1978 ANALYTICAL EPIDEMIOLOCY PROGRAM AREA REPORT

ANALYTICAL EPIDEMIOLOGY PROGRAM AREA REPORT
October 1, 1977 to September 30, 1978

Program Coordinators:

Dr. T. Hirayama
Dr. R. W. Miller

Administrative Report
The following is a listing of the past year's activities, which includes Meetings, Seminars, and Conferences; the Exchange of Scientists; and the Exchange of Materials.

MEETINGS, SEMINARS, AND CONFERENCES
The Japan-U.S. Conference on Biostatistics in the Study of Human Cancer was held at the Radiation Effects Research Foundation (RERF) in Hiroshima, May 22 to 25. 1978. Eight visitors from the United States, others from the RERF, and about 40 Japanese attended this rare interaction of statisticians and physicians (mostly epidemiologists). The purpose of the conference was to seek fresh views on medical statistics (scientific design and data analysis) as it relates especially to oncology. In Japan there has been no tradition of biostatistics among mathematicians. The conference may have encouraged developments between the two countries in this regard. As a next step, two biostatisticians in oncology, one of them a physician, are to be asked to participate in an inter-national conference on "Information Systems," to be held in Tokyo during the summer of 1979.
After the Hiroshima conference, five of the U.S. biostatisticians gave a one-day symposium at the Fukuoka Medical College, two spoke at the Institute of Statistical Mathematics in Tokyo, and one each spoke at Kawasaki University in Kurashiki,
Nagoya University, Osaka University, the Adult Health Center in Osaka, Chiba University, and Tokyo University. There was a substantial exchange of biostatistical viewpoints during these visits.

EXCHANGE OF SCIENTISTS
1. Saketami Tominaga, M.D., Chief of the Division of Epidemiology at the Aichi Cancer Research Institute, spent one month in the United States during September 1977. He visited several centers for cancer epidemiology, including the Johns Hopkins University School of Public Health, the American Health Foundation in New York, the National Cancer Institute (NCI), and the Cancer Center In Honolulu.
2. A group of four U.S. biostatisticians served as visiting scientists (see Meetings, Seminars, and Conferences above). They were James E. Grizzle, Ph.D., Professor and Chairman. Department of Biostatistics at the University of North Carolina, School of Public Health; Edmund A. Gehan, Ph.D., Chief, Department of Biomathematics, M.D. Anderson Cancer Center ; David G. Hoel, Ph. D., Chief, Biometry Branch and Acting Scientific Director, National Institute of Environmental Health Sciences; and John J. Gart, Ph.D., Head, Mathematical Statistics and Applied Mathematics Section, National Cancer Institute (NCI).

EXCHANGE OF MATERIALS
1. A sample of preserved mixed vegetables ("pickles") from Linhsien County, China, suspected of containing a carcinogen related to concurrent epidemics of esophageal cancer in man and gullet cancer in chickens, were brought by Dr. R. W. Miller to the laboratories of Dr. T. Sugimura to be tested in the Ames system. The test was positive, indicating the presence of a mutagen/carcinogen. The active principle could be isolated if a large sample of "pickles" were available, but so far such a sample has not been available.
2. The Chinese claimed that cigarette smoking was not carcinogenic in the People's Republic. Sample packs of two brands of Chinese cigarettes brought by Dr. Miller to Dr. Sugimura for Ames testing proved to be as mutagenic as European, Japanese or American cigarettes. Thus, the Chinese have not happened upon a safe cigarette.
3. Lyophilized urine specimens from several U.S. families with high frequencies of specific cancers have been sent from the Clinical Epidemiology Branch, NCI, to Dr. Sugimura for Ames testing. So far, one family with four children and three other relatives with acute myelogenous leukemia and possible DNA repair defect, has shown questionably abnormal Ames test results. Repeat specimens have been sent to Tokyo. Another family had urinary bladder cancer in three generations, and a third family had five members with renal cell carcinoma.

FUTURE MEETINGS
It is possible that two U.S. computer experts in medicine/oncology will be sent to participate in an international conference in Tokyo in the Summer of 1979 (see Meetings, Seminars, and Conferences above).

