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19 results

2012


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CSB: A Python framework for computational structural biology

Kalev, I., Mechelke, M., Kopec, K., Holder, T., Carstens, S., Habeck, M.

Bioinformatics, 28(22):2996-2997, 2012 (article)

Abstract
Summary: Computational Structural Biology Toolbox (CSB) is a cross-platform Python class library for reading, storing and analyzing biomolecular structures with rich support for statistical analyses. CSB is designed for reusability and extensibility and comes with a clean, well-documented API following good object-oriented engineering practice. Availability: Stable release packages are available for download from the Python Package Index (PyPI), as well as from the project’s web site http://csb.codeplex.com.

Web DOI Project Page [BibTex]

2012

Web DOI Project Page [BibTex]

2011


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Multi-way set enumeration in weight tensors

Georgii, E., Tsuda, K., Schölkopf, B.

Machine Learning, 82(2):123-155, February 2011 (article)

Abstract
The analysis of n-ary relations receives attention in many different fields, for instance biology, web mining, and social studies. In the basic setting, there are n sets of instances, and each observation associates n instances, one from each set. A common approach to explore these n-way data is the search for n-set patterns, the n-way equivalent of itemsets. More precisely, an n-set pattern consists of specific subsets of the n instance sets such that all possible associations between the corresponding instances are observed in the data. In contrast, traditional itemset mining approaches consider only two-way data, namely items versus transactions. The n-set patterns provide a higher-level view of the data, revealing associative relationships between groups of instances. Here, we generalize this approach in two respects. First, we tolerate missing observations to a certain degree, that means we are also interested in n-sets where most (although not all) of the possible associations have been recorded in the data. Second, we take association weights into account. In fact, we propose a method to enumerate all n-sets that satisfy a minimum threshold with respect to the average association weight. Technically, we solve the enumeration task using a reverse search strategy, which allows for effective pruning of the search space. In addition, our algorithm provides a ranking of the solutions and can consider further constraints. We show experimental results on artificial and real-world datasets from different domains.

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2011


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Statistical mechanics analysis of sparse data

Habeck, M.

Journal of Structural Biology, 173(3):541-548, March 2011 (article)

Abstract
Inferential structure determination uses Bayesian theory to combine experimental data with prior structural knowledge into a posterior probability distribution over protein conformational space. The posterior distribution encodes everything one can say objectively about the native structure in the light of the available data and additional prior assumptions and can be searched for structural representatives. Here an analogy is drawn between the posterior distribution and the canonical ensemble of statistical physics. A statistical mechanics analysis assesses the complexity of a structure calculation globally in terms of ensemble properties. Analogs of the free energy and density of states are introduced; partition functions evaluate the consistency of prior assumptions with data. Critical behavior is observed with dwindling restraint density, which impairs structure determination with too sparse data. However, prior distributions with improved realism ameliorate the situation by lowering the critical number of observations. An in-depth analysis of various experimentally accessible structural parameters and force field terms will facilitate a statistical approach to protein structure determination with sparse data that avoids bias as much as possible.

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PDF DOI Project Page [BibTex]


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A Blind Deconvolution Approach for Improving the Resolution of Cryo-EM Density Maps

Hirsch, M., Schölkopf, B., Habeck, M.

Journal of Computational Biology, 18(3):335-346, March 2011 (article)

Abstract
Cryo-electron microscopy (cryo-EM) plays an increasingly prominent role in structure elucidation of macromolecular assemblies. Advances in experimental instrumentation and computational power have spawned numerous cryo-EM studies of large biomolecular complexes resulting in the reconstruction of three-dimensional density maps at intermediate and low resolution. In this resolution range, identification and interpretation of structural elements and modeling of biomolecular structure with atomic detail becomes problematic. In this article, we present a novel algorithm that enhances the resolution of intermediate- and low-resolution density maps. Our underlying assumption is to model the low-resolution density map as a blurred and possibly noise-corrupted version of an unknown high-resolution map that we seek to recover by deconvolution. By exploiting the nonnegativity of both the high-resolution map and blur kernel, we derive multiplicative updates reminiscent of those used in nonnegative matrix factorization. Our framework allows for easy incorporation of additional prior knowledge such as smoothness and sparseness, on both the sharpened density map and the blur kernel. A probabilistic formulation enables us to derive updates for the hyperparameters; therefore, our approach has no parameter that needs adjustment. We apply the algorithm to simulated three-dimensional electron microscopic data. We show that our method provides better resolved density maps when compared with B-factor sharpening, especially in the presence of noise. Moreover, our method can use additional information provided by homologous structures, which helps to improve the resolution even further.

