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1.  New approaches to the representation and analysis of phenotype knowledge in human diseases and their animal models 
Briefings in Functional Genomics  2011;10(5):258-265.
The systematic investigation of the phenotypes associated with genotypes in model organisms holds the promise of revealing genotype–phenotype relations directly and without additional, intermediate inferences. Large-scale projects are now underway to catalog the complete phenome of a species, notably the mouse. With the increasing amount of phenotype information becoming available, a major challenge that biology faces today is the systematic analysis of this information and the translation of research results across species and into an improved understanding of human disease. The challenge is to integrate and combine phenotype descriptions within a species and to systematically relate them to phenotype descriptions in other species, in order to form a comprehensive understanding of the relations between those phenotypes and the genotypes involved in human disease. We distinguish between two major approaches for comparative phenotype analyses: the first relies on evolutionary relations to bridge the species gap, while the other approach compares phenotypes directly. In particular, the direct comparison of phenotypes relies heavily on the quality and coherence of phenotype and disease databases. We discuss major achievements and future challenges for these databases in light of their potential to contribute to the understanding of the molecular mechanisms underlying human disease. In particular, we discuss how the use of ontologies and automated reasoning can significantly contribute to the analysis of phenotypes and demonstrate their potential for enabling translational research.
PMCID: PMC3189694  PMID: 21987712
phenotype; animal model; disease; database; comparative phenomics; ontology
2.  The flora phenotype ontology (FLOPO): tool for integrating morphological traits and phenotypes of vascular plants 
The systematic analysis of a large number of comparable plant trait data can support investigations into phylogenetics and ecological adaptation, with broad applications in evolutionary biology, agriculture, conservation, and the functioning of ecosystems. Floras, i.e., books collecting the information on all known plant species found within a region, are a potentially rich source of such plant trait data. Floras describe plant traits with a focus on morphology and other traits relevant for species identification in addition to other characteristics of plant species, such as ecological affinities, distribution, economic value, health applications, traditional uses, and so on. However, a key limitation in systematically analyzing information in Floras is the lack of a standardized vocabulary for the described traits as well as the difficulties in extracting structured information from free text.
We have developed the Flora Phenotype Ontology (FLOPO), an ontology for describing traits of plant species found in Floras. We used the Plant Ontology (PO) and the Phenotype And Trait Ontology (PATO) to extract entity-quality relationships from digitized taxon descriptions in Floras, and used a formal ontological approach based on phenotype description patterns and automated reasoning to generate the FLOPO. The resulting ontology consists of 25,407 classes and is based on the PO and PATO. The classified ontology closely follows the structure of Plant Ontology in that the primary axis of classification is the observed plant anatomical structure, and more specific traits are then classified based on parthood and subclass relations between anatomical structures as well as subclass relations between phenotypic qualities.
The FLOPO is primarily intended as a framework based on which plant traits can be integrated computationally across all species and higher taxa of flowering plants. Importantly, it is not intended to replace established vocabularies or ontologies, but rather serve as an overarching framework based on which different application- and domain-specific ontologies, thesauri and vocabularies of phenotypes observed in flowering plants can be integrated.
Electronic supplementary material
The online version of this article (doi:10.1186/s13326-016-0107-8) contains supplementary material, which is available to authorized users.
PMCID: PMC5109718  PMID: 27842607
Phenotype; Biodiversity; Flora; Botany; Morphological traits
3.  Using AberOWL for fast and scalable reasoning over BioPortal ontologies 
Reasoning over biomedical ontologies using their OWL semantics has traditionally been a challenging task due to the high theoretical complexity of OWL-based automated reasoning. As a consequence, ontology repositories, as well as most other tools utilizing ontologies, either provide access to ontologies without use of automated reasoning, or limit the number of ontologies for which automated reasoning-based access is provided.
We apply the AberOWL infrastructure to provide automated reasoning-based access to all accessible and consistent ontologies in BioPortal (368 ontologies). We perform an extensive performance evaluation to determine query times, both for queries of different complexity and for queries that are performed in parallel over the ontologies.
Results and conclusions
We demonstrate that, with the exception of a few ontologies, even complex and parallel queries can now be answered in milliseconds, therefore allowing automated reasoning to be used on a large scale, to run in parallel, and with rapid response times.
