MSGene: a multistate model using genetic risk and the electronic health record applied to lifetime risk of coronary artery disease

Sarah M. Urbut, Ming Wai Yeung, Shaan Khurshid, So Mi Jemma Cho, Art Schuermans, Jakob German, Kodi Taraszka, Kaavya Paruchuri, Akl C. Fahed, Patrick T. Ellinor, Ludovic Trinquart, Giovanni Parmigiani, Alexander Gusev and Pradeep Natarajan ()
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Sarah M. Urbut: Harvard Medical School
Ming Wai Yeung: University of Groningen, University Medical Center Groningen
Shaan Khurshid: Broad Institute of MIT and Harvard
So Mi Jemma Cho: Broad Institute of MIT and Harvard
Art Schuermans: Broad Institute of MIT and Harvard
Jakob German: University of Helsinki
Kodi Taraszka: Harvard Medical School and Dana-Farber Cancer Institute
Kaavya Paruchuri: Harvard Medical School
Akl C. Fahed: Harvard Medical School
Patrick T. Ellinor: Harvard Medical School
Ludovic Trinquart: Tufts Medical Center
Giovanni Parmigiani: Dana Farber Cancer Institute
Alexander Gusev: Broad Institute of MIT and Harvard
Pradeep Natarajan: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods lack the ability to incorporate new information throughout the life course or to combine innate genetic risk factors with acquired lifetime risk. We designed a general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score. This model is designed to handle longitudinal data over the lifetime to address this unmet need and support clinical decision-making. We analyze longitudinal data from 480,638 UK Biobank participants and compared predicted lifetime risk with the 30-year Framingham risk score. MSGene improves discrimination (C-index 0.71 vs 0.66), age of high-risk detection (C-index 0.73 vs 0.52), and overall prediction (RMSE 1.1% vs 10.9%), in held-out data. We also use MSGene to refine estimates of lifetime absolute risk reduction from statin initiation. Our findings underscore our multistate model’s potential public health value for accurate lifetime CAD risk estimation using clinical factors and increasingly available genetics toward earlier more effective prevention.

Date: 2024
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DOI: 10.1038/s41467-024-49296-9

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