Gene regulatory networks have been long studied in model organisms as a means of identifying functional relationships among genes or their corresponding products. Despite many existing methods for genome-wide construction of such networks, solutions to the gene regulatory networks problem are however not trivial. Here, we present, a hybrid approach with gene expression profiles and gene ontology (HAEO). HAEO makes use of multimethods (overlapping clustering and reverse engineering methods) to effectively and efficiently construct gene regulatory networks from multisources (gene expression profiles and gene ontology). Application to yeast cell cycle dataset demonstrates HAEO's ability to construct validated gene regulatory networks, such as some potential gene regulatory pairs, which cannot be discovered by general inferring methods and identifying cycles (i.e., feedback loops) between genes. We also experimentally study the efficiency of building networks and show that the proposed method, HAEO is much faster than Bayesian networks method.

MOTIVATION: The large, complex networks of interactions between proteins provide a lens through which one can examine the structure and function of biological systems. Previous analyses of these continually growing networks have primarily followed either of two approaches: large-scale statistical analysis of holistic network properties, or small-scale analysis of local topological features. Meanwhile, investigation of meso-scale network structure (above that of individual functional modules, while maintaining the significance of individual proteins) has been hindered by the computational complexity of structural search in networks. Examining protein-protein interaction (PPI) networks at the meso-scale may provide insights into the presence and form of relationships between individual protein complexes and functional modules. RESULTS: In this article, we present an efficient algorithm for performing sub-graph isomorphism queries on a network and show its computational advantage over previous methods. We also present a novel application of this form of topological search which permits analysis of a network's structure at a scale between that of individual functional modules and that of network-wide properties. This analysis provides support for the presence of hierarchical modularity in the PPI network of Saccharomyces cerevisiae.

How best to present query search results is an important problem in search engines and information retrieval systems. When a single query retrieves many results, simply showing them as a long list will provide users with poor overview. Nowadays, ranking and clustering query search results have been two useful separate post-processing techniques to organize retrieved documents. In this paper, we proposed a spectral analysis method based on the content similarity networks to integrate the clustering and ranking techniques for improving literature search. The new approach organizes all these search results into categories intelligently and simultaneously rank the results in each category. A variety of theoretical and empirical studies have demonstrated that the presented method performs well in real applications, especially in biomedical literature retrieval. Moreover, any free text information can be analyzed with the new method, i.e., the proposed approach can be applied to various information systems, such as Web search engines and literature search service.

To support large-scale biomedical research projects, organizations need to share person-specific genomic sequences without violating the privacy of their data subjects. In the past, organizations protected subjects' identities by removing identifiers, such as name and social security number; however, recent investigations illustrate that deidentified genomic data can be "reidentified" to named individuals using simple automated methods. In this paper, we present a novel cryptographic framework that enables organizations to support genomic data mining without disclosing the raw genomic sequences. Organizations contribute encrypted genomic sequence records into a centralized repository, where the administrator can perform queries, such as frequency counts, without decrypting the data. We evaluate the efficiency of our framework with existing databases of single nucleotide polymorphism (SNP) sequences and demonstrate that the time needed to complete count queries is feasible for real world applications. For example, our experiments indicate that a count query over 40 SNPs in a database of 5000 records can be completed in approximately 30 min with off-the-shelf technology. We further show that approximation strategies can be applied to significantly speed up query execution times with minimal loss in accuracy. The framework can be implemented on top of existing information and network technologies in biomedical environments.

MOTIVATION: Dilution design (Mixed tissue RNA) has been utilized by some researchers to evaluate and assess the performance of multiple microarray platforms. Current microarray data analysis approaches assume that the quantified signal intensities are linearly related to the expression of the corresponding genes in the sample. However, there are sources of nonlinearity in microarray expression measurements. Such nonlinearity study in the expressions of the RNA mixtures provides a new way to analyze gene expression data, and we argue that the nonlinearity can reveal novel information for microarray data analysis. Therefore, we proposed a statistical model, called proportion model, which is based on the linear regression analysis. To approximately quantify the nonlinearity in the dilution design, a new calibration, beta ratio (BR) was derived from the proportion model. Furthermore, a new adjusted fold change (adj-FC) was proposed to predict the true FC without nonlinearity, in particular for large FC. RESULTS: We applied our method to one microarray dilution dataset. The experimental results indicated that, to some extent, there are global biases comparing with the linear assumption for the significant genes. Further analysis of those highly expressed genes with significant nonlinearity revealed some promising results, e.g. 'poison' effect was discovered for some genes in RNA mixtures. The adj-FCs of those genes with 'poison' effect, indicate that the nonlinearity can be also caused by the inherent feature of the genes besides signal noise and technical variation. Moreover, when percentage of overlapping genes (POG) was used as a cross-platform consistency measure, adj-FC outperformed simple fold change to show that Affymetrix and Illumina platforms are consistent. AVAILABILITY: The R codes which implements all described methods, and some Supplementary material, are freely available from http://www.utdallas.edu/~ying.liu/BetaRatio.htm

OBJECTIVE: A major problem faced in biomedical informatics involves how best to present information retrieval results. When a single query retrieves many results, simply showing them as a long list often provides poor overview. With a goal of presenting users with reduced sets of relevant citations, this study developed an approach that retrieved and organized MEDLINE citations into different topical groups and prioritized important citations in each group. DESIGN: A text mining system framework for automatic document clustering and ranking organized MEDLINE citations following simple PubMed queries. The system grouped the retrieved citations, ranked the citations in each cluster, and generated a set of keywords and MeSH terms to describe the common theme of each cluster. MEASUREMENTS: Several possible ranking functions were compared, including citation count per year (CCPY), citation count (CC), and journal impact factor (JIF). We evaluated this framework by identifying as "important" those articles selected by the Surgical Oncology Society. RESULTS: Our results showed that CCPY outperforms CC and JIF, i.e., CCPY better ranked important articles than did the others. Furthermore, our text clustering and knowledge extraction strategy grouped the retrieval results into informative clusters as revealed by the keywords and MeSH terms extracted from the documents in each cluster. CONCLUSIONS: The text mining system studied effectively integrated text clustering, text summarization, and text ranking and organized MEDLINE retrieval results into different topical groups.

