1. Role of Statisticians in Follow-Up of A-Bomb Survivors Donald A. Pierce Oregon Health & Sciences Univ. Retired from Radiation Effects Res. Fndn. Slides for talk, related things, at www.science.oregonstate.edu/~piercedo

3. OSU 50th3 Some brief history of ABCC/RERF, including role of statisticians General nature of the radiation-cancer dose response, including age-time variation (Note: Is primary source of quantitative information on radiation effects in humans -- medicine, workplace, environment) Why the continued research remains important after more than 50 years My Talk Today

4. OSU 50th4 Bombs August 1945, “Joint Commission” of Occupation, October 1945 Pres. Truman directive to NAS 1946, Atomic Bomb Casualty Commission (ABCC) Motivations: leukemia, cancer, acute effects, inherited effects, others By 1950 Depts of Genetics, OBGYN, PEDS, Internal Med, Radiology, Pathology, Biochem/Micro, Biometrics

5. OSU 50th5 Large-scale clinical and pathology programs: examinations and autopsies Enormous efforts interviewing survivors within 2 km for “shielding histories” More than 1500 employees at peak, now about 250 with 40 scientists Americans: Around 10-15 recently, with far more at peak (largely physicians – military and jointly with Yale)

6. OSU 50th6 Francis Committee (Jablon, Moore) 1955 profound effect establishing sound epidemiological study Fixed study cohort of around 100,000 that could be followed up (most importantly no addition of “cases only”; also for F1 and in- utero) Became bi-national Radiation Effects Research Foundation (RERF) 1975 Recurrent low ebbs, particularly in the late 1970’s

7. OSU 50th7 Statisticians played increasingly major role from around 1950 Gil Beebe, Seymour Jablon were the NAS contract officers during about 1955-85 Charles Land (OSU 1970-75) was in Hiroshima about 6 years, is still involved Many other US statisticians were there for 2 years or so in that era Several Japanese statisticians highly involved, but …

8. OSU 50th8 In 1978 Jablon set up a major contract with UW Biostats (low ebb thing) Ross Prentice, Art Peterson, others, were there in 1980-81 They recruited Dale Preston and me in 1981 – Preston stayed until 2004 and I was there for 16 years during 81-04. Other OSU connections include students Ken Kopecky and Bob Delongchamp By 1987 we had a Stats Dept of 15 that would have done well in a US university

9. OSU 50th9 Thanks to Beebe, Jablon & Land, by 1975 stat methods were state of art in testing for effects (Mantel-Haenszel methods) These methods did not lend themselves to estimation, so Preston and I took this on Relative risk regression notions had just become available; requiring adaptation for large study, suitable form of interactions, multiple “time scales” By 1986 we had this ready for use, with widely-used and general interactive software developed by Preston (Epicure)

10. OSU 50th10 Possibilities richer than most applications, due to size of study and small chance of confounding (can estimate RR’s of 1.1) Largely because the dose-distance gradient was very steep, so those with large and small doses differ little otherwise Also, the participation and follow-up rates were essentially 100% (interesting point) Finally, there is such a long-term strong interest, promoting continued efforts

11. OSU 50th11 To proceed, we need some perspective on radiation dose Gray 1 Gy to major organs causes severe illness, although seldom fatal A CT scan, although usually localized, is about 0.01 Gy ; GI series about half of that Occupational limits are about 0.02 Gy/yr, although cumulatively further limited Thus 0.10 Gy is a fairly large dose of considerable interest

12. OSU 50th12 General Summary Dose GyMean Distance Persons Followed CA Cases 1958-98 Est Excess Cases < 0.005368060,8009,6003.005 – 0.1199027,8004,40080 0.1 – 0.216305,50097075 0.2 – 0.515005,9001,100180 0.5 – 112803,170690210 1 – 211101,65046044 >290056418561 Tot excl <.0005 row 44,584 7,805 650 First row is a sample of distal survivors 5-10 km --- thus analyses are done totally within cohort

13. OSU 50th13 ERR is factor increasing baseline rates, here sex-averaged: F:M ratio is 6:4 (offsets baseline ratio) ---- EAR is absolute risk

14. OSU 50th14 ERR is factor increasing baseline rates, here sex averaged and at age 70 At 1 Gy rates are increased by about 50% over normal levels

15. OSU 50th15 Why such long follow-up, and such extensive analysis, is needed Lifelong effect for cancer was not expected Even when this became apparent the age- decline in RR was confused with effect of exposure age Understanding of such things is only emerging with continued follow-up and analysis

16. OSU 50th16 The left panel here shows the view of things until the late 1990s (still widely held) and the right panel shows our current understanding of the same data We now have a reasonable understanding of why the age-declining ERR should be expected

17. OSU 50th17 Simply, cancer is caused by accumulation of somatic mutations, and The radiogenic mutations persist for all remaining lifetime, but become relatively less important as more accumulate For any mutational exposure (including smoking) with age-cumulative dose D(a) it is plausible and explains well the data that

18. OSU 50th18 Continued follow-up and analysis is needed to clarify the effect of exposure age --- one of the most important remaining issues On another issue, some would like to believe that for small radiation doses, e.g. 0.05 Gy, there is no cancer risk at all But careful analysis based on the 30,000 survivors in the low-dose range shows that this is implausible Statisticians also have clarified the (modest) effect of random errors in dose estimates

19. OSU 50th19 Virtually no other data really bear strongly on the quantitative needs for radiation protection Less explicable effect on non-cancer mortality, much smaller ERR Possible that this is only for large doses, due to killing large proportions of marrow cells with immunological effects Virtually no evidence of inherited effects, where mechanisms seem mainly limited to gonadal mutations

20. OSU 50th20 The needs and opportunities at RERF, along with the “Golden Age” of biostatistics, made all this incredibly attractive My OSU career spanned 25 years and was very good for me, forming the basis for that “second career” Am really grateful for what both places have meant for me and my family

21. OSU 50th21 SOME REFERENCES Preston, D.L., Shimizu, Y., Pierce, D.A., Suyama, A. and Mabuchi, K. (2003b). Studies of mortality of atomic bomb survivors, Report 13: Solid cancer and noncancer mortality 1950 –1997. Radiation Research 160, 381- 407. Pierce, D.A. and Vaeth, M (2003e). Age-time patterns of cancer to be anticipated from exposure to general mutagens. Biostatistics 4, 231-248. Pierce, D.A. (2002). Age-time patterns of radiogenic cancer risk: their nature and likely explanations. Journal of Radiological Protection 22, A147- A154. Pierce, D.A., Stram, D.O., Vaeth, M., and Schafer, D.W. (1992b). The errors-in-variables problem: considerations provided by radiation dose- response analyses of the A-bomb survivor data. J. Amer. Statist. Assn. 87, 351-359. Pierce, D.A. and Preston, D.L. (2000a). Radiation-related cancer risks at low doses among atomic bomb survivors. Radiation Research 154, 178- 186.