Oct 22, 2019

An exact, unifying framework for region-based association testing in family-based designs, including higher criticism approaches, SKATs, multivariate and burden tests

Julian HeckerChristoph Lange


Analysis of rare variants in family-based studies remains a challenge. To perform a region/set-based association analysis of rare variants in family-based studies, we propose a general methodological framework that integrates higher criticism, maximum, SKATs, and burden approaches into the family-based association testing (FBAT) framework. Using the haplotype algorithm for FBATs to compute the conditional genotype distribution under the null hypothesis of Mendelian transmissions, virtually any association test statistics can be implemented in our approach and simulation-based or exact p-values can be computed without the need for asymptotic settings. Using simulations, we compare the features of the proposed test statistics in our framework with the existing region-based methodology for family-based studies under various scenarios. The tests of our framework outperform the existing approaches. We provide general guidelines for which scenarios, e.g., sparseness of the signals or local LD structure, which test statistic will have distinct power advantages over the others. We also illustrate our approach in an application to a whole-genome sequencing dataset with 897 asthmatic trios.

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Whole Genome Sequencing

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