Distributions of Hardy-Weinberg equilibrium test statistics.
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.
Rohlfs
R V
RV
Department of Genome Sciences, University of Washington, Seattle, Washington 98195-5065, USA. rrohlfs@u.washington.edu
Weir
B S
BS
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
Ann Hum Genet. 1999 Nov;63(Pt 6):535-8
11246455
Science. 1908 Jul 10;28(706):49-50
17779291
Biometrics. 2004 Sep;60(3):694-703
15339292
Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11654-9
1465380
Genetics. 1994 May;137(1):331-6
8056320
Biometrika. 1950 Jun;37(1-2):130-44
15420258
Nature. 2007 Jun 7;447(7145):661-78
17554300
Ann Hum Genet. 2006 Nov;70(Pt 6):923-33
17044866
Evolution. 1995 Dec;49(6):1280-1283
28568523
Biometrics. 1992 Jun;48(2):361-72
1637966
Genetica. 1995;96(1-2):169-78
7607454
Science. 1991 Aug 30;253(5023):1038-9
17775346
Genetics. 1995 Aug;140(4):1413-9
7498780
Genetics. 2005 Mar;169(3):1763-77
15654103
Hum Hered. 2002;54(3):151-6
12626847
Ann Hum Genet. 1997 Jan;61(Pt 1):71-7
9066929
Am J Hum Genet. 2005 May;76(5):887-93
15789306