Web DOI Project Page [BibTex]


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HHfrag: HMM-based fragment detection using HHpred

Kalev, I., Habeck, M.

Bioinformatics, 27(22):3110-3116, November 2011 (article)

Abstract
Motivation: Over the last decade, both static and dynamic fragment libraries for protein structure prediction have been introduced. The former are built from clusters in either sequence or structure space and aim to extract a universal structural alphabet. The latter are tailored for a particular query protein sequence and aim to provide local structural templates that need to be assembled in order to build the full-length structure. Results: Here, we introduce HHfrag, a dynamic HMM-based fragment search method built on the profile–profile comparison tool HHpred. We show that HHfrag provides advantages over existing fragment assignment methods in that it: (i) improves the precision of the fragments at the expense of a minor loss in sequence coverage; (ii) detects fragments of variable length (6–21 amino acid residues); (iii) allows for gapped fragments and (iv) does not assign fragments to regions where there is no clear sequence conservation. We illustrate the usefulness of fragments detected by HHfrag on targets from most recent CASP.

Web DOI Project Page [BibTex]

Web DOI Project Page [BibTex]


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EPIBLASTER-fast exhaustive two-locus epistasis detection strategy using graphical processing units

Kam-Thong, T., Czamara, D., Tsuda, K., Borgwardt, K., Lewis, C., Erhardt-Lehmann, A., Hemmer, B., Rieckmann, P., Daake, M., Weber, F., Wolf, C., Ziegler, A., Pütz, B., Holsboer, F., Schölkopf, B., Müller-Myhsok, B.

European Journal of Human Genetics, 19(4):465-471, April 2011 (article)

Abstract
Detection of epistatic interaction between loci has been postulated to provide a more in-depth understanding of the complex biological and biochemical pathways underlying human diseases. Studying the interaction between two loci is the natural progression following traditional and well-established single locus analysis. However, the added costs and time duration required for the computation involved have thus far deterred researchers from pursuing a genome-wide analysis of epistasis. In this paper, we propose a method allowing such analysis to be conducted very rapidly. The method, dubbed EPIBLASTER, is applicable to case–control studies and consists of a two-step process in which the difference in Pearson‘s correlation coefficients is computed between controls and cases across all possible SNP pairs as an indication of significant interaction warranting further analysis. For the subset of interactions deemed potentially significant, a second-stage analysis is performed using the likelihood ratio test from the logistic regression to obtain the P-value for the estimated coefficients of the individual effects and the interaction term. The algorithm is implemented using the parallel computational capability of commercially available graphical processing units to greatly reduce the computation time involved. In the current setup and example data sets (211 cases, 222 controls, 299468 SNPs; and 601 cases, 825 controls, 291095 SNPs), this coefficient evaluation stage can be completed in roughly 1 day. Our method allows for exhaustive and rapid detection of significant SNP pair interactions without imposing significant marginal effects of the single loci involved in the pair.

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PDF PDF DOI Project Page [BibTex]


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Epistasis detection on quantitative phenotypes by exhaustive enumeration using GPUs

Kam-Thong, T., Pütz, B., Karbalai, N., Müller-Myhsok, B., Borgwardt, K.

Bioinformatics, 27(13: ISMB/ECCB 2011):i214-i221, July 2011 (article)

Abstract
Motivation: In recent years, numerous genome-wide association studies have been conducted to identify genetic makeup that explains phenotypic differences observed in human population. Analytical tests on single loci are readily available and embedded in common genome analysis software toolset. The search for significant epistasis (gene–gene interactions) still poses as a computational challenge for modern day computing systems, due to the large number of hypotheses that have to be tested. Results: In this article, we present an approach to epistasis detection by exhaustive testing of all possible SNP pairs. The search strategy based on the Hilbert–Schmidt Independence Criterion can help delineate various forms of statistical dependence between the genetic markers and the phenotype. The actual implementation of this search is done on the highly parallelized architecture available on graphics processing units rendering the completion of the full search feasible within a day.

