Incorporating individual error rate into association test of unmatched case-control design

Objectives: Genotyping error commonly occurs and could reduce the power and bias statistical inference in genetics studies. In addition to genotypes, some automated biotechnologies also provide quality measurement of each individual genotype. We studied the relationship between the quality measurement and genotyping error rate. Furthermore, we propose two association tests incorporating the genotyping quality information with the goal to improve statistical power and inference. Methods: 50 pairs of DNA sample duplicates were typed for 232 SNPs by BeadArray technology. We used scatter plot, smoothing function and generalized additive models to investigate the relationship between genotype quality score (q) and inconsistency rate (i) among duplicates. We constructed two association tests: (1) weighted contingency table test (WCT) and (2) likelihood ratio test (LRT) to incorporate individual genotype error rate (epsilon(i)), in unmatched case-control setting. Results: In the 50 duplicates, we found q and (i) over tilde were in strong negative association, suggesting the genotypes with low quality score were more likely to be mistyped. The WCT improved the statistical power and partially corrects the bias in point estimation. The LRT offered moderate power gain, but was able to correct the bias in odds ratio estimation. The two new methods also performed favorably in some scenarios when epsilon(i) was mis-specified. Conclusions: With increasing number of genetic studies and application of automated genotyping technology, there is a growing need to adequately account for individual genotype error rate in statistical analysis. Our study represents an initial step to address this need and points out a promising direction for further research. Copyright (C) 2004 S. Karger AG, Basel.