MRIO: the Magnetic Resonance Imaging Acquisition and Analysis Ontology.

Magnetic resonance imaging of the brain is a useful tool in both the clinic and research settings, aiding in the diagnosis and treatments of neurological disease and expanding our knowledge of the brain. However, there are many challenges inherent in managing and analyzing MRI data, due in large part to the heterogeneity of data acquisition. To address this, we have developed MRIO, the Magnetic Resonance Imaging Acquisition and Analysis Ontology. MRIO provides well-reasoned classes and logical axioms for the acquisition of several MRI acquisition types and well-known, peer-reviewed analysis software, facilitating the use of MRI data. These classes provide a common language for the neuroimaging research process and help standardize the organization and analysis of MRI data for reproducible datasets. We also provide queries for automated assignment of analyses for given MRI types. MRIO aids researchers in managing neuroimaging studies by helping organize and annotate MRI data and integrating with existing standards such as Digital Imaging and Communications in Medicine and the Brain Imaging Data Structure, enhancing reproducibility and interoperability. MRIO was constructed according to Open Biomedical Ontologies Foundry principles and has contributed several classes to the Ontology for Biomedical Investigations to help bridge neuroimaging data to other domains. MRIO addresses the need for a "common language" for MRI that can help manage the neuroimaging research, by enabling researchers to identify appropriate analyses for sets of scans and facilitating data organization and reporting.

Ontology-based modeling, integration, and analysis of heterogeneous clinical, pathological, and molecular kidney data for precision medicine.

Many data resources generate, process, store, or provide kidney related molecular, pathological, and clinical data. Reference ontologies offer an opportunity to support knowledge and data integration. The Kidney Precision Medicine Project (KPMP) team contributed to the representation and addition of 329 kidney phenotype terms to the Human Phenotype Ontology (HPO), and identified many subcategories of acute kidney injury (AKI) or chronic kidney disease (CKD). The Kidney Tissue Atlas Ontology (KTAO) imports and integrates kidney-related terms from existing ontologies (e.g., HPO, CL, and Uberon) and represents 259 kidney-related biomarkers. We also developed a precision medicine metadata ontology (PMMO) to integrate 50 variables from KPMP and CZ CellxGene data resources and applied PMMO for integrative kidney data analysis. The gene expression profiles of kidney gene biomarkers were specifically analyzed under healthy control or AKI/CKD disease statuses. This work demonstrates how ontology-based approaches support multi-domain data and knowledge integration in precision medicine.

MRIO: The Magnetic Resonance Imaging Acquisition and Analysis Ontology.

Objective: Magnetic resonance imaging of the brain is a useful tool in both the clinic and research settings, aiding in the diagnosis and treatments of neurological disease and expanding our knowledge of the brain. However, there are many challenges inherent in managing and analyzing MRI data, due in large part to the heterogeneity of data acquisition. Materials and Methods: To address this, we have developed MRIO, the Magnetic Resonance Imaging Acquisition and Analysis Ontology. Results: MRIO provides well-reasoned classes and logical axioms for the acquisition of several MRI acquisition types and well-known, peer-reviewed analysis software, facilitating the use of MRI data. These classes provide a common language for the neuroimaging research process and help standardize the organization and analysis of MRI data for reproducible datasets. We also provide queries for automated assignment of analyses for given MRI types. Discussion: MRIO aids researchers in managing neuroimaging studies by helping organize and annotate MRI data and integrating with existing standards such as Digital Imaging and Communications in Medicine and the Brain Imaging Data Structure, enhancing reproducibility and interoperability. MRIO was constructed according to Open Biomedical Ontologies Foundry principals and has contributed several terms to the Ontology for Biomedical Investigations to help bridge neuroimaging data to other domains. Conclusion: MRIO addresses the need for a "common language" for MRI that can help manage the neuroimaging research, by enabling researchers to identify appropriate analyses for sets of scans and facilitating data organization and reporting.

