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Subjective methods have been reported to adapt a general-purpose ontology for a specific application. For example, Gene Ontology (GO) Slim was created from GO to generate a highly aggregated report of the human-genome annotation. We propose statistical methods to adapt the general purpose, OBO Foundry Disease Ontology (DO) for the identification of gene-disease associations. Thus, we need a simplified definition of disease categories derived from implicated genes. On the basis of the assumption that the DO terms having similar associated genes are closely related, we group the DO terms based on the similarity of gene-to-DO mapping profiles. Two types of binary distance metrics are defined to measure the overall and subset similarity between DO terms. A compactness-scalable fuzzy clustering method is then applied to group similar DO terms. To reduce false clustering, the semantic similarities between DO terms are also used to constrain clustering results. As such, the DO terms are aggregated and the redundant DO terms are largely removed. Using these methods, we constructed a simplified vocabulary list from the DO called Disease Ontology Lite (DOLite). We demonstrated that DOLite results in more interpretable results than DO for gene-disease association tests. The resultant DOLite has been used in the Functional Disease Ontology (FunDO) Web application at http://www.projects.bioinformatics.northwestern.edu/fundo.

Contact: s-lin2@northwestern.edu

Background

Semantic similarity measures are useful to assess the physiological relevance of protein-protein interactions (PPIs). They quantify similarity between proteins based on their function using annotation systems like the Gene Ontology (GO). Proteins that interact in the cell are likely to be in similar locations or involved in similar biological processes compared to proteins that do not interact. Thus the more semantically similar the gene function annotations are among the interacting proteins, more likely the interaction is physiologically relevant. However, most semantic similarity measures used for PPI confidence assessment do not consider the unequal depth of term hierarchies in different classes of cellular location, molecular function, and biological process ontologies of GO and thus may over-or under-estimate similarity.

Results

We describe an improved algorithm, Topological Clustering Semantic Similarity (TCSS), to compute semantic similarity between GO terms annotated to proteins in interaction datasets. Our algorithm, considers unequal depth of biological knowledge representation in different branches of the GO graph. The central idea is to divide the GO graph into sub-graphs and score PPIs higher if participating proteins belong to the same sub-graph as compared to if they belong to different sub-graphs.

Conclusions

The TCSS algorithm performs better than other semantic similarity measurement techniques that we evaluated in terms of their performance on distinguishing true from false protein interactions, and correlation with gene expression and protein families. We show an average improvement of 4.6 times the F1 score over Resnik, the next best method, on our Saccharomyces cerevisiae PPI dataset and 2 times on our Homo sapiens PPI dataset using cellular component, biological process and molecular function GO annotations.

Motivation: The results of initial analyses for many high-throughput technologies commonly take the form of gene or protein sets, and one of the ensuing tasks is to evaluate the functional coherence of these sets. The study of gene set function most commonly makes use of controlled vocabulary in the form of ontology annotations. For a given gene set, the statistical significance of observing these annotations or ‘enrichment’ may be tested using a number of methods. Instead of testing for significance of individual terms, this study is concerned with the task of assessing the global functional coherence of gene sets, for which novel metrics and statistical methods have been devised.

Results: The metrics of this study are based on the topological properties of graphs comprised of genes and their Gene Ontology annotations. A novel aspect of these methods is that both the enrichment of annotations and the relationships among annotations are considered when determining the significance of functional coherence. We applied our methods to perform analyses on an existing database and on microarray experimental results. Here, we demonstrated that our approach is highly discriminative in terms of differentiating coherent gene sets from random ones and that it provides biologically sensible evaluations in microarray analysis. We further used examples to show the utility of graph visualization as a tool for studying the functional coherence of gene sets.

Availability: The implementation is provided as a freely accessible web application at: http://projects.dbbe.musc.edu/gosteiner. Additionally, the source code written in the Python programming language, is available under the General Public License of the Free Software Foundation.

Contact: lux@musc.edu

Supplementary information: Supplementary data are available at Bioinformatics online.

