Influence of Material Parameter Variability on the Predicted Coronary Artery Biomechanical Environment via Uncertainty Quantification.

Central to the clinical adoption of patient-specific modeling strategies is demonstrating that simulation results are reliable and safe. Indeed, simulation frameworks must be robust to uncertainty in model input(s), and levels of confidence should accompany results. In this study, we applied a coupled uncertainty quantification-finite element (FE) framework to understand the impact of uncertainty in vascular material properties on variability in predicted stresses. Univariate probability distributions were fit to material parameters derived from layer-specific mechanical behavior testing of human coronary tissue. Parameters were assumed to be probabilistically independent, allowing for efficient parameter ensemble sampling. In an idealized coronary artery geometry, a forward FE model for each parameter ensemble was created to predict tissue stresses under physiologic loading. An emulator was constructed within the UncertainSCI software using polynomial chaos techniques, and statistics and sensitivities were directly computed. Results demonstrated that material parameter uncertainty propagates to variability in predicted stresses across the vessel wall, with the largest dispersions in stress within the adventitial layer. Variability in stress was most sensitive to uncertainties in the anisotropic component of the strain energy function. Moreover, unary and binary interactions within the adventitial layer were the main contributors to stress variance, and the leading factor in stress variability was uncertainty in the stress-like material parameter that describes the contribution of the embedded fibers to the overall artery stiffness. Results from a patient-specific coronary model confirmed many of these findings. Collectively, these data highlight the impact of material property variation on uncertainty in predicted artery stresses and present a pipeline to explore and characterize forward model uncertainty in computational biomechanics.

Influence of material parameter variability on the predicted coronary artery biomechanical environment via uncertainty quantification.

Central to the clinical adoption of patient-specific modeling strategies is demonstrating that simulation results are reliable and safe. Indeed, simulation frameworks must be robust to uncertainty in model input(s), and levels of confidence should accompany results. In this study, we applied a coupled uncertainty quantification-finite element (FE) framework to understand the impact of uncertainty in vascular material properties on variability in predicted stresses. Univariate probability distributions were fit to material parameters derived from layer-specific mechanical behavior testing of human coronary tissue. Parameters were assumed to be probabilistically independent, allowing for efficient parameter ensemble sampling. In an idealized coronary artery geometry, a forward FE model for each parameter ensemble was created to predict tissue stresses under physiologic loading. An emulator was constructed within the UncertainSCI software using polynomial chaos techniques, and statistics and sensitivities were directly computed. Results demonstrated that material parameter uncertainty propagates to variability in predicted stresses across the vessel wall, with the largest dispersions in stress within the adventitial layer. Variability in stress was most sensitive to uncertainties in the anisotropic component of the strain energy function. Moreover, unary and binary interactions within the adventitial layer were the main contributors to stress variance, and the leading factor in stress variability was uncertainty in the stress-like material parameter that describes the contribution of the embedded fibers to the overall artery stiffness. Results from a patient-specific coronary model confirmed many of these findings. Collectively, these data highlight the impact of material property variation on uncertainty in predicted artery stresses and present a pipeline to explore and characterize forward model uncertainty in computational biomechanics.

Uncertainty quantification of the effect of cardiac position variability in the inverse problem of electrocardiographic imaging.

Objective.Electrocardiographic imaging (ECGI) is a functional imaging modality that consists of two related problems, the forward problem of reconstructing body surface electrical signals given cardiac bioelectric activity, and the inverse problem of reconstructing cardiac bioelectric activity given measured body surface signals. ECGI relies on a model for how the heart generates bioelectric signals which is subject to variability in inputs. The study of how uncertainty in model inputs affects the model output is known as uncertainty quantification (UQ). This study establishes develops, and characterizes the application of UQ to ECGI.Approach.We establish two formulations for applying UQ to ECGI: a polynomial chaos expansion (PCE) based parametric UQ formulation (PCE-UQ formulation), and a novel UQ-aware inverse formulation which leverages our previously established 'joint-inverse' formulation (UQ joint-inverse formulation). We apply these to evaluate the effect of uncertainty in the heart position on the ECGI solutions across a range of ECGI datasets.Main results.We demonstrated the ability of our UQ-ECGI formulations to characterize the effect of parameter uncertainty on the ECGI inverse problem. We found that while the PCE-UQ inverse solution provided more complex outputs such as sensitivities and standard deviation, the UQ joint-inverse solution provided a more interpretable output in the form of a single ECGI solution. We find that between these two methods we are able to assess a wide range of effects that heart position variability has on the ECGI solution.Significance.This study, for the first time, characterizes in detail the application of UQ to the ECGI inverse problem. We demonstrated how UQ can provide insight into the behavior of ECGI using variability in cardiac position as a test case. This study lays the groundwork for future development of UQ-ECGI studies, as well as future development of ECGI formulations which are robust to input parameter variability.

