Strategies for genetic association analyses combining unrelated case-control individuals and family trios

In genetic association studies, analyses integrating data or estimates from unrelated case-control individuals and case trios (case offspring and their parents) can increase statistical power to identify disease susceptibility loci. Data on control trios may also be available, but how and when their use is advantageous is less familiar and is described here. In addition, the authors examine assumptions and properties of hybrid analyses combining association estimates from unrelated case-control individuals together with case and control family trios, focusing on low-prevalence disease. One such assumption is absence of population stratification bias (PSB), a potential source of confounding in case-control analyses. For detection of PSB, the authors discuss 4 possible tests that assess equality between individual-level and family-based estimates. Furthermore, a weighted framework is presented, in which estimates from analyses combining unrelated individuals and families (most powerful but subject to PSB) and family-based analyses (robust to PSB) are weighted according to the observed PSB test P value. In contrast to existing hybrid designs that combine individuals and families only if no significant PSB is detected, the weighted framework does not require specification of an arbitrary PSB testing level to establish significance. The statistical methods are evaluated using simulations and applied to a candidate gene study of childhood leukemia (Quebec Childhood Leukemia Study, 1980-2000).