Gene ontology analysis has become a popular and important tool in bioinformatics study, and current ontology analyses are mainly conducted in individual gene or a gene list. However, recent molecular network analysis reveals that the same list of genes with different interactions may perform different functions. Therefore, it is necessary to consider molecular interactions to correctly and specifically annotate biological networks. Here, we propose a novel Network Ontology Analysis (NOA) method to perform gene ontology enrichment analysis on biological networks. Specifically, NOA first defines link ontology that assigns functions to interactions based on the known annotations of joint genes via optimizing two novel indexes ‘Coverage’ and ‘Diversity’. Then, NOA generates two alternative reference sets to statistically rank the enriched functional terms for a given biological network. We compare NOA with traditional enrichment analysis methods in several biological networks, and find that: (i) NOA can capture the change of functions not only in dynamic transcription regulatory networks but also in rewiring protein interaction networks while the traditional methods cannot and (ii) NOA can find more relevant and specific functions than traditional methods in different types of static networks. Furthermore, a freely accessible web server for NOA has been developed at http://www.aporc.org/noa/.

The characterization of biological function among newly determined protein structures is a central challenge in structural genomics. One class of computational solutions to this problem is based on the similarity of protein structure. Here, we implement a simple yet efficient measure of protein structure similarity, the contact metric. Even though its computation avoids structural alignments and is therefore nearly instantaneous, we find that small values correlate with geometrical root mean square deviations obtained from structural alignments. To test whether the contact metric detects functional similarity, as defined by Gene Ontology (GO) terms, it was compared in large-scale computational experiments to four other measures of structural similarity, including alignment algorithms as well as alignment independent approaches. The contact metric was the fastest method and its sensitivity, at any given specificity level, was a close second only to Fast Alignment and Search Tool—a structural alignment method that is slower by three orders of magnitude. Critically, nearly 40% of correct functional inferences by the contact metric were not identified by any other approach, which shows that the contact metric is complementary and computationally efficient in detecting functional relationships between proteins. A public ‘Contact Metric Internet Server’ is provided.

Background

Recent analyses in systems biology pursue the discovery of functional modules within the cell. Recognition of such modules requires the integrative analysis of genome-wide experimental data together with available functional schemes. In this line, methods to bridge the gap between the abstract definitions of cellular processes in current schemes and the interlinked nature of biological networks are required.

Results

This work explores the use of the scientific literature to establish potential relationships among cellular processes. To this end we haveused a document based similarity method to compute pair-wise similarities of the biological processes described in the Gene Ontology (GO). The method has been applied to the biological processes annotated for the Saccharomyces cerevisiae genome. We compared our results with similarities obtained with two ontology-based metrics, as well as with gene product annotation relationships. We show that the literature-based metric conserves most direct ontological relationships, while reveals biologically sounded similarities that are not obtained using ontology-based metrics and/or genome annotation.

Conclusion

The scientific literature is a valuable source of information from which to compute similarities among biological processes. The associations discovered by literature analysis are a valuable complement to those encoded in existing functional schemes, and those that arise by genome annotation. These similarities can be used to conveniently map the interlinked structure of cellular processes in a particular organism.

Quantifying the functional similarity of genes and their products based on Gene Ontology annotation is an important tool for diverse applications like the analysis of gene expression data, the prediction and validation of protein functions and interactions, and the prioritization of disease genes. The Functional Similarity Matrix (FunSimMat, http://www.funsimmat.de) is a comprehensive database providing various precomputed functional similarity values for proteins in UniProtKB and for protein families in Pfam and SMART. With this update, we significantly increase the coverage of FunSimMat by adding data from the Gene Ontology Annotation project as well as new functional similarity measures. The applicability of the database is greatly extended by the implementation of a new Gene Ontology-based method for disease gene prioritization. Two new visualization tools allow an interactive analysis of the functional relationships between proteins or protein families. This is enhanced further by the introduction of an automatically derived hierarchy of annotation classes. Additional changes include a revised user front-end and a new RESTlike interface for improving the user-friendliness and online accessibility of FunSimMat.

Motivation: The Gene Ontology (GO) is a controlled vocabulary designed to represent the biological concepts pertaining to gene products. This study investigates the methods for identifying informative subsets of GO terms in an automatic and objective fashion. This task in turn requires addressing the following issues: how to represent the semantic context of GO terms, what metrics are suitable for measuring the semantic differences between terms, how to identify an informative subset that retains as much as possible of the original semantic information of GO.

