Whole-genome sequencing as an investigational device for return of hereditary disease risk and pharmacogenomic results as part of the All of Us Research Program

Abstract

Background: The All of Us Research Program (AoURP, "the program") is an initiative, sponsored by the National Institutes of Health (NIH), that aims to enroll one million people (or more) across the USA. Through repeated engagement of participants, a research resource is being created to enable a variety of future observational and interventional studies. The program has also committed to genomic data generation and returning important health-related information to participants.

Methods: Whole-genome sequencing (WGS), variant calling processes, data interpretation, and return-of-results procedures had to be created and receive an Investigational Device Exemption (IDE) from the United States Food and Drug Administration (FDA). The performance of the entire workflow was assessed through the largest known cross-center, WGS-based, validation activity that was refined iteratively through interactions with the FDA over many months.

Results: The accuracy and precision of the WGS process as a device for the return of certain health-related genomic results was determined to be sufficient, and an IDE was granted.

Conclusions: We present here both the process of navigating the IDE application process with the FDA and the results of the validation study as a guide to future projects which may need to follow a similar path. Changes to the program in the future will be covered in supplementary submissions to the IDE and will support additional variant classes, sample types, and any expansion to the reportable regions.

Fig. 1

Overview of All of Us Research Program return of genomic results workflow. Participants are enrolled at a variety of locations including mobile sites, hospitals, and walk-in clinics. Samples are sent to the Biobank (Mayo Clinic) where DNA is extracted and stored. Upon indication from the program to proceed, samples are sent to one of three Genome Centers—Baylor College of Medicine (BCM), Broad Institute (BI), or University of Washington (UW)—for whole-genome sequencing. For participants who have consented to return of genomic results, data are forwarded on to the Clinical Validation Laboratories (CVLs) for pharmacogenomics (PGx) analysis and variant interpretation and orthogonal confirmation for Hereditary Disease Risk (HDR) gene pathogenic or likely pathogenic variants. Reports are generated by the Report and Harmonization Platform (Color) and delivered to participants through the Genetic Counseling Resource (Color). QC quality control

Fig. 2

Timeline of the IDE application process. The requirements for the investigational device exemption (IDE) content were refined through a series of pre-IDE submissions and responses, in-person meetings, and teleconferences with the United States Food and Drug Administration (FDA) over a period of 19 months. AoURP, All of Us Research Program; CCP, Change Control Policy; IC, informed consent; PGx, pharmacogenomics; Pre-Sub, pre-submission; SR, significant risk; Sup, supplement