Breast cancer risk in atomic bomb survivors from multi-model inference with incidence data 1958–1998

Abstract

Breast cancer risk from radiation exposure has been analyzed in the cohort of Japanese a-bomb survivors using empirical models and mechanistic two-step clonal expansion (TSCE) models with incidence data from 1958 to 1998. TSCE models rely on a phenomenological representation of cell transition processes on the path to cancer. They describe the data as good as empirical models and this fact has been exploited for risk assessment. Adequate models of both types have been selected with a statistical protocol based on parsimonious parameter deployment and their risk estimates have been combined using multi-model inference techniques. TSCE models relate the radiation risk to cell processes which are controlled by age-increasing rates of initiating mutations and by changes in hormone levels due to menopause. For exposure at young age, they predict an enhanced excess relative risk (ERR) whereas the preferred empirical model shows no dependence on age at exposure. At attained age 70, the multi-model median of the ERR at 1 Gy decreases moderately from 1.2 Gy(-1) (90% CI 0.72; 2.1) for exposure at age 25 to a 30% lower value for exposure at age 55. For cohort strata with few cases, where model predictions diverge, uncertainty intervals from multi-model inference are enhanced by up to a factor of 1.6 compared to the preferred empirical model. Multi-model inference provides a joint risk estimate from several plausible models rather than relying on a single model of choice. It produces more reliable point estimates and improves the characterization of uncertainties. The method is recommended for risk assessment in practical radiation protection.

Breast cancer risk and possible mechanisms of radiation-induced genomic instability in the Swedish hemangioma cohort after reanalyzed dosimetry

“…In Ref. [4] the LSS cohort with 61,977 women and 1038 breast cancer cases was analyzed for breast cancer incidence with different descriptive ERR and TSCE models. The average person-year weighted age at exposure was 24 years.…”

“…Refs. [45,4], results in a preference for the lifelong model with more than 95% weight, thus the lifelong model is chosen as preferred model.…”

“…Ionizing radiation is known to increase the risk of female breast cancer, one of the most frequent cancers worldwide [1][2][3][4]. However, a pooled analysis of radio-epidemiological cohorts showed substantial differences in risk estimates between different cohorts [5].…”

Response to “model averaging in the analysis of leukaemia mortality among Japanese A-bomb survivors” by Richardson and Cole

“…In reality, the true model is not known and risk inference from a group of several plausible models appears justified. The selection of models for this so-called group of Occam (Hoeting et al 1999;Kaiser et al 2011) can be done in different ways. In Walsh and Kaiser (2011), we chose published risk models and simply ranked them according to their AIC.…”

“…The selection protocol involves a series of LRTs to improve a simple baseline model with additional parameters (for details see Kaiser et al 2011). A parameter is accepted as an improvement with a probability of 95%, if the deviance is lowered by at least 3.84 points.…”