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Wiley, Genetic Epidemiology, 7(35), p. 592-596, 2011

DOI: 10.1002/gepi.20607

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Bias due to two-stage residual-outcome regression analysis in genetic association studies

Journal article published in 2011 by Serkalem Demissie, L. Adrienne Cupples ORCID
This paper is available in a repository.
This paper is available in a repository.

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Abstract

Association studies of risk factors and complex diseases require careful assessment of potential confounding factors. Two-stage regression analysis, sometimes referred to as residual- or adjusted-outcome analysis, has been increasingly used in association studies of single nucleotide polymorphisms (SNPs) and quantitative traits. In this analysis, first, a residual-outcome is calculated from a regression of the outcome variable on covariates and then the relationship between the adjusted-outcome and the SNP is evaluated by a simple linear regression of the adjusted-outcome on the SNP. In this paper, we examine the performance of this 2-stage analysis as compared with multiple linear regression (MLR) analysis. Our findings show that when a SNP and a covariate are correlated, the 2-stage approach results in biased genotypic effect and loss of power. Bias is always toward the null and increases with the squared-correlation between the SNP and the covariate (ρSC2). For example, for ρSC2=0.0, 0.1 and 0.5, 2-stage analysis results in, respectively, 0%, 10% and 50% attenuation in the SNP effect. As expected, MLR was always unbiased. Since individual SNPs often show little or no correlation with covariates, a 2-stage analysis is expected to perform as well as MLR in many genetic studies; however, it produces considerably different results from MLR and may lead to incorrect conclusions when independent variables are highly correlated. While a useful alternative to MLR under ρSC2=0.0, the 2-stage approach has serious limitations. Its use as a simple substitute for MLR should be avoided.