GlycoEnzOnto: a GlycoEnzyme pathway and molecular function ontology.

MOTIVATION: The 'glycoEnzymes' include a set of proteins having related enzymatic, metabolic, transport, structural and cofactor functions. Currently, there is no established ontology to describe glycoEnzyme properties and to relate them to glycan biosynthesis pathways. RESULTS: We present GlycoEnzOnto, an ontology describing 403 human glycoEnzymes curated along 139 glycosylation pathways, 134 molecular functions and 22 cellular compartments. The pathways described regulate nucleotide-sugar metabolism, glycosyl-substrate/donor transport, glycan biosynthesis and degradation. The role of each enzyme in the glycosylation initiation, elongation/branching and capping/termination phases is described. IUPAC linear strings present systematic human/machine-readable descriptions of individual reaction steps and enable automated knowledge-based curation of biochemical networks. All GlycoEnzOnto knowledge is integrated with the Gene Ontology biological processes. GlycoEnzOnto enables improved transcript overrepresentation analyses and glycosylation pathway identification compared to other available schema, e.g. KEGG and Reactome. Overall, GlycoEnzOnto represents a holistic glycoinformatics resource for systems-level analyses. AVAILABILITY AND IMPLEMENTATION: https://github.com/neel-lab/GlycoEnzOnto. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

OBO Foundry in 2021: operationalizing open data principles to evaluate ontologies.

Biological ontologies are used to organize, curate and interpret the vast quantities of data arising from biological experiments. While this works well when using a single ontology, integrating multiple ontologies can be problematic, as they are developed independently, which can lead to incompatibilities. The Open Biological and Biomedical Ontologies (OBO) Foundry was created to address this by facilitating the development, harmonization, application and sharing of ontologies, guided by a set of overarching principles. One challenge in reaching these goals was that the OBO principles were not originally encoded in a precise fashion, and interpretation was subjective. Here, we show how we have addressed this by formally encoding the OBO principles as operational rules and implementing a suite of automated validation checks and a dashboard for objectively evaluating each ontology's compliance with each principle. This entailed a substantial effort to curate metadata across all ontologies and to coordinate with individual stakeholders. We have applied these checks across the full OBO suite of ontologies, revealing areas where individual ontologies require changes to conform to our principles. Our work demonstrates how a sizable, federated community can be organized and evaluated on objective criteria that help improve overall quality and interoperability, which is vital for the sustenance of the OBO project and towards the overall goals of making data Findable, Accessible, Interoperable, and Reusable (FAIR). Database URL http://obofoundry.org/.

Modelling kidney disease using ontology: insights from the Kidney Precision Medicine Project.

An important need exists to better understand and stratify kidney disease according to its underlying pathophysiology in order to develop more precise and effective therapeutic agents. National collaborative efforts such as the Kidney Precision Medicine Project are working towards this goal through the collection and integration of large, disparate clinical, biological and imaging data from patients with kidney disease. Ontologies are powerful tools that facilitate these efforts by enabling researchers to organize and make sense of different data elements and the relationships between them. Ontologies are critical to support the types of big data analysis necessary for kidney precision medicine, where heterogeneous clinical, imaging and biopsy data from diverse sources must be combined to define a patient's phenotype. The development of two new ontologies - the Kidney Tissue Atlas Ontology and the Ontology of Precision Medicine and Investigation - will support the creation of the Kidney Tissue Atlas, which aims to provide a comprehensive molecular, cellular and anatomical map of the kidney. These ontologies will improve the annotation of kidney-relevant data, and eventually lead to new definitions of kidney disease in support of precision medicine.

Foundations for a Realism-Based Ontology of Protein Aggregates.

