SCIENTIFIC COMPUTING AND IMAGING INSTITUTE
at the University of Utah

Advances in computational mechanics, constitutive modeling, and techniques for subject-specific modeling have opened the door to patient-specific simulation of the relationships between joint mechanics and osteoarthritis (OA), as well as patient-specific preoperative planning. This article reviews the application of computational biomechanics to the simulation of joint contact mechanics as relevant to the study of OA. This review begins with background regarding OA and the mechanical causes of OA in the context of simulations of joint mechanics. The broad range of technical considerations in creating validated subject-specific whole joint models is discussed. The types of computational models available for the study of joint mechanics are reviewed. The types of constitutive models that are available for articular cartilage are reviewed, with special attention to choosing an appropriate constitutive model for the application at hand. Issues related to model generation are discussed, including acquisition of model geometry from volumetric image data and specific considerations for acquisition of computed tomography and magnetic resonance imaging data. Approaches to model validation are reviewed. The areas of parametric analysis, factorial design, and probabilistic analysis are reviewed in the context of simulations of joint contact mechanics. Following the review of technical considerations, the article details insights that have been obtained from computational models of joint mechanics for normal joints; patient populations; the study of specific aspects of joint mechanics relevant to OA, such as congruency and instability; and preoperative planning. Finally, future directions for research and application are summarized.

Elastin is a structural protein that provides resilience to biological tissues. We examined the contributions of elastin to the quasi-static tensile response of porcine medial collateral ligament through targeted disruption of the elastin network with pancreatic elastase. Elastase concentration and treatment time were varied to determine a dose response. Whereas elastin content decreased with increasing elastase concentration and treatment time, the change in peak stress after cyclic loading reached a plateau above 1 U/ml elastase and 6 h treatment. For specimens treated with 2 U/ml elastase for 6 h, elastin content decreased approximately 35%. Mean peak tissue strain after cyclic loading (4.8%, p ≥ 0.300), modulus (275 MPa, p ≥ 0.114) and hysteresis (20%, p ≥ 0.553) were unaffected by elastase digestion, but stress decreased significantly after treatment (up to 2 MPa, p ≤ 0.049). Elastin degradation had no effect on failure properties, but tissue lengthened under the same pre-stress. Stiffness in the linear region was unaffected by elastase digestion, suggesting that enzyme treatment did not disrupt collagen. These results demonstrate that elastin primarily functions in the toe region of the stress–strain curve, yet contributes load support in the linear region. The increase in length after elastase digestion suggests that elastin may pre-stress and stabilize collagen crimp in ligaments

Background
A contributory factor to hip osteoarthritis (OA) is abnormal cartilage mechanics. Acetabular retroversion, a version deformity of the acetabulum, has been postulated to cause OA via decreased posterior contact area and increased posterior contact stress. Although cartilage mechanics cannot be measured directly in vivo to evaluate the causes of OA, they can be predicted using finite element (FE) modeling.

Objective
The objective of this study was to compare cartilage contact mechanics between hips with normal and retroverted acetabula using subject-specific FE modeling.

Methods
Twenty subjects were recruited and imaged: 10 with normal acetabula and 10 with retroverted acetabula. FE models were constructed using a validated protocol. Walking, stair ascent, stair descent and rising from a chair were simulated. Acetabular cartilage contact stress and contact area were compared between groups.

Results
Retroverted acetabula had superomedial cartilage contact patterns, while normal acetabula had widely distributed cartilage contact patterns. In the posterolateral acetabulum, average contact stress and contact area during walking and stair descent were 2.6–7.6 times larger in normal than retroverted acetabula (P ≤ 0.017). Conversely, in the superomedial acetabulum, peak contact stress during walking was 1.2–1.6 times larger in retroverted than normal acetabula (P ≤ 0.044). Further differences varied by region and activity.

