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American Journal of Epidemiology Advance Access originally published online on September 12, 2008
American Journal of Epidemiology 2008 168(8):878-889; doi:10.1093/aje/kwn208
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

PRACTICE OF EPIDEMIOLOGY

Estimating the Single Nucleotide Polymorphism Genotype Misclassification From Routine Double Measurements in a Large Epidemiologic Sample

Iris M. Heid, Claudia Lamina, Helmut Küchenhoff, Guido Fischer, Norman Klopp, Melanie Kolz, Harald Grallert, Caren Vollmert, Stefanie Wagner, Cornelia Huth, Julia Müller, Martina Müller, Steven C. Hunt, Annette Peters, Bernhard Paulweber, H.-Erich Wichmann, Florian Kronenberg and Thomas Illig

Correspondence to Dr. Iris M. Heid, Helmholtz Zentrum München–German Research Center for Environmental Health, Institute of Epidemiology, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany (e-mail: heid{at}helmholtz-muenchen.de).

Received for publication January 14, 2008. Accepted for publication June 13, 2008.

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.

bias (epidemiology); genetics; genotype; likelihood functions; polymorphism, single nucleotide

Abbreviations: HWE, Hardy-Weinberg equilibrium; MALDI-TOF MS, matrix-assisted laser desorption ionization time-of-flight mass spectrometry; MC-SIMEX, misclassification simulation and extrapolation; SNP, single nucleotide polymorphism


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