Survival analysis represents an important outcome measure in clinical research and clinical trials; further, survival ranking may offer additional advantages in clinical trials. In this study, we developed GuanRank, a non-parametric ranking-based technique to transform patients' survival data into a linear space of hazard ranks. The transformation enables the utilization of machine learning base-learners including Gaussian process regression, Lasso, and random forest on survival data. The method was submitted to the DREAM Amyotrophic Lateral Sclerosis (ALS) Stratification Challenge. Ranked first place, the model gave more accurate ranking predictions on the PRO-ACT ALS dataset in comparison to Cox proportional hazard model. By utilizing right-censored data in its training process, the method demonstrated its state-of-the-art predictive power in ALS survival ranking. Its feature selection identified multiple important factors, some of which conflicts with previous studies.

Big data workflows often require the assembly and exchange of complex, multi-element datasets. For example, in biomedical applications, the input to an analytic pipeline can be a dataset consisting thousands of images and genome sequences assembled from diverse repositories, requiring a description of the contents of the dataset in a concise and unambiguous form. Typical approaches to creating datasets for big data workflows assume that all data reside in a single location, requiring costly data marshaling and permitting errors of omission and commission because dataset members are not explicitly specified. We address these issues by proposing simple methods and tools for assembling, sharing, and analyzing large and complex datasets that scientists can easily integrate into their daily workflows. These tools combine a simple and robust method for describing data collections (BDBags), data descriptions (Research Objects), and simple persistent identifiers (Minids) to create a powerful ecosystem of tools and services for big data analysis and sharing. We present these tools and use biomedical case studies to illustrate their use for the rapid assembly, sharing, and analysis of large datasets.

Modern biomedical data collection is generating exponentially more data in a multitude of formats. This flood of complex data poses significant opportunities to discover and understand the critical interplay among such diverse domains as genomics, proteomics, metabolomics, and phenomics, including imaging, biometrics, and clinical data. The Big Data for Discovery Science Center is taking an "-ome to home" approach to discover linkages between these disparate data sources by mining existing databases of proteomic and genomic data, brain images, and clinical assessments. In support of this work, the authors developed new technological capabilities that make it easy for researchers to manage, aggregate, manipulate, integrate, and model large amounts of distributed data. Guided by biological domain expertise, the Center's computational resources and software will reveal relationships and patterns, aiding researchers in identifying biomarkers for the most confounding conditions and diseases, such as Parkinson's and Alzheimer's.

Scientific workflows provide the means to define, execute and reproduce computational experiments. However, reusing existing workflows still poses challenges for workflow designers. Workflows are often too large and too specific to reuse in their entirety, so reuse is more likely to happen for fragments of workflows. These fragments may be identified manually by users as sub-workflows, or detected automatically. In this paper we present the FragFlow approach, which detects workflow fragments automatically by analyzing existing workflow corpora with graph mining algorithms. FragFlow detects the most common workflow fragments, links them to the original workflows and visualizes them. We evaluate our approach by comparing FragFlow results against user-defined sub-workflows from three different corpora of the LONI Pipeline system. Based on this evaluation, we discuss how automated workflow fragment detection could facilitate workflow reuse.

Diffusion tensor imaging is widely used in brain connectivity research. As more and more studies recruit large numbers of subjects, it is important to design registration methods which are not only theoretically rigorous, but also computationally efficient. However, the requirement of reorienting diffusion tensors complicates and considerably slows down registration procedures, due to the correlated impacts of registration forces at adjacent voxel locations. Based on the diffeomorphic Demons algorithm (Vercauteren , 2009), we propose a fast local trust region algorithm for handling inseparable registration forces for quadratic energy functions. The method guarantees that, at any time and at any voxel location, the velocity is always within its local trust region. This local regularization allows efficient calculation of the transformation update with numeric integration instead of completely solving a large linear system at every iteration. It is able to incorporate exact reorientation and regularization into the velocity optimization, and preserve the linear complexity of the diffeomorphic Demons algorithm. In an experiment with 84 diffusion tensor images involving both pair-wise and group-wise registrations, the proposed algorithm achieves better registration in comparison with other methods solving large linear systems (Yeo , 2009). At the same time, this algorithm reduces the computation time and memory demand tenfold.

