Polygenic risk scores (PRSs) have shown improved predictive performance, but challenges remain before clinical implementation. This study, funded by the National Human Genome Research Institute's Electronic Medical Records and Genomics (eMERGE) Network, addresses these challenges by developing a framework for returning PRS-based genome-informed risk assessments to 25,000 diverse adults and children. Ten conditions were selected for implementation based on PRS performance, medical actionability, and clinical utility. A pipeline for clinical PRS implementation, including ancestry calibration, was developed and validated. A clinical report framework ensures regulatory compliance and effective communication. The eMERGE experience informs the approach needed for broader PRS-based testing.

Niall J. Lennon, Leah C. Kottyan, Christopher Kachulis, Noura S. Abul-Husn, Josh Arias, Gillian Belbin, Jennifer E. Below, Sonja I. Berndt, Wendy K. Chung, James J. Cimino, Ellen Wright Clayton, John J. Connolly, David R. Crosslin, Ozan Dikilitas, Digna R. Velez Edwards, QiPing Feng, Marissa Fisher, Robert R. Freimuth, Tian Ge, The GIANT Consortium, The All of Us Research Program, Joseph T. Glessner, Adam S. Gordon, Candace Patterson, Hakon Hakonarson, Maegan Harden, Margaret Harr, Joel N. Hirschhorn, Clive Hoggart, Li Hsu, Marguerite R. Irvin, Gail P. Jarvik, Elizabeth W. Karlson, Atlas Khan, Amit Khera, Krzysztof Kiryluk, Iftikhar Kullo, Katie Larkin, Nita Limdi, Jodell E. Linder, Ruth J. F. Loos, Yuan Luo, Edyta Malolepsza, Teri A. Manolio, Lisa J. Martin, Li McCarthy, Elizabeth M. McNally, James B. Meigs, Tesfaye B. Mersha, Jonathan D. Mosley, Anjene Musick, Bahram Namjou, Nihal Pai, Lorenzo L. Pesce, Ulrike Peters, Josh F. Peterson, Cynthia A. Prows, Megan J. Puckelwartz, Heidi L. Rehm, Dan M. Roden, Elisabeth A. Rosenthal, Robb Rowley, Konrad Teodor Sawicki, Daniel J. Schaid, Roelof A. J. Smit, Johanna L. Smith, Jordan W. Smoller, Minta Thomas, Hemant Tiwari, Diana M. Toledo, Nataraja Sarma Vaitinadin, David Veenstra, Theresa L. Walunas, Zhe Wang, Wei-Qi Wei, Chunhua Weng, Georgia L. Wiesner, Xianyong Yin, Eimear E. Kenny