PMCID: PMC4976511  PMID: 27502585
Ontology; Reasoning; Scalable reasoning; Description logics; OWL; AberOWL
4.  Duplication of the mitochondrial control region is associated with increased longevity in birds 
Aging (Albany NY)  2016;8(8):1781-1788.
Despite a number of biochemical and lifestyle differences which should increase risk of oxidative damage to their mitochondrial DNA (mtDNA) and thus reduce expected lifespan, avian species often display longer lifespans than mammals of similar body mass. Recent work in mammalian ageing has demonstrated that functional mitochondrial copy number declines with age. We noted that several bird species display duplication of the control region (CR) of the mtDNA to form a pseudo-control region (YCR), apparently an avian-specific phenomenon. To investigate whether the presence of this duplication may play a similar role in longevity to mitochondrial copy number in mammals, we correlated body mass and longevity in 92 avian families and demonstrate a significant association. Furthermore, outlier analysis demonstrated a significant (p=0.01) difference associated with presence of the YCR duplication in longer-lived avian species. Further research is required to determine if the YCR does indeed alter mitochondrial function or resilience to oxidative damage, but these findings provide an intriguing hint of how mitochondrial sequences may be related to an extended lifespan.
PMCID: PMC5032695  PMID: 27542284
control region duplication; mitochondrial genome; birds; lifespan; comparative genomics; genetics; ageing
5.  DermO; an ontology for the description of dermatologic disease 
There have been repeated initiatives to produce standard nosologies and terminologies for cutaneous disease, some dedicated to the domain and some part of bigger terminologies such as ICD-10. Recently, formally structured terminologies, ontologies, have been widely developed in many areas of biomedical research. Primarily, these address the aim of providing comprehensive working terminologies for domains of knowledge, but because of the knowledge contained in the relationships between terms they can also be used computationally for many purposes.
We have developed an ontology of cutaneous disease, constructed manually by domain experts. With more than 3000 terms, DermO represents the most comprehensive formal dermatological disease terminology available. The disease entities are categorized in 20 upper level terms, which use a variety of features such as anatomical location, heritability, affected cell or tissue type, or etiology, as the features for classification, in line with professional practice and nosology in dermatology. Available in OBO flatfile and OWL 2 formats, it is integrated semantically with other ontologies and terminologies describing diseases and phenotypes. We demonstrate the application of DermO to text mining the biomedical literature and in the creation of a network describing the phenotypic relationships between cutaneous diseases.
DermO is an ontology with broad coverage of the domain of dermatologic disease and we demonstrate here its utility for text mining and investigation of phenotypic relationships between dermatologic disorders. We envision that in the future it may be applied to the creation and mining of electronic health records, clinical training and basic research, as it supports automated inference and reasoning, and for the broader integration of skin disease information with that from other domains.
PMCID: PMC4907256  PMID: 27296450
Dermatology; Ontology; Disease; Dermatopathology
6.  Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases 
Scientific Reports  2015;5:10888.
Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.
PMCID: PMC4458913  PMID: 26051359
7.  The role of ontologies in biological and biomedical research: a functional perspective 
Briefings in Bioinformatics  2015;16(6):1069-1080.
Ontologies are widely used in biological and biomedical research. Their success lies in their combination of four main features present in almost all ontologies: provision of standard identifiers for classes and relations that represent the phenomena within a domain; provision of a vocabulary for a domain; provision of metadata that describes the intended meaning of the classes and relations in ontologies; and the provision of machine-readable axioms and definitions that enable computational access to some aspects of the meaning of classes and relations. While each of these features enables applications that facilitate data integration, data access and analysis, a great potential lies in the possibility of combining these four features to support integrative analysis and interpretation of multimodal data. Here, we provide a functional perspective on ontologies in biology and biomedicine, focusing on what ontologies can do and describing how they can be used in support of integrative research. We also outline perspectives for using ontologies in data-driven science, in particular their application in structured data mining and machine learning applications.
PMCID: PMC4652617  PMID: 25863278
ontology; Semantic Web; data integration; data mining
8.  An ontology approach to comparative phenomics in plants 
Plant Methods  2015;11:10.
