data sources. Rough estimates presented in the appendix suggest that, even in analyses limited to the subjects who participated in one or more cycle exams, the AFHS cohort is large enough to detect associations of realistic magnitude in future mortality analyses of health outcomes of potential interest to Vietnam veterans. The information needed to do such work could be obtained for no more than a few thousand dollars.
A second, more detailed level of involvement is to engage in further data gathering from the participants. Questionnaires administered through the mail, over the phone, or even via the web could be used to obtain information from all or from subsets of the cohort. Third parties could be contracted to administer limited physical exams to selected participants via in-home visits, or centralized locations could be used in areas where there were concentrations of subjects.
The committee believes that there is merit is keeping open the possibility of further data gathering, allowing future investigators to consider and pursue the additional avenues of research. As indicated above, compiling publicly available data is relatively straightforward and inexpensive, and serious consideration should be given to pursuing this. It is unclear whether further active data gathering efforts will be practicable—this will depend on whether enough study partici-
pants consent to be contacted to make this work worthwhile. The committee already recommends that the future custodian develop and implement strategies for apprising the research subjects about the ways in which their information is used and the scientific discoveries that result. Continuing communication with study subjects will help ensure that up-to-date contact information is available for the cohort for use in any data collection activities.
Conclusions Regarding the Future of the AFHS Data Assets
Given the discussions and findings presented above, the committee has reached the following conclusion:
It is advisable to extend the study of the AFHS assets by making the database and associated biospecimen collection available for study via a custodian. This custodian should take an active role in fostering research on the assets.
The committee is thus not recommending that the AFHS be extended in its current form as a research study characterized by periodic, cohort-wide data and biospecimen collection, and analysis by a dedicated team of researchers. Instead, the committee believes that the present data assets should be made available to the whole of the research community so that its collective creativity, expertise, and motivation can be tapped. This should be done in a manner that respects the privacy of the study subjects and the confidentiality of their data—a topic that is addressed later in this chapter.
The committee also concludes:
It is advisable to allow for the possibility of collecting additional data and specimens, work that could be conducted by the custodian or by independent researchers.
The committee does not explicitly endorse the collection of further morbidity or mortality data but believes that it is appropriate to leave the option open should both the need and support for such work be identified. Developing a future research agenda or setting research priorities is beyond the charge of the committee.
CHARACTERISTICS OF A GOOD CUSTODIAN OF THE AFHS DATA ASSETS
Any future custodian of the AFHS database and biospecimens needs to demonstrate the ability to properly house and manage these assets. It should have the capacity for data management, security, and backup data storage of very large and complex databases. For biospecimens, it should be able to show that these would be stored in appropriate conditions in a secure location. Persons staffing these functions must be trained to understand the importance of privacy, and
protocols must be in place to assure compliance with all relevant legal and ethical requirements.
The following sections address the technical; ethical, legal and social issues (ELSI); and other characteristics of a good custodian.
Technical Characteristics of a Good Custodian
A good future custodian of the AFHS research materials must be able to satisfy several operational requirements related to the supervision of and access to the data and biologic materials.
Data are only useful if used, and investigators are far less likely to pursue research on materials that present high barriers to access. The interim letter report (IOM, 2005a) offered several recommendations for organizing and documenting the AFHS medical records and other study data in ways that facilitates their management. If these are implemented, they will significantly ease the job of any custodian to supervise the data and share it with others.
The database currently resides on two servers—an IBM 580 (Kiowa) and a Compaq ProLiant ML370. Data take up ~525 GB of space on the machines, including operating system and backup files. A new custodian will need to have comparable hardware to store, access, and back up the files. These physical requirements are not unusual or remarkable, and the committee does not believe there is a need to offer specific recommendations regarding them. There are also, however, related considerations that pertain to maintaining the security and privacy of the data. These are addressed below in the discussion of ethical, legal, and related considerations.
The utility of the AFHS biospecimens in future research is influenced in part by the availability of evidence that they are being maintained in a manner consistent with current laboratory best practices. At present, they are contained in 21 Revco ultralow temperature freezers (model ULT-2186-5A), each with 20.2 ft3 (572 liter) capacity; two additional freezers are kept as backup should one of the primary units fail.
The committee recommends that their future custodian either possess or demonstrate the ability to provide the following:
A secure facility for −70°C or colder freezers, with controlled access and redundant power supplies (e.g., backup generators). Approximately
425 ft3 of freezer capacity is required to contain the AFHS biospecimen collection
Established protocols for continuous monitoring of freezer function as well as other quality control/assurance practices for long-term specimen preservation, including appropriate internal audits
Appropriate local and remote alarm systems to ensure the preservation and integrity of specimens
Staff trained to respond to freezer breakdowns, power outages, or other emergencies at any hour
A plan detailing specimen access and residual return policies. This plan should clearly document the entire specimen access application process, including the application review process, decision-making criteria, specimen processing and shipping costs, dissemination of results, and final disposition of specimens.
The committee also believes that the future custodian will need a mechanism for assessing requests to access these finite resources. This is taken up in a section on the oversight of the future uses of the AFHS data assets below.
Ethical, Legal, and Other Characteristics of a Good Custodian
Although using medical information and biologic samples independently for research each raise ethical, legal, and social issues, the combination of both types of collections into what are now sometimes called biobanks is widely acknowledged to be particularly complex (Rothstein and Knoppers, 2005). Proper future management of the AFHS resources will thus pose challenges and it is important to understand not only the safeguards required by the law but also the additional protections warranted by ethical and policy considerations.
In its analysis of such issues, the committee drew upon a variety of perspectives, ranging from legal to ethical and prudential. Legal requirements, such as those of the federal Policy for the Protection of Human Subjects (Common Rule8) and the federal Privacy Act, are essential to the disposition of the AFHS assets. Additional privacy standards like the Freedom of Information Act and the Public Health Service Act provide additional guidance for the disclosure of specific information collected or maintained by the federal government. Ethical precepts both underlie legal rules and provide additional guidance regarding the conduct of research.
Issues Presented by Collections of Data and Biologic Samples
In 2005, the Committee on the Review of the National Immunization Program’s Research Procedures and Data Sharing Program of the Institute of Medicine reviewed mechanisms for sharing data with other investigators. These range from the creation of public use datasets, through the developments of restricted use agreements, to the establishment of limited access data enclaves (IOM, 2005d). As a general rule, in order to protect privacy and confidentiality, the greater the access to the public, the less information can be contained with the dataset. In other words, access is inversely related to utility for research. The immunization program review committee identified several common characteristics governing resource access and use in major data enclaves:
Researchers must be specific about the variables needed.
Researchers must justify the need for and relevance of confidential data and state why public data will not suffice.
Researchers must provide a plan to protect the privacy of the individually identifiable information in the dataset.
Final proposals must be reviewed for feasibility, relevance to the purpose or mission of the organization, and risk of disclosure of confidential information.
A responsible person or board oversees a defined proposal review process.
Institutional Review Board (IRB) approval is required.
Researchers access data at designated data enclaves.
Only minimal data analysis assistance, if any, is offered; limited technical assistance is available in the data center.
Disclosure review for all information taken out of the data enclave is required. (p. 57)
Although not entirely applicable to the current case, these characteristics point to a number of areas that warrant attention if the AFHS resources are to be continued to be used. These include protection of the data and oversight of use.
As Chapter 5 notes, any disposition of the resources of the AFHS must address the related, but distinct requirements of privacy, confidentiality, and security. There are a number of possible future custodians for the resources of the AFHS, including federal agencies, universities, and other nongovernmental research institutions. These entities are subject to different legal rules, the varying requirements of which may be relevant to the ultimate disposition of the AFHS.
A maze of laws affects the protection of privacy and confidentiality of health data held by the federal government for research purposes. These laws include the Freedom of Information Act (FOIA) of 1966, the federal Privacy Act of 1974, and specific provisions of the Public Health Service Act. FOIA (5 U.S.C. § 552 (1988)) requires federal agencies to disclose certain federal government records kept by the executive branch on written request, unless an exemption applies.
FOIA stipulates nine exemptions in which information can be withheld, including, in particular, requests for information from personnel, medical, and other files involving personal privacy. The government may completely withhold such information, or may release the information with any potential identifiers removed or redacted.
The Privacy Act (5 U.S.C. § 552(a) (1988)) applies to any information that is maintained by a federal agency in a system of records.9 The Privacy Act protects individual privacy by specifying conditions under which an individual’s health information can be disclosed without that individual’s consent. In all other situations, consent must be obtained before information can be disclosed. The Privacy Act also prohibits the maintenance of identifiable health information by a governmental agency that is not relevant to the agency’s purposes, and requires agencies to publish notice about each record system, describing its purposes and identifying disclosures outside the agency. The National Academies’ Institute of Medicine is also subject to these provisions when it manages large datasets that have been obtained from other federal agencies (Berkowitz and Santangelo, 1999; IOM, 2005c).
The Public Health Service Act (42 U.S.C.A. § 242) contains specific provisions that protect the privacy of research and other health data. Section 308(d) protects individuals’ privacy in research and nonresearch projects and protects institutions in research and nonresearch projects by authorizing the execution of assurances of confidentiality. Section 301(d) protects individuals’ privacy in research projects by authorizing the execution of certificates of confidentiality.10 In combination, these sections provide mechanisms through which public health service agencies can assure research participants and other individuals that the confidentiality of their health data will be protected by restricting others from accessing the data.
