Georgios V. Gkoutos

The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, 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.

Uberon, an integrative multi-species anatomy ontology

We present Uberon, an integrated cross-species ontology consisting of over 6,500 classes representing a variety of anatomical entities, organized according to traditional anatomical classification criteria. The ontology represents structures in a species-neutral way and includes extensive associations to existing species-centric anatomical ontologies, allowing integration of model organism and human data. Uberon provides a necessary bridge between anatomical structures in different taxa for cross-species inference. It uses novel methods for representing taxonomic variation, and has proved to be essential for translational phenotype analyses. Uberon is available at http://uberon.org

EMPReSS: standardized phenotype screens for functional annotation of the mouse genome

To the editor: With the completion of the genome sequence of several mammals, attention is now focused on functional annotation of these genomes. The most versatile organism in which to study mammalian gene function is the mouse, as there is an extensive tool kit for modifying the genome including gene-driven and phenotypedriven approaches1–6. Underpinning this diversity is the recognition of the utility of a series of mutated alleles at every gene in the mouse genome. Such a resource would enable a full exploration of gene-phenotype space and provide a wider collection of models for translating gene function to human disease genetics. Such a program is crucially dependent on tools to investigate phenotype. Comprehensive phenotyping platforms depend on a number of features. First, they require the development of approaches to study, document and measure aspects of all body systems. Second, they require standardization to ensure that phenotyping is comparable both within and between laboratories and over time. If investigators are not able to compare phenotype outcome for two different alleles in the same gene reliably, then any interpretation of similarities or differences that might affect our understanding of gene function will be fraught with difficulties. Therefore, it will be important for centers undertaking large-scale efforts to phenotype mutant mouse collections to adopt standardized methods. It will be equally important that such procedures are accessible to and operable by smaller laboratories. The aim is to generate a set of standard operating procedures (SOPs) that will become a comprehensive reference point for mouse phenotyping. There already has been some effort to develop new, high-throughput phenotyping platforms for studying mouse mutants (e.g., SHIRPA)5,6. But the phenotype coverage of these platforms is restricted, and they were not developed using a process of systematic review and validation to ensure their robustness. Eumorphia (http://www.eumorphia.org/) is a consortium of 18 research institutes from across Europe that is developing a comprehensive, robust and validated phenotyping platform for the mouse. Initially, we focused on developing a phenotyping platform encompassing first-line screens, many of which are accessible to a typical mouse genetics lab. The new screen, EMPReSS (European Mouse Phenotyping Resource for Standardized Screens), incorporates more than 150 new SOPs. EMPReSS covers all of the main body systems including clinical chemistry, hormonal and metabolic systems, cardiovascular, allergy and infection, renal function, sensory function, neurological and behavioral function, cancer, bone and cartilage, and respiratory function. In addition, generic SOPs in histology, necropsy, pathology and gene expression have been established. We also investigated the effects of animal house regimes on a number of tests, including the effects of diet7. The available tests include procedural and data-generating SOPs; procedural SOPs (e.g., blood collection) are components of data-generating SOPs. Each SOP was developed by dedicated working groups. Draft SOPs were tested on a selected group of inbred strains (C57BL/6J, C3HeB/FeJ, BALB/cByJ and 129S2/SvPas) in the laboratories of each working group. Data-generating SOPs were the focus of validation. Validation might occur in a single laboratory to ensure operational consistency of the developed SOP, but many SOPs were validated between laboratories, and this process continues. Results were compared and, where appropriate, SOPs modified or further developed to ensure consistency. If necessary, additional rounds of validation took place. Current validation status for each SOP is indicated at the EMPReSS website (http://www.eumorphia.org/EMPReSS/). Each SOP was examined by the Eumorphia administration team for accuracy and consistency with the established SOP format. Finally, the SOP was reviewed and approved by a Eumorphia scientist outside the working group before being uploaded to the EMPReSS website. To facilitate storage and processing of SOPs, Eumorphia created SOPML, an XML language that allows the description of SOPs8 and that is integral to developing new combinatorial approaches to representing phenotypes as ontologies. The SOPs are automatically annotated using a SOP template and stored in SOPdb, the underlying database. The EMPReSS SOP database is accessible online (http://empress.har.mrc.ac.uk/). EMPReSS will continue to develop in a number of ways. First, the application of EMPReSS in large-scale screens will allow us to refine and validate current SOPs. Second, it will be important to expand the repertoire of phenotype tests that are available, including primary as well as secondary and tertiary screens. We plan to use EMPReSS as we begin the process of phenotyping the large numbers of mouse mutants generated through the planned largescale mouse mutagenesis programs9,10.

