Returning integrated genomic risk and clinical recommendations: The eMERGE study

Linder, Jodell E.; Allworth, Aimee; Bland, Sarah; Caraballo, Pedro J.; Chisholm, Rex L.; Clayton, Ellen Wright; Crosslin, David R.; Dikilitas, Ozan; DiVietro, Alanna; Esplin, Edward D.; Forman, Sophie; Freimuth, Robert R.; Gordon, Adam S.; Green, Richard; Harden, Maegan; Holm, Ingrid A.; Jarvik, Gail P.; Karlson, Elizabeth W.; Labrecque, Sofia; Lennon, Niall J.; Limdi, Nita A.; Mittendorf, Kathleen F.; Murphy, Shawn N.; Orlando, Lori A.; Prows, Cynthia A.; Rasmussen, Luke V.; Rasmussen‐Torvik, Laura J.; Rowley, Robb; Sawicki, Konrad Teodor; Schmidlen, Tara; Terek, Shannon; Veenstra, David L.; Edwards, Digna R. Velez; Absher, Devin; Abul‐Husn, Noura S.; Alsip, Jorge; Bangash, Hana; Beasley, Mark; Below, Jennifer E.; Berner, Eta S.; Booth, James; Chung, Wendy K.; Cimino, James J.; Connolly, John J.; Davis, Patrick J.; Devine, Beth; Fullerton, Stephanie M.; Guiducci, Candace; Habrat, Melissa L.; Hain, Heather S.; Hákonarson, Hákon; Harr, Margaret; Haverfield, Eden; Hernandez, Valentina; Hoell, Christin; Horike‐Pyne, Martha; Hripcsak, George; Irvin, Marguerite R.; Kachulis, Christopher; Karavite, Dean; Kenny, Eimear E.; Khan, Atlas; Kiryluk, Krzysztof; Korf, Bruce R.; Kottyan, Leah; Kullo, Iftikhar J.; Larkin, Katie; Liu, Cong; Małolepsza, Edyta; Manolio, Teri A.; May, Thomas; McNally, Elizabeth M.; Mentch, Frank; Miller, Alexandra; Mooney, Sean D.; Murali, Priyanka; Mutai, Brenda; Muthu, Naveen; Namjou, Bahram; Perez, Emma; Puckelwartz, Megan J.; Rakhra-Burris, Tejinder; Roden, Dan M.; Rosenthal, Elisabeth; Saadatagah, Seyedmohammad; Sabatello, Maya; Schaid, Dan; Schultz, Baergen I; Seabolt, Lynn; Shaibi, Gabriel Q.; Sharp, Richard R.; Shirts, Brian H.; Smith, Maureen E.; Smoller, Jordan W.; Sterling, Rene; Suckiel, Sabrina A.; Thayer, Jeritt G.; Tiwari, Hemant; Trinidad, Susan Brown; Walunas, Theresa L.; Wei, Wei‐Qi; Wells, Quinn S.; Weng, Chunhua; Wiesner, Georgia L.; Wiley, Ken; Peterson, Josh F.

doi:10.1016/j.gim.2023.100006

Cited by 42 publications

(33 citation statements)

References 37 publications

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“…The All of Us cohort is significantly more diverse than those of other large contemporary research studies generating WGS data 32 , 33 . This enables a more equitable future for precision medicine (for example, through constructing polygenic risk scores that are appropriately calibrated to diverse populations 34 , 35 as the eMERGE programme has done leveraging All of Us data 36 , 37 ). Developing new tools and regulatory frameworks to enable analyses across multiple biobanks in the cloud to harness the unique strengths of each is an active area of investigation addressed in a companion paper to this work 38 .…”

Section: Discussionmentioning

confidence: 99%

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Genomic data in the All of Us Research Program

Bick,

Metcalf,

Mayo

et al. 2024

Nature

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Comprehensively mapping the genetic basis of human disease across diverse individuals is a long-standing goal for the field of human genetics1–4. The All of Us Research Program is a longitudinal cohort study aiming to enrol a diverse group of at least one million individuals across the USA to accelerate biomedical research and improve human health5,6. Here we describe the programme’s genomics data release of 245,388 clinical-grade genome sequences. This resource is unique in its diversity as 77% of participants are from communities that are historically under-represented in biomedical research and 46% are individuals from under-represented racial and ethnic minorities. All of Us identified more than 1 billion genetic variants, including more than 275 million previously unreported genetic variants, more than 3.9 million of which had coding consequences. Leveraging linkage between genomic data and the longitudinal electronic health record, we evaluated 3,724 genetic variants associated with 117 diseases and found high replication rates across both participants of European ancestry and participants of African ancestry. Summary-level data are publicly available, and individual-level data can be accessed by researchers through the All of Us Researcher Workbench using a unique data passport model with a median time from initial researcher registration to data access of 29 hours. We anticipate that this diverse dataset will advance the promise of genomic medicine for all.

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Section: Discussionmentioning

confidence: 99%

“…Supplementary Table 4 summarizes both the steps that we took and the results obtained for the WGS data. More detailed information about the methods and specific parameters can be found in the All of Us Genomic Research Data Quality Report 36 .…”

Section: Methodsmentioning

confidence: 99%

Genomic data in the All of Us Research Program

Bick,

Metcalf,

Mayo

et al. 2024

Nature

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“…Various forms of PRSs are available to consumers through commercial platforms such as 23andMe, Myriad Genetics (riskScore), Allelica, Ambry Genetics, and others, and several noncommercial studies have explored the clinical use of PRSs in direct-to-participant models 19 – 21 ; however, there is limited information on the clinical implementation considerations of returning PRSs across multiple phenotypes in a primary care setting 20 . Even before assessing the ability of PRSs to improve health outcomes, reduce risk and enhance clinical care, large multicenter prospective pragmatic studies are needed to assess how patients and care providers interact with and respond to PRSs in a primary care setting 22 .…”

Section: Mainmentioning

confidence: 99%

“…The study plans for 25,000 individuals (aged 3–75 years) to be recruited from general healthcare system populations. Six of the ten recruitment sites are committed to recruiting an ‘enhanced diversity cohort’, meaning that their enrollment will target 75% of enrolled individuals belonging to a racial or ethnic minority or medically underserved population, whereas the remainder of clinical sites will target 35% minority participants 22 . Enrollment is not targeted to individuals with specific conditions, although individuals with prevalent conditions can be included.…”

Section: Mainmentioning

confidence: 99%

Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations

Lennon,

Kottyan,

Kachulis

et al. 2024

Nat Med

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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.

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“…The eMERGE-IV study will return a Genomic Informed Risk Assessment (GIRA) report to research participants, including PRS results for the selected chronic conditions. Individuals receiving high-risk GIRA will be informed about their results in a one-on-one meeting with a genetic expert (genetic counselor, physician, or PharmD); those with results that do not meet study thresholds for high risk will be informed via mail or electronically (further information about the GIRA is available in Linder et al., 2023 30 ). The reports will be incorporated into patients’ electronic health records, and their clinical utility and psychosocial impacts on research participants and clinicians will be assessed.…”

Section: Introductionmentioning

confidence: 99%

Return of polygenic risk scores in research: Stakeholders’ views on the eMERGE-IV study

Sabatello,

Bakken,

Chung

et al. 2024

Human Genetics and Genomics Advances

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Returning integrated genomic risk and clinical recommendations: The eMERGE study

Cited by 42 publications

References 37 publications

Genomic data in the All of Us Research Program

Genomic data in the All of Us Research Program

Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations

Return of polygenic risk scores in research: Stakeholders’ views on the eMERGE-IV study

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