MOTIVATION: Signalling entropy measures the uncertainty or randomness in the signalling pathways of a biological system. It reflects the complexity and variability of protein interactions and can indicate how information is processed within cells. Higher signalling entropy often indicates a more dynamic and adaptive state, whereas lower entropy may imply a more stable and less responsive condition. Estimating signalling entropy has become a valuable method for studying and understanding the complexity of biological processes. This measure has the potential to shed valuable insights into various phenomena, including the mechanisms behind cell fate decisions, drug resistance, and disease progression. To examine the molecular changes within a system, signalling entropy is quantified through the integration of expression measurements and protein interaction networks. Experimental and computational issues, such as false positives and additional noise, can all compromise the accuracy of protein interaction networks. Correction methods can be used to mitigate spurious results, correct for experimental bias, and integrate data from multiple sources. However, to date, the effect of such approaches on entropy calculations, together with the impact of different underlying networks, has yet to be evaluated. RESULTS: Here, we investigate how the topology of distinct protein interaction networks can alter the entropy calculation. We examine the entropy derived from different protein interaction networks. Additionally, we systematically evaluate different correction strategies, outlining their benefits and drawbacks along with identifying the most effective approaches for specific types of data and biological scenarios. This protocol outlines how to optimize the reliability of entropy calculations and ultimately leads to a deeper comprehension of biological processes and disease mechanisms.

MOTIVATION: Boolean networks can serve as straightforward models for understanding processes such as gene regulation, and employing logical rules. These rules can either be derived from existing literature or by data-driven approaches. However, in the context of large networks, the exhaustive search for intervention targets becomes challenging due to the exponential expansion of a Boolean network's state space and the multitude of potential target candidates, along with their various combinations. Instead, we can employ the logical rules and resultant interaction graph as a means to identify targets of specific interest within larger-scale models. This approach not only facilitates the screening process but also serves as a preliminary filtering step, enabling the focused investigation of candidates that hold promise for more profound dynamic analysis. However, applying this method requires a working knowledge of R, thus restricting the range of potential users. We, therefore, aim to provide an application that makes this method accessible to a broader scientific community. RESULTS: Here, we introduce GatekeepR, a graphical, web-based R Shiny application that enables scientists to screen Boolean network models for possible intervention targets whose perturbation is likely to have a large impact on the system's dynamics. This application does not require a local installation or knowledge of R and provides the suggested targets along with additional network information and visualizations in an intuitive, easy-to-use manner. The Supplementary Material describes the underlying method for identifying these nodes along with an example application in a network modeling pancreatic cancer. AVAILABILITY AND IMPLEMENTATION: https://www.github.com/sysbio-bioinf/GatekeepR https://abel.informatik.uni-ulm.de/shiny/GatekeepR/.

Abstract Invariant concept classes form the backbone of classification algorithms immune to specific data transformations, ensuring consistent predictions regardless of these alterations. However, this robustness can come at the cost of limited access to the original sample information, potentially impacting generalization performance. This study introduces an addition to these classes—the permutation-invariant linear classifiers. Distinguished by their structural characteristics, permutation-invariant linear classifiers are unaffected by permutations on feature vectors, a property not guaranteed by other non-constant linear classifiers. The study characterizes this new concept class, highlighting its constant capacity, independent of input dimensionality. In practical assessments using linear support vector machines, the permutation-invariant classifiers exhibit superior performance in permutation experiments on artificial datasets and real mutation profiles. Interestingly, they outperform general linear classifiers not only in permutation experiments but also in permutation-free settings, surpassing unconstrained counterparts. Additionally, findings from real mutation profiles support the significance of tumor mutational burden as a biomarker.

