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Basic Building Blocks for Biomedical Ontologies Barry Smith 1 Problems with UMLS-style approaches • let a million ontologies bloom, each one close to the terminological habits of its authors • in concordance with the “not invented here” syndrome • then map these ontologies, and use these mappings to integrate your different pots of data 2 Mappings are hard They create an N2 problem; are fragile, and expensive to maintain Need new authorities to maintain(one for each pair of mapped ontologies), yielding new risk of forking – who will police the mappings? The goal should be to minimize the need for mappings, by avoiding redundancy in the first place – one ontology for each domain Invest resources in disjoint ontology modules which work well together – reduce need for mappings to minimum possible 8 Why should you care? • you need to create systems for data mining and text processing which will yield useful digitally coded output • if the codes you use are constantly in need of ad hoc repair huge, resources will be wasted • serious investment in annotation will be defeated from the start • relevant data will not be found, because it will be lost in multiple semantic cemeteries 9 How to do it right? • how create an incremental, evolutionary process, where what is good survives, and what is bad fails • where the number of ontologies needing to be used together is small – integration = addition • where these ontologies are stable • by creating a scenario in which people will find it profitable to reuse ontologies, terminologies and coding systems which have been tried and tested 10 Reasons why GO has been successful It is a system for prospective standardization built with coherent top level but with content contributed and monitored by domain specialists Based on community consensus Updated every night Clear versioning principles ensure backwards compatibility; prior annotations do not lose their value Initially low-tech to encourage users, with movement to more powerful formal approaches (including OWL-DL – though still proceeding caution) 11 GO has learned the lessons of successful cooperation • Clear documentation • The terms chosen are already familiar • Fully open source (allows thorough testing in manifold combinations with other ontologies) • Subjected to considerable third-party critique • Tracker for user input and help desk with rapid turnaround 12 GO has been amazingly successful in overcoming the data balkanization problem but it covers only generic biological entities of three sorts: – cellular components – molecular functions – biological processes no diseases, symptoms, disease biomarkers, protein interactions, experimental processes … 13 RELATION TO TIME CONTINUANT INDEPENDENT OCCURRENT DEPENDENT GRANULARITY ORGAN AND ORGANISM Organism (NCBI Taxonomy) CELL AND CELLULAR COMPONENT Cell (CL) MOLECULE Anatomical Organ Entity Function (FMA, (FMP, CPRO) Phenotypic CARO) Quality (PaTO) Cellular Cellular Component Function (FMA, GO) (GO) Molecule (ChEBI, SO, RnaO, PrO) Molecular Function (GO) Biological Process (GO) Molecular Process (GO) OBO (Open Biomedical Ontology) Foundry proposal (Gene Ontology in yellow) 14 RELATION TO TIME CONTINUANT INDEPENDENT OCCURRENT DEPENDENT ORGAN AND ORGANISM CELL AND CELLULAR COMPONENT MOLECULE Organism (NCBI Taxonomy) Anatomical Entity (FMA, CARO) Cell (CL) Cellular Component (FMA, GO) Molecule (ChEBI, SO, RnaO, PrO) Environment Ontology (ENVO) GRANULARITY Organ Function (FMP, CPRO) Phenotypic Quality (PaTO) Biological Process (GO) Cellular Function (GO) Molecular Function (GO) Molecular Process (GO) Environment Ontology 15 RELATION TO TIME CONTINUANT INDEPENDENT OCCURRENT DEPENDENT GRANULARITY COMPLEX OF ORGANISMS ORGAN AND ORGANISM CELL AND CELLULAR COMPONENT MOLECULE Family, Community, Deme, Population Population Phenotype Organ Anatomical Function Organism Entity (FMP, CPRO) (NCBI (FMA, Phenotypic Taxonomy) CARO) Quality (PaTO) Cellular Cellular Cell Component Function (CL) (FMA, GO) (GO) Molecule (ChEBI, SO, RnaO, PrO) Molecular Function (GO) Population-level ontologies Population Process Biological Process (GO) Molecular Process (GO) 16 The OBO Foundry: a step-by-step, evidence-based approach to expanding the GO Developers commit to working to ensure that, for each