New statistical and computational tools for optimization of planarian behavioral chemical screens

用于优化涡虫行为化学筛选的新统计和计算工具

• 批准号: 10658688
• 负责人: Eva-Maria Schoetz Collins
• 金额: $ 13.95万
• 依托单位: SWARTHMORE COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658688
• 关键词: Acceleration; Accidents; Acute; Adult; Algorithms; Anatomy; Animal Testing; Anxiety; Bayesian Method; Bayesian Modeling; Behavior; Behavior monitoring; Behavioral; Benchmarking; Bioinformatics; Biological Assay; Categories; Chemical Exposure; Chemicals; Classification; Code; Communities; Complex; Computer Analysis; Computer Vision Systems; Contracts; Data; Development; Dugesia (turbellarian); Embryo; Entropy; Esthesia; Evaluation; Event; Fresh Water; Goals; Health; Human; In Vitro; Information Theory; Invertebrates; Letters; Libraries; Locomotion; Machine Learning; Measurement; Measures; Methodology; Methods; Modeling; Molecular; Morphology; Muscle; National Toxicology Program; Natural regeneration; Nematoda; Nerve Regeneration; Nervous System; Neurophysiology - biologic function; Neurotoxins; Organism; Organophosphorus Compounds; Phenotype; Planarians; Population; Rapid screening; Research; Resolution; Scheme; Sensitivity and Specificity; Severities; Shapes; Spasm; Speed; Strategic Planning; System; Terrorism; Testing; Therapeutic; Time; Toxic effect; Toxicology; United States National Institutes of Health; Whole Organism; Work; Xenobiotics; Zebrafish; adverse outcome; asexual; chemical safety; complex data; computerized tools; cost; cost effective; data library; design; developmental neurotoxicity; high throughput screening; improved; interoperability; mass casualty; neural; neural circuit; neurodevelopment; neuronal circuitry; neurotoxicity; neurotoxicology; novel therapeutics; prevent; response; safety assessment; screening; tool; treatment strategy; tv watching

Objectives. There is an urgent need to develop high-throughput screening (HTS) non-animal models to replace, refine, and/or reduce (“3Rs”) vertebrate toxicology testing. The development of HTS models is especially challenging for neurotoxicity (NT) and developmental neurotoxicity (DNT) where the functional relevancy of adverse outcomes needs to be assessed on the whole organism level. The overarching goal of this research is to develop a non-animal organismal HTS methodology to identify NT and DNT. The specific objective is to determine whether using state-of-the-art computational approaches will increase sensitivity and specificity of planarian HTS to identify NT and DNT using the verified National Toxicology Program 87-compound library (NTP87). As a partner in the NTP Neurotoxicology Screening Strategies Initiative, we previously screened the NTP87 library consisting of known and suspected developmental neurotoxicants in the asexual freshwater planarian Dugesia japonica using 9 readouts. Using this library, we demonstrated that planarian HTS can identify known (developmental-) neurotoxicants and adds complementary value to screens in developing zebrafish. Planarians are invertebrates of intermediate neural and anatomical complexity compared to nematodes and zebrafish and have tractable, evolutionarily conserved neuronal circuits. Planarians uniquely allow for direct comparison of xenobiotic effects on the adult and developing nervous systems. For asexual D. japonica, which reproduce via fission, neuroregeneration is the sole method of neurodevelopment and shares conserved key events with vertebrate neurodevelopment. These features and our previous work demonstrate the value of planarian HTS for first-tier screening of potential neurotoxicants. We hypothesize that we can augment sensitivity and specificity of this non-animal model by re-analyzing our NTP87 data using state-of-the- art machine learning and statistical tools. Experimental approach. In Aim 1, we will re-analyze the raw data using 18 new behavioral and 10 new morphological readouts using computer vision and machine learning. Thus, in total we assay 37 readouts evaluated at 5 concentrations, in intact and regenerating organisms. In Aim 2, we will re-analyze potency including all 37 readouts using a benchmark concentration approach with empirically determined, endpoint- specific benchmark responses. This analysis will overcome the intrinsic limitations associated with lowest- observed-effect levels that was previously applied. In Aim 3, we will use a Bayesian statistical model originally developed for zebrafish embryo screens to obtain a holistic toxicity summary score and evaluate the relative importance of the different readouts for the predictive capabilities of the planarian system. Expected results. By combining non-animal organismal behavioral HTS with state-of-the-art analytical approaches, this project will bolster the development of a non-animal organismal HTS methodology that can be integrated with predictive bioinformatics to meet the urgent need to fill the DNT data gap.

目标。迫切需要开发高通量筛选（HTS）非动物模型以替换， 精炼和/或减少（“ 3R”）脊椎动物毒理学测试。尤其是HTS模型的开发 神经毒性（NT）和发育神经毒性（DNT）的挑战，其中功能相关性 不良结果需要在整个生物体一级进行评估。这项研究的总体目标 是开发一种非动物有机HTS方法来识别NT和DNT。具体目标是 确定使用最先进的计算方法是否会提高灵敏度和特异性 使用经过验证的国家毒理学计划87混合图书馆识别NT和DNT的Planarian HTS （NTP87）。作为NTP神经毒理学筛查策略计划的合作伙伴，我们先前筛选了 NTP87库由无性淡水中的已知和可疑发育神经毒性组成 Planarian Dugesia Japonica使用9个读数。使用此图书馆，我们证明了Planarian HTS可以识别 已知的（发育 - ）神经毒性，并为发展斑马鱼的筛选增加了全部价值。 与线虫和线虫相比 斑马鱼具有可拖动的，进化配置的神经元电路。平面人独特地允许直接 比较异生物生物对成人和发展神经系统的影响。对于无性D. Japonica， 通过裂变繁殖，神经变成是神经发育的唯一方法，共享构成密钥 脊椎动物神经发育的事件。这些功能和我们以前的工作证明了 Planarian HTS用于对潜在神经毒性剂的第一层筛查。我们假设我们可以增加 通过使用最新的NTP87重新分析我们的NTP87数据，对这种非动物模型的敏感性和特异性 艺术机器学习和统计工具。 实验方法。在AIM 1中，我们将使用18个新行为和10个新的行为重新分析原始数据 使用计算机视觉和机器学习的形态读数。那总共我们分析了37个读数 以5个浓度评估，完整和再生组织。在AIM 2中，我们将重新分析效力 使用基准浓度方法包括所有37个读数，并具有经验确定的端点 - 特定的基准响应。该分析将克服与最低的固有局限性 先前应用的观察到效应水平。在AIM 3中，我们最初将使用贝叶斯统计模型 为斑马鱼胚胎筛选开发，以获得整体毒性摘要评分并评估相对 不同读数对Planarian系统的预测能力的重要性。 预期结果。通过将非动物有机行为HTS与最先进的分析相结合 方法是，该项目将加强可能是非动物有机HTS方法的发展 与预测性生物信息学集成在一起，以满足填补DNT数据差距的迫切需求。