Scientific Summary of Program Area

SUMMARY OF YEAR'S ACTIVITIES
1. The Japanese side published a volume on cancer morbidity in the United States and Japan (see Publications following).
2. A binational and multidisciplinary dialogue of physician-oncologists and statisticians may have been initiated.

SPECIFIC OBJECTIVES TO BE ACCOMPLISHED
1. Further encouragement of biostatistical exchanges.
2. New interactions between epidemiologic and laboratory research on carcinogenesis under the reorganized U.S.-Japan Cooperative Cancer Research Program, which brings both under the same overall leadership.

COOPERATIVE ACTIVITIES RESULTING FROM PAST MEETINGS
1. See Meetings, Seminars, and Conferences above.
2. Takashi Yanagawa, D.Sc., a statistician, completed a year as a Visiting Scientist (sponsored by National Institutes of Health (NIH) in the United States) in the Environmental Epidemiology Branch. He has returned to the Department of Mathematics at Kyushu University, where he played an important role in arranging for the conference described in Meetings, Seminars, and Conferences above. He apparently developed a substantial interest in medical statistics while at the National Cancer Institute.

Publications
l. Hirayama, T., ed., Comparative Epidemiology of Cancer in the U.S. and Japan: Morbidity. Japan Society for the Promotion of Science, Tokyo, May 1978, 107 pages.
2. "Proceedings of the Japan-U.S. Conference on Biostatistics in the Study of Human Cancer." Environmental Perspectives. In press.

SUMMARY OF FUTURE PROGRAM DEVELOPMENTS
In addition to the Program developments described above, many new interdisciplinary activities will be pursued under the new reorganized binational program.

Five Year-Summary Report

SUMMARY OF ACTIVITIES AND ACCOMPLISHMENTS
The U.S.-Japan Cooperative Cancer Research Program was established in May 1974. Except for the Chairmen, its Committee on Analytical Epidemiology has varied in membership from meeting to meeting in accord with the subject under discussion.

Host Susceptibility
During a visit to Japan on May 18, 1974, Dr. Robert Miller met in Tokyo with Dr. Takeshi Hirayama and other epidemiologists for a one-day symposium concerning the Japan Childhood Tumor Registry. Between 1969 and 1973, and continuing since then, this Registry recorded about 1000 new cases each year in six large metropolitan areas.
During the visit, Dr. Miller learned in advance that the Japanese planned to send 20 middle-level academic physicians annually to the United States for up to three months each. To make the most of this opportunity, it was agreed that Dr. Keiko Ohmi, a pediatric oncologist at Tokyo University who attended the one-day symposium, would be the first exchange scientist under the Program's Committee on Analytical Epidemiology. She would concentrate on family cancer studies as a source of clues to new understanding of the fundamental biology of cancer. The approach, although productive in the United States, was not widely applied there because it did not come easily to clinicians. In Japan, there appeared to be much wider susceptibility to the concept. Dr. Ohmi learned a great deal about U.S. oncology in general during her two month stay in early 1975 in the Epidemiology Branch, NCI. She also visited five pediatric cancer centers in other cities. The characteristic heavy case-load of hospital physicians in Japan permitted only limited application of the etiological research approaches she observed at the NCI.
A second opportunity to develop bedside etiologic studies arose later in the year when a conference on the genetics of human cancer was held in Orlando, Florida, December 2 to 4, 1975. The sessions were attended by about 100 persons, including Dr. Hirayama, six other Japanese epidemiologists, and the U.S.-U.S.S.R. Joint Working Group on Mammalian Somatic Cell Genetics Related to Neoplasia. After the conference, a one and one-half day symposium was held in Orlando, Florida, for the U.S.-Japan Committee on Analytical Epidemiology. The title, "Precious Cases for Epidemiological Studies," was suggested by Dr. Hirayama. Substantial information was exchanged, which affected future directions of the Committee and of individual participants. In particular, the concepts of family studies and host susceptibility seem more likely to gain ground through clinicians and laboratory scientists than through classical epidemiologists.