Plant phenotype datasets include many different types of data, formats, and terms from specialized vocabularies. Because these datasets were designed for different audiences, they frequently contain language and details tailored to investigators with different research objectives and backgrounds. Although phenotype comparisons across datasets have long been possible on a small scale, comprehensive queries and analyses that span a broad set of reference species, research disciplines, and knowledge domains continue to be severely limited by the absence of a common semantic framework.
We developed a workflow to curate and standardize existing phenotype datasets for six plant species, encompassing both model species and crop plants with established genetic resources. Our effort focused on mutant phenotypes associated with genes of known sequence in Arabidopsis thaliana (L.) Heynh. (Arabidopsis), Zea mays L. subsp. mays (maize), Medicago truncatula Gaertn. (barrel medic or Medicago), Oryza sativa L. (rice), Glycine max (L.) Merr. (soybean), and Solanum lycopersicum L. (tomato). We applied the same ontologies, annotation standards, formats, and best practices across all six species, thereby ensuring that the shared dataset could be used for cross-species querying and semantic similarity analyses. Curated phenotypes were first converted into a common format using taxonomically broad ontologies such as the Plant Ontology, Gene Ontology, and Phenotype and Trait Ontology. We then compared ontology-based phenotypic descriptions with an existing classification system for plant phenotypes and evaluated our semantic similarity dataset for its ability to enhance predictions of gene families, protein functions, and shared metabolic pathways that underlie informative plant phenotypes.
The use of ontologies, annotation standards, shared formats, and best practices for cross-taxon phenotype data analyses represents a novel approach to plant phenomics that enhances the utility of model genetic organisms and can be readily applied to species with fewer genetic resources and less well-characterized genomes. In addition, these tools should enhance future efforts to explore the relationships among phenotypic similarity, gene function, and sequence similarity in plants, and to make genotype-to-phenotype predictions relevant to plant biology, crop improvement, and potentially even human health.
Electronic supplementary material
The online version of this article (doi:10.1186/s13007-015-0053-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4359497  PMID: 25774204
9.  Similarity-based search of model organism, disease and drug effect phenotypes 
Semantic similarity measures over phenotype ontologies have been demonstrated to provide a powerful approach for the analysis of model organism phenotypes, the discovery of animal models of human disease, novel pathways, gene functions, druggable therapeutic targets, and determination of pathogenicity.
We have developed PhenomeNET 2, a system that enables similarity-based searches over a large repository of phenotypes in real-time. It can be used to identify strains of model organisms that are phenotypically similar to human patients, diseases that are phenotypically similar to model organism phenotypes, or drug effect profiles that are similar to the phenotypes observed in a patient or model organism. PhenomeNET 2 is available at
Phenotype-similarity searches can provide a powerful tool for the discovery and investigation of molecular mechanisms underlying an observed phenotypic manifestation. PhenomeNET 2 facilitates user-defined similarity searches and allows researchers to analyze their data within a large repository of human, mouse and rat phenotypes.
PMCID: PMC4355138  PMID: 25763178
Phenotype; Semantic similarity; Ontology
10.  Aber-OWL: a framework for ontology-based data access in biology 
BMC Bioinformatics  2015;16(1):26.
Many ontologies have been developed in biology and these ontologies increasingly contain large volumes of formalized knowledge commonly expressed in the Web Ontology Language (OWL). Computational access to the knowledge contained within these ontologies relies on the use of automated reasoning.
We have developed the Aber-OWL infrastructure that provides reasoning services for bio-ontologies. Aber-OWL consists of an ontology repository, a set of web services and web interfaces that enable ontology-based semantic access to biological data and literature. Aber-OWL is freely available at
Aber-OWL provides a framework for automatically accessing information that is annotated with ontologies or contains terms used to label classes in ontologies. When using Aber-OWL, access to ontologies and data annotated with them is not merely based on class names or identifiers but rather on the knowledge the ontologies contain and the inferences that can be drawn from it.
PMCID: PMC4384359  PMID: 25627673
Ontology-based data access; Linked data; OWL
11.  The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data 
Nucleic Acids Research  2013;42(Database issue):D966-D974.
The Human Phenotype Ontology (HPO) project, available at, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.
