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1.  Linking Human Diseases to Animal Models Using Ontology-Based Phenotype Annotation 
PLoS Biology  2009;7(11):e1000247.
A novel method for quantifying the similarity between phenotypes by the use of ontologies can be used to search for candidate genes, pathway members, and human disease models on the basis of phenotypes alone.
Scientists and clinicians who study genetic alterations and disease have traditionally described phenotypes in natural language. The considerable variation in these free-text descriptions has posed a hindrance to the important task of identifying candidate genes and models for human diseases and indicates the need for a computationally tractable method to mine data resources for mutant phenotypes. In this study, we tested the hypothesis that ontological annotation of disease phenotypes will facilitate the discovery of new genotype-phenotype relationships within and across species. To describe phenotypes using ontologies, we used an Entity-Quality (EQ) methodology, wherein the affected entity (E) and how it is affected (Q) are recorded using terms from a variety of ontologies. Using this EQ method, we annotated the phenotypes of 11 gene-linked human diseases described in Online Mendelian Inheritance in Man (OMIM). These human annotations were loaded into our Ontology-Based Database (OBD) along with other ontology-based phenotype descriptions of mutants from various model organism databases. Phenotypes recorded with this EQ method can be computationally compared based on the hierarchy of terms in the ontologies and the frequency of annotation. We utilized four similarity metrics to compare phenotypes and developed an ontology of homologous and analogous anatomical structures to compare phenotypes between species. Using these tools, we demonstrate that we can identify, through the similarity of the recorded phenotypes, other alleles of the same gene, other members of a signaling pathway, and orthologous genes and pathway members across species. We conclude that EQ-based annotation of phenotypes, in conjunction with a cross-species ontology, and a variety of similarity metrics can identify biologically meaningful similarities between genes by comparing phenotypes alone. This annotation and search method provides a novel and efficient means to identify gene candidates and animal models of human disease, which may shorten the lengthy path to identification and understanding of the genetic basis of human disease.
Author Summary
Model organisms such as fruit flies, mice, and zebrafish are useful for investigating gene function because they are easy to grow, dissect, and genetically manipulate in the laboratory. By examining mutations in these organisms, one can identify candidate genes that cause disease in humans, and develop models to better understand human disease and gene function. A fundamental roadblock for analysis is, however, the lack of a computational method for describing and comparing phenotypes of mutant animals and of human diseases when the genetic basis is unknown. We describe here a novel method using ontologies to record and quantify the similarity between phenotypes. We tested our method by using the annotated mutant phenotype of one member of the Hedgehog signaling pathway in zebrafish to identify other pathway members with similar recorded phenotypes. We also compared human disease phenotypes to those produced by mutation in model organisms, and show that orthologous and biologically relevant genes can be identified by this method. Given that the genetic basis of human disease is often unknown, this method provides a means for identifying candidate genes, pathway members, and disease models by computationally identifying similar phenotypes within and across species.
doi:10.1371/journal.pbio.1000247
PMCID: PMC2774506  PMID: 19956802
2.  Functional coherence metrics in protein families 
Background
Biological sequences, such as proteins, have been provided with annotations that assign functional information. These functional annotations are associations of proteins (or other biological sequences) with descriptors characterizing their biological roles. However, not all proteins are fully (or even at all) annotated. This annotation incompleteness limits our ability to make sound assertions about the functional coherence within sets of proteins. Annotation incompleteness is a problematic issue when measuring semantic functional similarity of biological sequences since they can only capture a limited amount of all the semantic aspects the sequences may encompass.
Methods
Instead of relying uniquely on single (reductive) metrics, this work proposes a comprehensive approach for assessing functional coherence within protein sets. The approach entails using visualization and term enrichment techniques anchored in specific domain knowledge, such as a protein family. For that purpose we evaluate two novel functional coherence metrics, mUI and mGIC that combine aspects of semantic similarity measures and term enrichment.
Results
These metrics were used to effectively capture and measure the local similarity cores within protein sets. Hence, these metrics coupled with visualization tools allow an improved grasp on three important functional annotation aspects: completeness, agreement and coherence.
Conclusions
Measuring the functional similarity between proteins based on their annotations is a non trivial task. Several metrics exist but due both to characteristics intrinsic to the nature of graphs and extrinsic natures related to the process of annotation each measure can only capture certain functional annotation aspects of proteins. Hence, when trying to measure the functional coherence of a set of proteins a single metric is too reductive. Therefore, it is valuable to be aware of how each employed similarity metric works and what similarity aspects it can best capture. Here we test the behaviour and resilience of some similarity metrics.