domain, there is community convergence on a single ontology and agree in advance to collaborate with developers of ontologies in adjacent domains. http://obofoundry.org 17 OBO Foundry Principles Common governance (coordinating editors) Common training Common architecture: • simple shared top level ontology (BFO) • shared Relation Ontology: www.obofoundry.org/ro 18 Open Biomedical Ontologies Foundry Seeks to create high quality, validated terminology modules across all of the life sciences which will be • one ontology for each domain, so no need for mappings • close to language use of experts • evidence-based • incorporate a strategy for motivating potential developers and users • revisable as science advances 19 Principles http://obofoundry.org/wiki/index.php/OBO_Foundry Principles 20 RELATION TO TIME GRANULARITY INDEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy) CELL AND CELLULAR COMPONENT Cell (CL) MOLECULE CONTINUANT DEPENDENT Anatomical Organ Entity Function (FMA, (FMP, CPRO) Phenotypic CARO) Quality (PaTO) Cellular Cellular Component Function (FMA, GO) (GO) Molecule (ChEBI, SO, RnaO, PrO) OCCURRENT Molecular Function (GO) Organism-Level Process (GO) Cellular Process (GO) Molecular Process (GO) OBO Foundry coverage 21 ORTHOGONALITY modularity ensures • • • • • annotations can be additive division of labor amongst domain experts high value of training in any given module lessons learned in one module can benefit work on other modules incentivization of those responsible for individual modules 22 Benefits of coordination • • • Can more easily reuse what is made by others Can more easily inspect and criticize what is made by others Leads to innovations (e.g. Mireot strategy for importing terms into ontologies) 23 RELATION TO TIME CONTINUANT INDEPENDENT OCCURRENT DEPENDENT GRANULARITY ORGAN AND ORGANISM Organism (NCBI Taxonomy) CELL AND CELLULAR COMPONENT Cell (CL) Anatomical Entity (FMA, CARO) Organ Function (FMP, CPRO) Phenotypic Quality XAO ZFA (PaTO) Cellular Component (FMA, GO) Molecule (SO, RnaO) MOLECULE ChEBI PRO Biological Process (GO) Cellular Function (GO) Molecular Function (GO) Molecular Process (GO) Current Foundry members in yellow 24 Foundry ontologies currently under review Plant Ontology (PO) Ontology for Biomedical Investigations (OBI) Ontology for General Medical Science (OBMS) Infectious Disease Ontology (IDO) 25 top level mid-level Basic Formal Ontology (BFO) Information Artifact Ontology (IAO) Ontology for Biomedical Investigations (OBI) Anatomy Ontology (FMA*, CARO) Cell Ontology (CL) domain level Cellular Component Ontology (FMA*, GO*) Environment Ontology (EnvO) Subcellular Anatomy Ontology (SAO) Sequence Ontology (SO*) Protein Ontology (PRO*) Ontology of General Medical Science (OGMS) Infectious Disease Ontology (IDO*) Phenotypic Quality Ontology (PaTO) Biological Process Ontology (GO*) Molecular Function (GO*) OBO Foundry Modular Organization 26 OBI The Ontology for Biomedical Investigations hfp://purl.org/obo/OBI_0000225 27 Purpose of OBI To provide a resource for the unambiguous description of the components of biomedical investigations such as the design, protocols and instrumentation, material, data and types of analysis and statistical tools applied to the data NOT designed to model biology 28 OBI Collaborating Communities Crop sciences Generation Challenge Programme (GCP), Environmental genomics MGED RSBI Group, www.mged.org/Workgroups/rsbi Genomic Standards Consortium (GSC), www.genomics.ceh.ac.uk/genomecatalogue HUPO Proteomics Standards Initiative (PSI), psidev.sourceforge.net Immunology Database and Analysis Portal, www.immport.org Immune Epitope Database and Analysis Resource (IEDB), http://www.immuneepitope.org/home.do International Society for Analytical Cytology, http://www.isac-net.org/ Metabolomics Standards Initiative (MSI), Neurogenetics, Biomedical Informatics Research Network (BIRN), Nutrigenomics MGED RSBI Group, www.mged.org/Workgroups/rsbi Polymorphism Toxicogenomics MGED RSBI Group, www.mged.org/Workgroups/rsbi Transcriptomics MGED Ontology Group 29 30 31 32 33 Ontology for General Medical Science http://code.google.com/p/ogms/ (OBO) http://purl.obolibrary.org/obo/ogms.obo (OWL) http://purl.obolibrary.org/obo/ogms.owl 34 OGMS-based initiatives Vital Signs Ontology (VSO) (Welch Allyn) EHR / Demographics