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. 2023 Apr;25(4):100006.
doi: 10.1016/j.gim.2023.100006. Epub 2023 Jan 6.

Returning integrated genomic risk and clinical recommendations: The eMERGE study

Jodell E Linder  1 , Aimee Allworth  2 , Harris T Bland  3 , Pedro J Caraballo  4 , Rex L Chisholm  5 , Ellen Wright Clayton  6 , David R Crosslin  7 , Ozan Dikilitas  8 , Alanna DiVietro  1 , Edward D Esplin  9 , Sophie Forman  1 , Robert R Freimuth  10 , Adam S Gordon  11 , Richard Green  12 , Maegan V Harden  13 , Ingrid A Holm  14 , Gail P Jarvik  15 , Elizabeth W Karlson  16 , Sofia Labrecque  1 , Niall J Lennon  13 , Nita A Limdi  17 , Kathleen F Mittendorf  18 , Shawn N Murphy  19 , Lori Orlando  20 , Cynthia A Prows  21 , Luke V Rasmussen  22 , Laura Rasmussen-Torvik  22 , Robb Rowley  23 , Konrad Teodor Sawicki  24 , Tara Schmidlen  9 , Shannon Terek  25 , David Veenstra  26 , Digna R Velez Edwards  27 , Devin Absher  28 , Noura S Abul-Husn  29 , Jorge Alsip  30 , Hana Bangash  31 , Mark Beasley  32 , Jennifer E Below  33 , Eta S Berner  34 , James Booth  35 , Wendy K Chung  36 , James J Cimino  37 , John Connolly  25 , Patrick Davis  12 , Beth Devine  26 , Stephanie M Fullerton  38 , Candace Guiducci  13 , Melissa L Habrat  12 , Heather Hain  25 , Hakon Hakonarson  25 , Margaret Harr  25 , Eden Haverfield  9 , Valentina Hernandez  39 , Christin Hoell  40 , Martha Horike-Pyne  2 , George Hripcsak  41 , Marguerite R Irvin  42 , Christopher Kachulis  13 , Dean Karavite  43 , Eimear E Kenny  29 , Atlas Khan  44 , Krzysztof Kiryluk  44 , Bruce Korf  45 , Leah Kottyan  46 , Iftikhar J Kullo  31 , Katie Larkin  13 , Cong Liu  41 , Edyta Malolepsza  13 , Teri A Manolio  23 , Thomas May  47 , Elizabeth M McNally  5 , Frank Mentch  25 , Alexandra Miller  31 , Sean D Mooney  12 , Priyanka Murali  2 , Brenda Mutai  2 , Naveen Muthu  43 , Bahram Namjou  46 , Emma F Perez  48 , Megan J Puckelwartz  11 , Tejinder Rakhra-Burris  20 , Dan M Roden  49 , Elisabeth A Rosenthal  2 , Seyedmohammad Saadatagah  31 , Maya Sabatello  50 , Dan J Schaid  51 , Baergen Schultz  23 , Lynn Seabolt  1 , Gabriel Q Shaibi  52 , Richard R Sharp  53 , Brian Shirts  54 , Maureen E Smith  24 , Jordan W Smoller  55 , Rene Sterling  56 , Sabrina A Suckiel  57 , Jeritt Thayer  43 , Hemant K Tiwari  32 , Susan B Trinidad  38 , Theresa Walunas  58 , Wei-Qi Wei  3 , Quinn S Wells  59 , Chunhua Weng  41 , Georgia L Wiesner  33 , Ken Wiley  23 ; eMERGE Consortium; Josh F Peterson  60
Collaborators, Affiliations

Returning integrated genomic risk and clinical recommendations: The eMERGE study

Jodell E Linder et al. Genet Med. 2023 Apr.

Abstract

Purpose: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.

Methods: To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report and will assess uptake of care recommendations after return of results.

Results: GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.

Conclusion: Return of a novel report for communicating monogenic, polygenic, and family history-based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Trial registration: ClinicalTrials.gov NCT05277116.

Keywords: Common variants; Family history; Genotyping; Monogenic risks; Polygenic risk scores.

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Conflict of interest statement

Conflict of Interest 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. T.W. has grant funding from Gilead Sciences, Inc. L.O. and T.R.-B are founders of a company developing MeTree. T.S., E.D.E., and E.H. are employees and stockholders of Invitae Corporation. E.M.M. has been a consultant for Avidity Bioscience, Amgen Inc, AstraZeneca, Cytokinetics, Invitae Corporation, Janssen Pharmaceuticals, Pfizer Inc, PepGen Inc, Tenaya Therapeutics, and Stealth BioTherapeutics Inc; she is also the founder of Ikaika Therapeutics. 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. B.K. is an advisory board member and stockholder of Genome Medical. M.S. is a member of the Institutional Review Board of the All of Us Research Program. E.F.P. is a paid consultant for Allecia Inc. J.F.P. is a paid consultant for Natera Inc. All other authors declare no conflicts of interest.

Figures

Figure 1:
Figure 1:. eMERGE network organizational structure.
Under the guidance of the NHGRI, External Scientific Panel, and Steering committee, the ten clinical sites, coordinating center, and network partners make up six workgroups charged with developing the network protocol, risk scores, and methods as well as recruiting and returning results to 25,000 individuals. VUMC: Vanderbilt University Medical Center; PRS: Polygenic Risk Score; ELSI: Ethical Legal & Social Implications; sIRB: Single Institutional Review Board; EHR: Electronic Health Records.
Figure 2:
Figure 2:. The GIRA report integrates multiple risk elements and is returned to individuals, providers, and the EHR.
Individuals in the eMERGE study are enrolled and provide both self-reported (clinical and family history) data as well as biological samples. Polygenic risk (Broad report); monogenic risk (Invitae report); family health history (MeTree pedigree); and clinical data (from electronic health records and participant surveys) are collected and combined to create the Genome Informed Risk Assessment (GIRA) report. Results are returned along with care recommendations that can be used to guide screening recommendations and next steps for primary care providers. Outcomes are assessed to determine changes in healthcare behavior after return.
Figure 3:
Figure 3:. Research infrastructure for assembling risk information from site enrollment data collection, site EHRs, partner laboratories, and point-of-care tools for collecting family history.
Data are transferred through APIs from partners and sites to the central VUMC housed REDCap system, R. Custom REDCap programming was developed to generate the overall Genome Informed Risk Assessment (GIRA) report which is made available to sites along with component data and polygenic risk score (PRS) and monogenic laboratory reports.
See this image and copyright information in PMC

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