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1.  A high-throughput framework to detect synapses in electron microscopy images 
Bioinformatics  2013;29(13):i9-i17.
Motivation: Synaptic connections underlie learning and memory in the brain and are dynamically formed and eliminated during development and in response to stimuli. Quantifying changes in overall density and strength of synapses is an important pre-requisite for studying connectivity and plasticity in these cases or in diseased conditions. Unfortunately, most techniques to detect such changes are either low-throughput (e.g. electrophysiology), prone to error and difficult to automate (e.g. standard electron microscopy) or too coarse (e.g. magnetic resonance imaging) to provide accurate and large-scale measurements.
Results: To facilitate high-throughput analyses, we used a 50-year-old experimental technique to selectively stain for synapses in electron microscopy images, and we developed a machine-learning framework to automatically detect synapses in these images. To validate our method, we experimentally imaged brain tissue of the somatosensory cortex in six mice. We detected thousands of synapses in these images and demonstrate the accuracy of our approach using cross-validation with manually labeled data and by comparing against existing algorithms and against tools that process standard electron microscopy images. We also used a semi-supervised algorithm that leverages unlabeled data to overcome sample heterogeneity and improve performance. Our algorithms are highly efficient and scalable and are freely available for others to use.
Availability: Code is available at http://www.cs.cmu.edu/∼saketn/detect_synapses/
Contact: zivbj@cs.cmu.edu
doi:10.1093/bioinformatics/btt222
PMCID: PMC3694654  PMID: 23813014
2.  Integrating sequence, expression and interaction data to determine condition-specific miRNA regulation 
Bioinformatics  2013;29(13):i89-i97.
Motivation: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. MiRNAs were shown to play an important role in development and disease, and accurately determining the networks regulated by these miRNAs in a specific condition is of great interest. Early work on miRNA target prediction has focused on using static sequence information. More recently, researchers have combined sequence and expression data to identify such targets in various conditions.
Results: We developed the Protein Interaction-based MicroRNA Modules (PIMiM), a regression-based probabilistic method that integrates sequence, expression and interaction data to identify modules of mRNAs controlled by small sets of miRNAs. We formulate an optimization problem and develop a learning framework to determine the module regulation and membership. Applying PIMiM to cancer data, we show that by adding protein interaction data and modeling cooperative regulation of mRNAs by a small number of miRNAs, PIMiM can accurately identify both miRNA and their targets improving on previous methods. We next used PIMiM to jointly analyze a number of different types of cancers and identified both common and cancer-type-specific miRNA regulators.
Contact: zivbj@cs.cmu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt231
PMCID: PMC3694655  PMID: 23813013
3.  Identifying proteins controlling key disease signaling pathways 
Bioinformatics  2013;29(13):i227-i236.
Motivation: Several types of studies, including genome-wide association studies and RNA interference screens, strive to link genes to diseases. Although these approaches have had some success, genetic variants are often only present in a small subset of the population, and screens are noisy with low overlap between experiments in different labs. Neither provides a mechanistic model explaining how identified genes impact the disease of interest or the dynamics of the pathways those genes regulate. Such mechanistic models could be used to accurately predict downstream effects of knocking down pathway members and allow comprehensive exploration of the effects of targeting pairs or higher-order combinations of genes.
Results: We developed methods to model the activation of signaling and dynamic regulatory networks involved in disease progression. Our model, SDREM, integrates static and time series data to link proteins and the pathways they regulate in these networks. SDREM uses prior information about proteins’ likelihood of involvement in a disease (e.g. from screens) to improve the quality of the predicted signaling pathways. We used our algorithms to study the human immune response to H1N1 influenza infection. The resulting networks correctly identified many of the known pathways and transcriptional regulators of this disease. Furthermore, they accurately predict RNA interference effects and can be used to infer genetic interactions, greatly improving over other methods suggested for this task. Applying our method to the more pathogenic H5N1 influenza allowed us to identify several strain-specific targets of this infection.
Availability: SDREM is available from http://sb.cs.cmu.edu/sdrem
Contact: zivbj@cs.cmu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt241
PMCID: PMC3694658  PMID: 23812988
4.  DECOD: fast and accurate discriminative DNA motif finding 
Bioinformatics  2011;27(17):2361-2367.
Motivation: Motif discovery is now routinely used in high-throughput studies including large-scale sequencing and proteomics. These datasets present new challenges. The first is speed. Many motif discovery methods do not scale well to large datasets. Another issue is identifying discriminative rather than generative motifs. Such discriminative motifs are important for identifying co-factors and for explaining changes in behavior between different conditions.
Results: To address these issues we developed a method for DECOnvolved Discriminative motif discovery (DECOD). DECOD uses a k-mer count table and so its running time is independent of the size of the input set. By deconvolving the k-mers DECOD considers context information without using the sequences directly. DECOD outperforms previous methods both in speed and in accuracy when using simulated and real biological benchmark data. We performed new binding experiments for p53 mutants and used DECOD to identify p53 co-factors, suggesting new mechanisms for p53 activation.
