title: Prioritizing rare variants with conditional likelihood ratios.
abstract: BACKGROUND
  Prioritizing individual rare variants within associated genes or regions often consists of an ad hoc combination of statistical and biological considerations. From the statistical perspective, rare variants are often ranked using Fisher's exact p values, which can lead to different rankings of the same set of variants depending on whether 1- or 2-sided p values are used.
  
  
  RESULTS
  We propose a likelihood ratio-based measure, maxLRc, for the statistical component of ranking rare variants under a case-control study design that avoids the hypothesis-testing paradigm. We prove analytically that the maxLRc is always well-defined, even when the data has zero cell counts in the 2×2 disease-variant table. Via simulation, we show that the maxLRc outperforms Fisher's exact p values in most practical scenarios considered. Using next-generation sequence data from 27 rolandic epilepsy cases and 200 controls in a region previously shown to be linked to and associated with rolandic epilepsy, we demonstrate that rankings assigned by the maxLRc and exact p values can differ substantially.
  
  
  CONCLUSIONS
  The maxLRc provides reliable statistical prioritization of rare variants using only the observed data, avoiding the need to specify parameters associated with hypothesis testing that can result in ranking discrepancies across p value procedures; and it is applicable to common variant prioritization.
authors: Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ont., Canada.
authors: Weili
authors: W
authors: Li
authors: Sara
authors: S
authors: Dobbins
authors: Ian
authors: I
authors: Tomlinson
authors: Richard
authors: R
authors: Houlston
authors: Deb K
authors: DK
authors: Pal
authors: Lisa J
authors: LJ
authors: Strug
mesh_terms: D016022:Case-Control Studies; D003198:Computer Simulation; D019305:Epilepsy, Rolandic / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D016013:Likelihood Functions