Model-driven optimal experimental design for calibrating cardiac electrophysiology models

Lei, Chon Lok; Clerx, Michael; Gavaghan, David J.; Mirams, Gary R.

Abstract

Background and Objective: Models of the cardiomyocyte action potential have contributed immensely to the understanding of heart function, pathophysiology, and the origin of heart rhythm disturbances. However, action potential models are highly nonlinear, making them difficult to parameterise and limiting to describing ‘average cell’ dynamics, when cell-specific models would be ideal to uncover inter-cell variability but are too experimentally challenging to be achieved. Here, we focus on automatically designing experimental protocols that allow us to better identify cell-specific maximum conductance values for each major current type.

Methods and Results: We developed an approach that applies optimal experimental designs to patch-clamp experiments, including both voltage-clamp and current-clamp experiments. We assessed the models calibrated to these new optimal designs by comparing them to the models calibrated to some of the commonly used designs in the literature. We showed that optimal designs are not only overall shorter in duration but also able to perform better than many of the existing experiment designs in terms of identifying model parameters and hence model predictive power.

Conclusions: For cardiac cellular electrophysiology, this approach will allow researchers to define their hypothesis of the dynamics of the system and automatically design experimental protocols that will result in theoretically optimal designs.

• Journal Article Type: Article
• Acceptance Date: Jun 22, 2023
• Online Publication Date: Jul 6, 2023
• Publication Date: 2023-10
• Deposit Date: Aug 14, 2023
• Publicly Available Date: Aug 15, 2023
• Journal: Computer Methods and Programs in Biomedicine
• Print ISSN: 0169-2607
• Electronic ISSN: 1872-7565
• Publisher: Elsevier BV
• Peer Reviewed: Peer Reviewed
• Volume: 240
• Article Number: 107690
• DOI: https://doi.org/10.1016/j.cmpb.2023.107690
• Keywords: Optimal experimental design; Mathematical modelling; Model calibration; Electrophysiology; Patch clamp; Action potential
• Public URL: https://nottingham-repository.worktribe.com/output/22726711
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0169260723003553?via%3Dihub