Model transformation languages are domain-specific languages used to define transformations of models. These transformations consist of the translation from one modeling formalism into another or just the updating of a given model. Such transformations are often described declaratively and are often implemented based on very small models that cover the language of the input model. As a result, transformation developers are often unable to assess the time required to transform a larger model. Hence, we propose a prediction approach based on machine learning which uses a set of model characteristics as input and provides a prediction of the execution time of a transformation defined in the Atlas Transformation Language (ATL). In our previous work (Groner et al., 2023), we already showed that support vector regression in combination with a model characterization based on the number of model elements, the number of references, and the number of attributes is the best choice in terms of usability and prediction accuracy for the transformations considered in our experiments. Our previous approach cannot predict the performance of transformations correctly which transform attributes whose values have an arbitrary size, like string attributes. Therefore, we investigate in this work whether an extension of our feature sets that describes the average size of string attributes can help to overcome this weakness. Our results show that the random forest approach in combination with model characterizations based on the number of model elements, the number of references, the number of attributes, and the average size of string attributes filtered by the 85th percentile of their variance is the best choice in terms of the simple way to describe a model and the quality of the obtained prediction. With this combination, we obtained a mean absolute percentage error (MAPE) of 5.07% over all modules and a MAPE of 4.82% over all modules excluding the transformation for which our previous approach failed. Whereas, we obtained previously a MAPE of 38.48% over all modules and a MAPE of 4.45% over all modules excluding the transformation for which our previous approach failed.

Glioblastoma is the most common malignant brain tumor with a poor survival rate due to its high intra- and intertumor heterogeneity. The current heterogeneity determination is based on a microscopic analysis of Hematoxilyn and Eosinstained tumor slides carried out by experienced neuropathologists. There is no standardized procedure yet, to quantify heterogeneity, though. With the hypothesis that the amount of heterogeneity impacts overall survival, we aim to develop an objective method to capture heterogeneity. We were able to successfully implement an initial Machine Learning classification model for determining heterogeneity. However, the available dataset was insufficient to train a resilient and stable system. Therefore, we propose an architecture for a semi-automatic data collection and preprocessing framework easing the collection of large quantities of required data. While there exists a multitude of frameworks tackling parts of the tumor research area, no simple ready-to-use solution is present for the easy collection of tumor data in daily clinical routine, especially for high-resolution pathological images. We plan to implement the proposed architecture at the University Hospital Augsburg, Germany in 2023. The dataset created in this process will then be used as a resilient basis for heterogeneity classification and for analyzing glioblastomas in general.

At the beginning of the COVID-19 pandemic, with a lack of knowledge about the novel virus and a lack of widely available tests, getting first feedback about being infected was not easy. To support all citizens in this respect, we developed the mobile health app Corona Check. Based on a self-reported questionnaire about symptoms and contact history, users get first feedback about a possible corona infection and advice on what to do. We developed Corona Check based on our existing software framework and released the app on Google Play and the Apple App Store on April 4, 2020. Until October 30, 2021, we collected 51,323 assessments from 35,118 users with explicit agreement of the users that their anonymized data may be used for research purposes. For 70.6% of the assessments, the users additionally shared their coarse geolocation with us. To the best of our knowledge, we are the first to report about such a large-scale study in this context of COVID-19 mHealth systems. Although users from some countries reported more symptoms on average than users from other countries, we did not find any statistically significant differences between symptom distributions (regarding country, age, and sex). Overall, the Corona Check app provided easily accessible information on corona symptoms and showed the potential to help overburdened corona telephone hotlines, especially during the beginning of the pandemic. Corona Check thus was able to support fighting the spread of the novel coronavirus. mHealth apps further prove to be valuable tools for longitudinal health data collection.