PMCID: PMC3965098  PMID: 24217912
12.  Mouse model phenotypes provide information about human drug targets 
Bioinformatics  2013;30(5):719-725.
Motivation: Methods for computational drug target identification use information from diverse information sources to predict or prioritize drug targets for known drugs. One set of resources that has been relatively neglected for drug repurposing is animal model phenotype.
Results: We investigate the use of mouse model phenotypes for drug target identification. To achieve this goal, we first integrate mouse model phenotypes and drug effects, and then systematically compare the phenotypic similarity between mouse models and drug effect profiles. We find a high similarity between phenotypes resulting from loss-of-function mutations and drug effects resulting from the inhibition of a protein through a drug action, and demonstrate how this approach can be used to suggest candidate drug targets.
Availability and implementation: Analysis code and supplementary data files are available on the project Web site at
Contact: or
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3933875  PMID: 24158600
13.  The Drosophila phenotype ontology 
Phenotype ontologies are queryable classifications of phenotypes. They provide a widely-used means for annotating phenotypes in a form that is human-readable, programatically accessible and that can be used to group annotations in biologically meaningful ways. Accurate manual annotation requires clear textual definitions for terms. Accurate grouping and fruitful programatic usage require high-quality formal definitions that can be used to automate classification. The Drosophila phenotype ontology (DPO) has been used to annotate over 159,000 phenotypes in FlyBase to date, but until recently lacked textual or formal definitions.
We have composed textual definitions for all DPO terms and formal definitions for 77% of them. Formal definitions reference terms from a range of widely-used ontologies including the Phenotype and Trait Ontology (PATO), the Gene Ontology (GO) and the Cell Ontology (CL). We also describe a generally applicable system, devised for the DPO, for recording and reasoning about the timing of death in populations. As a result of the new formalisations, 85% of classifications in the DPO are now inferred rather than asserted, with much of this classification leveraging the structure of the GO. This work has significantly improved the accuracy and completeness of classification and made further development of the DPO more sustainable.
The DPO provides a set of well-defined terms for annotating Drosophila phenotypes and for grouping and querying the resulting annotation sets in biologically meaningful ways. Such queries have already resulted in successful function predictions from phenotype annotation. Moreover, such formalisations make extended queries possible, including cross-species queries via the external ontologies used in formal definitions. The DPO is openly available under an open source license in both OBO and OWL formats. There is good potential for it to be used more broadly by the Drosophila community, which may ultimately result in its extension to cover a broader range of phenotypes.
PMCID: PMC3816596  PMID: 24138933
Drosophila; Phenotype; Ontology; OWL; OBO; Gene ontology; FlyBase
14.  Computational tools for comparative phenomics; the role and promise of ontologies 
A major aim of the biological sciences is to gain an understanding of human physiology and disease. One important step towards such a goal is the discovery of the function of genes that will lead to better understanding of the physiology and pathophysiology of organisms ultimately providing better understanding, diagnosis, and therapy. Our increasing ability to phenotypically characterise genetic variants of model organisms coupled with systematic and hypothesis-driven mutagenesis is resulting in a wealth of information that could potentially provide insight to the functions of all genes in an organism. The challenge we are now facing is to develop computational methods that can integrate and analyse such data. The introduction of formal ontologies that make their semantics explicit and accessible to automated reasoning promises the tantalizing possibility of standardizing biomedical knowledge allowing for novel, powerful queries that bridge multiple domains, disciplines, species and levels of granularity. We review recent computational approaches that facilitate the integration of experimental data from model organisms with clinical observations in humans. These methods foster novel cross species analysis approaches, thereby enabling comparative phenomics and leading to the potential of translating basic discoveries from the model systems into diagnostic and therapeutic advances at the clinical level.
PMCID: PMC3488439  PMID: 22814867
15.  The mouse pathology ontology, MPATH; structure and applications 
The capture and use of disease-related anatomic pathology data for both model organism phenotyping and human clinical practice requires a relatively simple nomenclature and coding system that can be integrated into data collection platforms (such as computerized medical record-keeping systems) to enable the pathologist to rapidly screen and accurately record observations. The MPATH ontology was originally constructed in 2,000 by a committee of pathologists for the annotation of rodent histopathology images, but is now widely used for coding and analysis of disease and phenotype data for rodents, humans and zebrafish.
