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Finding relevant references to genes and proteins in Medline using a Bayesian approach.

MOTIVATION: Mining the biomedical literature for references to genes and proteins always involves a tradeoff between high precision with false negatives, and high recall with false positives. Having a reliable method for assessing the relevance of literature mining results is crucial to finding ways to balance precision and recall, and for subsequently building automated systems to analyze these results. We hypothesize that abstracts and titles that discuss the same gene or protein use similar words. To validate this hypothesis, we built a dictionary- and rule-based system to mine Medline for references to genes and proteins, and used a Bayesian metric for scoring the relevance of each reference assignment. RESULTS: We analyzed the entire set of Medline records from 1966 to late 2001, and scored each gene and protein reference using a Bayesian estimated probability (EP) based on word frequency in a training set of 137837 known assignments from 30594 articles to 36197 gene and protein symbols. Two test sets of 148 and 150 randomly chosen assignments, respectively, were hand-validated and categorized as either good or bad. The distributions of EP values, when plotted on a log-scale histogram, are shown to markedly differ between good and bad assignments. Using EP values, recall was 100% at 61% precision (EP=2 x 10(-5)), 63% at 88% precision (EP=0.008), and 10% at 100% precision (EP=0.1). These results show that Medline entries discussing the same gene or protein have similar word usage, and that our method of assessing this similarity using EP values is valid, and enables an EP cutoff value to be determined that accurately and reproducibly balances precision and recall, allowing automated analysis of literature mining results. .

Abstracting and Indexing↗

Accomplishments and challenges in literature data mining for biology.

We review recent results in literature data mining for biology and discuss the need and the steps for a challenge evaluation for this field. Literature data mining has progressed from simple recognition of terms to extraction of interaction relationships from complex sentences, and has broadened from recognition of protein interactions to a range of problems such as improving homology search, identifying cellular location, and so on. To encourage participation and accelerate progress in this expanding field, we propose creating challenge evaluations, and we describe two specific applications in this context.

Benchmarking↗

The GeneAround GO viewer.

We have developed a system for visualizing the Gene Ontology((TM)) hierarchy. The graphical browser interactively displays diagrams of the inheritance relationship for each term to help understand the meanings of terms when handling gene annotation data.

Computer Graphics↗

Inferring sub-cellular localization through automated lexical analysis.

MOTIVATION: The SWISS-PROT sequence database contains keywords of functional annotations for many proteins. In contrast, information about the sub-cellular localization is available for only a few proteins. Experts can often infer localization from keywords describing protein function. We developed LOCkey, a fully automated method for lexical analysis of SWISS-PROT keywords that assigns sub-cellular localization. With the rapid growth in sequence data, the biochemical characterisation of sequences has been falling behind. Our method may be a useful tool for supplementing functional information already automatically available. RESULTS: The method reached a level of more than 82% accuracy in a full cross-validation test. Due to a lack of functional annotations, we could infer localization for fewer than half of all proteins in SWISS-PROT. We applied LOCkey to annotate five entirely sequenced proteomes, namely Saccharomyces cerevisiae (yeast), Caenorhabditis elegans (worm), Drosophila melanogaster (fly), Arabidopsis thaliana (plant) and a subset of all human proteins. LOCkey found about 8000 new annotations of sub-cellular localization for these eukaryotes.

Abstracting and Indexing↗

An approximate matching algorithm for finding (sub-)optimal sequences in S-attributed grammars.

MOTIVATION: S-attributed grammars (a generalization of classical Context-Free grammars) provide a versatile formalism for sequence analysis which allows to express long range constraints: the RNA folding problem is a typical example of application. Efficient algorithms have been developed to solve problems expressed with these tools, which generally compute the optimal attribute of the sequence w.r.t. the grammar. However, it is often more meaningful and/or interesting from the biological point of view to consider almost optimal attributes as well as approximate sequences; we thus need more flexible and powerful algorithms able to perform these generalized analyses. RESULTS: In this paper we present a basic algorithm which, given a grammar G and a sequence omega, computes the optimal attribute for all (approximate) strings omega(') in L(G) such that d(omega, omega(')) < or = M, and whose complexity is O(n(r + 1)) in time and O(n(2)) in space (r is the maximal length of the right-hand side of any production of G). We will also give some extensions and possible improvements of this algorithm.

Algorithms↗

Automated annotation of keywords for proteins related to mycoplasmataceae using machine learning techniques.

MOTIVATION: With the increase in submission of sequences to public databases, the curators of these are not able to cope with the amount of information. The motivation of this work is to generate a system for automated annotation of data we are particularly interested in, namely proteins related to the Mycoplasmataceae family. Following previous works on automatic annotation using symbolic machine learning techniques, the present work proposes a method of automatic annotation of keywords (a part of the SWISS-PROT annotation procedure), and the validation, by an expert, of the annotation rules generated. The aim of this procedure is twofold: to complete the annotation of keywords of those proteins which is far from adequate, and to produce a prototype of the validation environment, which is aimed at an expert who does not have a deep knowledge of the structure of the current databases containing the necessary information s/he needs. RESULTS: As for the first objective, a rate of correct keywords annotation of 60% is reported in the literature. Our preliminary results show that with a slightly different method, applied this method to data related to Mycoplasmataceae only, we are able to increase that rate of correct annotation.

