A powerful and adaptive association test for rare variants

Wei Pan, Junghi Kim, Yiwei Zhang, Xiaotong T Shen, Peng Wei

Research output: Contribution to journalArticlepeer-review

140 Scopus citations


This article focuses on conducting global testing for association between a binary trait and a set of rare variants (RVs), although its application can be much broader to other types of traits, common variants (CVs), and gene set or pathway analysis. We show that many of the existing tests have deteriorating performance in the presence of many nonassociated RVs: their power can dramatically drop as the proportion of nonassociated RVs in the group to be tested increases. We propose a class of so-called sum of powered score (SPU) tests, each of which is based on the score vector from a general regression model and hence can deal with different types of traits and adjust for covariates, e.g., principal components accounting for population stratification. The SPU tests generalize the sum test, a representative burden test based on pooling or collapsing genotypes of RVs, and a sum of squared score (SSU) test that is closely related to several other powerful variance component tests; a previous study (Basu and Pan 2011) has demonstrated good performance of one, but not both, of the Sum and SSU tests in many situations. The SPU tests are versatile in the sense that one of them is often powerful, although its identity varies with the unknown true association parameters. We propose an adaptive SPU (aSPU) test to approximate the most powerful SPU test for a given scenario, consequently maintaining high power and being highly adaptive across various scenarios. We conducted extensive simulations to show superior performance of the aSPU test over several state-of-the-art association tests in the presence of many nonassociated RVs. Finally we applied the SPU and aSPU tests to the GAW17 mini-exome sequence data to compare its practical performance with some existing tests, demonstrating their potential usefulness.

Original languageEnglish (US)
Pages (from-to)1081-1095
Number of pages15
Issue number4
StatePublished - 2014


  • Adaptive SPU (aSPU) test
  • Genome-wide association study (GWAS)
  • Score statistic
  • Sequencing data sum of powered score (SPU) test
  • Sum of squared score (SSU) test
  • Sum test


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