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This article is part of the supplement: Genetic Analysis Workshop 17: Unraveling Human Exome Data

Open Access Proceedings

Evaluation of pooled association tests for rare variant identification

Wan-Yu Lin1, Boshao Zhang1, Nengjun Yi1, Guimin Gao2 and Nianjun Liu1*

Author Affiliations

1 Department of Biostatistics, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL 35294, USA

2 Department of Biostatistics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0032, USA

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BMC Proceedings 2011, 5(Suppl 9):S118  doi:10.1186/1753-6561-5-S9-S118

Published: 29 November 2011


Genome-wide association studies have successfully identified many common variants associated with complex human diseases. However, a large portion of the remaining heritability cannot be explained by these common variants. Exploring rare variants associated with diseases is now catching more attention. Several methods have been recently proposed for identification of rare variants. Among them, the fixed-threshold, weighted-sum, and variable-threshold methods are effective in combining the information of multiple variants into a functional unit; these approaches are commonly used. We evaluate the performance of these three methods. Based on our analyses of the Genetic Analysis Workshop 17 data, we find that no method is universally better than the others. Furthermore, adjusting for potential covariates can not only increase the true-positive proportions but also reduce the false-positive proportions. Our study concludes that there is no uniformly most powerful test among the three methods we compared (the fixed-threshold, weighted-sum, and variable-threshold methods), and their performances depend on the underlying genetic architecture of a disease.