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--> 4 Recent Decades With the loss of core support, the Medical Follow-up Agency (MFUA) relied on the Committee on Epidemiology and Veterans Follow-up Studies (CEVFUS) and on agencies such as the Veterans Administration (VA) to continue to generate worthwhile projects. In this context, a VA decision late in 1971 to review the operations of the MFUA appeared troublesome. The review, in fact, turned out well: reviewers were favorably impressed with MFUA's general procedures and its record of useful studies. They urged the VA to raise its level of support for the agency, but criticized the committee for taking little initiative in suggesting studies.138 Gilbert Beebe himself was of two minds on this matter. On the one hand, he was at times attracted to a CEVFUS that would take a greater role in shaping the agency's program. On the other hand, he found the vagueness of the VA recommendations puzzling, feeling that they reflected Lyndon Lee's earlier attempts to reshape the committee to a model of his own design. Moreover, expanding the CEVFUS initiative would place even more demands on a staff that was already overburdened. The Executive Committee of the National Research Council's (NRC's) Division of Medical Sciences Executive Committee echoed Beebe's sentiments, urging him to go slow, not to risk the flexibility that the MFUA's current organization gave it. However, the question of sources for MFUA studies was by no means closed. A study in 1977 found that only 2 of the 57 "R projects" (active studies, not mere planning studies) funded at the time were committee inspired, 34 came from government agencies, 13 from university investigators, and 7 from MFUA staff. 139
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--> Other outside agencies offered proposals that had the potential to change the MFUA's mission dramatically. The National Institutes of Health's (NIH's) National Heart and Lung Institute (NHLI, later the National Heart, Lung and Blood Institute [NHLBI]) wrote to Beebe and the MFUA in early 1972, mentioning NHLI's interest in "maximizing the return" on its field studies by "providing the means for follow-up studies of prognosis and outcome through a central registry and follow-up mechanism." Beebe recalled a similar suggestion made some years earlier by Michael DeBakey in relation to the ongoing collaborative clinical trials sponsored by NIH. At the time, the MFUA felt ill-equipped to handle the problems of the "uncharted sea" that would arise in this new function and did not act on the suggestion.140 This time, the offer came from the NHLI itself, with implicit promise of funding, thus giving the MFUA an opportunity to broaden its program beyond the study of the mortality and morbidity of veterans. Although CEVFUS and MFUA staff gave serious consideration to the offer, they ultimately rejected it. As Beebe wrote to the NHLI's associate director, agency interest was piqued in part by the thought that this offer would allow the MFUA to refocus its efforts on morbidity studies, since follow-up data on veterans who were not using the VA system were increasingly limited in the decades since World War II. Only hospital insurance plans seemed likely prospects to offer these kinds of data in the near future, and there would be confidentiality problems in acquiring such information. This would not be an issue with the NHLI proposal. The committee's conclusion, however, was that the "technical means to facilitate studies of morbidity on a national basis did not now exist nor were they in near prospect. The task of attempting to develop methods applicable nationally would be very large, and is probably beyond the strength of the Follow-up Agency." Beebe did note some interest within CEVFUS in morbidity studies on a smaller scale and some flexibility on the question of extending the MFUA program beyond the veteran population in cases "where the value and feasibility of studies on other groups were assured." NHLI, however, chose to consider the book closed on MFUA involvement in this effort on any scale.141 Despite this decision, NHLI played a key role in funding the assembly and maintenance of the NAS-NRC Twin Registry for many years. Although MFUA spurned NHLI's proposal, the agency and the committee did gain some important additions in 1972. First, the agency found a replacement for Dean Nefzger: Dennis Robinette, a biological statistician who remained on staff until his death in 1992 and played an important role in program continuity during his tenure with the MFUA (see Box 10). The following year, Dr. James E. Norman, a statistician formerly at the University of Georgia, joined the MFUA staff. At its 1972 meeting, the committee also decided to appoint two subcommittees. One was an ad hoc subcommittee on the Army's ongoing modernization of the routine physical examination (MORPE) efforts. Of more importance was the appointment of a Subcommittee on Surgical Problems, charged to "review the
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--> Box 10 Study of Splenectomy and Subsequent Mortality "A long-term follow-up of 740 American servicemen splenectomised because of trauma during the 1939–1945 war showed significant excess mortality from pneumonia and ischemic heart disease. Mortality from cirrhosis was also increased, but not significantly. The findings confirm that the risk of fatal infections is increased by asplenia; however, the risk of cancer, was not increased, as it is in some other immunodeficiency states. Post-splenectomy thrombocytosis and hypercoagulability may account for the increased risk of fatal myocardial ischaemia in this group" (see Robinette and Fraumeni, 1977). These findings provided the principal basis for establishing Department of Defense policy regarding the nondeployable status of splenectomized individuals to tropical areas of the world. The findings of thrombocytosis, hypercoagulability, and increased risk of mortality due to ischemic heart disease preceded by a decade the studies on the value of aspirin in preventing myocardial infarction. Selected Reference Robinette, C.D., Fraumeni, J.F. Splenectomy and subsequent mortality in veterans of the 1939–45 war. Lancet 2(July): 127–129, 1977. scientific and clinical needs for information obtainable only by means of follow-up studies based on the surgical experience in Vietnam." Dunham appointed Dr. Stuart Roberts, who had been the Army's surgical consultant in Vietnam, to head the subcommittee, with membership including Michael DeBakey and others.142 At the annual meeting of the division of medical sciences in April 1972, members of the Executive Committee found, somewhat to their surprise, that this low-profile organization within the division was a "very active group." Indeed, during 1972, the Medical Follow-up Agency activities continued at a high rate. CEVFUS approved two new twin studies that year. One was a pilot study of a new effort in the ongoing examination of smoking and twins; the other was a study of headache patterns in twin pairs in relation to zygosity. A non-twins study that was approved was part of the continuing work on amyotrophic lateral sclerosis, a follow-up effort to chart its course and that of other motor neuron diseases over time and to search for prognostic indicators. Other ongoing studies included one on body build and mortality, using a study of 105,000 men being discharged from military service in 1946 developed by a group of physical anthropologists. MFUA investigators retrieved the data from the study and performed a mortality analysis of the more than 7,000 confirmed deaths in the cohort.143 The agency continued these commitments in a period of organizational uncertainty. In 1972, the NRC was undergoing one of a periodic series of reorganization efforts as it attempted to mold its mission to suit changing national needs. In a ripple effect from this larger effort, the NRC ordered that all committees
