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

Tox 21计划的联邦合作伙伴包括NIH，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，环境保护局（EPA）和食品药品监督管理局（FDA）。这些机构共同努力推进体外毒理学测试。Tox 21计划由以下专业组成：计算毒理学，系统毒理学和基因组毒理学。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 Systems毒理学团队鉴定、开发、优化和/或筛选的18种以上检测方法以及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），拟合和有效性的完整性，通过数据再现性评价测定性能，数据驱动的化合物选择用于后续研究，以及识别涉及细胞对化学暴露的反应的基因和途径。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2015财年筛选的所有检测的10 K数据已在PubChem中公开，共计100个检测条目（AIDS）和超过5500万个数据点。 Tox 21计算毒理学团队还完成了Tox 21 Data Challenge 2014，这是一项众包竞赛，基于来自12种途径检测的10 K数据开发了计算模型，包括来自核受体信号传导小组和应激反应途径小组的检测。挑战赛于2014年7月16日启动，并于2014年11月14日关闭评分。获奖名单于2015年1月26日公布。代表18个不同国家的125名参与者登记参加了挑战赛。共收到40个小组提交的378个模型供最后评价。获胜的模型都达到了80%以上的准确率，其中几个模型的准确率超过90%。获胜的模型将向科学界公开，以帮助确定化合物的优先级。《环境科学前沿》的特刊专门针对Tox 21挑战，发表挑战参与者的文章。 Tox 21数据存储库和浏览器（包括在线检测跟踪系统）已更新，以促进数据共享和检测注释。Tox 21计算毒理学团队一直在与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。这些结果已在公共Tox 21数据浏览器中发布，并提供了保存在PubChem中的Tox 21化合物的PDF链接。此外，还为NCATS BioPlanet数据库开发了一个新的网络浏览器。这一发展将使Tox 21计划能够收集所有人类途径的列表，并设计可以测量其化学反应的测定方法。BioPlanet将通过来源、物种、生物功能和过程、疾病和毒性相关性以及探测分析的可用性来注释近2,000种独特的人类途径。路径注释的手动管理仍在继续。这一工具将在适当时候提供给Tox 21伙伴和公众。

The Tox21 programs federal partners include NIH, with leadership from NCATS and the National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences (NIEHS), the Environmental Protection Agency (EPA), and the Food and Drug Administration (FDA). These agencies work together to advance in vitro toxicological testing. The Tox21 program is comprised of the following specialties: Computational Toxicology, Systems Toxicology and Genomic 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. The Tox21 Computational Toxicology team also has 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 FY 2015 have been made public in PubChem totaling 100 assay entries (AIDs) and over 55 million data points. The Tox21 Computational Toxicology team also has completed the Tox21 Data Challenge 2014, a crowdsourcing competition that developed computational models based on the 10K data from 12 pathway assays, including assays from both the nuclear receptor signaling panel and the stress response pathway panel. The Challenge was launched on July 16, 2014, and closed for scoring on November 14, 2014. The winners were announced on January 26, 2015. One hundred twenty-five participants registered for the Challenge representing 18 different countries. Three hundred seventy-eight model submissions from 40 teams were received for final evaluation. The winning models all achieved >80 percent accuracy, with several models exceeding 90 percent accuracy. The winning models will be made publicly available to the scientific community to aid in compound prioritization. A special issue in Frontiers in Environmental Science has been dedicated to the Tox21 Challenge to publish articles from the Challenge participants. The Tox21 data repository and browser, including the online assay tracking system, have been updated to facilitate data sharing and assay annotations. The Tox21 Computational Toxicology team has been working with the Tox21 chemical working group to generate PDF files for the Tox21 10K library chemical QC results. These results have been released in the public Tox21 Data Browser, and the links to the PDFs have been provided for Tox21 compounds deposited in PubChem. Furthermore, a new Web-based browser has been developed for the NCATS BioPlanet database. This development will allow the Tox21 program to collect a list of all human pathways and design assays that can measure their chemical responses. BioPlanet will annotate the nearly 2,000 unique human pathways by source, species, biological function and process, disease and toxicity relevance, and availability of probing assays. Manual curation of pathway annotations is continuing. This tool will be made available to the Tox21 partners and the public in due course.