STATISTICAL PROBLEMS IN BIOASSAY AND RISK ASSESSMENT

说明：本提案旨在解决统计问题 与动物生物测定的设计、分析和解释有关， 癌症和发育毒性。 这些动物研究 在风险评估过程中发挥重要作用， 有害化学化合物和其他环境因素。 发育毒性研究评估了暴露对小鼠的不良影响 发育中的胎儿 在某些时期对暴露的敏感性增加 妊娠周期的变化决定了暴露的时间和持续时间 尤其重要。 拟议研究的一个主要组成部分涉及 制定统计方法， 暴露于发育毒性风险评估过程。 在 特别是基准剂量的概念将被扩展到考虑 暴露持续时间。 发展性学习设计的改进方法 毒性实验涉及暴露水平、持续时间和时间， 也要发展。 对发育影响的评估往往依赖于多个终点， 例如产前死亡或存活能力、各种类型畸形和低 出生体重 因此，对这些数据的统计分析必须解决 对于相同终点的后代之间的两种相关性（即，猫砂 影响）和多个终点之间的相关性。 拟议 研究解决了与评估多个 发育毒性研究的结果。 第一，测试问题 暴露对多种结果的影响将得到解决， 结果可以观察到每个后代，无论是由于后勤或 经济限制。 第二，评估的统计方法 将考虑暴露对多个顺序结局的影响。 为 癌症和发育毒理学，最近的兴趣集中在 将额外的生物信息纳入剂量反应模型 进行风险评估。 拟议研究的一个组成部分涉及 发展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 致突变性、分子结构和化学特征等 活动 灵活的剂量反应模型将首先适合于一个大的 现有的啮齿动物生物测定数据。 荟萃分析技术将是 用于解释估计剂量-反应模式的变异性 对于不同性别/物种组合的特定化学品， 多个终点（肿瘤部位或发育结局）。

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).