Tools for Normalizing and Interpreting the Clinical Actionability of Genomic Variants

用于标准化和解释基因组变异临床可操作性的工具

• 批准号: 10212005
• 负责人: Alex Handler Wagner
• 金额: $ 9.21万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212005
• 关键词: Biological Markers; Biomedical Research; Client; Clinic; Clinical; Clinical Trials; Clinical assessments; Cohort Studies; Collection; Combined Modality Therapy; Communities; Consensus; Data; Databases; Development; Disease; Engineering; Explosion; Genes; Genome; Genomic medicine; Genomics; Goals; Health; Human; Human Genome; Internet; Knowledge; Level of Evidence; Link; Literature; Machine Learning; Malignant Neoplasms; Manuals; Methods; Patients; Pharmaceutical Preparations; Phase; Procedures; Recording of previous events; Reporting; Research; Research Personnel; Resource Development; Resources; Role; Services; Shapes; Side; Source; Structure; Suggestion; System; Techniques; The Vanderbilt-Ingram Cancer Center at the Vanderbilt University; Variant; Visualization; Work; application programming interface; base; cancer type; clinical practice; clinically actionable; cohort; cost; data modeling; design; drug discovery; drug resource; gene interaction; genetic variant; genomic variation; human disease; improved; individual patient; knowledge base; learning strategy; molecular marker; novel; novel therapeutics; open source; precision medicine; profiles in patients; programs; response; therapeutic biomarker; tool; tumor; user-friendly; web app; web interface; web-based tool

PROJECT SUMMARY/ABSTRACT The availability of high-throughput, low-cost sequencing has transformed the landscape of biomedical research by dramatically expanding our capacity to interrogate the sequence of the human genome. Consequently, there has been an explosion of biomedical literature describing the role of specific genomic variants and their impact on human diseases. These advances are bringing sequencing into the clinic to shape clinical practice from the patient’s genomic content, a paradigm colloquially referred to as genomic or precision medicine. There remain many obstacles to fully realizing our potential in the era of precision medicine. Among them is a recognized need for robust, well-engineered systems that provide knowledge about genomic variants and their role in disease. Ideally, such systems would provide a comprehensive summary of all knowledge that is relevant to the patient’s unique genomic content. An early bottleneck to realizing precision medicine was that, despite the substantial literature and several established knowledgebases that define interactions between drugs and genes, querying across them was extremely challenging. In response to this need, the Drug-Gene Interaction database (DGIdb, dgidb.org) was developed. Through a combination of automated processing and manual curation, drug-gene interaction information was collected, structured, and connected (normalized) from these diverse sources of data and entered into a database with a user-friendly search interface and an application programming interface (API). However, linking drug and drug-gene interaction concepts across resources remains an extremely challenging task, and aggregated drug-gene interactions are also challenging to represent in a way that highlights the utility of the collected knowledge for precision medicine efforts. This proposal seeks to improve our ability to normalize and interpret drug-gene interactions corresponding to patient genomic variants. We will achieve this goal through two specific aims. First, the DGIdb normalization routines will be improved through incorporation of new content and features. Among these, the DGIdb will support collections of drugs, including combination therapies and drug classes. Also, the DGIdb will have new community submission and curation features, allowing users to incorporate new knowledge into the database. Second, the Variant Interpretation Aggregator database (VIAdb) will be created to normalize knowledge across several disparate sources focused on the clinical interpretations of genomic variants. The VIAdb will operate as a stand-alone web tool and API and will behave as a source of relevant interpretations to DGIdb. Finally, we will develop techniques for automated identification of drug-gene interactions and variant interpretation consensus to assist community curation efforts. If successful, this research will improve breadth and consistency of variant interpretations and drug-gene interactions for precision medicine efforts.

项目概要/摘要 高通量、低成本测序的出现改变了生物医学研究的格局 通过极大地扩展我们询问所测试的人类基因组序列的能力。 描述特定基因组变异的作用及其影响的生物医学文献数量激增 这些进步正在将测序带入临床，以塑造临床实践。 患者的基因组内容，这种范式通俗地称为基因组或精准医学。 在精准医疗时代充分发挥我们的潜力存在许多障碍，其中一个是公认的。 需要强大的、精心设计的系统来提供有关基因组变异及其在疾病中的作用的知识 理想情况下，这样的系统将提供与疾病相关的所有知识的全面总结。 患者独特的基因组内容。 实现精准医疗的早期瓶颈是，尽管有大量文献和一些 建立了定义药物和基因之间相互作用的知识库，对它们进行查询 为了满足这一需求，药物基因相互作用数据库（DGIdb，dgidb.org）诞生了。 通过自动化处理和手动管理的结合，开发了药物-基因相互作用。 从这些不同的数据源中收集、结构化和连接（规范化）信息， 通过用户友好的搜索界面和应用程序编程接口（API）输入数据库。 然而，跨资源连接药物和药物基因相互作用概念仍然极具挑战性 任务和聚合的药物-基因相互作用也很难以突出效用的方式表示 该提案旨在提高我们标准化的能力。 并解释与患者基因组变异相对应的药物-基因相互作用。 我们将通过两个具体目标来实现这一目标：首先，改进 DGIdb 规范化例程。 通过纳入新的内容和功能，DGIdb 将支持药品的收集， 包括联合疗法和药物类别 此外，DGIdb 将有新的社区提交和 管理功能，允许用户将新知识纳入数据库。 将创建解释聚合数据库 (VIAdb)，以标准​​化多个不同领域的知识 VIAdb 将作为一个独立的网络运行。 工具和 API，并将作为 DGIdb 相关解释的来源。最后，我们将开发技术。 用于自动识别药物-基因相互作用和变异解释共识以协助社区 如果成功，这项研究将提高变体解释的广度和一致性。 精准医学努力的药物-基因相互作用。

项目成果

FHIR Genomics: enabling standardization for precision medicine use cases.

FHIR Genomics：实现精准医疗用例的标准化。

• 发表时间: 2020
• 作者: Alterovitz, Gil;Heale, Bret;Jones, James;Kreda, David;Lin, Fan;Liu, Lei;Liu, Xin;Mandl, Kenneth D;Poloway, David W;Ramoni, Rachel;Wagner, Ale;Warner, Jeremy L
• 通讯作者: Warner, Jeremy L

CIViCpy: A Python Software Development and Analysis Toolkit for the CIViC Knowledgebase.

CIViCpy：CIViC 知识库的 Python 软件开发和分析工具包。

• 发表时间: 2020
• 影响因子: 4.2
• 作者: Wagner, Alex H;Kiwala, Susanna;Coffman, Adam C;McMichael, Joshua F;Cotto, Kelsy C;Mooney, Thomas B;Barnell, Erica K;Krysiak, Kilannin;Danos, Arpad M;Walker, Jason;Griffith, Obi L;Griffith, Malachi
• 通讯作者: Griffith, Malachi

The GA4GH Variation Representation Specification: A computational framework for variation representation and federated identification.

GA4GH 变异表示规范：变异表示和联合识别的计算框架。

• 发表时间: 2021-11-10
• 作者: Wagner, Alex H;Babb, Lawrence;Alterovitz, Gil;Baudis, Michael;Brush, Matthew;Cameron, Daniel L;Cline, Melissa;Griffith, Malachi;Griffith, Obi L;Hunt, Sarah E;Kreda, David;Lee, Jennifer M;Li, Stephanie;Lopez, Javier;Moyer, Eric;Nelson, Trist
• 通讯作者: Nelson, Trist