STATISTICAL PROBLEMS IN BIOASSAY AND RISK ASSESSMENT

生物测定和风险评估中的统计问题

• 批准号: 2444233
• 负责人: PAIGE L WILLIAMS
• 金额: $ 10.21万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2444233
• 关键词: animal birth weight; bioassay; cancer risk; chemical carcinogen; drug administration rate /duration; embryo /fetus disorder; embryo /fetus drug adverse effect; embryo /fetus toxicology; environment related neoplasm /cancer; environmental toxicology; gestational age; mathematical model; meta analysis; statistics /biometry

DESCRIPTION: The purpose of this proposal is to address statistical issues related to the design, analysis, and interpretation of animal bioassays for both cancer and developmental toxicity. These types of animal studies play an essential role in the risk assessment process for evaluating poten-tially hazardous chemical compounds and other environmental agent. Developmental toxicity studies evaluate adverse effects of exposure on the developing fetus. Increased sensitivity to exposure during certain periods of the gestational cycle makes the timing and the duration of exposures particularly important. A major component of the proposed research involves developing statistical methods for incorporating duration and timing of exposure into the risk assessment process for developmental toxicity. In particular the concept of a Bench-mark Dose will be extended to account for exposure duration. Improved methods for study design of developmental toxicity experiments which address exposure level, duration, and timing will also be developed. The assessment of developmental effects often relies on multiple endpoints, such as prenatal death or viability, malformations of various types and low birth weight. The statistical analysis of such data must therefore address both correlations among offspring for the same end-point (i.e., the litter effect) and correlations among the multiple endpoints. The proposed research addresses several issues related to the assessment of multiple outcomes in developmental toxicity studies. First, the issue of testing for exposure effects on multiple outcomes will be addressed when not all outcomes can be observed on each offspring, either due to logistical or economic constraints. Secondly, statistical methods for assessing the effect of exposure on multiple ordinal outcomes will be considered. For both cancer and developmental toxicology, much recent interest has focused on incorporating additional biological information into dose-response models for risk assessment. One component of the proposed research concerns the development of statistical methods for assessing non-linearities in dose-response and their relationship with biological and chemical characteristics, such as mutagenicity, molecular structure, and chemical activity. Flexible dose response models will first be fit to a large existing body of rodent bioassay data. Meta-analysis techniques will be developed to account for the variability in estimated dose-response patterns for a given chemical across differing sex/species combinations and across multiple endpoint (tumor sites or developmental outcomes).

描述：该提案的目的是解决统计问题 与动物生物测定的设计、分析和解释有关 癌症和发育毒性。 这些类型的动物研究发挥着作用 在评估潜在风险的风险评估过程中发挥着重要作用 危险化学品和其他环境剂。 发育毒性研究评估暴露对 发育中的胎儿。 在某些时期对暴露的敏感性增加 妊娠周期的不同决定了暴露的时间和持续时间 特别重要。 拟议研究的一个主要组成部分涉及 制定统计方法以纳入持续时间和时间安排 暴露于发育毒性的风险评估过程。 在 特别是基准剂量的概念将扩展到考虑 曝光时间。 发展研究设计的改进方法 涉及暴露水平、持续时间和时间的毒性实验将 也得以开发。 发育影响的评估通常依赖于多个终点， 例如产前死亡或存活率、各种类型的畸形和低 出生体重。 因此，此类数据的统计分析必须解决 后代之间对于同一终点（即窝数）的两种相关性 效应）和多个端点之间的相关性。 拟议的 研究解决了与多个评估相关的几个问题 发育毒性研究的结果。 首先，测试的问题 当并非所有结果都暴露时，暴露对多种结果的影响就会得到解决 可以在每个后代中观察到结果，无论是由于后勤还是 经济限制。 其次，统计方法评估 将考虑暴露对多个顺序结果的影响。 为了 癌症和发育毒理学，最近的很多兴趣都集中在 将额外的生物信息纳入剂量反应模型 用于风险评估。 拟议研究的一个组成部分涉及 开发用于评估非线性的统计方法 剂量反应及其与生物和化学的关系 特性，例如致突变性、分子结构和化学性质 活动。 灵活的剂量反应模型将首先适用于大型 现有的啮齿动物生物测定数据。 荟萃分析技术将 开发用于解释估计剂量反应模式的可变性 对于不同性别/物种组合和不同性别/物种组合的给定化学物质 多个终点（肿瘤部位或发育结果）。