Ascertainment bias in rate ratio estimation from case-sibling control studies of variable age-at-onset diseases

Motivated by a Finnish case-control study of early onset diabetes in which diabetic children are matched to sibling controls, we investigate ascertainment bias of the usual rate ratio estimator from case-control data under simplex complete ascertainment of families during a fixed interval of time. Analytic results indicate that the assumptions necessary for valid estimation are that the disease is rare and the factors under study are exchangeable--essentially that the covariate distribution does not depend on calendar time or birth order. Further, we found that the rare disease assumption could be dropped by restricting to cases that were diagnosed during the enrollment period of the study or including all cases but eliminating the proband as a control for non-enrollment-period cases. An important consequence of this work is that standard family-based case-control studies are subject to ascertainment bias if exchangeability of the covariates under investigation does not hold.