Conclusions
This study demonstrated superomedial contact patterns in retroverted acetabula vs widely distributed contact patterns in normal acetabula. Smaller posterolateral contact stress in retroverted acetabula than in normal acetabula suggests that increased posterior contact stress alone may not be the link between retroversion and OA.

Hip osteoarthritis may be initiated and advanced by abnormal cartilage contact mechanics, and finite element (FE) modeling provides an approach with the potential to allow the study of this process. Previous FE models of the human hip have been limited by single specimen validation and the use of quasi-linear or linear elastic constitutive models of articular cartilage. The effects of the latter assumptions on model predictions are unknown, partially because data for the instantaneous behavior of healthy human hip cartilage are unavailable. The aims of this study were to develop and validate a series of specimen-specific FE models, to characterize the regional instantaneous response of healthy human hip cartilage in compression, and to assess the effects of material nonlinearity, inhomogeneity and specimen-specific material coefficients on FE predictions of cartilage contact stress and contact area. Five cadaveric specimens underwent experimental loading, cartilage material characterization and specimen-specific FE modeling. Cartilage in the FE models was represented by average neo-Hookean, average Veronda Westmann and specimen- and region-specific Veronda Westmann hyperelastic constitutive models. Experimental measurements and FE predictions compared well for all three cartilage representations, which was reflected in average RMS errors in contact stress of less than 25 %. The instantaneous material behavior of healthy human hip cartilage varied spatially, with stiffer acetabular cartilage than femoral cartilage and stiffer cartilage in lateral regions than in medial regions. The Veronda Westmann constitutive model with average material coefficients accurately predicted peak contact stress, average contact stress, contact area and contact patterns. The use of subject- and region-specific material coefficients did not increase the accuracy of FE model predictions. The neo-Hookean constitutive model underpredicted peak contact stress in areas of high stress. The results of this study support the use of average cartilage material coefficients in predictions of cartilage contact stress and contact area in the normal hip. The regional characterization of cartilage material behavior provides the necessary inputs for future computational studies, to investigate other mechanical parameters that may be correlated with OA and cartilage damage in the human hip. In the future, the results of this study can be applied to subject-specific models to better understand how abnormal hip contact stress and contact area contribute to OA.

The AGENT simulation system is used for detailed three-dimensional modeling of neutron transport and corresponding properties of nuclear reactors of any design. Numerical solution to the neutron transport equation in the AGENT system is based on the Method of Characteristics (MOCs) and the theory of R-functions. The latter of which is used for accurately describing current and future heterogeneous lattices of reactor core configurations. The AGENT code has been extensively verified to assure a high degree of accuracy for predicting neutron three-dimensional point-wise flux spatial distributions, power peaking factors, reaction rates, and eigenvalues. In this paper, a new AGENT code feature, a computational steering, is presented. This new feature provides a novel way for using deterministic codes for fast evaluation of reactor core parameters, at no loss to accuracy. The computational steering framework as developed at the Technische Universität München is smoothly integrated into the AGENT solver. This framework allows for an arbitrary interruption of AGENT simulation, allowing the solver to restart with updated parameters. One possible use of this is to accelerate the convergence of the final values resulting in significantly reduced simulation times. Using this computational steering in the AGENT system, coarse MOC resolution parameters can initially be selected and later update them – while the simulation is actively running – into fine resolution parameters. The utility of the steering framework is demonstrated using the geometry of a research reactor at the University of Utah: this new approach provides a savings in CPU time on the order of 50%.

Keywords: Numerical steering, AGENT code, Deterministic neutron transport codes, Method of Characteristics, R-functions, Numerical visualizations

Background: Magnetic resonance imaging (MRI) can visualize locations of both the ablation scar on the left atrium (LA) after atrial fibrillation (AF) ablation and epicardial fat pads (FPs) containing ganglionated plexi (GP).