Electronic supplementary material
The online version of this article (doi:10.1186/s13326-016-0076-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13326-016-0076-y
PMCID: PMC4917928  PMID: 27338101
3.  Improving the Measurement of Semantic Similarity between Gene Ontology Terms and Gene Products: Insights from an Edge- and IC-Based Hybrid Method 
PLoS ONE  2013;8(5):e66745.
Background
Explicit comparisons based on the semantic similarity of Gene Ontology terms provide a quantitative way to measure the functional similarity between gene products and are widely applied in large-scale genomic research via integration with other models. Previously, we presented an edge-based method, Relative Specificity Similarity (RSS), which takes the global position of relevant terms into account. However, edge-based semantic similarity metrics are sensitive to the intrinsic structure of GO and simply consider terms at the same level in the ontology to be equally specific nodes, revealing the weaknesses that could be complemented using information content (IC).
Results and Conclusions
Here, we used the IC-based nodes to improve RSS and proposed a new method, Hybrid Relative Specificity Similarity (HRSS). HRSS outperformed other methods in distinguishing true protein-protein interactions from false. HRSS values were divided into four different levels of confidence for protein interactions. In addition, HRSS was statistically the best at obtaining the highest average functional similarity among human-mouse orthologs. Both HRSS and the groupwise measure, simGIC, are superior in correlation with sequence and Pfam similarities. Because different measures are best suited for different circumstances, we compared two pairwise strategies, the maximum and the best-match average, in the evaluation. The former was more effective at inferring physical protein-protein interactions, and the latter at estimating the functional conservation of orthologs and analyzing the CESSM datasets. In conclusion, HRSS can be applied to different biological problems by quantifying the functional similarity between gene products. The algorithm HRSS was implemented in the C programming language, which is freely available from http://cmb.bnu.edu.cn/hrss.
doi:10.1371/journal.pone.0066745
PMCID: PMC3669204  PMID: 23741529
4.  A relation based measure of semantic similarity for Gene Ontology annotations 
BMC Bioinformatics  2008;9:468.
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.
doi:10.1186/1471-2105-9-468
PMCID: PMC2655092  PMID: 18983678
5.  TopoICSim: a new semantic similarity measure based on gene ontology 
BMC Bioinformatics  2016;17:296.
Background
The Gene Ontology (GO) is a dynamic, controlled vocabulary that describes the cellular function of genes and proteins according to tree major categories: biological process, molecular function and cellular component. It has become widely used in many bioinformatics applications for annotating genes and measuring their semantic similarity, rather than their sequence similarity. Generally speaking, semantic similarity measures involve the GO tree topology, information content of GO terms, or a combination of both.
Results
Here we present a new semantic similarity measure called TopoICSim (Topological Information Content Similarity) which uses information on the specific paths between GO terms based on the topology of the GO tree, and the distribution of information content along these paths. The TopoICSim algorithm was evaluated on two human benchmark datasets based on KEGG pathways and Pfam domains grouped as clans, using GO terms from either the biological process or molecular function. The performance of the TopoICSim measure compared favorably to five existing methods. Furthermore, the TopoICSim similarity was also tested on gene/protein sets defined by correlated gene expression, using three human datasets, and showed improved performance compared to two previously published similarity measures. Finally we used an online benchmarking resource which evaluates any similarity measure against a set of 11 similarity measures in three tests, using gene/protein sets based on sequence similarity, Pfam domains, and enzyme classifications. The results for TopoICSim showed improved performance relative to most of the measures included in the benchmarking, and in particular a very robust performance throughout the different tests.
Conclusions
The TopoICSim similarity measure provides a competitive method with robust performance for quantification of semantic similarity between genes and proteins based on GO annotations. An R script for TopoICSim is available at http://bigr.medisin.ntnu.no/tools/TopoICSim.R.
doi:10.1186/s12859-016-1160-0
PMCID: PMC4966780  PMID: 27473391
Gene ontology; Semantic similarity measure; Tree topology
6.  On the Use of Gene Ontology Annotations to Assess Functional Similarity among Orthologs and Paralogs: A Short Report 
PLoS Computational Biology  2012;8(2):e1002386.
