Regan M M, Catalano P J
Biometrics Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Risk Anal. 2000 Jun;20(3):363-76. doi: 10.1111/0272-4332.203035.
Multivariate dose-response models have recently been proposed for developmental toxicity data to simultaneously model malformation incidence (a binary outcome), and reductions in fetal weight (a continuous outcome). In this and other applications, the binary outcome often represents a dichotomization of another outcome or a composite of outcomes, which facilitates analysis. For example, in Segment II developmental toxicology studies, multiple malformation types (i.e., external, visceral, skeletal) are evaluated on each fetus; malformation status may also be ordinally measured (e.g., normal, signs of variation, full malformation). A model is proposed is for fetal weight and multiple malformation variables measured on an ordinal scale, where the correlations between the outcomes and between the offspring within a litter are taken into account. Fully specifying the joint distribution of outcomes within a litter is avoided by specifying only the distribution of the multivariate outcome for each fetus and using generalized estimating equation methodology to account for correlations due to litter clustering. The correlations between the outcomes are required to characterize joint risk to the fetus, and are therefore a focus of inference. Dose-response models and their application to quantitative risk assessment are illustrated using data from a recent developmental toxicology experiment of ethylene oxide in mice.
最近有人针对发育毒性数据提出了多变量剂量反应模型，以同时对畸形发生率（二元结局）和胎儿体重减轻（连续结局）进行建模。在本应用及其他应用中，二元结局通常代表另一个结局的二分法或结局的组合，这便于进行分析。例如，在第二阶段发育毒理学研究中，对每个胎儿评估多种畸形类型（即外部、内脏、骨骼）；畸形状态也可以进行有序测量（例如，正常、变异体征、完全畸形）。本文提出了一个针对按有序尺度测量的胎儿体重和多个畸形变量的模型，其中考虑了结局之间以及同窝幼崽之间的相关性。通过仅指定每个胎儿的多变量结局的分布，并使用广义估计方程方法来考虑由于同窝聚类引起的相关性，从而避免了完全指定同窝幼崽内结局的联合分布。结局之间的相关性对于表征对胎儿的联合风险是必需的，因此是推断的重点。使用来自最近一项关于小鼠环氧乙烷发育毒理学实验的数据，说明了剂量反应模型及其在定量风险评估中的应用。