Abstracting and Indexing↗

Knowledge acquisition, consistency checking and concurrency control for Gene Ontology (GO).

MOTIVATION: A critical element of the computational infrastructure required for functional genomics is a shared language for communicating biological data and knowledge. The Gene Ontology (GO; http://www.geneontology.org) provides a taxonomy of concepts and their attributes for annotating gene products. As GO increases in size, its ongoing construction and maintenance becomes more challenging. In this paper, we assess the applicability of a Knowledge Base Management System (KBMS), Protégé-2000, to the maintenance and development of GO. RESULTS: We transferred GO to Protégé-2000 in order to evaluate its suitability for GO. The graphical user interface supported browsing and editing of GO. Tools for consistency checking identified minor inconsistencies in GO and opportunities to reduce redundancy in its representation. The Protégé Axiom Language proved useful for checking ontological consistency. The PROMPT tool allowed us to track changes to GO. Using Protégé-2000, we tested our ability to make changes and extensions to GO to refine the semantics of attributes and classify more concepts. AVAILABILITY: Gene Ontology in Protégé-2000 and the associated code are located at http://smi.stanford.edu/projects/helix/gokbms/. Protégé-2000 is available from http://protege.stanford.edu.

Artificial Intelligence↗

A literature-based method for assessing the functional coherence of a gene group.

MOTIVATION: Many experimental and algorithmic approaches in biology generate groups of genes that need to be examined for related functional properties. For example, gene expression profiles are frequently organized into clusters of genes that may share functional properties. We evaluate a method, neighbor divergence per gene (NDPG), that uses scientific literature to assess whether a group of genes are functionally related. The method requires only a corpus of documents and an index connecting the documents to genes. RESULTS: We evaluate NDPG on 2796 functional groups generated by the Gene Ontology consortium in four organisms: mouse, fly, worm and yeast. NDPG finds functional coherence in 96, 92, 82 and 45% of the groups (at 99.9% specificity) in yeast, mouse, fly and worm respectively.

Abstracting and Indexing↗

Identification of key concepts in biomedical literature using a modified Markov heuristic.

MOTIVATION: The recent explosion of interest in mining the biomedical literature for associations between defined entities such as genes, diseases and drugs has made apparent the need for robust methods of identifying occurrences of these entities in biomedical text. Such concept-based indexing is strongly dependent on the availability of a comprehensive ontology or lexicon of biomedical terms. However, such ontologies are very difficult and expensive to construct, and often require extensive manual curation to render them suitable for use by automatic indexing programs. Furthermore, the use of statistically salient noun phrases as surrogates for curated terminology is not without difficulties, due to the lack of high-quality part-of-speech taggers specific to medical nomenclature. RESULTS: We describe a method of improving the quality of automatically extracted noun phrases by employing prior knowledge during the HMM training procedure for the tagger. This enhancement, when combined with appropriate training data, can greatly improve the quality and relevance of the extracted phrases, thereby enabling greater accuracy in downstream literature mining tasks.

Abstracting and Indexing↗

Cellerator: extending a computer algebra system to include biochemical arrows for signal transduction simulations.

Cellerator describes single and multi-cellular signal transduction networks (STN) with a compact, optionally palette-driven, arrow-based notation to represent biochemical reactions and transcriptional activation. Multi-compartment systems are represented as graphs with STNs embedded in each node. Interactions include mass-action, enzymatic, allosteric and connectionist models. Reactions are translated into differential equations and can be solved numerically to generate predictive time courses or output as systems of equations that can be read by other programs. Cellerator simulations are fully extensible and portable to any operating system that supports Mathematica, and can be indefinitely nested within larger data structures to produce highly scaleable models.

Computer Graphics↗

Stochastic modeling of RNA pseudoknotted structures: a grammatical approach.

MOTIVATION: Modeling RNA pseudoknotted structures remains challenging. Methods have previously been developed to model RNA stem-loops successfully using stochastic context-free grammars (SCFG) adapted from computational linguistics; however, the additional complexity of pseudoknots has made modeling them more difficult. Formally a context-sensitive grammar is required, which would impose a large increase in complexity. RESULTS: We introduce a new grammar modeling approach for RNA pseudoknotted structures based on parallel communicating grammar systems (PCGS). Our new approach can specify pseudoknotted structures, while avoiding context-sensitive rules, using a single CFG synchronized with a number of regular grammars. Technically, the stochastic version of the grammar model can be as simple as an SCFG. As with SCFG, the new approach permits automatic generation of a single-RNA structure prediction algorithm for each specified pseudoknotted structure model. This approach also makes it possible to develop full probabilistic models of pseudoknotted structures to allow the prediction of consensus structures by comparative analysis and structural homology recognition in database searches.

Algorithms↗

The discovery net system for high throughput bioinformatics.