Environmental and Demographic Studies
Meanwhile, Dr. Hirayama was invited to participate in a three-day conference sponsored primarily by the Epidemiology Branch, NCI, in Key Biscayne, Florida, on December 10 to 12, 1974. This meeting led to the publication of its very well received proceedings, "Persons at High Risk of Cancer," which has become a handbook on environmental cancer epidemiology. Also at the meeting was Dr. M. Hitosugi an environmental epidemiologist, who worked with Dr. Hirayama's group and has since moved to Kitasato University. Dr. Hitosugi's attendance took place during his six-month appointment as a visiting scientist in the Epidemiology Branch, NCI, beginning in October 1974, under the sponsorship of another binational program (the Panel on Environmental Mutagenesis and Carcinogenesis of the U.S.-Japan Cooperative Medical Science Program). Dr. Hitosugi has had an extraordinary exposure to developments in U.S. cancer epidemiology during the six-month period and during his attendance at the conference, both in the field of environmental cancer and in the field of genetics of human cancer.
On February 22, 1975, during a visit to Japan, Dr. Miller met for several hours with Dr. Hirayama and with four epidemiologists from elsewhere in Japan to discuss recent developments in epidemiology in each country. Special emphasis was placed on the desirability of comparing cancer mortality maps by county (or health care districts) in Japan with those being produced at the National Cancer Institute (NCI). Such maps have since been issued by both countries, and were independently "invented" in the People's Republic of China, where cancer mortality for specific anatomic sites is being mapped by commune for seven Provinces.
On May 4, 1976, Dr. Hirayama met in Bethesda, Maryland, with Dr. Miller to discuss future activities of the Committee. In preparation for its meeting in October, Dr. Hirayama requested that, by August 1976, data be provided to him on age-specific and sex-specific mortality rates for U.S. whites and blacks annually, 1950-1974, to be com-pared with Japanese data. Tapes, microfiche, and tabulations were hand carried to Tokyo in August by Dr. Miller, who was attending a meeting there. Dr. Hirayama has since published the data as a book on cancer mortality issued by the Japan Society for the Promotion of Science (see Publications below) He has also used published U.S. data on cancer morbidity as compared with Japanese data for a publication under the same auspices (see Publications below).
The second exchange scientist under the Pro-gram was Dr. T. Kawana, an obstetrician-virologist from Tokyo University interested in comparing Infection with herpesvirus type-2 in uterine vaginal cancer in Japan and in the U.S. He spent a productive three months each at Johns Hopkins and at Emory Universities beginning in February 1975.
On October 8 and 9, 1975, Dr. Kawana reported at a Tokyo meeting of the Committee that differences between the findings in the two countries in addition to other evidence, indicated that herpesvirus infection cannot account for a substantial proportion of cases of uterine cervical cancer. At the meeting, Dr. Hirayama presented the graphs for cancer mortality by age, sex, calendar time, and race (whites, blacks, Japanese) based in part on un-published U.S. data especially obtained and brought to him two months earlier.
The U.S. participants consisted of five scientists who were already in Japan for other reasons. In accord with their interests, a comparison was made of the etiologies, insofar as they are known, of leukemia, uterine cervical cancer, and urinary bladder cancer. Epidemiologic and laboratory evidence indicated that chromosomal abnormalities were associated with leukemia, that uterine cervical cancer seems to be horizontally transmitted as a venereal disease, and that bladder cancer is largely due to chemicals and cigarette smoking. The epidemiologic contrasts of these three cancers is marked, and indicates dissimilar origins.
The meeting generated several important questions or comments, which arose largely through the intermingling of scientists from different specialities. Of particular interest was the observation that the Japanese are "resistant" to five forms of lymphatic disease: chronic lymphocytic leukemia, lymphosar-coma, infectious mononucleosis, lymphoma after immunosuppression for renal transplantation, and Hodgkin's disease early in life that gives rise to the first of the bimodal age-peaks, absent in Japan but seen in all other countries. The sixth Japanese exchange scientist under the Program. Dr. T Miyake, an epidemiologist from Sapporo Medical College, has a special interest in leukemia, and discussions will be held with him on the above peculiarities of occurrence when he visits the United States for one month beginning late September 1978.