The Center for Computational Biology (CCB) is a multidisciplinary program where biomedical scientists, engineers, and clinicians work jointly to combine modern mathematical and computational techniques, to perform phenotypic and genotypic studies of biological structure, function, and physiology in health and disease. CCB has developed a computational framework built around the Manifold Atlas, an integrated biomedical computing environment that enables statistical inference on biological manifolds. These manifolds model biological structures, features, shapes, and flows, and support sophisticated morphometric and statistical analyses. The Manifold Atlas includes tools, workflows, and services for multimodal population-based modeling and analysis of biological manifolds. The broad spectrum of biomedical topics explored by CCB investigators include the study of normal and pathological brain development, maturation and aging, discovery of associations between neuroimaging and genetic biomarkers, and the modeling, analysis, and visualization of biological shape, form, and size. CCB supports a wide range of short-term and long-term collaborations with outside investigators, which drive the center's computational developments and focus the validation and dissemination of CCB resources to new areas and scientific domains.

We present a diffeomorphic approach for constructing intrinsic shape atlases of sulci on the human cortex. Sulci are represented as square-root velocity functions of continuous open curves in R³, and their shapes are studied as functional representations of an infinite-dimensional sphere. This spherical manifold has some advantageous properties--it is equipped with a Riemannian L² metric on the tangent space and facilitates computational analyses and correspondences between sulcal shapes. Sulcal shape mapping is achieved by computing geodesics in the quotient space of shapes modulo scales, translations, rigid rotations, and reparameterizations. The resulting sulcal shape atlas preserves important local geometry inherently present in the sample population. The sulcal shape atlas is integrated in a cortical registration framework and exhibits better geometric matching compared to the conventional euclidean method. We demonstrate experimental results for sulcal shape mapping, cortical surface registration, and sulcal classification for two different surface extraction protocols for separate subject populations.

We present a novel edge preserved interpolation scheme for fast upsampling of natural images. The proposed piecewise hyperbolic operator uses a slope-limiter function that conveniently lends itself to higher-order approximations and is responsible for restricting spatial oscillations arising due to the edges and sharp details in the image. As a consequence the upsampled image not only exhibits enhanced edges, and discontinuities across boundaries, but also preserves smoothly varying features in images. Experimental results show an improvement in the PSNR compared to typical cubic, and spline-based interpolation approaches.

MOTIVATION: Integrative mathematical and statistical models of cardiac anatomy and physiology can play a vital role in understanding cardiac disease phenotype and planning therapeutic strategies. However, the accuracy and predictive power of such models is dependent upon the breadth and depth of noninvasive imaging datasets. The Cardiac Atlas Project (CAP) has established a large-scale database of cardiac imaging examinations and associated clinical data in order to develop a shareable, web-accessible, structural and functional atlas of the normal and pathological heart for clinical, research and educational purposes. A goal of CAP is to facilitate collaborative statistical analysis of regional heart shape and wall motion and characterize cardiac function among and within population groups. RESULTS: Three main open-source software components were developed: (i) a database with web-interface; (ii) a modeling client for 3D + time visualization and parametric description of shape and motion; and (iii) open data formats for semantic characterization of models and annotations. The database was implemented using a three-tier architecture utilizing MySQL, JBoss and Dcm4chee, in compliance with the DICOM standard to provide compatibility with existing clinical networks and devices. Parts of Dcm4chee were extended to access image specific attributes as search parameters. To date, approximately 3000 de-identified cardiac imaging examinations are available in the database. All software components developed by the CAP are open source and are freely available under the Mozilla Public License Version 1.1 (http://www.mozilla.org/MPL/MPL-1.1.txt). AVAILABILITY: http://www.cardiacatlas.org CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Contemporary informatics and genomics research require efficient, flexible and robust management of large heterogeneous data, advanced computational tools, powerful visualization, reliable hardware infrastructure, interoperability of computational resources, and detailed data and analysis-protocol provenance. The Pipeline is a client-server distributed computational environment that facilitates the visual graphical construction, execution, monitoring, validation and dissemination of advanced data analysis protocols. RESULTS: This paper reports on the applications of the LONI Pipeline environment to address two informatics challenges - graphical management of diverse genomics tools, and the interoperability of informatics software. Specifically, this manuscript presents the concrete details of deploying general informatics suites and individual software tools to new hardware infrastructures, the design, validation and execution of new visual analysis protocols via the Pipeline graphical interface, and integration of diverse informatics tools via the Pipeline eXtensible Markup Language syntax. We demonstrate each of these processes using several established informatics packages (e.g., miBLAST, EMBOSS, mrFAST, GWASS, MAQ, SAMtools, Bowtie) for basic local sequence alignment and search, molecular biology data analysis, and genome-wide association studies. These examples demonstrate the power of the Pipeline graphical workflow environment to enable integration of bioinformatics resources which provide a well-defined syntax for dynamic specification of the input/output parameters and the run-time execution controls. CONCLUSIONS: The LONI Pipeline environment http://pipeline.loni.ucla.edu provides a flexible graphical infrastructure for efficient biomedical computing and distributed informatics research. The interactive Pipeline resource manager enables the utilization and interoperability of diverse types of informatics resources. The Pipeline client-server model provides computational power to a broad spectrum of informatics investigators--experienced developers and novice users, user with or without access to advanced computational-resources (e.g., Grid, data), as well as basic and translational scientists. The open development, validation and dissemination of computational networks (pipeline workflows) facilitates the sharing of knowledge, tools, protocols and best practices, and enables the unbiased validation and replication of scientific findings by the entire community.

