Heterogeneity analysis of breast cancer families by using age at onset as a covariate.

An extension of the usual mixture model of heterogeneity (two family types, one with and one without linkage) is proposed by introducing age at onset as a covariate. The extended model defines age-dependent penetrances where the exact parametrization of age-at-onset distributions depends on the given genotype and family type (linked or unlinked). This extension was applied to breast cancer families. We postulated that the mean age at onset in individuals affected by the linked gene was lower than the mean age at onset in all other affected individuals. Linkage heterogeneity for breast cancer families was detected at a significance level of .003.