MOTIVATION: Bioinformatics requires Grid technologies and protocols to build high performance applications without focusing on the low level detail of how the individual Grid components operate. RESULTS: The Discovery Net system is a middleware that allows service developers to integrate tools based on existing and emerging Grid standards such as web services. Once integrated, these tools can be used to compose reusable workflows using these services that can later be deployed as new services for others to use. Using the Discovery Net system and a range of different bioinformatics tools, we built a Grid based application for Genome Annotation. This includes workflows for automatic nucleotide annotation, annotation of predicted proteins and text analysis based on metabolic profiles and text analysis.

Algorithms↗

Extracting synonymous gene and protein terms from biological literature.

MOTIVATION: Genes and proteins are often associated with multiple names. More names are added as new functional or structural information is discovered. Because authors can use any one of the known names for a gene or protein, information retrieval and extraction would benefit from identifying the gene and protein terms that are synonyms of the same substance. RESULTS: We have explored four complementary approaches for extracting gene and protein synonyms from text, namely the unsupervised, partially supervised, and supervised machine-learning techniques, as well as the manual knowledge-based approach. We report results of a large scale evaluation of these alternatives over an archive of biological journal articles. Our evaluation shows that our extraction techniques could be a valuable supplement to resources such as SWISSPROT, as our systems were able to capture gene and protein synonyms not listed in the SWISSPROT database.

Abstracting and Indexing↗

SEMEDA: ontology based semantic integration of biological databases.

MOTIVATION: Many molecular biological databases are implemented on relational Database Management Systems, which provide standard interfaces like JDBC and ODBC for data and metadata exchange. By using these interfaces, many technical problems of database integration vanish and issues related to semantics remain, e.g. the use of different terms for the same things, different names for equivalent database attributes and missing links between relevant entries in different databases. RESULTS: In this publication, principles and methods that were used to implement SEMEDA (Semantic Meta Database) are described. Database owners can use SEMEDA to provide semantically integrated access to their databases as well as to collaboratively edit and maintain ontologies and controlled vocabularies. Biologists can use SEMEDA to query the integrated databases in real time without having to know the structure or any technical details of the underlying databases. AVAILABILITY: SEMEDA is available at http://www-bm.ipk-gatersleben.de/semeda/. Database providers who intend to grant access to their databases via SEMEDA are encouraged to contact the authors.

Computational Biology↗

SNOW: standard nomenclature wizard to help searching for (bio) chemical standardized names.

UNLABELLED: When developing bioinformatical tools dealing with enzymatic activity, metabolism or enzymatic networks, the problem of the lack of a clear nomenclature for biochemical compounds often arises. This problem leads us to develop a small web-based tool (SNOW, Standard NOmenclature Wizard) which may help to find recommended and trivial names or the correct closest spelling for a query compound name, if it exists. AVAILABILITY: Web-based interface available at http://ibb.uab.es/snow/ SUPPLEMENTARY INFORMATION: http://ibb.uab.es/snow/snow_moreinfo.html

Algorithms↗

Characterizing gene sets with FuncAssociate.

SUMMARY: FuncAssociate is a web-based tool to help researchers use Gene Ontology attributes to characterize large sets of genes derived from experiment. Distinguishing features of FuncAssociate include the ability to handle ranked input lists, and a Monte Carlo simulation approach that is more appropriate to determine significance than other methods, such as Bonferroni or idák p-value correction. FuncAssociate currently supports 10 organisms (Vibrio cholerae, Shewanella oneidensis, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, Caenorhaebditis elegans, Drosophila melanogaster, Mus musculus, Rattus norvegicus and Homo sapiens). AVAILABILITY: FuncAssociate is freely accessible at http://llama.med.harvard.edu/Software.html. Source code (in Perl and C) is freely available to academic users 'as is'.

Algorithms↗

GIS: a biomedical text-mining system for gene information discovery.

UNLABELLED: We present a biomedical text-mining system focused on four types of gene-related information: biological functions, associated diseases, related genes and gene-gene relations. The aim of this system is to provide researchers an easy-to-use bio-information service that will rapidly survey the rapidly burgeoning biomedical literature. AVAILABILITY: http://iir.csie.ncku.edu.tw/~yuhc/gis/

Abstracting and Indexing↗

Shared relationship analysis: ranking set cohesion and commonalities within a literature-derived relationship network.

MOTIVATION: There is a general scientific need to be able to identify and evaluate what any given set of 'objects' (e.g. genes, phenotypes, chemicals, diseases) has in common. Whether it is to classify, expand upon or identify commonalities and functional groupings, informational needs can be diverse and the best source to identify relationships among a potentially heterogeneous set of objects is the scientific literature. RESULTS: We first establish a network of related objects by their co-occurrence within MEDLINE records. A set of objects within this network can then be queried to identify shared relationships, and a method is presented to score their statistical relevance by comparing observed frequencies with what would be expected in a random network model. Using Gene Ontology (GO) categories, we demonstrate that this method enables a quantitative ranking of the 'cohesiveness' of a set of objects and, importantly, allows other objects related to this set to be identified and evaluated for their 'cohesion' to it. Supplemental information: A list of ranked genes related to each GO category analyzed can be found at http://innovation.swmed.edu/IRIDESCENT/GO_relationships.htm

Abstracting and Indexing↗