MOTIVATION: Reverse engineering gene regulatory networks, especially large size networks from time series gene expression data, remain a challenge to the systems biology community. In this article, a new hybrid algorithm integrating ordinary differential equation models with dynamic Bayesian network analysis, called Differential Equation-based Local Dynamic Bayesian Network (DELDBN), was proposed and implemented for gene regulatory network inference. RESULTS: The performance of DELDBN was benchmarked with an in vivo dataset from yeast. DELDBN significantly improved the accuracy and sensitivity of network inference compared with other approaches. The local causal discovery algorithm implemented in DELDBN also reduced the complexity of the network inference algorithm and improved its scalability to infer larger networks. We have demonstrated the applicability of the approach to a network containing thousands of genes with a dataset from human HeLa cell time series experiments. The local network around BRCA1 was particularly investigated and validated with independent published studies. BRAC1 network was significantly enriched with the known BRCA1-relevant interactions, indicating that DELDBN can effectively infer large size gene regulatory network from time series data. AVAILABILITY: The R scripts are provided in File 3 in Supplementary Material. CONTACT: [email protected]; [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

In this paper, we propose a learning-based algorithm for automatic medical image annotation based on robust aggregation of learned local appearance cues, achieving high accuracy and robustness against severe diseases, imaging artifacts, occlusion, or missing data. The algorithm starts with a number of landmark detectors to collect local appearance cues throughout the image, which are subsequently verified by a group of learned sparse spatial configuration models. In most cases, a decision could already be made at this stage by simply aggregating the verified detections. For the remaining cases, an additional global appearance filtering step is employed to provide complementary information to make the final decision. This approach is evaluated on a large-scale chest radiograph view identification task, demonstrating a very high accuracy ( > 99.9%) for a posteroanterior/anteroposterior (PA-AP) and lateral view position identification task, compared with the recently reported large-scale result of only 98.2% (Luo, , 2006). Our approach also achieved the best accuracies for a three-class and a multiclass radiograph annotation task, when compared with other state of the art algorithms. Our algorithm was used to enhance advanced image visualization workflows by enabling content-sensitive hanging-protocols and auto-invocation of a computer aided detection algorithm for identified PA-AP chest images. Finally, we show that the same methodology could be utilized for several image parsing applications including anatomy/organ region of interest prediction and optimized image visualization.

Diagnostic magnetic resonance (MR) image quality is highly dependent on the position and orientation of the slice groups, due to the intrinsic high in-slice and low through-slice resolutions of MR imaging. Hence, the higher speed, accuracy, and reproducibility of automatic slice positioning, make it highly desirable over manual slice positioning. However, imaging artifacts, diseases, joint articulation, variations across ages and demographics as well as the extremely high performance requirements prevent state-of-the-art methods, such as volumetric registration, to be an off-the-shelf solution. In this paper, we address all these issues through an automatic slice positioning framework based on redundant and hierarchical learning. Our method has two hallmarks that are specifically designed to achieve high robustness and accuracy. 1) A redundant set of anatomy detectors are learned to provide local appearance cues. These detections are pruned and assembled according to a distributed anatomy model, which captures group-wise spatial configurations among anatomy primitives. This strategy brings about a high level of robustness and works even if a large portion of the target is distorted, missing, or occluded. 2) The detectors are learned and invoked in a hierarchical fashion, with each local detection scheduled and iterated according to its intrinsic invariance property. This iterative alignment process is shown to dramatically improve alignment accuracy. The proposed system is extensively validated on a large dataset including 744 clinical MR scans. Compared to state-of-the-art methods, our method exhibits superior performance in terms of robustness, accuracy, and reproducibility. The methodology is general and can be applied to other anatomies and other imaging modalities.

