Global sensitivity analysis for developing biological models: Application to K+ channel model in mouse ventricular myocytes

Mathematical models of cardiac myocytes are highly nonlinear and involve a large number of model parameters. The parameters are estimated using experimental data, which are often corrupted by noise and uncertainty. Such uncertainty can be propagated onto model parameters during model calibration, which further affects model reliability and credibility. In order to improve model accuracy, it is important to quantify and reduce the uncertainty in model response resulting from parametric uncertainty. Sensitivity analysis is a key technique to investigate the significance of parametric uncertainty and its effect on model responses. This can identify and rank most sensitive parameters, and evaluate the effect of uncertainty on model outputs. In this work, a global sensitivity analysis is developed to determine the significance of parametric uncertainty on model responses using Sobol indices. This method is applied to nonlinear K+ channel models of mouse ventricular myocytes to demonstrate the efficacy of the developed algorithm.