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--> institute more regular rotation, including CEVFUS. Division of Medical Sciences Chairman Charles Dunham therefore brought in new committee leadership, appointing Dr. Richard Remington, a biostatistician and associate dean for research at the University of Texas School of Public Health, to the chairmanship. Remington was chosen in part because he had previously served as chairman of one of the VA research committees and thus was acceptable to Dr. Lee of the VA. Dr. Brian MacMahon's relationship with the Medical Follow-up Agency did not end, however; he returned to the chairmanship of the committee in later years.144 At Dr. Remington's first meeting as CEVFUS chairman in January 1973, he proposed changes in committee procedures. He called for more use of outside opinions of the scientific merit of technical proposals, more committee discussion of policy, a more active committee role in seeking MFUA funding, and more frequent meetings. For the first time since CEVFUS had been formed, the committee heard investigators, instead of MFUA staff, present their own proposals. Dr. Charlotte Silverman of the Public Health Service became the first female outside investigator to propose a study to the agency when she presented a proposal on exposure to microwave radiation (see Box 11). Like the other proposals presented that day by the investigators themselves, the project was approved, although this procedural innovation was rarely repeated thereafter. The other two proposals were a study of long-term effects of arsenic as used in the treatment of syphilis in World War II and a 30-year clinical follow-up of selected demyelinating diseases, related to the ongoing multiple sclerosis effort. The two major planning studies discussed that day both involved investigators who, although able to manage all other aspects of a study with their own resources, needed help in using the veterans' record files at the St. Louis center. Although the Medical Follow-up Agency had gone along with similar studies where appropriate to the workload of the St. Louis staff, it expressed reservations about these two studies. In particular, the study entitled "Prospective Studies of Mortality from Cerebrovascular Disease in Selected Groups of Pre-World War II and World War II Veterans," proposed by former MFUA staffer Dean Nefzger, required that no fewer than 120,000 records be examined over a period of three to four years. After lengthy discussions, the MFUA staff concluded that there was no way the agency could commit so much staff time to this effort without a fundamental reordering of its priorities. The committee therefore declined Nefzger's proposal and accepted the other, much smaller one.145 The Fire in Saint Louis Progress on MFUA projects was severely impeded when, on July 12, 1973, a fire broke out at the Military Personnel Records Center in St. Louis. There were no injuries, but the fire, which burned sporadically for the next three days, hampered all MFUA studies requiring World War II-era medical details from Army hospital
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--> BOX 11 Health Effects of Occupational Exposure to Microwave Radiation (RADAR) Concerns about the cancer-causing effects of nonionizing electromagnetic radiation increased in the aftermath of newspaper stories linking cellular phone use to cancer risk. Because cellular telephones are a relatively recent invention, however, a long-term follow-up of cell phone users is obviously not yet possible. Nevertheless, it has been possible to study the long-term health effects following exposure to microwave radiation, nonionizing radiation that occupies a similar place in the electromagnetic spectrum. Thus the Medical Follow-up Agency was asked to bring up to date an earlier study on the long-term effects of exposure to microwave radiation. In 1980, the MFUA published the results of a mortality follow-up of 40,000 Navy servicemen, of whom half had maximum opportunity for exposure to microwave radiation and the other half had minimum opportunity. The study compared the health experiences of those who repaired radar equipment (maximum opportunity) with those who operated it (minimum opportunity); all subjects were graduates of Navy technical schools in 1950 to 1954. Although a direct measure of physical exposure could not be determined, relative exposure was scaled using occupation, length of time in occupation, and power of the RADAR units aboard the ship on which a subject served. The study found no adverse health effects as reflected in mortality, military hospitalization or VA hospitalization, or VA disability compensation rates. The study's results were published not long after those from a study of persons who were exposed to microwave radiation white serving in the U.S. Embassy in Moscow, which found no appreciable health differences in those exposed to what were thought to be low levels of microwave radiation. A further mortality follow-up, which is to gather an additional 20 years of data, is under way as the MFUA enters its sixth decade. Selected Reference Robinette, C.D., Silverman, C., Jablon, S. Effects upon health of occupational exposure to microwave radiation (RADAR). American Journal of Epidemiology112:39–53 1980. charts or epidemiologic data from Army personnel records. The MFUA staff in St. Louis was forced to relocate during the laborious process of cleaning and restoring the building. In May 1974, Seymour Jablon surveyed the situation for the committee: 80 percent of the Army personnel and medical records from World War II and the Korean War were lost. Mortality follow-up studies were still possible with the continued existence of the Beneficiary Identification and Records Locator Subsystem (BIRLS) on magnetic tape. Studies that aimed at epidemiologic factors or required review of clinical records were largely no longer feasible. The fire forced the MFUA to rely more heavily on Navy records and less on
