Patient-specific computer simulations can be a powerful tool in clinical applications, helping in diagnostics and the development of new treatments. However, its practical use depends on the ...reliability of the models. The construction of cardiac simulations involves several steps with inherent uncertainties, including model parameters, the generation of personalized geometry and fibre orientation assignment, which are semi-manual processes subject to errors. Thus, it is important to quantify how these uncertainties impact model predictions. The present work performs uncertainty quantification and sensitivity analyses to assess the variability in important quantities of interest (QoI). Clinical quantities are analysed in terms of overall variability and to identify which parameters are the major contributors. The analyses are performed for simulations of the left ventricle function during the entire cardiac cycle. Uncertainties are incorporated in several model parameters, including regional wall thickness, fibre orientation, passive material parameters, active stress and the circulatory model. The results show that the QoI are very sensitive to active stress, wall thickness and fibre direction, where ejection fraction and ventricular torsion are the most impacted outputs. Thus, to improve the precision of models of cardiac mechanics, new methods should be considered to decrease uncertainties associated with geometrical reconstruction, estimation of active stress and of fibre orientation.
This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
Modelling of cardiac electrical behaviour has led to important mechanistic insights, but important challenges, including uncertainty in model formulations and parameter values, make it difficult to ...obtain quantitatively accurate results. An alternative approach is combining models with observations from experiments to produce a data-informed reconstruction of system states over time. Here, we extend our earlier data-assimilation studies using an ensemble Kalman filter to reconstruct a three-dimensional time series of states with complex spatio-temporal dynamics using only surface observations of voltage. We consider the effects of several algorithmic and model parameters on the accuracy of reconstructions of known scroll-wave truth states using synthetic observations. In particular, we study the algorithm’s sensitivity to parameters governing different parts of the process and its robustness to several model-error conditions. We find that the algorithm can achieve an acceptable level of error in many cases, with the weakest performance occurring for model-error cases and more extreme parameter regimes with more complex dynamics. Analysis of the poorest-performing cases indicates an initial decrease in error followed by an increase when the ensemble spread is reduced. Our results suggest avenues for further improvement through increasing ensemble spread by incorporating additive inflation or using a parameter or multi-model ensemble.
This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
An audit of uncertainty in multi-scale cardiac electrophysiology models Clayton, Richard H.; Aboelkassem, Yasser; Cantwell, Chris D. ...
Philosophical transactions of the Royal Society of London. Series A: Mathematical, physical, and engineering sciences,
06/2020, Volume:
378, Issue:
2173
Journal Article
Peer reviewed
Models of electrical activation and recovery in cardiac cells and tissue have become valuable research tools, and are beginning to be used in safety-critical applications including guidance for ...clinical procedures and for drug safety assessment. As a consequence, there is an urgent need for a more detailed and quantitative understanding of the ways that uncertainty and variability influence model predictions. In this paper, we review the sources of uncertainty in these models at different spatial scales, discuss how uncertainties are communicated across scales, and begin to assess their relative importance. We conclude by highlighting important challenges that continue to face the cardiac modelling community, identifying open questions, and making recommendations for future studies.
This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
Uncertainty quantification (UQ) is a vital step in using mathematical models and simulations to take decisions. The field of cardiac simulation has begun to explore and adopt UQ methods to ...characterize uncertainty in model inputs and how that propagates through to outputs or predictions; examples of this can be seen in the papers of this issue. In this review and perspective piece, we draw attention to an important and under-addressed source of uncertainty in our predictions—that of uncertainty in the model structure or the equations themselves. The difference between imperfect models and reality is termed model discrepancy, and we are often uncertain as to the size and consequences of this discrepancy. Here, we provide two examples of the consequences of discrepancy when calibrating models at the ion channel and action potential scales. Furthermore, we attempt to account for this discrepancy when calibrating and validating an ion channel model using different methods, based on modelling the discrepancy using Gaussian processes and autoregressive-moving-average models, then highlight the advantages and shortcomings of each approach. Finally, suggestions and lines of enquiry for future work are provided.
This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
Here, we present a novel network model of the pulmonary arterial adventitial fibroblast (PAAF) that represents seven signalling pathways, confirmed to be important in pulmonary arterial fibrosis, as ...92 reactions and 64 state variables. Without optimizing parameters, the model correctly predicted 80% of 39 results of input–output and inhibition experiments reported in 20 independent papers not used to formulate the original network. Parameter uncertainty quantification (UQ) showed that this measure of model accuracy is robust to changes in input weights and half-maximal activation levels (EC50), but is more affected by uncertainty in the Hill coefficient (n), which governs the biochemical cooperativity or steepness of the sigmoidal activation function of each state variable. Epistemic uncertainty in model structure, due to the reliance of some network components and interactions on experiments using non-PAAF cell types, suggested that this source of uncertainty had a smaller impact on model accuracy than the alternative of reducing the network to only those interactions reported in PAAFs. UQ highlighted model parameters that can be optimized to improve prediction accuracy and network modules where there is the greatest need for new experiments.
