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This regulatory science tool presents a computer model of a canine action potential model appropriate for comprehensive parameter sensitivity analysis and uncertainty quantification.
Technical Description
Cardiac electrophysiological computational models are comprised of numerous complex non-linear equations that predict the action potential in the heart at one or multiple sites. Cardiac electrophysiological modeling is a mature field which has been integrated with experimental studies to develop and test hypotheses for decades. Such models are highly modular and equations are often reused and/or modified.
This model of the canine action potential is moderately complex with six currents, seven variables, and 36 parameters. This model was constructed by combining Hodgkin-Huxley formulations of the six major currents and all parameters are directly derived from experimental voltage clamp data. This fact allows for comprehensive parameter sensitivity analysis and uncertainty quantification.
The tool is entirely self-contained, although the cardiac model developer or user can modify the equations representing the cell kinetics, stimulation protocol, and numerical solvers to generate the corresponding output for any cardiac model.
Intended Purpose
This canine action potential model is appropriate for comprehensive (e.g, studying the effect of all parameters) parameter sensitivity analysis and uncertainty quantification.
The level of validation required for a model depends on its “context of use” and the consequences of incorrect model predictions; hence further validation is expected to be required for each specific context.
The model may be appropriate for the design and analysis of device function in experimental studies involving dogs. The tool is intended to be used by cardiac model developers and users.
This tool presents a standalone model (no user input required) for simulating the canine action potential in single cardiac cells and tissue.
Relevant FDA guidance documents and FDA-recognized standards include:
- FDA guidance “Reporting of Computational Modeling Studies in Medical Device Submissions”
- FDA draft guidance “Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions”
- ASME V&V40-2018, “Assessing Credibility of Computational Modeling through Verification and Validation: Application to Medical DevicesExternal Link Disclaimer”
Testing
Model calibration and validation is described in detail in the manuscripts listed below. Briefly, the model was derived from voltage clamp experimental data from canine ventricular myocytes/tissue under nearly identical and physiological conditions. The model was calibrated to both action potential duration restitution and conduction speed. The design of the model allows for comprehensive parameter sensitivity analysis and uncertainty quantification.
More details are provided in the following two manuscripts:
Pathmanathan P, Cordeiro JM, Gray RA. Comprehensive uncertainty quantification and sensitivity analysis for cardiac action potential models. Frontiers in Physiology, Frontiers in Physiology, 2019: doi.org/10.3389/fphys.2019.00721.
Pathmanathan P, Galappaththige S, Cordeiro JM, Kaboudian A, Fenton FH, Gray RA. Data-driven uncertainty quantification for cardiac electrophysiological models: impact of physiological variability on action potential and spiral wave dynamics. Frontiers in Physiology, Frontiers in Physiology, 2020, doi.org /10.3389/fphys.2020.585400
The level of validation required for a model depends on its “context of use” and the consequences of incorrect model predictions; hence further validation is expected to be required for each specific context.
Limitations
- The model assumes that intra- and extracellular concentrations of ions are constant.
- The equations are of Hodgkin-Huxley type, Markov models are required to replicate certain features of voltage clamp experiments including drug binding kinetics.
Supporting Documentation
The model is implemented in CellMLhttps://www.cellml.org/External Link Disclaimer. The CellML language is an open standard based on the XML markup language. CellML is being developed by the Auckland Bioengineering Institute at the University of Auckland and affiliated research groups.
These models are very similar, but the parameter values are slightly different. The specifics of these differences are described in the two manuscripts.
The files are available for download from GitHubExternal Link Disclaimer.
The code itself is provided in two files:
- PathmanathanGrayCanine2019.cellmlExternal Link Disclaimer
- PathmanathanGrayCanine2020mean.cellmlExternal Link Disclaimer
Pathmanathan P, Cordeiro JM, Gray RA. Comprehensive uncertainty quantification and sensitivity analysis for cardiac action potential models. Frontiers in Physiology, Frontiers in Physiology, 2019: doi.org/10.3389/fphys.2019.00721.
Related Tools:
- Parsimonious Cardiac Action Potential Model of the Rabbit
- Identifiability of Cardiac Electrophysiology Models