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--> the Army records with which it was so comfortable. "[O]ne of the great values of the program was precisely that it had been possible to study reasonably large groups of men with relatively rare conditions, and this would no longer be possible," the committee noted. Indeed, except for studies where the indexing was already complete, it became very difficult to develop studies for some diseases.146 As part of his effort to hold more meetings, Remington convened the committee for a second time in 1973. The committee faced a changed external environment with the completion of the NRC reorganization. The Medical Follow-up Agency and CEVFUS now formed parts of the new Assembly of Life Sciences. The old Division of Medical Sciences continued to exist but as a much reduced entity. With the retirement of Charles Dunham, the MFUA staff and CEVFUS had to get to know an all-new hierarchy, including Leonard Laster, executive director of the new Assembly of Life Sciences. In addition to discussing the new organizational structure, the committee devoted the bulk of its time at the second 1973 meeting to its subcommittee on MORPE and the revision of the Army's induction examination. The subcommittee focused on the data for cardiovascular research that could be retrieved from the revised examination. The larger committee chose to accept the subcommittee's report without forwarding it to the Army staff on the grounds that the proposal was not "original" enough.147 In 1975, the issue of the MORPE program arose again. Since the Army had delegated MORPE interests to the Air Force, the current effort to modernize the examination system was directed to Armed Forces Entrance Examination Station (AFEES) operation, with a pilot run to commence at the Baltimore AFEES in 1975. Although the committee expressed its regret that no greater effort was being made to standardize examination procedures, yielding universally applicable data, it was encouraged by the fact that the new record system might make it possible to maintain a data base on those who had been rejected. Such a data base would be useful in controlling for the so-called healthy veteran syndrome, which postulated that men on the MFUA's veteran rosters were less susceptible to disease than the general population since they had passed the physical examination on induction. MFUA staff officer Robert J. Keehn suggested that new data arising from MORPE and the AFEES modernization impelled the committee to take the lead in the establishment of data bases for future studies, rather than relying on data bases laid down and preserved by others. 148 As it worked with the subcommittees, the MFUA could also report progress in a number of ongoing projects. The group at the VA responsible for research on alcoholism approached the MFUA, anxious to set up long-term studies of alcoholism in association with the armed forces but confused as to how to proceed. Changing attitudes within the military regarding alcoholism—that is, considering it a disease worthy of treatment rather than a reason for summary dismissal—opened up new possibilities for research.149 Plans were being made to update prisoner of war (POW) mortality for the POW study through 1972, to verify if the
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--> excess mortality reported in the first follow-up of World War II Pacific prisoners and Korean War prisoners continued to level off as it had in the 1965 results. Twin studies centering on schizophrenia, cancer morbidity, headache, and economic success were under way. A final report on the epidemiology of herniated lumbar disks was in preparation, following presentation of a preliminary report on this work at the annual meeting of the Society for Epidemiologic Research in May 1972. Also, the ongoing study of multiple sclerosis cases diagnosed in World War II entered a new phase as investigators made efforts to trace the course and prognosis of the disease for 30 years after its diagnosis. Three new studies were approved in late 1973, including a longitudinal study of cardiovascular disease, an examination of childhood cancer in relation to prenatal irradiation, and a series of related epidemiologic studies of various conditions for evidence of later death from cancer among World War II veterans. 150 In 1974, despite the damage done to the MFUA program by the St. Louis fire, the agency made important strides in other areas. The committee met the new executive director of the Assembly of Life Sciences, Dr. Leonard Laster, who expressed approval of the Medical Follow-up Agency's history and current procedures, and promised not to get in the agency's way. He did, however, affirm a commitment to increase committee turnover, meaning that new CEVFUS members had to learn the ropes very quickly. In later years, this problem was handled by rotating a fixed group of members. The etiquette of statistical reporting also commanded the committee's attention in 1974. The committee heard discussions of problems with the VA's new BIRLS system. CEVFUS unofficially affirmed its support for the creation of the National Death Index being proposed by the National Center for Health Statistics, a more efficient way to determine mortality for large numbers of people than the then-current system of making inquiries of each state. The National Death Index came on-line in 1979 and eventually proved to be very helpful in the work of the Medical Follow-up Agency.151 Updating the core statistical resources of the agency remained a common theme in the mid-1970s. Jablon continued his efforts to adapt Navy records to MFUA uses, reporting to CEVFUS on his progress at their 1975 meeting. The Navy records were problematic in that no machine-readable diagnostic index to the Navy files for World War II existed, making these files extremely difficult to use. Although "F card files," containing information on admissions to Navy hospitals during World War II existed, they were filed sequentially by hospital and year of admission, and the cards were not punched. When Jablon took a sample of 1,500 cards and examined them for diagnosis, he found that the top two diagnoses were for infectious and parasitic diseases and for acute infections of the respiratory system. Hence, reliance on these records meant a shift in program emphasis to tropical diseases and other common naval ailments. After studying the matter for some time, Jablon estimated in 1976 that $100,000 would be needed for punching items and producing a magnetic tape file in diagnostic
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--> sequence for MFUA use, if the agency wished to organize and preserve all of the Navy cards. With support from the National Cancer Institute, 6 million Navy hospital admissions from 1944 to 1945 had been preserved on magnetic tape by the early 1980s.152 Although Dr. Zdenek Hrubec's absence during 1974, on a year's detachment at the Karolinska Institute in Stockholm, meant that no new twin studies were launched, the committee approved a new statement of ''Principles Which Govern Use of the NAS-NRC Twin Registry." Among the innovative studies in the area was one by Dr. Paul Taubman. Taubman, an economist rather than an epidemiologist, used the roster of twins to generate data on genetics and earnings. Of 6,000 twin pairs, 2,500 pairs responded to a questionnaire. Taubman ultimately reported his results in a monograph as well as several journal articles.153 At Mid-Decade In 1975, CEVFUS discussed the future of the MFUA program. Dr. Robert W. Miller of the National Cancer Institute noted a retreat from the emphasis on studies of trauma. In fact, no studies of trauma were being undertaken, in part because methods of treating trauma in the 1970s were so different from those used in World War II. As chairman of the MFUA's advisory committee, Richard Remington urged the agency to approach the Department of Defense for possible consultation efforts, to tailor its program to better fit the needs of the VA, and to try to publish an account of its program in a journal such as the New England Journal of Medicine. Few of these proposals were carried out, however.154 As a result, in the bicentennial year 1976, the MFUA faced a number of internal and external challenges. As Gilbert Beebe prepared to turn over the reins of the agency upon reaching the age of 65 in 1977, he surveyed the changes in the kind of epidemiologic studies that the MFUA undertook in the 1970s as opposed to the 1940s. He noted a number of complicating factors, including the 1973 fire, the difficulty in contacting the veterans due to the passage of time, the national concern with privacy and confidentiality, the fragmentation of VA files in numerous locations, the destruction of the previous automatic link between VA hospitalization and the claims folder, the growing resistance of veterans to questionnaires or other studies, and the numerous non-VA alternatives open to veterans seeking hospitalization. On the positive side, such developments as the creation of magnetic tape files, the development of epidemiologic knowledge, the creation of BIRLS, the adoption of the Social Security number as the military service serial number, the growing number of veterans, and increasing concern with the effects of environmental factors on human health aided the MFUA program. One matter that occupied Beebe's attention was the passage of the 1974 Privacy Act by Congress.155 Beebe prevailed on National Academy of Sciences (NAS) President Philip Handler to bring the committee's concerns to the atten-