The biomedical research community relies on a diverse set of resources, both within their own institutions and at other research centers. In addition, an increasing number of shared electronic resources have been developed. Without effective means to locate and query these resources, it is challenging, if not impossible, for investigators to be aware of the myriad resources available, or to effectively perform resource discovery when the need arises. In this paper, we describe the development and use of the Biomedical Resource Ontology (BRO) to enable semantic annotation and discovery of biomedical resources. We also describe the Resource Discovery System (RDS) which is a federated, inter-institutional pilot project that uses the BRO to facilitate resource discovery on the Internet. Through the RDS framework and its associated Biositemaps infrastructure, the BRO facilitates semantic search and discovery of biomedical resources, breaking down barriers and streamlining scientific research that will improve human health.

We develop a computational model of shape that extends existing Riemannian models of curves to multidimensional objects of general topological type. We construct shape spaces equipped with geodesic metrics that measure how costly it is to interpolate two shapes through elastic deformations. The model employs a representation of shape based on the discrete exterior derivative of parametrizations over a finite simplicial complex. We develop algorithms to calculate geodesics and geodesic distances, as well as tools to quantify local shape similarities and contrasts, thus obtaining a formulation that accounts for regional differences and integrates them into a global measure of dissimilarity. The Riemannian shape spaces provide a common framework to treat numerous problems such as the statistical modeling of shapes, the comparison of shapes associated with different individuals or groups, and modeling and simulation of shape dynamics. We give multiple examples of geodesic interpolations and illustrations of the use of the models in brain mapping, particularly, the analysis of anatomical variation based on neuroimaging data.

In medical shape analysis, a critical problem is reconstructing a smooth surface of correct topology from a binary mask that typically has spurious features due to segmentation artifacts. The challenge is the robust removal of these outliers without affecting the accuracy of other parts of the boundary. In this paper, we propose a novel approach for this problem based on the Laplace-Beltrami (LB) eigen-projection and properly designed boundary deformations. Using the metric distortion during the LB eigen-projection, our method automatically detects the location of outliers and feeds this information to a well-composed and topology-preserving deformation. By iterating between these two steps of outlier detection and boundary deformation, we can robustly filter out the outliers without moving the smooth part of the boundary. The final surface is the eigen-projection of the filtered mask boundary that has the correct topology, desired accuracy and smoothness. In our experiments, we illustrate the robustness of our method on different input masks of the same structure, and compare with the popular SPHARM tool and the topology preserving level set method to show that our method can reconstruct accurate surface representations without introducing artificial oscillations. We also successfully validate our method on a large data set of more than 900 hippocampal masks and demonstrate that the reconstructed surfaces retain volume information accurately.

In this paper, we propose an automated approach for the joint detection of major sulci on cortical surfaces. By representing sulci as nodes in a graphical model, we incorporate Markovian relations between sulci and formulate their detection as a maximum a posteriori (MAP) estimation problem over the joint space of major sulci. To make the inference tractable, a sample space with a finite number of candidate curves is automatically generated at each node based on the Hamilton-Jacobi skeleton of sulcal regions. Using the AdaBoost algorithm, we learn both individual and pairwise shape priors of sulcal curves from training data, which are then used to define potential functions in the graphical model based on the connection between AdaBoost and logistic regression. Finally belief propagation is used to perform the MAP inference and select the joint detection results from the sample spaces of candidate curves. In our experiments, we quantitatively validate our algorithm with manually traced curves and demonstrate the automatically detected curves can capture the main body of sulci very accurately. A comparison with independently detected results is also conducted to illustrate the advantage of the joint detection approach.

In this paper, we propose a new method to construct graphical representations of cortical folding patterns by computing skeletons on triangulated cortical surfaces. In our approach, a cortical surface is first partitioned into sulcal and gyral regions via the solution of a variational problem using graph cuts, which can guarantee global optimality. After that, we extend the method of Hamilton-Jacobi skeleton [1] to subsets of triangulated surfaces, together with a geometrically intuitive pruning process that can trade off between skeleton complexity and the completeness of representing folding patterns. Compared with previous work that uses skeletons of 3-D volumes to represent sulcal patterns, the skeletons on cortical surfaces can be easily decomposed into branches and provide a simpler way to construct graphical representations of cortical morphometry. In our experiments, we demonstrate our method on two different cortical surface models, its ability of capturing major sulcal patterns and its application to compute skeletons of gyral regions.