Methods: We investigated 60 patients who underwent pulmonary vein antrum (PVA) isolation along with LA posterior wall and septal debulking for AF. FPs around the LA surface in well-known GP areas (which were considered as the substitution of GP areas around the LA) were segmented from the dark-blood MRI. Then the FP and the ablation scar image visualized by late gadolinium enhancement (LGE)-MRI on the LA were merged together. Overlapping areas of FP and the ablation scar image were considered as the ablated FP areas containing GP. Patients underwent 24-hour Holter monitoring after ablation for the analysis of heart rate variability.

Results: Ablated FP area was significantly wider in patients without AF recurrence than those in patients with recurrence (5.6 ± 3.1 cm² vs 4.2 ± 2.7 cm² ,P = 0.03). The mean values of both percentage of differences greater than 50 ms in the RR intervals (pRR > 50) and standard deviation of RR intervals over the entire analyzed period (SDNN), which were obtained from 24-hour Holter monitoring 1-day post-AF ablation, were significantly lower in patients without recurrence than those in patients with recurrence (5.8 ± 6.0% vs 14.0 ± 10.1%; P = 0.0005, 78.7 ± 32.4 ms vs 109.2 ± 43.5 ms; P = 0.005). There was a significant negative correlation between SDNN and the percentage of ablated FP area (Y =- 1.3168X + 118.96, R² = 0.1576, P = 0.003).

Conclusion: Extensively ablating LA covering GP areas along with PVA isolation enhanced the denervation of autonomic nerve system and seemed to improve procedural outcome in patients with AF.

Keywords: ganglionated plexi, fat pad, atrial fibrillation, catheter ablation, LGE-MRI

We present a novel integrated visualization system that enables interactive visual analysis of ensemble simulations used in ocean forecasting, i.e, simulations of sea surface elevation. Our system enables the interactive planning of both the placement and operation of off-shore structures. We illustrate this using a real-world simulation of the Gulf of Mexico. Off-shore structures, such as those used for oil exploration, are vulnerable to hazards caused by strong loop currents. The oil and gas industry therefore relies on accurate ocean forecasting systems for planning their operations. Nowadays, these forecasts are based on multiple spatio-temporal simulations resulting in multidimensional, multivariate and multivalued data, so-called ensemble data. Changes in sea surface elevation are a good indicator for the movement of loop current eddies, and our visualization approach enables their interactive exploration and analysis. We enable analysis of the spatial domain, for planning the placement of structures, as well as detailed exploration of the temporal evolution at any chosen position, for the prediction of critical ocean states that require the shutdown of rig operations.

Keywords: Uncertainty, Ensemble Simulation, Risk Estimate

In this paper, we propose a new and accurate technique for uncertainty analysis and uncertainty visualization based on fiber orientation distribution function (ODF) glyphs, associated with high angular resolution diffusion imaging (HARDI). Our visualization applies volume rendering techniques to an ensemble of 3D ODF glyphs, which we call SIP functions of diffusion shapes, to capture their variability due to underlying uncertainty. This rendering elucidates the complex heteroscedastic structural variation in these shapes. Furthermore, we quantify the extent of this variation by measuring the fraction of the volume of these shapes, which is consistent across all noise levels, the certain volume ratio. Our uncertainty analysis and visualization framework is then applied to synthetic data, as well as to HARDI human-brain data, to study the impact of various image acquisition parameters and background noise levels on the diffusion shapes.

We introduce a novel method for utilizing user input to sparsely label membranes in electron microscopy images. Using gridlines as guides, the user marks where the guides cross the membrane to generate a sparsely labeled image. We use a best path algorithm to connect each of the sparse membrane labels. The resulting segmentation has a significantly better Rand error than automatic methods while requiring as little as 2\% of the image to be labeled.

In connectomics, neuroscientists seek to identify the synaptic connections between neurons. Segmentation of cell membranes using supervised learning algorithms on electron microscopy images of brain tissue is often done to assist in this effort. Here we present a partial differential equation with a novel growth term to improve the results of a supervised learning algorithm. We also introduce a new method for representing the resulting image that allows for a more dynamic thresholding to further improve the result. Using these two processes we are able to close small to medium sized gaps in the cell membrane detection and improve the Rand error by as much as 9\% over the initial supervised segmentation.

