Catalano P, Ryan L, Scharfstein D
Department of Biostatistics, Dana Farber Cancer Institute, Boston, Massachusetts.
Risk Anal. 1994 Aug;14(4):629-37. doi: 10.1111/j.1539-6924.1994.tb00276.x.
We review approaches to dose-response modeling and risk assessment for binary data from developmental toxicity studies. In particular, we focus on jointly modeling fetal death and malformation and use a continuation ratio formulation of the multinomial distribution to provide a model for risk. Generalized estimating equations are used to account for clustering of animals within litters. The fitted model is then used to calculate doses corresponding to a specified level of excess risk. Two methods of arriving at a lower confidence limit or Benchmark dose are illustrated and compared. We also discuss models based on single binary end points and compare our approach to a binary analysis of whether or not the animal was 'affected' (either dead or malformed). The models are illustrated using data from four developmental toxicity studies in EG, DEHP, TGDM, and DYME conducted through the National Toxicology Program.
我们回顾了发育毒性研究中二元数据的剂量反应建模和风险评估方法。特别地，我们专注于对胎儿死亡和畸形进行联合建模，并使用多项分布的连续比例公式来提供风险模型。广义估计方程用于考虑窝内动物的聚类情况。然后，使用拟合模型计算与特定超额风险水平相对应的剂量。阐述并比较了得出较低置信限或基准剂量的两种方法。我们还讨论了基于单一二元终点的模型，并将我们的方法与对动物是否“受影响”（死亡或畸形）进行的二元分析进行比较。使用通过国家毒理学计划进行的四项关于乙二醇（EG）、邻苯二甲酸二（2-乙基己基）酯（DEHP）、三甘醇二甲基醚（TGDM）和二乙二醇单甲醚（DYME）的发育毒性研究数据对模型进行了说明。