Results: We represented the semantic context of a GO term using the word-usage-profile associated with the term, which enables one to measure the semantic differences between terms based on the differences in their semantic contexts. We further employed the information bottleneck methods to automatically identify subsets of GO terms that retain as much as possible of the semantic information in an annotation database. The automatically retrieved informative subsets align well with an expert-picked GO slim subset, cover important concepts and proteins, and enhance literature-based GO annotation.

Availability: http://carcweb.musc.edu/TextminingProjects/

Contact: xinghua@pitt.edu

Supplementary information: Supplementary data are available at Bioinformatics online.

Background

Various measures of semantic similarity of terms in bio-ontologies such as the Gene Ontology (GO) have been used to compare gene products. Such measures of similarity have been used to annotate uncharacterized gene products and group gene products into functional groups. There are various ways to measure semantic similarity, either using the topological structure of the ontology, the instances (gene products) associated with terms or a mixture of both. We focus on an instance level definition of semantic similarity while using the information contained in the ontology, both in the graphical structure of the ontology and the semantics of relations between terms, to provide constraints on our instance level description.

Semantic similarity of terms is extended to annotations by various approaches, either though aggregation operations such as min, max and average or through an extrapolative method. These approaches introduce assumptions about how semantic similarity of terms relates to the semantic similarity of annotations that do not necessarily reflect how terms relate to each other.

Results

We exploit the semantics of relations in the GO to construct an algorithm called SSA that provides the basis of a framework that naturally extends instance based methods of semantic similarity of terms, such as Resnik's measure, to describing annotations and not just terms. Our measure attempts to correctly interpret how terms combine via their relationships in the ontological hierarchy. SSA uses these relationships to identify the most specific common ancestors between terms. We outline the set of cases in which terms can combine and associate partial order constraints with each case that order the specificity of terms. These cases form the basis for the SSA algorithm. The set of associated constraints also provide a set of principles that any improvement on our method should seek to satisfy.

Conclusion

We derive a measure of semantic similarity between annotations that exploits all available information without introducing assumptions about the nature of the ontology or data. We preserve the principles underlying instance based methods of semantic similarity of terms at the annotation level. As a result our measure better describes the information contained in annotations associated with gene products and as a result is better suited to characterizing and classifying gene products through their annotations.

Background

Many biological processes recognize in particular the importance of protein complexes, and various computational approaches have been developed to identify complexes from protein-protein interaction (PPI) networks. However, high false-positive rate of PPIs leads to challenging identification.

Results

A protein semantic similarity measure is proposed in this study, based on the ontology structure of Gene Ontology (GO) terms and GO annotations to estimate the reliability of interactions in PPI networks. Interaction pairs with low GO semantic similarity are removed from the network as unreliable interactions. Then, a cluster-expanding algorithm is used to detect complexes with core-attachment structure on filtered network. Our method is applied to three different yeast PPI networks. The effectiveness of our method is examined on two benchmark complex datasets. Experimental results show that our method performed better than other state-of-the-art approaches in most evaluation metrics.

Conclusions

The method detects protein complexes from large scale PPI networks by filtering GO semantic similarity. Removing interactions with low GO similarity significantly improves the performance of complex identification. The expanding strategy is also effective to identify attachment proteins of complexes.

Advanced statistical methods used to analyze high-throughput data (e.g. gene-expression assays) result in long lists of “significant genes.” One way to gain insight into the significance of altered expression levels is to determine whether Gene Ontology (GO) terms associated with a particular biological process, molecular function, or cellular component are over- or under-represented in the set of genes deemed significant. This process, referred to as enrichment analysis, profiles a gene-set, and is relevant for and extensible to data analysis with other high-throughput measurement modalities such as proteomics, metabolomics, and tissue-microarray assays. With the availability of tools for automatic ontology-based annotation of datasets with terms from biomedical ontologies besides the GO, we need not restrict enrichment analysis to the GO. We describe, RANSUM – Rich Annotation Summarizer – which performs enrichment analysis using any ontology in the National Center for Biomedical Ontology’s (NCBO) BioPortal. We outline the methodology of enrichment analysis, the associated challenges, and discuss novel analyses enabled by RANSUM.