The automatic detection of lung nodules attached to other pulmonary structures is a useful yet challenging task in lung CAD systems. In this paper, we propose a stratified statistical learning approach to recognize whether a candidate nodule detected in CT images connects to any of three other major lung anatomies, namely vessel, fissure and lung wall, or is solitary with background parenchyma. First, we develop a fully automated voxel-by-voxel labeling/segmentation method of nodule, vessel, fissure, lung wall and parenchyma given a 3D lung image, via a unified feature set and classifier under conditional random field. Second, the generated Class Probability Response Maps (PRM) by voxel-level classifiers, are used to form the so-called pairwise Probability Co-occurrence Maps (PCM) which encode the spatial contextual correlations of the candidate nodule, in relation to other anatomical landmarks. Based on PCMs, higher level classifiers are trained to recognize whether the nodule touches other pulmonary structures, as a multi-label problem. We also present a new iterative fissure structure enhancement filter with superior performance. For experimental validation, we create an annotated database of 784 subvolumes with nodules of various sizes, shapes, densities and contextual anatomies, and from 239 patients. High accuracy of multi-class voxel labeling is achieved 89.3% ∼ 91.2%. The Area under ROC Curve (AUC) of vessel, fissure and lung wall connectivity classification reaches 0.8676, 0.8692 and 0.9275, respectively.

Automatic coronary artery centerline extraction from 3D CT Angiography (CTA) has significant clinical importance for diagnosis of atherosclerotic heart disease. The focus of past literature is dominated by segmenting the complete coronary artery system as trees by computer. Though the labeling of different vessel branches (defined by their medical semantics) is much needed clinically, this task has been performed manually. In this paper, we propose a hierarchical machine learning approach to tackle the problem of tubular structure parsing in medical imaging. It has a progressive three-tiered classification process at volumetric voxel level, vessel segment level, and inter-segment level. Generative models are employed to project from low-level, ambiguous data to class-conditional probabilities; and discriminative classifiers are trained on the upper-level structural patterns of probabilities to label and parse the vessel segments. Our method is validated by experiments of detecting and segmenting clinically defined coronary arteries, from the initial noisy vessel segment networks generated by low-level heuristics-based tracing algorithms. The proposed framework is also generically applicable to other tubular structure parsing tasks.

BACKGROUND: There has been a lot of interest in recent years focusing on the modeling and simulation of Gene Regulatory Networks (GRNs). However, the evolutionary mechanisms that give rise to GRNs in the first place are still largely unknown. In an earlier work, we developed a framework to analyze the effect of objective functions, input types and starting populations on the evolution of GRNs with a specific emphasis on the robustness of evolved GRNs. RESULTS: In this work, we present a parallel software package, GeNESiS for the modeling and simulation of the evolution of gene regulatory networks (GRNs). The software models the process of gene regulation through a combination of finite-state and stochastic models. The evolution of GRNs is then simulated by means of a genetic algorithm with the network connections represented as binary strings. The software allows users to simulate the evolution under varying selective pressures and starting conditions. We believe that the software provides a way for researchers to understand the evolutionary behavior of populations of GRNs. CONCLUSION: We believe that GeNESiS will serve as a useful tool for scientists interested in understanding the evolution of gene regulatory networks under a range of different conditions and selective pressures. Such modeling efforts can lead to a greater understanding of the network characteristics of GRNs.

We propose a novel semi-automatic figure-ground segmentation solution for blob-like objects in multi-dimensional images. The blob-like structure constitutes various objects of interest that are hard to segment in many application domains, such as tumor lesions in 3D medical data. The proposed solution is motivated towards computer-aided diagnosis medical applications, justifying our semi-automatic and figure-ground approach. The efficient segmentation is realized by combining the robust anisotropic Gaussian model fitting and the likelihood ratio test (LRT)-based non-parametric segmentation in joint space-intensity domain. The robustly fitted Gaussian is exploited to estimate the foreground and background likelihoods for both spatial and intensity variables. We demonstrate that the LRT with the bootstrapped likelihoods is assured to be the optimal Bayesian classification while automatically determining the LRT threshold. A 3D implementation of the proposed algorithm is applied to the lung nodule segmentation in CT data and validated with 1310 cases. Our efficient solution segments a target nodule in less than 3 seconds in average.

