The Use of Joint Models in Analysis of Aggregate Endpoints in RERF Cohort Studies.

In radiation risk estimation based on the Radiation Effects Research Foundation (RERF) cohort studies, one common analysis is Poisson regression on radiation dose and background and effect modifying variables of an aggregate endpoint such as all solid cancer incidence or all non-cancer mortality. As currently performed, these analyses require selection of a surrogate radiation organ dose, (e.g., colon dose), which could conceptually be problematic since the aggregate endpoint comprises events arising from a variety of organs. We use maximum likelihood theory to compare inference from the usual aggregate endpoint analysis to analyses based on joint analysis. These two approaches are also compared in a re-analysis of RERF Life Span Study all cancer mortality. We show that, except for a trivial difference, these two analytic approaches yield identical inference with respect to radiation dose response and background and effect modification when based on a single surrogate organ radiation dose. When repeating the analysis with organ-specific doses, an interesting issue of bias in intercept parameters arises when dose estimates are undefined for one sex when sex-specific outcomes are included in the aggregate endpoint, but a simple correction will avoid this issue. Lastly, while the joint analysis formulation allows use of organ-specific doses, the interpretation of such an analysis for inference regarding an aggregate endpoint can be problematic. To the extent that analysis of radiation risk for an aggregate endpoint is of interest, the joint-analysis formulation with a single surrogate dose is an appropriate analytic approach, whereas joint analysis with organ-specific doses may only be interpretable if endpoints are considered separately for estimating dose response. However, for neither approach is inference about dose response well defined.

Neurocognitive Function in Aged Survivors Exposed to Atomic Bomb Radiation In Utero: The Radiation Effects Research Foundation Adult Health Study.

Although some adverse effects on neurocognitive function have been reported in children and adolescents irradiated prenatally during the atomic bombings and the Chernobyl nuclear accident, little information is available for effects on the elderly. Here we evaluate the effects of prenatal exposure to atomic bomb radiation on subjective neurocognitive function in aged survivors. To evaluate neurocognitive impairment, we mailed the Neurocognitive Questionnaire (NCQ), a self-administered scale, to prenatally exposed survivors, including clinic visitors and non-visitors at the time of the 2011 and 2013 Adult Health Study (AHS) examinations. We received replies from 444 individuals (mean age, 66.9 ± 0.6 years). After adjusting for sex, city, and educational background, we found no significant effects of radiation, clinic visit, or interaction between radiation and clinic visit on the scores of the 4 NCQ factors of metacognition, emotional regulation, motivation/organization, and processing speed. Even in analyses considering gestational age at the time of the bombings, none of the 4 NCQ factor scores was related to maternal uterine dose. There remains the limitation that this study consisted of healthy survivors, but we found no significant radiation effect on late-life cognition in people prenatally exposed to atomic bomb radiation.

Comparison of Proportional Mortality Between Korean Atomic Bomb Survivors and the General Population During 1992-2019.

BACKGROUND: Atomic bombs dropped on Hiroshima and Nagasaki in Japan in August 1945 were estimated to have killed approximately 70,000 Koreans. In Japan, studies on the health status and mortality of atomic bomb survivors compared with the non-exposed population have been conducted. However, there have been no studies related to the mortality of Korean atomic bomb survivors. Therefore, we aimed to study the cause of death of atomic bomb survivors compared to that of the general population. METHODS: Of 2,299 atomic bomb survivors registered with the Korean Red Cross, 2,176 were included in the study. In the general population, the number of deaths by age group was calculated from 1992 to 2019, and 6,377,781 individuals were assessed. Causes of death were categorized according to the Korean Standard Classification of Diseases. To compare the proportional mortality between the two groups, the P value for the ratio test was confirmed, and the Cochran-Armitage trend test and χ² test were performed to determine the cause of death according to the distance from the hypocenter. RESULTS: Diseases of the circulatory system were the most common cause of death (25.4%), followed by neoplasms (25.1%) and diseases of the respiratory system (10.6%) in atomic bomb survivors who died between 1992 and 2019. The proportional mortality associated with respiratory diseases, nervous system diseases, and other diseases among atomic bomb survivors was higher than that of the general population. Of the dead people between 1992 and 2019, the age at death of survivors who were exposed at a close distance was younger than those who were exposed at a greater distance. CONCLUSION: Overall, proportional mortality of respiratory diseases and nervous system diseases was high in atomic bomb survivors, compared with the general population. Further studies on the health status of Korean atomic bomb survivors are needed.

Cohort Study Protocol: A Cohort of Korean Atomic Bomb Survivors and Their Offspring.

