Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.28.224782v1?rss=1 Authors: Pain, O., Glanville, K. P., Hagenaars, S. P., Selzam, S. P., Fürtjes, A. E., Gaspar, H. A., Coleman, J. R., Rimfeld, K., Breen, G., Plomin, R., Folkersen, L., Lewis, C. M. Abstract: Background: The predictive utility of polygenic scores is increasing, and many polygenic scoring methods are available, but it is unclear which method performs best. This study evaluates the predictive utility of polygenic scoring methods within a reference-standardized framework, which uses a common set of variants and reference-based estimates of linkage disequilibrium and allele frequencies to construct scores. Methods: Six polygenic score methods were tested: p-value thresholding and clumping (pT+clump), SBLUP, lassosum, LDPred, PRScs and SBayesR, evaluating their performance to predict outcomes in UK Biobank and the Twins Early Development Study (TEDS). Strategies to identify optimal p-value threshold and shrinkage parameters were compared, including 10-fold cross validation, pseudovalidation (with no validation sample), and multi-polygenic score elastic net models. Results: lassosum, PRScs and LDPred performed strongly using 10-fold cross-validation to identify the most predictive p-value threshold or shrinkage parameter, giving a relative improvement of 14-17% over pT+clump in the correlation between observed and predicted outcome values. Using pseudovalidation, the best method was PRScs, with a relative improvement of >11% over other pseudovalidation methods (lassosum, SBLUP, SBayesR, LDPred), and only 1% less than the best polygenic score identified by 10-fold cross validation. Elastic net models containing polygenic scores based on a range of parameters consistently improved prediction over any single polygenic score. Conclusion: Within a reference-standardized framework, the best polygenic prediction was achieved using lassosum and PRScs, modeling multiple polygenic scores derived using multiple parameters. This study will help researchers performing polygenic score studies to select the most powerful and predictive analysis methods. Copy rights belong to original authors. Visit the link for more info