Web DOI Project Page [BibTex]

Web DOI Project Page [BibTex]


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Weisfeiler-Lehman Graph Kernels

Shervashidze, N., Schweitzer, P., van Leeuwen, E., Mehlhorn, K., Borgwardt, M.

Journal of Machine Learning Research, 12, pages: 2539-2561, September 2011 (article)

Abstract
In this article, we propose a family of efficient kernels for large graphs with discrete node labels. Key to our method is a rapid feature extraction scheme based on the Weisfeiler-Lehman test of isomorphism on graphs. It maps the original graph to a sequence of graphs, whose node attributes capture topological and label information. A family of kernels can be defined based on this Weisfeiler-Lehman sequence of graphs, including a highly efficient kernel comparing subtree-like patterns. Its runtime scales only linearly in the number of edges of the graphs and the length of the Weisfeiler-Lehman graph sequence. In our experimental evaluation, our kernels outperform state-of-the-art graph kernels on several graph classification benchmark data sets in terms of accuracy and runtime. Our kernels open the door to large-scale applications of graph kernels in various disciplines such as computational biology and social network analysis.

PDF Web Project Page [BibTex]

PDF Web Project Page [BibTex]


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Two-locus association mapping in subquadratic time

Achlioptas, P., Schölkopf, B., Borgwardt, K.

In pages: 726-734, (Editors: C Apté and J Ghosh and P Smyth), ACM Press, New York, NY, USA, 17th ACM SIGKKD Conference on Knowledge Discovery and Data Mining (KDD) , August 2011 (inproceedings)

Abstract
Genome-wide association studies (GWAS) have not been able to discover strong associations between many complex human diseases and single genetic loci. Mapping these phenotypes to pairs of genetic loci is hindered by the huge number of candidates leading to enormous computational and statistical problems. In GWAS on single nucleotide polymorphisms (SNPs), one has to consider in the order of 1010 to 1014 pairs, which is infeasible in practice. In this article, we give the first algorithm for 2-locus genome-wide association studies that is subquadratic in the number, n, of SNPs. The running time of our algorithm is data-dependent, but large experiments over real genomic data suggest that it scales empirically as n3/2. As a result, our algorithm can easily cope with n ~ 107, i.e., it can efficiently search all pairs of SNPs in the human genome.

Web DOI Project Page [BibTex]

Web DOI Project Page [BibTex]


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Hierarchical Multitask Structured Output Learning for Large-scale Sequence Segmentation

Görnitz, N., Widmer, C., Zeller, G., Kahles, A., Sonnenburg, S., Rätsch, G.

In Advances in Neural Information Processing Systems 24, pages: 2690-2698, (Editors: J Shawe-Taylor and RS Zemel and P Bartlett and FCN Pereira and KQ Weinberger), Curran Associates, Inc., Red Hook, NY, USA, Twenty-Fifth Annual Conference on Neural Information Processing Systems (NIPS), 2011 (inproceedings)

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PDF Project Page [BibTex]

2010


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Inferring latent task structure for Multitask Learning by Multiple Kernel Learning

Widmer, C., Toussaint, N., Altun, Y., Rätsch, G.

BMC Bioinformatics, 11 Suppl 8, pages: S5, 2010 (article)

Abstract
The lack of sufficient training data is the limiting factor for many Machine Learning applications in Computational Biology. If data is available for several different but related problem domains, Multitask Learning algorithms can be used to learn a model based on all available information. In Bioinformatics, many problems can be cast into the Multitask Learning scenario by incorporating data from several organisms. However, combining information from several tasks requires careful consideration of the degree of similarity between tasks. Our proposed method simultaneously learns or refines the similarity between tasks along with the Multitask Learning classifier. This is done by formulating the Multitask Learning problem as Multiple Kernel Learning, using the recently published q-Norm MKL algorithm.

Web DOI Project Page [BibTex]

2010

Web DOI Project Page [BibTex]


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Leveraging Sequence Classification by Taxonomy-based Multitask Learning

Widmer, C., Leiva, J., Altun, Y., Rätsch, G.

