PROJECT SUMMARY Estimating risk for common diseases is challenging because of their complex and multifactorial etiology. Common diseases pose an enormous health care burden, therefore even modest improvements in the accuracy of risk estimates could have a substantial impact. A promising avenue for refining risk stratification is to incorporate measures of genetic risk, clinical variables, and environmental factors, into comprehensive risk profiles. By providing orthogonal and incremental information, polygenic risk scores (PRS) could improve risk prediction for common diseases, which are collectively responsible for most of the mortality and morbidity worldwide. To inform use of PRS in the clinical setting there is need for an evidence base on the clinical utility of integrating PRS with other risk factors, for disease risk prediction. Randomized control trials to demonstrate the clinical utility of a PRS in prolonging survival or improving the quality of life, are generally infeasible, mainly because of time needed, significant expense, and the possibility that the PRS may need updating while the trials are still ongoing. In the absence of such trials, an analytical framework is needed to collect the appropriate evidence. As part of this administrative supplement application, we will conduct systematic evidence reviews assessing the state of the science on the clinical utility of PRS for common disease risk assessment, using coronary heart disease (CHD) as an example. Our systematic review will be based on the ACCE (analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications) framework. Since analytic validity of genotyping is established, our focus is on the ‘..CCE’ components. The systematic reviews will collate evidence for the following: 1) clinical validity of PRS for CHD (PRSCHD); 2) clinical utility of using PRSCHD for risk assessment; including net reclassification improvement (NRI), integrated discrimination improvement (IDI), and change in outcomes (process, intermediate and clinical); 3) ethical, legal, social implications of using PRSCHD in the clinical setting.

PROJECT NARRATIVE We will conduct systematic reviews of the scientific literature to assess the clinical validity and utility of polygenic risk scores (PRS) when integrated with clinical risk factors, for common disease risk assessment, using coronary heart disease as an example. The reviews will collate the evidence base for clinical validity and utility for PRS, generate insights to guide clinical translation and implementation of PRS for common diseases, and inform future trials and research directions.