Biological ontologies are now being widely used for annotation, sharing and retrieval of the biological data. Many of these ontologies are hosted under the umbrella of the Open Biological Ontologies Foundry. In order to support interterminology mapping, composite terms in these ontologies need to be translated into atomic or primitive terms in other, orthogonal ontologies, for example, gluconeogenesis (biological process term) to glucose (chemical ontology term). Identifying such decompositional ontology translations is a challenging problem. In this paper, we propose a network-theoretic approach based on the structure of the integrated OBO relationship graph. We use a network-theoretic measure, called the clustering coefficient, to find relevant atomic terms in the neighborhood of a composite term. By eliminating the existing GO to ChEBI Ontology mappings from OBO, we evaluate whether the proposed approach can re-identify the corresponding relationships. The results indicate that the network structure provides strong cues for decompositional ontology translation and the existing relationships can be used to identify new translations.

Ontologies have emerged as a fast growing research topic in the area of semantic web during last decade. Currently there are 204 ontologies that are available through OBO Foundry and BioPortal. Several excellent tools for navigating the ontological structure are available, however most of them are dedicated to a specific annotation data or integrated with specific analysis applications, and do not offer flexibility in terms of general-purpose usage for ontology exploration. We developed OntoVisT, a web based ontological visualization tool. This application is designed for interactive visualization of any ontological hierarchy for a specific node of interest, up to the chosen level of children and/or ancestor. It takes any ontology file in OBO format as input and generates output as DAG hierarchical graph for the chosen query. To enhance the navigation capabilities of complex networks, we have embedded several features such as search criteria, zoom in/out, center focus, nearest neighbor highlights and mouse hover events. The application has been tested on all 72 data sets available in OBO format through OBO foundry. The results for few of them can be accessed through OntoVisT-Gallery.

Availability

The database is available for free at http://ccbb.jnu.ac.in/OntoVisT.html

Background

Numerous ontologies have recently been developed in life sciences to support a consistent annotation of biological objects, such as genes or proteins. These ontologies underlie continuous changes which can impact existing annotations. Therefore, it is valuable for users of ontologies to study the stability of ontologies and to see how many and what kind of ontology changes occurred.

Results

We present OnEX (Ontology Evolution EXplorer) a system for exploring ontology changes. Currently, OnEX provides access to about 560 versions of 16 well-known life science ontologies. The system is based on a three-tier architecture including an ontology version repository, a middleware component and the OnEX web application. Interactive workflows allow a systematic and explorative change analysis of ontologies and their concepts as well as the semi-automatic migration of out-dated annotations to the current version of an ontology.

Conclusion

OnEX provides a user-friendly web interface to explore information about changes in current life science ontologies. It is available at .

Background

Researchers in biomedical informatics use ontologies and terminologies to annotate their data in order to facilitate data integration and translational discoveries. As the use of ontologies for annotation of biomedical datasets has risen, a common challenge is to identify ontologies that are best suited to annotating specific datasets. The number and variety of biomedical ontologies is large, and it is cumbersome for a researcher to figure out which ontology to use.

Methods

We present the Biomedical Ontology Recommender web service. The system uses textual metadata or a set of keywords describing a domain of interest and suggests appropriate ontologies for annotating or representing the data. The service makes a decision based on three criteria. The first one is coverage, or the ontologies that provide most terms covering the input text. The second is connectivity, or the ontologies that are most often mapped to by other ontologies. The final criterion is size, or the number of concepts in the ontologies. The service scores the ontologies as a function of scores of the annotations created using the National Center for Biomedical Ontology (NCBO) Annotator web service. We used all the ontologies from the UMLS Metathesaurus and the NCBO BioPortal.

Results

We compare and contrast our Recommender by an exhaustive functional comparison to previously published efforts. We evaluate and discuss the results of several recommendation heuristics in the context of three real world use cases. The best recommendations heuristics, rated ‘very relevant’ by expert evaluators, are the ones based on coverage and connectivity criteria. The Recommender service (alpha version) is available to the community and is embedded into BioPortal.