Construction and content
MPATH is divided into two main branches describing pathological processes and structures based on traditional histopathological principles. It does not aim to include definitive diagnoses, which would generally be regarded as disease concepts. It contains 888 core pathology terms in an almost exclusively is_a hierarchy nine layers deep. Currently, 86% of the terms have textual definitions and contain relationships as well as logical axioms to other ontologies such the Gene Ontology.
Application and utility
MPATH was originally devised for the annotation of histopathological images from mice but is now being used much more widely in the recording of diagnostic and phenotypic data from both mice and humans, and in the construction of logical definitions for phenotype and disease ontologies. We discuss the use of MPATH to generate cross-products with qualifiers derived from a subset of the Phenotype and Trait Ontology (PATO) and its application to large-scale high-throughput phenotyping studies. MPATH provides a largely species-agnostic ontology for the descriptions of anatomic pathology, which can be applied to most amniotes and is now finding extensive use in species other than mice. It enables investigators to interrogate large datasets at a variety of depths, use semantic analysis to identify the relations between diseases in different species and integrate pathology data with other data types, such as pharmacogenomics.
PMCID: PMC3851164  PMID: 24033988
Pathology; Ontology; Disease; Mouse; Phenotype
16.  Identifying aberrant pathways through integrated analysis of knowledge in pharmacogenomics 
Bioinformatics  2012;28(16):2169-2175.
Motivation: Many complex diseases are the result of abnormal pathway functions instead of single abnormalities. Disease diagnosis and intervention strategies must target these pathways while minimizing the interference with normal physiological processes. Large-scale identification of disease pathways and chemicals that may be used to perturb them requires the integration of information about drugs, genes, diseases and pathways. This information is currently distributed over several pharmacogenomics databases. An integrated analysis of the information in these databases can reveal disease pathways and facilitate novel biomedical analyses.
Results: We demonstrate how to integrate pharmacogenomics databases through integration of the biomedical ontologies that are used as meta-data in these databases. The additional background knowledge in these ontologies can then be used to enable novel analyses. We identify disease pathways using a novel multi-ontology enrichment analysis over the Human Disease Ontology, and we identify significant associations between chemicals and pathways using an enrichment analysis over a chemical ontology. The drug–pathway and disease–pathway associations are a valuable resource for research in disease and drug mechanisms and can be used to improve computational drug repurposing.
PMCID: PMC3493115  PMID: 22711793
17.  Semantic integration of physiology phenotypes with an application to the Cellular Phenotype Ontology 
Bioinformatics  2012;28(13):1783-1789.
Motivation: The systematic observation of phenotypes has become a crucial tool of functional genomics, and several large international projects are currently underway to identify and characterize the phenotypes that are associated with genotypes in several species. To integrate phenotype descriptions within and across species, phenotype ontologies have been developed. Applying ontologies to unify phenotype descriptions in the domain of physiology has been a particular challenge due to the high complexity of the underlying domain.
Results: In this study, we present the outline of a theory and its implementation for an ontology of physiology-related phenotypes. We provide a formal description of process attributes and relate them to the attributes of their temporal parts and participants. We apply our theory to create the Cellular Phenotype Ontology (CPO). The CPO is an ontology of morphological and physiological phenotypic characteristics of cells, cell components and cellular processes. Its prime application is to provide terms and uniform definition patterns for the annotation of cellular phenotypes. The CPO can be used for the annotation of observed abnormalities in domains, such as systems microscopy, in which cellular abnormalities are observed and for which no phenotype ontology has been created.
Availability and implementation: The CPO and the source code we generated to create the CPO are freely available on
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3381966  PMID: 22539675
18.  MouseFinder: candidate disease genes from mouse phenotype data 
Human Mutation  2012;33(5):858-866.