Biostatistical Innovations
Apart from the staff of the Radiation Effects Research Foundation (RERF) in Hiroshima, Japan (formerly the Atomic Bomb Casualty Commission). U.S. biostatisticians are seldom involved with activities in Japan. Traditionally, Japanese statisticians have not been concerned with biology or medicine, thus accounting for the near absence of contact between the two countries in biostatistics.
Early in 1975, Dr. Miller initiated inquiries about the possibility of a conference of U.S. and Japanese biostatisticians. As a first step in this direction, Dr. William J. Blot, a biostatistician in the Epidemiology Branch, National Cancer Institute (NCI), spent three weeks at various Japanese research centers in October 1975 describing his specialty as it is applied in the United States. A spark of interest was struck in Dr. A. Kudo, a mathematical statistician at Kyushu University, who had spent several years in the United States using his creative mathematical talents in genetics and other biomedical subjects.
A second step involved the appointment of Dr. T. Yanagawa, a Ph.D. and a student of Dr. Kudo, for one year as a visiting scientist, sponsored by the NIH, under the direction of Dr. Blot at the National Cancer Institute (NCI). Dr. Yanagawa researched publications on biostatistics, wrote several papers on his ideas about them, and later helped immensely in planning the U.S.-Japan conference on biostatistics.
Japanese leaders in statistics agreed to participate, and the conference was organized by Drs. Kudo and Blot. Sponsorship by the Japanese side of the U.S.-Japan Cooperative Cancer Research Program depended on including medical epidemiologists, a wise decision.
The meeting was held at the Radiation Effects Research Foundation (RERF) on May 22 to 25, 1978, in Hiroshima. Seven biostatisticians and one epidemiologist attended from the United States, plus others from the RERF. About 25 Japanese mathematicians and medical epidemiologists attended in addition to those from RERF. Among them were an impressive group of Japanese "alumni" of a Visiting Scientist Program of ABCC/RERF sponsored by the NCI, under which several young physicians or statisticians each year came from government or universities to spend two months in the United States at a summer session on statistics or epidemiology at a School of Public Health, and ten months at the RERF in cancer epidemiology.
We learned at the conference that statistics as an independent discipline has not developed in Japan as it has in the United States, where over 190 universities offer graduate degrees in this field, and where about 35 universities specialize in biostatistics. In Japan no such degrees are offered, but mathematical statistics is taught at several universities. Not only did U.S. and Japanese statisticians meet for the first time, but so did physicians and statisticians within Japan, who found that they had interests in common. The meeting revealed that opportunities for statisticians in cancer research vary according to sub-area. Ingenuity can be vigorously tested in studies related to animal models, and essentially all recent advances in studies of human cancer survival data have come from biostatistics. By contrast, case-control studies require statisticians for proper planning and analysis, but not for statistical invention at this time.
After the conference, the U.S. biostatisticians served as short-term visiting scientists by speaking at eight academic centers. Three of the visitors expressed a desire to have young Japanese on fellowships in their departments. The Japanese senior statisticians in turn have asked if the United States can cover the expenses of two U.S. computer experts (one medical, one non-medical) to participate in an international conference on information systems in Tokyo to be held for a few days in the summer of 1979. After the conference the two computer experts would serve as exchange scientists for a short time at several universities. It is of interest that medical uses of the computer are being included in this conference organized by Japanese mathematicians.

Interaction of Epidemiology and Laboratory Research
New clues to the cause and prevention of cancer can come from clinical, epidemiological, or laboratory observations, but progress tends to be most rapid when the three research approaches interact with one another. Recently there has been such an exchange between the Clinical Epidemiology Branch of the NCI and Dr. Sugimura's laboratory. Pickles thought to be related to parallel epidemics of cancer of the esophagus/gullet in people and chickens of Linhsien County, China, were brought by Dr. Miller to Dr. Sugimura's laboratory for testing in the Ames system. They proved to be mutagenic, and may therefore also be carcinogenic. As yet, additional samples have not been available for isolation of the active principle. Two brands of Chinese cigarettes have been Ames-tested by Dr. Sugimura's group to determine if the claim that lung cancer is not related to smoking is due to a lack of carcinogens in their cigarettes. It is not, for the cigarettes were just as mutagenic as those made elsewhere in the world. Lyophilized urine specimens from several families heavily affected by specific cancers and under study by Dr. Miller's group have been sent to Tokyo for Ames testing by Dr. Sugimura's staff. In one family so far, the results were thought to be abnormal. The test is being repeated on new specimens.

