Center for Integrated Approaches to Undiagnosed Diseases

未确诊疾病综合治疗中心

基本信息

批准号：
10696373
负责人：
Joseph Loscalzo
金额：
$ 51.8万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696373
关键词：
Adult Boston Chemical Agents Child Clinical Clinical Data Clinical assessments Collaborations Communities Complex Computer Models Computerized Medical Record Contracts DNA Sequence Data Data Analyses Data Analytics Data Collection Dedications Development Diagnosis Disease Disease Management Ecosystem Elements Environmental Exposure Environmental Risk Factor Etiology Evaluation Family member Funding General Hospitals Genetic Genomic medicine Genomics Genotype Goals Hospitals Human Resources Image Immunophenotyping Individual Infectious Agent Inpatients Laboratories Massachusetts Methodology Methods Modeling Molecular Molecular Analysis Network-based Occupational Outpatients Pathway interactions Patient Recruitments Patients Pediatric Hospitals Persons Phase Phenotype Physiological Population Proteomics Protocols documentation Quality Control Quantitative Evaluations Research Resolution Resources Site Stochastic Processes Syndrome System Systems Biology Techniques Tissues Training Triage Uninsured United States National Institutes of Health Validation Variant Vision Woman Work analytical method clinical research site cost crowdsourcing data resource design disease diagnosis exome functional genomics genome analysis genome sequencing genomic data genomic tools health disparity populations improved individual patient infrastructure development innovation insight interdisciplinary approach interest medical schools member metabolomics multidisciplinary multiple omics network models novel predictive modeling programs prospective quality assurance remote assessment research clinical testing success systematic review tool transcriptome sequencing translational scientist whole genome

项目摘要

PROJECT SUMMARY Undiagnosed diseases are likely to be determined by genetic, environmental, and developmental factors. While some undiagnosed diseases will represent novel rare genetic syndromes with monogenic or oligogenic etiologies and others will reflect rare manifestations of known diseases, many are likely to result from a more analytically challenging combination of multiple genetic, environmental, and developmental factors. Whole exome and whole genome sequencing are powerful tools with which to ascertain the genetic contributions to undiagnosed diseases; however, these methods alone are unlikely to elucidate the basis for many, if not most, undiagnosed diseases. The overarching approach we have taken in this Continuation application is to extend the methodologies that we have established in earlier phases of the UDN and to add key components specifically designed to continue to optimize case ascertainment and phenotyping (Aim 1), to refine integrated multidisciplinary disease diagnosis (Aim 2) and to directly support the deployment and further optimization of a fully sustainable UDN model (Aim 3). These specific elements include: • Broadening of the initial case assessment population (including enrichment for health disparity populations) to enable better definition of the difficult-to-diagnose patient who might benefit from UDN approaches; • Development of quantitative triage tools for difficult-to-diagnose patients enabling continued optimization of case selection and the utility of individual techniques; • Deployment of innovative new sequence interpretation pipelines merging the best techniques and personnel from across the entire Boston ecosystem (with additional engagement from BUMC and the Broad Institute); • Broader integration of functional genomics tools in the initial assessment of cases entering the UDN; • Formal deployment and quantitative evaluation of a Boston-wide UDN center funded through active commercial contracts with payers and DHHS (and cross-subsidized through other non-UDN genetics programs in our system, such as Brigham Genomic Medicine); and • Prospective design of all of these elements to allow dissemination of successful components across the entire UDN and beyond. These efforts will maximize the yield of UDN resources while progressively broadening access in a fully sustainable (both practically and financially) model.

项目概要未确诊的疾病可能是由遗传、环境和发育因素决定的，虽然一些未确诊的疾病代表具有单基因或寡基因病因的新型罕见遗传综合征，而其他疾病则反映了已知疾病的罕见表现，但许多未诊断的疾病可能是由更分析性的结果造成的。全外显子组和全基因组测序是确定未确诊疾病的遗传因素的有力工具，但单靠这些方法不太可能阐明这一问题。我们在此延续应用程序中采取的总体方法是扩展我们在 UDN 早期阶段建立的方法，并添加专门设计的关键组件，以继续优化病例确定和诊断。表型分析（目标 1），完善综合多学科疾病诊断（目标 2），并直接支持完全可持续的 UDN 模型的部署和进一步优化（目标 3）。这些具体要素包括： • 拓宽。初始病例评估人群（包括丰富健康差异人群），以便更好地定义可能受益于 UDN 方法的难以诊断的患者； • 为难以诊断的患者开发定量分诊工具，从而能够持续优化案例选择和个别技术的实用性； • 部署创新的新序列解释管道，融合整个波士顿生态系统的最佳技术和人员（以及 BUMC 和 Broad 研究所的额外参与）； • 更广泛地整合功能基因组学工具；对进入 UDN 的病例进行初步评估； • 波士顿范围内的 UDN 中心的正式部署和评估，该中心通过与付款人和 DHHS 的有效商业合同提供资金（并通过我们系统中的其他非 UDN 遗传学项目进行交叉补贴，例如 Brigham 和• 对所有这些要素进行前瞻性设计，以便在整个 UDN 及其他地区传播成功的组成部分。这些努力将最大限度地提高 UDN 资源的产量，同时以完全可持续的方式逐步扩大访问范围（在实践和财务上）。模型。