title: Variability in cardiac electrophysiology: Using experimentally-calibrated populations of models to move beyond the single virtual physiological human paradigm.
abstract: Physiological variability manifests itself via differences in physiological function between individuals of the same species, and has crucial implications in disease progression and treatment. Despite its importance, physiological variability has traditionally been ignored in experimental and computational investigations due to averaging over samples from multiple individuals. Recently, modelling frameworks have been devised for studying mechanisms underlying physiological variability in cardiac electrophysiology and pro-arrhythmic risk under a variety of conditions and for several animal species as well as human. One such methodology exploits populations of cardiac cell models constrained with experimental data, or experimentally-calibrated populations of models. In this review, we outline the considerations behind constructing an experimentally-calibrated population of models and review the studies that have employed this approach to investigate variability in cardiac electrophysiology in physiological and pathological conditions, as well as under drug action. We also describe the methodology and compare it with alternative approaches for studying variability in cardiac electrophysiology, including cell-specific modelling approaches, sensitivity-analysis based methods, and populations-of-models frameworks that do not consider the experimental calibration step. We conclude with an outlook for the future, predicting the potential of new methodologies for patient-specific modelling extending beyond the single virtual physiological human paradigm.
authors.affiliation: Department of Computer Science, University of Oxford, Parks Road, Oxford OX1 3QD, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Muszkiewicz
authors.affiliation: Department of Computer Science, University of Oxford, Parks Road, Oxford OX1 3QD, United Kingdom.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Britton
authors.affiliation: Clyde Biosciences Ltd, West Medical Building, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Gemmell
authors.affiliation: Department of Computer Science, University of Oxford, Parks Road, Oxford OX1 3QD, United Kingdom.
authors.forename: Elisa
authors.initials: E
authors.lastname: Passini
authors.affiliation: Center for Computational Medicine in Cardiology (CCMC), Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sánchez
authors.affiliation: Department of Computer Science, University of Oxford, Parks Road, Oxford OX1 3QD, United Kingdom.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Medical Humanities, University of Sheffield, United Kingdom.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Carusi
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: T Alexander
authors.initials: TA
authors.lastname: Quinn
authors.affiliation: Department of Computer Science, University of Oxford, Parks Road, Oxford OX1 3QD, United Kingdom; Mathematical Sciences, Queensland University of Technology, Queensland 4072, Australia; ACEMS, ARC Centre of Excellence for Mathematical and Statistical Frontiers, Queensland University of Technology, Queensland 4072, Australia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Burrage
authors.affiliation: Department of Computer Science, University of Oxford, Parks Road, Oxford OX1 3QD, United Kingdom.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bueno-Orovio
authors.affiliation: Department of Computer Science, University of Oxford, Parks Road, Oxford OX1 3QD, United Kingdom. Electronic address: blanca.rodriguez@cs.ox.ac.uk.
authors.forename: Blanca
authors.initials: B
authors.lastname: Rodriguez
mesh_terms: D002138:Calibration; D055724:Electrophysiological Phenomena; D006321:Heart / Q000502:physiology*; D006801:Humans; D008955:Models, Cardiovascular; D014584:User-Computer Interface
keywords: Action potential; Arrhythmias; Cardiac electrophysiology; In silico high-throughput screening; Physiological variability; Populations of models