Biomedical Computing

The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies.

Purpose
Patients routinely undergo ablation for atrial fibrillation (AF) but the recurrence rate remains high. We explored in this study whether poor scar formation as seen on late-gadolinium enhancement magnetic resonance imaging (LGE-MRI) correlates with AF recurrence following ablation.

Methods
We retrospectively identified 94 consecutive patients who underwent their initial ablation for AF at our institution and had pre-procedural magnetic resonance angiography (MRA) merged with left atrial (LA) anatomy in an electroanatomic mapping (EAM) system, ablated areas marked intraprocedurally in EAM, 3-month post-ablation LGE-MRI for assessment of scar, and minimum of 3-months of clinical follow-up. Ablated area was quantified retrospectively in EAM and scarred area was quantified in the 3-month post-ablation LGE-MRI.

Results
With the mean follow-up of 336 days, 26 out of 94 patients had AF recurrence. Age, hypertension, and heart failure were not associated with AF recurrence, but LA size and difference between EAM ablated area and LGE-MRI scar area was associated with higher AF recurrence. For each percent higher difference between EAM ablated area and LGE-MRI scar area, there was a 7–9 % higher AF recurrence (p values 0.001–0.003) depending on the multivariate analysis.

Conclusions
In AF ablation, poor scar formation as seen on LGE-MRI was associated with AF recurrence. Improved mapping and ablation techniques are necessary to achieve the desired LA scar and reduce AF recurrence.

Registering and combining anatomical components from different image modalities, like MRI and CT that have different tissue contrast, could result in patient-specific models that more closely represent underlying anatomical structures.

In this study, we combined a pair of CT and MRI scans of a pig thorax to make a tetrahedral mesh and compared different registration techniques including rigid, affine, thin plate spline morphing (TPSM), and iterative closest point (ICP), to  superimpose the segmented bones from the CT scan on the soft tissues segmented from the MRI. The TPSM and affine-registered bones remained close to, but not overlapping, important soft tissue.

Simulation models, including an ECG forward model and a defibrillation model, were computed on generated multi-modality meshes after TPSM and affine registration and compared to those based on the original torso mesh.

In multiatlas segmentation, one typically registers several atlases to the novel image, and their respective segmented label images are transformed and fused to form the final segmentation. In this work, we provide a new dynamical system perspective for multiatlas segmentation, inspired by the following fact: The transformation that aligns the current atlas to the novel image can be not only computed by direct registration but also inferred from the transformation that aligns the previous atlas to the image together with the transformation between the two atlases. This process is similar to the global positioning system on a vehicle, which gets position by inquiring from the satellite and by employing the previous location and velocity—neither answer in isolation being perfect. To solve this problem, a dynamical system scheme is crucial to combine the two pieces of information; for example, a Kalman filtering scheme is used. Accordingly, in this work, a Kalman multiatlas segmentation is proposed to stabilize the global/affine registration step. The contributions of this work are twofold. First, it provides a new dynamical systematic perspective for standard independent multiatlas registrations, and it is solved by Kalman filtering. Second, with very little extra computation, it can be combined with most existing multiatlas segmentation schemes for better registration/segmentation accuracy.

Research has indicated that atrial fibrillation (AF) ablation failure is related to the presence of atrial fibrosis. However it remains unclear whether this information can be successfully used in predicting the optimal ablation targets for AF termination. We aimed to provide a proof-of-concept that patient-specific virtual electrophysiological study that combines i) atrial structure and fibrosis distribution from clinical MRI and ii) modeling of atrial electrophysiology, could be used to predict: (1) how fibrosis distribution determines the locations from which paced beats degrade into AF; (2) the dynamic behavior of persistent AF rotors; and (3) the optimal ablation targets in each patient. Four MRI-based patient-specific models of fibrotic left atria were generated, ranging in fibrosis amount. Virtual electrophysiological studies were performed in these models, and where AF was inducible, the dynamics of AF were used to determine the ablation locations that render AF non-inducible. In 2 of the 4 models patient-specific models AF was induced; in these models the distance between a given pacing location and the closest fibrotic region determined whether AF was inducible from that particular location, with only the mid-range distances resulting in arrhythmia. Phase singularities of persistent rotors were found to move within restricted regions of tissue, which were independent of the pacing location from which AF was induced. Electrophysiological sensitivity analysis demonstrated that these regions changed little with variations in electrophysiological parameters. Patient-specific distribution of fibrosis was thus found to be a critical component of AF initiation and maintenance. When the restricted regions encompassing the meander of the persistent phase singularities were modeled as ablation lesions, AF could no longer be induced. The study demonstrates that a patient-specific modeling approach to identify non-invasively AF ablation targets prior to the clinical procedure is feasible.

