A Frailty-Model-Based Approach to Estimating the Age-Dependent Penetrance Function of a Gene Mutation Using Family-Based Study Designs

• Activity Number: 283
• Type: Topic Contributed
• Date/Time: Tuesday, August 3, 2010 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Yun-Hee Choi*+ and Laurent Briollais
• Companies: The University of Western Ontario and Samuel Lunenfeld Research Institute
• Keywords: Frailty ; Risk estimation ; Correlated time-to-event ; ascertainment ; Missing data ; Gene mutation

Abstract

In genetic studies, the estimation of familial correlation is often important for the identification and characterization of genetic factors underlying a complex disorder. Once a major genetic factor has been identified, the estimation of residual familial correlation is also needed to make a correct inference about the major gene and lifetime risk in gene carriers (i.e. the penetrance). We propose a general frailty-model approach to estimate a major gene effect in a family-based study design, where the frailty accounts for shared risks among family members not due to the major gene. This approach is further extended to accommodate missing genotypes in family members and the ascertainment of the families. Simulation results show that the proposed method performs well in realistic settings. Finally, a family-based study on early-onset breast cancer is used to illustrate the method.