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

Tox21项目的联邦合作伙伴包括美国环境保护局（EPA）、美国食品和药物管理局（FDA）和美国国立卫生研究院（NIH），由美国国家毒理学研究所（NCATS）和美国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试验。Tox21项目可分为三个NCATS小组：系统毒理学、基因组毒理学和计算毒理学。Tox21计算毒理学团队改进了多种工具，这些工具是Tox21合作伙伴经常使用的，可以相互访问数据。该团队对Tox21系统毒理学团队鉴定、开发、优化和/或筛选的20种检测方法以及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。这些活动包括标准化和校正，拟合浓度-反应曲线以产生效力和功效测量，基于一系列标准的曲线分类，这些标准包括拟合的显著性（通过p值测量），拟合的完整性和功效，通过数据可重复性评估分析性能，为后续研究选择数据驱动的化合物，以及识别参与细胞对化学物质反应的基因和途径。此外，Tox21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，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、详细的实验条件和筛选方案。截至2019财年筛选的所有检测的10K数据已在PubChem上公开，总计223个检测条目（AIDs）和超过9900万个数据点。

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.