Family-based studies, in which individuals are ascertained from family pedigrees, offer a unique solution to population stratification. Family-Based Association Tests that focus on within-family information (generalizing the Transmission Disequilibrium Test26) are immune to stratification, since transmitted and untransmitted alleles have the same genetic ancestry27–29 (FBAT and QTDT; see Web Resources). However, fully powered statistics for family-based studies will need to incorporate between-family information, which is still susceptible to stratification. A recent suggestion is to transform between-family information into a rank statistic before combining within-family and between-family information, guaranteeing that both sources of information are immune to stratification30–31. This approach performs favorably compared to previous family-based approaches30–31, but places an upper bound on the statistical power that can be extracted from the between-family component of the overall signal, because the transformed rank statistic cannot be more statistically significant than one divided by the number of samples.