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--> tion of the Privacy Protection Study Commission in connection with the commission's consideration of regulations to enforce the Privacy Act. Committee members feared that these regulations would make epidemiological studies of the sort that the Medical Follow-up Agency had conducted in the past impossible; confidentiality concerns would preclude the release of patient data by the relevant agencies. Handler wrote the commission's executive director that he hoped its "deliberations on the uses of records will give adequate representation to scientific uses of records in furthering public health." With Handler's support, the MFUA successfully persuaded the commission to issue regulations that made allowance for the use of medical records for the agency's kinds of epidemiological studies.156 The Assembly of Life Sciences Closer to home, however, things did not go so well. The Executive Committee of the recently created Assembly of Life Sciences (ALS) experienced as much trouble getting used to the MFUA as had some of its predecessors in the Division of Medical Sciences. In examining the MFUA program in 1976, the Executive Committee called particular attention to the ongoing surgical adjuvant cancer therapy trials, probably the most atypical part of the agency's program. Some Executive Committee members thought the work "too pedestrian and unproductive to justify continuation." Recognizing that it was an ongoing effort, the Executive Committee approved it for fiscal year 1977 with the stipulation that CEVFUS should review the question of continuing MFUA involvement in the series of trials. At its May 25, 1976, meeting, CEVFUS agreed to appoint an ad hoc subcommittee, headed by Dr. Thomas C. Chalmers of the Mount Sinai School of Medicine, to review the matter. Chalmers's subcommittee recommended that the MFUA continue its collaborative role in the studies. He based his recommendations on the finding that although the trials had produced largely negative results thus far point, hope for more successful therapies still existed. Moreover, the protocols were well constructed and the studies well executed, statistical aspects of the design and analysis were of high quality, the work was efficiently managed with little use of precious staff time, and working relations with the coinvestigators were excellent. Calling the trials "an appropriate form of diversification for the MFUA," and arguing that "the future of MFUA collaboration should not be contingent upon showing positive results,'' the committee voted to send the Chalmers subcommittee report to the ALS Executive Committee as its reply to the concern about cancer trials.157 The matter did not end there. Paul Marks, Columbia's vice president for health sciences and former chairman of the Division of Medical Sciences, became a critic of the Medical Follow-up Agency within the ALS Executive Committee. In response, Beebe, Jablon, and Remington proposed that Marks and other representatives of the Executive Committee organize a "visiting commit-
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--> tee'' that would make an informal site visit to examine the MFUA program and its relation to the larger ALS unit. Alvin Lazen, associate executive director of the ALS went so far as to propose formally the creation and mandate of such a committee to Dr. Marks, who would head it. However, Marks did not convene the committee. When the ALS Executive Committee considered the MFUA's contract proposals in 1977, "things went badly," particularly the discussion of blood pressure and multiple sclerosis projects. Beebe worried that he was leaving the agency at a time when the program was vulnerable to attack from within the NRC. Finally, a review committee was appointed by ALS Chairman James Ebert, a biologist with the Carnegie Institution, to "recapitulate the history of MFUA, identify the nature of questions now being raised concerning the Agency and determine how the panel can best address the questions." The presence of both MacMahon and Remington on the six-man panel ensured that the agency would receive a favorable hearing, and Beebe could retire from the Medical Follow-up Agency knowing that, at least for the time being, it was not in danger from within.158 In 1976, Beebe's imminent retirement, as well as a sense that the agency's program was not growing rapidly enough, led Remington to assign to various committee members the task of assessing the future needs of specific disciplines for Medical Follow-up Agency studies. Dr. Robert H. Felix of the Bi-State Regional Medical Program in St. Louis and the distinguished former head of the National Institute of Mental Health was assigned to consider the field of psychiatry; Dr. DeBakey, surgery; and Dr. Reuel A. Stallones of the University of Texas School of Public Health, cardiovascular disease. At the December 1976 meeting, Dr. Stallones presented his report on cardiovascular disease and the MFUA program, recommending that a summary of the agency's usefulness as a resource be reprinted periodically in the American Journal of Epidemiology and that the agency seek special funding from the NHLBI for planning cardiovascular disease studies. DeBakey presented a number of potential surgical studies that could be undertaken by the agency, including follow-up of studies done in its earliest days, as well as some new ideas such as a study of men with spinal cord injuries. Since Felix was unable to complete his overview of the psychiatric field due to illness, Dr. Ransom J. Arthur of the Neuropsychiatric Institute at the University of California at Los Angeles (UCLA) took his place.159 Seymour Jablon in Charge After Beebe retired in 1977, Seymour Jablon took over the day-to-day operations of the Medical Follow-up Agency, as well as those of the Atomic Bomb Casualty Commission's (ABCC's) successor agency, the Radiation Effects Research Foundation (RERF). Jablon had been with the agency almost since the beginning and was a well-respected statistician. As such he possessed the necessary experience to run the agency. Unfortunately, he presided over a difficult
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--> Group photo at the annual meeting of the Radiation Effects Research Foundation Board of Directors, held in Washington, D.C., Photo courtesy of Dr. Gilbert Beebe.