Introduction
The "Experimental Data and Geometric Analysis Repository", or EDGAR is an Internet-based archive of curated data that are freely distributed to the international research community for the application and validation of electrocardiographic imaging (ECGI) techniques. The EDGAR project is a collaborative effort by the Consortium for ECG Imaging (CEI, ecg-imaging.org), and focused on two specific aims. One aim is to host an online repository that provides access to a wide spectrum of data, and the second aim is to provide a standard information format for the exchange of these diverse datasets.

Methods
The EDGAR system is composed of two interrelated components: 1) a metadata model, which includes a set of descriptive parameters and information, time signals from both the cardiac source and body-surface, and extensive geometric information, including images, geometric models, and measure locations used during the data acquisition/generation; and 2) a web interface. This web interface provides efficient, search, browsing, and retrieval of data from the repository.

Results
An aggregation of experimental, clinical and simulation data from various centers is being made available through the EDGAR project including experimental data from animal studies provided by the University of Utah (USA), clinical data from multiple human subjects provided by the Charles University Hospital (Czech Republic), and computer simulation data provided by the Karlsruhe Institute of Technology (Germany).

Conclusions
It is our hope that EDGAR will serve as a communal forum for sharing and distribution of cardiac electrophysiology data and geometric models for use in ECGI research.

Quantification and visualization of uncertainty in cardiac forward and inverse problems with complex geometries is subject to various challenges. Specific to visualization is the observation that occlusion and clutter obscure important regions of interest, making visual assessment difficult. In order to overcome these limitations in uncertainty visualization, we have developed and implemented a collection of novel approaches. To highlight the utility of these techniques, we evaluated the uncertainty associated with two examples of modeling myocardial activity. In one case we studied cardiac potentials during the repolarization phase as a function of variability in tissue conductivities of the ischemic heart (forward case). In a second case, we evaluated uncertainty in reconstructed activation times on the epicardium resulting from variation in the control parameter of Tikhonov regularization (inverse case). To overcome difficulties associated with uncertainty visualization, we implemented linked-view windows and interactive animation to the two respective cases. Through dimensionality reduction and superimposed mean and standard deviation measures over time, we were able to display key features in large ensembles of data and highlight regions of interest where larger uncertainties exist.

To search for evolutionary forces that might act upon transcript length, we use the singular value decomposition (SVD) to identify the length distribution functions of sets and subsets of human and yeast transcripts from profiles of mRNA abundance levels across gel electrophoresis migration distances that were previously measured by DNA microarrays. We show that the SVD identifies the transcript length distribution functions as “asymmetric generalized coherent states” from the DNA microarray data and with no a-priori assumptions. Comparing subsets of human and yeast transcripts of the same gene ontology annotations, we find that in both disparate eukaryotes, transcripts involved in protein synthesis or mitochondrial metabolism are significantly shorter than typical, and in particular, significantly shorter than those involved in glucose metabolism. Comparing the subsets of human transcripts that are overexpressed in glioblastoma multiforme (GBM) or normal brain tissue samples from The Cancer Genome Atlas, we find that GBM maintains normal brain overexpression of significantly short transcripts, enriched in transcripts that are involved in protein synthesis or mitochondrial metabolism, but suppresses normal overexpression of significantly longer transcripts, enriched in transcripts that are involved in glucose metabolism and brain activity. These global relations among transcript length, cellular metabolism and tumor development suggest a previously unrecognized physical mode for tumor and normal cells to differentially regulate metabolism in a transcript length-dependent manner. The identified distribution functions support a previous hypothesis from mathematical modeling of evolutionary forces that act upon transcript length in the manner of the restoring force of the harmonic oscillator.