In 1945, atomic bombs were dropped on Hiroshima and Nagasaki. Approximately 70 000 Koreans are estimated to have been exposed to radiation from atomic bombs at that time. After Korea's Liberation Day, approximately 23 000 of these people returned to Korea. To investigate the long-term health and hereditary effects of atomic bomb exposure on the offspring, cohort studies have been conducted on atomic bomb survivors in Japan. This study is an ongoing cohort study to determine the health status of Korean atomic bomb survivors and investigate whether any health effects were inherited by their offspring. Atomic bomb survivors are defined by the Special Act On the Support for Korean Atomic Bomb Victims, and their offspring are identified by participating atomic bomb survivors. As of 2024, we plan to recruit 1500 atomic bomb survivors and their offspring, including 200 trios with more than 300 people. Questionnaires regarding socio-demographic factors, health behaviors, past medical history, laboratory tests, and pedigree information comprise the data collected to minimize survival bias. For the 200 trios, whole-genome analysis is planned to identify de novo mutations in atomic bomb survivors and to compare the prevalence of de novo mutations with trios in the general population. Active follow-up based on telephone surveys and passive follow-up with linkage to the Korean Red Cross, National Health Insurance Service, death registry, and Korea Central Cancer Registry data are ongoing. By combining pedigree information with the findings of trio-based whole-genome analysis, the results will elucidate the hereditary health effects of atomic bomb exposure.

Mathematical models of the solid cancer induced by atomic bomb and the spontaneous cancer in the daily life-Proposal of a new medical treatment for cancers.

BACKGROUND: A mathematical model of the radiation-induced cancer was devised to explain the change of incidence rates pursued by Radiation Effect Research Foundation for 25 years. AIM: The aim of this work is construction of mechanisms of radiation-induced cancer and cancers observed in the daily life. METHODS AND RESULTS: First, we found a way to separate spontaneous cancers from radiation-induced cancers observed among atomic-bomb victims in Hiroshima and Nagasaki districts by using a constructed algorithm. The isolated incidence rates of radiation-induced cancers were reproduced by a two-stage model mechanical collision of impinging radiation with cells and succeeding mutation of the damaged cell to cancer. This model satisfactorily reproduced observed solid cancer incidence rates. We further attempted to construct a mathematical model for the age-dependence of spontaneous cancers appearing in the daily life and concluded that the cancer should be generated at cell division. CONCLUSION: With these findings, we reached to a conclusion that cancers may be suppressed by eliminating damaged cells with mild-dose radiation.

Concepts of association between cancer and ionising radiation: accounting for specific biological mechanisms.

The probability that an observed cancer was caused by radiation exposure is usually estimated using cancer rates and risk models from radioepidemiological cohorts and is called assigned share (AS). This definition implicitly assumes that an ongoing carcinogenic process is unaffected by the studied radiation exposure. However, there is strong evidence that radiation can also accelerate an existing clonal development towards cancer. In this work, we define different association measures that an observed cancer was newly induced, accelerated, or retarded. The measures were quantified exemplarily by Monte Carlo simulations that track the development of individual cells. Three biologically based two-stage clonal expansion (TSCE) models were applied. In the first model, radiation initiates cancer development, while in the other two, radiation has a promoting effect, i.e. radiation accelerates the clonal expansion of pre-cancerous cells. The parameters of the TSCE models were derived from breast cancer data from the atomic bomb survivors of Hiroshima and Nagasaki. For exposure at age 30, all three models resulted in similar estimates of AS at age 60. For the initiation model, estimates of association were nearly identical to AS. However, for the promotion models, the cancerous clonal development was frequently accelerated towards younger ages, resulting in associations substantially higher than AS. This work shows that the association between a given cancer and exposure in an affected person depends on the underlying biological mechanism and can be substantially larger than the AS derived from classic radioepidemiology.

The Association of Radiation Exposure with Stable Chromosome Aberrations in Atomic Bomb Survivors Based on DS02R1 Dosimetry and FISH Methods.

The frequency of stable chromosome aberrations (sCA) in lymphocytes is a recognized radiation biological dosimeter. Its analysis can provide insights into factors that affect individual susceptibility as well as into the adequacy of radiation dose estimates used in studies of atomic bomb survivors. We analyzed the relationship between atomic bomb radiation exposure using the most recent DS02R1 dose estimates and the frequency of sCA as determined by FISH in 1,868 atomic bomb survivors. We investigated factors that may affect the background sCA rate and the shape and magnitude of the dose response. As in previous analyses of sCA in atomic bomb survivors that were based on Giemsa staining methods and used older DS86 dose estimates, the relationship between radiation dose and sCA rate was significant (P < 0.0001) with a linear-quadratic relationship at lower doses that did not persist at higher doses. As before, age at the time of the bombing and type of radiation shielding were significant dose-effect modifiers (P < 0.0001), but in contrast the difference in dose response by city was not so pronounced (P = 0.026) with a city effect not evident at doses below 1.25Gy. Background sCA rate increased with age at the time of examination (P < 0.0001), but neither sex, city, nor smoking was significantly associated with background rate. Based on FISH methods and recent dosimetry, the relationship between radiation dose and sCA frequency is largely consistent with previous findings, although the lesser importance of city as an effect modifier may reflect better dosimetry as well as more reproducible scoring of sCA. The persisting difference in sCA dose response by shielding category points to remaining problems with the accuracy or precision of radiation dose estimates in some A-bomb survivors.

