title: Exact Inference for Hardy-Weinberg Proportions with Missing Genotypes: Single and Multiple Imputation.
abstract: This paper addresses the issue of exact-test based statistical inference for Hardy-Weinberg equilibrium in the presence of missing genotype data. Missing genotypes often are discarded when markers are tested for Hardy-Weinberg equilibrium, which can lead to bias in the statistical inference about equilibrium. Single and multiple imputation can improve inference on equilibrium. We develop tests for equilibrium in the presence of missingness by using both inbreeding coefficients (or, equivalently, χ(2) statistics) and exact p-values. The analysis of a set of markers with a high missing rate from the GENEVA project on prematurity shows that exact inference on equilibrium can be altered considerably when missingness is taken into account. For markers with a high missing rate (>5%), we found that both single and multiple imputation tend to diminish evidence for Hardy-Weinberg disequilibrium. Depending on the imputation method used, 6-13% of the test results changed qualitatively at the 5% level.
authors.affiliation: Department of Statistics and Operations Research, Universitat Politècnica de Catalunya, 08028 Barcelona, Spain.
authors.forename: Jan
authors.identifier: http://orcid.org/0000-0003-3900-0780
authors.initials: J
authors.lastname: Graffelman
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington 98105-9461.
authors.forename: S
authors.initials: S
authors.lastname: Nelson
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington 98105-9461.
authors.forename: S M
authors.initials: SM
authors.lastname: Gogarten
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington 98105-9461 bsweir@uw.edu.
authors.forename: B S
authors.initials: BS
authors.lastname: Weir
mesh_terms: D000465:Algorithms; D000068598:Data Accuracy; D005828:Genetics, Population / Q000379:methods; D007178:Inbreeding; D015810:Linkage Disequilibrium; D008957:Models, Genetic
keywords: Hardy−Weinberg equilibrium; exact test; imputation; missing data