title: Uncertainty quantification of fast sodium current steady-state inactivation for multi-scale models of cardiac electrophysiology.
abstract: Perhaps the most mature area of multi-scale systems biology is the modelling of the heart. Current models are grounded in over fifty years of research in the development of biophysically detailed models of the electrophysiology (EP) of cardiac cells, but one aspect which is inadequately addressed is the incorporation of uncertainty and physiological variability. Uncertainty quantification (UQ) is the identification and characterisation of the uncertainty in model parameters derived from experimental data, and the computation of the resultant uncertainty in model outputs. It is a necessary tool for establishing the credibility of computational models, and will likely be expected of EP models for future safety-critical clinical applications. The focus of this paper is formal UQ of one major sub-component of cardiac EP models, the steady-state inactivation of the fast sodium current, INa. To better capture average behaviour and quantify variability across cells, we have applied for the first time an 'individual-based' statistical methodology to assess voltage clamp data. Advantages of this approach over a more traditional 'population-averaged' approach are highlighted. The method was used to characterise variability amongst cells isolated from canine epi and endocardium, and this variability was then 'propagated forward' through a canine model to determine the resultant uncertainty in model predictions at different scales, such as of upstroke velocity and spiral wave dynamics. Statistically significant differences between epi and endocardial cells (greater half-inactivation and less steep slope of steady state inactivation curve for endo) was observed, and the forward propagation revealed a lack of robustness of the model to underlying variability, but also surprising robustness to variability at the tissue scale. Overall, the methodology can be used to: (i) better analyse voltage clamp data; (ii) characterise underlying population variability; (iii) investigate consequences of variability; and (iv) improve the ability to validate a model. To our knowledge this article is the first to quantify population variability in membrane dynamics in this manner, and the first to perform formal UQ for a component of a cardiac model. The approach is likely to find much wider applicability across systems biology as current application domains reach greater levels of maturity.
authors: U.S. Food and Drug Administration, 10903 New Hampshire Avenue (WO 62), Silver Spring, MD 20993, USA. Electronic address: pras.pathmanathan@fda.hhs.gov.
authors: Pras
authors: P
authors: Pathmanathan
authors: Department of Biostatistics, Vanderbilt University Medical Center, 2525 West End, Ste. 11000, Nashville, TN 37203, USA. Electronic address: matt.shotwell@vanderbilt.edu.
authors: Matthew S
authors: MS
authors: Shotwell
authors: Department of Computer Science, University of Oxford, Parks Road, Oxford OX1 3QD, UK. Electronic address: gavaghan@cs.ox.ac.uk.
authors: David J
authors: DJ
authors: Gavaghan
authors: Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 1350, USA. Electronic address: jcordeiro@mmrl.edu.
authors: Jonathan M
authors: JM
authors: Cordeiro
authors: U.S. Food and Drug Administration, 10903 New Hampshire Avenue (WO 62), Silver Spring, MD 20993, USA. Electronic address: richard.gray@fda.hhs.gov.
authors: Richard A
authors: RA
authors: Gray
mesh_terms: D000818:Animals; D055724:Electrophysiological Phenomena; D006321:Heart / Q000502:physiology*; D008955:Models, Cardiovascular; D009206:Myocardium / Q000166:cytology; D012964:Sodium / Q000378:metabolism*; D035501:Uncertainty
chemical_list: D012964:Sodium
keywords: Cardiac modelling; Nonlinear mixed effects modelling; Population variability; Uncertainty quantification