STATISTICAL PROBLEMS IN BIOASSAY AND RISK ASSESSMENT

描述：这项提议的目的是解决统计问题 与动物生物测定的设计、分析和解释有关的 包括癌症和发育毒性。这些类型的动物研究发挥了作用 潜在评估在风险评估过程中的重要作用 有害化合物和其他环境制剂。 发育毒性研究评估暴露对儿童的不良影响 发育中的胎儿。对某些时期暴露的敏感度增加 决定了暴露的时间和持续时间 尤其重要的是。拟议研究的一个主要组成部分包括 制定纳入持续时间和时间安排的统计方法 暴露在发育毒性的风险评估过程中。在……里面 特别是，基准剂量的概念将扩大到考虑到 曝光持续时间。发展性学习设计的改进方法 针对暴露水平、持续时间和时间的毒性试验将 也被开发出来。 对发育影响的评估通常依赖于多个终点， 如产前死亡或存活、各种类型的畸形和低 出生体重。因此，对这类数据的统计分析必须处理 同一终点(即，窝产仔)的后代之间的两种相关性 效果)和多个端点之间的相关性。建议数 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 暴露对多种结果的影响将在不是所有结果的情况下解决 结果可以在每个后代身上观察到，要么是由于后勤方面的原因，要么是因为 经济上的限制。其次，评估的统计方法 暴露对多个顺序结果的影响将被考虑。为 癌症和发育毒理学，最近的许多兴趣都集中在 在剂量-反应模型中加入额外的生物信息 用于风险评估。拟议研究的一个组成部分涉及 非线性统计评估方法的研究进展 剂量效应及其与生物和化学的关系 特征，如致突变性、分子结构和化学成分 活动。灵活的剂量反应模型将首先适用于大型 现有的啮齿动物体内生物化验数据。元分析技术将是 考虑到估计剂量-反应模式的可变性而开发的 对于不同性别/物种组合的给定化学物质 多个终点(肿瘤部位或发育结果)。

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).