Semantic-similarity measures quantify concept similarities in a given ontology. Potential applications for these measures include search, data mining, and knowledge discovery in database or decision-support systems that utilize ontologies. To date, there have not been comparisons of the different semantic-similarity approaches on a single ontology. Such a comparison can offer insight on the validity of different approaches. We compared 3 approaches to semantic similarity-metrics (which rely on expert opinion, ontologies only, and information content) with 4 metrics applied to SNOMED-CT. We found that there was poor agreement among those metrics based on information content with the ontology only metric. The metric based only on the ontology structure correlated most with expert opinion. Our results suggest that metrics based on the ontology only may be preferable to information-content–based metrics, and point to the need for more research on validating the different approaches.

A map of protein–protein interactions provides valuable insight into the cellular function and machinery of a proteome. By measuring the similarity between two Gene Ontology (GO) terms with a relative specificity semantic relation, here, we proposed a new method of reconstructing a yeast protein–protein interaction map that is solely based on the GO annotations. The method was validated using high-quality interaction datasets for its effectiveness. Based on a Z-score analysis, a positive dataset and a negative dataset for protein–protein interactions were derived. Moreover, a gold standard positive (GSP) dataset with the highest level of confidence that covered 78% of the high-quality interaction dataset and a gold standard negative (GSN) dataset with the lowest level of confidence were derived. In addition, we assessed four high-throughput experimental interaction datasets using the positives and the negatives as well as GSPs and GSNs. Our predicted network reconstructed from GSPs consists of 40 753 interactions among 2259 proteins, and forms 16 connected components. We mapped all of the MIPS complexes except for homodimers onto the predicted network. As a result, ∼35% of complexes were identified interconnected. For seven complexes, we also identified some nonmember proteins that may be functionally related to the complexes concerned. This analysis is expected to provide a new approach for predicting the protein–protein interaction maps from other completely sequenced genomes with high-quality GO-based annotations.

Background

The Gene Ontology (GO) is a well known controlled vocabulary describing the biological process, molecular function and cellular component aspects of gene annotation. It has become a widely used knowledge source in bioinformatics for annotating genes and measuring their semantic similarity. These measures generally involve the GO graph structure, the information content of GO aspects, or a combination of both. However, only a few of the semantic similarity measures described so far can handle GO annotations differently according to their origin (i.e. their evidence codes).

Results

We present here a new semantic similarity measure called IntelliGO which integrates several complementary properties in a novel vector space model. The coefficients associated with each GO term that annotates a given gene or protein include its information content as well as a customized value for each type of GO evidence code. The generalized cosine similarity measure, used for calculating the dot product between two vectors, has been rigorously adapted to the context of the GO graph. The IntelliGO similarity measure is tested on two benchmark datasets consisting of KEGG pathways and Pfam domains grouped as clans, considering the GO biological process and molecular function terms, respectively, for a total of 683 yeast and human genes and involving more than 67,900 pair-wise comparisons. The ability of the IntelliGO similarity measure to express the biological cohesion of sets of genes compares favourably to four existing similarity measures. For inter-set comparison, it consistently discriminates between distinct sets of genes. Furthermore, the IntelliGO similarity measure allows the influence of weights assigned to evidence codes to be checked. Finally, the results obtained with a complementary reference technique give intermediate but correct correlation values with the sequence similarity, Pfam, and Enzyme classifications when compared to previously published measures.

Conclusions

The IntelliGO similarity measure provides a customizable and comprehensive method for quantifying gene similarity based on GO annotations. It also displays a robust set-discriminating power which suggests it will be useful for functional clustering.

Availability

An on-line version of the IntelliGO similarity measure is available at: http://bioinfo.loria.fr/Members/benabdsi/intelligo_project/

Motivation: There is a growing interest in improving the cluster analysis of expression data by incorporating into it prior knowledge, such as the Gene Ontology (GO) annotations of genes, in order to improve the biological relevance of the clusters that are subjected to subsequent scrutiny. The structure of the GO is another source of background knowledge that can be exploited through the use of semantic similarity.

