The Broad-LMM-Color Genome Center for All of Us

适合所有人的宽 LMM 颜色基因组中心

• 批准号: 10003430
• 负责人: Stacey Gabriel
• 金额: $ 2300.53万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10003430
• 关键词: All of Us Research Program; Area; Bioinformatics; CLIA certified; Clinical; Color; Communities; Complex; Conflict (Psychology); Data; Diagnostic; Disease; Environment; Generations; Genes; Genome; Genomics; Genotype; Healthcare; Institutes; International; Laboratories; Molecular Medicine; Participant; Pathogenicity; Pharmacogenomics; Play; Population; Reporting; Research; Resources; Risk; Role; Sampling; Site; United States National Institutes of Health; Variant; Work; adjudication; clinical diagnostics; clinical sequencing; computerized data processing; cost; data pipeline; data resource; data sharing; experience; genomic data; genomic platform; innovation; programs; rare variant; success; whole genome; working group

Building on a 30-year track record in large-scale genomics and resource creation for the scientific community, we propose to combine the strengths of the Broad Institute (Broad), Color Genomics (Color) , and the Partners Healthcare Laboratory for Molecular Medicine (LMM) to serve the All of Us Research Program ( AoURP ) (Figure 1). The Broad Genomics Platform has sequenced >100,000 whole genomes to date, operates in a CLIA/CAP environment and has played a central role in numerous large-scale NIH initiatives. Color and LMM are both CLIA-accredited diagnostic laboratories with extensive experience in clinical sequencing and variant interpretation, with combined volume of >150,000 samples and over 32,000 variants interpreted clinically and submitted to ClinVar. The rationale to unite these three entities is to bring together Broad’s unparalleled experience and scale in genomic data generation, Color’s innovative combination of computational and clinical expertise to offer low-cost, easy-access to clinical sequencing panels at population scale, and LMM’s international reputation in leading high-quality variant interpretation and data sharing efforts. These three organizations already work together pairwise , with Broad and LMM jointly supporting several clinical genomics programs (e.g. eMERGE, BabySeq, clinical diagnostics); LMM and Color working together over the past year on variant interpretation and through the ClinGen program; and Broad and Color collaborating on scientific projects on generation and application of polygenic risk scores. Moreover, the three sites together successfully completed a pilot of the proposed AoURP Genome Center workflow. ● Broad will generate in Year 1 array genotype data for >100,000 samples and Whole Genome Sequence (WGS) for > 20,000 samples . We will perform WGS for $475 direct ($635 total), allowing us to double the number of Year 1 genomes required by the RFA. (In Scenario C, the five-year average WGS cost will be $275 direct ($350 total)). Broad’s bioinformatics pipeline for data processing and variant calling will operate in the same platform environment as the AoURP Data Resource Center (DRC), which is being built through a partnership between Vanderbilt, Verily, and Broad. ● Color will perform interpretation of all rare variants in the ACMG59 gene list (with orthogonal confirmation of all pathogenic and likely pathogenic variants), issue actionable reports for positive participants, and will generate pharmacogenomics (PGx), ancestry, and if desired by the AoURP, polygenic risk score (PRS) results for all participants . ● LMM will review challenging variants (e.g. where a primary curator is uncertain or the interpretation conflicts with other submitters to ClinVar) through its Variant Adjudication Committee (VAC) and will integrate with the ClinGen Variant Interpretation Discrepancy Working Group as well as ClinGen Expert Panels for additional disease-specific variant interpretation expertise. Broad, Color, and LMM already perform high-quality sequencing, genotyping, and interpretation at the scale required by the AoURP , providing an immediate ready-to-launch capability . Success in this ambitious research program will require deep expertise in numerous complex, integrated areas.

建立在大规模基因组学和科学资源创建方面 30 年的记录基础上 社区，我们建议结合博德研究所（Broad）、彩色基因组学（Color）的优势， 和合作伙伴分子医学医疗保健实验室 (LMM) 为我们所有人的研究服务 计划 (AoURP)（图 1）。Broad Genomics Platform 已对超过 100,000 个全基因组进行了测序。 日期，在 CLIA/CAP 环境中运行，并在许多大型 NIH 中发挥了核心作用 Color 和 LMM 都是 CLIA 认可的诊断实验室，在这方面拥有丰富的经验。 临床测序和变异解释，总样本量超过 150,000 个，超过 32,000 个 临床解释的变体并提交给 ClinVar 统一这三个实体的基本原理是引入。 结合 Broad 在基因组数据生成方面无与伦比的经验和规模，Color 的创新 计算和临床专业知识的结合，提供低成本、易于访问的临床测序面板 在人口规模上，以及 LMM 在领先的高质量变异解释和数据方面的国际声誉 分享努力。 这三个组织已经结对合作，Broad 和 LMM 共同支持多个组织。 临床基因组学项目（例如 eMERGE、BabySeq、LMM 和 Color 合作）； 过去一年中通过 ClinGen 项目和 Broad and Color 进行变异解释； 此外，三者还在多基因风险评分的生成和应用方面合作开展科学项目。 站点共同成功完成了拟议的 AoURP 基因组中心工作流程的试点。 ● Broad 将在第一年生成超过 100,000 个样本的阵列基因型数据和全基因组 对超过 20,000 个样本进行测序 (WGS) 我们将直接支付 475 美元（总计 635 美元）进行全基因组测序，这使我们能够 RFA 所需的第一年基因组数量翻倍（在场景 C 中，五年平均 WGS 成本。 直接费用为 275 美元（总计 350 美元））。 与正在建设的AoURP数据资源中心（DRC）运行在相同的平台环境中 通过范德比尔特、Verily 和 Broad 之间的合作。 ● 颜色将对 ACMG59 基因列表中的所有罕见变异进行解释（正交 确认所有致病性和可能的​​致病性变异），发布可操作的阳性报告， 并将生成药物基因组学 (PGx)、血统，如果 AoURP 需要，还可以生成多基因风险评分 (PRS) 所有参与者的结果。 ● LMM 将审查具有挑战性的变体（例如，主要策展人不确定或解释 通过其变体裁决委员会 (VAC) 与 ClinVar 的其他提交者发生冲突，并将 与 ClinGen 变异解释差异工作组以及 ClinGen 专家小组整合 获得额外的疾病特异性变异解释专业知识。 Broad、Color 和 LMM 已经在 AoURP 所需的规模，提供立即准备启动的能力，帮助实现这一雄心勃勃的目标。 研究项目将需要在许多复杂的综合领域拥有深厚的专业知识。