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Predictive accuracy of a polygenic risk score-enhanced prediction model vs a clinical risk score for coronary artery disease

Title: Predictive accuracy of a polygenic risk score-enhanced prediction model vs a clinical risk score for coronary artery disease
Authors: Elliott, J
Bodinier, B
Bond, TA
Chadeau-Hyam, M
Evangelou, E
Moons, KGM
Dehghan, A
Muller, DC
Elliott, P
Tzoulaki, I
Item Type: Journal Article
Abstract: Importance The incremental value of polygenic risk scores in addition to well-established risk prediction models for coronary artery disease (CAD) is uncertain. Objective To examine whether a polygenic risk score for CAD improves risk prediction beyond pooled cohort equations. Design, Setting, and Participants Observational study of UK Biobank participants enrolled from 2006 to 2010. A case-control sample of 15 947 prevalent CAD cases and equal number of age and sex frequency–matched controls was used to optimize the predictive performance of a polygenic risk score for CAD based on summary statistics from published genome-wide association studies. A separate cohort of 352 660 individuals (with follow-up to 2017) was used to evaluate the predictive accuracy of the polygenic risk score, pooled cohort equations, and both combined for incident CAD. Exposures Polygenic risk score for CAD, pooled cohort equations, and both combined. Main Outcomes and Measures CAD (myocardial infarction and its related sequelae). Discrimination, calibration, and reclassification using a risk threshold of 7.5% were assessed. Results In the cohort of 352 660 participants (mean age, 55.9 years; 205 297 women [58.2%]) used to evaluate the predictive accuracy of the examined models, there were 6272 incident CAD events over a median of 8 years of follow-up. CAD discrimination for polygenic risk score, pooled cohort equations, and both combined resulted in C statistics of 0.61 (95% CI, 0.60 to 0.62), 0.76 (95% CI, 0.75 to 0.77), and 0.78 (95% CI, 0.77 to 0.79), respectively. The change in C statistic between the latter 2 models was 0.02 (95% CI, 0.01 to 0.03). Calibration of the models showed overestimation of risk by pooled cohort equations, which was corrected after recalibration. Using a risk threshold of 7.5%, addition of the polygenic risk score to pooled cohort equations resulted in a net reclassification improvement of 4.4% (95% CI, 3.5% to 5.3%) for cases and −0.4% (95% CI, −0.5% to −0.4%) for noncases (overall net reclassification improvement, 4.0% [95% CI, 3.1% to 4.9%]). Conclusions and Relevance The addition of a polygenic risk score for CAD to pooled cohort equations was associated with a statistically significant, yet modest, improvement in the predictive accuracy for incident CAD and improved risk stratification for only a small proportion of individuals. The use of genetic information over the pooled cohort equations model warrants further investigation before clinical implementation.
Issue Date: 18-Feb-2020
Date of Acceptance: 20-Dec-2019
URI: http://hdl.handle.net/10044/1/85895
DOI: 10.1001/jama.2019.22241
ISSN: 0098-7484
Publisher: American Medical Association
Start Page: 636
End Page: 645
Journal / Book Title: JAMA: Journal of the American Medical Association
Volume: 323
Issue: 7
Copyright Statement: © 2020 American Medical Association. All Rights Reserved.
Sponsor/Funder: Health Data Research Uk
Cancer Research UK
Cancer Research UK
Cancer Research UK
Medical Research Council (MRC)
Funder's Grant Number: Health Data Research UK
‘Mechanomics’ PRC project grant 22184
C57955/A24390
24390
MR/L01341X/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
HEART-DISEASE
ASSOCIATION
VALIDATION
Adult
Aged
Case-Control Studies
Coronary Artery Disease
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Male
Middle Aged
Multifactorial Inheritance
Predictive Value of Tests
ROC Curve
Risk
Risk Assessment
Humans
Genetic Predisposition to Disease
Risk
Risk Assessment
Case-Control Studies
Predictive Value of Tests
ROC Curve
Genotype
Multifactorial Inheritance
Adult
Aged
Middle Aged
Female
Male
Coronary Artery Disease
Genome-Wide Association Study
Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
HEART-DISEASE
ASSOCIATION
VALIDATION
11 Medical and Health Sciences
General & Internal Medicine
Publication Status: Published
Open Access location: https://www.ncbi.nlm.nih.gov/pubmed/32068818
Online Publication Date: 2020-02-18
Appears in Collections:School of Public Health