An integrated and diverse genomic medicine program for undiagnosed diseases

Duke University, Durham NC

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Abstract

Program Director/Principal Investigator (Last, First, Middle): Shashi, Vandana ABSTRACT The Duke clinical site has the strongest record of productivity in Phases 1 and 2. In Phase 3, as a Diagnostic Center of Excellence (DCoE), while continuing our current activities, we align with new priorities in PAR-23-289, to increase the enrollment of patients with health disparities, scale the UDN to more patients and expand non- genomic approaches. Specific Aim 1: Scale our comprehensive UDN evaluations to more patients with undiagnosed diseases. We will enroll 50 undiagnosed patients in year 1 (compared to 30/year in Phase 2) and evaluate them in three tiers predicated upon diagnostic needs. Due to our existing and proposed efficiencies, we can scale enrollment in subsequent years, dependent on additional resources. Our niche is pediatric genomic disorders, but we will continue to evaluate adults and children with varied phenotypes, including those with non- genomic disorders. Specific Aim 2: Perform research analysis of the genomic data and utilize adjunct research genomic technologies to achieve diagnoses. In an individualized manner, our innovative and updated phenotype- agnostic research bioinformatics pipeline will be utilized to increase diagnoses and new disease gene discoveries. We expect patients in Tiers 3 and 4 to enter the study with a non-diagnostic exome/genome; for these patients, we will first re-analyze the pre-UDN genomic data. UDN-generated genomic data for patients in all tiers will also undergo research analysis. We will expand our pursuit of research technologies such as RNAseq and optical genome mapping to investigate etiologies for unresolved patients. Specific Aim 3: Utilize community- based participatory research (CBPR) principles to increase UDN participation by patients with health disparities (those living in the HRSA-designated rural MUA of NC and of minority background). Building upon relationships with the NC Office of Rural Health, the NC Area Health Education Centers, and the NC Family Support Network, we will engage constituents and stakeholders, to mitigate patient and provider barriers to the UDN, disseminate UDN information and collaboratively partner with community providers, to enroll patients with health disparities to approximate regional demographics. We will also engage the providers to be active participants in their patients’ UDN evaluations. As an exploratory sub-aim, we will assess our community collaborations to provide pre-implementation observational data. Specific Aim 4: Collaboratively contribute to new network priorities and ongoing activities. We will work with the Data Management and Coordinating Center (DMCC) to increase efficiencies within all Tiers 1-4. We plan to refine the environmental exposures survey to create separate pediatric and adult surveys and will share these for network implementation and validation. We will collaborate with the DMCC for artificial intelligence methodologies for medical information analysis and for health economics assessments, as per PAR-23-289. Finally, we will continue our current network-wide studies (e.g. studying the psychological impact of being undiagnosed) and our leadership roles in working groups. In summary, the Duke DCoE is well-positioned to further the UDN mission/science in Phase 3. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page