Motivation: A common difficulty in large-scale microarray studies is the presence of confounding factors, which may significantly skew estimates of statistical significance, cause unreliable feature selection and high false negative rates. To deal with these difficulties, an algorithmic framework known as Surrogate Variable Analysis (SVA) was recently proposed. Results: Based on the notion that data can be viewed as an interference pattern, reflecting the superposition of independent effects

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... random noise, we present a modified SVA, called Independent Surrogate Variable Analysis (ISVA), to identify features correlating with a phenotype of interest in the presence of potential confounding factors. Using simulated data, we show that ISVA performs well in identifying confounders as well as outperforming methods which do not adjust for confounding. Using four large-scale Illumina Infinium DNA methylation datasets subject to low signal to noise ratios and substantial confounding by beadchip effects and variable bisulfite conversion efficiency, we show that ISVA improves the identifiability of confounders and that this enables a framework for feature selection that is more robust to model misspecification and heterogeneous phenotypes. Finally, we demonstrate similar improvements of ISVA across four mRNA expression datasets. Thus, ISVA should be useful as a feature selection tool in studies that are subject to confounding. Availability: An R-package isva is available from www.cran.r-project .org.