The objective of this paper is to propose formal definitions for the terms 'protein aggregate' and 'protein-containing complex' such that the descriptions and usages of these terms in biomedical literature are unified and that those portions of reality are correctly represented. To this end, we surveyed the literature to assess the need for a distinction between these entities, then compared the features of usages and definitions found in the literature to the definitions for those terms found in Bioportal ontologies. Based on the results of this comparison, we propose updated definitions for the terms 'protein aggregate' and 'protein-containing complex'. Thus far, we propose the following distinguishing factors: first, that one important difference lies in whether an entity is disposed to change type in response to certain structural alterations, such as dissociation of a continuant part, and second that an important difference lies in the ability of the entity to realize its function after such an event occurs. These distinctions are reflected in the proposed definitions.

An ontology for representing hematologic malignancies: the cancer cell ontology.

BACKGROUND: Within the cancer domain, ontologies play an important role in the integration and annotation of data in order to support numerous biomedical tools and applications. This work seeks to leverage existing standards in immunophenotyping cell types found in hematologic malignancies to provide an ontological representation of them to aid in data annotation and analysis for patient data. RESULTS: We have developed the Cancer Cell Ontology according to OBO Foundry principles as an extension of the Cell Ontology. We define classes in Cancer Cell Ontology by using a genus-differentia approach using logical axioms capturing the expression of cellular surface markers in order to represent types of hematologic malignancies. By adopting conventions used in the Cell Ontology, we have created human and computer-readable definitions for 300 classes of blood cancers, based on the EGIL classification system for leukemias, and relying upon additional classification approaches for multiple myelomas and other hematologic malignancies. CONCLUSION: We have demonstrated a proof of concept for leveraging the built-in logical axioms of the ontology in order to classify patient surface marker data into appropriate diagnostic categories. We plan to integrate our ontology into existing tools for flow cytometry data analysis to facilitate the automated diagnosis of hematologic malignancies.

Cells in ExperimentaL Life Sciences (CELLS-2018): capturing the knowledge of normal and diseased cells with ontologies.

Cell cultures and cell lines are widely used in life science experiments. In conjunction with the 2018 International Conference on Biomedical Ontology (ICBO-2018), the 2nd International Workshop on Cells in ExperimentaL Life Science (CELLS-2018) focused on two themes of knowledge representation, for newly-discovered cell types and for cells in disease states. This workshop included five oral presentations and a general discussion session. Two new ontologies, including the Cancer Cell Ontology (CCL) and the Ontology for Stem Cell Investigations (OSCI), were reported in the workshop. In another representation, the Cell Line Ontology (CLO) framework was applied and extended to represent cell line cells used in China and their Chinese representation. Other presentations included a report on the application of ontologies to cross-compare cell types and marker patterns used in flow cytometry studies, and a presentation on new experimental findings about novel cell types based on single cell RNA sequencing assay and their corresponding ontological representation. The general discussion session focused on the ontology design patterns in representing newly-discovered cell types and cells in disease states.

OSCI: standardized stem cell ontology representation and use cases for stem cell investigation.

BACKGROUND: Stem cells and stem cell lines are widely used in biomedical research. The Cell Ontology (CL) and Cell Line Ontology (CLO) are two community-based OBO Foundry ontologies in the domains of in vivo cells and in vitro cell line cells, respectively. RESULTS: To support standardized stem cell investigations, we have developed an Ontology for Stem Cell Investigations (OSCI). OSCI imports stem cell and cell line terms from CL and CLO, and investigation-related terms from existing ontologies. A novel focus of OSCI is its application in representing metadata types associated with various stem cell investigations. We also applied OSCI to systematically categorize experimental variables in an induced pluripotent stem cell line cell study related to bipolar disorder. In addition, we used a semi-automated literature mining approach to identify over 200 stem cell gene markers. The relations between these genes and stem cells are modeled and represented in OSCI. CONCLUSIONS: OSCI standardizes stem cells found in vivo and in vitro and in various stem cell investigation processes and entities. The presented use cases demonstrate the utility of OSCI in iPSC studies and literature mining related to bipolar disorder.

