Conditioning adaptive combination of P-values method to analyze case-parent trios with or without population controls

Detection of rare causal variants can help uncover the etiology of complex diseases. Recruiting case-parent trios is a popular study design in family-based studies. If researchers can obtain data from population controls, utilizing them in trio analyses can improve the power of methods. The transmission disequilibrium test (TDT) is a well-known method to analyze case-parent trio data. It has been extended to rare-variant association testing (abbreviated as "rvTDT"), with the flexibility to incorporate population controls. The rvTDT method is robust to population stratification. However, power loss may occur in the conditioning process. Here we propose a "conditioning adaptive combination of P-values method" (abbreviated as "conADA"), to analyze trios with/without unrelated controls. By first truncating the variants with larger P-values, we decrease the vulnerability of conADA to the inclusion of neutral variants. Moreover, because the test statistic is developed by conditioning on parental genotypes, conADA generates valid statistical inference in the presence of population stratification. With regard to statistical methods for next-generation sequencing data analyses, validity may be hampered by population stratification, whereas power may be affected by the inclusion of neutral variants. We recommend conADA for its robustness to these two factors (population stratification and the inclusion of neutral variants).