UncertainSCI: Uncertainty quantification for computational models in biomedicine and bioengineering.

BACKGROUND: Computational biomedical simulations frequently contain parameters that model physical features, material coefficients, and physiological effects, whose values are typically assumed known a priori. Understanding the effect of variability in those assumed values is currently a topic of great interest. A general-purpose software tool that quantifies how variation in these parameters affects model outputs is not broadly available in biomedicine. For this reason, we developed the 'UncertainSCI' uncertainty quantification software suite to facilitate analysis of uncertainty due to parametric variability. METHODS: We developed and distributed a new open-source Python-based software tool, UncertainSCI, which employs advanced parameter sampling techniques to build polynomial chaos (PC) emulators that can be used to predict model outputs for general parameter values. Uncertainty of model outputs is studied by modeling parameters as random variables, and model output statistics and sensitivities are then easily computed from the emulator. Our approaches utilize modern, near-optimal techniques for sampling and PC construction based on weighted Fekete points constructed by subsampling from a suitably randomized candidate set. RESULTS: Concentrating on two test cases-modeling bioelectric potentials in the heart and electric stimulation in the brain-we illustrate the use of UncertainSCI to estimate variability, statistics, and sensitivities associated with multiple parameters in these models. CONCLUSION: UncertainSCI is a powerful yet lightweight tool enabling sophisticated probing of parametric variability and uncertainty in biomedical simulations. Its non-intrusive pipeline allows users to leverage existing software libraries and suites to accurately ascertain parametric uncertainty in a variety of applications.

Uncertainty Quantification of Fiber Orientation and Epicardial Activation.

Predictive models and simulations of cardiac function require accurate representations of anatomy, often to the scale of local myocardial fiber structure. However, acquiring this information in a patient-specific manner is challenging. Moreover, the impact of physiological variability in fiber orientation on simulations of cardiac activation is poorly understood. To explore these effects, we implemented bi-ventricular activation simulations using rule-based fiber algorithms and robust uncertainty quantification techniques to generate detailed maps of model variability. Specifically, we utilized polynomial chaos expansion, enabling efficient exploration with reduced computational demand through an emulator function approximating the underlying forward model. Our study focused on examining the epicardial activation sequences of the heart in response to six stimuli locations and five metrics of activation. Our findings revealed that physiological variability in fiber orientation does not significantly affect the location of activation features, but it does impact the overall spread of activation. We observed low variability near the earliest activation sites, but high variability across the rest of the epicardial surface. We conclude that the level of accuracy of myocardial fiber orientation required for simulation depends on the specific goals of the model and the related research or clinical goals.

Uncertainty Quantification of the Effect of Variable Conductivity in Ventricular Fibrotic Regions on Ventricular Tachycardia.

Ventricular tachycardia (VT) is a life-threatening cardiac arrhythmia for which a common treatment pathway is electroanatomical mapping and ablation. Recent advances in both noninvasive ablation techniques and computational modeling have motivated the development of patient-specific computational models of VT. Such models are parameterized by a wide range of inputs, each of which is associated with an often unknown amount of error and uncertainty. Uncertainty quantification (UQ) is a technique to assess how variability in the inputs to a model affects its outputs. UQ has seen increased attention in computational cardiology as an avenue to further improve, understand, and develop patient-specific models. In this study we applied polynomial chaos-based UQ to explore the effect of varying the tissue conductivity of fibrotic border zones in a patient-specific model on the resulting VT simulation. We found that over a range of inputs, the model was most sensitive to fibrotic sheet direction, and uncertainty in fibrotic conductivity resulted in substantial variability in the VT reentry duration and cycle length. Overall, this study paves the way for future UQ applications to improve and understand VT models.

Capturing the Influence of Conduction Velocity on Epicardial Activation Patterns Using Uncertainty Quantification.

Individual variability in parameter settings, due to either user selection or disease states, can impact accuracy when simulating the electrical behavior of the heart. Here, we aim to test the impact of inevitable uncertainty in conduction velocities (CVs) on the output of simulations of cardiac propagation, given three stimulus locations on the left ventricular (LV) free wall. To understand the role of physiological variability in CV in simulations of cardiac activation, we generated detailed maps of the variability in propagation simulations by implementing bi-ventricular activation simulations and quantified the effects by deploying robust uncertainty quantification techniques based on polynomial chaos expansion (PCE). PCE allows efficient stochastic exploration with reduced computational demand by utilizing an emulator for the underlying forward model. Our results suggest that CV within healthy physiological ranges plays a small role in the activation times across all stimulation locations. However, we noticed differences in variation coefficients depending on the stimulation site, i.e., LV endocardium, midmyocardium, and epicardium. We observed low levels of variation in activation times near the earliest activation sites, whereas there was higher variation toward the termination sites. These results suggest that CV variability can play a role when simulating healthy and diseased states.

