Fitting two human atrial cell models to experimental data using Bayesian history matching

Cardiac cell models are potentially valuable tools for applications such as quantitative safety pharmacology, but have many parameters. Action potentials in real cardiac cells also vary from beat to beat, and from one cell to another. Calibrating cardiac cell models to experimental observations is difficult, because the parameter space is large and high-dimensional. In this study we have demonstrated the use of history matching to calibrate the maximum conductance of ion channels and exchangers in two detailed models of the human atrial action potential against measurements of action potential biomarkers. History matching is an approach developed in other modelling communities, based on constructing fast-running Gaussian process emulators of the model. Emulators were constructed from a small number of model runs (around 10 2 ), and then run many times (>10 6) at low computational cost, each time with a different set of model parameters. Emulator outputs were compared with experimental biomarkers using an implausibility measure, which took into account experimental variance as well as emulator variance. By repeating this process, the region of non-implausible parameter space was iteratively reduced. Both cardiac cell models were successfully calibrated to experimental datasets, resulting in sets of parameters that could be sampled to produce variable action potentials. However, model parameters did not occupy a small range of values. Instead, the history matching process exposed inputs that can co-vary across a wide range and still be consistent with a particular biomarker. We also found correlations between some biomarkers, indicating a need for better descriptors of action potential shape.