Abstract Summary: Modelling and simulation of complex cellular transactions involve development of platforms that understand diverse mathematical representations and are capable of handling large backend computations. Grid Cellware, an integrated modelling and simulation tool, has been developed to precisely address these niche requirements of the modelling community. Grid Cellware implements various pathway simulation algorithms along with adaptive Swarm algorithm for parameter estimation. For enchanced computational productivity Grid Cellware uses grid technology with Globus as the middleware. Availability: https://www.bii-sg.org/sbg/cellware Contact: [email protected] Supplementary information: User Manual is available as PDF file. Examples are attached to expedite mastering of the software.

UNLABELLED: WebAllergen is a web server that predicts the potential allergenicity of proteins. The query protein will be compared against a set of prebuilt allergenic motifs that have been obtained from 664 known allergen proteins. The query will also be compared with known allergens that do not have detectable allergenic motifs. Moreover, users are allowed to upload their own allergens as alternative training sequences on which a new set of allergenic motifs will be built. The query sequences can also be compared with these motifs. AVAILABILITY: http://weballergen.bii.a-star.edu.sg/

BACKGROUND: Accurate diagnosis of cancer subtypes remains a challenging problem. Building classifiers based on gene expression data is a promising approach; yet the selection of non-redundant but relevant genes is difficult. The selected gene set should be small enough to allow diagnosis even in regular clinical laboratories and ideally identify genes involved in cancer-specific regulatory pathways. Here an entropy-based method is proposed that selects genes related to the different cancer classes while at the same time reducing the redundancy among the genes. RESULTS: The present study identifies a subset of features by maximizing the relevance and minimizing the redundancy of the selected genes. A merit called normalized mutual information is employed to measure the relevance and the redundancy of the genes. In order to find a more representative subset of features, an iterative procedure is adopted that incorporates an initial clustering followed by data partitioning and the application of the algorithm to each of the partitions. A leave-one-out approach then selects the most commonly selected genes across all the different runs and the gene selection algorithm is applied again to pare down the list of selected genes until a minimal subset is obtained that gives a satisfactory accuracy of classification. The algorithm was applied to three different data sets and the results obtained were compared to work done by others using the same data sets. CONCLUSION: This study presents an entropy-based iterative algorithm for selecting genes from microarray data that are able to classify various cancer sub-types with high accuracy. In addition, the feature set obtained is very compact, that is, the redundancy between genes is reduced to a large extent. This implies that classifiers can be built with a smaller subset of genes.

BACKGROUND: Protein subcellular localization is an important determinant of protein function and hence, reliable methods for prediction of localization are needed. A number of prediction algorithms have been developed based on amino acid compositions or on the N-terminal characteristics (signal peptides) of proteins. However, such approaches lead to a loss of contextual information. Moreover, where information about the physicochemical properties of amino acids has been used, the methods employed to exploit that information are less than optimal and could use the information more effectively. RESULTS: In this paper, we propose a new algorithm called pSLIP which uses Support Vector Machines (SVMs) in conjunction with multiple physicochemical properties of amino acids to predict protein subcellular localization in eukaryotes across six different locations, namely, chloroplast, cytoplasmic, extracellular, mitochondrial, nuclear and plasma membrane. The algorithm was applied to the dataset provided by Park and Kanehisa and we obtained prediction accuracies for the different classes ranging from 87.7%-97.0% with an overall accuracy of 93.1%. CONCLUSION: This study presents a physicochemical property based protein localization prediction algorithm. Unlike other algorithms, contextual information is preserved by dividing the protein sequences into clusters. The prediction accuracy shows an improvement over other algorithms based on various types of amino acid composition (single, pair and gapped pair). We have also implemented a web server to predict protein localization across the six classes (available at http://pslip.bii.a-star.edu.sg/).