Ontology Infectious Disease Ontology Mental Health Ontology Emotion Ontology 35 Ontology for General Medical Science Jobst Landgrebe (then Co-Chair of the HL7 Vocabulary Group): “the best ontology effort in the whole biomedical domain by far” 36 EXPERIMENTAL ARTIFACTS Ontology for Biomedical Investigations (OBI) CLINICAL MEDICINE Ontology of General Medical Science (OGMS) INFORMATION ARTIFACTS Information Artifact Ontology (IAO) How to keep clear about the distinction • processes of observation, • results of such processes (measurement data) • the entities observed 37 How is the OBO Foundry organized? • Top-Level: Basic Formal Ontology (BFO) • Mid-Level: IAO, OBI, OGMS ... • Domain-Level: Foundry Bio-Ontologies 38 top level mid-level Basic Formal Ontology (BFO) Information Artifact Ontology (IAO) Ontology for Biomedical Investigations (OBI) Anatomy Ontology (FMA*, CARO) Cell Ontology (CL) domain level Cellular Component Ontology (FMA*, GO*) Environment Ontology (EnvO) Subcellular Anatomy Ontology (SAO) Sequence Ontology (SO*) Protein Ontology (PRO*) Ontology of General Medical Science (OGMS) Infectious Disease Ontology (IDO*) Phenotypic Quality Ontology (PaTO) Biological Process Ontology (GO*) Molecular Function (GO*) OBO Foundry Modular Organization 39 BFO: the very top Continuant Independent Continuant Occurrent (Process, Event) Dependent Continuant 40 RELATION TO TIME CONTINUANT INDEPENDENT OCCURRENT DEPENDENT GRANULARITY ORGAN AND ORGANISM Organism (NCBI Taxonomy) CELL AND CELLULAR COMPONENT Cell (CL) MOLECULE Anatomical Organ Entity Function (FMA, (FMP, CPRO) Phenotypic CARO) Quality (PaTO) Cellular Cellular Component Function (FMA, GO) (GO) Molecule (ChEBI, SO, RnaO, PrO) Molecular Function (GO) Biological Process (GO) Molecular Process (GO) 41 RELATION TO TIME GRANULARITY CONTINUANT INDEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy) CELL AND CELLULAR COMPONENT Cell (CL) MOLECULE DEPENDENT Anatomical Organ Entity Function (FMA, (FMP, CPRO) Phenotypic CARO) Quality (PaTO) Cellular Cellular Component Function (FMA, GO) (GO) Molecule (ChEBI, SO, RnaO, PrO) OCCURRENT Molecular Function (GO) obofoundry.org Organism-Level Process (GO) Cellular Process (GO) Molecular Process (GO) 42 BFO & GO continuant independent continuant dependent continuant cellular component molecular function occurrent biological processes 43 Basic Formal Ontology types Continuant Independent Continuant Dependent Continuant thing quality Occurrent process, event .... ..... ....... instances 44 Experience with BFO in building ontologies provides • a community of skilled ontology developers and users (user group has 120 members) • associated logical tools • documentation for different types of users • a methodology for building conformant ontologies by starting with BFO and populating downwards 45 Example: The Cell Ontology How to build an ontology import BFO into ontology editor such as Protégé work with domain experts to create an initial midlevel classification find ~50 most commonly used terms corresponding to types in reality arrange these terms into an informal is_a hierarchy according to this universality principle A is_a B every instance of A is an instance of B fill in missing terms to give a complete hierarchy (leave it to domain experts to populate the lower levels of the hierarchy) 47 Users of BFO PharmaOntology (W3C HCLS SIG) MediCognos / Microsoft Healthvault Cleveland Clinic Semantic Database in Cardiothoracic Surgery Major Histocompatibility Complex (MHC) Ontology (NIAID) Neuroscience Information Framework Standard (NIFSTD) and Constituent Ontologies Interdisciplinary Prostate Ontology (IPO) Nanoparticle Ontology (NPO): Ontology for Cancer Nanotechnology Research Neural Electromagnetic Ontologies (NEMO) ChemAxiom – Ontology for Chemistry 49 :. Users of BFO GO Gene Ontology CL Cell Ontology SO Sequence Ontology ChEBI Chemical Ontology PATO Phenotype (Quality) Ontology FMA Foundational Model of Anatomy Ontology ChEBI Chemical Entities of Biological Interest PRO Protein Ontology Plant Ontology Environment Ontology Ontology for Biomedical Investigations RNA Ontology :. 