Technologies for generating high-density arrays of cDNAs and oligonucleotides are developing rapidly, and changing the landscape of biological and biomedical research. They enable, for the first time, a global, simultaneous view on the transcription levels of many thousands of genes, when the cell undergoes specific conditions or processes. For several organisms that had their genomes completely sequenced, the full set of genes can already be monitored this way today. The potential of such technologies is tremendous: The information obtained by monitoring gene expression levels in different developmental stages, tissue types, clinical conditions and di erent organisms can help understanding gene function and gene networks, and assist in the diagnostic of disease conditions and of effects of medical treatments. Undoubtedly, other applications will emerge in coming years. A key step in the analysis of gene expression data is the identification of groups of genes that manifest...

Abstract—DNA microarray technology has now made it possible to simultaneously monitor the expression levels of thousands of genes during important biological processes and across collections of related samples. Elucidating the patterns hidden in gene expression data offers a tremendous opportunity for an enhanced understanding of functional genomics. However, the large number of genes and the complexity of biological networks greatly increases the challenges of comprehending and interpreting the resulting mass of data, which often consists of millions of measurements. A first step toward addressing this challenge is the use of clustering techniques, which is essential in the data mining process to reveal natural structures and identify interesting patterns in the underlying data. Cluster analysis seeks to partition a given data set into groups based on specified features so that the data points within a group are more similar to each other than the points in different groups. A very rich literature on cluster analysis has developed over the past three decades. Many conventional clustering algorithms have been adapted or directly applied to gene expression data, and also new algorithms have recently been proposed specifically aiming at gene expression data. These clustering algorithms have been proven useful for identifying biologically relevant groups of genes and samples. In this paper, we first briefly introduce the concepts of microarray technology and discuss the basic elements of clustering on gene expression data. In particular, we divide cluster analysis for gene expression data into three categories. Then, we present specific challenges pertinent to each clustering category and introduce several representative approaches. We also discuss the problem of cluster validation in three aspects and review various methods to assess the quality and reliability of clustering results. Finally, we conclude this paper and suggest the promising trends in this field. Index Terms—Microarray technology, gene expression data, clustering.

A promising approach to graph clustering is based on the intuitive notion of intra-cluster density vs. inter-cluster sparsity. While both formalizations and algorithms focusing on particular aspects of this rather vague concept have been proposed no conclusive argument on their appropriateness has been given.

Motivation: Microarrays have become a central tool in biological research. Their applications range from functional annotation to tissue classification and genetic network inference. A key step in the analysis of gene expression data is the identification of groups of genes that manifest similar expression patterns. This translates to the algorithmic problem of clustering genes based on their expression patterns. Results: We present a novel clustering algorithm, called CLICK, and its applications to gene expression analysis. The algorithm utilizes graph-theoretic and statistical techniques to identify tight groups (kernels) of highly similar elements, which are likely to belong to the same true cluster. Several heuristic procedures are then used to expand the kernels into the full clusters. We report on the application of CLICK to a variety of gene expression data sets. In all those applications it outperformed extant algorithms according to several common figures of merit. We also point out that CLICK can be successfully used for the identification of common regulatory motifs in the upstream regions of co-regulated genes. Furthermore, we demonstrate how CLICK can be used to accurately classify tissue samples into disease types, based on their expression profiles. Finally, we present a new java-based graphical tool, called EXPANDER, for gene expression analysis and visualization, which incorporates CLICK and several other popular clustering algorithms.

Joint mining of multiple data sets can often discover interesting, novel, and reliable patterns which cannot be obtained solely from any single source. For example, in cross-market customer segmentation, a group of customers who behave similarly in multiple markets should be considered as a more coherent and more reliable cluster than clusters found in a single market. As another example, in bioinformatics, by joint mining of gene expression data and protein interaction data, we can find clusters of genes which show coherent expression patterns and also produce interacting proteins. Such clusters may be potential pathways. In this paper, we investigate a novel data mining problem, mining cross-graph quasi-cliques, which is generalized from several interesting applications such as cross-market customer segmentation and joint mining of gene expression data and protein interaction data. We build a general model for mining cross-graph quasicliques, show why the complete set of cross-graph quasi-cliques cannot be found by previous data mining methods, and study the complexity of the problem. While the problem is difficult, we develop an efficient algorithm, Crochet, which exploits several interesting and effective techniques and heuristics to efficaciously mine cross-graph quasi-cliques. A systematic performance study is reported on both synthetic and real data sets. We demonstrate some interesting and meaningful cross-graph quasi-cliques in bioinformatics. The experimental results also show that algorithm Crochet is efficient and scalable.

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A promising approach to graph clustering is based on the intuitive notion of intracluster density versus intercluster sparsity. As for the weighted case, clusters should accumulate lots of weight, in contrast to their connection to the remaining graph, which should be light. While both formalizations and algorithms focusing on particular aspects of this rather vague concept have been proposed, no conclusive argument on their appropriateness has been given. In order to deepen the understanding of particular concepts, including both quality assessment as well as designing new algorithms, we conducted an experimental evaluation of graph-clustering approaches. By combining proved techniques from graph partitioning and geometric clustering, we also introduce a new approach that compares favorably.

Computational and comparative analysis of protein-protein interaction (PPI) networks enable understanding of the modular organization of the cell through identification of functional modules and protein complexes. These analysis techniques generally rely on topological features such as connectedness, based on the premise that functionally related proteins are likely to interact densely and that these interactions follow similar evolutionary trajectories. Significant recent work in our lab, and in other labs has focused on efficient algorithms for identification of modules and their conservation. Application of these methods to a variety of networks has yielded novel biological insights. In spite of algorithmic advances, development of a comprehensive infrastructure for interaction databases is in relative infancy compared to corresponding sequence analysis tools such as BLAST and CLUSTAL. One critical component of this infrastructure is a measure of the statistical significance of a match or a dense subcomponent. Corresponding sequence-based measures such as E-values are key components of sequence matching tools. In the absence of an analytical measure, conventional methods rely on computer simulations based on ad-hoc models for quantifying significance. This paper presents the first such effort, to the best of our knowledge, aimed at analytically quantifying statistical significance

DNA microarray provides a powerful basis for analysis of gene expression. Data mining methods such as clustering have been widely applied to microarray data to link genes that show similar expression patterns. However, this approach usually fails to unveil gene-gene interactions in the same cluster. Association rule mining and loglinear models have been used for this purpose, but their inherent limitations as well as information loss due to discretization limit the applicability of the results. Here we propose the use of a Graphical Gaussian Model to discover pairwise gene interactions. We have constructed a prototype system that permits rapid interactive exploration of gene relationships; results can be validated by experts or known information, or suggest new experiments. We have tested our methodology using the yeast microarray data. Our results reveal some previously unknown interactions that have solid biological explanations.