Mouse phenotype data represents a valuable resource for the identification of disease-associated genes, especially where the molecular basis is unknown and there is no clue to the candidate gene’s function, pathway involvement or expression pattern. However, until recently these data have not been systematically used due to difficulties in mapping between clinical features observed in humans and mouse phenotype annotations. Here, we describe a semantic approach to solve this problem and demonstrate highly significant recall of known disease-gene associations and orthology relationships. A web application (MouseFinder; has been developed to allow users to search the results of our whole-phenome comparison of human and mouse. We demonstrate its use in identifying ARTN as a strong candidate gene within the 1p34.1-p32 mapped locus for a hereditary form of ptosis.
PMCID: PMC3327758  PMID: 22331800
phenotype; candidate disease genes; model organism; mouse
19.  Mouse genetic and phenotypic resources for human genetics 
Human mutation  2012;33(5):826-836.
The use of model organisms to provide information on gene function has proved to be a powerful approach to our understanding of both human disease and fundamental mammalian biology. Large-scale community projects using mice, based on forward and reverse genetics, and now the pan-genomic phenotyping efforts of the International Mouse Phenotyping Consortium (IMPC), are generating resources on an unprecedented scale which will be extremely valuable to human genetics and medicine. We discuss the nature and availability of data, mice and ES cells from these large-scale programmes, the use of these resources to help prioritise and validate candidate genes in human genetic association studies, and how they can improve our understanding of the underlying pathobiology of human disease.
PMCID: PMC3473354  PMID: 22422677
mouse; genetics; phenotyping; human; ontology; GWAS; CNV; database
20.  Systematic Analysis of Experimental Phenotype Data Reveals Gene Functions 
PLoS ONE  2013;8(4):e60847.
High-throughput phenotyping projects in model organisms have the potential to improve our understanding of gene functions and their role in living organisms. We have developed a computational, knowledge-based approach to automatically infer gene functions from phenotypic manifestations and applied this approach to yeast (Saccharomyces cerevisiae), nematode worm (Caenorhabditis elegans), zebrafish (Danio rerio), fruitfly (Drosophila melanogaster) and mouse (Mus musculus) phenotypes. Our approach is based on the assumption that, if a mutation in a gene leads to a phenotypic abnormality in a process , then must have been involved in , either directly or indirectly. We systematically analyze recorded phenotypes in animal models using the formal definitions created for phenotype ontologies. We evaluate the validity of the inferred functions manually and by demonstrating a significant improvement in predicting genetic interactions and protein-protein interactions based on functional similarity. Our knowledge-based approach is generally applicable to phenotypes recorded in model organism databases, including phenotypes from large-scale, high throughput community projects whose primary mode of dissemination is direct publication on-line rather than in the literature.
PMCID: PMC3628905  PMID: 23626672
21.  Representing physiological processes and their participants with PhysioMaps 
Journal of Biomedical Semantics  2013;4(Suppl 1):S2.
As the number and size of biological knowledge resources for physiology grows, researchers need improved tools for searching and integrating knowledge and physiological models. Unfortunately, current resources—databases, simulation models, and knowledge bases, for example—are only occasionally and idiosyncratically explicit about the semantics of the biological entities and processes that they describe.
We present a formal approach, based on the semantics of biophysics as represented in the Ontology of Physics for Biology, that divides physiological knowledge into three partitions: structural knowledge, process knowledge and biophysical knowledge. We then computationally integrate these partitions across multiple structural and biophysical domains as computable ontologies by which such knowledge can be archived, reused, and displayed. Our key result is the semi-automatic parsing of biosimulation model code into PhysioMaps that can be displayed and interrogated for qualitative responses to hypothetical perturbations.
Strong, explicit semantics of biophysics can provide a formal, computational basis for integrating physiological knowledge in a manner that supports visualization of the physiological content of biosimulation models across spatial scales and biophysical domains.
PMCID: PMC3632997  PMID: 23735231
22.  An integrative, translational approach to understanding rare and orphan genetically based diseases 
Interface Focus  2013;3(2):20120055.
