A promising extension of the case-parent design, originally proposed by Nagelkerke, incorporates some controls from the population, as a kind of hybrid between the case-control and the case-parent triad approach [12]. In a recent variant of this design [13], the exposures for controls are studied, but one genotypes the parents of controls and not the controls themselves. The inclusion of control parents allows one to capture information related to enrichment for causative alleles in the parents of cases compared to parents of controls, information that is sacrificed by triad methods, which condition on the parental genotypes. The inclusion of controls greatly enhances the power of the design for detecting genetic effects. There are also advantages for studying gene-by-environment interaction. Provided one can safely assume Mendelian transmission, nondifferential survival (vis a vis the gene) to the age at study, and absence of bias due to genetic population stratification, this hybrid approach now allows estimation of the main effects of exposures, as well as the main effects of autosomal genetic variants, and hence provides both improved power and enhanced flexibility for modeling joint effects of genetic and environmental factors.
