Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations
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Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Medicine |
| Vol/bind | 30 |
| Udgave nummer | 2 |
| Sider (fra-til) | 480-487 |
| Antal sider | 8 |
| ISSN | 1078-8956 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
We thank the past and future participants of the eMERGE Network projects. We thank M. O’Reilly for help with figure creation. We thank our All of Us Research Program colleagues, A. Ramirez, S. Lim, B. Mapes, A. Green and A. Musick, for providing their support and input throughout the ancestry calibration demonstration project lifecycle. We also thank the All of Us Science Committee and All of Us Steering Committee for their efforts evaluating and finalizing the approved demonstration projects. The All of Us Research Program would not be possible without the partnership of contributions made by its participants. To learn more about the All of Us Research Program’s research data repository, please visit https://www.researchallofus.org/ . This phase of the eMERGE Network was initiated and funded by the National Human Genome Research Institute through the following grants: U01HG011172 (Cincinnati Children’s Hospital Medical Center); U01HG011175 (Children’s Hospital of Philadelphia); U01HG008680 (Columbia University); U01HG011176 (Icahn School of Medicine at Mount Sinai); U01HG008685 (Mass General Brigham); U01HG006379 (Mayo Clinic); U01HG011169 (Northwestern University); U01HG011167 (University of Alabama at Birmingham); U01HG008657 (University of Washington); U01HG011181 (Vanderbilt University Medical Center); U01HG011166 (Vanderbilt University Medical Center serving as the Coordinating Center). The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA#: AOD 16037; Federally Qualified Health Centers: 75N98019F01202; Data and Research Center: 1 OT2 OD35404; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 OT2 OD030043; Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276.
Funding Information:
We thank the past and future participants of the eMERGE Network projects. We thank M. O’Reilly for help with figure creation. We thank our All of Us Research Program colleagues, A. Ramirez, S. Lim, B. Mapes, A. Green and A. Musick, for providing their support and input throughout the ancestry calibration demonstration project lifecycle. We also thank the All of Us Science Committee and All of Us Steering Committee for their efforts evaluating and finalizing the approved demonstration projects. The All of Us Research Program would not be possible without the partnership of contributions made by its participants. To learn more about the All of Us Research Program’s research data repository, please visit https://www.researchallofus.org/. This phase of the eMERGE Network was initiated and funded by the National Human Genome Research Institute through the following grants: U01HG011172 (Cincinnati Children’s Hospital Medical Center); U01HG011175 (Children’s Hospital of Philadelphia); U01HG008680 (Columbia University); U01HG011176 (Icahn School of Medicine at Mount Sinai); U01HG008685 (Mass General Brigham); U01HG006379 (Mayo Clinic); U01HG011169 (Northwestern University); U01HG011167 (University of Alabama at Birmingham); U01HG008657 (University of Washington); U01HG011181 (Vanderbilt University Medical Center); U01HG011166 (Vanderbilt University Medical Center serving as the Coordinating Center). The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA#: AOD 16037; Federally Qualified Health Centers: 75N98019F01202; Data and Research Center: 1 OT2 OD35404; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 OT2 OD030043; Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276.
Funding Information:
N.S.A.-H. is an employee and equity holder of 23andMe; serves as a scientific advisory board member for Allelica, Inc; received personal fees from Genentech Inc, Allelica Inc, and 23andMe; received research funding from Akcea Therapeutics; and was previously employed by Regeneron Pharmaceuticals. E.E.K. received personal fees from Illumina Inc, 23andMe and Regeneron Pharmaceuticals and serves as a scientific advisory board member for Encompass Bioscience, Foresite Labs and Galateo Bio. J.N.H. has equity in Camp4 Therapeutics and has been a consultant to Amgen, AstraZeneca, Cytokinetics, PepGen, Pfizer and Tenaya Therapeutics and is the founder of Ikaika Therapeutics. J.F.P. is a paid consultant for Natera Inc. A. Khera. is an employee of Verve Therapeutics. N.L. received personal fees from Illumina Inc and is a scientific advisory board member for FYR Diagnostics. J.F.P. is a consultant for Myome. D.V. is a consultant for Illumina and has grant support from GeneDx. T.L.W. has grant funding from Gilead Sciences, Inc. The other authors declare no competing interests.
Publisher Copyright:
© The Author(s) 2024.
ID: 385588190