title: Weighted Score Tests Implementing Model-Averaging Schemes in Detection of Rare Variants in Case-Control Studies.
abstract: Multi-locus effect modeling is a powerful approach for detection of genes influencing a complex disease. Especially for rare variants, we need to analyze multiple variants together to achieve adequate power for detection. In this paper, we propose several parsimonious branching model techniques to assess the joint effect of a group of rare variants in a case-control study. These models implement a data reduction strategy within a likelihood framework and use a weighted score test to assess the statistical significance of the effect of the group of variants on the disease. The primary advantage of the proposed approach is that it performs model-averaging over a substantially smaller set of models supported by the data and thus gains power to detect multi-locus effects. We illustrate these proposed approaches on simulated and real data and study their performance compared to several existing rare variant detection approaches. The primary goal of this paper is to assess if there is any gain in power to detect association by averaging over a number of models instead of selecting the best model. Extensive simulations and real data application demonstrate the advantage the proposed approach in presence of causal variants with opposite directional effects along with a moderate number of null variants in linkage disequilibrium.
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Brandon
authors.initials: B
authors.lastname: Coombes
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Saonli
authors.initials: S
authors.lastname: Basu
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Guha
authors.affiliation: J. Craig Venter Institute, La Jolla, CA, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Schork
mesh_terms: D000465:Algorithms; D000483:Alleles; D000581:Amidohydrolases / Q000235:genetics; D016022:Case-Control Studies; D003198:Computer Simulation; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008957:Models, Genetic; D008994:Monoacylglycerol Lipases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D008994:Monoacylglycerol Lipases; D000099252:Fatty Acid Amide Hydrolases