Recent advances in high throughput experiments and annotations via published literature have provided a wealth of interaction maps of several biomolecular networks, including metabolic, protein-protein, and protein-DNA interaction networks. The architecture of these molecular networks reveals important principles of cellular organization and molecular functions. Analyzing such networks, i.e., discovering dense regions in the network, is an important way to identify protein complexes and functional modules. This task has been formulated as the problem of finding heavy subgraphs, the Heaviest k-Subgraph Problem (k-HSP), which itself is NP-hard. However, any method based on the k-HSP requires the parameter k and an exact solution of k-HSP may still end up as a "spurious" heavy subgraph, thus reducing its practicability in analyzing large scale biological networks. We proposed a new formulation, called the rank-HSP, and two dynamical systems to approximate its results. In addition, a novel metric, called the Standard deviation and Mean Ratio (SMR), is proposed for use in "spurious" heavy subgraphs to automate the discovery by setting a fixed threshold. Empirical results on both the simulated graphs and biological networks have demonstrated the efficiency and effectiveness of our proposal.

For many clustering algorithms, such as K-Means, EM, and CLOPE, there is usually a requirement to set some parameters. Often, these parameters directly or indirectly control the number of clusters, that is, k, to return. In the presence of different data characteristics and analysis contexts, it is often difficult for the user to estimate the number of clusters in the data set. This is especially true in text collections such as Web documents, images, or biological data. In an effort to improve the effectiveness of clustering, we seek the answer to a fundamental question: How can we effectively estimate the number of clusters in a given data set? We propose an efficient method based on spectra analysis of eigenvalues (not eigenvectors) of the data set as the solution to the above. We first present the relationship between a data set and its underlying spectra with theoretical and experimental results. We then show how our method is capable of suggesting a range of k that is well suited to different analysis contexts. Finally, we conclude with further empirical results to show how the answer to this fundamental question enhances the clustering process for large text collections.

More and more ontologies are emerging across bioinformatics domains to represent and define domain knowledge, such as gene ontology, anatomy ontology and disease ontology. To integrate these heterogeneous ontologies is becoming critically important for applications utilizing multiple ontologies. Because the entities described in the ontology often overlap with other entities in other ontologies, a mapping between two corresponding terms is required and becoming the key to the integration of heterogeneous ontologies. Based on a previously developed schema matching algorithm, this paper presents a framework for mapping and integration of heterogeneous biomedical ontologies. The framework detects possible false mappings intelligently and provides intuitive interfaces for users to customize mappings and for applications to integrate and access biomedical ontologies

A common step in drug design is the formation of a quantitative structure-activity relationship (QSAR) to model an exploratory series of compounds. A QSAR generalizes how the structure of a compound relates to its biological activity. There is growing interest in the application of machine learning techniques in QSAR modeling research. However, no single technique can claim to be uniformly superior to any other. This study introduced the ensemble machine learning, a set of classifiers whose individual decisions are combined in some way (typically by weighted or unweighted voting) to improve the performance of the overall system. A comparative study was carried out of two popular ensemble learning algorithms, Bagging and AdaBoost, for QSAR modeling. Two test case problems were studied: the inhibition of Escherichia coli dihydrofolate reductase (DHFR) by pyrimidines, and the inhibition of rat/mouse tumor DHFR by triazines. It was observed that the ensemble learning algorithms, Bagging and AdaBoost, can significantly improve the performance of decision tree C4.5 and 1-R (p - 0.05), while naive Bayesian and 1-nearest neighbor did not benefit from ensemble learning. Furthermore, in general, AdaBoost outperformed Bagging on the tested data sets.

Partitioning closely related genes into clusters has become an important element of practically all statistical analyses of microarray data. A number of computer algorithms have been developed for this task. Although these algorithms have demonstrated their usefulness for gene clustering, some basic problems remain. This paper describes our work on extracting functional keywords from MEDLINE for a set of genes that are isolated for further study from microarray experiments based on their differential expression patterns. The sharing of functional keywords among genes is used as a basis for clustering in a new approach called BEA-PARTITION in this paper. Functional keywords associated with genes were extracted from MEDLINE abstracts. We modified the Bond Energy Algorithm (BEA), which is widely accepted in psychology and database design but is virtually unknown in bioinformatics, to cluster genes by functional keyword associations. The results showed that BEA-PARTITION and hierarchical clustering algorithm outperformed k-means clustering and self-organizing map by correctly assigning 25 of 26 genes in a test set of four known gene groups. To evaluate the effectiveness of BEA-PARTITION for clustering genes identified by microarray profiles, 44 yeast genes that are differentially expressed during the cell cycle and have been widely studied in the literature were used as a second test set. Using established measures of cluster quality, the results produced by BEA-PARTITION had higher purity, lower entropy, and higher mutual information than those produced by k-means and self-organizing map. Whereas BEA-PARTITION and the hierarchical clustering produced similar quality of clusters, BEA-PARTITION provides clear cluster boundaries compared to the hierarchical clustering. BEA-PARTITION is simple to implement and provides a powerful approach to clustering genes or to any clustering problem where starting matrices are available from experimental observations.