Search

Kernel machine based association tests (KAT) have been increasingly used in testing the association between an outcome and a set of biological measurements due to its power to combine multiple weak signals of complex relationship with the outcome through the specification of a relevant kernel. Human genetic and microbiome association studies are two important applications of KAT. However, the classic KAT framework relies on large sample theory, and conservativeness has been observed for small sample studies, especially for microbiome association studies. The common approach for addressing the small sample problem relies on computationally intensive resampling methods. Here, we derive an exact test for KAT with continuous traits, which resolve the small sample conservatism of KAT without the need for resampling. The exact test has significantly improved power to detect association for microbiome studies. For binary traits, we propose a similar approximate test, and we show that the approximate test is very powerful for a wide range of kernels including common variant- and microbiome-based kernels, and the approximate test controls the type I error well for these kernels. In contrast, the sequence kernel association tests have slightly inflated genomic inflation factors after small sample adjustment. Extensive simulations and application to a real microbiome association study are used to demonstrate the utility of our method.

Recently, Wen and Stephens (Wen and Stephens [2010] Ann Appl Stat 4(3):1158-1182) proposed a linear predictor, called BLIMP, that uses conditional multivariate normal moments to impute genotypes with accuracy similar to current state-of-the-art methods. One novelty is that it regularized the estimated covariance matrix based on a model from population genetics. We extended multivariate moments to impute genotypes in pedigrees. Our proposed method, PedBLIMP, utilizes both the linkage-disequilibrium (LD) information estimated from external panel data and the pedigree structure or identity-by-descent (IBD) information. The proposed method was evaluated on a pedigree design where some individuals were genotyped with dense markers and the rest with sparse markers. We found that incorporating the pedigree/IBD information can improve imputation accuracy compared to BLIMP. Because rare variants usually have low LD with other single-nucleotide polymorphisms (SNPs), incorporating pedigree/IBD information largely improved imputation accuracy for rare variants. We also compared PedBLIMP with IMPUTE2 and GIGI. Results show that when sparse markers are in a certain density range, our method can outperform both IMPUTE2 and GIGI.