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.

在大规模基因组学和科学资源创造方面30年的记录基础上， 社区，我们建议联合收割机的广泛研究所（广泛），颜色基因组学（颜色）， 和合作伙伴医疗保健实验室的分子医学（LMM），以服务于我们所有的研究 程序（AoURP）（图1）。Broad Genomics平台已经测序了超过100，000个全基因组， 迄今为止，在CLIA/CAP环境中运作，并在许多大型NIH中发挥了核心作用。 举措Color和LMM都是CLIA认证的诊断实验室，在以下方面拥有丰富的经验： 临床测序和变异解读，总样本量超过150，000份， 临床解释的变体并提交给ClinVar。联合这三个实体的理由是， 结合Broad在基因组数据生成方面无与伦比的经验和规模， 结合计算和临床专业知识，提供低成本，易于访问的临床测序面板 LMM在高质量变异解释和数据方面享有国际声誉 分享努力。 这三个组织已经成对合作，Broad和LMM共同支持几个 临床基因组学程序（例如eMERGE、BabySeq、临床诊断）; LMM和Color共同工作 在过去的一年里，通过ClinGen项目和Broad和Color， 就多基因风险评分的生成和应用开展科学项目合作。而且三 研究中心一起成功地完成了拟议的AoURP基因组中心工作流程的试点。 ● Broad将在第1年生成> 100，000个样本和全基因组的阵列基因型数据 > 20，000个样品的序列（WGS）。我们将执行WGS为$475直接（$635总数），允许我们 RFA所需的第一年基因组数量翻了一番。(In情景C，五年平均WGS成本 将直接收取275美元（总计350美元）。布罗德用于数据处理和变异识别的生物信息学管道将 在与正在建设的AoURP数据资源中心（DRC）相同的平台环境中运行 通过范德比尔特、Verily和Broad之间的合作。 ●颜色将执行ACMG 59基因列表中所有罕见变异的解释（具有正交 确认所有致病性和可能的致病性变体），为阳性参与者发布可采取行动的报告， 并将生成药物基因组学（PGx）、血统，如果AoURP需要，还将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，当主要策展人不确定或解释不确定时 与ClinVar的其他提交者发生冲突），并将 与ClinGen变异解释离散工作组以及ClinGen专家小组整合 获得更多疾病特异性变异解读专业知识。 Broad、Color和LMM已经在美国进行高质量的测序、基因分型和判读。 AoURP所需的规模，提供立即准备发射的能力。在这个雄心勃勃的 研究计划将需要在许多复杂的，综合领域的深厚专业知识。