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--> BOX 13 Follow-up of Veterans Experimentally Exposed to Chemical Agents Interest in the effects of exposure to anticholinesterase agents—for example, the nerve gas sarin—grew in response to reports of the possible exposure of Persian Gulf War veterans to such agents. Thus, the Medical Follow-up Agency was asked to conduct an additional long-term follow-up study of a group of soldiers who had been experimentally exposed to chemical agents in the past. The MFUA had already conducted an initial follow-up of some 6,720 Army soldiers who were enrolled in a program of experimental exposure to chemical warfare and other agents at the Edgewood Arsenal, Maryland, between 1955 and 1975. A three-volume report was issued in 1980; the last volume—of which MFUA staff had lead authorship—dealt with the current health status of test subjects, including 1,581 men exposed to anticholinesterase compounds such as GA (tabun), GB (sarin), GD (soman), GF, and VX. Subjects exposed to such compounds did not differ substantially from those exposed to other compounds or from unexposed comparison individuals in their replies to questions about current health. However, given the limitations of the study design, only large health effects were likely to be uncovered. As this volume goes to print, the MFUA is waiting word on funding of the proposed study to continue follow-up of these same subjects. The new study, however, will be of a more focused nature than the earlier investigation; in particular, research is expected to focus on the neurological and neuropsychological sequelae of low-level exposures to organophosphate pesticides, which are somewhat similar in their chemical action to the nerve agents tested at Edgewood Arsenal. Selected Reference National Research Council. Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents, Volume 3: Final Report: Current Health Status of Test Subjects. Washington, D.C.: National Academy Press, 1985. budget that showed steady growth was the Department of Defense (DOD). With MFUA funding constricted in all directions, Jablon looked to this department for new studies. The MFUA and the DOD were an ideal fit. The Defense Department sought experts to study the exposure of various veteran cohorts to atomic radiation. Jablon's experience with the ABCC and some related, smaller-scale studies in the 1970s, gave him and his staff experience needed to carry out such work. Beginning in 1978, the Medical Follow-up Agency and the Defense Department's Defense Nuclear Agency entered into a series of contracts that would last into the 1990s. These radiation contracts were almost the agency's predominant means of support for much of the early 1980s. They were not without political conflicts. Jablon's first study, on the incidence of cancer among veterans who entered Hiroshima and Nagasaki in 1945 immediately after atomic bombs leveled these two Japanese cities, found no unusual incidence of multiple myeloma among
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--> these "atomic veterans." However, the protocols and the conclusions of the study came under such intense scrutiny from Capitol Hill and the press, that Jablon agreed to do the study again.166 Other related studies undertaken by the agency concentrated on servicemen who were present at a number of atmospheric atomic bomb tests between 1946 and 1962, with code names such as SMOKY and CROSSROADS. A series of MFUA subcommittees organized the protocols for these epidemiologic studies, all of which reported results similar to the original Hiroshima and Nagasaki studies. Disappointed veterans groups criticized Jablon, who publicly defended the method behind the studies but privately admitted that they were not the best kind of science. Since the agency needed the money, Jablon continued to take the lead on these studies well after he left the agency staff. His position in the atomic test exposure studies continued until Kenneth Shine, president of the Institute of Medicine, removed him from the CROSSROADS study in 1993 under pressure from atomic veteran groups who were hoping for study results closer to their own, less scientific, predispositions.167 The studies continued however to demonstrate the essential soundness of Jablon's methodologies and conclusions. Even without substantial funds, the agency remained "actively involved" in building a new Vietnam-Era Twin Registry, as well as in the study of yellow fever vaccine and hepatitis in World War II veterans (see Box 14), and the ongoing POW work. In building the registry the agency ran into troubles with the Social Security Administration that were reminiscent of its problems with the Federal Bureau of Investigations two decades earlier. Social Security numbers had become standardized military case markers, replacing old serial numbers in the post-Korean War period. When the agency knew a veteran's name and date of birth, it needed the veteran's Social Security number. If it knew the veteran's name and Social Security number, it still required the date of birth. Both processes were easy enough to automate, but the Social Security Administration refused to cooperate on grounds of legal difficulties over the matter of disclosure. Failure to obtain these data made using the National Death Index and obtaining a mailing address from the Internal Revenue Service more difficult. In 1986, however, the Social Security Administration published a routine-use statement for the VA that allowed the Medical Follow-up Agency to gain more ready access to the data it needed.168 Between 1983 and 1985, the MFUA completed a study of mesothelioma and employment, intended to improve understanding of the health risks presented by exposure to asbestos and other fibers, the data for which were then being analyzed by the National Cancer Institute. Even as the agency expanded the Twin Registry to Vietnam veterans, it mailed new health questionnaires to the living members of the older registry (approximately 24,000 of the original 32,000 members remained in 1985) and planned future studies of diabetes and of possible links between handedness and neurological disease. At this point in the agency's history, proposals tended to focus on diseases
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--> BOX 14 A 41-Year Follow-up of Hepatitis B Epidemic in the U.S. Army Between late 1941 and early 1942 an epidemic of jaundice occurred in Army training camps across the United States. The epidemic was later determined to have resulted from the inoculation of an estimated 330,000 persons with contaminated yellow fever vaccine. The subsequent discovery of hepatitis B (HBV) provided an opportunity to (1) verify that the infectious agent was HBV and (2) test the hypothesis that adult infection with the virus in the United States leads to a carrier state with a high risk of hepatocellular carcinoma (HCC). Three groups totaling nearly 70,000 men were the subjects of a cohort study: group 1 was comprised of men hospitalized with hepatitis in 1942; group 2 consisted of men who were subclinically infected in 1942 by virtue of their having received vaccine from a contaminated lot without developing clinical disease; and group 3 contained comparison individuals who entered service after use of the contaminated vaccine had been discontinued. Approximately 200 men from each of these groups were located in 1985–1986 and their blood was tested for HBV markers. This serological survey demonstrated that the epidemic was caused by HBV infection: antibodies to HBV were detected in 98, 77, and 13 percent of groups 1, 2, and 3 respectively, while antibodies to hepatitis A were identified in similar percentages of each group. Only one carrier of the hepatitis B surface antigen marker, from group 1, was found in the 392 men from groups I and 2. The corresponding carrier rate of 0.3 percent contrasted markedly with the assumed rate of 5–10 percent following acute HBV infection. The mortality follow-up study of the three cohorts covering the period 1946–1983, which employed expert review of clinical and pathology records to select HCC from among all causes of death so diagnosed, found only a slight excess in mortality due to HCC in group 2, but not in group 1, compared with group 3 comparison individuals. Mortality from nonalcoholic chronic liver disease was lower in group 2 than in group 3. A case-control study of 24 HCC cases and 63 control subjects drawn from Department of Veterans Affairs hospital discharge files yielded an estimated relative risk for HCC due to receipt of contaminated vaccine of 3.3 (p = 0.06). The slightly elevated risk estimates from the mortality study, and the suggestive excess in the small case-control study, are consistent with the established etiological role of HBV infection in liver cancer. The serology study provided a rationale for these results, demonstrating that in comparison to neonates, young children, and immunosuppressed individuals of any age, healthy adults seldom become carriers of acute HBV infection. The mortality study provided evidence that the risk of HCC following FIBV infection is probably small. Selected References Norman, J.E., Beebe, G.W., Hoofnagle, J.H., Seeff, L.B. Mortality follow-up of the 1942 epidemic of hepatitis B in the U.S. Army. Hepatology 18:790–797, 1993. Seeff, L.B., Beebe, G.W., Hoofnagle, J.H., Norman, J.E., et al. A serologic follow-up of the 1942 epidemic of post-vaccination hepatitis in the U.S. Army. New England Journal of Medicine 316:965–970, 1987.