MOTIVATION: Biological processes are complex systems with distinct behaviour. Despite the growing amount of available data, knowledge is sparse and often insufficient to investigate the complex regulatory behaviour of these systems. Moreover, different cellular phenotypes are possible under varying conditions. Mathematical models attempt to unravel these mechanisms by investigating the dynamics of regulatory networks. Therefore, a major challenge is to combine regulations and phenotypical information as well as the underlying mechanisms. To predict regulatory links in these models, we established an approach called CANTATA to support the integration of information into regulatory networks and retrieve potential underlying regulations. This is achieved by optimizing both static and dynamic properties of these networks. RESULTS: Initial results show that the algorithm predicts missing interactions by recapitulating the known phenotypes while preserving the original topology and optimizing the robustness of the model. The resulting models allow for hypothesizing about the biological impact of certain regulatory dependencies. AVAILABILITY AND IMPLEMENTATION: Source code of the application, example files and results are available at https://github.com/sysbio-bioinf/Cantata. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

In his letter to the editor, Luis Rocha addresses the concern that other researchers might be discouraged from further investigation of dynamic analyses in Boolean networks based on a statement from our recently published manuscript (Weidner et al., 2021). In particular, the author refers to a phrase in our abstract on the feasibility of dynamic investigations in large Boolean models. We value the discussion on this crucial topic in the field of Boolean networks. However, we kindly disagree on the interpretation of the respective parts of our manuscript. First, we want to refer to the point addressed in our abstract. Here, we state: ‘However, since dynamic complexity of these models grows exponentially with their size, exhaustive analyses of the dynamics and consequently screening all possible interventions eventually becomes infeasible’. In addition, in our introduction, we report that: ‘Nevertheless, also for BNs, it holds that dynamic complexity scales exponentially with network size, again limiting the possibility of complete dynamic investigations’. This sentence comes with a reference explaining the feasibility of exhaustive attractor computation in Boolean network models. Here, we are entirely in line with the view given, and this is also what is elaborated throughout our manuscript. Foremost, when it comes to screening potential interventions targets using Boolean networks, dynamic analyses in the sense of exhaustive screening become very complex with a growing number of compounds in the model and potential targets or even combinations of targets. Our method does not aim to be a replacement of dynamic analysis but a step in the screening for intervention targets, scaling down the number of interventions to screen. Subsequently, the identified targets can be evaluated by different perturbation analyses based on network dynamics, such as more detailed studies of the attractor landscape (Müssel et al., 2010), or an automated screening (Schwab and Kestler, 2018). Especially when adding another layer of complexity, such as with large reconstructed networks or even populations of those (Schwab et al., 2021), detailed intervention screening on top of attractor evaluation becomes complex, and interaction graph-based pre-screening methods become helpful. Financial Support: none declared. Conflict of Interest: none declared.

This article describes some use case studies and self-assessments of FAIR status of de.NBI services to illustrate the challenges and requirements for the definition of the needs of adhering to the FAIR (findable, accessible, interoperable and reusable) data principles in a large distributed bioinformatics infrastructure. We address the challenge of heterogeneity of wet lab technologies, data, metadata, software, computational workflows and the levels of implementation and monitoring of FAIR principles within the different bioinformatics sub-disciplines joint in de.NBI. On the one hand, this broad service landscape and the excellent network of experts are a strong basis for the development of useful research data management plans. On the other hand, the large number of tools and techniques maintained by distributed teams renders FAIR compliance challenging.

MOTIVATION: Cancer is a complex and heterogeneous disease involving multiple somatic mutations that accumulate during its progression. In the past years, the wide availability of genomic data from patients' samples opened new perspectives in the analysis of gene mutations and alterations. Hence, visualizing and further identifying genes mutated in massive sets of patients are nowadays a critical task that sheds light on more personalized intervention approaches. RESULTS: Here, we extensively review existing tools for visualization and analysis of alteration data. We compare different approaches to study mutual exclusivity and sample coverage in large-scale omics data. We complement our review with the standalone software AVAtar ('analysis and visualization of alteration data') that integrates diverse aspects known from different tools into a comprehensive platform. AVAtar supplements customizable alteration plots by a multi-objective evolutionary algorithm for subset identification and provides an innovative and user-friendly interface for the evaluation of concurrent solutions. A use case from personalized medicine demonstrates its unique features showing an application on vaccination target selection. AVAILABILITY: AVAtar is available at: https://github.com/sysbio-bioinf/avatar. CONTACT: [email protected], phone: +49 (0) 731 500 24 500, fax: +49 (0) 731 500 24 502.