Uncertainty quantification for ecological models with random parameters.

There is often considerable uncertainty in parameters in ecological models. This uncertainty can be incorporated into models by treating parameters as random variables with distributions, rather than fixed quantities. Recent advances in uncertainty quantification methods, such as polynomial chaos approaches, allow for the analysis of models with random parameters. We introduce these methods with a motivating case study of sea ice algal blooms in heterogeneous environments. We compare Monte Carlo methods with polynomial chaos techniques to help understand the dynamics of an algal bloom model with random parameters. Modelling key parameters in the algal bloom model as random variables changes the timing, intensity and overall productivity of the modelled bloom. The computational efficiency of polynomial chaos methods provides a promising avenue for the broader inclusion of parametric uncertainty in ecological models, leading to improved model predictions and synthesis between models and data.

Effect of Segmentation Uncertainty on the ECGI Inverse Problem Solution and Source Localization.

Electrocardiographic Imaging (ECGI) is a promising tool to non-invasively map the electrical activity of the heart using body surface potentials (BSPs) and the patient specific anatomical data. One of the first steps of ECGI is the segmentation of the heart and torso geometries. In the clinical practice, the segmentation procedure is not fully-automated yet and is in consequence operator-dependent. We expect that the inter-operator variation in cardiac segmentation would influence the ECGI solution. This effect remains however non quantified. In the present work, we study the effect of segmentation variability on the ECGI estimation of the cardiac activity with 262 shape models generated from fifteen different segmentations. Therefore, we designed two test cases: with and without shape model uncertainty. Moreover, we used four cases for ectopic ventricular excitation and compared the ECGI results in terms of reconstructed activation times and excitation origins. The preliminary results indicate that a small variation of the activation maps can be observed with a model uncertainty but no significant effect on the source localization is observed.

The Effect of Segmentation Variability in Forward ECG Simulation.

Segmentation of patient-specific anatomical models is one of the first steps in Electrocardiographic imaging (ECGI). However, the effect of segmentation variability on ECGI remains unexplored. In this study, we assess the effect of heart segmentation variability on ECG simulation. We generated a statistical shape model from segmentations of the same patient and generated 262 cardiac geometries to run in an ECG forward computation of body surface potentials (BSPs) using an equivalent dipole layer cardiac source model and 5 ventricular stimulation protocols. Variability between simulated BSPs for all models and protocols was assessed using Pearson's correlation coefficient (CC). Compared to the BSPs of the mean cardiac shape model, the lowest variability (average CC = 0.98 ± 0.03) was found for apical pacing whereas the highest variability (average CC = 0.90 ± 0.23) was found for right ventricular free wall pacing. Furthermore, low amplitude BSPs show a larger variation in QRS morphology compared to high amplitude signals. The results indicate that the uncertainty in cardiac shape has a significant impact on ECGI.

On the computation of recurrence coefficients for univariate orthogonal polynomials.

Associated to a finite measure on the real line with finite moments are recurrence coefficients in a three-term formula for orthogonal polynomials with respect to this measure. These recurrence coefficients are frequently inputs to modern computational tools that facilitate evaluation and manipulation of polynomials with respect to the measure, and such tasks are foundational in numerical approximation and quadrature. Although the recurrence coefficients for classical measures are known explicitly, those for nonclassical measures must typically be numerically computed. We survey and review existing approaches for computing these recurrence coefficients for univariate orthogonal polynomial families and propose a novel "predictor-corrector" algorithm for a general class of continuous measures. We combine the predictor-corrector scheme with a stabilized Lanczos procedure for a new hybrid algorithm that computes recurrence coefficients for a fairly wide class of measures that can have both continuous and discrete parts. We evaluate the new algorithms against existing methods in terms of accuracy and efficiency.

Uncertainty Quantification in Simulations of Myocardial Ischemia.

Computational models of myocardial ischemia are parameterized using assumptions of tissue properties and physiological values such as conductivity ratios in cardiac tissue and conductivity changes between healthy and ischemic tissues. Understanding the effect of uncertainty in these parameter selections would provide useful insight into the performance and variability of the modeling outputs. Recently developed uncertainty quantification tools allow for the application of polynomial chaos expansion uncertainty quantification to such bioelectric models in order to parsimoniously examine model response to input uncertainty. We applied uncertainty quantification to examine reconstructed extracellular potentials from the cardiac passive bidomain based on variation in the conductivity values for the ischemic tissue. We investigated the model response in both a synthetic dataset with simulated ischemic regions and a dataset with ischemic regions derived from experimental recordings. We found that extracellular longitudinal and intracellular longitudinal conductivities predominately affected simulation output, with the highest standard deviations in regions of extracellular potential elevations. We found that transverse conductivity had almost no effect on model output.