A recent paper (Nehrt et al., PLoS Comput. Biol. 7:e1002073, 2011) has proposed a metric for the “functional similarity” between two genes that uses only the Gene Ontology (GO) annotations directly derived from published experimental results. Applying this metric, the authors concluded that paralogous genes within the mouse genome or the human genome are more functionally similar on average than orthologous genes between these genomes, an unexpected result with broad implications if true. We suggest, based on both theoretical and empirical considerations, that this proposed metric should not be interpreted as a functional similarity, and therefore cannot be used to support any conclusions about the “ortholog conjecture” (or, more properly, the “ortholog functional conservation hypothesis”). First, we reexamine the case studies presented by Nehrt et al. as examples of orthologs with divergent functions, and come to a very different conclusion: they actually exemplify how GO annotations for orthologous genes provide complementary information about conserved biological functions. We then show that there is a global ascertainment bias in the experiment-based GO annotations for human and mouse genes: particular types of experiments tend to be performed in different model organisms. We conclude that the reported statistical differences in annotations between pairs of orthologous genes do not reflect differences in biological function, but rather complementarity in experimental approaches. Our results underscore two general considerations for researchers proposing novel types of analysis based on the GO: 1) that GO annotations are often incomplete, potentially in a biased manner, and subject to an “open world assumption” (absence of an annotation does not imply absence of a function), and 2) that conclusions drawn from a novel, large-scale GO analysis should whenever possible be supported by careful, in-depth examination of examples, to help ensure the conclusions have a justifiable biological basis.
Author Summary
Understanding gene function—how individual genes contribute to the biology of an organism at the molecular, cellular and organism levels—is one of the primary aims of biomedical research. It has been a longstanding tenet of model organism research that experimental knowledge obtained in one organism is often applicable to other organisms, particularly if the organisms share the relevant genes because they inherited them from their common ancestor. Nevertheless this tenet is, like any hypothesis, not beyond question. A recent paper has termed this hypothesis a “conjecture,” and performed a statistical analysis, the results of which were interpreted as evidence against the hypothesis. This statistical analysis relied on a computational representation of gene function, the Gene Ontology (GO). As representatives of the international consortium that produces the GO, we show how the apparent evidence against the “ortholog conjecture” can be better explained as an artifact of how molecular biology knowledge is accumulated. In short, a complementarity between knowledge obtained in mouse and human experimental systems was incorrectly interpreted as a disagreement. We discuss the proper interpretation of GO annotations and potential sources of bias, with an eye toward enhancing the informed use of the GO by the scientific community.
doi:10.1371/journal.pcbi.1002386
PMCID: PMC3280971  PMID: 22359495
7.  Assessing the functional coherence of gene sets with metrics based on the Gene Ontology graph 
Bioinformatics  2010;26(12):i79-i87.
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.
doi:10.1093/bioinformatics/btq203
PMCID: PMC2881388  PMID: 20529941
8.  The use of semantic similarity measures for optimally integrating heterogeneous Gene Ontology data from large scale annotation pipelines 
Frontiers in Genetics  2014;5:264.
With the advancement of new high throughput sequencing technologies, there has been an increase in the number of genome sequencing projects worldwide, which has yielded complete genome sequences of human, animals and plants. Subsequently, several labs have focused on genome annotation, consisting of assigning functions to gene products, mostly using Gene Ontology (GO) terms. As a consequence, there is an increased heterogeneity in annotations across genomes due to different approaches used by different pipelines to infer these annotations and also due to the nature of the GO structure itself. This makes a curator's task difficult, even if they adhere to the established guidelines for assessing these protein annotations. Here we develop a genome-scale approach for integrating GO annotations from different pipelines using semantic similarity measures. We used this approach to identify inconsistencies and similarities in functional annotations between orthologs of human and Drosophila melanogaster, to assess the quality of GO annotations derived from InterPro2GO mappings compared to manually annotated GO annotations for the Drosophila melanogaster proteome from a FlyBase dataset and human, and to filter GO annotation data for these proteomes. Results obtained indicate that an efficient integration of GO annotations eliminates redundancy up to 27.08 and 22.32% in the Drosophila melanogaster and human GO annotation datasets, respectively. Furthermore, we identified lack of and missing annotations for some orthologs, and annotation mismatches between InterPro2GO and manual pipelines in these two proteomes, thus requiring further curation. This simplifies and facilitates tasks of curators in assessing protein annotations, reduces redundancy and eliminates inconsistencies in large annotation datasets for ease of comparative functional genomics.
doi:10.3389/fgene.2014.00264
PMCID: PMC4123725  PMID: 25147557
functional annotation; Gene Ontology annotation; annotation pipeline; manual annotation; electronic annotation
9.  Gene Ontology annotation of the rice blast fungus, Magnaporthe oryzae 
BMC Microbiology  2009;9(Suppl 1):S8.
Background
Magnaporthe oryzae, the causal agent of blast disease of rice, is the most destructive disease of rice worldwide. The genome of this fungal pathogen has been sequenced and an automated annotation has recently been updated to Version 6 . However, a comprehensive manual curation remains to be performed. Gene Ontology (GO) annotation is a valuable means of assigning functional information using standardized vocabulary. We report an overview of the GO annotation for Version 5 of M. oryzae genome assembly.