Individuals with multiple osteochondromas (MO) demonstrate shortened long bones. Ext1 or Ext2 haploinsufficiency cannot recapitulate the phenotype in mice. Loss of heterozygosity for Ext1 may induce shortening by steal of longitudinal growth into osteochondromas or by a general derangement of physeal signaling. We induced osteochondromagenesis at different time points during skeletal growth in a mouse genetic model, then analyzed femora and tibiae at 12 weeks using micro-CT and a point-distribution-based shape analysis. Bone lengths and volumes were compared. Metaphyseal volume deviations from normal, as a measure of phenotypic widening, were tested for correlation with length deviations. Mice with osteochondromas had shorter femora and tibiae than controls, more consistently when osteochondromagenesis was induced earlier during skeletal growth. Volumetric metaphyseal widening did not correlate with longitudinal shortening, although some of the most severe shortening was in bones with abundant osteochondromas. Loss of heterozygosity for Ext1 was sufficient to drive bone shortening in a mouse model of MO, but shortening did not correlate with osteochondroma volumetric growth. While a steal phenomenon seems apparent in individual cases, some other mechanism must also be capable of contributing to the short bone phenotype, independent of osteochondroma formation. Clones of chondrocytes lacking functional heparan sulfate must blunt physeal signaling generally, rather than stealing growth potential focally. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 651-657, 2013.

Background: Late Gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging can be used to visualise regions of fibrosis and scarring in the left atrium (LA) myocardium. This can be important for treatment stratification of patients with atrial fibrillation (AF) and for assessment of treatment after radio frequency catheter ablation (RFCA). In this paper we present a standardised evaluation benchmarking framework for algorithms segmenting fibrosis and scar from LGE CMR images. The algorithms reported are the response to an open challenge that was put to the medical imaging community through an ISBI (IEEE International Symposium on Biomedical Imaging) workshop.

Methods: The image database consisted of 60 multicenter, multivendor LGE CMR image datasets from patients with AF, with 30 images taken before and 30 after RFCA for the treatment of AF. A reference standard for scar and fibrosis was established by merging manual segmentations from three observers. Furthermore, scar was also quantified using 2, 3 and 4 standard deviations (SD) and full-width-at-half-maximum (FWHM) methods. Seven institutions responded to the challenge: Imperial College (IC), Mevis Fraunhofer (MV), Sunnybrook Health Sciences (SY), Harvard/Boston University (HB), Yale School of Medicine (YL), King’s College London (KCL) and Utah CARMA (UTA, UTB). There were 8 different algorithms evaluated in this study.

Results: Some algorithms were able to perform significantly better than SD and FWHM methods in both pre- and post-ablation imaging. Segmentation in pre-ablation images was challenging and good correlation with the reference standard was found in post-ablation images. Overlap scores (out of 100) with the reference standard were as follows: Pre: IC = 37, MV = 22, SY = 17, YL = 48, KCL = 30, UTA = 42, UTB = 45; Post: IC = 76, MV = 85, SY = 73, HB = 76, YL = 84, KCL = 78, UTA = 78, UTB = 72.

Conclusions: The study concludes that currently no algorithm is deemed clearly better than others. There is scope for further algorithmic developments in LA fibrosis and scar quantification from LGE CMR images. Benchmarking of future scar segmentation algorithms is thus important. The proposed benchmarking framework is made available as open-source and new participants can evaluate their algorithms via a web-based interface.