Some of the above laws act to protect information, while others permit or even mandate disclosure and use. Which ones apply to any particular collection of information depend to a significant degree on the identity of the custodian. For example, in discussions leading to the creation of the AFHS, USAF leadership vowed to make every effort to protect the participants’ information, relying on the Privacy Act (AFHS, 1982). At the same time, the USAF concluded that it was unable to promise absolute protection, recognizing the possibility of requests under FOIA, judicial and other subpoenas, and the risk that medical examinations might uncover conditions that posed a serious risk to the health of the public and would thus have to be reported to appropriate authorities. These sorts of disclo-
sures may be curtailed through protections like those available through the Public Health Service Act, although the custodian must take specific steps to seek these protections.
If the data were transferred in an identifiable format to a covered entity under the Health Insurance Portability and Accountability Act (HIPAA) (Pub. L. No. 104-191, 110 Stat. 1936 (1996)), such as an academic medical center performing covered functions, the privacy and security regulations of the HIPAA Privacy Rule may be implicated. The HIPAA Privacy Rule, which had a compliance date of April 14, 2003, for most covered entities, protects most individually identifiable health information that is created or received by a covered entity (a health plan, health care clearinghouse, or health care provider that conducts transactions electronically, or others performing covered functions) (Hodge, 2004). Covered entities are required to establish and adhere to privacy protections including notification of individuals regarding their privacy rights and the use and disclosure of their health information, the implementation of internal privacy policies, and the establishment of administrative, technical, and physical safeguards to protect identifiable health information.
In general, a covered entity may not disclose identifiable health information11 without individual written authorization outside of standard health care transactions. However, the Privacy Rule provides a few exceptions under which a covered entity may disclose such information. These include broad disclosures for public health purposes (CDC, 2003). The Privacy Rule also expressly excludes three types of research from its coverage: studies done in preparation for research so long as the protected health information is not removed from the institution and is necessary to develop the protocol; studies involving decedents so long as living individuals will not be studied (45 CFR § 164.512(i)); and research involving limited data sets, defined as those from which 16 of the 18 identifiers (listed in the Rule) have been removed, so long as the investigator executes a data use agreement (45 CFR § 164.514(e)(1)). The Privacy Rule also allows for waivers of written authorization for research purposes under standards that mimic Common Rule provisions (45 CFR § 164.512(i)). Thus, even under national privacy standards, identifiable health data may be shared for research purposes without individual informed consent under specific circumstances.
Geographic location of the new repository may be important because a number of states have enacted specific privacy laws. Most states have statutory provisions similar to FOIA and the federal Privacy Act that regulate the disclosure of specific health data. However, some states feature comprehensive privacy protections like those set forth in the HIPAA Privacy Rule (Hodge, 2004). States may also feature genetic-specific or other topical privacy laws that apply to tissue samples or genetic information contained in the electronic records (Gostin and
Hodge, 1999). Thus, the legal implications of any proposed repository would need to be analyzed individually according to federal, state, and even local regulations of the jurisdiction in which it would exist.
The future custodian must also adhere to current standards for data security practices. Modern security requirements developed by the Department of Health and Human Services (DHHS) pursuant to HIPAA (45 CFR Parts 160, 162, and 164) require that covered entities ensure the confidentiality, integrity, and availability of all electronic, identifiable health information; protect against any threats to the security or integrity of such information; and protect against any uses or disclosures of such information not permitted by the Privacy Rule. Specific security standards require development of appropriate electronic or physical safeguards to limit the potential for data theft, inadvertent disclosures, or unlawful acquisitions.
Different types of AFHS resources present different challenges to efforts to protect privacy and confidentiality and ensure security, although these challenges are not intrinsically different from other large-scale studies. The collection’s medical records on paper are interwoven with identifying information that would require considerable effort to remove. Even if such an effort were undertaken, the information would have to be removed piece-by-piece, inherently intruding to some extent on the subjects’ privacy. Paper, however, is difficult to search and it is relatively easy to protect such documents from outside intruders. As the committee noted above, modern privacy and security practices indicate that unneeded hard copy records should be disposed of in a manner that prevents the opportunity for unwarranted acquisitions, uses, or disclosures. It therefore recommends that the AFHS paper records be destroyed unless the National Archivist concludes they must be retained.
Electronic records have different liabilities and strengths. Greater effort is required to protect such resources from outside hacking, but much progress has been made in developing strategies to provide the necessary security.12 The committee noted in its discussion of procedural limitations to retaining the AFHS database (Chapter 3) that the exceptionally large amount of information available on each subject may make it possible for their identities to be determined through triangulation of the data with public sources. It is possible, though, to reduce the opportunity for this by only allowing limited datasets with one-time-use case numbers to be analyzed, or enforcing signed confidentiality agreements. In other circumstances, it may be appropriate not to disclose certain results on the ground that the cell size is so small that it increases the risk to privacy. The National
Academies reports Protecting Data Privacy in Health Services Research (IOM, 2000), Protecting Participants and Facilitating Social and Behavioral Sciences Research (NRC, 2003), and Expanding Access to Research Data: Reconciling Risks and Opportunities (NRC, 2005) address the topic of privacy protections in greater detail; Vaccine Safety Research, Data Access, and Public Trust (IOM, 2005d) contains an extended discussion of the use of enclaves to securely manage data access.
One of the strengths of the AFHS is the availability of biospecimens, which can have identifying information removed. Concerns that DNA is inherently identifiable are misplaced. Although each individual’s DNA sequence is unique, no one can be identified simply by examining their genetic makeup. To be identifiable, another known sequence must be available. Nonetheless, it is critical that the biospecimens and medical records be coded in a way that permits information from them to be combined after identifiers are removed.
Recommendations Regarding the Characteristics of a Future Custodian of the AFHS Assets
Given the ethical, legal, and social issue considerations discussed above, the committee recommends:
The future custodian of the resources of the AFHS should be able to demonstrate in advance its capacity to protect the privacy and security of the research participants and their data to the greatest extent possible. It should thereafter manage access to the electronic data resources of the AFHS in a manner that accomplishes these goals.
The custodian should comply with the information and publication restrictions in Section 308(d) of the Public Health Act and should seek a certificate of confidentiality under Section 301(d) of the Public Health Act.
CONSENT ISSUES REGARDING FUTURE USES OF THE AFHS DATA ASSETS
Respect for persons is the main ethical principle underlying the requirement of specific informed consent. This concept is particularly salient in the setting of the AFHS where thousands of research participants devoted a great deal of time and underwent significant inconvenience and discomfort to contribute to this study. Their wishes must be considered in deciding whether and how to use these data in future research. Thus, it is important to examine whether the existing consent obtained from the subjects provides an adequate foundation for the relocation and future uses of the AFHS data assets. In the last round of examinations for the AFHS (Cycle 6), the study participants were asked to sign a document
containing the following language regarding future use of information and biologic samples that they had provided (AFHS, 2005c):
PURPOSE OF THIS CONSENT DOCUMENT
During the period 1982 to 2002, you have participated in the Air Force Health Study. Since the study is projected to end in October 2006, we would like to know if your data and biologic samples may be used for future research. If you agree, your data and samples may be used for medical research. Research that may be done with your data and samples may not help you personally.
The greatest risk to you is the release of information from your study records. However, Privacy Act and laws and regulations governing health studies will protect your privacy.
ALTERNATIVES/IMPLICATIONS OF YOUR CHOICE
In the choices below, please indicate your decision regarding the use of your data. No matter what you decide, your decision will not affect your participation in the Air Force Health Study. If you decide now that your samples can [be] used for future research, you can change your mind at any time by contacting the Air Force at (210) 536-2600.
After 30 Sept. 2006, your data and biological samples may
[ ] Be used for Agent Orange research or other military health issues
[ ] Be used for research relating to only Agent Orange research (sic)
[ ] Not be used for any purpose
Almost all of the participants (94.1 percent of Ranch Hand subjects and 96.9 percent of comparison subjects; 95.8 percent overall) elected the first option, while 2.8 percent (4.1 percent of Ranch Hand subjects and 2 percent of comparison subjects) opted for Agent Orange research only (Michalek, 2005).
This language demonstrates laudable anticipation by the AFHS investigators and the IRB responsible for the study, but it also presents a number of challenges for the potential future uses discussed in this report.13 The most notable is that even the most permissive option addresses only use for research regarding Agent Orange and other military health issues. The term military health is nowhere defined, but even a generous reading probably would not include the full range of future investigations that might be conducted with the resources of the AFHS. Personnel associated with the study offered the opinion that many of the research participants would have chosen to give broader permission had that option been
available (Michalek, 2005), which suggests that the subjects, too, understood the consent document to be limited in its scope.
More generally, the last decade has seen an enormous amount of debate regarding the ethical and legal requirements of informed consent for the use of medical information and human biologic materials for research (Clayton et al., 1995; Knoppers et al., 1997; NBAC, 1999; Clayton, 2005; NCI, 2005a). Among the issues that are often addressed in current consent forms are what types of research may be conducted; who is going to hold and have access to these resources; what privacy and security protections are going to be used; under what conditions, if any, individuals may be recontacted either to obtain further consent or to be provided specific health-related results; and the possibility that intellectual property may be developed.14 None of these matters were addressed in any depth in the consent document that the AFHS research participants received regarding future use.