In Research in Computational Molecular Biology, LNCS, Vol. 6044, pages: 522-534, (Editors: B Berger), Springer, Berlin, Germany, 14th Annual International Conference, RECOMB, 2010 (inproceedings)

DOI Project Page [BibTex]

DOI Project Page [BibTex]

2009


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The DICS repository: module-assisted analysis of disease-related gene lists

Dietmann, S., Georgii, E., Antonov, A., Tsuda, K., Mewes, H.

Bioinformatics, 25(6):830-831, January 2009 (article)

Abstract
The DICS database is a dynamic web repository of computationally predicted functional modules from the human protein–protein interaction network. It provides references to the CORUM, DrugBank, KEGG and Reactome pathway databases. DICS can be accessed for retrieving sets of overlapping modules and protein complexes that are significantly enriched in a gene list, thereby providing valuable information about the functional context.

Web DOI Project Page [BibTex]

2009

Web DOI Project Page [BibTex]


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Enumeration of condition-dependent dense modules in protein interaction networks

Georgii, E., Dietmann, S., Uno, T., Pagel, P., Tsuda, K.

Bioinformatics, 25(7):933-940, February 2009 (article)

Abstract
Motivation: Modern systems biology aims at understanding how the different molecular components of a biological cell interact. Often, cellular functions are performed by complexes consisting of many different proteins. The composition of these complexes may change according to the cellular environment, and one protein may be involved in several different processes. The automatic discovery of functional complexes from protein interaction data is challenging. While previous approaches use approximations to extract dense modules, our approach exactly solves the problem of dense module enumeration. Furthermore, constraints from additional information sources such as gene expression and phenotype data can be integrated, so we can systematically mine for dense modules with interesting profiles. Results: Given a weighted protein interaction network, our method discovers all protein sets that satisfy a user-defined minimum density threshold. We employ a reverse search strategy, which allows us to exploit the density criterion in an efficient way. Our experiments show that the novel approach is feasible and produces biologically meaningful results. In comparative validation studies using yeast data, the method achieved the best overall prediction performance with respect to confirmed complexes. Moreover, by enhancing the yeast network with phenotypic and phylogenetic profiles and the human network with tissue-specific expression data, we identified condition-dependent complex variants.

Web DOI Project Page [BibTex]

Web DOI Project Page [BibTex]


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mGene.web: a web service for accurate computational gene finding

Schweikert, G., Behr, J., Zien, A., Zeller, G., Ong, C., Sonnenburg, S., Rätsch, G.

Nucleic Acids Research, 37, pages: W312-6, 2009 (article)

Abstract
We describe mGene.web, a web service for the genome-wide prediction of protein coding genes from eukaryotic DNA sequences. It offers pre-trained models for the recognition of gene structures including untranslated regions in an increasing number of organisms. With mGene.web, users have the additional possibility to train the system with their own data for other organisms on the push of a button, a functionality that will greatly accelerate the annotation of newly sequenced genomes. The system is built in a highly modular way, such that individual components of the framework, like the promoter prediction tool or the splice site predictor, can be used autonomously. The underlying gene finding system mGene is based on discriminative machine learning techniques and its high accuracy has been demonstrated in an international competition on nematode genomes. mGene.web is available at http://www.mgene.org/web, it is free of charge and can be used for eukaryotic genomes of small to moderate size (several hundred Mbp).

DOI Project Page [BibTex]

DOI Project Page [BibTex]


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mGene: accurate SVM-based gene finding with an application to nematode genomes

Schweikert, G., Zien, A., Zeller, G., Behr, J., Dieterich, C., Ong, C., Philips, P., De Bona, F., Hartmann, L., Bohlen, A., Krüger, N., Sonnenburg, S., Rätsch, G.