In this paper, a hybrid discriminative/generative model for brain anatomical structure segmentation is proposed. The learning aspect of the approach is emphasized. In the discriminative appearance models, various cues such as intensity and curvatures are combined to locally capture the complex appearances of different anatomical structures. A probabilistic boosting tree (PBT) framework is adopted to learn multiclass discriminative models that combine hundreds of features across different scales. On the generative model side, both global and local shape models are used to capture the shape information about each anatomical structure. The parameters to combine the discriminative appearance and generative shape models are also automatically learned. Thus, low-level and high-level information is learned and integrated in a hybrid model. Segmentations are obtained by minimizing an energy function associated with the proposed hybrid model. Finally, a grid-face structure is designed to explicitly represent the 3-D region topology. This representation handles an arbitrary number of regions and facilitates fast surface evolution. Our system was trained and tested on a set of 3-D magnetic resonance imaging (MRI) volumes and the results obtained are encouraging.

Finite mixture models (FMMs) are an indispensable tool for unsupervised classification in brain imaging. Fitting an FMM to the data leads to a complex optimization problem. This optimization problem is difficult to solve by standard local optimization methods, such as the expectation-maximization (EM) algorithm, if a principled initialization is not available. In this paper, we propose a new global optimization algorithm for the FMM parameter estimation problem, which is based on real coded genetic algorithms. Our specific contributions are two-fold: 1) we propose to use blended crossover in order to reduce the premature convergence problem to its minimum and 2) we introduce a completely new permutation operator specifically meant for the FMM parameter estimation. In addition to improving the optimization results, the permutation operator allows for imposing biologically meaningful constraints to the FMM parameter values. We also introduce a hybrid of the genetic algorithm and the EM algorithm for efficient solution of multidimensional FMM fitting problems. We compare our algorithm to the self-annealing EM-algorithm and a standard real coded genetic algorithm with the voxel classification tasks within the brain imaging. The algorithms are tested on synthetic data as well as real three-dimensional image data from human magnetic resonance imaging, positron emission tomography, and mouse brain MRI. The tissue classification results by our method are shown to be consistently more reliable and accurate than with the competing parameter estimation methods.

It is important to detect and extract the major cortical sulci from brain images, but manually annotating these sulci is a time-consuming task and requires the labeler to follow complex protocols. This paper proposes a learning-based algorithm for automated extraction of the major cortical sulci from magnetic resonance imaging (MRI) volumes and cortical surfaces. Unlike alternative methods for detecting the major cortical sulci, which use a small number of predefined rules based on properties of the cortical surface such as the mean curvature, our approach learns a discriminative model using the probabilistic boosting tree algorithm (PBT). PBT is a supervised learning approach which selects and combines hundreds of features at different scales, such as curvatures, gradients and shape index. Our method can be applied to either MRI volumes or cortical surfaces. It first outputs a probability map which indicates how likely each voxel lies on a major sulcal curve. Next, it applies dynamic programming to extract the best curve based on the probability map and a shape prior. The algorithm has almost no parameters to tune for extracting different major sulci. It is very fast (it runs in under 1 min per sulcus including the time to compute the discriminative models) due to efficient implementation of the features (e.g., using the integral volume to rapidly compute the responses of 3-D Haar filters). Because the algorithm can be applied to MRI volumes directly, there is no need to perform preprocessing such as tissue segmentation or mapping to a canonical space. The learning aspect of our approach makes the system very flexible and general. For illustration, we use volumes of the right hemisphere with several major cortical sulci manually labeled. The algorithm is tested on two groups of data, including some brains from patients with Williams Syndrome, and the results are very encouraging.

In the field of template-based medical image analysis, image registration and normalization are frequently used to evaluate and interpret data in a standard template or reference atlas space. Despite the large number of image-registration (warping) techniques developed recently in the literature, only a few studies have been undertaken to numerically characterize and compare various alignment methods. In this paper, we introduce a new approach for analyzing image registration based on a selective-wavelet reconstruction technique using a frequency-adaptive wavelet shrinkage. We study four polynomial-based and two higher complexity nonaffine warping methods applied to groups of stereotaxic human brain structural (magnetic resonance imaging) and functional (positron emission tomography) data. Depending upon the aim of the image registration, we present several warp classification schemes. Our method uses a concise representation of the native and resliced (pre- and post-warp) data in compressed wavelet space to assess quality of registration. This technique is computationally inexpensive and utilizes the image compression, image enhancement, and denoising characteristics of the wavelet-based function representation, as well as the optimality properties of frequency-dependent wavelet shrinkage.