A topic that has generated a particularly large amount of controversy in recent years is whether research participants should be permitted to provide so-called blanket consent for future research uses. The committee feels that the application of the oversight and ELSI provisions recommended in this chapter provide sufficient protection to the interests of research participants to make such broad-based consent ethically permissible. Some members of the National Bioethics Advisory Commission, however, have opined that it was not possible to give meaningful consent for future unspecified uses (NBAC, 1999). Were the new custodian to be subject to the HIPAA Privacy Rule, an argument could be made that authorization for unspecified future research use would be forbidden as a matter of law (45 CFR § 164.508(f)). A number of commentators have urged that the Privacy Rule and the Common Rule be harmonized in this regard (Clayton, 2005; Rothstein and Knoppers, 2005). There is ongoing debate, however, about the reach of the HIPAA Privacy Rule in academic medical centers. These centers often include medical and public health components that perform what the Privacy Rule refers to as covered functions. A covered function is “any function the performance of which makes the performer a health plan, a health care provider, or a health care clearinghouse” (NIH, 2004)—providing and seeking electronic reimbursement for medical care, for example. To distinguish between their covered and non-covered (e.g., research) functions, most centers elect to become so-called hybrid entities under the Privacy Rule. The practical effect of this status is that only those designated parts of the center performing covered functions are subject to the Privacy Rule (45 C.F.R. § 164.504). Some confusion remains within medical centers as to what may constitute a covered function, and specifically who is responsible (or not) for adhering to the Privacy Rule. Although these issues
are in stages of resolution, such factors may be relevant in identifying a new custodian for the AFHS data assets.
In the course of the AFHS, information was collected about the health status of the research participants’ wives, partners, and children. Separate consent needs to be sought from these women and the children who have reached maturity for retaining this information. For children who are not yet capable of providing informed consent, their assent and parental permission should be obtained in accordance with subpart D of the Common Rule.
The committee believes that the optimal course is to obtain new consent for future research that reflects the changes that will occur in the control and possibly the use of the resources of the AFHS. Such an effort would provide a more solid basis for new investigations and honor the significant commitment these research participants have made to this project over the years.
The committee recognizes that timing is a serious problem. The AFHS is likely to end before a new custodian is identified, and participants may understandably be wary of renewing their consent before a new custodian is named. At the same time, it seems at best imprudent to let the current study expire and then have the new custodian approach the participants seemingly out of the blue. Recognizing that complexity can be confusing, the committee recommends the following two part process to ensure a smooth transfer:
Prior to the end of the study, the Air Force Health Study should notify the participants of the following:
The study, as currently constituted, is ending.
The assets will be transferred to a successor custodian, the characteristics of which will be described to the extent feasible.
The successor custodian will seek additional informed consent for future research involving identifiable data from the research participants, which will cover the topics enumerated below, prior to conducting any research.
This notification should offer the participants the opportunity to decide that information and specimens relating to them should not be transferred.
The successor custodian should obtain new informed consent that includes at least the following topics:
Notice of the types of participant data and samples that will be maintained by the custodian.
The procedural protections that will be provided for the data and specimens, including access policies, and oversight.
The specific privacy and security protections that will protect the data and specimens.
The types of studies that the participant is willing to have his data and specimens used for.
Whether the participant is willing to be approached in the future by investigators to seek participation in additional studies, including information regarding notice and recontact criteria.
Which individual study results the participant will and will not receive.
If health information regarding the wives and children of the AFHS research participants is made available for future research, consent, and where appropriate, parental permission and assent, must be sought from these individuals.
OVERSIGHT OF THE FUTURE USES OF THE AFHS DATA ASSETS
To comply with the Common Rule and ethical precepts, research projects must be scientifically sound: that is, designed so that they can achieve valid results. At the same time, projects should be designed so as to minimize intrusion on the interests of the research participants. Independent oversight of the conduct of a research study and the specific applications to which its data assets are put is a means of assuring that these principles are adhered to.
This section focuses on the committee’s charge to evaluate “[t]he advisability of providing independent oversight of the medical records, other study data, and laboratory specimens [and] the mechanism for providing such oversight.” The committee concludes that
Independent oversight of the medical records, other study data, and laboratory specimens collected in the course of the Air Force Health Study is advisable.
Indeed, such oversight is common in the conduct of major epidemiologic studies. The discussion that follows addresses three mechanisms for providing it, via an IRB, an advisory and oversight board, and communications with study’s subjects.
The Role of an Institutional Review Board
An IRB is “a specially constituted review body established or designated by an entity to protect the welfare of human subjects recruited to participate in biomedical or behavioral research” (OHRP, 1993). By the authority granted through the DHHS and Food and Drug Administration (FDA) Protection of Human Subjects regulations—45 CFR part 46 [HHS] and 21 CFR parts 50 and 56 [FDA]—IRBs can approve or reject any research activities involving human subjects that are conducted or funded by participating federal agencies. The AFHS has been
subject to DOD and USAF regulations regarding research on human subjects. These requirements,15 which parallel the civilian strictures, are under the aegis of the USAF Office of the Surgeon General’s Division of Biomedical Research and Regulatory Compliance (USAF, 2004). The IRB responsible for reviewing and approving AFHS activities is located in the Human Effectiveness Directorate of the Air Force Research Laboratory at Brooks City-Base in Texas.
The committee notes that future IRB review of research on the AFHS data assets is not guaranteed. According to recent guidance from the DHHS Office of Human Research Protections (OHRP), it would be possible to exclude research using the resources of the AFHS for studies beyond those initially contemplated in that project from IRB review so long as the resources were coded to limit the possibility of identification of subjects. Specifically, the guidance states that:
OHRP does not consider research involving only [emphasis original] coded private information or specimens to involve human subjects as defined under 45 CFR 46.102(f) if the following conditions are both met:
(1) the private information or specimens were not collected specifically for the currently proposed research project through an interaction or intervention with living individuals;
(2) the investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain because, for example:
(a) the key to decipher the code is destroyed before the research begins;
(b) the investigators and the holder of the key enter into an agreement prohibiting the release of the key to the investigators under any circumstances, until the individuals are deceased (note that the HHS regulations do not require the IRB to review and approve this agreement);
(c) there are IRB-approved written policies and operating procedures for a repository or data management center that prohibit the release of the key to the investigators under any circumstances, until the individuals are deceased; or
(d) there are other legal requirements prohibiting the release of the key to the investigators, until the individuals are deceased (OHRP, 2004).
Notwithstanding this guidance, which in some ways is more permissive than the requirements of HIPAA, the committee believes that review by an IRB must be required in order to honor the commitments made by these research partici-
pants and to ensure optimal use of these resources. The committee thus recommends that:
The successor custodian of the AFHS data and biospecimens should commit to review of future research involving the assets by an Institutional Review Board constituted in accordance with the Common Rule. This commitment should be a prerequisite to the transfer of the assets.
The Role of an Advisory and Oversight Board
Currently, the work of the AFHS is overseen by the Ranch Hand Advisory Committee16 (RHAC), a body constituted in January 1981 to provide independent monitoring and oversight to the epidemiologic studies by the USAF on the Ranch Hand personnel and related research (Coene, 2000). The committee is made up of nine members, one-third of who are nominated by veterans’ organizations as specified in the committee’s charter (NCTR-FDA, 2001). The mandate of the RHAC expires with the scheduled end of the AFHS in September 2006.
The resources of the AFHS study consist of vast quantities of clinical, lifestyle, and environmental data, as well as biospecimens collected over a 20-year period. The specimens, including repeated serum and urine collections, are both a unique and finite resource. It is increasingly common that advisory and oversight boards are constituted for complex studies where multiple scientists may wish to use the data, particularly those with finite biologic resources. Examples include the advisory bodies for the Nurses’ Health Study (NHS, 2002), Health Professionals Follow-up Study (HPFS, 2005), and the Multiethnic/Minority Cohort Study (MMCS, 2005).
An advisory and oversight board would provide several important benefits to the future custodian of the AFHS data assets. It would serve as a gatekeeper to help assure appropriate and scientifically valid use of the materials. Responsibilities in this arena would be to review and approve (or disapprove) study proposals submitted by investigators to utilize the preexisting resources or possibly to collect additional data or biologic samples from study participants. The board would make decisions not only regarding the feasibility, conformity to subjects’ consent, and scientific merit of particular proposals, but also, where use of the biologic samples is proposed, whether the quantity of sample to be used is appropriate given the nature of the questions being asked and the finite nature of the resource. For example, any single proposal that would lead to the depletion of a specific type of biologic sample would in all likelihood not be approved even if
the question posed was generally meritorious.17 Board members might also suggest additional areas of research that are important and to which the AFHS resources could potentially contribute, hence, helping to maximize the overall scientific contribution of the study.
