Iterative approach to model identification of biological networks

BACKGROUND: Recent advances in molecular biology techniques provide an opportunity for developing detailed mathematical models of biological processes. An iterative scheme is introduced for model identification using available system knowledge and experimental measurements. RESULTS: The scheme includes a state regulator algorithm that provides estimates of all system unknowns (concentrations of the system components and the reaction rates of their inter-conversion). The full system information is used for estimation of the model parameters. An optimal experiment design using the parameter identifiability and D-optimality criteria is formulated to provide "rich" experimental data for maximizing the accuracy of the parameter estimates in subsequent iterations. The importance of model identifiability tests for optimal measurement selection is also considered. The iterative scheme is tested on a model for the caspase function in apoptosis where it is demonstrated that model accuracy improves with each iteration. Optimal experiment design was determined to be critical for model identification. CONCLUSION: The proposed algorithm has general application to modeling a wide range of cellular processes, which include gene regulation networks, signal transduction and metabolic networks.