title: Distributions of Hardy-Weinberg equilibrium test statistics.
abstract: It is well established that test statistics and P-values derived from discrete data, such as genetic markers, are also discrete. In most genetic applications, the null distribution for a discrete test statistic is approximated with a continuous distribution, but this approximation may not be reasonable. In some cases using the continuous approximation for the expected null distribution may cause truly null test statistics to appear nonnull. We explore the implications of using continuous distributions to approximate the discrete distributions of Hardy-Weinberg equilibrium test statistics and P-values. We derive exact P-value distributions under the null and alternative hypotheses, enabling a more accurate analysis than is possible with continuous approximations. We apply these methods to biological data and find that using continuous distribution theory with exact tests may underestimate the extent of Hardy-Weinberg disequilibrium in a sample. The implications may be most important for the widespread use of whole-genome case-control association studies and Hardy-Weinberg equilibrium (HWE) testing for data quality control.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195-5065, USA. rrohlfs@u.washington.edu
authors.forename: R V
authors.initials: RV
authors.lastname: Rohlfs
authors.forename: B S
authors.initials: BS
authors.lastname: Weir
mesh_terms: D016022:Case-Control Studies; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D016008:Statistical Distributions
references.citation: Ann Hum Genet. 1999 Nov;63(Pt 6):535-8
references.pmid: 11246455
references.citation: Science. 1908 Jul 10;28(706):49-50
references.pmid: 17779291
references.citation: Biometrics. 2004 Sep;60(3):694-703
references.pmid: 15339292
references.citation: Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11654-9
references.pmid: 1465380
references.citation: Genetics. 1994 May;137(1):331-6
references.pmid: 8056320
references.citation: Biometrika. 1950 Jun;37(1-2):130-44
references.pmid: 15420258
references.citation: Nature. 2007 Jun 7;447(7145):661-78
references.pmid: 17554300
references.citation: Ann Hum Genet. 2006 Nov;70(Pt 6):923-33
references.pmid: 17044866
references.citation: Evolution. 1995 Dec;49(6):1280-1283
references.pmid: 28568523
references.citation: Biometrics. 1992 Jun;48(2):361-72
references.pmid: 1637966
references.citation: Genetica. 1995;96(1-2):169-78
references.pmid: 7607454
references.citation: Science. 1991 Aug 30;253(5023):1038-9
references.pmid: 17775346
references.citation: Genetics. 1995 Aug;140(4):1413-9
references.pmid: 7498780
references.citation: Genetics. 2005 Mar;169(3):1763-77
references.pmid: 15654103
references.citation: Hum Hered. 2002;54(3):151-6
references.pmid: 12626847
references.citation: Ann Hum Genet. 1997 Jan;61(Pt 1):71-7
references.pmid: 9066929
references.citation: Am J Hum Genet. 2005 May;76(5):887-93
references.pmid: 15789306