PhenomeNet is an approach for integrating phenotypes across species and identifying candidate genes for genetic diseases based on the similarity between a disease and animal model phenotypes. In contrast to ‘guilt-by-association’ approaches, PhenomeNet relies exclusively on the comparison of phenotypes to suggest candidate genes, and can, therefore, be applied to study the molecular basis of rare and orphan diseases for which the molecular basis is unknown. In addition to disease phenotypes from the Online Mendelian Inheritance in Man (OMIM) database, we have now integrated the clinical signs from Orphanet into PhenomeNet. We demonstrate that our approach can efficiently identify known candidate genes for genetic diseases in Orphanet and OMIM. Furthermore, we find evidence that mutations in the HIP1 gene might cause Bassoe syndrome, a rare disorder with unknown genetic aetiology. Our results demonstrate that integration and computational analysis of human disease and animal model phenotypes using PhenomeNet has the potential to reveal novel insights into the pathobiology underlying genetic diseases.
PMCID: PMC3638468  PMID: 23853703
phenotype; animal model; rare disease; orphan disease; Orphanet; biomedical informatics
23.  Phenotypic overlap in the contribution of individual genes to CNV pathogenicity revealed by cross-species computational analysis of single-gene mutations in humans, mice and zebrafish 
Disease Models & Mechanisms  2012;6(2):358-372.
Numerous disease syndromes are associated with regions of copy number variation (CNV) in the human genome and, in most cases, the pathogenicity of the CNV is thought to be related to altered dosage of the genes contained within the affected segment. However, establishing the contribution of individual genes to the overall pathogenicity of CNV syndromes is difficult and often relies on the identification of potential candidates through manual searches of the literature and online resources. We describe here the development of a computational framework to comprehensively search phenotypic information from model organisms and single-gene human hereditary disorders, and thus speed the interpretation of the complex phenotypes of CNV disorders. There are currently more than 5000 human genes about which nothing is known phenotypically but for which detailed phenotypic information for the mouse and/or zebrafish orthologs is available. Here, we present an ontology-based approach to identify similarities between human disease manifestations and the mutational phenotypes in characterized model organism genes; this approach can therefore be used even in cases where there is little or no information about the function of the human genes. We applied this algorithm to detect candidate genes for 27 recurrent CNV disorders and identified 802 gene-phenotype associations, approximately half of which involved genes that were previously reported to be associated with individual phenotypic features and half of which were novel candidates. A total of 431 associations were made solely on the basis of model organism phenotype data. Additionally, we observed a striking, statistically significant tendency for individual disease phenotypes to be associated with multiple genes located within a single CNV region, a phenomenon that we denote as pheno-clustering. Many of the clusters also display statistically significant similarities in protein function or vicinity within the protein-protein interaction network. Our results provide a basis for understanding previously un-interpretable genotype-phenotype correlations in pathogenic CNVs and for mobilizing the large amount of model organism phenotype data to provide insights into human genetic disorders.
PMCID: PMC3597018  PMID: 23104991
24.  The Units Ontology: a tool for integrating units of measurement in science 
Units are basic scientific tools that render meaning to numerical data. Their standardization and formalization caters for the report, exchange, process, reproducibility and integration of quantitative measurements. Ontologies are means that facilitate the integration of data and knowledge allowing interoperability and semantic information processing between diverse biomedical resources and domains. Here, we present the Units Ontology (UO), an ontology currently being used in many scientific resources for the standardized description of units of measurements.
PMCID: PMC3468815  PMID: 23060432
25.  Quantitative comparison of mapping methods between Human and Mammalian Phenotype Ontology 
Journal of Biomedical Semantics  2012;3(Suppl 2):S1.
Researchers use animal studies to better understand human diseases. In recent years, large-scale phenotype studies such as Phenoscape and EuroPhenome have been initiated to identify genetic causes of a species' phenome. Species-specific phenotype ontologies are required to capture and report about all findings and to automatically infer results relevant to human diseases. The integration of the different phenotype ontologies into a coherent framework is necessary to achieve interoperability for cross-species research.
Here, we investigate the quality and completeness of two different methods to align the Human Phenotype Ontology and the Mammalian Phenotype Ontology. The first method combines lexical matching with inference over the ontologies' taxonomic structures, while the second method uses a mapping algorithm based on the formal definitions of the ontologies. Neither method could map all concepts. Despite the formal definitions method provides mappings for more concepts than does the lexical matching method, it does not outperform the lexical matching in a biological use case. Our results suggest that combining both approaches will yield a better mappings in terms of completeness, specificity and application purposes.
PMCID: PMC3448526  PMID: 23046555

Results 1-25 (39)