BACKGROUND: We observe two trends in bioinformatics: (i) analyses are increasing in complexity, often requiring several applications to be run as a workflow; and (ii) multiple CPU clusters and Grids are available to more scientists. The traditional solution to the problem of running workflows across multiple CPUs required programming, often in a scripting language such as perl. Programming places such solutions beyond the reach of many bioinformatics consumers. RESULTS: We present Wildfire, a graphical user interface for constructing and running workflows. Wildfire borrows user interface features from Jemboss and adds a drag-and-drop interface allowing the user to compose EMBOSS (and other) programs into workflows. For execution, Wildfire uses GEL, the underlying workflow execution engine, which can exploit available parallelism on multiple CPU machines including Beowulf-class clusters and Grids. CONCLUSION: Wildfire simplifies the tasks of constructing and executing bioinformatics workflows.

BACKGROUND: Predicting the subcellular localization of proteins is important for determining the function of proteins. Previous works focused on predicting protein localization in Gram-negative bacteria obtained good results. However, these methods had relatively low accuracies for the localization of extracellular proteins. This paper studies ways to improve the accuracy for predicting extracellular localization in Gram-negative bacteria. RESULTS: We have developed a system for predicting the subcellular localization of proteins for Gram-negative bacteria based on amino acid subalphabets and a combination of multiple support vector machines. The recall of the extracellular site and overall recall of our predictor reach 86.0% and 89.8%, respectively, in 5-fold cross-validation. To the best of our knowledge, these are the most accurate results for predicting subcellular localization in Gram-negative bacteria. CONCLUSION: Clustering 20 amino acids into a few groups by the proposed greedy algorithm provides a new way to extract features from protein sequences to cover more adjacent amino acids and hence reduce the dimensionality of the input vector of protein features. It was observed that a good amino acid grouping leads to an increase in prediction performance. Furthermore, a proper choice of a subset of complementary support vector machines constructed by different features of proteins maximizes the prediction accuracy.

Improvements in the performance of processors and networks have made it feasible to treat collections of workstations, servers, clusters and supercomputers as integrated computing resources or Grids. However, the very heterogeneity that is the strength of computational and data Grids can also make application development for such an environment extremely difficult. Application development in a Grid computing environment faces significant challenges in the form of problem granularity, latency and bandwidth issues as well as job scheduling. Currently existing Grid technologies limit the development of Grid applications to certain classes, namely, embarrassingly parallel, hierarchical parallelism, work flow and database applications. Of all these classes, embarrassingly parallel applications are the easiest to develop in a Grid computing framework. The work presented here deals with creating a Grid-enabled, high-throughput, standalone version of a bioinformatics application, BLAST, using Globus as the Grid middleware. BLAST is a sequence alignment and search technique that is embarrassingly parallel in nature and thus amenable to adaptation to a Grid environment. A detailed methodology for creating the Grid-enabled application is presented, which can be used as a template for the development of similar applications. The application has been tested on a ‘mini-Grid’ testbed and the results presented here show that for large problem sizes, a distributed, Grid-enabled version can help in significantly reducing execution times. Copyright © 2005 John Wiley & Sons, Ltd.

This paper proposes a robust statistical estimation and verification framework for characterizing the ellipsoidal (anisotropic) geometrical structure of pulmonary nodules in the Multislice X-ray computed tomography (CT) images. Given a marker indicating a rough location of a target, the proposed solution estimates the target's center location, ellipsoidal boundary approximation, volume, maximum/average diameters, and isotropy by robustly and efficiently fitting an anisotropic Gaussian intensity model. We propose a novel multiscale joint segmentation and model fitting solution which extends the robust mean shift-based analysis to the linear scale-space theory. The design is motivated for enhancing the robustness against margin-truncation induced by neighboring structures, data with large deviations from the chosen model, and marker location variability. A chi-square-based statistical verification and analytical volumetric measurement solutions are also proposed to complement this estimation framework. Experiments with synthetic one-dimensional and two-dimensional data clearly demonstrate the advantage of our solution in comparison with the gamma-normalized Laplacian approach (Linderberg, 1998) and the standard sample estimation approach (Matei, 2001). A quasi-real-time three-dimensional nodule characterization system is developed using this framework and validated with two clinical data sets of thin-section chest CT images. Our experiments with 1310 nodules resulted in (1) robustness against intraoperator and interoperator variability due to varying marker locations, (2) 81% correct estimation rate, (3) 3% false acceptance and 5% false rejection rates, and (4) correct characterization of clinically significant nonsolid ground-glass opacity nodules. This system processes each 33-voxel volume-of-interest by an average of 2 s with a 2.4-GHz Intel CPU. Our solution is generic and can be applied for the analysis of blob-like structures in various other applications.