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--> and conditions of the elderly, a natural result of the advancing age of the World War II cohort at the heart of the MFUA program. Proposals during this time included studies of Alzheimer's disease and head injury, brain cancer in elderly men, radio-frequency radiation and cancer, and Vietnam veterans with spinal cord injury.169 In 1986, the MFUA emerged from the doldrums that had predominated during the early 1980s. During this time, two important staffing changes took place. Robert Keehn retired from the agency and Dr. William Page, a biostatistician on temporary assignment from the VA, joined the staff. Dr. Page eventually made the temporary assignment a permanent one and subsequently came to play an important role in the modern history of the agency. The National Cancer Institute proposed that the MFUA collaborate on studies of cancer epidemiology based on hospital clinical records. Dr. Richard Miller, the future director of the agency but then the director of Walter Reed Army Institute of Research's residency program in general preventive medicine, began work with the agency on AIDS studies, developing a follow-up study of HIV-positive military personnel.170 In 1987, the ALS commissioned yet another task force to review the work and mission of the MFUA. Chaired by Brian MacMahon, it produced a laudatory report, calling the MFUA a "national resource which should be maintained and strengthened." It recommended keeping the agency within the NRC, securing core funding from the NIH, the VA, and other key governmental agencies, and suggested an immediate search for a new director with the retirement of Seymour Jablon in October 1987. The task force also mentioned the need for greater ties to investigators in academia and government agencies, as well as the possibility of changing the agency's name to reflect the breadth of its mission. 171 William Page's Interim With Jablon leaving, Alvin Lazen, executive director of the Commission on Life Sciences (the new functional equivalent of the former ALS), appointed William Page as acting director of the MFUA, effective June 15, 1987. In addition to running the day-to-day affairs of the agency, Page continued to manage important components of the program. At first, it appeared that Page would indeed be a transition figure; CEVFUS membership was extended for a year in the fall of 1987 with the idea that "by that time more should be known about the future direction of the Medical Follow-up Agency." Circumstances contrived to make Page's "transition" acting directorship about half as long as Jablon's actual tenure, however.172 Despite the confusion associated with the leadership transition, the MFUA was clearly on its way back. Lack of core funding was a key dilemma, and Gilbert Beebe acted from his "advisory" role to provide it. In August 1987, he initiated discussions with staff of the Senate Veterans Affairs Committee concerning the status of the agency. Beebe acted because, even with more grant money coming
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--> to the agency in 1987, the staff in St. Louis was reduced to very small numbers and put on temporary leave. Beebe's Senate meeting produced a "workshop" review of the Medical Follow-up Agency by the Office of Technology Assessment (OTA), held at the request of the Senate Veterans Affairs Committee in 1988. In the meantime, Page reapplied for core funding from the agency's major grant sources. The MFUA made it past the worst of a particularly difficult time when the POW and cancer studies were renewed and new studies of atomic veterans and oil adjuvant vaccines were launched.173 In 1987, the Medical Follow-up Agency once again reported on numerous accomplishments. Three papers had been generated by the POW study. Work continued on projects related to the long-term effects of the 1942 hepatitis epidemic in the Army. The agency sought to determine the prevalence in victims of various hepatitis markers and to estimate their mortality rates, especially from liver cancer and other liver diseases. Various multiple sclerosis and twin projects were under way or planned, and planning was also being undertaken on a 33-year follow-up of Army recruits immunized with adjuvant influenza vaccine to determine if long-term problems could be associated with this vaccine. In the same year, the committee approved two new studies, one on nephrectomies performed subsequent to trauma and another on posttraumatic stress in riflemen.174 In the midst of this activity, the appearance of OTA's report in November 1988 became a crucial milestone in the Medical Follow-up Agency's recent history. OTA staff argued that the MFUA was too important to wither away and that only the presence of core funding from NIH, the VA, and the Department of Defense could keep this from happening. As a short-term solution, OTA recommended shared core support for the agency among these three governmental bodies, beginning with fiscal year 1990. OTA staff advocated immediate core funding of $100,000 to allow the agency to carry on its work and search for a strong director. Thereafter, it recommended a total of $500,000 per year over five years. OTA also suggested that the NAS amend its rules on competitive bidding to allow the MFUA to bid for contracts within its natural purview.175 In the same year, the MFUA again gained a new parent entity within the National Academy of Sciences. This time, however, it left the NRC entirely. The so-called Rosenblith committee, led by Walter Rosenblith of the Massachusetts Institute of Technology, decided to transfer the MFUA, along with the better-known Food and Nutrition Board, to the Institute of Medicine (IOM). The IOM, an entity analogous in the Academy structure to the National Academy of Engineering (NAE), had developed out of discussions in the 1960s regarding the need for a "National Academy of Medicine," led by Dr. Irvine Page of the Cleveland Clinic (no relation to William Page of the MFUA). The entity that became the IOM started as the Board on Medicine. After the 1972 NRC reorganization, the IOM became a full-fledged "sister" organization to the NAS, NRC, and NAE.