In the originally published version of this manuscript, there was an error in co-author Thomas K. Hoffmann's name. The full name should read: “Thomas K. Hoffmann” instead of “Thomas K. Hoffman”. This error has now been corrected online.

MOTIVATION: Interaction graphs are able to describe regulatory dependencies between compounds without capturing dynamics. In contrast, mathematical models that are based on interaction graphs allow to investigate the dynamics of biological systems. However, since dynamic complexity of these models grows exponentially with their size, exhaustive analyses of the dynamics and consequently screening all possible interventions eventually becomes infeasible. Thus, we designed an approach to identify dynamically relevant compounds based on the static network topology. RESULTS: Here, we present a method only based on static properties to identify dynamically influencing nodes. Coupling vertex betweenness and determinative power, we could capture relevant nodes for changing dynamics with an accuracy of 75% in a set of 35 published logical models. Further analyses of the selected compounds' connectivity unravelled a new class of not highly connected nodes with high impact on the networks' dynamics, which we call gatekeepers. We validated our method's working concept on logical models, which can be readily scaled up to complex interaction networks, where dynamic analyses are not even feasible. AVAILABILITY AND IMPLEMENTATION: Code is freely available at https://github.com/sysbio-bioinf/BNStatic. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Abstract Ordinal classifier cascades are constrained by a hypothesised order of the semantic class labels of a dataset. This order determines the overall structure of the decision regions in feature space. Assuming the correct order on these class labels will allow a high generalisation performance, while an incorrect one will lead to diminished results. In this way ordinal classifier systems can facilitate explorative data analysis allowing to screen for potential candidate orders of the class labels. Previously, we have shown that screening is possible for total orders of all class labels. However, as datasets might comprise samples of ordinal as well as non-ordinal classes, the assumption of a total ordering might be not appropriate. An analysis of subsets of classes is required to detect such hidden ordinal substructures. In this work, we devise a novel screening procedure for exhaustive evaluations of all order permutations of all subsets of classes by bounding the number of enumerations we have to examine. Experiments with multi-class data from diverse applications revealed ordinal substructures that generate new and support known relations.

BACKGROUND: The Ageing Factor Database AgeFactDB contains a large number of lifespan observations for ageing-related factors like genes, chemical compounds, and other factors such as dietary restriction in different organisms. These data provide quantitative information on the effect of ageing factors from genetic interventions or manipulations of lifespan. Analysis strategies beyond common static database queries are highly desirable for the inspection of complex relationships between AgeFactDB data sets. 3D visualisation can be extremely valuable for advanced data exploration. RESULTS: Different types of networks and visualisation strategies are proposed, ranging from basic networks of individual ageing factors for a single species to complex multi-species networks. The augmentation of lifespan observation networks by annotation nodes, like gene ontology terms, is shown to facilitate and speed up data analysis. We developed a new Javascript 3D network viewer JANet that provides the proposed visualisation strategies and has a customised interface for AgeFactDB data. It enables the analysis of gene lists in combination with AgeFactDB data and the interactive visualisation of the results. CONCLUSION: Interactive 3D network visualisation allows to supplement complex database queries by a visually guided exploration process. The JANet interface allows gaining deeper insights into lifespan data patterns not accessible by common database queries alone. These concepts can be utilised in many other research fields.