Reporting and connecting cell type names and gating definitions through ontologies.

BACKGROUND: Human immunology studies often rely on the isolation and quantification of cell populations from an input sample based on flow cytometry and related techniques. Such techniques classify cells into populations based on the detection of a pattern of markers. The description of the cell populations targeted in such experiments typically have two complementary components: the description of the cell type targeted (e.g. 'T cells'), and the description of the marker pattern utilized (e.g. CD14-, CD3+). RESULTS: We here describe our attempts to use ontologies to cross-compare cell types and marker patterns (also referred to as gating definitions). We used a large set of such gating definitions and corresponding cell types submitted by different investigators into ImmPort, a central database for immunology studies, to examine the ability to parse gating definitions using terms from the Protein Ontology (PRO) and cell type descriptions, using the Cell Ontology (CL). We then used logical axioms from CL to detect discrepancies between the two. CONCLUSIONS: We suggest adoption of our proposed format for describing gating and cell type definitions to make comparisons easier. We also suggest a number of new terms to describe gating definitions in flow cytometry that are not based on molecular markers captured in PRO, but on forward- and side-scatter of light during data acquisition, which is more appropriate to capture in the Ontology for Biomedical Investigations (OBI). Finally, our approach results in suggestions on what logical axioms and new cell types could be considered for addition to the Cell Ontology.

Cell type discovery using single-cell transcriptomics: implications for ontological representation.

Cells are fundamental function units of multicellular organisms, with different cell types playing distinct physiological roles in the body. The recent advent of single-cell transcriptional profiling using RNA sequencing is producing 'big data', enabling the identification of novel human cell types at an unprecedented rate. In this review, we summarize recent work characterizing cell types in the human central nervous and immune systems using single-cell and single-nuclei RNA sequencing, and discuss the implications that these discoveries are having on the representation of cell types in the reference Cell Ontology (CL). We propose a method, based on random forest machine learning, for identifying sets of necessary and sufficient marker genes, which can be used to assemble consistent and reproducible cell type definitions for incorporation into the CL. The representation of defined cell type classes and their relationships in the CL using this strategy will make the cell type classes being identified by high-throughput/high-content technologies findable, accessible, interoperable and reusable (FAIR), allowing the CL to serve as a reference knowledgebase of information about the role that distinct cellular phenotypes play in human health and disease.

Ontological Realism for the Research Domain Criteria for Mental Disorders.

At the heart of the Research Domain Criteria for Mental Disorders is a matrix in which functional aspects of behavior are related to genotypic and (endo-)phenotypic research findings, and the various techniques through which they can been observed. The matrix is work in progress. As such it currently suffers from several shortcomings, the resolution of which, we contend, are essential to success of NIMH's goal of fostering translational science on mental disorders. Using well-established criteria for assessing the terminological and ontological quality of biomedical representations we identified the major problems to be (1) the abundant presence of terms that lack face value, (2) the absence of what the exact nature of the represented relationships are, and (3) referential imprecision with respect to the intended granularity of what the terms denote. We propose to eliminate these shortcomings by resorting to definitions and formal representations under the umbrella of Ontological Realism as they already have been developed in the areas of mental health, anatomy and biological functions.

Protein Ontology (PRO): enhancing and scaling up the representation of protein entities.

The Protein Ontology (PRO; http://purl.obolibrary.org/obo/pr) formally defines and describes taxon-specific and taxon-neutral protein-related entities in three major areas: proteins related by evolution; proteins produced from a given gene; and protein-containing complexes. PRO thus serves as a tool for referencing protein entities at any level of specificity. To enhance this ability, and to facilitate the comparison of such entities described in different resources, we developed a standardized representation of proteoforms using UniProtKB as a sequence reference and PSI-MOD as a post-translational modification reference. We illustrate its use in facilitating an alignment between PRO and Reactome protein entities. We also address issues of scalability, describing our first steps into the use of text mining to identify protein-related entities, the large-scale import of proteoform information from expert curated resources, and our ability to dynamically generate PRO terms. Web views for individual terms are now more informative about closely-related terms, including for example an interactive multiple sequence alignment. Finally, we describe recent improvement in semantic utility, with PRO now represented in OWL and as a SPARQL endpoint. These developments will further support the anticipated growth of PRO and facilitate discoverability of and allow aggregation of data relating to protein entities.

