A practical remedy to problems associated with population stratification is to fit ancestry principal components in the analysis of discovery samples. We note that differential bias between cases and controls65 can also lead to spurious prediction R2 if discovery and validation samples exhibit the same differential bias, as could occur when using 10-fold cross-validation. A remedy for differential bias is to perform stringent quality control and/or to validate in a completely independent sample, in lieu of 10-fold cross-validation. One QC step that can be done is to use the genotyped SNPs that are in the predictor and quantify the estimated relatedness between the application sample and the discovery and validation samples, for example in a principal component analysis (PCA)66 or related methods67. If the application sample is an outlier on the PCA then the prediction accuracy in the target may be less than expected from the validation procedure.
