Using a 2-level hierarchical frailty model, we analyzed population-wide data on testicular germ-cell tumor (TGCT) status in 1,135,320 two-generational Norwegian families to examine the risk of TGCT in family members of patients. Follow-up extended from 1954 (cases) or 1960 (unaffected persons) to 2008. The first-level frailty variable was compound Poisson-distributed. The underlying Poisson parameter was randomized to model the frailty variation between families and was decomposed additively to characterize the correlation structure within a family. The frailty relative risk (FRR) for a son, given a diseased father, was 4.03 (95% confidence interval (CI): 3.12, 5.19), with a borderline significantly higher FRR for nonseminoma than for seminoma (P = 0.06). Given 1 affected brother, the lifetime FRR was 5.88 (95% CI: 4.70, 7.36), with no difference between subtypes. Given 2 affected brothers, the FRR was 21.71 (95% CI: 8.93, 52.76). These estimates decreased with the number of additional healthy brothers. The estimated FRRs support previous findings. However, the present hierarchical frailty approach allows for a very precise definition of familial risk. These FRRs, estimated according to numbers of affected/nonaffected family members, provide new insight into familial TGCT. Furthermore, new light is shed on the different familial risks of seminoma and nonseminoma.
Keywords: cancer, familial; frailty; hierarchical models; nonseminoma; seminoma; survival analysis; susceptibility; testicular germ-cell tumors.