We propose a novel difference metric, called the graph diffusion distance (GDD), for quantifying the difference between two weighted graphs with the same number of vertices. Our approach is based on measuring the average similarity of heat diffusion on each graph. We compute the graph Laplacian exponential kernel matrices, corresponding to repeatedly solving the heat diffusion problem with initial conditions localized to single vertices. The GDD is then given by the Frobenius norm of the difference of the kernels, at the diffusion time yielding the maximum difference. We study properties of the proposed distance on both synthetic examples, and on real-data graphs representing human anatomical brain connectivity.

With the goal of non-invasively localizing cardiac ischemic disease using bodysurface potential recordings, we attempted to reconstruct the transmembrane potential (TMP) throughout the myocardium with the bidomain heart model. The task is an inverse source problem governed by partial differential equations (PDE). Our main contribution is solving the inverse problem within a PDE-constrained optimization framework that enables various physically-based constraints in both equality and inequality forms. We formulated the optimality conditions rigorously in the continuum before deriving finite element discretization, thereby making the optimization independent of discretization choice. Such a formulation was derived for the L2-norm Tikhonov regularization and the total variation minimization. The subsequent numerical optimization was fulfilled by a primal-dual interior-point method tailored to our problem's specific structure. Our simulations used realistic, fiberincluded heart models consisting of up to 18,000 nodes, much finer than any inverse models previously reported. With synthetic ischemia data we localized ischemic regions with roughly a 10% false-negative rate or a 20% false-positive rate under conditions up to 5% input noise. With ischemia data measured from animal experiments, we reconstructed TMPs with roughly 0.9 correlation with the ground truth. While precisely estimating the TMP in general cases remains an open problem, our study shows the feasibility of reconstructing TMP during the ST interval as a means of ischemia localization.

Keywords: cvrti, 2P41 GM103545-14

We have created the Myocardial Uncertainty Viewer (muView) tool for exploring data stemming from the forward simulation of cardiac ischemia. The simulation uses a collection of conductivity values to understand how ischemic regions effect the undamaged anisotropic heart tissue. The data resulting from the simulation is multivalued and volumetric and thus, for every data point, we have a collection of samples describing cardiac electrical properties. muView combines a suite of visual analysis methods to explore the area surrounding the ischemic zone and identify how perturbations of variables changes the propagation of their effects.

Despite recent large-scale profiling efforts, the best prognostic predictor of glioblastoma multiforme (GBM) remains the patient's age at diagnosis. We describe a global pattern of tumor-exclusive co-occurring copy-number alterations (CNAs) that is correlated, possibly coordinated with GBM patients' survival and response to chemotherapy. The pattern is revealed by GSVD comparison of patient-matched but probe-independent GBM and normal aCGH datasets from The Cancer Genome Atlas (TCGA). We find that, first, the GSVD, formulated as a framework for comparatively modeling two composite datasets, removes from the pattern copy-number variations (CNVs) that occur in the normal human genome (e.g., female-specific X chromosome amplification) and experimental variations (e.g., in tissue batch, genomic center, hybridization date and scanner), without a-priori knowledge of these variations. Second, the pattern includes most known GBM-associated changes in chromosome numbers and focal CNAs, as well as several previously unreported CNAs in greater than 3\% of the patients. These include the biochemically putative drug target, cell cycle-regulated serine/threonine kinase-encoding TLK2, the cyclin E1-encoding CCNE1, and the Rb-binding histone demethylase-encoding KDM5A. Third, the pattern provides a better prognostic predictor than the chromosome numbers or any one focal CNA that it identifies, suggesting that the GBM survival phenotype is an outcome of its global genotype. The pattern is independent of age, and combined with age, makes a better predictor than age alone. GSVD comparison of matched profiles of a larger set of TCGA patients, inclusive of the initial set, confirms the global pattern. GSVD classification of the GBM profiles of an independent set of patients validates the prognostic contribution of the pattern.