Methods
A similarity-based (i.e., computational) GO annotation with manual review was conducted, which was then integrated with a literature-based GO annotation with computational assistance. For similarity-based GO annotation a stringent reciprocal best hits method was used to identify similarity between predicted proteins of M. oryzae and GO proteins from multiple organisms with published associations to GO terms. Significant alignment pairs were manually reviewed. Functional assignments were further cross-validated with manually reviewed data, conserved domains, or data determined by wet lab experiments. Additionally, biological appropriateness of the functional assignments was manually checked.
Results
In total, 6,286 proteins received GO term assignment via the homology-based annotation, including 2,870 hypothetical proteins. Literature-based experimental evidence, such as microarray, MPSS, T-DNA insertion mutation, or gene knockout mutation, resulted in 2,810 proteins being annotated with GO terms. Of these, 1,673 proteins were annotated with new terms developed for Plant-Associated Microbe Gene Ontology (PAMGO). In addition, 67 experiment-determined secreted proteins were annotated with PAMGO terms. Integration of the two data sets resulted in 7,412 proteins (57%) being annotated with 1,957 distinct and specific GO terms. Unannotated proteins were assigned to the 3 root terms. The Version 5 GO annotation is publically queryable via the GO site . Additionally, the genome of M. oryzae is constantly being refined and updated as new information is incorporated. For the latest GO annotation of Version 6 genome, please visit our website . The preliminary GO annotation of Version 6 genome is placed at a local MySql database that is publically queryable via a user-friendly interface Adhoc Query System.
Conclusion
Our analysis provides comprehensive and robust GO annotations of the M. oryzae genome assemblies that will be solid foundations for further functional interrogation of M. oryzae.
doi:10.1186/1471-2180-9-S1-S8
PMCID: PMC2654668  PMID: 19278556
10.  Methodology for the inference of gene function from phenotype data 
BMC Bioinformatics  2014;15(1):405.
Background
Biomedical ontologies are increasingly instrumental in the advancement of biological research primarily through their use to efficiently consolidate large amounts of data into structured, accessible sets. However, ontology development and usage can be hampered by the segregation of knowledge by domain that occurs due to independent development and use of the ontologies. The ability to infer data associated with one ontology to data associated with another ontology would prove useful in expanding information content and scope. We here focus on relating two ontologies: the Gene Ontology (GO), which encodes canonical gene function, and the Mammalian Phenotype Ontology (MP), which describes non-canonical phenotypes, using statistical methods to suggest GO functional annotations from existing MP phenotype annotations. This work is in contrast to previous studies that have focused on inferring gene function from phenotype primarily through lexical or semantic similarity measures.
Results
We have designed and tested a set of algorithms that represents a novel methodology to define rules for predicting gene function by examining the emergent structure and relationships between the gene functions and phenotypes rather than inspecting the terms semantically. The algorithms inspect relationships among multiple phenotype terms to deduce if there are cases where they all arise from a single gene function.
We apply this methodology to data about genes in the laboratory mouse that are formally represented in the Mouse Genome Informatics (MGI) resource. From the data, 7444 rule instances were generated from five generalized rules, resulting in 4818 unique GO functional predictions for 1796 genes.
Conclusions
We show that our method is capable of inferring high-quality functional annotations from curated phenotype data. As well as creating inferred annotations, our method has the potential to allow for the elucidation of unforeseen, biologically significant associations between gene function and phenotypes that would be overlooked by a semantics-based approach. Future work will include the implementation of the described algorithms for a variety of other model organism databases, taking full advantage of the abundance of available high quality curated data.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-014-0405-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-014-0405-z
PMCID: PMC4302099  PMID: 25495798
Gene ontology; Mammalian phenotype ontology; Function prediction; Ontology development
11.  A literature-based similarity metric for biological processes 
BMC Bioinformatics  2006;7:363.
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.
doi:10.1186/1471-2105-7-363
PMCID: PMC1579237  PMID: 16872502
12.  Automatic extraction of gene ontology annotation and its correlation with clusters in protein networks 
BMC Bioinformatics  2007;8:243.
Background
Uncovering cellular roles of a protein is a task of tremendous importance and complexity that requires dedicated experimental work as well as often sophisticated data mining and processing tools. Protein functions, often referred to as its annotations, are believed to manifest themselves through topology of the networks of inter-proteins interactions. In particular, there is a growing body of evidence that proteins performing the same function are more likely to interact with each other than with proteins with other functions. However, since functional annotation and protein network topology are often studied separately, the direct relationship between them has not been comprehensively demonstrated. In addition to having the general biological significance, such demonstration would further validate the data extraction and processing methods used to compose protein annotation and protein-protein interactions datasets.
