Introducing return of results in the Million Veteran Program: Design and pilot results of the MVP-ROAR Familial Hypercholesterolemia Study

Abstract

BackgroundAs a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care and health outcomes of participants. Return of genetic research results at this scale presents challenges and complexities. MethodsTo determine the feasibility and outcomes of returning medically actionable genetic results to MVP participants, the program launched the MVP Return Of Actionable Results (MVP-ROAR) Study, with familial hypercholesterolemia (FH) as the exemplar actionable condition. The MVP-ROAR-FH Study consists of a completed pilot phase and an ongoing randomized clinical trial (RCT), in which MVP participants are recontacted and invited to receive clinical confirmatory gene sequencing testing and a telegenetic counseling intervention. The primary outcome of the RCT is 6-month change in low-density lipoprotein cholesterol (LDL-C) between participants receiving results at baseline and those receiving results after 6 months. ResultsNine MVP participants suspected to have a pathogenic variant in low-density lipoprotein receptor (LDLR) enrolled in the single-arm pilot phase of the study; one was lost to follow-up prior to confirmatory testing. Clinical sequencing confirmed the pathogenic variant for 5 of the remaining 8 participants. Six-month {Delta}LDL-C among enrollees after the genetic counseling intervention was -37 mg/dL (95% CI: -12 to -61; p=0.03). ConclusionsWhile underscoring the importance of analytic validity and clinical confirmation of research results, the pilot phase of the MVP-ROAR-FH Study demonstrates the feasibility of a protocol to return genetic results to MVP participants and their providers. The ongoing RCT will contribute to understanding of how such a program might improve patient health care and outcomes.