Andreas Gerasch

GeneTrailExpress: a web-based pipeline for the statistical evaluation of microarray experiments

BackgroundHigh-throughput methods that allow for measuring the expression of thousands of genes or proteins simultaneously have opened new avenues for studying biochemical processes. While the noisiness of the data necessitates an extensive pre-processing of the raw data, the high dimensionality requires effective statistical analysis methods that facilitate the identification of crucial biological features and relations. For these reasons, the evaluation and interpretation of expression data is a complex, labor-intensive multi-step process. While a variety of tools for normalizing, analysing, or visualizing expression profiles has been developed in the last years, most of these tools offer only functionality for accomplishing certain steps of the evaluation pipeline.ResultsHere, we present a web-based toolbox that provides rich functionality for all steps of the evaluation pipeline. Our tool GeneTrailExpress offers besides standard normalization procedures powerful statistical analysis methods for studying a large variety of biological categories and pathways. Furthermore, an integrated graph visualization tool, BiNA, enables the user to draw the relevant biological pathways applying cutting-edge graph-layout algorithms.ConclusionOur gene expression toolbox with its interactive visualization of the pathways and the expression values projected onto the nodes will simplify the analysis and interpretation of biochemical pathways considerably.

FASIMU: flexible software for flux-balance computation series in large metabolic networks.

BackgroundFlux-balance analysis based on linear optimization is widely used to compute metabolic fluxes in large metabolic networks and gains increasingly importance in network curation and structural analysis. Thus, a computational tool flexible enough to realize a wide variety of FBA algorithms and able to handle batch series of flux-balance optimizations is of great benefit.ResultsWe present FASIMU, a command line oriented software for the computation of flux distributions using a variety of the most common FBA algorithms, including the first available implementation of (i) weighted flux minimization, (ii) fitness maximization for partially inhibited enzymes, and (iii) of the concentration-based thermodynamic feasibility constraint. It allows batch computation with varying objectives and constraints suited for network pruning, leak analysis, flux-variability analysis, and systematic probing of metabolic objectives for network curation. Input and output supports SBML. FASIMU can work with free (lp_solve and GLPK) or commercial solvers (CPLEX, LINDO). A new plugin (faBiNA) for BiNA allows to conveniently visualize calculated flux distributions. The platform-independent program is an open-source project, freely available under GNU public license at http://www.bioinformatics.org/fasimu including manual, tutorial, and plugins.ConclusionsWe present a flux-balance optimization program whose main merits are the implementation of thermodynamics as a constraint, batch series of computations, free availability of sources, choice on various external solvers, and the flexibility on metabolic objectives and constraints.

A novel algorithm for detecting differentially regulated paths based on gene set enrichment analysis

Motivation: Deregulated signaling cascades are known to play a crucial role in many pathogenic processes, among them are tumor initiation and progression. In the recent past, modern experimental techniques that allow for measuring the amount of mRNA transcripts of almost all known human genes in a tissue or even in a single cell have opened new avenues for studying the activity of the signaling cascades and for understanding the information flow in the networks. Results: We present a novel dynamic programming algorithm for detecting deregulated signaling cascades. The so-called FiDePa (Finding Deregulated Paths) algorithm interprets differences in the expression profiles of tumor and normal tissues. It relies on the well-known gene set enrichment analysis (GSEA) and efficiently detects all paths in a given regulatory or signaling network that are significantly enriched with differentially expressed genes or proteins. Since our algorithm allows for comparing a single tumor expression profile with the control group, it facilitates the detection of specific regulatory features of a tumor that may help to optimize tumor therapy. To demonstrate the capabilities of our algorithm, we analyzed a glioma expression dataset with respect to a directed graph that combined the regulatory networks of the KEGG and TRANSPATH database. The resulting glioma consensus network that encompasses all detected deregulated paths contained many genes and pathways that are known to be key players in glioma or cancer-related pathogenic processes. Moreover, we were able to correlate clinically relevant features like necrosis or metastasis with the detected paths. Availability: C++ source code is freely available, BiNA can be downloaded from http://www.bnplusplus.org/. Contact: ack@bioinf.uni-sb.de Supplementary information: Supplementary data are available at Bioinformatics online.

