Unlocking data sets by calibrating populations of models to data density: A study in atrial electrophysiology

We describe a statistically informed calibration of in silico populations to explore variability in complex systems. The understanding of complex physical or biological systems nearly always requires a characterization of the variability that underpins these processes. In addition, the data used to calibrate these models may also often exhibit considerable variability. A recent approach to deal with these issues has been to calibrate populations of models (POMs), multiple copies of a single mathematical model but with different parameter values, in response to experimental data. To date, this calibration has been largely limited to selecting models that produce outputs that fall within the ranges of the data set, ignoring any trends that might be present in the data. We present here a novel and general methodology for calibrating POMs to the distributions of a set of measured values in a data set. We demonstrate our technique using a data set from a cardiac electrophysiology study based on the differences in atrial action potential readings between patients exhibiting sinus rhythm (SR) or chronic atrial fibrillation (cAF) and the Courtemanche-Ramirez-Nattel model for human atrial action potentials. Not only does our approach accurately capture the variability inherent in the experimental population, but we also demonstrate how the POMs that it produces may be used to extract additional information from the data used for calibration, including improved identification of the differences underlying stratified data. We also show how our approach allows different hypotheses regarding the variability in complex systems to be quantitatively compared.