Summary: Mathematical models and their simulation are increasingly used to gain insights into cellular pathways and regulatory networks. Dynamics of regulatory factors can be modeled using Boolean networks (BNs), among others. Text-based representations of models are precise descriptions, but hard to understand and interpret. ViSiBooL aims at providing a graphical way of modeling and simulating networks. By providing visualizations of static and dynamic network properties simultaneously, it is possible to directly observe the effects of changes in the network structure on the behavior. In order to address the challenges of clear design and a user-friendly graphical user interface (GUI), ViSiBooL implements visual representations of BNs. Additionally temporal extensions of the BNs for the modeling of regulatory time delays are incorporated. The GUI of ViSiBooL allows to model, organize, simulate and visualize BNs as well as corresponding simulation results such as attractors. Attractor searches are performed in parallel to the modeling process. Hence, changes in the network behavior are visualized at the same time. Availability and Implementation: ViSiBooL (Java 8) is freely available at http://sysbio.uni-ulm.de/?Software:ViSiBooL . Contact: [email protected].

Cells and tissues are exposed to stress from numerous sources. Senescence is a protective mechanism that prevents malignant tissue changes and constitutes a fundamental mechanism of aging. It can be accompanied by a senescence associated secretory phenotype (SASP) that causes chronic inflammation. We present a Boolean network model-based gene regulatory network of the SASP, incorporating published gene interaction data. The simulation results describe current biological knowledge. The model predicts different in-silico knockouts that prevent key SASP-mediators, IL-6 and IL-8, from getting activated upon DNA damage. The NF-κB Essential Modulator (NEMO) was the most promising in-silico knockout candidate and we were able to show its importance in the inhibition of IL-6 and IL-8 following DNA-damage in murine dermal fibroblasts in-vitro. We strengthen the speculated regulator function of the NF-κB signaling pathway in the onset and maintenance of the SASP using in-silico and in-vitro approaches. We were able to mechanistically show, that DNA damage mediated SASP triggering of IL-6 and IL-8 is mainly relayed through NF-κB, giving access to possible therapy targets for SASP-accompanied diseases.

MOTIVATION: When processing gene expression profiles or other biological data, it is often required to assign measurements to distinct categories (e.g. 'high' and 'low' and possibly 'intermediate'). Subsequent analyses strongly depend on the results of this quantization. Poor quantization will have potentially misleading effects on further investigations. We propose the BiTrinA package that integrates different multiscale algorithms for binarization and for trinarization of one-dimensional data with methods for quality assessment and visualization of the results. By identifying measurements that show large variations over different time points or conditions, this quality assessment can determine candidates that are related to the specific experimental setting. AVAILABILITY AND IMPLEMENTATION: BiTrinA is freely available on CRAN. CONTACT: [email protected] or [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

UNLABELLED: Over the past years growing knowledge about biological processes and pathways revealed complex interaction networks involving many genes. In order to understand these networks, analysis of differential expression has continuously moved from single genes towards the study of gene sets. Various approaches for the assessment of gene sets have been developed in the context of gene set analysis (GSA). These approaches are bridging the gap between raw measurements and semantically meaningful terms.We present a novel approach for assessing uncertainty in the definition of gene sets. This is an essential step when new gene sets are constructed from domain knowledge or given gene sets are suspected to be affected by uncertainty. Quantification of uncertainty is implemented in the R-package GiANT. We also included widely used GSA methods, embedded in a generic framework that can readily be extended by custom methods. The package provides an easy to use front end and allows for fast parallelization. AVAILABILITY AND IMPLEMENTATION: The package GiANT is available on CRAN. CONTACTS: [email protected] or [email protected].

Recent developments in molecular biology have led to the massive discovery of new marker candidates for the prediction of patient survival. To evaluate the predictive value of these markers, statistical tools for measuring the performance of survival models are needed. We consider estimators of discrimination measures, which are a popular approach to evaluate survival predictions in biomarker studies. Estimators of discrimination measures are usually based on regularity assumptions such as the proportional hazards assumption. Based on two sets of molecular data and a simulation study, we show that violations of the regularity assumptions may lead to over-optimistic estimates of prediction accuracy and may therefore result in biased conclusions regarding the clinical utility of new biomarkers. In particular, we demonstrate that biased medical decision making is possible even if statistical checks indicate that all regularity assumptions are satisfied.

