Polygenic risk scores in the clinic: new perspectives needed on familiar ethical issues

Abstract

Clinical use of polygenic risk scores (PRS) will look very different to the more familiar monogenic testing. Here we argue that despite these differences, most of the ethical, legal, and social issues (ELSI) raised in the monogenic setting, such as the relevance of results to family members, the approach to secondary and incidental findings, and the role of expert mediators, continue to be relevant in the polygenic context, albeit in modified form. In addition, PRS will reanimate other old debates. Their use has been proposed both in the practice of clinical medicine and of public health, two contexts with differing norms. In each of these domains, it is unclear what endpoints clinical use of PRS should aim to maximize and under what constraints. Reducing health disparities is a key value for public health, but clinical use of PRS could exacerbate race-based health disparities owing to differences in predictive power across ancestry groups. Finally, PRS will force a reckoning with pre-existing questions concerning biomarkers, namely the relevance of self-reported race, ethnicity and ancestry, and the relationship of risk factors to disease diagnoses. In this Opinion, we argue that despite the parallels to the monogenic setting, new work is urgently needed to gather data, consider normative implications, and develop best practices around this emerging branch of genomics.

Machine Learning Prediction of Biomarkers from SNPs and of Disease Risk from Biomarkers in the UK Biobank

“…This paper concerns the application of sparse linear ML to genetic and health information in order to make predictions that could be useful in a clinical setting. Recent work has highlighted that ML, in particular polygenic predictors, have high potential impact in clinical settings [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], especially for coronary artery disease (CAD) [ 11 , 12 , 22 ]. Additionally, over the past quarter century it has been advocated (e.g., Joint Task Force of the European Society of Cardiology and Other Societies [ 23 ], American College of Cardiology(ACC)/American Heart Association (AHA) [ 24 ], and the Scottish Intercollegiate Guidelines Network [ 25 ]) that physicians should use risk scores based on statistical summaries of biomarkers.…”

Clinical validation, implementation, and reporting of polygenic risk scores for common diseases

“…Much has been written about the reduced validity of most PRS among populations of non-European ancestry, due to their use of non-causal loci and effect sizes from GWAS in predominantly European discovery cohorts 19,20,78,79 . As the genomics community awaits larger data sets from more diverse populations and develops improved methods for deriving trans-ancestry PRS, 10,15,80 a laboratory aiming to develop a clinical PRS assay for a given disease has a few options: 1) postpone implementation; 2) implement separate ancestry-speci c published PRS in those ancestries where it is available; or 3) implement a single PRS and report transparently any applicable limitations in the underlying evidence and its interpretation for speci c individuals.…”

Statistical genetics and polygenic risk score for precision medicine

“…Fourth, the prospect of clinical use of PRS is associated with a wide variety of ELSI (ethical, legal, and social implications) concerns, which have been also discussed in the context of monogenic genetic results and is also present in the polygenic context [ 29 ]. One of the ELSI concerns about PRS is the relevance of findings of PRS to family members.…”