Comparison and multi-model inference of excess risks models for radiation-related solid cancer.

In assessments of detrimental health risks from exposures to ionising radiation, many forms of risk to dose-response models are available in the literature. The usual practice is to base risk assessment on one specific model and ignore model uncertainty. The analysis illustrated here considers model uncertainty for the outcome all solid cancer incidence, when modelled as a function of colon organ dose, using the most recent publicly available data from the Life Span Study on atomic bomb survivors of Japan. Seven recent publications reporting all solid cancer risk models currently deemed plausible by the scientific community have been included in a model averaging procedure so that the main conclusions do not depend on just one type of model. The models have been estimated with different baselines and presented for males and females at various attained ages and ages at exposure, to obtain specially computed model-averaged Excess Relative Risks (ERR) and Excess Absolute Risks (EAR). Monte Carlo simulated estimation of uncertainty on excess risks was accounted for by applying realisations including correlations in the risk model parameters. Three models were found to weight the model-averaged risks most strongly depending on the baseline and information criteria used for the weighting. Fitting all excess risk models with the same baseline, one model dominates for both information criteria considered in this study. Based on the analysis presented here, it is generally recommended to take model uncertainty into account in future risk analyses.

Radiation-induced increases in cancer mortality result from an earlier onset of the disease in mice and atomic bomb survivors.

PURPOSE: It has long been thought that the carcinogenic effect of radiation is due to the induction of oncogenic mutations, which means that a fraction of the irradiated individuals will be affected in a dose-dependent manner. This dogma was recently challenged because it was found that the model does not properly explain the life shortening effect of radiation which is seen as a parallel shift of mouse survival curves toward younger ages following an exposure to radiation. Specifically, according to the mutation induction theory, an irradiated mouse or human population evolves into two subpopulations with different mean lifespans, which would lead to a wider distribution of individual lifespans, and hence to a shallower slope in the survival curve, which is not what is observed. Instead, the parallel shift indicates that a large fraction of the irradiated mice are affected (but there are exceptions). Thus, it was thought important to pursue how the excess risk for cancer develops following an exposure to radiation. METHOD: In the present study, cancer mortality data from mice and atomic-bomb survivors is presented to understand the increasing patterns of cancer risks. RESULTS: In both species, it was found that cancer mortality starts to increase earlier in the exposed group. CONCLUSION: The results are consistent with the notion that in many irradiated organs (but not all) radiation-induced tissue damage can lead to the development of an altered microenvironment (most probably inflammation), which is favorable to the growth of spontaneously arising tumor cells and can lead to an earlier onset of the diseases or to an apparently increased risk of cancer.

Solid cancer mortality risk among a cohort of Hiroshima early entrants after the atomic bombing, 1970-2010: implications regarding health effects of residual radiation.

There are two types of exposure to atomic bomb (A-bomb) radiation: exposure to initial radiation released at the time of the detonation of the bomb, and exposure to residual radiation, which remains afterwards. Health hazards caused by exposure from residual radiation have not yet been clarified. The purpose of our study was to reveal the relationships between mortality risk from solid cancer and residual radiation based on data from the early entrants to Hiroshima. It is hard to identify the individual residual radiation doses. However, these are assumed to depend on the date of entry and the entrants' behavior. Individual behavior is thought to be closely related to gender and age at exposure. We investigated a cohort of 45 809 individuals who were living in Hiroshima Prefecture on 1 January 1970 and were registered on the Database of Atomic Bomb Survivors as entrants after the bombing. Poisson regression methods were used to estimate excess relative risks (ERR) with data cross-classified by sex, age at entry, and date of entry. In males in their 20s, 30s, and 40s at entry and in females less than 10 years old and in their 40s at entry, solid cancer mortality risks were significantly higher among persons who entered the city on the day of the bombing than those who entered three or more days later. With adjustments for the age-dependent sensitivities to radiation exposure, it was extrapolated that middle-aged people who entered the city on the day of the bombing were exposed to higher levels of residual radiation than younger people.

Comparison of All Solid Cancer Mortality and Incidence Dose-Response in the Life Span Study of Atomic Bomb Survivors, 1958-2009.

