A Comparison of Methods for Estimating the Benchmark Dose Based on Overdispersed Data from Developmental Toxicity Studies
- 1 June 1998
- journal article
- research article
- Published by Wiley in Risk Analysis
- Vol. 18 (3), 329-342
- https://doi.org/10.1111/j.1539-6924.1998.tb01299.x
Abstract
Developmental anomalies resulting from prenatal toxicity can be manifested in terms of both malformations among surviving offspring and prenatal death. Although these two endpoints have traditionally been analyzed separately in the assessment of risk, multivariate methods of risk characterization have recently been proposed. We examined this and other issues in developmental toxicity risk assessment by evaluating the accuracy and precision of estimates of the effective dose (ED05) and the benchmark dose (BMD05) using computer simulation. Our results indicated that different variance structures (Dirichlet‐trinomial and generalized linear model) used to characterize overdispersion yielded comparable results when fitting joint dose response models based on generalized estimating equations. (The choice of variance structure in separate modeling was also not critical.) However, using the Rao‐Scott transformation to eliminate overdispersion tended to produce estimates of the ED05 with reduced bias and mean squared error. Because joint modeling ensures that the ED05 for overall toxicity (based on both malformations and prenatal death) is always less than the ED05 for either malformations or prenatal death, joint modeling is preferred to separate modeling for risk assessment purposes.Keywords
This publication has 28 references indexed in Scilit:
- A Simple Data Transformation for Estimating Benchmark Doses in Developmental Toxicity ExperimentsRisk Analysis, 1995
- Dose-Response Assessment for Developmental Toxicity II. Comparison of Generic Benchmark Dose Estimates with No Observed Adverse Effect LevelsFundamental and Applied Toxicology, 1994
- Applications of Multinomial Dose‐Response Models in Developmental Toxicity Risk AssessmentRisk Analysis, 1994
- Dose-Response Models for Correlated Multinomial Data from Developmental Toxicity StudiesJournal of the Royal Statistical Society Series C: Applied Statistics, 1994
- Bivariate Latent Variable Models for Clustered Discrete and Continuous OutcomesJournal of the American Statistical Association, 1992
- The Analysis of Multiple Correlated Binary Outcomes: Application to Rodent Teratology ExperimentsJournal of the American Statistical Association, 1989
- Binary Regression Using an Extended Beta-Binomial Distribution, with Discussion of Correlation Induced by Covariate Measurement ErrorsJournal of the American Statistical Association, 1986
- Longitudinal data analysis using generalized linear modelsBiometrika, 1986
- Beta-Binomial Anova for ProportionsJournal of the Royal Statistical Society Series C: Applied Statistics, 1978
- Proportions with Extraneous Variance: Single and Independent SampleJournal of the American Statistical Association, 1973