Robustness of metabolic networks: a review of existing definitions.

Describing the determinants of robustness of biological systems has become one of the central questions in systems biology. Despite the increasing research efforts, it has proven difficult to arrive at a unifying definition for this important concept. We argue that this is due to the multifaceted nature of the concept of robustness and the possibility to formally capture it at different levels of systemic formalisms (e.g., topology and dynamic behavior). Here we provide a comprehensive review of the existing definitions of robustness pertaining to metabolic networks. As kinetic approaches have been excellently reviewed elsewhere, we focus on definitions of robustness proposed within graph-theoretic and constraint-based formalisms.

Designing logical rules to model the response of biomolecular networks with complex interactions: an application to cancer modeling.

We discuss the propagation of constraints in eukaryotic interaction networks in relation to model prediction and the identification of critical pathways. In order to cope with posttranslational interactions, we consider two types of nodes in the network, corresponding to proteins and to RNA. Microarray data provides very lacunar information for such types of networks because protein nodes, although needed in the model, are not observed. Propagation of observations in such networks leads to poor and nonsignificant model predictions, mainly because rules used to propagate information--usually disjunctive constraints--are weak. Here, we propose a new, stronger type of logical constraints that allow us to strengthen the analysis of the relation between microarray and interaction data. We use these rules to identify the nodes which are responsible for a phenotype, in particular for cell cycle progression. As the benchmark, we use an interaction network describing major pathways implied in Ewing's tumor development. The Python library used to obtain our results is publicly available on our supplementary web page.

Constraint-based knowledge discovery from SAGE data.

Current analyses of co-expressed genes are often based on global approaches such as clustering or bi-clustering. An alternative way is to employ local methods and search for patterns--sets of genes displaying specific expression properties in a set of situations. The main bottleneck of this type of analysis is twofold--computational costs and an overwhelming number of candidate patterns which can hardly be further exploited. A timely application of background knowledge available in literature databases, biological ontologies and other sources can help to focus on the most plausible patterns only. The paper proposes, implements and tests a flexible constraint-based framework that enables the effective mining and representation of meaningful over-expression patterns representing intrinsic associations among genes and biological situations. The framework can be simultaneously applied to a wide spectrum of genomic data and we demonstrate that it allows to generate new biological hypotheses with clinical implications.

SQUAT: A web tool to mine human, murine and avian SAGE data.

BACKGROUND: There is an increasing need in transcriptome research for gene expression data and pattern warehouses. It is of importance to integrate in these warehouses both raw transcriptomic data, as well as some properties encoded in these data, like local patterns. DESCRIPTION: We have developed an application called SQUAT (SAGE Querying and Analysis Tools) which is available at: http://bsmc.insa-lyon.fr/squat/. This database gives access to both raw SAGE data and patterns mined from these data, for three species (human, mouse and chicken). This database allows to make simple queries like "In which biological situations is my favorite gene expressed?" as well as much more complex queries like: <>. Connections with external web databases enrich biological interpretations, and enable sophisticated queries. To illustrate the power of SQUAT, we show and analyze the results of three different queries, one of which led to a biological hypothesis that was experimentally validated. CONCLUSION: SQUAT is a user-friendly information retrieval platform, which aims at bringing some of the state-of-the-art mining tools to biologists.

Clustering formal concepts to discover biologically relevant knowledge from gene expression data.

The production of high-throughput gene expression data has generated a crucial need for bioinformatics tools to generate biologically interesting hypotheses. Whereas many tools are available for extracting global patterns, less attention has been focused on local pattern discovery. We propose here an original way to discover knowledge from gene expression data by means of the so-called formal concepts which hold in derived Boolean gene expression datasets. We first encoded the over-expression properties of genes in human cells using human SAGE data. It has given rise to a Boolean matrix from which we extracted the complete collection of formal concepts, i.e., all the largest sets of over-expressed genes associated to a largest set of biological situations in which their over-expression is observed. Complete collections of such patterns tend to be huge. Since their interpretation is a time-consuming task, we propose a new method to rapidly visualize clusters of formal concepts. This designates a reasonable number of Quasi-Synexpression-Groups (QSGs) for further analysis. The interest of our approach is illustrated using human SAGE data and interpreting one of the extracted QSGs. The assessment of its biological relevancy leads to the formulation of both previously proposed and new biological hypotheses.

Strong-association-rule mining for large-scale gene-expression data analysis: a case study on human SAGE data.

BACKGROUND: The association-rules discovery (ARD) technique has yet to be applied to gene-expression data analysis. Even in the absence of previous biological knowledge, it should identify sets of genes whose expression is correlated. The first association-rule miners appeared six years ago and proved efficient at dealing with sparse and weakly correlated data. A huge international research effort has led to new algorithms for tackling difficult contexts and these are particularly suited to analysis of large gene-expression matrices. To validate the ARD technique we have applied it to freely available human serial analysis of gene expression (SAGE) data. RESULTS: The approach described here enables us to designate sets of strong association rules. We normalized the SAGE data before applying our association rule miner. Depending on the discretization algorithm used, different properties of the data were highlighted. Both common and specific interpretations could be made from the extracted rules. In each and every case the extracted collections of rules indicated that a very strong co-regulation of mRNA encoding ribosomal proteins occurs in the dataset. Several rules associating proteins involved in signal transduction were obtained and analyzed, some pointing to yet-unexplored directions. Furthermore, by examining a subset of these rules, we were able both to reassign a wrongly labeled tag, and to propose a function for an expressed sequence tag encoding a protein of unknown function. CONCLUSIONS: We show that ARD is a promising technique that turns out to be complementary to existing gene-expression clustering techniques.