There is no set formula for determining the proper size, membership, and operation of an advisory and oversight board.18 The committee suggests that the board’s membership should consist of 8–12 established scientists representing a range of appropriate disciplines. Such disciplines would include, for example, experts on herbicide exposure health effects, military health, epidemiology (including molecular epidemiology), biostatistics, and aging. Two lay members, study subjects if possible, should be included to provide insights from the participant and veteran perspectives. The committee does not believe that a federally administered advisory committee like the RHAC is necessary to obtain independent advice on the future conduct of studies of the AFHS data assets and cohort. Other ongoing studies of veterans’ health appear to operate in a scientifically sound and objective manner, and with respect for their subjects, without this form of oversight. The salient issue is that such a board operates in a manner that is transparent to the subjects and public, and that outside parties have the opportunity to present information for its consideration.
The committee recommends that:
The new custodian of the AFHS data and biospecimens should commit to constituting and maintaining an independent advisory and oversight board to provide guidance on the conduct of future research and to review and evaluate proposals for use of the data and biologic samples. This commitment should be a prerequisite to the transfer of the assets.
The Role of Communication with Study Subjects
The increasing emphasis on transparency in research reflects the interest of research participants and of the public at large in knowing what is being done and accomplished. The committee has already recommended several steps that promote this transparency. A central one is obtaining new consent from the participants. This will ensure that they know about and agree to the change in the custodian and to any expansion in the use of the AFHS data assets. The committee has also recommended that all future research protocols be reviewed at least by an
IRB and an independent advisory and oversight board, both of which will have public representation.
Additional steps are warranted as well. If a participant chooses to have further communications with the custodian, efforts should be made to inform him about new findings. Among the strategies that can be employed are sending each participant periodic newsletters, making presentations at meetings of or attended by these people, and creating a website with the newsletters as well as links to other information and research publications for those who are interested.
Ongoing communication with the research participants is important for another reason as well. Great controversy exists about whether to reveal individual research results to participants. Both participants and investigators often express interest in this, but research laboratory practices differ from those of clinical laboratories, and people often choose not to get results when the opportunity arises. Informing participants of general research results reconciles much of this tension by enabling the participants to decide with their clinicians about whether to undergo testing in the clinical setting.
Increasingly, custodians of medical information and biologic materials are establishing relationships with lay groups to increase the transparency of the research process and to recognize the interests of research participants in the outcomes of the research (Rothstein, 2005). Such groups can contribute to informing the research participants of new findings and, to that end, some of these custodians provide modest support for the lay bodies. The Coriell Institute for Medical Research, for example, provides up to $1,000 per year to the community advisory groups for the International HapMap Project, which have played a large role in educating their populations (International HapMap Consortium, 2004).
The committee recommends that:
The new custodian of the AFHS data and biospecimens should commit to developing and implementing strategies for apprising the research subjects about the ways in which their information is used and the scientific discoveries that result. This commitment should be a prerequisite to the transfer of the assets.
One of the primary sources of information on the AFHS is the website it maintains, which describes the study and provides links to or summaries of its reports, papers, presentations, testimony, and the like. This site is an important conduit for communication between the AFHS and its study subjects and the general public. The committee thus recommends that:
The AFHS website (http://www.brooks.af.mil/AFRL/HED/hedb/default.html) and associated pages, files, and linkages should be maintained by the USAF until such a time that its contents and the responsibility for managing such a site can be turned over to a custodian. After the turnover takes place, the committee recommends that the
USAF maintain a link to the successor site from the URL(s) of the AFHS website.
The Mechanism for Providing Independent Oversight of Future Research
The sections above thus recommend a three-pronged approach to providing independent oversight for future research using the AFHS data assets: the review of proposals for scientific merit and adherence to ethical, legal, and related considerations by an IRB and, separately, an advisory and oversight board. In addition, the committee recommends that steps be taken to ensure that the research is carried out in a manner transparent to study subjects, through systematic communication of research plans and results.
It is difficult to assess the cost of such oversight. Some entities that conduct research involving human subjects have essentially no-cost access to an IRB through their home institution. Universities do not typically charge nonprofit enterprises or academic researchers for this service. However, in other circumstances fees are assessed. These vary widely depending on several factors such as the location of the institution, if the submission is new or a renewal, or whether a full or expedited review is needed—and the committee cannot offer an estimate of the cost of implementing this recommendation. Investigators budget the cost of IRB review into their proposals where required.
Advisory and oversight boards also differ in their costs, depending on their size, the frequency of their meetings, and the logistics involved in convening them. The estimated annual operating cost of the RHAC, a body organized under the Federal Advisory Committees Act (Pub. L. 92-463) and subject to its requirements, was ~$106,000 in 2001 (NCTR-FDA, 2001). As already noted, the committee does not believe that such an expenditure is needed—or is desirable for budget reasons—in order to obtain independent advice and oversight. Some custodians may already maintain advisory and oversight boards that could take on this responsibility with the appropriate augmentation of their membership for a fraction of the cost of establishing a new body. Communications with study subjects can be done quite inexpensively and at the same time still result in the provision of large amounts of information.
The committee notes that some institutions impose oversight requirements additional to those discussed here: for example, approval of studies using biospecimens by a biologic safety committee.
OPTIONS FOR THE FUTURE MANAGEMENT OF THE AFHS DATA ASSETS
The committee considered seven possible alternatives for future access to and management of AFHS data assets. The alternatives, addressed below, are
based on the committee’s research into the range of entities administering large epidemiologic databases, workshop presentations, and their own experience as researchers.
Generally speaking, the committee believes that it would be desirable for the future custodian of the AFHS assets to have a demonstrated track record of publishing epidemiologic research on databases that contain large amounts of complex data and associated biospecimens. The organization should also be, or have the capability to be, highly visible to the research community, with a record of attracting interest in and funding for new research initiatives. The committee also believes that the AFHS assets will be best served by an entity that has the management and support of scientific research activities as a core function. An experienced entity will be better able to manage the complex logistic requirements for managing data flow and biospecimen inventories.
Utilize the National Archives Data Management and Distribution Mechanisms
The role of the National Archives in evaluating and possibly storing and disseminating the AFHS data was addressed earlier in this chapter in discussions of records retention requirements and alternatives for future research. The Archives will make its own determination of whether it will retain the data and make it available to researchers upon acquisition or at some point in the future. This determination does not affect the ability of another custodian to hold and disseminate the resources.
The primary advantages of having the National Archives as the custodian of the AFHS data are that they have the mission and—unlike any other potential custodian—the funding to act as a repository. The Archives manages access to other epidemiologic databases, and have legal mandates to protect privacy and provide security for the data. However, it is uncertain whether the Archives will decide to make AFHS data a part of their collection and, even if they do, make it available to the public. The Archives does not provide research support, so investigators would not have the benefit of a consulting or collaborative relationship with the custodian. There is no means for the National Archives to store biospecimens, and this asset would be lost.
Utilize the Existing AFHS Infrastructure
The AFHS has evaluated the parameters of a 5-year extension to the study and developed cost estimates for a number of alternatives, including conducting another full physical exam and analysis cycle; collecting and analyzing participant provided morbidity and mortality data only; performing a morbidity follow-up only; and acting as a data clearinghouse for the existing assets (AFHS, 2005a). The budget projections for these options varied widely. A 5-year continuation of
the study as it is presently constituted was anticipated to cost ~$47 million, over $24 million of which were exam-related expenses associated with an outside prime contractor (AFHS, 2005b). Acting as a clearinghouse for the dissemination of data and specimens was estimated to run ~$1.4 million per year in FY 2007 dollars. These expenses appear to reflect the use of dedicated staff and space—that is, 100% of time and overhead. No assumption of a home institution is listed, but this presumably would be at Brooks City-Base in San Antonio, Texas.
Current AFHS staff, if retained for such an extension, would clearly have an advantage over other potential custodians in terms of their familiarity with the data assets and perhaps their rapport with the study subjects. Extending the AFHS would also eliminate or at least simplify consent issues. However, the committee notes that the study has already lost its long-standing principal investigator and that further attrition is likely. The high estimated cost of extending the AFHS and the reported lack of interest by the USAF in conducting epidemiologic studies of veterans (RHAC, 2000) are other significant factors in considering this option.
Utilize DOD Epidemiologic Data Management and Distribution Mechanisms
The DOD and the individual military services conduct a number of epidemiologic studies of personnel and—in some circumstances—civilians involved in support functions. Although most of these address persons on active duty, there is at least one current DOD study other than AFHS that addresses postservice health: the Millennium Cohort Study (MCS), which is following both active duty and postservice health of Army, Navy, and USAF personnel for up to 21 years (MCS, 2005). The study is using questionnaires and linkages to supplemental medical and administrative information as their data-gathering instruments (Gray et al., 2002), one model for further data AFHS cohort data collection. The MCS is being conducted in collaboration with the VA.
AFHS is consistent with the mission of the DOD Center for Deployment Health Research, whose portfolio includes studies of the effects of exposure to pesticides, oil well smoke, and nerve agents (Naval Health Research Center, 2005). The DOD also has experience with large-scale, long-term biologic specimen storage and management. The Department of Defense Serum Repository maintains ~35,000,000 specimens, along with relevant demographic, occupational, and medical information (Army Medical Surveillance Activity, 2005). The AFIP National Pathology Repository “comprises written records and over 50 million microscopic slides, 30 million paraffin tissue blocks, and 12 million preserved wet tissue specimens” (AFIP, 2005).
