Impact of misclassification in genotype-exposure interaction studies: example of N-acetyltransferase 2 (NAT2), smoking, and bladder cancer.
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.
Deitz
Anne C
AC
Center for Cancer Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, USA.
Rothman
Nathanial
N
Rebbeck
Timothy R
TR
Hayes
Richard B
RB
Chow
Wong-Ho
WH
Zheng
Wei
W
Hein
David W
DW
García-Closas
Montserrat
M
D000483:Alleles; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D015982:Bias; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics; D002273:Carcinogens / Q000009:adverse effects*; D016022:Case-Control Studies; D003043:Cocarcinogenesis; D015331:Cohort Studies; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008957:Models, Genetic; D015233:Models, Statistical; D016017:Odds Ratio; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics; D018570:Risk Assessment; D018401:Sample Size; D012907:Smoking / Q000009:adverse effects*; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology* / Q000235:genetics
D002273:Carcinogens; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human