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

Tox21项目的联邦合作伙伴包括NIH，NCATS和国家环境健康科学研究所(NIEHS)、环境保护局(EPA)和食品和药物管理局(FDA)的国家毒理学计划(NTP)的领导。这些机构共同努力，推进体外毒理学测试。Tox21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。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18种以上分析方法以及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，其中包括拟合度的重要性(以p值衡量)、拟合度和效度的完整性、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。Tox21计算毒理学团队还更新了PubChem沉积工具，以便于将Tox21 10K三重屏幕数据沉积到PubChem中。截至2015财年，所有化验的10K数据已在PubChem中公开，总计100个化验条目(艾滋病)和超过5500万个数据点。 Tox21计算毒理学团队还完成了Tox21 2014年数据挑战，这是一项众包竞赛，基于12种途径分析的10K数据开发了计算模型，包括核受体信号转导小组和应激反应途径小组的分析。挑战赛于2014年7月16日启动，2014年11月14日截止评分。获奖者名单于2015年1月26日公布。来自18个不同国家的125名参赛者登记参加了这次挑战赛。收到了来自40个团队的378份模型，供最终评估。获奖的模型都达到了&gt；80%的准确率，有几个模型的准确率超过90%。获奖模型将向科学界公开，以帮助确定复合优先顺序。《环境科学前沿》的一期特刊专门介绍了Tox21挑战赛，以发表挑战赛参与者的文章。 Tox21数据储存库和浏览器，包括在线化验跟踪系统，已经更新，以促进数据共享和化验注释。Tox21计算毒理学团队一直在与Tox21化学工作组合作，为Tox21 10K库化学QC结果生成PDF文件。这些结果已经在公共的Tox21数据浏览器中发布，并提供了存放在PubChem中的Tox21化合物的PDF链接。此外，还为NCATS生物星球数据库开发了一个新的基于Web的浏览器。这一进展将使Tox21计划能够收集所有人类途径的清单，并设计能够测量它们的化学反应的检测方法。BioPlanet将按来源、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对近2000条独特的人类路径进行注释。路径注释的人工整理工作仍在继续。该工具将在适当的时候向Tox21合作伙伴和公众提供。

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.