50 Users of BFO Ontology for Risks Against Patient Safety (RAPS/REMINE) eagle-i an VIVO (NCRR) IDO Infectious Disease Ontology (NIAID) National Cancer Institute Biomedical Grid Terminology (BiomedGT) US Army Biometrics Ontology US Army Command and Control Ontology Sleep Domain Ontology Subcellular Anatomy Ontology (SAO) Translaftional Medicine On (VO) Yeast Ontology (yOWL) Zebrafish Anatomical Ontology (ZAO) 51 :. Basic Formal Ontology continuant independent continuant occurrent dependent continuant organism 54 Continuants • continue to exist through time, preserving their identity while undergoing different sorts of changes • independent continuants – objects, things, ... • dependent continuants – qualities, attributes, shapes, potentialities ... 55 Occurrents • processes, events, happenings – your life – this process of accelerated cell division 56 Qualities temperature blood pressure mass ... are continuants they exist through time while undergoing changes 57 Qualities temperature / blood pressure / mass ... are dimensions of variation within the structure of the entity a quality is something which can change while its bearer remains one and the same 58 A Chart representing how John’s temperature changes 59 A Chart representing how John’s temperature changes 60 BFO: The Very Top continuant independent continuant occurrent dependent continuant quality temperature 62 Blinding Flash of the Obvious independent continuant dependent continuant quality organism John temperature John’s temperature types instances 63 Blinding Flash of the Obvious independent continuant dependent continuant quality organism John temperature John’s temperature types instances 64 Blinding Flash of the Obvious inheres_in organism John temperature John’s temperature types instances 65 types temperature 37ºC instantiates at t1 37.1ºC instantiates at t2 37.2ºC instantiates at t3 37.3ºC instantiates at t4 37.4ºC instantiates at t5 37.5ºC instantiates at t6 John’s temperature instances 66 types human embryo instantiates at t1 fetus instantiates at t2 neonate instantiates at t3 infant child instantiates at t4 instantiates at t5 adult instantiates at t6 John instances 67 Temperature subtypes Development-stage subtypes are threshold divisions (hence we do not have sharp boundaries, and we have a certain degree of choice, e.g. in how many subtypes to distinguish, though not in their ordering) 68 independent continuant dependent continuant quality organism John temperature types John’s temperature instances 69 independent continuant organism John dependent continuant occurrent quality process temperature John’s temperature course of temperature changes John’s temperature history 70 independent continuant organism John dependent continuant occurrent quality process temperature John’s temperature life of an organism John’s life 71 BFO: The Very Top continuant independent continuant occurrent dependent continuant quality disposition 72 BFO: The Very Top continuant independent continuant occurrent dependent continuant quality function role disposition 73 disposition - of of of of a glass vase, to shatter if dropped a human, to eat a banana, to ripen John, to lose hair 74 disposition if it ceases to exist, then its bearer and/or its immediate surrounding environment is physically changed its realization occurs when its bearer is in some special physical circumstances its realization is what it is in virtue of the bearer’s physical make-up 75 independent continuant eye John’s eye dependent continuant occurrent function process to see process of seeing function of John’s eye: to see John seeing 80 OGMS Ontology for General Medical Science http://code.google.com/p/ogms 88 R T U New York State Center of Excellence in Bioinformatics & Life Sciences Ontology of General Medical Science (OGMS) • ontology for the representation of – diseases, signs, symptoms – clinical processes – diagnosis, treatment and outcomes • fundamental idea: – a disease is a disposition rooted in some (physical) disorder in the organism 89 R T U New York State Center of Excellence in Bioinformatics & Life Sciences Motivation • Clarity about: – disease etiology and progression – disease and the diagnostic process – phenotype and signs/symptoms – entities in reality and observations of sucn entities 90 Physical Disorder 91 Physical Disorder – independent continuant fiat object part A causally linked combination of physical components of the extended organism that is clinically abnormal. 