Keywords: Late gadolinium enhancement, Cardiovascular magnetic resonance, Atrial fibrillation, Segmentation, Algorithm benchmarking

The degree of white matter (WM) myelination is rather inhomogeneous across the brain. White matter appears differently across the cortical lobes in MR images acquired during early postnatal development. Specifically at 1-year of age, the gray/white matter contrast of MR T1 and T2 weighted images in prefrontal and temporal lobes is reduced as compared to the rest of the brain, and thus, tissue segmentation results commonly show lower accuracy in these lobes. In this novel work, we propose the use of spatial intensity growth maps (IGM) for T1 and T2 weighted images to compensate for local appearance inhomogeneity. The IGM captures expected intensity changes from 1 to 2 years of age, as appearance homogeneity is greatly improved by the age of 24 months. The IGM was computed as the coefficient of a voxel-wise linear regression model between corresponding intensities at 1 and 2 years. The proposed IGM method revealed low regression values of 1–10\% in GM and CSF regions, as well as in WM regions at maturation stage of myelination at 1 year. However, in the prefrontal and temporal lobes we observed regression values of 20–25\%, indicating that the IGM appropriately captures the expected large intensity change in these lobes mainly due to myelination. The IGM is applied to cross-sectional MRI datasets of 1-year-old subjects via registration, correction and tissue segmentation of the IGM-corrected dataset. We validated our approach in a small leave-one-out study of images with known, manual 'ground truth' segmentations.

In 1987, Bruce McCormick and his colleagues outlined the current state and future vision of visualization in scientific computing.¹ That same year, Donna Cox pioneered her concept of the "Renaissance team"-a multidisciplinary team of experts focused on solving visualization problems.² Even if a member of the visualization community has never read McCormick and his colleagues' report or heard Donna Cox speak, he or she has probably been affected by some of their ideas.

Of particular interest to us is their vision for collaboration. McCormick and his colleagues envisioned an interdisciplinary team that through close interaction would develop visualization tools that not only were effective in the context of their immediate collaborative environment but also could be reused by scientists and engineers in other fields. McCormick and his colleagues categorized the types of researchers they imagined constituting these teams, one type being the "visualization scientist/engineer." They even commented on the skills these individuals might have. However, they provided little guidance on how to make such teams successful.

In the more than 25 years since the report, researchers have refined the concepts of interaction versus collaboration,³ interdisciplinary versus multidisciplinary teams,^4,5 and independence versus interdependence.⁶ Here, we use observations from our collective 18 years of collaborative visualization research to help shed light on not just the composition of current and future visualization collaborative teams but also pitfalls and recommendations for successful collaboration. Although our statements might reflect what seasoned visualization researchers are already doing, we believe that reexpressing and possibly reaffirming basic collaboration principles provide benefits.

Visualizing large molecular data requires efficient means of rendering millions of data elements that combine glyphs, geometry and volumetric techniques. The geometric and volumetric loads challenge traditional rasterization-based vis methods. Ray casting presents a scalable and memory- efficient alternative, but modern techniques typically rely on GPU-based acceleration to achieve interactive rendering rates. In this paper, we present bnsView, a molecular visualization ray tracing framework that delivers fast volume rendering and ball-and-stick ray casting on both multi-core CPUs andmany-core Intel ® Xeon Phi^TM co-processors, implemented in a SPMD language that generates efficient SIMD vector code for multiple platforms without source modification. We show that our approach running on co- processors is competitive with similar techniques running on GPU accelerators, and we demonstrate large-scale parallel remote visualization from TACC's Stampede supercomputer to large-format display walls using this system.

Parallel I/O library performance can vary greatly in response to user-tunable parameter values such as aggregator count, file count, and aggregation strategy. Unfortunately, manual selection of these values is time consuming and dependent on characteristics of the target machine, the underlying file system, and the dataset itself. Some characteristics, such as the amount of memory per core, can also impose hard constraints on the range of viable parameter values. In this work we address these problems by using machine learning techniques to model the performance of the PIDX parallel I/O library and select appropriate tunable parameter values. We characterize both the network and I/O phases of PIDX on a Cray XE6 as well as an IBM Blue Gene/P system. We use the results of this study to develop a machine learning model for parameter space exploration and performance prediction.

Keywords: I/O, Network Characterization, Performance Modeling