Results
We developed a method for automatic extraction of protein functional annotation from scientific text based on the Natural Language Processing (NLP) technology. For the protein annotation extracted from the entire PubMed, we evaluated the precision and recall rates, and compared the performance of the automatic extraction technology to that of manual curation used in public Gene Ontology (GO) annotation. In the second part of our presentation, we reported a large-scale investigation into the correspondence between communities in the literature-based protein networks and GO annotation groups of functionally related proteins. We found a comprehensive two-way match: proteins within biological annotation groups form significantly denser linked network clusters than expected by chance and, conversely, densely linked network communities exhibit a pronounced non-random overlap with GO groups. We also expanded the publicly available GO biological process annotation using the relations extracted by our NLP technology. An increase in the number and size of GO groups without any noticeable decrease of the link density within the groups indicated that this expansion significantly broadens the public GO annotation without diluting its quality. We revealed that functional GO annotation correlates mostly with clustering in a physical interaction protein network, while its overlap with indirect regulatory network communities is two to three times smaller.
Conclusion
Protein functional annotations extracted by the NLP technology expand and enrich the existing GO annotation system. The GO functional modularity correlates mostly with the clustering in the physical interaction network, suggesting that the essential role of structural organization maintained by these interactions. Reciprocally, clustering of proteins in physical interaction networks can serve as an evidence for their functional similarity.
doi:10.1186/1471-2105-8-243
PMCID: PMC1940026  PMID: 17620146
13.  Incorporating functional inter-relationships into protein function prediction algorithms 
BMC Bioinformatics  2009;10:142.
Background
Functional classification schemes (e.g. the Gene Ontology) that serve as the basis for annotation efforts in several organisms are often the source of gold standard information for computational efforts at supervised protein function prediction. While successful function prediction algorithms have been developed, few previous efforts have utilized more than the protein-to-functional class label information provided by such knowledge bases. For instance, the Gene Ontology not only captures protein annotations to a set of functional classes, but it also arranges these classes in a DAG-based hierarchy that captures rich inter-relationships between different classes. These inter-relationships present both opportunities, such as the potential for additional training examples for small classes from larger related classes, and challenges, such as a harder to learn distinction between similar GO terms, for standard classification-based approaches.
Results
We propose a method to enhance the performance of classification-based protein function prediction algorithms by addressing the issue of using these interrelationships between functional classes constituting functional classification schemes. Using a standard measure for evaluating the semantic similarity between nodes in an ontology, we quantify and incorporate these inter-relationships into the k-nearest neighbor classifier. We present experiments on several large genomic data sets, each of which is used for the modeling and prediction of over hundred classes from the GO Biological Process ontology. The results show that this incorporation produces more accurate predictions for a large number of the functional classes considered, and also that the classes benefitted most by this approach are those containing the fewest members. In addition, we show how our proposed framework can be used for integrating information from the entire GO hierarchy for improving the accuracy of predictions made over a set of base classes. Finally, we provide qualitative and quantitative evidence that this incorporation of functional inter-relationships enables the discovery of interesting biology in the form of novel functional annotations for several yeast proteins, such as Sna4, Rtn1 and Lin1.
Conclusion
We implemented and evaluated a methodology for incorporating interrelationships between functional classes into a standard classification-based protein function prediction algorithm. Our results show that this incorporation can help improve the accuracy of such algorithms, and help uncover novel biology in the form of previously unknown functional annotations. The complete source code, a sample data set and the additional files for this paper are available free of charge for non-commercial use at .
doi:10.1186/1471-2105-10-142
PMCID: PMC2693438  PMID: 19435516
14.  IntelliGO: a new vector-based semantic similarity measure including annotation origin 
BMC Bioinformatics  2010;11:588.
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/
doi:10.1186/1471-2105-11-588
PMCID: PMC3098105  PMID: 21122125
15.  An improved method for scoring protein-protein interactions using semantic similarity within the gene ontology 
BMC Bioinformatics  2010;11:562.
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.
doi:10.1186/1471-2105-11-562
PMCID: PMC2998529  PMID: 21078182
16.  GRYFUN: A Web Application for GO Term Annotation Visualization and Analysis in Protein Sets 
PLoS ONE  2015;10(3):e0119631.
Functional context for biological sequence is provided in the form of annotations. However, within a group of similar sequences there can be annotation heterogeneity in terms of coverage and specificity. This in turn can introduce issues regarding the interpretation of actual functional similarity and overall functional coherence of such a group. One way to mitigate such issues is through the use of visualization and statistical techniques. Therefore, in order to help interpret this annotation heterogeneity we created a web application that generates Gene Ontology annotation graphs for protein sets and their associated statistics from simple frequencies to enrichment values and Information Content based metrics. The publicly accessible website http://xldb.di.fc.ul.pt/gryfun/ currently accepts lists of UniProt accession numbers in order to create user-defined protein sets for subsequent annotation visualization and statistical assessment. GRYFUN is a freely available web application that allows GO annotation visualization of protein sets and which can be used for annotation coherence and cohesiveness analysis and annotation extension assessments within under-annotated protein sets.
doi:10.1371/journal.pone.0119631
PMCID: PMC4368792  PMID: 25794277
17.  Gene ontology based transfer learning for protein subcellular localization 
BMC Bioinformatics  2011;12:44.
