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Incremental Value of Polygenic Risk Scores in Primary Prevention of Coronary Heart DiseaseA Review

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Importance  Risk prediction for coronary heart disease (CHD) is a cornerstone of primary prevention strategies. Polygenic risk scores (PRSs) have emerged as a new approach to predict risk in asymptomatic people. Polygenic risk scores for CHD have been studied in several populations, but there is lack of agreement about the incremental value of PRS beyond traditional risk factor scores in the primary prevention of CHD.

Observations  This narrative review critically appraised the 5 most highly cited studies published through 2021 that also included a large number (>45 000) of single-nucleotide variations (formerly single-nucleotide polymorphisms) and evaluated the incremental value of PRS in CHD risk prediction according to published PRS reporting standards. The cohorts studied included the Atherosclerosis Risk in Communities Study, FINRISK, the Framingham Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the UK Biobank. All of the studies focused predominantly on populations of European ancestry. The hazard ratio per standard deviation of PRS ranged from 1.24 (95% CI, 1.15-1.34) to 1.74 (95% CI, 1.61-1.86). The C statistic for PRS alone ranged from 0.549 to 0.623. The change in C statistic when PRS was added to a standard risk factor model ranged between −0.001 to +0.021. Net reclassification index was reported in 4 of the 5 studies and varied from 0.001 to 0.097. At a sensitivity (true-positive rate) of 90%, positive predictive values ranged from 1.8% to 16.6%, and false-positive rates ranged from 77.1% to 85.7%.

Conclusions and Relevance  In this review, PRS was significantly associated with CHD risk in all studies. The degree of improvement in C statistic and the net reclassification indexes when PRS was added to traditional risk scores ranged from negligible to modest. Based on established metrics to assess risk prediction scores, the addition of PRS to traditional risk scores does not appear to provide meaningful improvements in clinical decision-making in primary prevention populations.

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Article Information

Accepted for Publication: June 6, 2022.

Published Online: August 22, 2022. doi:10.1001/jamainternmed.2022.3171

Corresponding Author: Philip Greenland, MD, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N Lake Shore Dr, Ste 1400, Chicago, IL 60611 (p-greenland@northwestern.edu).

Author Contributions: Drs Greenland and Khan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Groenendyk.

Administrative, technical, or material support: Greenland, Khan.

Supervision: Greenland, Khan.

Conflict of Interest Disclosures: Dr Greenland reported receiving grants from the National Institutes of Health and the American Heart Association outside the submitted work. Dr Khan reported receiving grants from the American Heart Association (19TPA34890060) and the National Institutes of Health (R01HL159250, R01HL161514, and U01HL160279) outside the submitted work. No other disclosures were reported.

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