title: Hodgkin-Huxley revisited: reparametrization and identifiability analysis of the classic action potential model with approximate Bayesian methods.
abstract: As cardiac cell models become increasingly complex, a correspondingly complex 'genealogy' of inherited parameter values has also emerged. The result has been the loss of a direct link between model parameters and experimental data, limiting both reproducibility and the ability to re-fit to new data. We examine the ability of approximate Bayesian computation (ABC) to infer parameter distributions in the seminal action potential model of Hodgkin and Huxley, for which an immediate and documented connection to experimental results exists. The ability of ABC to produce tight posteriors around the reported values for the gating rates of sodium and potassium ion channels validates the precision of this early work, while the highly variable posteriors around certain voltage dependency parameters suggests that voltage clamp experiments alone are insufficient to constrain the full model. Despite this, Hodgkin and Huxley's estimates are shown to be competitive with those produced by ABC, and the variable behaviour of posterior parametrized models under complex voltage protocols suggests that with additional data the model could be fully constrained. This work will provide the starting point for a full identifiability analysis of commonly used cardiac models, as well as a template for informative, data-driven parametrization of newly proposed models.
authors.affiliation: Department of Computer Science University of Oxford Oxford, UK.
authors.forename: Aidan C
authors.initials: AC
authors.lastname: Daly
authors.affiliation: Department of Computer Science University of Oxford Oxford, UK.
authors.forename: David J
authors.identifier: 0000-0001-8311-3200
authors.initials: DJ
authors.lastname: Gavaghan
authors.affiliation: Department of Statistics University of Oxford Oxford, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Holmes
authors.affiliation: Department of Computer Science University of Oxford Oxford, UK.
authors.forename: Jonathan
authors.identifier: 0000-0001-6009-3542
authors.initials: J
authors.lastname: Cooper
keywords: Hodgkin Huxley; approximate Bayesian computation; cardiac cell modelling; functional curation; identifiability; parameter fitting