Genome Research, 19(11):2133-43, 2009 (article)

Abstract
We present a highly accurate gene-prediction system for eukaryotic genomes, called mGene. It combines in an unprecedented manner the flexibility of generalized hidden Markov models (gHMMs) with the predictive power of modern machine learning methods, such as Support Vector Machines (SVMs). Its excellent performance was proved in an objective competition based on the genome of the nematode Caenorhabditis elegans. Considering the average of sensitivity and specificity, the developmental version of mGene exhibited the best prediction performance on nucleotide, exon, and transcript level for ab initio and multiple-genome gene-prediction tasks. The fully developed version shows superior performance in 10 out of 12 evaluation criteria compared with the other participating gene finders, including Fgenesh++ and Augustus. An in-depth analysis of mGene's genome-wide predictions revealed that approximately 2200 predicted genes were not contained in the current genome annotation. Testing a subset of 57 of these genes by RT-PCR and sequencing, we confirmed expression for 24 (42%) of them. mGene missed 300 annotated genes, out of which 205 were unconfirmed. RT-PCR testing of 24 of these genes resulted in a success rate of merely 8%. These findings suggest that even the gene catalog of a well-studied organism such as C. elegans can be substantially improved by mGene's predictions. We also provide gene predictions for the four nematodes C. briggsae, C. brenneri, C. japonica, and C. remanei. Comparing the resulting proteomes among these organisms and to the known protein universe, we identified many species-specific gene inventions. In a quality assessment of several available annotations for these genomes, we find that mGene's predictions are most accurate.

DOI Project Page [BibTex]

DOI Project Page [BibTex]


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An Empirical Analysis of Domain Adaptation Algorithms for Genomic Sequence Analysis

Schweikert, G., Widmer, C., Schölkopf, B., Rätsch, G.

In Advances in neural information processing systems 21, pages: 1433-1440, (Editors: D Koller and D Schuurmans and Y Bengio and L Bottou), Curran, Red Hook, NY, USA, 22nd Annual Conference on Neural Information Processing Systems (NIPS), June 2009 (inproceedings)

Abstract
We study the problem of domain transfer for a supervised classification task in mRNA splicing. We consider a number of recent domain transfer methods from machine learning, including some that are novel, and evaluate them on genomic sequence data from model organisms of varying evolutionary distance. We find that in cases where the organisms are not closely related, the use of domain adaptation methods can help improve classification performance.

PDF Web Project Page [BibTex]

PDF Web Project Page [BibTex]


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Fast subtree kernels on graphs

Shervashidze, N., Borgwardt, K.

In Advances in Neural Information Processing Systems 22, pages: 1660-1668, (Editors: Bengio, Y. , D. Schuurmans, J. Lafferty, C. Williams, A. Culotta), Curran, Red Hook, NY, USA, 23rd Annual Conference on Neural Information Processing Systems (NIPS), 2009 (inproceedings)

Abstract
In this article, we propose fast subtree kernels on graphs. On graphs with n nodes and m edges and maximum degree d, these kernels comparing subtrees of height h can be computed in O(mh), whereas the classic subtree kernel by Ramon & G{\"a}rtner scales as O(n24dh). Key to this efficiency is the observation that the Weisfeiler-Lehman test of isomorphism from graph theory elegantly computes a subtree kernel as a byproduct. Our fast subtree kernels can deal with labeled graphs, scale up easily to large graphs and outperform state-of-the-art graph kernels on several classification benchmark datasets in terms of accuracy and runtime.

PDF Web Project Page [BibTex]

PDF Web Project Page [BibTex]

2008


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Structure of the human voltage-dependent anion channel

Bayrhuber, M., Meins, T., Habeck, M., Becker, S., Giller, K., Villinger, S., Vonrhein, C., Griesinger, C., Zweckstetter, M., Zeth, K.

Proceedings of the National Academy of Sciences of the United States of America, 105(40):15370-15375, October 2008 (article)

Abstract
The voltage-dependent anion channel (VDAC), also known as mitochondrial porin, is the most abundant protein in the mitochondrial outer membrane (MOM). VDAC is the channel known to guide the metabolic flux across the MOM and plays a key role in mitochondrially induced apoptosis. Here, we present the 3D structure of human VDAC1, which was solved conjointly by NMR spectroscopy and x-ray crystallography. Human VDAC1 (hVDAC1) adopts a β-barrel architecture composed of 19 β-strands with an α-helix located horizontally midway within the pore. Bioinformatic analysis indicates that this channel architecture is common to all VDAC proteins and is adopted by the general import pore TOM40 of mammals, which is also located in the MOM.

Web DOI Project Page [BibTex]

2008

Web DOI Project Page [BibTex]