Johannes T Neumann1,2,3, Moeen Riaz1, Andrew Bakshi1, Galina Polekhina1, Le T P Thao1, Mark R Nelson1,4, Robyn L Woods1, Gad Abraham5, Michael Inouye5,6, Christopher M Reid1,7, Andrew M Tonkin1, Jeff D Williamson8, Geoffrey A Donnan9, Amy Brodtmann9,10, Geoffrey C Cloud11,12, John J McNeil1, Paul Lacaze1. 1. Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine (J.T.N., M.R., A. Bakshi, G.P., L.T.P.T., M.R.N., R.L.W., C.M.R., A.M.T., J.J.M., P.L.), Monash University, Melbourne, Australia. 2. Department of Cardiology, University Heart and Vascular Centre, Hamburg, Germany (J.T.N.). 3. German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Germany (J.T.N.). 4. Menzies Institute for Medical Research, University of Tasmania, Hobart (M.R.N.). 5. Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (G.A., M.I.). 6. Department of Public Health and Primary Care, University of Cambridge, United Kingdom (M.I.). 7. School of Public Health, Curtin University, Perth, Western Australia, Australia (C.M.R.). 8. Department of Internal Medicine, Sticht Center on Aging and Alzheimer's Prevention, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.D.W.). 9. Melbourne Brain Centre, Royal Melbourne Hospital (G.A.D., A. Brodtmann), University of Melbourne, Australia. 10. The Florey Institute of Neuroscience and Mental Health (A. Brodtmann), University of Melbourne, Australia. 11. Department of Neuroscience, Central Clinical School (G.C.C.), Monash University, Melbourne, Australia. 12. Department of Neurology, Alfred Hospital, Melbourne, Australia (G.C.C.).
Abstract
Background and Purpose: Polygenic risk scores (PRSs) can be used to predict ischemic stroke (IS). However, further validation of PRS performance is required in independent populations, particularly older adults in whom the majority of strokes occur. Methods: We predicted risk of incident IS events in a population of 12 792 healthy older individuals enrolled in the ASPREE trial (Aspirin in Reducing Events in the Elderly). The PRS was calculated using 3.6 million genetic variants. Participants had no previous history of cardiovascular events, dementia, or persistent physical disability at enrollment. The primary outcome was IS over 5 years, with stroke subtypes as secondary outcomes. A multivariable model including conventional risk factors was applied and reevaluated after adding PRS. Area under the curve and net reclassification were evaluated. Results: At baseline, mean population age was 75 years. In total, 173 incident IS events occurred over a median follow-up of 4.7 years. When PRS was added to the multivariable model as a continuous variable, it was independently associated with IS (hazard ratio, 1.41 [95% CI, 1.20–1.65] per SD of the PRS; P<0.001). The PRS alone was a better discriminator for IS events than most conventional risk factors. PRS as a categorical variable was a significant predictor in the highest tertile (hazard ratio, 1.74; P=0.004) compared with the lowest. The area under the curve of the conventional model was 66.6% (95% CI, 62.2–71.1) and after inclusion of the PRS, improved to 68.5 ([95% CI, 64.0–73.0] P=0.095). In subgroup analysis, the continuous PRS remained an independent predictor for large vessel and cardioembolic stroke subtypes but not for small vessel stroke. Reclassification was improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95% CI, 0.17–0.43). Conclusions: PRS predicts incident IS in a healthy older population but only moderately improves prediction over conventional risk factors. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.
Background and Purpose: Polygenic risk scores (PRSs) can be used to predict ischemic stroke (IS). However, further validation of PRS performance is required in independent populations, particularly older adults in whom the majority of strokes occur. Methods: We predicted risk of incident IS events in a population of 12 792 healthy older individuals enrolled in the ASPREE trial (Aspirin in Reducing Events in the Elderly). The PRS was calculated using 3.6 million genetic variants. Participants had no previous history of cardiovascular events, dementia, or persistent physical disability at enrollment. The primary outcome was IS over 5 years, with stroke subtypes as secondary outcomes. A multivariable model including conventional risk factors was applied and reevaluated after adding PRS. Area under the curve and net reclassification were evaluated. Results: At baseline, mean population age was 75 years. In total, 173 incident IS events occurred over a median follow-up of 4.7 years. When PRS was added to the multivariable model as a continuous variable, it was independently associated with IS (hazard ratio, 1.41 [95% CI, 1.20–1.65] per SD of the PRS; P<0.001). The PRS alone was a better discriminator for IS events than most conventional risk factors. PRS as a categorical variable was a significant predictor in the highest tertile (hazard ratio, 1.74; P=0.004) compared with the lowest. The area under the curve of the conventional model was 66.6% (95% CI, 62.2–71.1) and after inclusion of the PRS, improved to 68.5 ([95% CI, 64.0–73.0] P=0.095). In subgroup analysis, the continuous PRS remained an independent predictor for large vessel and cardioembolic stroke subtypes but not for small vessel stroke. Reclassification was improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95% CI, 0.17–0.43). Conclusions: PRS predicts incident IS in a healthy older population but only moderately improves prediction over conventional risk factors. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.
Entities:
Keywords:
aged; area under curve; dementia; risk factors; stroke
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