Reverse Phenotyping Core

National Human Genome Research Institute

Investigators

Linked publications & trials

Abstract

RPC was formally established this past year with significant progress made towards the goal of providing an NHGRI core resource for facilitating genomic-ascertainment based clinical research. RPCs progress in its first year of existence can be divided into three domains: 1) infrastructure of RPC operations, 2) aggregation and management of genomic data, 3) scientific pursuits. Infrastructure of RPC operations: RPC was established as an expansion of the Genomic Ascertainment Cohort clinical protocol. RPC has been staffed by an acting director (Alexander Katz) and has hired three additional full-time positions: genetic counselor (Caralynn Wilczewski), research nurse (Felicia Akinwande), and postbac IRTA (Vera Zanker). The full-time team has been able to establish a workflow for reverse phenotyping research projects, which can be summarized as: evaluation of reverse phenotyping proposal from NIH investigator, review of specific variants of interest identified by proposing investigator, plan for collection of linked electronic health record data from potential participants, re-contact of potential participants, enrollment onto RPC clinical protocol, targeted clinical evaluation and deep phenotyping at the NIH Clinical Center of eligible participants. The nature of RPC is to enable research projects in which the proposed phenotyping is tailored specifically to the variants of interest identified, and the RPC team is tasked with ensuring the operation of different phenotyping needs for different proposals. Aggregation and management of genomic data: Since its establishment, RPC has been maintaining a genomic database that includes sequence data for individuals eligible for re-contact for research studies. These individuals currently come from three primary cohorts: NHGRIs ClinSeq cohort (n=1,514), NIAIDs CenSeq cohort (n=557), and the Inova Healthcare Systems longitudinal sequencing cohort (n=4,724). RPC works with the NHGRI bioinformatics core to ensure data harmonization from the raw sequence data obtained from the different cohorts. Deidentified, unlinked genomic data has been made available to the NIH community on a genome browser, and RPC ensures that the browser is formatted to optimize investigators ability to identify variants of interest and subsequently propose reverse phenotyping projects. In addition, RPC has been working to bring in more sequence data from eligible participants to the shared genomic cohort. RPC is currently negotiating a data transfer agreement to include approximately 4,000 genomes from NIEHSs Personalized Environment and Genes study. RPC is also exploring the feasibility of incorporating additional sequence data from the Inova Healthcare System. Scientific Pursuits: RPC is actively recruiting, enrolling, and evaluating participants for reverse phenotyping projects. RPC has received several inquiries and has begun research activity for six new proposals in the past year. Among the six new projects, two are evaluating a novel gene-disease association, three aim to measure the clinical yield of variants of interest in known disease associated genes, and one aims to measure an ex-vivo phenotype that may be associated with a common variant using blood samples from participants. In addition, there are seven previous projects for which active work has continued through the last year (these projects were begun as collaborations with the Genomic Ascertainment Cohort but have since transitioned to RPC projects). Two previous Genomic Ascertainment Cohort projects have been completed and published. As RPC continues to expand operations, the number of active projects is expected to increase.