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Impact of Misclassification in Genotype-Exposure Interaction Studies: Example of N-Acetyltransferase 2 (NAT2), Smoking, and Bladder Cancer

¹ Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ² Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; ³ Health Services Research, Vanderbilt University, Nashville, Tennessee; and ⁴ Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky

Requests for reprints: Montserrat García-Closas, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892. Phone: 301-435-3981; Fax: 301-402-0916. E-mail: garciacm{at}exchange.nih.gov

Errors in genotype determination can lead to bias in the estimation of genotype effects and gene-environment interactions and increases in the sample size required for molecular epidemiologic studies. We evaluated the effect of genotype misclassification on odds ratio estimates and sample size requirements for a study of NAT2 acetylation status, smoking, and bladder cancer risk. Errors in the assignment of NAT2 acetylation status by a commonly used 3-single nucleotide polymorphism (SNP) genotyping assay, compared with an 11-SNP assay, were relatively small (sensitivity of 94% and specificity of 100%) and resulted in only slight biases of the interaction parameters. However, use of the 11-SNP assay resulted in a substantial decrease in sample size needs to detect a previously reported NAT2-smoking interaction for bladder cancer: 1,121 cases instead of 1,444 cases, assuming a 1:1 case-control ratio. This example illustrates how reducing genotype misclassification can result in substantial decreases in sample size requirements and possibly substantial decreases in the cost of studies to evaluate interactions.

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