DOD thus appears to have the capacity to serve as a manager and analyst of the AFHS data assets, and—separately or in addition—function as a repository for the specimens. Debatably, maintenance of these resources falls under the Department’s obligation to understand the health consequences of military ser-
vice. As noted above, though, the USAF has not expressed an interest in continuing to serve as custodian, and the DOD’s focus is on those currently in its ranks rather than veterans populations.
Utilize VA or VA-Affiliated Epidemiologic Data Management and Distribution Mechanisms
The U.S. Department of Veterans Affairs (VA) mission—first articulated by Abraham Lincoln during his second inaugural address—is “[t]o care for him who shall have borne the battle and for his widow and his orphan” (VA, 2005b). In partial fulfillment of that mission, the VA carries out or funds a number of epidemiologic studies of veterans’ health and well-being. These include19 an ongoing examination of the health of members of the Army Chemical Corps who were responsible for ground-based herbicide handling and spraying during the Vietnam War (Kang et al., 2001).
Studies are conducted both in-house and by collaborators based in other institutions. In-house research is carried out by the Environmental Epidemiology Service. The service, among other activities, does the following:
conducts health surveillance of … Vietnam veterans and or other veterans exposed to environmental hazards, i.e., phenoxy herbicides … [and] creates and maintains unique databases which may lend themselves to research of veterans and promote their use in collaboration with other interested researchers. (VA, 2003)
The VA also maintains three Epidemiologic Research and Information Centers (ERICs) under their Cooperative Studies Program (CSP) whose primary mission is “to enhance VA health care delivery by promoting VA-based population research and to convert those results into a format that [Veterans Health Administration] providers and administrators can apply to improve patient care” (VA, 2005a). Two of the centers20—the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) and the Seattle Epidemiologic Research and Information Center (Seattle ERIC)—manage data assets that are in some respects similar to AFHS’s and make these assets available to independent, outside researchers under controlled circumstances. They are described below.
Appendix C cites and summarizes VA epidemiologic studies of Vietnam veterans that were reviewed in the Institute of Medicine’s Veterans and Agent Orange series of reports through Update 2004 (IOM, 2005e).
The other center is the Durham ERIC, which is affiliated with the Duke University School of Medicine and the University of North Carolina School of Public Health. A clinical epidemiology research center, clinical research pharmacy, and health economics resource center are also a part of the CSP (VA, 2005a).
MAVERIC is a collaboration between the CSP, the VA Boston health care system, and the Boston University and Harvard University schools of medicine and public health. It is the home of the VA Normative Aging Study, a continuing longitudinal investigation of the biomedical and psychosocial parameters of normal aging. The study cohort comprises 2,280 initially healthy men from the Boston, Massachusetts area, almost all of whom are veterans of World War II or the Korean War. The investigation began in 1963 and, over most of this time period, participants have been subject to exams every three years. Among the data collected over the course of the study are basic physical examination parameters, serum samples, anthropometric data, information on health behaviors (smoking, alcohol intake, and the like), sociodemographic data, and the results of a number of standardized psychosocial tests (Niaura, 2000). Approximately half of the cohort also participate in a companion investigation of oral health.
MAVERIC identifies itself as “a national resource to foster epidemiologic research in the VA” and “a clearinghouse for VA and non-VA databases [with] the expertise to harvest them for epidemiologic research projects” (MAVERIC, 2005a). Studies must be approved by an IRB and pass scientific review prior to initiation. A MAVERIC collaborator is required to be among the investigators in order to both assure the appropriate use of the data assets and to facilitate access to them. The facility’s core laboratory stores ~200,000 specimens from multiple collections—including transferred archived collections—comprising serum, plasma, urine, buffy coats, DNA, and immortalized cell lines (MAVERIC, 2005b). The laboratory also carries out DNA and RNA extraction, genotyping, and other analyses.
Over the more than 40 years of the Normative Aging Study, some 400 papers, book chapters, and books have been generated. A small amount of the study’s published research directly addresses military health issues—a study of combat exposure, post-traumatic stress disorder (PTSD) symptoms, and health behaviors as predictors of self-reported physical health, for example (Schnurr and Spiro, 1999). Most, though, deal with general health and aging issues that are relevant to veterans as aging males, including diabetes (Cassano et al., 1992; Lazarus et al., 1998) and coronary heart disease (Todaro et al., 2003; Scott et al., 2004).
Seattle ERIC—a collaboration between VA and the University of Washington—is the home of the Vietnam-Era Twins (VET) Registry (Seattle ERIC, 2005). The registry was conceived in the early 1980s as a means of evaluating the long-term effects of wartime service on Vietnam veterans’ health. Its cohort consists of 7,369 male–male twin pairs, both of whom served in the military during the Vietnam era (1965–1975) (Goldberg et al., 2002). There have
been five data collection initiatives that involved the entire cohort: the initial compilation of information from military records; a survey of combat exposure, physical and mental health, health-related behaviors, and demographic information in 1987; a cardiovascular survey conducted for NIH’s National Heart, Lung, and Blood Institute in 1990; a substance abuse and psychiatric disorders survey funded by the National Institute on Drug Abuse in 1993; and a two-page questionnaire focused on male health problems in 1999. There have also been several rounds of data collection using subsets of the cohort, some including clinical or laboratory testing. Since 2003, the registry has required all newly funded projects that involve in-person examinations to seek participants’ consent to draw blood and submit it to a DNA repository. They estimate that this effort will accumulate DNA specimens on approximately 1,000 twin pairs by 2008.
The registry database and cohort are in demand by researchers because of the value of twins in epidemiologic studies.21 Strict protocols are applied to protect participants’ privacy and confidentiality. Investigators seeking access must have their own source(s) of funding and their proposals reviewed by registry staff, a scientific advisory committee, and an IRB. No direct access to participants is allowed: if contact is required for data-gathering purposes, it must be managed through either the registry or an approved third-party contractor, and identifying information must be destroyed after use. Registry policy also requires a respite period between contacts with the participants. Collected data are integrated into the database for possible future use in other studies.
Several studies of Vietnam War combat exposure and PTSD have been conducted using the cohort (Koenen et al., 2003, 2005; Roy-Byrne et al., 2004). Other research has examined Vietnam veteran status and insomnia (McCarren et al., 1994), self-reported health status (Eisen et al., 1991), and alcohol consumption (Richards et al., 1990). A study of the health effects of wartime exposure to herbicides was contemplated in the 1980s but was not carried out (Goldberg et al., 2002). There have also been several studies related to more general male health and aging issues.
Issues Regarding VA and VA-Affiliated Epidemiologic Data Management and Distribution Mechanisms
The VA Epidemiologic Research and Information Centers—both the existing ERICs and the general ERIC concept—have several attributes that are desirable in a future custodian of the AFHS data assets. The centers have mechanisms in place for the collection, management, analysis, and dissemination of veterans’ health data. Funding mechanisms to support their work are established. As VA
collaborators, they have the mission to address veterans’ health issues; however, they do so outside of the functional control of that agency. MAVERIC and Seattle ERIC have track records for successfully maintaining subject’s privacy and confidentiality; managing contacts with their veterans cohorts; providing data to and collaborating with outside investigators; and yielding peer-reviewed scientific publications. Both maintain biospecimens as part of their collections.
However, it is uncertain whether the VA would want to establish a new ERIC or whether the existing centers would be interested in taking on responsibility for the AFHS data assets. Unless appropriate support—including start-up costs if a new center were to be established—was provided by Congress, transferring responsibility would divert funds from other, vital research efforts that are being carried out by the VA.
Utilize NIH/CDC Epidemiologic Data Management and Distribution Mechanisms
The National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC) and several institutes of the National Institutes of Health (NIH) manage access to epidemiologic data and specimen collections as part of their missions. NCHS’s National Health and Nutrition Examination Survey (NHANES), for example, is a large database of linked data and biospecimens (serum and urine) made available to researchers (NCHS, 2005a,b).
One means used to manage this dissemination is the Research Data Center22 (RDC) (NCHS, 2005c). The RDC was established “to provide a mechanism whereby researchers can access detailed data files in a secure environment, without jeopardizing the confidentiality of respondents” (CDC, 2004). It is a form of a data enclave. A 2005 IOM report summarized access procedures at such enclaves as follows:
To access data at a data enclave, researchers submit a proposal outlining their proposed study and describing why confidential or sensitive data not available in other ways are needed. Researchers conduct their analyses at the data enclave, and all output must be reviewed for the risk of disclosure before it can leave the data enclave. (IOM, 2005d)
Appendix E contains a table outlining the operation of five large enclaves in the NIH and elsewhere that is reproduced from that 2005 report. Included is information on how the application for data access is made, confidentiality protection measures, proposal review, costs and fees, and availability of assistance from program staff. This table illustrates the major considerations that go into a data dissemination program.
The AFHS cohort is entering an age range where adverse pulmonary, hepatic, immunologic, cognitive, neurologic, and other outcomes are becoming more common. The detailed information available on subjects’ health and personal histories over the past 20 years could thus potentially be of interest to several Institutes. Arguably, the National Institute of Aging (NIA) might be the most compatible of these, as its research programs include the broad range of issues related to “the mechanisms of aging, the processes of aging, aging and the nervous system, and aging in relation to health and disease” (NIA, 2005b). NIA maintains a list of databases of longitudinal studies (NIA, 2005a) and provides funding to researchers to study them.