Entity/quality-based logical definitions for the human skeletal phenome using PATO

This paper describes an approach to providing computer-interpretable logical definitions for the terms of the Human Phenotype Ontology (HPO) using PATO, the ontology of phenotypic qualities, to link terms of the HPO to the anatomic and other entities that are affected by abnormal phenotypic qualities. This approach will allow improved computerized reasoning as well as a facility to compare phenotypes between different species. The PATO mapping will also provide direct links from phenotypic abnormalities and underlying anatomic structures encoded using the Foundational Model of Anatomy, which will be a valuable resource for computational investigations of the links between anatomical components and concepts representing diseases with abnormal phenotypes and associated genes.

EMPReSS: European Mouse Phenotyping Resource for Standardized Screens

UNLABELLED Standardized phenotyping protocols are essential for the characterization of phenotypes so that results are comparable between different laboratories and phenotypic data can be related to ontological descriptions in an automated manner. We describe a web-based resource for the visualization, searching and downloading of standard operating procedures and other documents, the European Mouse Phenotyping Resource for Standardized Screens-EMPReSS. AVAILABILITY Direct access: http://www.empress.har.mrc.ac.uk CONTACT e.green@har.mrc.ac.uk.

Evaluation of research in biomedical ontologies

Ontologies are now pervasive in biomedicine, where they serve as a means to standardize terminology, to enable access to domain knowledge, to verify data consistency and to facilitate integrative analyses over heterogeneous biomedical data. For this purpose, research on biomedical ontologies applies theories and methods from diverse disciplines such as information management, knowledge representation, cognitive science, linguistics and philosophy. Depending on the desired applications in which ontologies are being applied, the evaluation of research in biomedical ontologies must follow different strategies. Here, we provide a classification of research problems in which ontologies are being applied, focusing on the use of ontologies in basic and translational research, and we demonstrate how research results in biomedical ontologies can be evaluated. The evaluation strategies depend on the desired application and measure the success of using an ontology for a particular biomedical problem. For many applications, the success can be quantified, thereby facilitating the objective evaluation and comparison of research in biomedical ontology. The objective, quantifiable comparison of research results based on scientific applications opens up the possibility for systematically improving the utility of ontologies in biomedical research.

Construction and accessibility of a cross-species phenotype ontology along with gene annotations for biomedical research

Phenotype analyses, e.g. investigating metabolic processes, tissue formation, or organism behavior, are an important element of most biological and medical research activities. Biomedical researchers are making increased use of ontological standards and methods to capture the results of such analyses, with one focus being the comparison and analysis of phenotype information between species. We have generated a cross-species phenotype ontology for human, mouse and zebrafish that contains classes from the Human Phenotype Ontology, Mammalian Phenotype Ontology, and generated classes for zebrafish phenotypes. We also provide up-to-date annotation data connecting human genes to phenotype classes from the generated ontology. We have included the data generation pipeline into our continuous integration system ensuring stable and up-to-date releases. This article describes the data generation process and is intended to help interested researchers access both the phenotype annotation data and the associated cross-species phenotype ontology. The resource described here can be used in sophisticated semantic similarity and gene set enrichment analyses for phenotype data across species. The stable releases of this resource can be obtained from http://purl.obolibrary.org/obo/hp/uberpheno/.

MouseFinder: Candidate disease genes from mouse phenotype data†

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 genes 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; www.mousemodels.org) 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. Hum Mutat 33:858–866, 2012.

Integrating systems biology models and biomedical ontologies

BackgroundSystems biology is an approach to biology that emphasizes the structure and dynamic behavior of biological systems and the interactions that occur within them. To succeed, systems biology crucially depends on the accessibility and integration of data across domains and levels of granularity. Biomedical ontologies were developed to facilitate such an integration of data and are often used to annotate biosimulation models in systems biology.ResultsWe provide a framework to integrate representations of in silico systems biology with those of in vivo biology as described by biomedical ontologies and demonstrate this framework using the Systems Biology Markup Language. We developed the SBML Harvester software that automatically converts annotated SBML models into OWL and we apply our software to those biosimulation models that are contained in the BioModels Database. We utilize the resulting knowledge base for complex biological queries that can bridge levels of granularity, verify models based on the biological phenomenon they represent and provide a means to establish a basic qualitative layer on which to express the semantics of biosimulation models.ConclusionsWe establish an information flow between biomedical ontologies and biosimulation models and we demonstrate that the integration of annotated biosimulation models and biomedical ontologies enables the verification of models as well as expressive queries. Establishing a bi-directional information flow between systems biology and biomedical ontologies has the potential to enable large-scale analyses of biological systems that span levels of granularity from molecules to organisms.

Mouse genetic and phenotypic resources for human genetics

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, 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 embryonic stem cells from these large‐scale programmes, the use of these resources to help prioritize and validate candidate genes in human genetic association studies, and how they can improve our understanding of the underlying pathobiology of human disease. Hum Mutat 33:826–836, 2012.