Bayesian Analysis of A Rat Formaldehyde DNA–Protein Cross-Link Model

Abstract

As the initial effort in a multi-step uncertainty analysis of a biologically based cancer model for formaldehyde, a Markov chain Monte Carlo (MCMC) analysis was performed for a compartmental model that predicts DNA–protein cross-links (DPX) produced by formaldehyde exposure. The Bayesian approach represented by the MCMC analysis integrates existing knowledge of the model parameters with observed, formaldehyde-DPX-specific data, providing a statistically sound basis for estimating model output uncertainty. Uncertainty and variability were evaluated through a hierarchical structure, where interindividual variability was considered for all model parameters and that variability was assumed to be uncertain on population levels. The uncertainty of the population mean and that of the population variance were significantly reduced through the MCMC analysis. Our investigation highlights several issues that must be dealt with in many real-world analyses (e.g., issues of parameters' nonidentifiability due to limited data) while demonstrating the feasibility of conducting a comprehensive quantitative uncertainty evaluation. The current analysis can be viewed as a case study, for a relatively simple model, illustrating some of the constraints that analysts will face when applying Bayesian approaches to biologically or physiologically based models of increasing complexity.