Improved estimates of cancer site-specific risks for A-bomb survivors

Pawel, D. J., Preston, D. L., Pierce, D. A. and Cologne, J. B. Improved Estimates of Cancer Site-Specific Risks for A-Bomb Survivors. Radiat. Res. 169, 87-98 (2008). Simple methods are investigated for improving summary site-specific radiogenic risk estimates. Estimates in this report are derived from cancer incidence data from the Life Span Study (LSS) cohort of A-bomb survivors that are followed up by the Radiation Effects Research Foundation (RERF). Estimates from the LSS of excess relative risk (ERR) for solid cancer sites have typically been derived separately for each site. Even though the data for this are extensive, the statistical imprecision in site-specific (organ-specific) risk estimates is substantial, and it is clear that a large portion of the site-specific variation in estimates is due to this imprecision. Empirical Bayes (EB) estimates offer a reasonable approach for moderating this variation. The simple version of EB estimates that we applied to the LSS data are weighted averages of a pooled overall estimate of ERR and separately derived site-specific estimates, with weights determined by the data. Results indicate that the EB estimates are most useful for sites such as esophageal or bladder cancer, for which the separately derived ERR estimates are less precise than for other sites.     

The effect of diagnostic misclassification on non-cancer and cancer mortality dose response in A-bomb survivors.

We used the EM algorithm in the context of a joint Poisson regression analysis of cancer and non-cancer mortality in the Radiation Effects Research Foundation (RERF) Life Span Study (LSS) to assess whether the observed increased risk of non-cancer death due to radiation exposure (Shimizu et al., RERF Technical Report 02-91, 1991) can be attributed solely to misclassification of cancer as non-cancer on death certificates. We show that greater levels of dose-independent misclassification than are indicated by a series of autopsies conducted on a subset of LSS members would be required to explain the non-cancer dose response, but that a relatively small amount of dose-dependence in the misclassification of cancer would explain the result. The adjustment for misclassification also results in higher risk estimates for cancer mortality. We review applications of similar statistical methods in other contexts and discuss extensions of the methods to more than two causes of death.     

Model averaging in the analysis of leukemia mortality among Japanese A-bomb survivors

Epidemiological studies often include numerous covariates, with a variety of possible approaches to control for confounding of the association of primary interest, as well as a variety of possible models for the exposure–response association of interest. Walsh and Kaiser (Radiat Environ Biophys 50:21–35, 2011) advocate a weighted averaging of the models, where the weights are a function of overall model goodness of fit and degrees of freedom. They apply this method to analyses of radiation–leukemia mortality associations among Japanese A-bomb survivors. We caution against such an approach, noting that the proposed model averaging approach prioritizes the inclusion of covariates that are strong predictors of the outcome, but which may be irrelevant as confounders of the association of interest, and penalizes adjustment for covariates that are confounders of the association of interest, but may contribute little to overall model goodness of fit. We offer a simple illustration of how this approach can lead to biased results. The proposed model averaging approach may also be suboptimal as way to handle competing model forms for an exposure–response association of interest, given adjustment for the same set of confounders; alternative approaches, such as hierarchical regression, may provide a more useful way to stabilize risk estimates in this setting.     

Studies of the mortality of A-bomb survivors. 8. Cancer mortality, 1950-1982

This study extends an earlier one by 4 years (1979-1982) and includes mortality data on 11,393 additional Nagasaki survivors. Significant dose responses are observed for leukemia, multiple myeloma, and cancers of the lung, female breast, stomach, colon, esophagus, and urinary tract. Due to diagnostic difficulties, results for liver and ovarian cancers, while suggestive of significant dose responses, do not provide convincing evidence for radiogenic effects. No significant dose responses are seen for cancers of the gallbladder, prostate, rectum, pancreas, or uterus, or for lymphoma. For solid tumors, largely due to sex-specific differences in the background rates, the relative risk of radiation-induced mortality is greater for women than for men. For nonleukemic cancers the relative risk seen in those who were young when exposed has decreased with time, while the smaller risks for those who were older at exposure have tended to increase. While the absolute excess risks of radiation-induced mortality due to nonleukemic cancer have increased with time for all age-at-exposure groups, both excess and relative risks of leukemia have generally decreased with time. For leukemia, the rate of decrease in risk and the initial level of risk are inversely related to age at exposure.     