BNDB – The Biochemical Network Database

BackgroundTechnological advances in high-throughput techniques and efficient data acquisition methods have resulted in a massive amount of life science data. The data is stored in numerous databases that have been established over the last decades and are essential resources for scientists nowadays. However, the diversity of the databases and the underlying data models make it difficult to combine this information for solving complex problems in systems biology. Currently, researchers typically have to browse several, often highly focused, databases to obtain the required information. Hence, there is a pressing need for more efficient systems for integrating, analyzing, and interpreting these data. The standardization and virtual consolidation of the databases is a major challenge resulting in a unified access to a variety of data sources.DescriptionWe present the Biochemical Network Database (BNDB), a powerful relational database platform, allowing a complete semantic integration of an extensive collection of external databases. BNDB is built upon a comprehensive and extensible object model called BioCore, which is powerful enough to model most known biochemical processes and at the same time easily extensible to be adapted to new biological concepts. Besides a web interface for the search and curation of the data, a Java-based viewer (BiNA) provides a powerful platform-independent visualization and navigation of the data. BiNA uses sophisticated graph layout algorithms for an interactive visualization and navigation of BNDB.ConclusionBNDB allows a simple, unified access to a variety of external data sources. Its tight integration with the biochemical network library BN++ offers the possibility for import, integration, analysis, and visualization of the data. BNDB is freely accessible at http://www.bndb.org.

BN++ - A Biological Information System

Summary Recent years have seen an explosive growth in the amount of biochemical data available. Numerous databases have been established and are being used as an essential resource by biologists around the world. The sheer amount and heterogeneity of these data poses a major challenge: data integration and, based thereupon, the integrative analysis of these data. We present BN++, the biochemical network library, a powerful software package for integrating, analyzing, and visualizing biochemical data in the context of networks. BN++ is based on a comprehensive and extensible object model (BioCore), which has been implemented as a C++ framework, a Java class library, and a relational database. The C++ framework is used to efficiently import, integrate, and analyze the data, which is stored in a data warehouse. The Java-based viewer (BiNA) provides a powerful platform-independent visualization of the data using sophisticated graph layout algorithms. Currently, the data warehouse imports and integrates data from about a dozen important databases including, among others, sequence data, metabolic and regulatory networks, and protein interaction data. We illustrate the usefulness of BN++ with a few select example applications. Availability: BN++ is open source software available from our website at www.bnplusplus.org.

Multi-omics enrichment analysis using the GeneTrail2 web service

MOTIVATION Gene set analysis has revolutionized the interpretation of high-throughput transcriptomic data. Nowadays, with comprehensive studies that measure multiple -omics from the same sample, powerful tools for the integrative analysis of multi-omics datasets are required. RESULTS Here, we present GeneTrail2, a web service allowing the integrated analysis of transcriptomic, miRNomic, genomic and proteomic datasets. It offers multiple statistical tests, a large number of predefined reference sets, as well as a comprehensive collection of biological categories and enables direct comparisons between the computed results. We used GeneTrail2 to explore pathogenic mechanisms of Wilms tumors. We not only succeeded in revealing signaling cascades that may contribute to the malignancy of blastemal subtype tumors but also identified potential biomarkers for nephroblastoma with adverse prognosis. The presented use-case demonstrates that GeneTrail2 is well equipped for the integrative analysis of comprehensive -omics data and may help to shed light on complex pathogenic mechanisms in cancer and other diseases. AVAILABILITY AND IMPLEMENTATION GeneTrail2 can be freely accessed under https://genetrail2.bioinf.uni-sb.de CONTACT : dstoeckel@bioinf.uni-sb.de SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