Results: We propose here a novel algorithm that integrates semantic similarities (derived from the ontology structure) into the procedure of deriving clusters from the dendrogram constructed during expression-based hierarchical clustering. Our approach can handle the multiple annotations, from different levels of the GO hierarchy, which most genes have. Moreover, it treats annotated and unannotated genes in a uniform manner. Consequently, the clusters obtained by our algorithm are characterized by significantly enriched annotations. In both cross-validation tests and when using an external index such as protein–protein interactions, our algorithm performs better than previous approaches. When applied to human cancer expression data, our algorithm identifies, among others, clusters of genes related to immune response and glucose metabolism. These clusters are also supported by protein–protein interaction data.

Contact: dotna@cs.bgu.ac.il

Supplementary information: Supplementary data are available at Bioinformatics online.

Background

The systematic analysis of protein-protein interactions can enable a better understanding of cellular organization, processes and functions. Functional modules can be identified from the protein interaction networks derived from experimental data sets. However, these analyses are challenging because of the presence of unreliable interactions and the complex connectivity of the network. The integration of protein-protein interactions with the data from other sources can be leveraged for improving the effectiveness of functional module detection algorithms.

Results

We have developed novel metrics, called semantic similarity and semantic interactivity, which use Gene Ontology (GO) annotations to measure the reliability of protein-protein interactions. The protein interaction networks can be converted into a weighted graph representation by assigning the reliability values to each interaction as a weight. We presented a flow-based modularization algorithm to efficiently identify overlapping modules in the weighted interaction networks. The experimental results show that the semantic similarity and semantic interactivity of interacting pairs were positively correlated with functional co-occurrence. The effectiveness of the algorithm for identifying modules was evaluated using functional categories from the MIPS database. We demonstrated that our algorithm had higher accuracy compared to other competing approaches.

Conclusion

The integration of protein interaction networks with GO annotation data and the capability of detecting overlapping modules substantially improve the accuracy of module identification.

Background

Gene Ontology (GO) has been widely used in biological databases, annotation projects, and computational analyses. Although the three GO categories are structured as independent ontologies, the biological relationships across the categories are not negligible for biological reasoning and knowledge integration. However, the existing cross-category ontology term similarity measures are either developed by utilizing the GO data only or based on manually curated term name similarities, ignoring the fact that GO is evolving quickly and the gene annotations are far from complete.

Results

In this paper we introduce a new cross-category similarity measurement called CroGO by incorporating genome-specific gene co-function network data. The performance study showed that our measurement outperforms the existing algorithms. We also generated genome-specific term association networks for yeast and human. An enrichment based test showed our networks are better than those generated by the other measures.

Conclusions

The genome-specific term association networks constructed using CroGO provided a platform to enable a more consistent use of GO. In the networks, the frequently occurred MF-centered hub indicates that a molecular function may be shared by different genes in multiple biological processes, or a set of genes with the same functions may participate in distinct biological processes. And common subgraphs in multiple organisms also revealed conserved GO term relationships. Software and data are available online at http://www.msu.edu/˜jinchen/CroGO.

Summary: We introduce GO-Elite, a flexible and powerful pathway analysis tool for a wide array of species, identifiers (IDs), pathways, ontologies and gene sets. In addition to the Gene Ontology (GO), GO-Elite allows the user to perform over-representation analysis on any structured ontology annotations, pathway database or biological IDs (e.g. gene, protein or metabolite). GO-Elite exploits the structured nature of biological ontologies to report a minimal set of non-overlapping terms. The results can be visualized on WikiPathways or as networks. Built-in support is provided for over 60 species and 50 ID systems, covering gene, disease and phenotype ontologies, multiple pathway databases, biomarkers, and transcription factor and microRNA targets. GO-Elite is available as a web interface, GenMAPP-CS plugin and as a cross-platform application.

Availability: http://www.genmapp.org/go_elite

Contact: nsalomonis@gladstone.ucsf.edu

Supplementary Information: Supplementary data are available at Bioinformatics online.

