regression analysis for constraining free parameters in electrophysiological models of cardiac cells限制自由参数的回归分析心肌细胞的电生理模型.pdfVIP

Regression Analysis for Constraining Free Parameters in Electrophysiological Models of Cardiac Cells Amrita X. Sarkar, Eric A. Sobie* Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, United States of America Abstract A major challenge in computational biology is constraining free parameters in mathematical models. Adjusting a parameter to make a given model output more realistic sometimes has unexpected and undesirable effects on other model behaviors. Here, we extend a regression-based method for parameter sensitivity analysis and show that a straightforward procedure can uniquely define most ionic conductances in a well-known model of the human ventricular myocyte. The model’s parameter sensitivity was analyzed by randomizing ionic conductances, running repeated simulations to measure physiological outputs, then collecting the randomized parameters and simulation results as ‘‘input’’ and ‘‘output’’ matrices, respectively. Multivariable regression derived a matrix whose elements indicate how changes in conductances influence model outputs. We show here that if the number of linearly-independent outputs equals the number of inputs, the regression matrix can be inverted. This is significant, because it implies that the inverted matrix can specify the ionic conductances that are required to generate a particular combination of model outputs. Applying this idea to the myocyte model tested, we found that most ionic conductances could be specified with precision (R2 . 0.77 for 12 out of 16 parameters). We also applied this method to a test case of changes in electrophysiology caused by heart failure and found that changes in most parameters could be well predicted. We complemented our findings