The identification of large regulatory and signalling networks involved in the control of crucial cellular processes calls for proper modelling approaches. Indeed, models can help elucidate properties of these networks, understand their behaviour and provide (testable) predictions by performing in silico experiments. In this context, qualitative, logical frameworks have emerged as relevant approaches, as demonstrated by a growing number of published models, along with new methodologies and software tools. This productive activity now requires a concerted effort to ensure model reusability and interoperability between tools. Following an outline of the logical modelling framework, we present the most important achievements of the Consortium for Logical Models and Tools, along with future objectives. Our aim is to advertise this open community, which welcomes contributions from all researchers interested in logical modelling or in related mathematical and computational developments.

MOTIVATION: In bioinformatic applications, computationally demanding algorithms are often parallelized to speed up computation. Nevertheless, setting up computational environments for distributed computation is often tedious. Aim of this project were the lightweight ad hoc set up and fault-tolerant computation requiring only a Java runtime, no administrator rights, while utilizing all CPU cores most effectively. RESULTS: The Sputnik framework provides ad hoc distributed computation on the Java Virtual Machine which uses all supplied CPU cores fully. It provides a graphical user interface for deployment setup and a web user interface displaying the current status of current computation jobs. Neither a permanent setup nor administrator privileges are required. We demonstrate the utility of our approach on feature selection of microarray data. AVAILABILITY AND IMPLEMENTATION: The Sputnik framework is available on Github http://github.com/sysbio-bioinf/sputnik under the Eclipse Public License. CONTACT: [email protected] or [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

We introduce Group Learning for Ant Colony Optimization applied to combinatorial optimization problems with group-structured solution encodings. In contrast to the common assignment of one pheromone value per solution component in Group Learning each solution component has one pheromone value per group. Hence, the algorithm has the possibility to learn the optimal group membership of the components. We present different strategies for Group Learning and evaluate these in simulation experiments for the Vehicle Routing Problem with Time Windows using the problem instances of Solomon. We describe a revised Ant Colony System (ACS) algorithm which does not use a local pheromone update while maintaining the general ideas of ACS. We evaluate the revised ACS experimentally comparing it to the original ACS. Our experimental results show that Group Learning is a valuable modification for Ant Colony Optimization. Additionally, the results indicate that the revised ACS performs at least as well as the original algorithms.

We introduce Group-Based Ant Colony Optimization which uses a parallel construction principle on group-structured solution encodings. We compare the parallel construction method with the classical sequential one. In this context we also perform simulation experiments for the Vehicle Routing Problem with Time Windows using the Solomon [8] and the Homberger & Gehring [5] instances.

MOTIVATION: The calculation of reliable alignments for structured RNA is still considered as an open problem. One approach is the incorporation of secondary structure information into the optimization criteria by using a weighted sum of sequence and structure components as an objective function. As it is not clear how to choose the weighting parameters, we use multi-objective optimization to calculate a set of Pareto-optimal RNA sequence-structure alignments. The solutions in this set then represent all possible trade-offs between the different objectives, independent of any previous weighting. RESULTS: We present a practical multi-objective dynamic programming algorithm, which is a new method for the calculation of the set of Pareto-optimal solutions to the pairwise RNA sequence-structure alignment problem. In selected examples, we show the usefulness of this approach, and its advantages over state-of-the-art single-objective algorithms. AVAILABILITY AND IMPLEMENTATION: The source code of our software (ISO C++11) is freely available at http://sysbio.uni-ulm.de/?Software and is licensed under the GNU GPLv3. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Abstract Summary: Incorporating secondary structure information into the alignment process improves the quality of RNA sequence alignments. Instead of using fixed weighting parameters, sequence and structure components can be treated as different objectives and optimized simultaneously. The result is not a single, but a Pareto-set of equally optimal solutions, which all represent different possible weighting parameters. We now provide the interactive graphical software tool RNA-Pareto, which allows a direct inspection of all feasible results to the pairwise RNA sequence-structure alignment problem and greatly facilitates the exploration of the optimal solution set. Availability and implementation: The software is written in Java 6 (graphical user interface) and C++ (dynamic programming algorithms). The source code and binaries for Linux, Windows and Mac OS are freely available at http://sysbio.uni-ulm.de and are licensed under the GNU GPLv3. Contact: [email protected]