The Role of Myocardial Fiber Direction in Epicardial Activation Patterns via Uncertainty Quantification.

Fiber structure governs the spread of excitation in the heart; however, little is known about the effects of physiological variability in fiber orientation on epicardial activation. To investigate these effects, we implemented ventricular simulations of activation using rule-based fiber orientations, and robust uncertainty quantification algorithms to capture detailed maps of model sensitivity. Specifically, we implemented polynomial chaos expansion, which allows for robust exploration with reduced computational demand through an emulator function to approximate the underlying forward model. We applied these techniques to examine the activation sequence of the heart in response to both epicardial and endocardial stimuli within the left ventricular free wall and variations in fiber orientation. Our results showed that physiological variation in fiber orientation does not significantly impact the location of activation features, but it does impact the overall spread of activation. Future studies will investigate under which circumstances physiological changes in fiber orientation might alter electrical propagation such that the resulting simulations produce misleading outcomes.

Uncertainty Quantification of the Effects of Segmentation Variability in ECGI.

Despite advances in many of the techniques used in Electrocardiographic Imaging (ECGI), uncertainty remains insufficiently quantified for many aspects of the pipeline. The effect of geometric uncertainty, particularly due to segmentation variability, may be the least explored to date. We use statistical shape modeling and uncertainty quantification (UQ) to compute the effect of segmentation variability on ECGI solutions. The shape model was made with Shapeworks from nine segmentations of the same patient and incorporated into an ECGI pipeline. We computed uncertainty of the pericardial potentials and local activation times (LATs) using polynomial chaos expansion (PCE) implemented in UncertainSCI. Uncertainty in pericardial potentials from segmentation variation mirrored areas of high variability in the shape model, near the base of the heart and the right ventricular outflow tract, and that ECGI was less sensitive to uncertainty in the posterior region of the heart. Subsequently LAT calculations could vary dramatically due to segmentation variability, with a standard deviation as high as 126ms, yet mainly in regions with low conduction velocity. Our shape modeling and UQ pipeline presented possible uncertainty in ECGI due to segmentation variability and can be used by researchers to reduce said uncertainty or mitigate its effects. The demonstrated use of statistical shape modeling and UQ can also be extended to other types of modeling pipelines.

Efficient sampling for polynomial chaos-based uncertainty quantification and sensitivity analysis using weighted approximate Fekete points.

Performing uncertainty quantification (UQ) and sensitivity analysis (SA) is vital when developing a patient-specific physiological model because it can quantify model output uncertainty and estimate the effect of each of the model's input parameters on the mathematical model. By providing this information, UQ and SA act as diagnostic tools to evaluate model fidelity and compare model characteristics with expert knowledge and real world observation. Computational efficiency is an important part of UQ and SA methods and thus optimization is an active area of research. In this work, we investigate a new efficient sampling method for least-squares polynomial approximation, weighted approximate Fekete points (WAFP). We analyze the performance of this method by demonstrating its utility in stochastic analysis of a cardiovascular model that estimates changes in oxyhemoglobin saturation response. Polynomial chaos (PC) expansion using WAFP produced results similar to the more standard Monte Carlo in quantifying uncertainty and identifying the most influential model inputs (including input interactions) when modeling oxyhemoglobin saturation, PC expansion using WAFP was far more efficient. These findings show the usefulness of using WAFP based PC expansion to quantify uncertainty and analyze sensitivity of a oxyhemoglobin dissociation response model. Applying these techniques could help analyze the fidelity of other relevant models in preparation for clinical application.

Using UncertainSCI to Quantify Uncertainty in Cardiac Simulations.

Cardiac simulations have become increasingly accurate at representing physiological processes. However, simulations often fail to capture the impact of parameter uncertainty in predictions. Uncertainty quantification (UQ) is a set of techniques that captures variability in simulation output based on model assumptions. Although many UQ methods exist, practical implementation can be challenging. We created UncertainSCI, a UQ framework that uses polynomial chaos (PC) expansion to model the forward stochastic error in simulations parameterized with random variables. UncertainSCI uses non-intrusive methods that parsimoniously explores parameter space. The result is an efficient, stable, and accurate PC emulator that can be analyzed to compute output statistics. We created a Python API to run UncertainSCI, minimizing user inputs needed to guide the UQ process. We have implemented UncertainSCI to: (1) quantify the sensitivity of computed torso potentials using the boundary element method to uncertainty in the heart position, and (2) quantify the sensitivity of computed torso potentials using the finite element method to uncertainty in the conductivities of biological tissues. With UncertainSCI, it is possible to evaluate the robustness of simulations to parameter uncertainty and establish realistic expectations on the accuracy of the model results and the clinical guidance they can provide.