In recent years, ontologies have become a mainstream topic in biomedical research. When biological entities are described using a common schema, such as an ontology, they can be compared by means of their annotations. This type of comparison is called semantic similarity, since it assesses the degree of relatedness between two entities by the similarity in meaning of their annotations. The application of semantic similarity to biomedical ontologies is recent; nevertheless, several studies have been published in the last few years describing and evaluating diverse approaches. Semantic similarity has become a valuable tool for validating the results drawn from biomedical studies such as gene clustering, gene expression data analysis, prediction and validation of molecular interactions, and disease gene prioritization.

We review semantic similarity measures applied to biomedical ontologies and propose their classification according to the strategies they employ: node-based versus edge-based and pairwise versus groupwise. We also present comparative assessment studies and discuss the implications of their results. We survey the existing implementations of semantic similarity measures, and we describe examples of applications to biomedical research. This will clarify how biomedical researchers can benefit from semantic similarity measures and help them choose the approach most suitable for their studies.

Biomedical ontologies are evolving toward increased coverage, formality, and integration, and their use for annotation is increasingly becoming a focus of both effort by biomedical experts and application of automated annotation procedures to create corpora of higher quality and completeness than are currently available. Given that semantic similarity measures are directly dependent on these evolutions, we can expect to see them gaining more relevance and even becoming as essential as sequence similarity is today in biomedical research.

Background

In the current climate of high-throughput computational biology, the inference of a protein's function from related measurements, such as protein-protein interaction relations, has become a canonical task. Most existing technologies pursue this task as a classification problem, on a term-by-term basis, for each term in a database, such as the Gene Ontology (GO) database, a popular rigorous vocabulary for biological functions. However, ontology structures are essentially hierarchies, with certain top to bottom annotation rules which protein function predictions should in principle follow. Currently, the most common approach to imposing these hierarchical constraints on network-based classifiers is through the use of transitive closure to predictions.

Results

We propose a probabilistic framework to integrate information in relational data, in the form of a protein-protein interaction network, and a hierarchically structured database of terms, in the form of the GO database, for the purpose of protein function prediction. At the heart of our framework is a factorization of local neighborhood information in the protein-protein interaction network across successive ancestral terms in the GO hierarchy. We introduce a classifier within this framework, with computationally efficient implementation, that produces GO-term predictions that naturally obey a hierarchical 'true-path' consistency from root to leaves, without the need for further post-processing.

Conclusion

A cross-validation study, using data from the yeast Saccharomyces cerevisiae, shows our method offers substantial improvements over both standard 'guilt-by-association' (i.e., Nearest-Neighbor) and more refined Markov random field methods, whether in their original form or when post-processed to artificially impose 'true-path' consistency. Further analysis of the results indicates that these improvements are associated with increased predictive capabilities (i.e., increased positive predictive value), and that this increase is consistent uniformly with GO-term depth. Additional in silico validation on a collection of new annotations recently added to GO confirms the advantages suggested by the cross-validation study. Taken as a whole, our results show that a hierarchical approach to network-based protein function prediction, that exploits the ontological structure of protein annotation databases in a principled manner, can offer substantial advantages over the successive application of 'flat' network-based methods.

Background

Semantic similarity analysis facilitates automated semantic explanations of biological and clinical data annotated by biomedical ontologies. Gene ontology (GO) has become one of the most important biomedical ontologies with a set of controlled vocabularies, providing rich semantic annotations for genes and molecular phenotypes for diseases. Current methods for measuring GO semantic similarities are limited to considering only the ancestor terms while neglecting the descendants. One can find many GO term pairs whose ancestors are identical but whose descendants are very different and vice versa. Moreover, the lower parts of GO trees are full of terms with more specific semantics.

Methods

This study proposed a method of measuring semantic similarities between GO terms using the entire GO tree structure, including both the upper (ancestral) and the lower (descendant) parts. Comprehensive comparison studies were performed with well-known information content-based and graph structure-based semantic similarity measures with protein sequence similarities, gene expression-profile correlations, protein–protein interactions, and biological pathway analyses.

Conclusion

The proposed bidirectional measure of semantic similarity outperformed other graph-based and information content-based methods.