title: Estimating the single nucleotide polymorphism genotype misclassification from routine double measurements in a large epidemiologic sample.
abstract: Previously, estimation of genotype misclassification of single nucleotide polymorphisms (SNPs) as encountered in epidemiologic practice and involving thousands of subjects was lacking. The authors collected representative data on approximately 14,000 subjects from 8 studies and 646,558 genotypes assessed in 2005 by means of matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Overall discordance among 57,805 double genotypes from routine quality control was 0.36%. Fitting different misclassification models by maximum likelihood assuming identical misclassification for all SNPs, the estimated misclassification probabilities ranged from 0.0000 to 0.0035. When applying the misclassification simulation and extrapolation (MC-SIMEX) method for the first time to genetic data to account for the misclassification in a reanalysis of adiponectin-encoding (APM1) gene SNP associations with plasma adiponectin in 1,770 subjects, the authors found no impact of this small error on association estimates but increased estimates for a more substantial error. This study is the first to provide large-scale epidemiologic data on SNP genotype misclassification. The estimated misclassification in this example was small and negligible for association estimates, which is reassuring and essential for detecting SNP associations. In situations with more substantial error, the presented approach using duplicate genotyping and the MC-SIMEX method is practical and helpful for quantifying the genotyping error and its impact.
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of Epidemiology, 85764 Neuherberg, Germany. heid@helmholtz-muenchen.de
authors.forename: Iris M
authors.initials: IM
authors.lastname: Heid
authors.forename: Claudia
authors.initials: C
authors.lastname: Lamina
authors.forename: Helmut
authors.initials: H
authors.lastname: Küchenhoff
authors.forename: Guido
authors.initials: G
authors.lastname: Fischer
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Melanie
authors.initials: M
authors.lastname: Kolz
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.forename: Caren
authors.initials: C
authors.lastname: Vollmert
authors.forename: Stefanie
authors.initials: S
authors.lastname: Wagner
authors.forename: Cornelia
authors.initials: C
authors.lastname: Huth
authors.forename: Julia
authors.initials: J
authors.lastname: Müller
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.forename: Bernhard
authors.initials: B
authors.lastname: Paulweber
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
mesh_terms: D015982:Bias; D003951:Diagnostic Errors; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide
chemical_list: D005819:Genetic Markers
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