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--> This medical branch of the National Academy of Sciences was by no means an illogical place for the MFUA's epidemiological methods, and Page found himself as comfortable there as he had been in the NRC.176 However, the IOM was as uncomfortable with the MFUA as the agency's other parental entities had been in its more than 40 years of existence. A site visit by two outside investigators to familiarize the IOM with the workings of the MFUA took place in 1989. Pronouncing themselves ''shocked" to learn that the Medical Follow-up Agency's very existence was in peril (although they admitted to being previously unaware of its existence themselves), the investigators called for "important changes" so that the agency might "continue, or even perhaps become again, the national resource it was intended to be." To quell the "interim'' feelings that they detected on the part of the staff (only about ten persons at that time), the investigators recommended that the MFUA fill the position of a permanent director as soon as possible, preferably with a physician or epidemiologist. They urged securing long-term core funding, subsequent staff growth, and computer upgrades and spoke of the need for the agency to reach out better to the scientific community and the VA.177 By 1990, the Medical Follow-up Agency was again pursuing an active mandate. The agency sponsored a conference on epidemiology in military and veteran populations, as a sort of sequel to the workshop held in 1988, even publishing the proceedings with Dr. Page as editor. Seventy people attended the conference, which was intended both to report on the work of the agency and to draw new investigators into its orbit. After two years of wrangling and arm twisting by Senator Alan Cranston (D-California) and other members of the Senate Committee on Veterans Affairs, some of it public, first the NIH and then the VA agreed to fund the core program of the MFUA. Page and his staff believed that the funding derived from these agencies was more than sufficient for planning activities as the MFUA continued to grow in size for the second time in its history.178 In 1990, CEVFUS met again to discuss the agency's program and discovered an abundant amount of research done under MFUA auspices. Staff reported on the completed POW questionnaire, which found depressive symptomatology in POWs at a level three to five times higher than expected in a comparable general population. A study of hepatitis B and liver cancer in World War II veterans discovered little incidence of liver cancer in the study group. Ongoing efforts featured an examination study of former POWs, two other hepatitis studies, the mineral oil adjuvant study, and a pilot study of World War II veteran death reporting. Studies that awaited funding included the HIV study, an examination of Korean hemorrhagic fever (see Box 15), a study of multiple sclerosis, three twin studies, and a follow-up of nuclear veterans. In addition, the committee heard discussions of the body build registry, posttraumatic stress disorder in World War II riflemen, Alzheimer's disease, and head injury.179
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--> BOX 15 Study of Hemorrhagic Fever with Renal Syndrome Interest in hantavirus infection was abruptly stimulated by a 1993 outbreak of hantavirus pulmonary syndrome in the Four Corners area of the United States—with case fatality rates as high as 50 percent. A newly discovered hantavirus, ultimately named Sin Nombre, was determined to be the cause of the outbreak. This marked the first occurrence of severe, acute disease in the United States causally linked to a hantavirus. The Four Corners outbreak brought with it concerns about the presence of newly identified infectious disease agents in the United States, as well as concerns regarding the possible long-term sequelae of a disease of this severity. During the Korean War (1951–1963), American troops were exposed to another hantavirus: Hantaan. The Hantaan virus disease, initially called Korean hemorrhagic fever (KHF), is probably contracted through inhalation of the infected urine, saliva, or faces of the striped field mouse, Apodemus agrarius . Although the disease has been known for decades, no data are available on its long-term sequelae among American survivors. A study published in 1960, in which the medical records of 1,416 KHF cases and 831 comparison individuals (all white) were reviewed, found a small but significant increase in renal injury and genitourinary disease three to five years after the acute phase of KHF. The Medical Follow-up Agency is currently involved in a follow-up study to determine longer-term outcomes in the original cohort, including the frequency of end-stage renal disease. The MFUA, in collaboration with the University of Minnesota School of Public Health and the Centers for Disease Control and Prevention, is conducting a study of the long-term health effects of KHF in military personnel. The purpose of this study is to compare morbidity and mortality data from 1,416 white and 187 non-white surviving KHF cases with 831 white and 99 nonwhite comparison individuals. The study is scheduled for completion in the year 2000. Selected Reference Rubini, M.E., Jablon, S., McDowell, M.E. Renal residuals of acute epidemic hemorrhagic fever. Archives of Internal Medicine 106(Sept.):378–387, 1960. The 1990s The 1990s proved to be a decade of positive developments for the MFUA. In 1991, Page could report that core funding had been secured from the National Institutes of Health, the Department of Defense, and the Veterans Administration. Two years later, this was again jeopardized by indifference within the funding agencies, but a follow-up OTA study in 1994 persuaded all three agencies to provide the money. In 1991, the agency completed its study of Army recruits immunized with oil adjuvant influenza vaccine, finding no statistically signifi-
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--> cant adverse effects of the oil adjuvant. With core funding in hand, Page urged the committee to broaden the agency's horizons. He discussed pilot studies of Health Care Finance Administration hospitalization and Social Security Administration mortality records, as well as MFUA's various computer needs in both hardware and software. Among the new projects proposed in that year were a follow-up study of 1950 Air Force recruits infected with hepatitis C, a follow-up of the West Point Class of 1956, and studies using the Navy hospitalization files that Seymour Jablon had preserved on computer tape with funding from the National Cancer Institute more than a decade before.180 BOX 16 Health Consequences of Persian Gulf War Service In the years following Operations Desert Shield and Desert Storm in 1990–1991, reports of illnesses among Gulf War veterans raised public concerns about a "mystery illness" in this population. In 1993, Congress mandated that the Department of Veterans Affairs (VA) and the Department of Defense (DOD) arrange with the Medical Follow-up Agency to review existing scientific, medical, and other information on the health consequences of military service in the Persian Gulf War. A committee was constituted to assess the activities of the VA and DOD and to make recommendations concerning the collection and maintenance of information useful for evaluating the health consequences of service in the Persian Gulf. The committee was also to weigh the scientific basis for an epidemiologic study or studies to evaluate the health consequences of this service. The committee worked for two years, providing an interim report in January 1995, and a final report in late 1996. The interim report noted limitations in the usefulness of the VA Persian Gulf Health Registry, urged better coordination of research related to Gulf War illnesses, and suggested improvements in the design of future projects to include population-based studies. The recommendation of the final report emphasized the need for medical information systems in the VA and DOD that would permit a single, continuous, retrievable medical record for each service person, a goal echoed by the President of the United States in November 1997. The report noted the need to monitor environmental exposures during deployment to allow for rapid response and appropriate data collection. It also stressed the need for data to better identify risk factors for stress-related disorders and other health outcomes among military personnel. Selected References Institute of Medicine. Committee to Review the Health Consequences of Service During the Persian Gulf War. Health Consequences of Service During the Persian Gulf War Initial Findings and Recommendations for Immediate Action. Washington, D.C.: National Academy Press, 1995. Institute of Medicine. Committee to Review the Health Consequences of Service During the Persian Gulf War. Health Consequences of Service During the Persian Gulf War: Recommendations for Research and Information Systems. Washington, D.C.: National Academy Press, 1996.