MOTIVATION: Approximate tandem repeats (ATR) occur frequently in the genomes of organisms, and are a source of polymorphisms observed in individuals, and thus are of interest to those studying genetic disorders. Though extensive work has been done in order to identify ATRs, there are inherent limitations with the current approaches in terms of the number of pattern sizes that can be searched or the size of the input length. RESULTS: This paper describes (1) a new algorithm which exhaustively finds all variable-length ATRs in a genomic sequence and (2) a precise description of, and an algorithm to significantly reduce, redundancy in the output. Our ATR definition is parameterized by a mismatch ratio p which allows for more mismatches in longer tandem repeats (and fewer in shorter). Furthermore, our algorithm is embarrassingly parallel and thus can attain near-linear speed-up on Beowulf clusters. We present results of our algorithm applied to sequences of widely differing lengths (from genes to chromosomes). AVAILABILITY: Source and binaries are available on request.

MOTIVATION: With many transgenic proteins introduced today, the ability to predict their potential allergenicity has become an important issue. Previous studies were based on either sequence similarity or the protein motifs identified from known allergen databases. The similarity-based approaches, although being able to produce high recalls, usually have low prediction precisions. Previous motif-based approaches have been shown to be able to improve the precisions on cross-validation experiments. In this study, a system that combines the advantages of similarity-based and motif-based prediction is described. RESULTS: The new prediction system uses a clustering algorithm that groups the known allergenic proteins into clusters. Proteins within each cluster are assumed to carry one or more common motifs. After a multiple sequence alignment, proteins in each cluster go through a wavelet analysis program whereby conserved motifs will be identified. A hidden Markov model (HMM) profile will then be prepared for each identified motif. The allergens that do not appear to carry detectable allergen motifs will be saved in a small database. The allergenicity of an unknown protein may be predicted by comparing it against the HMM profiles, and, if no matching profiles are found, against the small allergen database by BLASTP. Over 70% of recall and over 90% of precision were observed using cross-validation experiments. Using the entire Swiss-Prot as the query, we predicted about 2000 potential allergens. AVAILABILITY: The software is available upon request from the authors.

The objective of active recognition is to iteratively collect the next "best" measurements (e.g., camera angles or viewpoints), to maximally reduce ambiguities in recognition. However, existing work largely overlooked feature interaction issues. Feature selection, on the other hand, focuses on the selection of a subset of measurements for a given classification task, but is not context sensitive (i.e., the decision does not depend on the current input). This paper proposes a unified perspective through conditional feature sensitivity analysis, taking into account both current context and feature interactions. Based on different representations of the contextual uncertainties, we present three treatment models and exploit their joint power for dealing with complex feature interactions. Synthetic examples are used to systematically test the validity of the proposed models. A practical application in medical domain is illustrated using an echocardiography database with more than 2000 video segments with both subjective (from experts) and objective validations.

This paper is concerned with acquiring panoramic focused images using a small field of view video camera. When scene points are distributed over a range of distances from the sensor, obtaining a focused composite image involves focus computations and mechanically changing some sensor parameters (translation of sensor plane, panning of camera etc.) which can be time intensive. In this paper we present methods to optimize the image acquisition strategy in order to reduce redundancy. We show that panning a camera about a point f (focal length) in front of the camera eliminates redundancy. The non-frontal imaging camera (NICAM) with tilted sensor plane has been previously introduced as a sensor that can acquire focused panoramic images. In this paper we also describe strategies for optimal selection of panning angle increments and sensor plane tilt for NICAM. Experimental results are presented for panoramic image acquisition using a regular camera as well as using NICAM.