Bayesian Active Learning for Personalization and Uncertainty Quantification in Cardiac Electrophysiological Model

Cardiacvascular disease is the top death causing disease worldwide. In recent years, high-fidelity personalized models of the heart have shown an increasing capability to supplement clinical cardiology for improved patient-specific diagnosis, prediction, and treatment planning. In addition, they have shown promise to improve scientific understanding of a variety of disease mechanisms. However, model personalization by estimating the patient-specific tissue properties that are in the form of parameters of a physiological model is challenging. This is because tissue properties, in general, cannot be directly measured and they need to be estimated from measurements that are indirectly related to them through a physiological model. Moreover, these unknown tissue properties are heterogeneous and spatially varying throughout the heart volume presenting a difficulty of high-dimensional (HD) estimation from indirect and limited measurement data. The challenge in model personalization, therefore, summarizes to solving an ill-posed inverse problem where the unknown parameters are HD and the forward model is complex with a non-linear and computationally expensive physiological model. In this dissertation, we address the above challenge with following contributions. First, to address the concern of a complex forward model, we propose the surrogate modeling of the complex target function containing the forward model – an objective function in deterministic estimation or a posterior probability density function in probabilistic estimation – by actively selecting a set of training samples and a Bayesian update of the prior over the target function. The efficient and accurate surrogate of the expensive target function obtained in this manner is then utilized to accelerate either deterministic or probabilistic parameter estimation. Next, within the framework of Bayesian active learning we enable active surrogate learning over a HD parameter space with two novel approaches: 1) a multi-scale optimization that can adaptively allocate higher resolution to heterogeneous tissue regions and lower resolution to homogeneous tissue regions; and 2) a generative model from low-dimensional (LD) latent code to HD tissue properties. Both of these approaches are independently developed and tested within a parameter optimization framework. Furthermore, we devise a novel method that utilizes the surrogate pdf learned on an estimated LD parameter space to improve the proposal distribution of Metropolis Hastings for an accelerated sampling of the exact posterior pdf. We evaluate the presented methods on estimating local tissue excitability of a cardiac electrophysiological model in both synthetic data experiments and real data experiments. Results demonstrate that the presented methods are able to improve the accuracy and efficiency in patient-specific model parameter estimation in comparison to the existing approaches used for model personalization

Bayesian inference and prediction in cardiac electrophysiology models with an application to representing variability

Many different techniques have been used for parameter estimation in cardiac electrophysiology models, from optimization algorithms to heuristic and frequentist statistical methods. However, the fixed parameter values obtained from such approaches cannot provide a complete description of variability within an individual or across a population. To overcome this shortcoming, in this work we adopt a Bayesian approach by applying the Hamiltonian Monte Carlo (HMC) algorithm to cardiac electrophysiology models and data for the first time through three studies. (i) Using HMC, we fit synthetic and experimental cardiac voltage data from different pacing rates and find the probability distributions of the parameters of two relatively low-dimensional models, the Mitchell-Schaeffer (MS) and Fenton-Karma (FK) models. We successfully fit synthetic and experimental voltage traces and build populations of action potentials with the posterior probability distributions of the parameters. (ii) We compare the performance of HMC with that of the main Bayesian approach used previously for similar applications, the Approximate Bayesian Computation Sequential Monte Carlo (ABC SMC) algorithm. Both techniques are able to describe the dynamics of synthetic and experimental voltage data using the MS and FK models, with HMC more consistent and ABC SMC more versatile and easier to implement. (iii) We study the variability of cardiac action potentials in space within an individual. We use HMC and a novel approach employing a Gaussian process prior for one spatially varying MS model parameter along with a hierarchical model for the remaining parameters, considered spatially invariant. Using this approach, we do inference and prediction on synthetic cardiac voltage data, exploiting the spatial correlations in cardiac tissue that arise from cellular coupling to use voltage information from a small number of sites to predict parameter value distributions and families of voltage data in other locations. Together these three studies show the potential of Bayesian inference and prediction in providing a framework to represent variability within cardiac electrophysiology modeling

Identification of weakly coupled multiphysics problems. Application to the inverse problem of electrocardiography

This work addresses the inverse problem of electrocardiography from a new perspective, by combining electrical and mechanical measurements. Our strategy relies on the defini-tion of a model of the electromechanical contraction which is registered on ECG data but also on measured mechanical displacements of the heart tissue typically extracted from medical images. In this respect, we establish in this work the convergence of a sequential estimator which combines for such coupled problems various state of the art sequential data assimilation methods in a unified consistent and efficient framework. Indeed we ag-gregate a Luenberger observer for the mechanical state and a Reduced Order Unscented Kalman Filter applied on the parameters to be identified and a POD projection of the electrical state. Then using synthetic data we show the benefits of our approach for the estimation of the electrical state of the ventricles along the heart beat compared with more classical strategies which only consider an electrophysiological model with ECG measurements. Our numerical results actually show that the mechanical measurements improve the identifiability of the electrical problem allowing to reconstruct the electrical state of the coupled system more precisely. Therefore, this work is intended to be a first proof of concept, with theoretical justifications and numerical investigations, of the ad-vantage of using available multi-modal observations for the estimation and identification of an electromechanical model of the heart

Data-driven modelling of biological multi-scale processes

Biological processes involve a variety of spatial and temporal scales. A holistic understanding of many biological processes therefore requires multi-scale models which capture the relevant properties on all these scales. In this manuscript we review mathematical modelling approaches used to describe the individual spatial scales and how they are integrated into holistic models. We discuss the relation between spatial and temporal scales and the implication of that on multi-scale modelling. Based upon this overview over state-of-the-art modelling approaches, we formulate key challenges in mathematical and computational modelling of biological multi-scale and multi-physics processes. In particular, we considered the availability of analysis tools for multi-scale models and model-based multi-scale data integration. We provide a compact review of methods for model-based data integration and model-based hypothesis testing. Furthermore, novel approaches and recent trends are discussed, including computation time reduction using reduced order and surrogate models, which contribute to the solution of inference problems. We conclude the manuscript by providing a few ideas for the development of tailored multi-scale inference methods.Comment: This manuscript will appear in the Journal of Coupled Systems and Multiscale Dynamics (American Scientific Publishers

Sparse Bayesian Non-linear Regression for Multiple Onsets Estimation in Non-invasive Cardiac Electrophysiology

Best paper award FIMH 2017, category: ElectrophysiologyInternational audienceIn the scope of modelling cardiac electrophysiology (EP) for understanding pathologies and predicting the response to therapies, patient-specific model parameters need to be estimated. Although per-sonalisation from non-invasive data (body surface potential mapping, BSPM) has been investigated on simple cases mostly with a single pacing site, there is a need for a method able to handle more complex situations such as sinus rhythm with several onsets. In the scope of estimating cardiac activation maps, we propose a sparse Bayesian kernel-based regression (relevance vector machine, RVM) from a large patient-specific simulated database. RVM additionally provides a confidence on the result and an automatic selection of relevant features. With the use of specific BSPM descriptors and a reduced space for the myocardial geometry, we detail this framework on a real case of simultaneous biventricular pacing where both onsets were precisely localised. The obtained results (mean distance to the two ground truth pacing leads is 18.4mm) demonstrate the usefulness of this non-linear approach