Network inference algorithms can assist life scientists in unraveling gene-regulatory systems on a molecular level. In recent years, great attention has been drawn to the reconstruction of Boolean networks from time series. These need to be binarized, as such networks model genes as binary variables (either “expressed” or “not expressed”). Common binarization methods often cluster measurements or separate them according to statistical or information theoretic characteristics and may require many data points to determine a robust threshold. Yet, time series measurements frequently comprise only a small number of samples. To overcome this limitation, we propose a binarization that incorporates measurements at multiple resolutions. We introduce two such binarization approaches which determine thresholds based on limited numbers of samples and additionally provide a measure of threshold validity. Thus, network reconstruction and further analysis can be restricted to genes with meaningful thresholds. This reduces the complexity of network inference. The performance of our binarization algorithms was evaluated in network reconstruction experiments using artificial data as well as real-world yeast expression time series. The new approaches yield considerably improved correct network identification rates compared to other binarization techniques by effectively reducing the amount of candidate networks.

MOTIVATION: Accurate, context-specific regulation of gene expression is essential for all organisms. Accordingly, it is very important to understand the complex relations within cellular gene regulatory networks. A tool to describe and analyze the behavior of such networks are Boolean models. The reconstruction of a Boolean network from biological data requires identification of dependencies within the network. This task becomes increasingly computationally demanding with large amounts of data created by recent high-throughput technologies. Thus, we developed a method that is especially suited for network structure reconstruction from large-scale data. In our approach, we took advantage of the fact that a specific transcription factor often will consistently either activate or inhibit a specific target gene, and this kind of regulatory behavior can be modeled using monotone functions. RESULTS: To detect regulatory dependencies in a network, we examined how the expression of different genes correlates to successive network states. For this purpose, we used Pearson correlation as an elementary correlation measure. Given a Boolean network containing only monotone Boolean functions, we prove that the correlation of successive states can identify the dependencies in the network. This method not only finds dependencies in randomly created artificial networks to very high percentage, but also reconstructed large fractions of both a published Escherichia coli regulatory network from simulated data and a yeast cell cycle network from real microarray data.

MOTIVATION: As the study of information processing in living cells moves from individual pathways to complex regulatory networks, mathematical models and simulation become indispensable tools for analyzing the complex behavior of such networks and can provide deep insights into the functioning of cells. The dynamics of gene expression, for example, can be modeled with Boolean networks (BNs). These are mathematical models of low complexity, but have the advantage of being able to capture essential properties of gene-regulatory networks. However, current implementations of BNs only focus on different sub-aspects of this model and do not allow for a seamless integration into existing preprocessing pipelines. RESULTS: BoolNet efficiently integrates methods for synchronous, asynchronous and probabilistic BNs. This includes reconstructing networks from time series, generating random networks, robustness analysis via perturbation, Markov chain simulations, and identification and visualization of attractors. AVAILABILITY: The package BoolNet is freely available from the R project at http://cran.r-project.org/ or http://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/boolnet/ under Artistic License 2.0. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: In recent years, the demand for computational power in computational biology has increased due to rapidly growing data sets from microarray and other high-throughput technologies. This demand is likely to increase. Standard algorithms for analyzing data, such as cluster algorithms, need to be parallelized for fast processing. Unfortunately, most approaches for parallelizing algorithms largely rely on network communication protocols connecting and requiring multiple computers. One answer to this problem is to utilize the intrinsic capabilities in current multi-core hardware to distribute the tasks among the different cores of one computer. RESULTS: We introduce a multi-core parallelization of the k-means and k-modes cluster algorithms based on the design principles of transactional memory for clustering gene expression microarray type data and categorial SNP data. Our new shared memory parallel algorithms show to be highly efficient. We demonstrate their computational power and show their utility in cluster stability and sensitivity analysis employing repeated runs with slightly changed parameters. Computation speed of our Java based algorithm was increased by a factor of 10 for large data sets while preserving computational accuracy compared to single-core implementations and a recently published network based parallelization. CONCLUSIONS: Most desktop computers and even notebooks provide at least dual-core processors. Our multi-core algorithms show that using modern algorithmic concepts, parallelization makes it possible to perform even such laborious tasks as cluster sensitivity and cluster number estimation on the laboratory computer.