BiNA: A Visual Analytics Tool for Biological Network Data

Interactive visual analysis of biological high-throughput data in the context of the underlying networks is an essential task in modern biomedicine with applications ranging from metabolic engineering to personalized medicine. The complexity and heterogeneity of data sets require flexible software architectures for data analysis. Concise and easily readable graphical representation of data and interactive navigation of large data sets are essential in this context. We present BiNA - the Biological Network Analyzer - a flexible open-source software for analyzing and visualizing biological networks. Highly configurable visualization styles for regulatory and metabolic network data offer sophisticated drawings and intuitive navigation and exploration techniques using hierarchical graph concepts. The generic projection and analysis framework provides powerful functionalities for visual analyses of high-throughput omics data in the context of networks, in particular for the differential analysis and the analysis of time series data. A direct interface to an underlying data warehouse provides fast access to a wide range of semantically integrated biological network databases. A plugin system allows simple customization and integration of new analysis algorithms or visual representations. BiNA is available under the 3-clause BSD license at http://bina.unipax.info/.

NetworkTrail—a web service for identifying and visualizing deregulated subnetworks

UNLABELLED The deregulation of biochemical pathways plays a central role in many diseases like cancer or Parkinsonss disease. In silico tools for calculating these deregulated pathways may help to gain new insights into pathogenic mechanisms and may open novel avenues for therapy stratification in the sense of personalized medicine. Here, we present NetworkTrail, a web service for the detection of deregulated pathways and subgraphs in biological networks. NetworkTrail uses a state-of-the-art integer linear programming-based approach for this task and offers interfaces to the Biological Network Analyzer (BiNA) and Cytoscape Web for visualizing the resulting subnetworks. By providing an accessible interface to otherwise hard-to-use command line tools, the new web service enables non-experts to quickly and reliably carry out this type of network analyses. AVAILABILITY AND IMPLEMENTATION NetworkTrail is a JavaServer Pages-based web service. The algorithm for finding deregulated subnetworks has been implemented in C++. NetworkTrail is available at http://networktrail.bioinf.uni-sb.de/.

Linear-Time Algorithms for Hole-free Rectilinear Proportional Contact Graph Representations

In a proportional contact representation of a planar graph, each vertex is represented by a simple polygon with area proportional to a given weight, and edges are represented by adjacencies between the corresponding pairs of polygons. In this paper we first study proportional contact representations that use rectilinear polygons without wasted areas (white space). In this setting, the best known algorithm for proportional contact representation of a maximal planar graph uses 12-sided rectilinear polygons and takes O(nlogn) time. We describe a new algorithm that guarantees 10-sided rectilinear polygons and runs in O(n) time. We also describe a linear-time algorithm for proportional contact representation of planar 3-trees with 8-sided rectilinear polygons and show that this is optimal, as there exist planar 3-trees that require 8-sided polygons. We then show that a maximal outer-planar graph admits a proportional contact representation using rectilinear polygons with 6 sides when the outer-boundary is a rectangle and with 4 sides otherwise. Finally we study maximal series-parallel graphs. Here we show that O(1)-sided rectilinear polygons are not possible unless we allow holes, but 6-sided polygons can be achieved with arbitrarily small holes.

Linear-time algorithms for hole-free rectilinear proportional contact graph representations

In a proportional contact representation of a planar graph, each vertex is represented by a simple polygon with area proportional to a given weight, and edges are represented by adjacencies between the corresponding pairs of polygons. In this paper we study proportional contact representations that use rectilinear polygons without wasted areas (white space). In this setting, the best known algorithm for proportional contact representation of a maximal planar graph uses 12-sided rectilinear polygons and takes O(nlogn) time. We describe a new algorithm that guarantees 10-sided rectilinear polygons and runs in O(n) time. We also describe a linear-time algorithm for proportional contact representation of planar 3-trees with 8-sided rectilinear polygons and show that this is optimal, as there exist planar 3-trees that require 8-sided polygons. Finally, we show that a maximal outer-planar graph admits a proportional contact representation using rectilinear polygons with 6 sides when the outer-boundary is a rectangle and with 4 sides otherwise.