By combining a static bidomain heart model with a torso conduction model, we studied the inverse electrocardiographic problem of computing the transmembrane potentials (TMPs) throughout the myocardium from a body-surface potential map, and then used the recovered potentials to localize myocardial ischemia. Our main contribution is solving the inverse problem within a constrained optimization framework, which is a generalization of previous methods for calculating transmembrane potentials. The framework offers ample flexibility for users to apply various physiologically-based constraints, and is well supported by mature algorithms and solvers developed by the optimization community. By avoiding the traditional inverse ECG approach of building the lead-field matrix, the framework greatly reduces computation cost and, by setting the associated forward problem as a constraint, the framework enables one to flexibly set individualized resolutions for each physical variable, a desirable feature for balancing model accuracy, ill-conditioning and computation tractability. Although the task of computing myocardial TMPs at an arbitrary time instance remains an open problem, we showed that it is possible to obtain TMPs with moderate accuracy during the ST segment by assuming all cardiac cells are at the plateau phase. Moreover, the calculated TMPs yielded a good estimate of ischemic regions, which was of more clinical interest than the voltage values themselves. We conducted finite element simulations of a phantom experiment over a 2D torso model with synthetic ischemic data. Preliminary results indicated that our approach is feasible and suitably accurate for the common case of transmural myocardial ischemia.

We present a sensitivity analysis of the optimization of the probe placement in radiofrequency (RF) ablation which takes the uncertainty associated with bio-physical tissue properties (electrical and thermal conductivity) into account. Our forward simulation of RF ablation is based upon a system of partial differential equations (PDEs) that describe the electric potential of the probe and the steady state of the induced heat. The probe placement is optimized by minimizing a temperature-based objective function such that the volume of destroyed tumor tissue is maximized. The resulting optimality system is solved with a multi-level gradient descent approach. By evaluating the corresponding optimality system for certain realizations of tissue parameters (i.e. at certain, well-chosen points in the stochastic space) the sensitivity of the system can be analyzed with respect to variations in the tissue parameters. For the interpolation in the stochastic space we use a stochastic finite element approach with piecewise multilinear ansatz functions on adaptively refined, hierarchical grids. We underscore the significance of the approach by applying the optimization to CT data obtained from a real RF ablation case.

Keywords: netl, stochastic sensitivity analysis, stochastic partial dierential equations, stochastic nite element method, adaptive sparse grid, heat transfer, multiscale modeling, representation of uncertainty

The electrocardiogram (ECG) is ubiquitously employed as a diagnostic and monitoring tool for patients experiencing cardiac distress and/or disease. It is widely known that changes in heart position resulting from, for example, posture of the patient (sitting, standing, lying) and respiration significantly affect the body-surface potentials; however, few studies have quantitatively and systematically evaluated the effects of heart displacement on the ECG. The goal of this study was to evaluate the impact of positional changes of the heart on the ECG in the specific clinical setting of myocardial ischemia. To carry out the necessary comprehensive sensitivity analysis, we applied a relatively novel and highly efficient statistical approach, the generalized polynomial chaos-stochastic collocation method, to a boundary element formulation of the electrocardiographic forward problem, and we drove these simulations with measured epicardial potentials from whole-heart experiments. Results of the analysis identified regions on the body-surface where the potentials were especially sensitive to realistic heart motion. The standard deviation (STD) of ST-segment voltage changes caused by the apex of a normal heart, swinging forward and backward or side-to-side was approximately 0.2 mV. Variations were even larger, 0.3 mV, for a heart exhibiting elevated ischemic potentials. These variations could be large enough to mask or to mimic signs of ischemia in the ECG. Our results suggest possible modifications to ECG protocols that could reduce the diagnostic error related to postural changes in patients possibly suffering from myocardial ischemia.

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step toward establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.

Keywords: Minimum Information Standard; Cardiac electrophysiology; Data sharing; Reproducibility; Integration; Computational modelling