BACKGROUND: Microarray experiments generate vast amounts of data. The functional context of differentially expressed genes can be assessed by querying the Gene Ontology (GO) database via GoMiner. Directed acyclic graph representations, which are used to depict GO categories enriched with differentially expressed genes, are difficult to interpret and, depending on the particular analysis, may not be well suited for formulating new hypotheses. Additional graphical methods are therefore needed to augment the GO graphical representation. RESULTS: We present an alternative visualization approach, area-proportional Euler diagrams, showing set relationships with semi-quantitative size information in a single diagram to support biological hypothesis formulation. The cardinalities of sets and intersection sets are represented by area-proportional Euler diagrams and their corresponding graphical (circular or polygonal) intersection areas. Optimally proportional representations are obtained using swarm and evolutionary optimization algorithms. CONCLUSION: VennMaster's area-proportional Euler diagrams effectively structure and visualize the results of a GO analysis by indicating to what extent flagged genes are shared by different categories. In addition to reducing the complexity of the output, the visualizations facilitate generation of novel hypotheses from the analysis of seemingly unrelated categories that share differentially expressed genes.

MOTIVATION: DNA copy number aberrations are frequently found in different types of cancer. Recent developments of microarray-based approaches have broadened the knowledge on number and structure of such aberrations. High-density single nucleotide polymorphism (SNP) microarrays provide an extremely high resolution with up to 500,000 SNPs per genome. Owing to the enormous amount of data the detection of common aberrations in large datasets is a great challenge. We describe a novel open source software tool--IdeogramBrowser--which was specifically designed for use with the Affymetrix SNP arrays. It provides an interactive karyotypic visualization of multiple aberration profiles and direct links to GeneCards. Visualization of consensus regions together with gene representation allows the explorative assessment of the data. AVAILABILITY: IdeogramBrowser and its source code are freely available under a creative commons license and can be obtained from http://www.informatik.uni-ulm.de/ni/staff/HKestler/ideo/. IdeogramBrowser is a platform independent Java application.

MOTIVATION: Microarray experiments generate vast amounts of data. The unknown or only partially known functional context of differentially expressed genes may be assessed by querying the Gene Ontology database via GOMiner. Resulting tree representations are difficult to interpret and are not suited for visualization of this type of data. Methods are needed to effectively visualize these complex set relationships. RESULTS: We present a visualization approach for set relationships based on Venn diagrams. The proposed extension enhances the usual notion of Venn diagrams by incorporating set size information. The cardinality of the sets and intersection sets is represented by their corresponding circle (polygon) sizes. To avoid local minima, solutions to this problem are sought by evolutionary optimization. This generalized Venn diagram approach has been implemented as an interactive Java application (VennMaster) specifically designed for use with GOMiner in the context of the Gene Ontology database. AVAILABILITY: VennMaster is platform-independent (Java 1.4.2) and has been tested on Windows (XP, 2000), Mac OS X, and Linux. Supplementary information and the software (free for non-commercial use) are available at http://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/vennm together with a user documentation. CONTACT: [email protected].

We present different training algorithms for radial basis function (RBF) networks. The behaviour of RBF classifiers in three different pattern recognition applications is presented: the classification of 3-D visual objects, high-resolution electrocardiograms and handwritten digits.