Selection bias in cancer risk estimation from A-bomb survivors

We consider the possible bias in cancer risk estimation from A-bomb survivors due to selection of the cohort by survival. The paper considers both relevant information from the data and basic theoretical issues involved. The most direct information from the data comes from making various restrictions on the dose-distance range, partly to reduce differential selection and partly just to reduce the magnitude of the selection. These analyses suggest that there are no serious biases, but they are not conclusive. Theoretical considerations include laying out more explicitly than usual just how biases could result from the selection. This involves heterogeneities in the ability to survive acute effects, in baseline and radiogenic cancer rates, and most importantly the correlation between survival-related and cancer-related heterogeneities. Following on this, idealized modeling is used to quantify the extent of possible bias in terms of the assumed values of the magnitude of these heterogeneities and their correlation. It is indicated that these values would need to be very large to introduce substantial bias. Based on all these considerations, it seems unlikely that the bias in cancer risk estimation could be large in relation to other uncertainties in generalizing from what is seen among A-bomb survivors; in particular, indications are that the bias in relative risks is unlikely to be as large as 0.05 to 0.07. For solid cancer this would correspond to bias in the excess relative risk at 1 Sv of at most about 15-20%.     

The observed relationship between the occurrence of acute radiation effects and leukemia mortality among A-bomb survivors

In an analysis of a follow-up study of a fixed population of 73,330 atomic bomb survivors in Hiroshima and Nagasaki, the slope of an estimated dose response between ionizing radiation and leukemia mortality was found to be steeper (P less than 0.002), by a factor of 2.4, among those who reported epilation within 60 days of the bombings, compared to those who did not experience this sign of acute radiation exposure. The strength of this empirical finding as evidence of biological association in individual radiosensitivity for these two end points is studied here. The major factor complicating the interpretation of this finding as evidence of such an association is the degree of imprecision of the radiation dosimetry system used in assignment of radiation doses to the A-bomb survivors. Using models recently suggested for dealing with dosimetry errors in epidemiological analysis of the A-bomb survivor data, the sensitivity of the apparent association between leukemia mortality and severe epilation to the assumed level of dosimetry error is investigated.     

Threshold and other departures from linear-quadratic curvature in the non-cancer mortality dose-response curve in the Japanese atomic bomb survivors

Recently released data on non-cancer mortality in Japanese atomic bomb survivors are analysed using a variety of generalised relative risk models that take account of errors in estimates of dose to assess the dose-response at low doses. If linear-threshold, quadratic-threshold or linear-quadratic-threshold relative risk models (the dose-response is assumed to be linear, quadratic or linear-quadratic above the threshold, respectively) are fitted to the non-cancer data there are no statistically significant (p>0.10) indications of threshold departures from linearity, quadratic curvature or linear-quadratic curvature. These findings are true irrespective of the assumed magnitude of dosimetric error, between 25%–45% geometric standard deviations. In general, increasing the assumed magnitude of dosimetric error had little effect on the central estimates of the threshold, but somewhat widened the associated confidence intervals. If a power of dose model is fitted, there is little evidence (p>0.10) that the power of dose in the dose-response is statistically significantly different from 1, again irrespective of the assumed magnitude of dosimetric errors in the range 25%–45%. Again, increasing the size of the errors resulted in wider confidence intervals on the power of dose, without marked effect on the central estimates. In general these findings remain true for various non-cancer disease subtypes.     

Immunological responses of aging Japanese A-bomb survivors

Immune response parameters were studied on 1341 A-bomb survivors residing in Hiroshima, Japan. Mononuclear cells were isolated from venous blood and tested for interleukin-2 production; lymphocytes were purified and tested for natural killer (NK) cell activity and interferon (IFN) production; and serum was tested for IFN and circulating immune complex (CIC) levels. Statistical analyses were performed for each type of assay using a linear models procedure including sex, age at the time of the bomb, radiation exposure, all the interaction variables, and the categorical variable day-of-assay in the model. The findings showed that (1) none of the immunologic variables were significantly affected by radiation exposure; (2) NK activity and CIC levels were positively associated with age; and (3) NK activity was on average higher for males than females. The data exemplify the difficulty in reaching firm conclusions concerning associations with radiation exposure when the dependent variable exhibits a large degree of interindividual and day-of-assay variability.     

