Using family members to augment genetic case-control studies of a life-threatening disease.

Survival bias is difficult to detect and adjust for in case-control genetic association studies but can invalidate findings when only surviving cases are studied and survival is associated with the genetic variants under study. Here, we propose a design where one genotypes genetically informative family members (such as offspring, parents, and spouses) of deceased cases and incorporates that surrogate genetic information into a retrospective maximum likelihood analysis. We show that inclusion of genotype data from first-degree relatives permits unbiased estimation of genotype association parameters. We derive closed-form maximum likelihood estimates for association parameters under the widely used log-additive and dominant association models. Our proposed design not only permits a valid analysis but also enhances statistical power by augmenting the sample with indirectly studied individuals. Gene variants associated with poor prognosis can also be identified under this design. We provide simulation results to assess performance of the methods.