The cohort’s past exposure to herbicides and experience as veterans does not present a barrier to studies of them via NIH or CDC research channels,23 and these bodies have considerable experience in managing, analyzing, and disseminating epidemiologic data and biologic specimens. They are subject to stringent statutory requirements for protecting participants’ privacy and confidentiality. The interest of the NIH or CDC in managing the AFHS is uncertain, though, because of the perception of it as a veterans database and the small and unrepresentative (of the general population) nature of the cohort. It is also unclear whether the AFHS subjects would be agreeable to having—as would be inevitable in such a transfer of custodianship—the focus of study of their data change from veterans’ health issues to aging, cancer outcomes, or other research areas. As was the case for the VA, transferring responsibility for the assets to the NIH or CDC would divert funding from other, vital research efforts unless appropriate support was provided by Congress.
Utilize the IOM Medical Follow-Up Agency
The IOM’s Medical Follow-up Agency (MFUA) conducts epidemiologic studies of military and veterans health under DOD, VA, and other federal sponsorship. MFUA focuses on records-based research—primarily retrospective cohort studies of morbidity outcomes and mortality. Studies are subject to a multi-layered review and oversight process. Proposals are subject to internal approval and IRB review; an advisory panel (drawn from a standing board of senior medical, epidemiology, and public health researchers) oversees the conduct of the major studies; and the final product(s) are subject to scientific review before publication. IOM maintains a web-based information outlet that provides summary information to the public on study conduct and allows comments to be submitted. During some studies, public meetings are conducted that collect information from
outside researchers and stakeholders. Veterans service organizations (VSOs) are advised of studies and results on an informal basis.
MFUA also maintains The Cohort Catalog, a collection of data on study populations of former military personnel (MFUA, 2005). The catalog comprised 48 cohorts as of December 2005 that range from the specific (Vietnam War battle-injured Marines who received blood transfusions, plus controls) to the general (all persons admitted to military hospitals from 1941 to 1944).24 Outside investigators wishing to analyze the data may only do so in collaboration with MFUA researchers, and studies are subject to the approvals, reviews, and oversight delineated above. MFUA does not maintain any biospecimens collections but collaborates with federal agencies and universities that do. One cohort in their catalog25 has an associated serum collection that is housed at an academic institution, and these assets have been jointly analyzed (Seeff et al., 2000).
Although it is not an agency of the federal government, MFUA has been granted some privileges that are typically available only to such entities. It is designated as a “routine user” of military medical and personnel records, allowing it more ready access to these materials. Additionally, MFUA operates an office at the National Personnel Records Center in St. Louis, Missouri, to facilitate research involving materials in the National Archives’ primary repository for service, health, and medical information on discharged and deceased veterans.
Established in 1946, MFUA has produced a number of National Academy of Sciences reports, and written or collaborated in over 460 papers published in the peer-reviewed scientific literature. Its early work consisted primarily of clinical follow-up studies of the aftereffects of injuries and diseases of World War II veterans. Later studies have a broader scope, and include recent reports and papers regarding veterans of other conflicts (Rollison et al., 2004; Wallin et al., 2004; Mathes et al., 2005), biowarfare agents countermeasures (IOM, 2004), and a long-running set of studies of health, behavior, and socioeconomic status of pairs of twins who served in the military (Gurland et al., 2004; Page et al., 2003) derived from data in their twin registry (IOM, 2005b).
Among the alternatives listed here, MFUA is the nongovernmental body with the longest history of veterans’ health research. It has proven track records of protecting participants’ privacy and confidentiality; managing, analyzing, and disseminating epidemiologic data; and maintaining channels of communication with stakeholders. However, MFUA does not store biologic specimens, so a home and
funding would need to be found for the AFHS collection if it were to be maintained. Because it does not have a federally appropriated or independent funding stream,26 MFUA could not take responsibility for the assets unless external support was provided.
Identify a New Custodian Through a Competitive Process
The above described options for future access to and management of AFHS data assets all involve designating an existing institution as either the custodian itself or as the parent body for a new custodian established under its aegis. However, one could alternatively open up the management of the data assets to a competitive process wherein universities, nonprofit or private research entities, research consortia, and the like could submit proposals. These would be evaluated according to announced criteria and the strongest candidate chosen to carry the work forward.
Such an approach would permit a high degree of control over the characteristics of the custodian. The request for proposals (RFP) could impose whatever requirements and constraints thought appropriate: for example, the qualifications of the data administrators, what types of research would be allowed, and how the subjects’ privacy and confidentiality would be protected.27 This approach would ensure that a motivated party with an explicit data management plan would assume responsibility. It would, though, require significant planning, time, and costs. A body would need to be designated and funded to write the RFP, circulate it, choose who would review responses, conduct the review, choose the custodian, and perhaps oversee the custodian’s operation. A multiyear commitment to supporting the custodian would likely be required in advance to attract candidates to apply. The cost of establishing a new body would likely exceed that of utilizing an already existing entity or means of management. And, the extended period between the end of the AFHS and the beginning of the new custodian’s responsibility might weaken the cohesiveness of the cohort and thus result in lowered participation rates.
OBSERVATIONS AND RECOMMENDATIONS REGARDING THE CHOICE OF A FUTURE CUSTODIAN
Decisions by the National Archives regarding the retention of the AFHS materials and their availability to the public under the Archives’ auspices are outside the scope of this study. Uncertainties concerning their actions, and their
inability to deal with biologic specimens and provide an infrastructure to facilitate research make the Archives an inappropriate choice as sole future custodian of the AFHS data. It should also be reiterated that the National Archives does not have exclusive rights to the data assets of the AFHS.
Thus, the committee recommended (above) that, no matter what decision is made by the National Archives regarding the retention of the records, a separate complete set of electronic copies of these records should be kept for possible placement with another custodian. Even if the data were to be made publicly available, the committee believes it is unlikely that their research potential would be realized if they were only available from a custodian that neither promoted their use nor supported analysis of them.
The committee found that the AFHS staff has properly maintained the data assets over the course of the study. However, it does not believe that continuation of the study under their custodianship is the best option. There is no assurance that the AFHS staff who are most knowledgeable about the data assets would be a part of a continuing effort and—even if they were—they do not have the experience in administrating a data dissemination effort28 that other potential custodians do. USAF has not indicated an interest in continuing the work, which addresses a population that is no longer on active duty and exposures that are unlikely to be an issue for future operations. Continuation of work on the cohort via other DOD epidemiologic research channels does not appear to be a strong candidate for these same reasons.
The committee believes that one viable option is to develop a competitive process to identify a new custodian and that institutions that have data enclaves or biobanks—and this includes many universities across the country—may be interested in such an opportunity. The committee is, however, concerned about the logistic difficulties involved in going forward with this process. Such an effort would require Congress—as a first step—to make a commitment to funding the search, designating who would be responsible for carrying it out, and presumably specifying what the parameters of the request for proposals would be. The committee believes that, even with the swiftest action and best intentions, that the effort could not be completed in less than a year and would likely take longer. Any extended gap between the end of the AFHS and the beginning of a new custodianship has the potential to weaken the bond between the subjects and the study, possibly making future work more problematic.
The National Center for Health Statistics of the CDC and the NIH have extensive infrastructures in place to manage the dissemination of epidemiologic data and biospecimens. Statutory constraints and agency practices would ensure that ethical, legal, and social issues in handling the AFHS data assets were taken into account. The major issue in the eyes of the committee is whether there is
interest in either side of an agency/subject relationship in going forward. For all of its positive attributes, the AFHS data assets remain a small and highly circumscribed sample, unrepresentative of the population at large. To be sure, there are other datasets that have similar limitations, but AFHS suffers from the two additional disadvantages. It was collected outside of the CDC or NIH, leaving it without a known internal advocate or natural home. And, the database describes a military population.
The committee notes anecdotally that there appears to be reluctance on the part of funding agencies outside of the DOD and VA to support research on military populations, even if that research addresses topics that do not relate directly to the military experience. This reluctance may well result in less interest in and support for future studies of the AFHS database than would otherwise be the case for a cohort for which such detailed information is available. Consent for any change in the primary focus of the study away from Vietnam service or military health engendered by a CDC/NIH custodianship29 would have to be sought beforehand, as the database would be of little use if a large number of subjects chose not to participate further. If the study subjects were comfortable with any focus change and if a champion for the data assets stepped forward, one of these agencies could be an appropriate home for the data assets.
The VA’s ERICs and IOM’s MFUA share several positive attributes. MAVERIC, Seattle ERIC, and MFUA all have prior experience in veterans’ health studies: collecting and storing epidemiologic data; disseminating it to independent researchers; fostering collaborations with those researchers; maintaining quality control over the studies that use their datasets; and publishing results in the peer-reviewed literature. All have military or veterans health issues as the central focus of their operations, but also conduct other types of studies with their data assets. To the committee’s knowledge, none has experienced a breach in their system of protecting subjects’ privacy and the security of their data. There are some differences among them. MAVERIC and Seattle ERIC manage biospecimen collections; MFUA cooperates with another institution that maintains a biospecimen collection related to one of their datasets. MFUA is a part of the independent, nongovernmental Institute of Medicine of the U.S. National Academy of Sciences; the ERICs are affiliated with universities and operate under the umbrella of the VA’s Cooperative Studies Program.
