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）非动物模型来替代， 改进和/或减少（“3R”）脊椎动物毒理学测试。特别是高温超导模型的发展 神经毒性（NT）和发育神经毒性（DNT）具有挑战性，其中 不良后果需要在整个生物体水平上进行评估。这项研究的首要目标是 是发展一种非动物有机体HTS方法来鉴定NT和DNT。具体目标是 确定使用最先进的计算方法是否会增加灵敏度和特异性， Planarian HTS使用经过验证的国家毒理学计划87化合物库识别NT和DNT （NTP87）。作为NTP神经毒理学筛查策略计划的合作伙伴，我们之前筛查了 由无性淡水中已知和疑似发育神经毒物组成的NTP 87文库 利用9个读数对日本三角涡虫进行了研究。利用这个文库，我们证明了涡虫HTS可以识别 已知的（发育）神经毒素，并增加了补充价值，以筛选在发展中的斑马鱼。 Planarians是无脊椎动物，与线虫相比，神经和解剖复杂性居中， 斑马鱼和有听话的，进化保守的神经回路。Planarians独特地允许直接 异生素对成人和发育中的神经系统的影响的比较。无性系D.日本， 通过分裂繁殖，神经再生是神经发育的唯一方法， 与脊椎动物神经发育的关系这些特征和我们以前的工作证明了 涡虫HTS用于潜在神经毒物的一级筛选。我们假设我们可以增加 通过重新分析我们的NTP 87数据，使用最新的 艺术机器学习和统计工具。 实验方法。在目标1中，我们将使用18种新的行为和10种新的行为来重新分析原始数据。 使用计算机视觉和机器学习的形态学读数。因此，我们总共测定了37个读数 在完整和再生生物体中以5种浓度进行评价。在目标2中，我们将重新分析效价 包括使用基准浓度方法的所有37个读数， 具体的基准反应。这种分析将克服与最低- 先前应用的无效水平。在目标3中，我们将使用贝叶斯统计模型， 开发用于斑马鱼胚胎筛选，以获得整体毒性汇总评分并评估相对毒性。 不同的读数对于涡虫系统的预测能力的重要性。 预期成果。通过将非动物有机体行为HTS与最先进的分析 方法，该项目将支持非动物有机体HTS方法的发展， 与预测生物信息学相结合，以满足填补DNT数据缺口的迫切需要。