92 :. Clinically abnormal – (1) not part of the life plan for an organism of the relevant type (unlike aging or pregnancy), – (2) causally linked to an elevated risk either of pain or other feelings of illness, or of death or dysfunction, and – (3) such that the elevated risk exceeds a certain threshold level.* *Compare: baldness 93 Big Picture 94 Pathological Process =def. A bodily process that is a manifestation of a disorder and is clinically abnormal. Disease =def. – A disposition to undergo pathological processes that exists in an organism because of one or more disorders in that organism. 95 Cirrhosis - environmental exposure • Etiological process - phenobarbitol-induced hepatic cell death – produces • Disorder - necrotic liver – bears • Disposition (disease) - cirrhosis – realized_in • Pathological process - abnormal tissue repair with cell proliferation and fibrosis that exceed a certain threshold; hypoxia-induced cell death – produces • Abnormal bodily features – recognized_as • Symptoms - fatigue, anorexia • Signs - jaundice, enlarged spleen 96 Dispositions and Predispositions All diseases are dispositions; not all dispositions are diseases. Predisposition to Disease =def. – A disposition in an organism that constitutes an increased risk of the organism’s subsequently developing some disease. 97 HNPCC - genetic pre-disposition • Etiological process - inheritance of a mutant mismatch repair gene – produces • Disorder - chromosome 3 with abnormal hMLH1 – bears • Disposition (disease) - Lynch syndrome – realized_in • Pathological process - abnormal repair of DNA mismatches – produces • Disorder - mutations in proto-oncogenes and tumor suppressor genes with microsatellite repeats (e.g. TGF-beta R2) – bears • Disposition (disease) - non-polyposis colon cancer – realized in • Symptoms (including pain) 98 Huntington’s Disease - genetic • • • • • • • Etiological process - inheritance of >39 CAG repeats in the HTT gene – produces Disorder - chromosome 4 with abnormal mHTT – bears Disposition (disease) - Huntington’s disease – realized_in Pathological process - accumulation of mHTT protein fragments, abnormal transcription regulation, neuronal cell death in striatum – produces Abnormal bodily features – recognized_as Symptoms - anxiety, depression Signs - difficulties in speaking and swallowing Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out Huntington’s suggests Laboratory tests produces Test results - molecular detection of the HTT gene with >39CAG repeats used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease Huntington’s disease 99 HNPCC - genetic pre-disposition • Etiological process - inheritance of a mutant mismatch repair gene – produces • Disorder - chromosome 3 with abnormal hMLH1 – bears • Disposition (disease) - Lynch syndrome – realized_in • Pathological process - abnormal repair of DNA mismatches – produces • Disorder - mutations in proto-oncogenes and tumor suppressor genes with microsatellite repeats (e.g. TGF-beta R2) – bears • Disposition (disease) - non-polyposis colon cancer 100 Cirrhosis - environmental exposure • • • • • • • Etiological process - phenobarbitolinduced hepatic cell death – produces Disorder - necrotic liver – bears Disposition (disease) - cirrhosis – realized_in Pathological process - abnormal tissue repair with cell proliferation and fibrosis that exceed a certain threshold; hypoxia-induced cell death – produces Abnormal bodily features – recognized_as Symptoms - fatigue, anorexia Signs - jaundice, splenomegaly Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out cirrhosis suggests Laboratory tests produces Test results - elevated liver enzymes in serum used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease cirrhosis 101 Systemic arterial hypertension • • • • • • • Etiological process – abnormal reabsorption of NaCl by the kidney – produces Disorder – abnormally large scattered molecular aggregate of salt in the blood – bears Disposition (disease) - hypertension – realized_in Pathological process – exertion of abnormal pressure against arterial wall – produces Abnormal bodily features – recognized_as Symptoms - headaches, dizziness Signs – elevated blood pressure Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out hypertension suggests Laboratory tests produces Test results used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease