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. 2011 Nov;35(7):632-7.
doi: 10.1002/gepi.20612. Epub 2011 Sep 15.

Approximate and exact tests of Hardy-Weinberg equilibrium using uncertain genotypes

Daniel Shriner  1
Affiliations

Approximate and exact tests of Hardy-Weinberg equilibrium using uncertain genotypes

Daniel Shriner. Genet Epidemiol. 2011 Nov.

Abstract

Testing for Hardy-Weinberg equilibrium (HWE) is commonly used as a quality control filter in genome-wide scans for markers with experimentally determined genotypes. In contrast, for markers with imputed genotypes, there are post-imputation metrics of quality that can be used as screens but there are no formal tests of deviation from HWE. Similarly, there are no formal tests of deviation from HWE for probabilistic genotypes that are generated by sequencing projects. Here, I describe generalizations of the approximate χ(2) and exact tests of HWE for use with uncertain genotypes. The tests fully account for the probabilities of all possible genotypes at a marker for each individual. By computer simulation, the approximate and exact tests are shown to maintain valid control of the type I error rate. Calculations of the loss of power as the uncertainty in genotypes increases are illustrated. The tests are compatible with chip-based genotypes for single-nucleotide polymorphisms and copy number polymorphisms, imputed genotypes, and probabilistic assignments of genotype from variable-coverage sequence data.

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Figures

Fig. 1
Fig. 1
Type I error rates at a significance level of 0.05. Black represents the uncorrected χ2 test, red represents the χ2 test with the Yates continuity correction, and blue represents the exact test. (A and B) The error rates ε1 and ε2 were both 0. (C and D) The error rates ε1 and ε2 were both 0.01. (E and F) The error rates ε1 and ε2 were both 0.05. (G and H) The error rates ε1 and ε2 were both 0.10. (A, C, E, and G) The sample size was 100. (B, D, F, and H) The sample size was 1,000. Type I error rates were estimated from 10,000 independent replicates with random sampling of the multinomial distribution given the sample size and the minor allele frequency, assuming Hardy-Weinberg equilibrium.
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