Cells in experimental life sciences - challenges and solution to the rapid evolution of knowledge.

Cell cultures used in biomedical experiments come in the form of both sample biopsy primary cells, and maintainable immortalised cell lineages. The rise of bioinformatics and high-throughput technologies has led us to the requirement of ontology representation of cell types and cell lines. The Cell Ontology (CL) and Cell Line Ontology (CLO) have long been established as reference ontologies in the OBO framework. We have compiled a series of the challenges and the proposals of solutions in this CELLS (Cells in ExperimentaL Life Sciences) thematic series that cover the grounds of standing issues and the directions, which were discussed in the First International Workshop on CELLS at the the International Conference on Biomedical Ontology (ICBO). This workshop focused on the extension of the current CL and CLO to cover a wider set of biological questions and challenges needing semantic infrastructure for information modeling. We discussed data-driven use cases that leverage linkage of CL, CLO and other bio-ontologies. This is an established approach in data-driven ontologies such as the Experimental Factor Ontology (EFO), and the Ontology for Biomedical Investigation (OBI). The First International Workshop on CELLS at the International Conference on Biomedical Ontology has brought together experimental biologists and biomedical ontologists to discuss solutions to organizing and representing the rapidly evolving knowledge gained from experimental cells. The workshop has successfully identified the areas of challenge, and the gap in connecting the two domains of knowledge. The outcome of this workshop yielded practical implementation plans to filled in this gap.This CELLS workshop also provided a venue for panel discussions of innovative solutions as well as challenges in the development and applications of biomedical ontologies to represent and analyze experimental cell data.

The Cell Ontology 2016: enhanced content, modularization, and ontology interoperability.

BACKGROUND: The Cell Ontology (CL) is an OBO Foundry candidate ontology covering the domain of canonical, natural biological cell types. Since its inception in 2005, the CL has undergone multiple rounds of revision and expansion, most notably in its representation of hematopoietic cells. For in vivo cells, the CL focuses on vertebrates but provides general classes that can be used for other metazoans, which can be subtyped in species-specific ontologies. CONSTRUCTION AND CONTENT: Recent work on the CL has focused on extending the representation of various cell types, and developing new modules in the CL itself, and in related ontologies in coordination with the CL. For example, the Kidney and Urinary Pathway Ontology was used as a template to populate the CL with additional cell types. In addition, subtypes of the class 'cell in vitro' have received improved definitions and labels to provide for modularity with the representation of cells in the Cell Line Ontology and Reagent Ontology. Recent changes in the ontology development methodology for CL include a switch from OBO to OWL for the primary encoding of the ontology, and an increasing reliance on logical definitions for improved reasoning. UTILITY AND DISCUSSION: The CL is now mandated as a metadata standard for large functional genomics and transcriptomics projects, and is used extensively for annotation, querying, and analyses of cell type specific data in sequencing consortia such as FANTOM5 and ENCODE, as well as for the NIAID ImmPort database and the Cell Image Library. The CL is also a vital component used in the modular construction of other biomedical ontologies-for example, the Gene Ontology and the cross-species anatomy ontology, Uberon, use CL to support the consistent representation of cell types across different levels of anatomical granularity, such as tissues and organs. CONCLUSIONS: The ongoing improvements to the CL make it a valuable resource to both the OBO Foundry community and the wider scientific community, and we continue to experience increased interest in the CL both among developers and within the user community.

Representing vision and blindness.