This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
Computer models of left ventricular (LV) electro-mechanics (EM) show promise as a tool for assessing the impact of increased afterload upon LV performance. However, the identification of unique ...afterload model parameters and the personalization of EM LV models remains challenging due to significant clinical input uncertainties. Here, we personalized a virtual cohort of N = 17 EM LV models under pressure overload conditions. A global–local optimizer was developed to uniquely identify parameters of a three-element Windkessel (Wk3) afterload model. The sensitivity of Wk3 parameters to input uncertainty and of the EM LV model to Wk3 parameter uncertainty was analysed. The optimizer uniquely identified Wk3 parameters, and outputs of the personalized EM LV models showed close agreement with clinical data in all cases. Sensitivity analysis revealed a strong dependence of Wk3 parameters on input uncertainty. However, this had limited impact on outputs of EM LV models. A unique identification of Wk3 parameters from clinical data appears feasible, but it is sensitive to input uncertainty, thus depending on accurate invasive measurements. By contrast, the EM LV model outputs were less sensitive, with errors of less than 8.14% for input data errors of 10%, which is within the bounds of clinical data uncertainty.
This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
Creation and application of virtual patient cohorts of heart models Niederer, S. A.; Aboelkassem, Y.; Cantwell, C. D. ...
Philosophical transactions of the Royal Society of London. Series A: Mathematical, physical, and engineering sciences,
06/2020, Volume:
378, Issue:
2173
Journal Article
Peer reviewed
Patient-specific cardiac models are now being used to guide therapies. The increased use of patient-specific cardiac simulations in clinical care will give rise to the development of virtual cohorts ...of cardiac models. These cohorts will allow cardiac simulations to capture and quantify inter-patient variability. However, the development of virtual cohorts of cardiac models will require the transformation of cardiac modelling from small numbers of bespoke models to robust and rapid workflows that can create large numbers of models. In this review, we describe the state of the art in virtual cohorts of cardiac models, the process of creating virtual cohorts of cardiac models, and how to generate the individual cohort member models, followed by a discussion of the potential and future applications of virtual cohorts of cardiac models.
This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease, clinically characterized by life-threatening ventricular arrhythmias and progressive cardiac dysfunction. Patient-specific ...computational models could help understand the disease progression and may help in clinical decision-making. We propose an inverse modelling approach using the CircAdapt model to estimate patient-specific regional abnormalities in tissue properties in AC subjects. However, the number of parameters (n = 110) and their complex interactions make personalized parameter estimation challenging. The goal of this study is to develop a framework for parameter reduction and estimation combining Morris screening, quasi-Monte Carlo (qMC) simulations and particle swarm optimization (PSO). This framework identifies the best subset of tissue properties based on clinical measurements allowing patient-specific identification of right ventricular tissue abnormalities. We applied this framework on 15 AC genotype-positive subjects with varying degrees of myocardial disease. Cohort studies have shown that atypical regional right ventricular (RV) deformation patterns reveal an early-stage AC disease. The CircAdapt model of cardiovascular mechanics and haemodynamics has already demonstrated its ability to capture typical deformation patterns of AC subjects. We, therefore, use clinically measured cardiac deformation patterns to estimate model parameters describing myocardial disease substrates underlying these AC-related RV deformation abnormalities. Morris screening reduced the subset to 48 parameters. qMC and PSO further reduced the subset to a final selection of 16 parameters, including regional tissue contractility, passive stiffness, activation delay and wall reference area.
This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
Ischaemia, in which inadequate blood supply compromises and eventually kills regions of cardiac tissue, can cause many types of arrhythmia, some life-threatening. A significant component of this is ...the effects of the resulting hypoxia, and concomitant hyperklaemia and acidosis, on the electrophysiological properties of myocytes. Clinical and experimental data have also shown that regions of structural heterogeneity (fibrosis, necrosis, fibro-fatty infiltration) can act as triggers for arrhythmias under acute ischaemic conditions. Mechanistic models have successfully captured these effects in silico. However, the relative significance of these separate facets of the condition, and how sensitive arrhythmic risk is to the extents of each, is far less explored. In this work, we use partitioned Gaussian process emulation and new metrics for source-sink mismatch that rely on simulations of bifurcating cardiac fibresto interrogate a model of heterogeneous ischaemic tissue. Re-entries were most sensitive to the level of hypoxia and the fraction of non-excitable tissue. In addition, our results reveal both protective and pro-arrhythmic effects of hyperklaemia, and present the levels of hyperklaemia, hypoxia and percentage of non-excitable tissue that pose the highest arrhythmic risks.
This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
The paper proposes a mathematical framework for the use of fractional-order impedance models to capture fluid mechanics properties in frequencydomain experimental datasets. An overview of non- ...Newtonian (NN) fluid classification is given as to motivate the use of fractional-order models as natural solutions to capture fluid dynamics. Four classes of fluids are tested: oil, sugar, detergent and liquid soap. Three nonlinear identification methods are used to fit the model: nonlinear least squares, genetic algorithms and particle swarm optimization. The model identification results obtained from experimental datasets suggest the proposed model is useful to characterize various degree of viscoelasticity in NN fluids. The advantage of the proposed model is that it is compact, while capturing the fluid properties and can be identified in real-time for further use in prediction or control applications.
This article is part of the theme issue ‘Advanced materials modelling via fractional calculus: challenges and perspectives’.
