If the validation sample is more closely related to the discovery population than to the target population, then the prediction accuracy will be over-estimated. In humans, a polygenic prediction analysis of height in 5,117 individuals from the Framingham Heart Study (FHS; original and offspring cohorts only) reported a prediction R2 of 0.25 using 10-fold cross-validation when including all individuals in the analysis60. However, because FHS includes many related individuals, the authors repeated the analysis restricting the 10-fold cross-validation samples to individuals with no known close relatives (parent-offspring, sibling, or half-sib) in the data set based on pedigree information. In this restricted analysis, the prediction R2 decreased to 0.15. We caution that cryptic relatedness can still inflate prediction accuracy even when known close relatives are excluded. To demonstrate this, we conducted a polygenic prediction analysis of height using 7,434 individuals from the FHS SHARe data61 (BOX 3). Our results demonstrate that cryptic relatedness, beyond the close relatives inferred from pedigrees, can inflate prediction accuracy relative to the prediction accuracy that could be achieved in an independent validation sample.
