Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network

Anna C F Lewis¹, Rex L Chisholm², John J Connolly³, Edward D Esplin⁴, Joe Glessner³, Adam Gordon⁵, Robert C Green⁶, Hakon Hakonarson⁷, Margaret Harr³, Ingrid A Holm⁸, Gail P Jarvik⁹, Elizabeth Karlson¹⁰, Eimear E Kenny¹¹, Leah Kottyan¹², Niall Lennon¹³, Jodell E Linder¹⁴, Yuan Luo¹⁵, Lisa J Martin¹⁶, Emma Perez¹⁷, Megan J Puckelwartz⁵, Laura J Rasmussen-Torvik¹⁸, Maya Sabatello¹⁹, Richard R Sharp²⁰, Jordan W Smoller²¹, Rene Sterling²², Shannon Terek³, Wei-Qi Wei²³, Stephanie M Fullerton²⁴

Affiliations

¹ Edmond and Lily Safra Center for Ethics, Harvard University, Cambridge, MA, USA; Department of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: aclewis@bwh.harvard.edu.
² Center for Genetic Medicine, Northwestern University, Evanston, IL, USA.
³ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴ Invitae, San Francisco, CA, USA.
⁵ Center for Genetic Medicine, Northwestern University, Evanston, IL, USA; Department of Pharmacology, Northwestern University, Evanston, IL, USA.
⁶ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ariadne Labs, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
⁷ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁹ Division of Medical Genetics, Department of Medicine and Department of Genome Science, University of Washington Medical Center, Seattle, WA, USA.
¹⁰ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Mass General Brigham Personalized Medicine, Boston, MA, USA.
¹¹ Institute for Genomic Health, Icahn School of Medicine, New York City, NY, USA; Center for Clinical Translational Genomics, Icahn School of Medicine, New York City, NY, USA; Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine, New York City, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine, New York City, NY, USA.
¹² Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴ Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁵ Department of Preventive Medicine, Northwestern University, Evanston, IL, USA.
¹⁶ Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁷ Mass General Brigham Personalized Medicine, Boston, MA, USA.
¹⁸ Center for Genetic Medicine, Northwestern University, Evanston, IL, USA; Department of Preventive Medicine, Northwestern University, Evanston, IL, USA.
¹⁹ Center for Precision Medicine and Genomics, Department of Medicine, Columbia University Irving Medical Center, New York City, NY, USA; Division of Ethics, Department of Medical Humanities and Ethics, Columbia University Irving Medical Center, New York City, NY, USA.
²⁰ Biomedical Ethics Program, Mayo Clinic, Rochester, MN, USA.
²¹ Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Psychiatric & Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
²² Division of Genomics and Society, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
²³ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁴ Department of Bioethics & Humanities, University of Washington School of Medicine, Seattle, WA, USA.

PMID: 38688278
PMCID: PMC11179244
DOI: 10.1016/j.ajhg.2024.04.005

Review

Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network

Anna C F Lewis et al. Am J Hum Genet. 2024.

. 2024 Jun 6;111(6):999-1005.

doi: 10.1016/j.ajhg.2024.04.005. Epub 2024 Apr 29.

Authors

Affiliations

¹ Edmond and Lily Safra Center for Ethics, Harvard University, Cambridge, MA, USA; Department of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: aclewis@bwh.harvard.edu.
² Center for Genetic Medicine, Northwestern University, Evanston, IL, USA.
³ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴ Invitae, San Francisco, CA, USA.
⁵ Center for Genetic Medicine, Northwestern University, Evanston, IL, USA; Department of Pharmacology, Northwestern University, Evanston, IL, USA.
⁶ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ariadne Labs, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
⁷ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁹ Division of Medical Genetics, Department of Medicine and Department of Genome Science, University of Washington Medical Center, Seattle, WA, USA.
¹⁰ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Mass General Brigham Personalized Medicine, Boston, MA, USA.
¹¹ Institute for Genomic Health, Icahn School of Medicine, New York City, NY, USA; Center for Clinical Translational Genomics, Icahn School of Medicine, New York City, NY, USA; Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine, New York City, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine, New York City, NY, USA.
¹² Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴ Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁵ Department of Preventive Medicine, Northwestern University, Evanston, IL, USA.
¹⁶ Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁷ Mass General Brigham Personalized Medicine, Boston, MA, USA.
¹⁸ Center for Genetic Medicine, Northwestern University, Evanston, IL, USA; Department of Preventive Medicine, Northwestern University, Evanston, IL, USA.
¹⁹ Center for Precision Medicine and Genomics, Department of Medicine, Columbia University Irving Medical Center, New York City, NY, USA; Division of Ethics, Department of Medical Humanities and Ethics, Columbia University Irving Medical Center, New York City, NY, USA.
²⁰ Biomedical Ethics Program, Mayo Clinic, Rochester, MN, USA.
²¹ Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Psychiatric & Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
²² Division of Genomics and Society, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
²³ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁴ Department of Bioethics & Humanities, University of Washington School of Medicine, Seattle, WA, USA.

PMID: 38688278
PMCID: PMC11179244
DOI: 10.1016/j.ajhg.2024.04.005

Abstract

The differential performance of polygenic risk scores (PRSs) by group is one of the major ethical barriers to their clinical use. It is also one of the main practical challenges for any implementation effort. The social repercussions of how people are grouped in PRS research must be considered in communications with research participants, including return of results. Here, we outline the decisions faced and choices made by a large multi-site clinical implementation study returning PRSs to diverse participants in handling this issue of differential performance. Our approach to managing the complexities associated with the differential performance of PRSs serves as a case study that can help future implementers of PRSs to plot an anticipatory course in response to this issue.

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Conflict of interest statement

Declaration of interests A.C.F.L. owns some stock in Fabric Genomics; E.D.E. is an employee and stockholder of Invitae, advisor and stockholder of Taproot Health, and advisor and stockholder of Exir; R.C.G. receives compensation for advising the following companies: Allelica, Atria, Fabric, Genomic Life, and Juniper Genomics; and is co-founder of Genome Medical and Nurture Genomics; E.E.K. has received personal fees from Regeneron Pharmaceuticals, 23&Me, Allelica, and Illumina; has received research funding from Allelica; and serves on the advisory boards for Encompass Biosciences, Overtone, and Galatea Bio; N.L. received personal fees from Illumina Inc; E.P. is a paid consultant for Allelica Inc.; M.S. is a member of the Institutional Review Board of the All of Us Research Program; J.W.S. is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity), has received grant support from Biogen, Inc., and is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments.

Figures

**Figure 1**
The layered strategy adopted by the eMERGE Network to communicate PRS results, including differential performance (A) The summary of findings for type 2 diabetes on the GIRA. (B) Detailed results for the high PRS result for type 2 diabetes on the GIRA (see Linder et al. for complete context for A and B). (C) Summary and detailed results on the PRS report for high type 2 diabetes.

See this image and copyright information in PMC

References

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Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network

Affiliations

Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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