EXCHANGE OF SCIENTISTS
The following Japanese scientists visited their counterparts in the United States.
February to March 1975:
Dr. Keiko Ohmi, a pediatric oncologist from the Department of Pediatrics at Tokyo University, spent two months in the Epidemiology Branch, National Cancer Institute (NCI), learning about clinical aspects of epidemiology especially as they relate to family cancers. She also observed the U.S. style of chemotherapy and psychological aspects of childhood leukemia. She visited the pediatric oncology units at Memorial Hospital in New York, Cincinnati Children's Hospital, St. Jude Hospital, the M.D. Anderson Hospital, and the Texas Children's Hospital in Houston.
February to July 1975:
Dr. T. Kawana, an obstetrician-virologist at Tokyo University, worked in the laboratories of Dr. L. Aurelian at Johns Hopkins University and Dr. A. Nahmias at Emory University studying infection with herpesvirus type-2 in relation to cancer of the uterine cervix in Japan as compared with the U.S.
July to December 1975:
Dr. K. Fukuda, an epidemiologist from Sapporo University, spent six months with Dr. T. Hirohata in the Department of Epidemiology at the University of Hawaii School of Public Health in studies of epidemiologic methods.
March 29 to April 28, 1977:
Dr. M. Nagao, a biochemist from the National Cancer Research Institute in Tokyo, spent two weeks in the Clinical Epidemiology Branch, National Cancer Institute (NCI), and two weeks with Dr. K, Nakanishi at Columbia University to discuss case-ascertainment for studies using the Ames test and sister-chromatid exchange evaluation as measures of mutagenicity/carclnogenicity and to demonstrate her methods for heightening the sensitivity of the Ames test.
September 13 to October 12, 1977:
Dr. S. Tominaga, from his new position as Chief, Division of Epidemiology, Aichi Cancer Center Research Institute, visited several centers for cancer epidemiology in the U.S. for background in developing plans for his program in Nagoya.
September 25 to October 24, 1978:
Dr. H. Miyake, Professor of Public Health at Sapporo Medical College, will visit Roswell Park Memorial Institute in Buffalo and the National Cancer Institute (NCI) to discuss the epidemiology of leukemia and methods for teaching the subject.

The following U.S. scientists visited their counterparts in Japan:
October 1975:
Dr. William J. Blot, a biostatistician in the Epidemiology Branch, NCI, spent three weeks discussing and lecturing on the importance of biostatistics in biomedical research, with special reference to oncology. He visited the National Cancer Center Research Institute, the Institute for Statistical Mathematics, the Institute of Public Health (all three in Tokyo), the Department of Preventive Medicine of Kitasato University, the Department of Public Health of Sapporo Medical College, the Department of Epidemiology of Aichi Cancer Center, the Adult Health Center in Osaka, the Radiation Effects Research Foundation in Hiroshima, the Department of Public Health and Mathematics at Kyushu University, and the Department of Human Genetics at the National Institute of Genetics in Mishima. The trip laid the groundwork for a binational conference three years in the future.
May 22 to 31, 1978:
Four U.S. biostatisticians visited Japan along with four other U.S. participants in a Japan-U.S. Conference on Biostatistics in the Study of Human Cancer, May 22 to 25, 1978. After the Conference they visited singly, in pairs, or as a group, the Fukuoka Medical College, the Adult Health Center in Osaka, Osaka University, Nagoya University, Chiba University, and the Institute for Statistical Mathematics in Tokyo. Seminars or lectures were given at each place during the interval of May 27 to 31, 1978.

PUBLICATIONS
1. Hirayama, T., ed., Comparative Epidemiology of Cancer in the U.S. and Japan: Mortality. The U.S.-Japan Cooperative Cancer Research Program. January 1977, pp. 122.
2. Hirayama, T., ed., Comparative Epidemiology of Cancer in the U,S. and Japan: Morbidity. Japan Society for the Promotion of Science, Tokyo, May 1978, pp. 107.
3. "Proceedings of a Japan-U.S. Conference on Biostatistics in the Study of Human Cancer." Environmental Perspectives. In press.

FUTURE DEVELOPMENTS
Future exchanges of scientists in biostatistics and computer technology as related to cancer research are contemplated, along with a continued exchange of medical epidemiologists. A greater interaction of epidemiology and laboratory research is anticipated under the reorganized binational program.