BACKGROUND: There have been relatively few attempts to represent vision or blindness ontologically. This is unsurprising as the related phenomena of sight and blindness are difficult to represent ontologically for a variety of reasons. Blindness has escaped ontological capture at least in part because: blindness or the employment of the term 'blindness' seems to vary from context to context, blindness can present in a myriad of types and degrees, and there is no precedent for representing complex phenomena such as blindness. METHODS: We explore current attempts to represent vision or blindness, and show how these attempts fail at representing subtypes of blindness (viz., color blindness, flash blindness, and inattentional blindness). We examine the results found through a review of current attempts and identify where they have failed. RESULTS: By analyzing our test cases of different types of blindness along with the strengths and weaknesses of previous attempts, we have identified the general features of blindness and vision. We propose an ontological solution to represent vision and blindness, which capitalizes on resources afforded to one who utilizes the Basic Formal Ontology as an upper-level ontology. CONCLUSIONS: The solution we propose here involves specifying the trigger conditions of a disposition as well as the processes that realize that disposition. Once these are specified we can characterize vision as a function that is realized by certain (in this case) biological processes under a range of triggering conditions. When the range of conditions under which the processes can be realized are reduced beyond a certain threshold, we are able to say that blindness is present. We characterize vision as a function that is realized as a seeing process and blindness as a reduction in the conditions under which the sight function is realized. This solution is desirable because it leverages current features of a major upper-level ontology, accurately captures the phenomenon of blindness, and can be implemented in many domain-specific ontologies.

Gateways to the FANTOM5 promoter level mammalian expression atlas.

The FANTOM5 project investigates transcription initiation activities in more than 1,000 human and mouse primary cells, cell lines and tissues using CAGE. Based on manual curation of sample information and development of an ontology for sample classification, we assemble the resulting data into a centralized data resource (http://fantom.gsc.riken.jp/5/). This resource contains web-based tools and data-access points for the research community to search and extract data related to samples, genes, promoter activities, transcription factors and enhancers across the FANTOM5 atlas.

flowCL: ontology-based cell population labelling in flow cytometry.

MOTIVATION: Finding one or more cell populations of interest, such as those correlating to a specific disease, is critical when analysing flow cytometry data. However, labelling of cell populations is not well defined, making it difficult to integrate the output of algorithms to external knowledge sources. RESULTS: We developed flowCL, a software package that performs semantic labelling of cell populations based on their surface markers and applied it to labelling of the Federation of Clinical Immunology Societies Human Immunology Project Consortium lyoplate populations as a use case. CONCLUSION: By providing automated labelling of cell populations based on their immunophenotype, flowCL allows for unambiguous and reproducible identification of standardized cell types. AVAILABILITY AND IMPLEMENTATION: Code, R script and documentation are available under the Artistic 2.0 license through Bioconductor (http://www.bioconductor.org/packages/devel/bioc/html/flowCL.html). CONTACT: rbrinkman@bccrc.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Protein Ontology: a controlled structured network of protein entities.

The Protein Ontology (PRO; http://proconsortium.org) formally defines protein entities and explicitly represents their major forms and interrelations. Protein entities represented in PRO corresponding to single amino acid chains are categorized by level of specificity into family, gene, sequence and modification metaclasses, and there is a separate metaclass for protein complexes. All metaclasses also have organism-specific derivatives. PRO complements established sequence databases such as UniProtKB, and interoperates with other biomedical and biological ontologies such as the Gene Ontology (GO). PRO relates to UniProtKB in that PRO's organism-specific classes of proteins encoded by a specific gene correspond to entities documented in UniProtKB entries. PRO relates to the GO in that PRO's representations of organism-specific protein complexes are subclasses of the organism-agnostic protein complex terms in the GO Cellular Component Ontology. The past few years have seen growth and changes to the PRO, as well as new points of access to the data and new applications of PRO in immunology and proteomics. Here we describe some of these developments.