Toxicology in the 21st Century Program (Tox21) - Computational Toxicology

Tox21项目的联邦合作伙伴包括环境保护局(EPA)、食品和药物管理局(FDA)和NIH，NCATS和国家环境健康科学研究所(NIEHS)的国家毒理学计划(NTP)领导下的合作伙伴。这些机构共同努力，推进体外毒理学测试。Tox21计划可以分为三个NCATS团队：系统毒理学、基因组毒理学和计算毒理学。Tox21计算毒理学团队增强了Tox21合作伙伴经常使用的各种工具，以访问彼此的数据。该团队对Tox21系统毒理学团队识别、开发、优化和/或筛选的20种分析方法以及Tox21基因组毒理学团队生成的基因表达数据进行了数据分析。这些活动包括归一化和校正，对浓度-反应曲线进行拟合以产生效力和功效衡量标准，根据一套标准对曲线进行分类，这些标准包括拟合的重要性(以p值衡量)、拟合的完整性和效力、通过数据的重复性评价分析性能、对用于后续研究的化合物进行数据驱动的选择，以及确定参与细胞对化学物质暴露的反应的基因和途径。此外，Tox21计算毒理学团队已更新了基于网络的自动化结构-活性关系(SAR)分析工具，供系统毒理学团队在所有10K库屏幕上进行SAR分析。Tox21计算毒理学团队还更新了Tox21检测跟踪系统，该系统存储了所有Tox21检测的检测注释和详细的实验条件和筛选方案。截至19财年的所有检测的10K数据已经在PubChem中公开，总共有223个检测条目(艾滋病)和超过9900万个数据点。 Tox21公共数据浏览器已经更新了来自10K文库屏幕的总计72个检测的最新检测结果。该浏览器为公众提供了Tox21 qHTS数据的可视化，包括浓度-响应曲线、曲线拟合结果和不同的活性度量以及化学结构和分析QC结果。数据可以通过化验和/或化学方法进行搜索。可以将来自多个化验和/或化学物质的结果重叠，以便于比较。所有数据以及分析说明和详细的筛查方案(SLP)均可下载。为了便于其他Tox21合作伙伴进行分析，Tox21数据下载网站已更新了列格式的新化验结果文件，将原始数据和更正数据结合在一起。Tox21计算毒理学团队继续与Tox21化学工作组合作，为Tox21 10K库化学QC结果生成PDF文件，包括4个月的化合物稳定性测试结果。所有质量控制结果已在公共Tox21浏览器(https://tripod.nih.gov/tox21/))中发布，并提供了存放在PubChem中的Tox21化合物的PDF链接。在19财年，Tox21计算毒理学团队一直在与其他NCATS团队合作，更新NCATS药物收藏(NPC)，该收藏是Tox21 10K化合物库的一部分，近年来批准的药物包括所有批准药物的最新清单。一篇描述鼻咽癌历史和最新进展的论文已于19财年发表在《今日药物发现》杂志上。Tox21计算毒理学团队还领导着Tox21交叉合作伙伴项目之一通过Tox21高通量筛查分析扩大路径覆盖范围，以更好地预测药物不良反应，该项目利用NCATS BioPlanet(https://tripod.nih.gov/bioplanet/))作为定义生物空间和确定筛查检测方法的工具。该项目产生的数据将用于建立预测肝脏和心脏毒性的计算模型。此外，Tox21计算毒理学团队继续与Tox21基因组毒理学团队合作，完善浓度响应基因表达数据分析的方法，包括确定出发点(POD)的策略，以及毒物和调节剂(ToxMatrix)的组合筛选数据分析。用于显示和分析浓度反应基因表达数据的软件平台的网络版本正在建设中，并将在适当时候公布。

The Tox21 Programs federal partners include the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA) and NIH, with leadership from NCATS and the National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences (NIEHS). These agencies work together to advance in vitro toxicological testing. The Tox21 Program can be separated into three NCATS teams: Systems Toxicology, Genomic Toxicology, and Computational Toxicology. The Tox21 Computational Toxicology team has enhanced a variety of tools that are routinely used by Tox21 partners to access each others data. The team performed data analysis of 20 assays that were identified, developed, optimized, and/or screened by the Tox21 systems toxicology team and gene expression data generated by the Tox21 Genomic Toxicology team. These activities include normalization and correction, fitting of concentration-response curves to generate potency and efficacy measures, classification of curves based on a set of criteria that included significance of fit (measured by p-values), completeness of fit, and efficacy, evaluation of assay performance by data reproducibility, data driven selection of compounds for follow up studies, and identification of genes and pathways involved in cell responses to chemical exposure. In addition, the Tox21 Computational Toxicology team has updated the web-based, automated structure-activity relationship (SAR) analysis tool for the systems toxicology team to conduct SAR analysis on all 10K library screens. The Tox21 Computational Toxicology team has also updated the Tox21 Assay Tracking System that stores the assay annotations and detailed experimental conditions and screening protocols for all the Tox21 assays. The 10K data from all assays screened up to FY19 have been made public in PubChem totaling 223 assay entries (AIDs) and over 99 million data points. The Tox21 public data browser has been updated with the latest assay results from the 10K library screens totaling 72 assays. This browser provides the public with visualization of Tox21 qHTS data including concentration-response curves, curve fitting results and different activity metrics along with chemical structure and analytical QC results. Data are searchable by assay and/or chemical. Results from multiple assays and/or chemicals can be overlaid for ease of comparison. All data as well as assay descriptions and detailed screening protocols (SLPs) are available for download. The Tox21 data download site has been updated with new assay result files in the column format, combing raw data and corrected data, for ease of analysis by other Tox21 partners. The Tox21 Computational Toxicology team has continued to work with the Tox21 chemical working group to generate PDF files for the Tox21 10K library chemical QC results, including the 4-month compound stability test results. All QC results have been released in the public Tox21 Browser (https://tripod.nih.gov/tox21/) and the links to the PDFs have been provided for Tox21 compounds deposited in PubChem. In FY19, the Tox21 Computational Toxicology team has been working with other NCATS teams to update the NCATS Pharmaceutical Collection (NPC), which is part of the Tox21 10K compound library, with drugs approved in recent years to include an up-to-date list of all approved drugs. A paper describing the history and update of NPC has been published in Drug Discovery Today in FY19. The Tox21 Computational Toxicology team is also leading one of the Tox21 cross-partner projects Expansion of Pathway Coverage by Tox21 High-Throughput Screening Assays for Better Prediction of Adverse Drug Effects, which utilizes the NCATS BioPlanet (https://tripod.nih.gov/bioplanet/) as a tool to define the biological space and identify assays for screening. The data generated from this project will be used to build computational models to predict liver and cardiotoxicity. In addition, the Tox21 Computational Toxicology team has continued to work with the Tox21 Genomic Toxicology team to refine methods for concentration response gene expression data analysis including strategies for point-of-departure (PoD) determination, as well as combination screening data analysis of toxicants and modulators (the ToxMatrix). A web version of the software platform for visualization and analysis of concentration response gene expression data has been under construction and will be made public in due course.