Recent studies showed that population substructure (PS) can have more complex impact on rare variant tests and that similarity-based collapsing tests (e.g., SKAT) may suffer more severely by PS than burden-based tests. In this work, we evaluate the performance of SKAT coupling with principal components (PC) or variance components (VC) based PS correction methods. We consider confounding effects caused by PS including stratified populations, admixed populations, and spatially distributed nongenetic risk; we investigate which types of variants (e.g., common, less frequent, rare, or all variants) should be used to effectively control for confounding effects. We found that (i) PC-based methods can account for confounding effects in most scenarios except for admixture, although the number of sufficient PCs depends on the PS complexity and the type of variants used. (ii) PCs based on all variants (i.e., common + less frequent + rare) tend to require equal or fewer sufficient PCs and often achieve higher power than PCs based on other variant types. (iii) VC-based methods can effectively adjust for confounding in all scenarios (even for admixture), though the type of variants should be used to construct VC may vary. (iv) VC based on all variants works consistently in all scenarios, though its power may be sometimes lower than VC based on other variant types. Given that the best-performed method and which variants to use depend on the underlying unknown confounding mechanisms, a robust strategy is to perform SKAT analyses using VC-based methods based on all variants.
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