Temporal analysis of a dose-response relationship: leukemia mortality in atomic bomb survivors

A data analysis that incorporates time dependencies is demonstrated for the dose response of leukemia mortality in the atomic bomb survivors. The time dependencies are initially left unspecified and the data on leukemia mortality--up to the end of 1978--are used to infer them. Several findings based on T65 revised doses (T65DR) are obtained. First, it is shown that the fits to the data of time-dependent L (linear in gamma dose)-Q (quadratic in gamma dose)-L (linear in neutron dose), L-L, and Q-L dose-response models are significantly improved (P less than 0.001) by using the corresponding time-dependent dose-response models. Second, it is shown that the increased risk of leukemia mortality due to gamma irradiation decreases in time while the increased risk due to neutron exposure decreases more slowly, if at all, in time. Consequently, relative biological effectiveness (RBE) of neutrons is shown to increase in time (P = 0.002) and the current definition of RBE as a time-independent quantity is therefore challenged. It is demonstrated with time-dependent models that the L-L model has a poor fit (P = 0.01) to the data for the first 7 years of study, but has an adequate fit for the remaining 21 years. In contrast the Q-L model has an adequate fit for the entire follow-up period (P greater than 0.30).     

Natural cell-mediated cytotoxicity among A-bomb survivors residing in the United States

Natural cell-mediated cytotoxicity (NCMC) by lymphocytes from Japanese atomic bomb survivors now living in the United States was measured. Seventy-one individuals were exposed to an estimated '0.00' Gy ('0 rads') (S0 group) and 58 to greater than '0.00 Gy' (S+ group) at the time of the bomb. Of this 58, 51 (88 per cent) received less than 0.50 Gy and 30 (52 per cent) received less than 0.10 Gy. NCMC was measured against 51Cr-labelled K562 target cells. Activity by lymphocytes from S+ group donors was significantly greater than that for the S0 group (p = 0.028 by the stratified Wilcoxon rank-sum test). This difference between the S+ and S0 populations was detected 35 years after exposure to the bomb. It is therefore feasible and important to examine appropriate biologic parameters to elucidate the effects of low doses of radiation in humans.     

Dietary factors and cancer mortality among atomic-bomb survivors

Dietary factors such as fruit and vegetables are thought to reduce the risk of cancer incidence and mortality. We investigated the effect of a diet rich in fruit and vegetables against the long-term effects of radiation exposure on the risk of cancer. A cohort of 36,228 atomic-bomb survivors of Hiroshima and Nagasaki, for whom radiation dose estimates were currently available, had their diet assessed in 1980. They were followed for a period of 20 years for cancer mortality. The joint-effect of fruit and vegetables intake and radiation exposure on risk of cancer death was examined, in additive (sum of effects of diet alone and radiation alone) and multiplicative (product of effects of diet alone and radiation alone) models. In the additive model, a daily intake of fruit and vegetables significantly reduced the risk of cancer deaths by 13%, compared to an intake of once or less per week. Radiation exposure of 1 Sievert (Sv) increased significantly the risk of cancer death by 48-49%. The additive joint-effects showed a lower risk of cancer among those exposed to 1 Sv who had a diet rich in vegetables (49%-13%=36%) or fruit (48%-13%=35%). The multiplicative model gave similar results. The cancer risk reduction by vegetables in exposed persons went from 52% (effect of radiation alone) to 32% (product of effect of vegetables and radiation), and cancer risk reduction by fruit was 52% (radiation alone) to 34% (product of effect of fruit and radiation). There was no significant evidence to reject either the additive or the multiplicative model. A daily intake of fruit and vegetables was beneficial to the persons exposed to radiation in reducing their risks of cancer death.     

Modeling the low-LET dose-response of BCR-ABL formation: predicting stem cell numbers from A-bomb data

Formation of the BCR-ABL chromosomal translocation t(9;22)(q34;q11) is essential to the genesis of chronic myeloid leukemia (CML). An interest in the dose-response of radiation induced CML therefore leads naturally to an interest in the dose-response of BCR-ABL formation. To predict the BCR-ABL dose-response to low-linear energy transfer (LET) ionizing radiation, three models valid over three different dose ranges are examined: the first for doses greater than 80 Gy, the second for doses less than 5 Gy and the third for doses greater than 2 Gy. The first of the models, due to Holley and Chatterjee, ignores the accidental binary eurejoining of DNA double-strand break (DSB) free ends ('eurejoining' refers to the accidental restitution of DSB free ends with their own proper mates). As a result, the model is valid only in the limit of high doses. The second model is derived directly from cytogenetic data. This model has the attractive feature that it implicitly accounts for single-track effects at low doses. The third model, based on the Sax-Markov binary eurejoining/misrejoining (SMBE) algorithm, does not account for single-track effects and is therefore limited to moderate doses greater than approximately 2 Gy. Comparing the second model to lifetime excess CML risks expected after 1 Gy, estimates of the number of hematopoietic stem cells capable of causing CML were obtained for male and female atomic bomb survivors in Hiroshima and Nagasaki. The stem cell number estimates lie in the range of 5 x 10(7)-3 x 10(8) cells.     

