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 shape of the cancer mortality dose-response curve for the A-bomb survivors

The shape of the dose-response curve for cancer mortality in the A-bomb survivor data is analyzed in the context of linear-quadratic models. Results are given for all cancers except leukemia as a group, for leukemia, and for combined inferences assuming common curvature. Since there is substantial information aside from these data suggesting a dose-response curve with upward curvature, the emphasis here is not on estimating the best-fitting dose-response curve, but rather on assessing the maximum curvature under linear-quadratic models which is consistent with the data. The apparent shape of the dose-response curve is substantially affected by imprecision in the dose estimates, and methods are applied to correct for this. The extent of curvature can be expressed as the factor by which linear risk estimates from these data should be divided to arrive at appropriate estimates of risk at low doses. Influential committees have in the past recommended ranges of 1.5-4 and of 2-10 for such a factor. Results here suggest that values greater than about 2.0-2.5 are at least moderately inconsistent with these data, within the context of linear-quadratic models. It is emphasized, however, that there is little direct information in these data regarding risks following low doses; the inferences here depend strongly on the assumption of a linear-quadratic model.     

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.     

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.     

Possible selection effects for radiation risk estimates in Japanese A-bomb survivors: reanalysis of acute radiation symptoms data

An earlier analysis examined the possibility of bias in the Life Span Study (LSS) cohort by studying Japanese A-bomb survivors with bomb-related acute injuries and those without such injuries (Stewart and Kneale in Int J Epidemiol 29:708–714, 2000). The authors reported significantly higher radiation risks, both for cancers and non-cancers, among those survivors with acute injuries compared with those without. The risks were reported to be particularly large among survivors aged <10 or ≥55 years of age at the time of bombings. The aim of this paper is to examine these findings more closely using the LSS acute effects data. All the analyses were carried out using Poisson regression. Relative risk models were fitted with adjustment for sex and other factors. Significant differences in relative risk between survivors with epilation and burns and those without epilation and burns are found for leukaemia. There is also some evidence for heterogeneity in the leukaemia risk between survivors with two or more acute injuries and those with no injuries, but the evidence is disappeared when survivors with one or more injuries are compared with those without injuries. For solid cancers, cardiovascular disease and all deaths combined, the risks do not differ to a statistically significant extent between survivors with and without injuries. There is no statistically significant heterogeneity in risk across age-at-exposure categories for survivors with injuries. For all deaths combined, relative risk estimates and their uncertainties are significantly higher for survivors exposed at ages <10 years when compared with other exposure ages, but risks are not significantly raised for survivors exposed at ≥55 years of age. With the exception of leukaemia, the findings from the present work are inconsistent with those of Stewart and Kneale.     

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.     

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.     

Mortality of registered A-bomb survivors in Nagasaki, Japan, 1970-1984

A follow-up study of A-bomb survivors registered in Nagasaki was conducted from 1970 to 1984 by the Scientific Data Center of A-Bomb Disaster at Nagasaki University, which has collected medical and administrative data on A-bomb survivors with the help of Nagasaki City Hall and other organizations. The purpose of this study was to investigate the following two points. (1) Has the health screening program for A-bomb survivors reduced the mortality rate? (2) If so, how much has it reduced it, and what would the life-shortening effect of radiation be without the health screening program? The results revealed that the effect of radiation on mortality would be underestimated if the health screening factor were ignored. The estimated effect of radiation dose was compared with that estimated by the Radiation Effects Research Foundation (RERF).     

Age and dose related alteration of in vitro mixed lymphocyte culture response of blood lymphocytes from A-bomb survivors

The responsiveness of peripheral blood lymphocytes to allogenic antigens in mixed lymphocyte culture (MLC) was measured in 139 atomic-bomb survivors. The study revealed a significant decrease in MLC response with increasing dose of previous radiation exposure. This decline was marked in the survivors who were older than 15 at the time of the bomb (ATB). The results suggest a possible relationship between the recovery of T-cell-related function and the thymic function which processes mature T cells for the immune system. Thus it may be that in the advanced age ATB group, the thymus function had started to involute, allowing less recovery of T-cell function compared to young survivors who had adequate processing T-cell activity.     

Large upward bias in estimation of locus-specific effects from genomewide scans

The primary goal of a genomewide scan is to estimate the genomic locations of genes influencing a trait of interest. It is sometimes said that a secondary goal is to estimate the phenotypic effects of each identified locus. Here, it is shown that these two objectives cannot be met reliably by use of a single data set of a currently realistic size. Simulation and analytical results, based on variance-components linkage analysis as an example, demonstrate that estimates of locus-specific effect size at genomewide LOD score peaks tend to be grossly inflated and can even be virtually independent of the true effect size, even for studies on large samples when the true effect size is small. However, the bias diminishes asymptotically. The explanation for the bias is that the LOD score is a function of the locus-specific effect-size estimate, such that there is a high correlation between the observed statistical significance and the effect-size estimate. When the LOD score is maximized over the many pointwise tests being conducted throughout the genome, the locus-specific effect-size estimate is therefore effectively maximized as well. We argue that attempts at bias correction give unsatisfactory results, and that pointwise estimation in an independent data set may be the only way of obtaining reliable estimates of locus-specific effect-and then only if one does not condition on statistical significance being obtained. We further show that the same factors causing this bias are responsible for frequent failures to replicate initial claims of linkage or association for complex traits, even when the initial localization is, in fact, correct. The findings of this study have wide-ranging implications, as they apply to all statistical methods of gene localization. It is hoped that, by keeping this bias in mind, we will more realistically interpret and extrapolate from the results of genomewide scans.     

Radiation-related ophthalmological changes and aging among Hiroshima and Nagasaki A-bomb survivors: a reanalysis.

The relationship of ionizing radiation to the age-related ophthalmological findings of the 1978-1980 ophthalmological examination of A-bomb survivors of Hiroshima and Nagasaki has been reanalyzed using DS86 eye organ dose estimates. The main purpose of this reevaluation was to determine whether age and radiation exposure, as measured using the recently revised dosimetry information (DS86), have an additive, synergistic, or antagonistic effect. The data in this study are limited to axial opacities and posterior subcapsular changes, for which a definite radiation-induced effect has been observed in Hiroshima and Nagasaki A-bomb survivors. The best model fitting for axial opacities gives a significant positive effect for both linear dose and linear age-related regression coefficients and a significant negative effect for an interaction between radiation dose and age. Such a negative interaction implies an antagonistic effect in that the relative risks in relation to radiation exposure doses become smaller with an increase in age. On the other hand, the best-fitting relationship for posterior subcapsular changes suggested a linear-quadratic dose and linear age-related effect. The estimate of the quadratic dose coefficient shows a highly negative correlation with age, but the negative quadratic dose term is extremely small and is of little biological significance.     

Upward bias in estimation of genetic effects

Because of the large number of tests for linkage that are performed in genome scans, the naive estimator of the size of a genetic effect in cases of borderline significance can be inflated and lead to unrealistic expectations for successful replication. As a remedy, this report proposes lower confidence limits that account for the multiple comparisons of the genome scan.