The committee believes the ERICs—either one of the existing centers or a new one created on the ERIC model—are good candidates for custodianship, and that the IOM’s MFUA is also a good candidate. These entities are not, however, without weaknesses.
Although the ERICs are not under the formal control of the VA, there could be stakeholder concerns with VA involvement with a study management mecha-
nism where the results involve compensation issues related to herbicide exposure, given the very sensitive nature of this topic among veterans. It is also unknown whether or how the AFHS data assets could be integrated into the existing ERICs or whether those entities would welcome the prospect. Establishing a new ERIC to administer the assets would entail start-up costs and uncertainties about the qualifications and experience of the administrators. A new entity would additionally have to establish an identity with funding sources and within the community of scholars.
Because MFUA is not a government entity, it cannot be instructed by the Congress or an agency to take responsibility for the AFHS data assets. Instead, a request would have to be made to and approved by the National Academy of Sciences. There would also be logistic challenges involved in assuming responsibility for the biospecimens as MFUA does not have direct access to a repository. Although management of the specimens could be contracted out to a commercial firm, this would be a relatively expensive option. The alternatives would be finding a collaborating institution willing and able to offer their services at a reduced fee, having a governmental body take responsibility for the specimens, or choosing not to retain them.
A common issue for these entities is a secure source of funding. The committee notes above that assigning responsibility for the assets to a component of the VA without a budget allocation would sap funds in a time of constrained resources, and that MFUA has no independent support that it could use to cover expenses. Cost issues in administrating the data and storing the biospecimens are addressed below.
The committee thus does not believe there is any clearly superior candidate(s) that it can recommend to be the future custodian of the AFHS data assets. The considerations listed above should inform the decision of what entity should take on this responsibility. The charge to the committee did not specify where the authority to make decisions regarding a new custodian will rest, and the committee has not made any assumptions regarding this. It believes that, no matter whom the decision maker is, that party needs to take action expeditiously. If a custodian is not identified prior to the scheduled end of the AFHS, the committee believes that it is incumbent on the USAF—as the custodian of the AFHS research materials—to properly preserve them until a decision is made on their disposition. This will entail expenses as the maintenance of the biospecimens requires a secure and continuously monitored facility and support personal that can respond to equipment failures. The medical records and other study data must also be securely stored.
As the discussion of options shows, there is no one ideal candidate to assume custodianship of the AFHS data assets. All of the alternatives have advantages and disadvantages, and all of the options could be made to work with the appropriate provision of funds, commitment on the part of the new custodian, and application of requirements on the management of the resources.
Therefore, the committee cannot offer a specific recommendation on the federal or nonfederal entity best suited to continue the AFHS, if extended, but has identified a number of options that could be pursued successfully.
COST ISSUES IN EXTENDING STUDY OF THE AFHS DATA ASSETS
The committee was charged with evaluating the potential costs of extending the AFHS and of conducting research on its data assets. Such costs fall into four broad categories:
Costs associated with preparing the data assets for use by researchers outside of the AFHS and transferring them to the successor custodian
Costs associated with managing the database
Costs associated with managing the biospecimen collection
Costs associated with conducting research on the data assets
These categories are addressed in turn below. As the committee recommended that the AFHS be extended by making the database and associated biospecimen collection available for study via a custodian, potential costs are considered from this perspective.
If the decision is made to identify a new custodian through a competitive process, additional costs would be incurred in managing this process. The Congress would need to allocate funding to cover these costs, which would depend on which agency or institutional body was assigned the task and how much time was allotted to complete it.
Costs Associated with Preparing the Data Assets for Use by Researchers Outside of the AFHS and Transferring Them to the Successor Custodian
Preparation of the data assets for analysis by researchers outside of the AFHS entails documenting and reorganizing them in a form and format that allows them to be easily understood, evaluated, managed, or analyzed by persons who are not already familiar with them. This topic was addressed in the committee’s interim letter report (IOM, 2005a) and in Chapters 3 and 4.
The interim letter report stated that it was difficult to estimate the potential cost of implementing the documentation and reorganization recommendations. These costs would depend on several factors, including the ease with which existing documentation could be adapted to satisfy the recommendations,30 whether
the AFHS personnel performed the work themselves or contracted it out, and the amount of time available to accomplish the tasks once the decision was made to undertake them. However, at least some of the actions recommended by the committee were already planned by the AFHS investigators and may be underway. Other work may well fall under existing budget items and should thus not represent an incremental cost to the study. As noted in Chapter 2, the AFHS Fiscal Year 2006 (FY06) budget (DTIC, 2005) includes allocations to perform documentation and organization of the data assets in anticipation of their future disposition. It also includes funds to prepare for and complete turnover of the assets. These activities are contained in the descriptions of two overlapping tasks:
Continue to process and document examination data and to verify the physical examination database. Continue new medical records coding and verify existing medical records coding…. Process and document Cycle 6 examination data to include updating of the participant database…. Prepare for project termination and turnover of archives/biological samples to designated agencies. Terminate project in FY06.
Continue to process and document examination data. Continue archiving previous cycles’ examination data and digitize and archive the Cycle 6 data as received. Conduct medical records coding and verification of examination database and Cycles 1 through 6 coding…. Prepare for and complete transition or turnover of archives and specimens to designated agencies. Terminate project in FY06.
A total of $3,289,000 was assigned to these and other data analysis and support tasks.31
The committee believes that it is incumbent on the USAF, as the current custodian of the AFHS research materials, to ensure their proper documentation and organization. As stated in Chapters 3 and 4, the committee recommended that—if available AFHS program funds are not sufficient to accomplish the documentation and reorganizations actions they elucidated—supplemental funding should be provided to carry out such work in a complete and timely manner. Funding for activities related to the turnover of the database and biospecimen collection to the successor custodian appear to be explicitly covered in the existing AFHS budget. Should that party not be identified by the end of FY06, the USAF’s custodial obligations include properly maintaining the assets until they can be turned over.
Costs Associated with Managing the Database
The primary costs of maintaining AFHS’s medical records and other study data are associated with storage and handling of the electronic materials. The custodian will need to have or obtain sufficient space on servers to contain at least ~525 GB of files. Software for database management and possibly analysis will be required and a modest amount of file cabinet space needed. If collaborating researchers are allowed direct access to the electronic files, a secure room will be needed for this purpose. There will also be some one-time costs associated with the start of the custodianship, including those connected with transferring files, setting up storage, creating protocols for managing the data, and obtaining new consent from the subjects for the continued use of the materials. Earlier in the chapter, the committee recommended that all of the hard copy records of the AFHS that have been saved in PDF form be destroyed unless the National Archivist concludes that these records must be maintained or they are subject to other records retention requirements. There is no need for the custodian to hold the hard copy versions of these materials.
The primary means for providing data to researchers for studies are to create public use databases, prepare custom data sets for specific research projects, and supply access via a limited access data enclave mechanism. Chapter 3 notes that, for a time in the early 2000’s, deidentified data from physical examination Cycles 2–5 were available to the public. However, AFHS later withdrew access, owing to questions over whether the study subjects had given consent for the posting. Explicitly obtaining such consent would allow relatively limited amounts of data to be freely available for research without the need for staff time after the datasets and associated documentation were created. The limitations imposed by the need to protect the interests of subjects would, however, greatly limit the kind and scope of research that would be permitted with these data. Preparation of custom datasets allows for far greater flexibility in type and scope of available data at the expense of the time to assemble them.32 This approach used by Seattle ERIC, MAVERIC, and MFUA as a mechanism for data dissemination. Limited access data enclaves, which are discussed earlier in this chapter and in Appendix E, require staff time for supervision of researchers and secure space and equipment for their use.
Generally speaking, the ease with which data can be retrieved and correspondingly the cost of pulling data for research purposes depends on the quality of the assets’ documentation. If the committee’s documentation recommendations are followed, there will be abundant information for prospective researchers
to use in planning studies and for the custodian’s staff to use in facilitating that work. Less time and effort will be expended by both parties in the mechanics of getting research done, leading to lower labor costs per study. However, better documentation may well lead to more demand for the data assets and thus greater time commitments from the staff.
The custodian will also incur costs associated with implementing the committee’s recommendations for providing independent oversight of future research. A three-pronged approach was put forward: the review of proposals for scientific merit and adherence to ethical, legal, and related considerations by an IRB and, separately, an advisory and oversight board, and systematic communication of research plans and results to study subjects. In brief, the boards will require time from the custodian’s staff for managing applications for data access and interactions with board members, while communications with subjects will involve the development and dissemination of newsletters, websites, or other media. Details of the committee’s observations on this topic are presented earlier in this chapter in a section entitled “Oversight of the Future Uses of the AFHS Data Assets.”
Expenses related to database management are best expressed in terms of workforce needs, as the allocations required to cover direct and indirect costs vary by location and type of institution (government, nonprofit, commercial) as well as over time. The committee spoke with investigators responsible for other epidemiologic datasets that permit public access. They indicated that typical needs would be for time from a principal investigator or project director, database manager, programmer(s), clerical personnel, and perhaps a webmaster or participant liaison. With the possible exception of a database manager, there would be no need to allocate an entire full-time equivalent (FTE)33 to any of these tasks.