The shape of the blacklight dose photoreactivation curve for chick embryo fibroblasts

The curves of UV (254 nm) induced pyrimidine dimers (endonuclease sensitive sites) vs. photoreactivating blacklight (365 nm) dose for cultured chick embryo fibroblasts reveal several new features. When the cells are incubated in the dark at 37 degrees following UV (254 nm) treatment, the efficiency of subsequent photorepair increases for the first few hours post-UV. The efficiency then remains approximately constant for several hours. Photorepair data obtained during this later period were plotted as the logarithm of dimer-enzyme complexes available for photoreactivation vs. blacklight (365 nm) dose. For a fixed damaging UV (254 nm) dose, the resulting curve has a shoulder of approximately 6-10 kJ/m2 followed by a straight line portion with a slope of magnitude about 1.5 X 10(-4) m2/J for UV doses up to 15 J/m2. For higher UV doses the shoulder remains about the same, but the slope decreases in magnitude. The shoulder is interpreted to indicate that a light-dependent step is necessary to activate the enzyme. The decrease in slope with increased UV dose together with some split photoreactivation dose experiments suggests that some site-to-site motion and multiple site function of the photorepair enzyme molecules may come into play at the higher levels of damage, but the evidence indicates that these complications are relatively unimportant at low UV doses.     

Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 1. Comparison of risk coefficients for site-specific cancer mortality based on the DS86 and T65DR shielded kerma and organ doses

As a result of the reassessment of the A-bomb dosimetry, new (DS86) doses were calculated in 1986. In this paper, site-specific estimates of cancer mortality in the years 1950-1985, based on these new doses, are compared with those using the T65DR doses. The subjects of the study are 75,991 members of the Life Span Study sample for whom DS86 doses have been calculated. This reevaluation of the exposures does not change the list of radiation-related cancers. Most differences in dose response between Hiroshima and Nagasaki are no longer significant with the DS86 doses. The dose-response curve is closer to linear with the DS86 than the T65DR doses even for leukemia in the entire dose range, though, statistically, many other models cannot be excluded. However, in the low-dose range, the risk of leukemia remains nonlinear. Assuming a linear model at an RBE of 1, and using organ-absorbed doses, the risk coefficients derived from the two dosimetries are very similar, whereas those based on shielded kerma are about 40% higher with the new dosimetry. If RBE values larger than 1 are assumed, the disparity between the two dosimetries increases because the neutron dose is much greater in the T65DR. At an RBE of 10, for the five specific cancers, i.e., female breast, colon, leukemia, lung, and stomach, the increase in excess number of deaths per 10(4) PYSv under the DS86 varies from 12% (colon) to 133% (female breast). The magnitude of the effects of such modifiers of radiation-induced cancer as age at time of bomb and sex do not differ between the two dose systems.     

Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 3. Noncancer mortality based on the revised doses (DS86).

Deaths in the RERF Life Span Study (LSS) sample have been determined for the years 1950-1985 and an analysis of cancer mortality with the revised DS86 doses has been described separately. In this report, we examine the relationship to dose of deaths from all diseases other than cancer. Although the evidence is still limited, there seems to be an excess risk from noncancer death at high doses (2 or 3 Gy and over). Statistically, a pure quadratic or a linear-threshold model [the estimated threshold dose is 1.4 Gy (0.6-2.8 Gy)] is found to fit better than a simple linear or linear-quadratic model. This increase in noncancer mortality is statistically demonstrable, generally, after 1965 and among the younger survivors (less than 40 at the time of the bombing), suggesting a sensitivity for this age group. For specific causes of death, an excess in relative risk at the high dose level, that is, 2 Gy or more, is seen in circulatory and digestive diseases. The relative risk is, however, much smaller than that for cancer. These findings, based as they are on death certificates, have their limitations. Most significant, perhaps, is the possible erroneous attribution of radiation-related cancer deaths to other causes. At present, the contribution such errors may make to the apparent increase in non-cancer deaths at the higher doses cannot be estimated as rigorously as is obviously desirable. However, even now, this increase does not appear to be fully explicable in terms of errors in classification. Further follow-up of mortality in this LSS cohort as well as disease revealed by the biennial physical examinations of the morbidity subsample (Adult Health Study) of the LSS cohort will be needed to confirm this suggestion of a radiation-related increase in mortality from causes other than cancer, and to determine whether it results in a demonstrable life shortening among the heavily exposed A-bomb survivors.