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bioRxiv · 10.1101/2022.03.11.483794

Ion channel model reduction using manifold boundaries

Whittaker, D. G.·Wang, J.·Shuttleworth, J.·Venkateshappa, R.·Kemp, J. M.·Claydon, T. W.·Mirams, G. R.
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Abstract

Mathematical models of voltage-gated ion channels are used in basic research, industrial and clinical settings. These models range in complexity, but typically contain numerous variables representing the proportion of channels in a given state, and parameters describing the voltage-dependent rates of transition between states. An open problem is selecting the appropriate degree of complexity and structure for an ion channel model given data availability. Here, we simplify a model of the cardiac human Ether-a-go-go Related Gene (hERG) potassium ion channel, which carries cardiac IKr, using the manifold boundary approximation method (MBAM). The MBAM approximates high-dimensional model-output manifolds by reduced models describing their boundaries, resulting in models with fewer parameters (and often variables). We produced a series of models of reducing complexity starting from an established 5-state hERG model with 15 parameters. Models with up to 3 fewer states and 8 fewer parameters were shown to retain much of the predictive capability of the full model and were validated using experimental hERG1a data collected in HEK293 cells at 37{degrees}C. The method provides a way to simplify complex models of ion channels that improves parameter identifiability and will aid in future model development.

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Whittaker, D. G., Wang, J., Shuttleworth, J., Venkateshappa, R., Kemp, J. M., Claydon, T. W., Mirams, G. R.. 2022-03-12. Ion channel model reduction using manifold boundaries. https://doi.org/10.1101/2022.03.11.483794

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