Model averaging using fractional polynomials to estimate a safe level of exposure

Risk Anal. 2007 Feb;27(1):111-23. doi: 10.1111/j.1539-6924.2006.00863.x.

Abstract

Quantitative risk assessment involves the determination of a safe level of exposure. Recent techniques use the estimated dose-response curve to estimate such a safe dose level. Although such methods have attractive features, a low-dose extrapolation is highly dependent on the model choice. Fractional polynomials, basically being a set of (generalized) linear models, are a nice extension of classical polynomials, providing the necessary flexibility to estimate the dose-response curve. Typically, one selects the best-fitting model in this set of polynomials and proceeds as if no model selection were carried out. We show that model averaging using a set of fractional polynomials reduces bias and has better precision in estimating a safe level of exposure (say, the benchmark dose), as compared to an estimator from the selected best model. To estimate a lower limit of this benchmark dose, an approximation of the variance of the model-averaged estimator, as proposed by Burnham and Anderson, can be used. However, this is a conservative method, often resulting in unrealistically low safe doses. Therefore, a bootstrap-based method to more accurately estimate the variance of the model averaged parameter is proposed.

MeSH terms

  • Animals
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Environmental Exposure*
  • Ethylene Glycol / pharmacology
  • Female
  • Linear Models
  • Maternal Exposure
  • Mice
  • Models, Statistical
  • Models, Theoretical
  • Multivariate Analysis
  • No-Observed-Adverse-Effect Level
  • Pregnancy
  • Probability
  • Risk Assessment*

Substances

  • Ethylene Glycol