Background
Prediction of protein subcellular localization generally involves many complex factors, and using only one or two aspects of data information may not tell the true story. For this reason, some recent predictive models are deliberately designed to integrate multiple heterogeneous data sources for exploiting multi-aspect protein feature information. Gene ontology, hereinafter referred to as GO, uses a controlled vocabulary to depict biological molecules or gene products in terms of biological process, molecular function and cellular component. With the rapid expansion of annotated protein sequences, gene ontology has become a general protein feature that can be used to construct predictive models in computational biology. Existing models generally either concatenated the GO terms into a flat binary vector or applied majority-vote based ensemble learning for protein subcellular localization, both of which can not estimate the individual discriminative abilities of the three aspects of gene ontology.
Results
In this paper, we propose a Gene Ontology Based Transfer Learning Model (GO-TLM) for large-scale protein subcellular localization. The model transfers the signature-based homologous GO terms to the target proteins, and further constructs a reliable learning system to reduce the adverse affect of the potential false GO terms that are resulted from evolutionary divergence. We derive three GO kernels from the three aspects of gene ontology to measure the GO similarity of two proteins, and derive two other spectrum kernels to measure the similarity of two protein sequences. We use simple non-parametric cross validation to explicitly weigh the discriminative abilities of the five kernels, such that the time & space computational complexities are greatly reduced when compared to the complicated semi-definite programming and semi-indefinite linear programming. The five kernels are then linearly merged into one single kernel for protein subcellular localization. We evaluate GO-TLM performance against three baseline models: MultiLoc, MultiLoc-GO and Euk-mPLoc on the benchmark datasets the baseline models adopted. 5-fold cross validation experiments show that GO-TLM achieves substantial accuracy improvement against the baseline models: 80.38% against model Euk-mPLoc 67.40% with 12.98% substantial increase; 96.65% and 96.27% against model MultiLoc-GO 89.60% and 89.60%, with 7.05% and 6.67% accuracy increase on dataset MultiLoc plant and dataset MultiLoc animal, respectively; 97.14%, 95.90% and 96.85% against model MultiLoc-GO 83.70%, 90.10% and 85.70%, with accuracy increase 13.44%, 5.8% and 11.15% on dataset BaCelLoc plant, dataset BaCelLoc fungi and dataset BaCelLoc animal respectively. For BaCelLoc independent sets, GO-TLM achieves 81.25%, 80.45% and 79.46% on dataset BaCelLoc plant holdout, dataset BaCelLoc plant holdout and dataset BaCelLoc animal holdout, respectively, as compared against baseline model MultiLoc-GO 76%, 60.00% and 73.00%, with accuracy increase 5.25%, 20.45% and 6.46%, respectively.
Conclusions
Since direct homology-based GO term transfer may be prone to introducing noise and outliers to the target protein, we design an explicitly weighted kernel learning system (called Gene Ontology Based Transfer Learning Model, GO-TLM) to transfer to the target protein the known knowledge about related homologous proteins, which can reduce the risk of outliers and share knowledge between homologous proteins, and thus achieve better predictive performance for protein subcellular localization. Cross validation and independent test experimental results show that the homology-based GO term transfer and explicitly weighing the GO kernels substantially improve the prediction performance.
doi:10.1186/1471-2105-12-44
PMCID: PMC3039576  PMID: 21284890
18.  M-Finder: Uncovering functionally associated proteins from interactome data integrated with GO annotations 
Proteome Science  2013;11(Suppl 1):S3.
Background
Protein-protein interactions (PPIs) play a key role in understanding the mechanisms of cellular processes. The availability of interactome data has catalyzed the development of computational approaches to elucidate functional behaviors of proteins on a system level. Gene Ontology (GO) and its annotations are a significant resource for functional characterization of proteins. Because of wide coverage, GO data have often been adopted as a benchmark for protein function prediction on the genomic scale.