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--> William Page's tenure as acting director reached an end in 1992 with the appointment of Chris Howson as interim director. After the ensuing search, IOM leadership recruited Dr. Richard Miller from the Walter Reed Medical Center as the new director of the program in 1993. Coming from both a medical and a military background, Miller fit many of the stipulations for a successful director set forth by the site visit group shortly after Jablon left the agency. Miller continued efforts begun under both Page and Howson. One especially notable study begun under Howson was designed to monitor the health status of Persian Gulf veterans (see Box 16). The mere fact of this study indicated that the agency fit better into the 1990s than at any time in decades. Page, Howson, and Miller would not let the opportunity presented by the Gulf War slip the way the Vietnam War had through the fingers of the MFUA staff in the early 1970s. Miller took steps to make the agency more visible within the IOM structure, successfully arguing that the MFUA's oversight group should be a board instead BOX 17 Studies of Participants in Atmospheric Tests of Nuclear Weapons In 1976 the case report of a paratrooper diagnosed with acute myelocytic leukemia reached the Centers for Disease Control and Prevention (CDC). The paratrooper attributed the leukemia's occurrence to his presence at the test detonation of the nuclear device "SMOKY." Subsequent preliminary investigations by the CDC and others raised concerns about increased mortality rates due to leukemia among all participants in atmospheric nuclear weapons tests. In 1979, the Medical Follow-up Agency was commissioned to investigate mortality among individuals present at these tests. This investigation culminated in a National Research Council (NRC) report Mortality of Nuclear Weapons Test Participants , published in 1985. This report examined the records of soldiers participating in at least one of five select nuclear weapons test series between 1951 and 1957. Researchers did not identify any statistically significant increase in mortality attributed to radiation-related disease (e.g., leukemia or other malignancies) among the individuals studied, other than those leukemias previously noted among SMOKY participants. However, in 1992 the U.S. General Accounting Office distributed a report concluding that the data provided by the Defense Nuclear Agency (DNA), and used by the MFUA in the preparation of its 1985 report, contained misclassification errors that rendered the study flawed. The MFUA was asked to redo its earlier research. This study, scheduled for completion in 1999, uses a DNA-corrected and updated participant list, a comparison group of military personnel who did not participate in the atomic tests, and the addition of mortality data for 10 years since the earlier publication. Meanwhile, in 1996, the NRC published another MFUA report examining mortality among participants in atmospheric tests of nuclear weapons. This study (Johnson et al. 1996) compared the mortality of Navy personnel participating in the CROSSROADS test series with the mortality of those in a comparison group. Although the study found a small but statistically significant increase in mortality
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--> of a committee. Looking toward the future, Miller and his staff envisioned a Medical Follow-up Agency that would balance ongoing follow-up as in the multiple sclerosis or POW studies, cutting-edge research as in the various twin studies, and politically delicate studies such as those of Persian Gulf veterans or of atomic veterans (see Box 17).181 Conclusion Since its founding in 1946, the Medical Follow-up Agency has successfully met many challenges. The agency continues to contribute to the research community because of the ingenuity and resolve of researchers such as Dr. Michael DeBakey. DeBakey and Gilbert Beebe sensed the opportunity to create a medical organization that would be a force for good in post-World War II America by channeling the experience of the war into useful medical knowledge. Beebe and among the participants, its findings did not support the hypothesis that radiation exposure was the cause. In part as an outgrowth of the MFUA's reputation in the field of atmospheric test participant research, the Army surgeon general asked the MFUA to assemble an expert committee to review a set of proposed NATO guidelines for the exposure of soldiers to radiation doses that are well short of those that cause acute effects but that may carry the risk of subsequent cancers. The committee's interim report addressed the technical aspects of the NATO documents. In its final report the committee discussed an ethical framework for considering when to put soldiers at risk and what obligations might then follow. Although this last activity does not directly benefit the test participants, it may contribute to the military's avoidance of unnecessary radiation exposures in the future and may help to improve the decision-making and operating procedures in place to protect personnel in cases where exposure is deemed warranted. Selected References Institute of Medicine. A Review of the Dosimetry Data Available in the Nuclear Test Personnel Review (NTPR) Program: An Interim Letter Report of the Committee to Study the Mortality of Military Personnel Present at Atmospheric Tests of Nuclear Weapons. Washington, D.C.: National Academy Press, 1995. Institute of Medicine. An Evaluation of Radiation Exposure Guidance for Military Operations, Interim Report. J.C. Johnson and S. Thaul (eds.). Washington, D.C.: National Academy Press, 1997. Institute of Medicine. Potential Radiation Exposure in Military Operations: Protecting the Soldier Before, During, and After. S. Thaul and H. O'Maonaigh (eds.). Washington, D.C.: National Academy Press, 1999. Johnson, J.C., Thaul, S., Page, W.F., Crawford, H. Mortality of Veteran Participants in the CROSSROADS Nuclear Test. Washington, D.C.: National Academy Press, 1996. National Research Council. Mortality of Nuclear Weapons Test Participants . Washington, D.C.: National Academy Press, 1985.
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--> Past and present MFUA leadership gathered at the 50th Anniversary Meeting on October 16, 1996. From left to right, back row: Dr. William Page, Dr. Richard Miller, and Mr. Seymour Jablon; front row: Dr. Michael DeBakey and Dr. Gilbert Beebe. Photo courtesy of Dr. William Page. his successors—Jablon, Page, Miller, and numerous others have fostered an entity flexible enough to mold itself to the times but resolute enough to overcome the numerous obstacles in its path. Although DeBakey and Beebe thought the agency would help guide clinical practice, the entity they created instead developed great expertise in epidemiology. The agency remains a central repository of data and analytical talent. It continues to nurture some of the best epidemiological and medical research of the postwar period. This body of work is its central legacy and its best claim to excellence.
Representative terms from entire chapter: