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Brian Wolpin

Publications and source records attributed to Brian Wolpin.

2 recordsLinked to original sources

Playing Musical Chairs in Big Data to Reveal Variables Associations

Testing for associations in big data faces the problem of multiple comparisons, with true signals buried inside the noise of all associations queried. This is particularly true in genetic association studies where a substantial proportion of the variation of human phenotypes is driven by numerous genetic variants of small effect. The current strategy to improve power to identify these weak associations consists of applying standard marginal statistical approaches and increasing study sample sizes. While successful, this approach does not leverage the environmental and genetic factors shared between the multiple phenotypes collected in contemporary cohorts. Here we develop a method that improves the power of detecting associations when a large number of correlated variables have been measured on the same samples. Our analyses over real and simulated data provide direct support that large sets of correlated variables can be leveraged to achieve dramatic increases in statistical power equivalent to a two or even three folds increase in sample size.

Genetics

Winners curse correction and variable thresholding improve performance of polygenic risk modeling based on summary-level data from genome-wide association studies

Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winners-curse adjustments for marginal association coefficients that are used to weight the SNPs in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winners curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25-50% increase in the prediction R2) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winners curse correction improved prediction R2 from 2.29% based on the standard PRS to 3.10% (P=0.0017) and incorporating functional annotation data further improved R2 to 3.53% (P=2{chi}10-5). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure.

Genetics