Results
We propose a computational approach, called M-Finder, for functional association pattern mining. This method employs semantic analytics to integrate the genome-wide PPIs with GO data. We also introduce an interactive web application tool that visualizes a functional association network linked to a protein specified by a user. The proposed approach comprises two major components. First, the PPIs that have been generated by high-throughput methods are weighted in terms of their functional consistency using GO and its annotations. We assess two advanced semantic similarity metrics which quantify the functional association level of each interacting protein pair. We demonstrate that these measures outperform the other existing methods by evaluating their agreement to other biological features, such as sequence similarity, the presence of common Pfam domains, and core PPIs. Second, the information flow-based algorithm is employed to discover a set of proteins functionally associated with the protein in a query and their links efficiently. This algorithm reconstructs a functional association network of the query protein. The output network size can be flexibly determined by parameters.
Conclusions
M-Finder provides a useful framework to investigate functional association patterns with any protein. This software will also allow users to perform further systematic analysis of a set of proteins for any specific function. It is available online at http://bionet.ecs.baylor.edu/mfinder
doi:10.1186/1477-5956-11-S1-S3
PMCID: PMC3909039  PMID: 24565382
19.  Prior knowledge based mining functional modules from Yeast PPI networks with gene ontology 
BMC Bioinformatics  2010;11(Suppl 11):S3.
Background
In the literature, there are fruitful algorithmic approaches for identification functional modules in protein-protein interactions (PPI) networks. Because of accumulation of large-scale interaction data on multiple organisms and non-recording interaction data in the existing PPI database, it is still emergent to design novel computational techniques that can be able to correctly and scalably analyze interaction data sets. Indeed there are a number of large scale biological data sets providing indirect evidence for protein-protein interaction relationships.
Results
The main aim of this paper is to present a prior knowledge based mining strategy to identify functional modules from PPI networks with the aid of Gene Ontology. Higher similarity value in Gene Ontology means that two gene products are more functionally related to each other, so it is better to group such gene products into one functional module. We study (i) to encode the functional pairs into the existing PPI networks; and (ii) to use these functional pairs as pairwise constraints to supervise the existing functional module identification algorithms. Topology-based modularity metric and complex annotation in MIPs will be used to evaluate the identified functional modules by these two approaches.
Conclusions
The experimental results on Yeast PPI networks and GO have shown that the prior knowledge based learning methods perform better than the existing algorithms.
doi:10.1186/1471-2105-11-S11-S3
PMCID: PMC3024868  PMID: 21172053
20.  Finding New Order in Biological Functions from the Network Structure of Gene Annotations 
PLoS Computational Biology  2015;11(11):e1004565.
The Gene Ontology (GO) provides biologists with a controlled terminology that describes how genes are associated with functions and how functional terms are related to one another. These term-term relationships encode how scientists conceive the organization of biological functions, and they take the form of a directed acyclic graph (DAG). Here, we propose that the network structure of gene-term annotations made using GO can be employed to establish an alternative approach for grouping functional terms that captures intrinsic functional relationships that are not evident in the hierarchical structure established in the GO DAG. Instead of relying on an externally defined organization for biological functions, our approach connects biological functions together if they are performed by the same genes, as indicated in a compendium of gene annotation data from numerous different sources. We show that grouping terms by this alternate scheme provides a new framework with which to describe and predict the functions of experimentally identified sets of genes.
Author Summary
Investigating how a set of genes might collectively work together to perform various cellular processes has become a routine part of many biological analyses. In such analyses, genes of interest are compared to sets of genes annotated to various biological functions (or pathways) defined within carefully curated databases. One of the most comprehensive and widely used resources of this type is the Gene Ontology (GO) database. The Gene Ontology database is comprised of two important elements: (1) the ontology itself, which provides a controlled vocabulary of terms describing genetic function and also specifies how these functional terms are related to one another via a hierarchical structure; and (2) the set of annotations made using GO that connect individual genes to different functional terms. In our paper we investigate a method for organizing functional terms that results from connecting terms based on shared gene annotations. We find that this alternate classification has an organization that is highly distinct from the Gene Ontology hierarchy, challenging the way we think about the relationships between different biological functions. Finally, we show that these alternate collections of terms are highly associated with published cancer gene signatures, demonstrating that this alternative organization of biological functions can highlight important relationships between cellular processes and has the potential to lead to new insights and discoveries.
doi:10.1371/journal.pcbi.1004565
PMCID: PMC4654495  PMID: 26588252
21.  Integration of relational and hierarchical network information for protein function prediction 
BMC Bioinformatics  2008;9:350.
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.
doi:10.1186/1471-2105-9-350
PMCID: PMC2535605  PMID: 18721473
22.  From disease ontology to disease-ontology lite: statistical methods to adapt a general-purpose ontology for the test of gene-ontology associations 
Bioinformatics  2009;25(12):i63-i68.
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
doi:10.1093/bioinformatics/btp193
PMCID: PMC2687947  PMID: 19478018
23.  Topology-function conservation in protein–protein interaction networks 
Bioinformatics  2015;31(10):1632-1639.