Recent analysis of all solid cancer incidence (1958-2009) in the Life Span Study (LSS) revealed evidence of upward curvature in the radiation dose response among males but not females. Upward curvature in sex-averaged excess relative risk (ERR) for all solid cancer mortality (1950-2003) was also observed in the 0-2 Gy dose range. As reasons for non-linearity in the LSS are not completely understood, we conducted dose-response analyses for all solid cancer mortality and incidence applying similar methods [1958-2009 follow-up, DS02R1 doses, including subjects not-in-city (NIC) at the time of the bombing] and statistical models. Incident cancers were ascertained from Hiroshima and Nagasaki cancer registries, while cause of death was ascertained from death certificates throughout Japan. The study included 105,444 LSS subjects who were alive and not known to have cancer before January 1, 1958 (80,205 with dose estimates and 25,239 NIC subjects). Between 1958 and 2009, there were 3.1 million person-years (PY) and 22,538 solid cancers for incidence analysis and 3.8 million PY and 15,419 solid cancer deaths for mortality analysis. We fitted sex-specific ERR models adjusted for smoking to both types of data. Over the entire range of doses, solid cancer mortality dose-response exhibited a borderline significant upward curvature among males (P = 0.062) and significant upward curvature among females (P = 0.010); for solid cancer incidence, as before, we found a significant upward curvature among males (P = 0.001) but not among females (P = 0.624). The sex difference in magnitude of dose-response curvature was statistically significant for cancer incidence (P = 0.017) but not for cancer mortality (P = 0.781). The results of analyses in the 0-2 Gy range and restricted lower dose ranges generally supported inferences made about the sex-specific dose-response shape over the entire range of doses for each outcome. Patterns of sex-specific curvature by calendar period (1958-1987 vs. 1988-2009) and age at exposure (0-19 vs. 20-83) varied between mortality and incidence data, particularly among females, although for each outcome there was an indication of curvature among 0-19-year-old male survivors in both calendar periods and among 0-19-year-old female survivors in the recent period. Collectively, our findings indicate that the upward curvature in all solid cancer dose response in the LSS is neither specific to males nor to incidence data; its evidence appears to depend on the composition of sites comprising all solid cancer group and age at exposure or time. Further follow up and site-specific analyses of cancer mortality and incidence will be important to confirm the emerging trend in dose-response curvature among young survivors and unveil the contributing factors and sites.

Chromosome aberrations among atomic-bomb survivors exposed in utero: updated analysis accounting for revised radiation doses and smoking.

A previous study of peripheral blood lymphocyte translocations around age 40 among atomic-bomb survivors exposed in utero revealed no overall association with radiation dose-despite a clear association between translocations and dose among their mothers-but the data suggested an increase at doses below 100 mGy with a definite peak. That analysis of the in utero-exposed survivors did not adjust for their subsequent smoking behavior, an established cause of chromosomal aberrations, or their subsequent exposures to medical irradiation, a potential mediator. In addition, atomic-bomb survivor radiation dose estimates have subsequently been updated and refined. We therefore re-estimated the dose response using the latest DS02R1 dose estimates and adjusting for smoking as well as for city and proximal-distal location at the time of exposure to the atomic bomb. Sex of the survivor, mother's age around the time of conception, and approximate trimester of gestation at the time of exposure were also considered as explanatory variables and modifiers. Precision of the estimated dose response was slightly lower due to greater variability near zero in the updated dose estimates, but there was little change in evidence of a low-dose increase and still no suggestion of an overall increase across the entire dose range. Adjustment for smoking behavior led to a decline in background number of translocations (the dose-response intercept), but smoking did not interact with dose overall (across the entire dose range). Adjustment for medical irradiation did not alter the association between dose and translocation frequency. Sex, mother's age, and trimester were not associated with number of translocations, nor did they interact with dose overall. Interactions with dose in the low-dose range could not be evaluated because of numerical instability.

Radiation cancer risk at different dose rates: new dose-rate effectiveness factors derived from revised A-bomb radiation dosimetry data and non-tumor doses.

The dose rate of atomic bomb (A-bomb) radiation to the survivors has still remained unclear, although the dose-response data of A-bomb cancers has been taken as a standard in estimating the cancer risk of radiation and the dose and dose-rate effectiveness factor (DDREF). Since the applicability of the currently used DDREF of 2 derived from A-bomb data is limited in a narrow dose-rate range, 0.25-75 Gy/min as estimated from analysis of DS86 dosimetry data in the present study, a non-tumor dose (Dnt) was applied in an attempt to gain a more universal dose-rate effectiveness factor (DREF), where Dnt is an empirical parameter defined as the highest dose at which no statistically significant tumor increase is observed above the control level and its magnitude depends on the dose rate. The new DREF values were expressed as a function of the dose rate at four exposure categories, i.e. partial body low LET, whole body low linear energy transfer (LET), partial body high LET and whole body high LET and provided a value of 14 for environmental level radiation at a dose rate of 10-9 Gy/min for whole body low LET.