Power, Validity, Bias and Robustness of Family‐based Association Analysis Methods in the Presence of Linkage for Late Onset Diseases

This simulation-based report compares the performance of five methods of association analysis in the presence of linkage using extended sibships: the Family-Based Association Test (FBAT), Empirical Variance FBAT (EV-FBAT), Conditional Logistic Regression (CLR), Robust CLR (R-CLR) and Sibship Disequilibrium Test (SDT). The two tests accounting for residual familial correlation (EV-FBAT and R-CLR) and the model-free SDT showed correct test size in all simulated designs, while FBAT and CLR were only valid for small effect sizes. SDT had the lowest power, while CLR had the highest power, generally similar to FBAT and the robust variance analogues. The power of all model-dependent tests dropped when the model was misspecified, although often not substantially. Estimates of genetic effect with CLR and R-CLR were unbiased when the disease locus was analysed but biased when a nearby marker was analysed. This study demonstrates that the genetic effect does not need to be extreme to invalidate tests that ignore familial correlation and confirms that analogous methods using robust variance estimation provide a valid alternative at little cost to power. Overall R-CLR is the best-performing method among these alternatives for the analysis of extended sibship data.