Motivation: Proteins underlay the functioning of a cell and the wiring of proteins in protein–protein interaction network (PIN) relates to their biological functions. Proteins with similar wiring in the PIN (topology around them) have been shown to have similar functions. This property has been successfully exploited for predicting protein functions. Topological similarity is also used to guide network alignment algorithms that find similarly wired proteins between PINs of different species; these similarities are used to transfer annotation across PINs, e.g. from model organisms to human. To refine these functional predictions and annotation transfers, we need to gain insight into the variability of the topology-function relationships. For example, a function may be significantly associated with specific topologies, while another function may be weakly associated with several different topologies. Also, the topology-function relationships may differ between different species.
Results: To improve our understanding of topology-function relationships and of their conservation among species, we develop a statistical framework that is built upon canonical correlation analysis. Using the graphlet degrees to represent the wiring around proteins in PINs and gene ontology (GO) annotations to describe their functions, our framework: (i) characterizes statistically significant topology-function relationships in a given species, and (ii) uncovers the functions that have conserved topology in PINs of different species, which we term topologically orthologous functions. We apply our framework to PINs of yeast and human, identifying seven biological process and two cellular component GO terms to be topologically orthologous for the two organisms.
Availability and implementation: http://bio-nets.doc.ic.ac.uk/goCCA.zip
Contact: natasha@imperial.ac.uk
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btv026
PMCID: PMC4426845  PMID: 25609797
24.  Benchmarking Ontologies: Bigger or Better? 
PLoS Computational Biology  2011;7(1):e1001055.
A scientific ontology is a formal representation of knowledge within a domain, typically including central concepts, their properties, and relations. With the rise of computers and high-throughput data collection, ontologies have become essential to data mining and sharing across communities in the biomedical sciences. Powerful approaches exist for testing the internal consistency of an ontology, but not for assessing the fidelity of its domain representation. We introduce a family of metrics that describe the breadth and depth with which an ontology represents its knowledge domain. We then test these metrics using (1) four of the most common medical ontologies with respect to a corpus of medical documents and (2) seven of the most popular English thesauri with respect to three corpora that sample language from medicine, news, and novels. Here we show that our approach captures the quality of ontological representation and guides efforts to narrow the breach between ontology and collective discourse within a domain. Our results also demonstrate key features of medical ontologies, English thesauri, and discourse from different domains. Medical ontologies have a small intersection, as do English thesauri. Moreover, dialects characteristic of distinct domains vary strikingly as many of the same words are used quite differently in medicine, news, and novels. As ontologies are intended to mirror the state of knowledge, our methods to tighten the fit between ontology and domain will increase their relevance for new areas of biomedical science and improve the accuracy and power of inferences computed across them.
Author Summary
An ontology represents the concepts and their interrelation within a knowledge domain. Several ontologies have been developed in biomedicine, which provide standardized vocabularies to describe diseases, genes and gene products, physiological phenotypes, anatomical structures, and many other phenomena. Scientists use them to encode the results of complex experiments and observations and to perform integrative analysis to discover new knowledge. A remaining challenge in ontology development is how to evaluate an ontology's representation of knowledge within its scientific domain. Building on classic measures from information retrieval, we introduce a family of metrics including breadth and depth that capture the conceptual coverage and parsimony of an ontology. We test these measures using (1) four commonly used medical ontologies in relation to a corpus of medical documents and (2) seven popular English thesauri (ontologies of synonyms) with respect to text from medicine, news, and novels. Results demonstrate that both medical ontologies and English thesauri have a small overlap in concepts and relations. Our methods suggest efforts to tighten the fit between ontologies and biomedical knowledge.
doi:10.1371/journal.pcbi.1001055
PMCID: PMC3020923  PMID: 21249231
25.  PrOnto database : GO term functional dissimilarity inferred from biological data 
Frontiers in Genetics  2015;6:200.
Moonlighting proteins are defined by their involvement in multiple, unrelated functions. The computational prediction of such proteins requires a formal method of assessing the similarity of cellular processes, for example, by identifying dissimilar Gene Ontology terms. While many measures of Gene Ontology term similarity exist, most depend on abstract mathematical analyses of the structure of the GO tree and do not necessarily represent the underlying biology. Here, we propose two metrics of GO term functional dissimilarity derived from biological information, one based on the protein annotations and the other on the interactions between proteins. They have been collected in the PrOnto database, a novel tool which can be of particular use for the identification of moonlighting proteins. The database can be queried via an web-based interface which is freely available at http://tagc.univ-mrs.fr/pronto.
doi:10.3389/fgene.2015.00200
PMCID: PMC4452890  PMID: 26089836
moonlighting protein; gene ontology; functional similarity; protein-protein interactions; database

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