Availability: The source code and binaries for DECOD are available at http://www.sb.cs.cmu.edu/DECOD
Contact: zivbj@cs.cmu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr412
PMCID: PMC3157928  PMID: 21752801
5.  Cross-species queries of large gene expression databases 
Bioinformatics  2010;26(19):2416-2423.
Motivation: Expression databases, including the Gene Expression Omnibus and ArrayExpress, have experienced significant growth over the past decade and now hold hundreds of thousands of arrays from multiple species. Since most drugs are initially tested on model organisms, the ability to compare expression experiments across species may help identify pathways that are activated in a similar way in humans and other organisms. However, while several methods exist for finding co-expressed genes in the same species as a query gene, looking at co-expression of homologs or arbitrary genes in other species is challenging. Unlike sequence, which is static, expression is dynamic and changes between tissues, conditions and time. Thus, to carry out cross-species analysis using these databases, we need methods that can match experiments in one species with experiments in another species.
Results: To facilitate queries in large databases, we developed a new method for comparing expression experiments from different species. We define a distance metric between the ranking of orthologous genes in the two species. We show how to solve an optimization problem for learning the parameters of this function using a training dataset of known similar expression experiments pairs. The function we learn outperforms previous methods and simpler rank comparison methods that have been used in the past for single species analysis. We used our method to compare millions of array pairs from mouse and human expression experiments. The resulting matches can be used to find functionally related genes, to hypothesize about biological response mechanisms and to highlight conditions and diseases that are activating similar pathways in both species.
Availability: Supporting methods, results and a Matlab implementation are available from http://sb.cs.cmu.edu/ExpQ/
Contact: zivbj@cs.cmu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq451
PMCID: PMC2944203  PMID: 20702396
6.  Cross species analysis of microarray expression data 
Bioinformatics  2009;25(12):1476-1483.
Motivation: Many biological systems operate in a similar manner across a large number of species or conditions. Cross-species analysis of sequence and interaction data is often applied to determine the function of new genes. In contrast to these static measurements, microarrays measure the dynamic, condition-specific response of complex biological systems. The recent exponential growth in microarray expression datasets allows researchers to combine expression experiments from multiple species to identify genes that are not only conserved in sequence but also operated in a similar way in the different species studied.
Results: In this review we discuss the computational and technical challenges associated with these studies, the approaches that have been developed to address these challenges and the advantages of cross-species analysis of microarray data. We show how successful application of these methods lead to insights that cannot be obtained when analyzing data from a single species. We also highlight current open problems and discuss possible ways to address them.
Contact: zivbj@cs.cmu.edu
doi:10.1093/bioinformatics/btp247
PMCID: PMC2732912  PMID: 19357096
7.  Protein complex identification by supervised graph local clustering 
Bioinformatics  2008;24(13):i250-i268.
Motivation: Protein complexes integrate multiple gene products to coordinate many biological functions. Given a graph representing pairwise protein interaction data one can search for subgraphs representing protein complexes. Previous methods for performing such search relied on the assumption that complexes form a clique in that graph. While this assumption is true for some complexes, it does not hold for many others. New algorithms are required in order to recover complexes with other types of topological structure.
Results: We present an algorithm for inferring protein complexes from weighted interaction graphs. By using graph topological patterns and biological properties as features, we model each complex subgraph by a probabilistic Bayesian network (BN). We use a training set of known complexes to learn the parameters of this BN model. The log-likelihood ratio derived from the BN is then used to score subgraphs in the protein interaction graph and identify new complexes. We applied our method to protein interaction data in yeast. As we show our algorithm achieved a considerable improvement over clique based algorithms in terms of its ability to recover known complexes. We discuss some of the new complexes predicted by our algorithm and determine that they likely represent true complexes.
Availability: Matlab implementation is available on the supporting website: www.cs.cmu.edu/~qyj/SuperComplex
Contact: zivbj@cs.cmu.edu
doi:10.1093/bioinformatics/btn164
PMCID: PMC2718642  PMID: 18586722
8.  Alignment and classification of time series gene expression in clinical studies 
Bioinformatics  2008;24(13):i147-i155.
Motivation: Classification of tissues using static gene-expression data has received considerable attention. Recently, a growing number of expression datasets are measured as a time series. Methods that are specifically designed for this temporal data can both utilize its unique features (temporal evolution of profiles) and address its unique challenges (different response rates of patients in the same class).
Results: We present a method that utilizes hidden Markov models (HMMs) for the classification task. We use HMMs with less states than time points leading to an alignment of the different patient response rates. To focus on the differences between the two classes we develop a discriminative HMM classifier. Unlike the traditional generative HMM, discriminative HMM can use examples from both classes when learning the model for a specific class. We have tested our method on both simulated and real time series expression data. As we show, our method improves upon prior methods and can suggest markers for specific disease and response stages that are not found when using traditional classifiers.
Availability: Matlab implementation is available from http://www.cs.cmu.edu/~thlin/tram/
Contact: zivbj@cs.cmu.edu
doi:10.1093/bioinformatics/btn152
PMCID: PMC2718630  PMID: 18586707

Results 1-8 (8)