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

Tox 21计划的联邦合作伙伴包括环境保护局（EPA）、食品药品监督管理局（FDA）和NIH，并由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。这些机构共同努力推进体外毒理学测试。Tox 21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。Tox 21计算毒理学团队增强了Tox 21合作伙伴访问彼此数据时经常使用的各种工具。该团队对Tox 21系统毒理学团队鉴定、开发、优化和/或筛选的超过18种检测方法以及Tox 21基因组毒理学团队生成的基因表达数据进行了数据分析。这些活动包括标准化和校正、拟合浓度-响应曲线以生成效价和疗效指标、基于一组标准（包括拟合显著性）对曲线进行分类（通过p值测量）、拟合的完整性和功效，通过数据再现性评价测定性能，数据驱动选择用于后续研究的化合物，以及识别涉及细胞对化学暴露的反应的基因和途径。此外，Tox 21计算毒理学团队更新了基于网络的自动化结构-活性关系（SAR）分析工具，以便系统毒理学团队对所有10 K库屏幕进行SAR分析。Tox 21计算毒理学团队还更新了PubChem沉积工具，以便于将Tox 21 10 K一式三份筛选数据沉积到PubChem中。截至2017财年筛选的所有检测的10 K数据已在PubChem中公开，共计191个检测条目（AID）和超过8500万个数据点。 Tox 21公共数据浏览器已更新了来自10 K文库筛选的最新测定结果，共计54个测定。该浏览器为公众提供Tox 21 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指标沿着化学结构和分析QC结果。数据可通过分析和/或化学品进行检索。多个检测和/或化学品的结果可以重叠，以便于比较。所有数据以及分析描述和详细的筛选方案（SLP）可供下载。Tox 21数据下载网站已更新，采用列格式的新检测结果文件，结合原始数据和校正数据，以便于其他Tox 21合作伙伴进行分析。Tox 21计算毒理学团队继续与Tox 21化学工作组合作，为Tox 21 10 K库化学QC结果生成PDF文件，包括4个月化合物稳定性试验结果。这些结果已经在公共Tox 21浏览器（https：//tripod.nih.gov/tox21/）中发布，并且已经为保存在PubChem中的Tox 21化合物提供了PDF的链接。在2017财年，Tox 21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），这是Tox 21 10 K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列表。此外，更新了NCATS BioPlanet数据库的网络浏览器，包括一个指导网页。BioPlanet收集了所有人类途径的列表，允许Tox 21计划设计测定方法来测量其化学反应。BioPlanet目前通过来源，生物功能和过程，疾病和毒性相关性以及探测检测的可用性注释了近1，700种独特的人类途径。该工具已于2017财年向Tox 21合作伙伴和公众提供（https：//tripod.nih.gov/bioplanet/）。此外，Tox 21计算毒理学团队继续与Tox 21基因组毒理学团队合作，完善浓度响应基因表达数据分析方法，包括出发点（PoD）确定策略，以及毒物和调节剂的组合筛选数据分析（ToxMatrix）。用于浓度响应基因表达数据可视化和分析的软件平台已更新，具有更多功能。

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 more than 18 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 PubChem deposition tool to facilitate the deposition of the Tox21 10K triplicate screen data into PubChem. The 10K data from all assays screened up to FY17 have been made public in PubChem totaling 191 assay entries (AIDs) and over 85 million data points. The Tox21 public data browser has been updated with the latest assay results from the 10K library screens totaling 54 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. These 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 FY17, 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. Furthermore, the Web based browser for the NCATS BioPlanet database has been updated including a tutorial page. The BioPlanet collects a list of all human pathways that allow the Tox21 Program to design assays to measure their chemical responses. The BioPlanet currently annotates nearly 1,700 unique human pathways by source, biological function and process, disease and toxicity relevance, and availability of probing assays. This tool has been made available (https://tripod.nih.gov/bioplanet/) to the Tox21 partners and the public in FY17. 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). The software platform for visualization and analysis of concentration response gene expression data has been updated with more functionalities.