Roughly speaking, the committee estimates that $150,000–300,000 per year would be required to support a data management and access operation of the type proposed here. The actual amount would depend critically on the custodian chosen and the number and type of studies proposed for and conducted with the data assets (which would in turn influence the amount of staff time required to support those studies). At least some of these funds would presumably be derived from fees assessed to researchers seeking access to the resources. It is important, especially in the early years of this new phase in the life of the AFHS resources, that such fees be set a level that will facilitate use of the resource.
Costs Associated with Managing the Biospecimen Collection
The costs associated with the maintenance of the biospecimen collection are related to its physical maintenance and retrieval of materials for research purposes.
Physical Maintenance of the Collection
The cost for physical maintenance of the AFHS biospecimens vary considerably depending upon the setting in which the collection is housed. A research university with a large capacity biospecimens repository may impose relatively modest costs to store materials for a project that has some affiliation with it. A government repository would incur costs in accepting and storing specimens, but there is no set means for factoring how this would be handled for budgeting purposes. Informal discussions with commercial repositories suggest that such institutions would charge $200,000 or more per year to house a collection the size of the AFHS’s. Biospecimens may need to undergo inventorying and labeling (barcoding, for example) upon receipt so that they can be integrated into a repository’s management system. This would result in additional costs in the range of dollars per vial in the first year of the custodian’s operation.34 It is not clear whether secure transfer of the biospecimen collection under cryogenic conditions is covered under AFHS funds allocated for the “turnover of archives/biological samples to designated agencies” (DTIC, 2005).
If the specimens are instead maintained by a freestanding entity that does not have oversight for other biologic materials, costs for establishing and maintaining the repository will be higher than if the materials are received and maintained by an entity with an existing repository. Expenses such as rental space for freezers will vary, depending upon where in the country35 and possibly the type of institution at which the specimens are maintained. Other expenditures related to the set-up of a new facility—the purchase or rental of laboratory-quality ultralow temperature freezers and creation of a specimen inventory management system, for example—will also be required.
Regardless of where the specimens are housed, maintenance of the collection requires space for the 23 freezers currently used for specimen storage and backup freezers or the equivalent volume in comparable storage conditions, space for additional freezers for future aliquots, personnel to monitor freezer function, costs for preventive maintenance and repair when compressors fail, and electricity costs. An alarm system must also be used to monitor freezer function and alert personnel of problems whether or not they are on site. If the specimens were housed in a preexisting facility, then monitoring would be subsumed into the staff’s existing responsibilities and could be accomplished with only a nominal increase in existing overhead costs that would be covered in the storage fee. In a freestanding facility, sufficient staff to respond to failures at all times would be required.
Retrieval of Materials for Research Purposes
Costs associated with the retrieval of biospecimens from storage may include those related to locating, pulling, realiquoting, packing, and proper shipping. In addition, time from a database manager may be needed to select the study subjects and exam cycles to be included in a specific project, identify locations of the specimens requested and to update the repository database when specimens are removed. If the custodian maintains its own repository, laboratory space will be required for the technical staff to work on dry ice to maintain the specimens during handling and do any realiquoting. Associated laboratory supplies (e.g., pipettes and tips, gloves) will also be needed. For specimens labeled with the subject’s name, it will be necessary to relabel or carefully delete the identifying information before shipment, if complete vials are being sent. A source of specimens for use in quality control for laboratory testing will also need to be identified. If new specimens are collected, additional freezers or space will be required. Realiquoting the specimens into smaller volume vials might result in some space saving, at the expense of a freeze-thaw cycle.
Repositories do not, in general, publicly post the amount they charge for their services, making cost estimates difficult. Informal discussions with such organizations suggest it will cost between dollars and tens of dollars per specimen for samples to be extracted and shipped from a repository. Economies of scale may be realized with larger numbers of samples. Many, but not all, repositories can carry out in-house laboratory testing, obviating the need for shipment and lowering the access cost.
Laboratory testing costs, which are in addition to retrieval fees, vary quite widely depending on the procedure. Simple clinical parameters—many of which, it should be noted, were already measured and coded in the AFHS database36—cost tens of dollars per sample; newer and more complex tests, hundreds of dollars per sample. University and government laboratories may have different cost structures for resident researchers; this also affects estimates.
The committee assumes that the custodian would follow the practice of other repositories and impose fees for biospecimens access that would recover at least some their costs. As the committee noted in its discussion of database access management, it is important—especially in the early years of this new phase in the life of the AFHS resources—that such fees be set a level that will facilitate use of the resource.
Costs Associated with Conducting Research on the AFHS Data Assets
The committee recommends that further study of the AFHS medical records, other study data, and laboratory specimens be accomplished by making these
materials available for research via a custodian that takes an active role in fostering use of the assets. It does not propose that particular studies or type of studies be conducted nor does it put forward a research agenda. A number of possible topics for future work are listed in Chapter 5.
The cost of conducting new studies will greatly depend on their scope and whether they need to use other databases, analyze biospecimens, or contact subjects. Pilot studies and empirical analyses of the existing AFHS dataset could have relatively modest needs for support—tens of thousands of dollars—while investigations that include gathering additional data and specimens from all of the subjects in the cohort could easily cost millions of dollars. The studies that will be conducted on the data assets will depend on the initiative and imagination of prospective researchers, as tempered in the crucible of funding, institutional, and scientific review.
The committee believes that funds are needed to establish the AFHS data assets as a resource for independent researchers. Its judgment is that a limited-life, small grant program is the best way to accomplish this goal. The committee anticipates that this program will stimulate prospective researchers to also seek external funding from other existing sources for further or more in-depth projects. Such an approach has been successfully used by the federal government in other circumstances. The committee therefore recommends that:
The Congress should allocate a minimum of $250,000 per year of direct costs for three years for small grants for secondary data analysis or pilot projects using the data assets of the AFHS. These funds should be in addition to already-planned or contemplated support of Vietnam veterans’ health research—funding should not be diverted from other research efforts for this initiative.
An allocation of at least $250,000 per year will provide at least partial support to one to three research projects. This seed money is intended to raise the visibility of the AFHS data assets in the research community and stimulate prospective researchers to seek additional sources of support. Such sources could include the National Institutes of Health, Centers for Disease Control and Prevention, Department of Veterans Affairs, and private foundations. MAVERIC provides a listing of these for prospective users of their assets (MAVERIC, 2006). The Seattle ERIC program has administered a pilot study grant program, details of which are available at their website (Seattle ERIC, 2006). It is the committee’s judgment that a 3-year trial will be sufficient to establish the AFHS assets as a research resource and that, thereafter, it is appropriate that research projects that propose to use them obtain support through customary funding channels.
The committee has no recommendation regarding the mechanism by which the support proposed here should be administered. This could take place through a federal entity such as the NIH or VA, or the responsibility could be assigned to
the custodian. Outreach activities by the custodian—conference presentations, articles in professional journals, or informational workshops, and the like—would help ensure that the scientific community is made aware of the small grant program and, more generally, the research possibilities presented by the data assets.
Although the committee is enthusiastic about the potential for future studies of the AFHS data assets, it understands that the viability of such work is not assured. It therefore believes that it is appropriate to revisit the question of support for further work after the committee’s recommendations have been implemented and have had time to play out in the research realm. A 5-year commitment—that is, two years after the last small grants proposed above are made—should be sufficient to establish whether the AFHS resources have value and relevance as a resource. The committee therefore recommends that:
Five years after the chosen custodian assumes responsibility, a committee should be convened to evaluate the potential value and relevance of extending further support to the maintenance of access to the data or the biospecimens collected in the course of the AFHS.
Summary Remarks Regarding the Costs Associated with Extending the AFHS
As the discussion above makes clear, there are a number of uncertainties and variables in the costs associated with extending the AFHS as a data resource managed by a custodian. It is therefore difficult for the committee to present a bottom-line estimate for the total cost of implementing its recommendations. The major fixed costs for the custodian are those related to the management of the database and biospecimens. Roughly speaking, the committee estimates that $150,000–300,000 per year would be required to support database management responsibilities and an additional $200,000 or more per year for proper maintenance of the biospecimens. First year costs would be higher because a number of one-time only tasks would have to be performed to set up the operation. Reinventorying of the biospecimens, if required, would be a major component of such start-up costs. Estimates of the fixed costs could be refined once a decision is made on the custodian.
The committee also recommends that a minimum of $250,000 per year of direct costs be allocated to a limited-life small-grants program to stimulate interest in and awareness of the AFHS data assets within the research community. The program should span the first three years after the successor custodian establishes operations. Other than the limited-life grant program figures, no estimate can be offered of the costs associated with conducting research on the AFHS data assets as these depend so heavily on the form of research contemplated. However, these costs are the responsibility of prospective researchers, who will need to obtain their own support from funding sources.
The committee believes that the costs of properly documenting the data assets, making them available to the research community, and implementing the proposed 5-year program to encourage their use are small in comparison with the government’s investment of ~$143 million to date. The potential benefits of these actions, while subject to considerable uncertainty, appear to greatly outweigh the costs.
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