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

Background As 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. Methods To 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. Results Nine 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 ΔLDL-C among enrollees after the genetic counseling intervention was −37 mg/dL (95% CI: −12 to −61; p =0.03). Conclusions While 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. ### Competing Interest Statement KDC was supported by a research grant from Sanford Health. PN reports research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech / Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Eli Lilly & Co, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio, scientific co-founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. ACS is an employee of 23andMe, Inc. All other authors report no competing interests. ### Clinical Trial ClinicalTrials.gov Identifier: [NCT04178122][1] ### Funding Statement This study was funded by the Million Veteran Program, Office of Research and Development, Veterans Health Administration (Award number MVP030). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The VA Central IRB gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data produced in the present study are not currently available. Some of these data will be made available through a data repository after publication of the full clinical trial. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04178122&atom=%2Fmedrxiv%2Fearly%2F2023%2F10%2F17%2F2023.10.07.23295899.atom