The effect of phenotypic outliers and non-normality on rare-variant association testing

Eur J Hum Genet. 2016 Aug;24(8):1188-94. doi: 10.1038/ejhg.2015.270. Epub 2016 Jan 6.

Abstract

Rare-variant association studies (RVAS) have made important contributions to human complex trait genetics. These studies rely on specialized statistical methods for analyzing rare-variant associations, both individually and in aggregate. We investigated the impact that phenotypic outliers and non-normality have on the performance of rare-variant association testing procedures. Ignoring outliers or non-normality can significantly inflate Type I error rates. We found that rank-based inverse normal transformation (INT) and trait winsorisation were both effective at maintaining Type I error control without sacrificing power in the presence of outliers. INT was the optimal method for non-normally distributed traits. For RVAS of quantitative traits with outliers or non-normality, we recommend using INT to transform phenotypic values before association testing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Bias
  • Genome-Wide Association Study / methods*
  • Genome-Wide Association Study / standards
  • Humans
  • Models, Genetic
  • Mutation Rate
  • Mutation*
  • Phenotype*