hypertension 102 Type 2 Diabetes Mellitus • • • • • • • Etiological process – – produces Disorder – abnormal pancreatic beta cells and abnormal muscle/fat cells – bears Disposition (disease) – diabetes mellitus – realized_in Pathological processes – diminished insulin production , diminished muscle/fat uptake of glucose – produces Abnormal bodily features – recognized_as Symptoms – polydipsia, polyuria, polyphagia, blurred vision Signs – elevated blood glucose and hemoglobin A1c Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out diabetes mellitus suggests Laboratory tests – fasting serum blood glucose, oral glucose challenge test, and/or blood hemoglobin A1c produces Test results used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease type 2 diabetes mellitus 103 Type 1 hypersensitivity to penicillin • • • • • • • Etiological process – sensitizing of mast cells and basophils during exposure to penicillin-class substance – produces Disorder – mast cells and basophils with epitope-specific IgE bound to Fc epsilon receptor I – bears Disposition (disease) – type I hypersensitivity – realized_in Pathological process – type I hypersensitivity reaction – produces Abnormal bodily features – recognized_as Symptoms – pruritis, shortness of breath Signs – rash, urticaria, anaphylaxis Symptoms & Signs used_in Interpretive process produces Hypothesis suggests Laboratory tests – produces Test results – occasionally, skin testing used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease type 1 hypersensitivity to penicillin 104 105 Disease vs. Disease course Disease =def. – A disposition to undergo pathological processes that exists in an organism because of one or more disorders in that organism. Disease course =def. – The aggregate of processes in which a disease disposition is realized. 106 coronary heart disease disease associated with early lesions and small fibrous plaques instantiates at t1 disease associated with asymptomatic (‘silent’) infarction instantiates at t2 disease associated with surface disruption of plaque instantiates at t3 unstable angina instantiates at t4 stable angina instantiates at t5 John’s coronary heart disease time 107 independent continuant disorder John’s disordered heart dependent continuant occurrent disposition process disease course of disease John’s coronary heart disease course of John’s disease 108 Examples of ontology terms Independent Continuant Dependent Continuant Occurrent OGMS IDO Disorder Infectious disorder Disease Infectious disease Predisposition to disease Protective resistance Disease course Infectious disease course IDO (Infectious Disease Ontology) Core Follows GO strategy of providing a canonical ontology of what is involved in every infectious disease – host, pathogen, vector, virulence, vaccine, transmission – accompanied by IDO Extensions for specific diseases, pathogens and vectors Provides common terminology resources and tested common guidelines for a vast array of different disease communities 110 Infectious Disease Ontology Consortium • MITRE, Mount Sinai, UTSouthwestern – Influenza • IMBB/VectorBase – Vector borne diseases (A. gambiae, A. aegypti, I. scapularis, C. pipiens, P. humanus) • Colorado State University – Dengue Fever • Duke University – Tuberculosis, Staph. aureus • Cleveland Clinic – Infective Endocarditis • University of Michigan – Brucellosis • Duke University, University at Buffalo – HIV 111 Influenza - infectious • Etiological process - infection of airway epithelial cells with influenza virus – produces • Disorder - viable cells with influenza virus – bears • Disposition (disease) - flu – realized_in • Pathological process - acute inflammation – produces • Abnormal bodily features – recognized_as • Symptoms - weakness, dizziness • Signs - fever 112 Influenza – disease course • Etiological process - infection of airway epithelial cells with influenza virus – produces • Disorder - viable cells with influenza virus – bears • Disposition (disease) - flu – realized_in • Pathological process - The acutedisorder inflammation also induces normal – produces physiological processes (immune • Abnormal bodily features response) that can results in the – recognized_as elimination of the disorder (transient • Symptoms - weakness, dizziness disease course). • Signs - fever 113 Big Picture 114