Introducing Parameter Clustering to the OED Procedure for Model Calibration of a Synthetic Inducible Promoter in S. cerevisiae

Abstract

In recent years, synthetic gene circuits for adding new cell features have become one of the most powerful tools in biological and pharmaceutical research and development. However, because of the inherent non-linearity and noisy experimental data, the experiment-based model calibration of these synthetic parts is perceived as a laborious and time-consuming procedure. Although the optimal experimental design (OED) based on the Fisher information matrix (FIM) has been proved to be an effective means to improve the calibration efficiency, the required calculation increases dramatically with the model size (parameter number). To reduce the OED complexity without losing the calibration accuracy, this paper proposes two OED approaches with different parameter clustering methods and validates the accuracy of calibrated models with in-silico experiments. A model of an inducible synthetic promoter in S. cerevisiae is adopted for bench-marking. The comparison with the traditional off-line OED approach suggests that the OED approaches with both of the clustering methods significantly reduce the complexity of OED problems (for at least 49.0%), while slightly improving the calibration accuracy (11.8% and 19.6% lower estimation error in average for FIM-based and sensitivity-based approaches). This study implicates that for calibrating non-linear models of biological pathways, cluster-based OED could be a beneficial approach to improve the efficiency of optimal experimental design.