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What is an ontology? Barry Smith http://ontology.buffalo.edu/smith 1 You’re interested in which genes control heart muscle development 17,536 results 2 time Defense response Immune response Response to stimulus Toll regulated genes JAK-STAT regulated genes Microarray data shows changed expression of thousands of genes. Puparial adhesion Molting cycle hemocyanin Amino acid catabolism Lipid metobolism How will you spot the patterns? Peptidase activity Protein catabloism Immune response Immune response Toll regulated genes attacked control Tree: pearson Coloredby: by: arson lw n3d ... lw n3d ... Colored Copy of Copy C5_RMA Copy ofofCopy of(Defa... C5_RMA (Defa... 3 Lab / pathology data EHR data Clinical trial data Family history data Medical image data Microarray data Model organism data Flow cytometry Mass spec Genotype / SNP data How will you find the data you need? 4 − − − − − − Human Mouse Rat Fish Yeast E. coli How will you find the compare the data? How will you integrate the data 5 The GO Idea GlyProt MouseEcotope sphingolipid transporter activity DiabetInGene GluChem :. annotation using common ontologies yields integration of databases GlyProt MouseEcotope Holliday junction helicase complex DiabetInGene GluChem :. ontologies are legends for data 8 they provide a growing set of natural language labels to make the data cognitively accessible to human beings and algorithmically accessible to reasoning systems 9 compare: legends for maps compare: legends for maps 10 legends for textbook diagrams :. ontologies as legends for images :. 13 what lesion ? what brain function ? 14 legends for literature 15 ontologies as legends for mathematical equations xi = vector of measurements of gene i k = the state of the gene ( as “on” or “off”) θi = set of parameters of the Gaussian model ... ... 16 17 Pathway diagrams as ontologically annotated dynamic cartoons 18 two kinds of annotations 19 names of instances 20 names of types 21 Ontologies are representations of types 22 ... types which are instantiated e.g. in the lab or clinic 23 multiple kinds of relations between represented types provide a tool for algorithmic reasoning 24 Gene Ontology: The Very Top cellular component molecular function biological process 25 Gene Ontology: The Very Top continuant cellular component molecular function occurrent biological process 26 BFO: The Very Top continuant independent continuant dependent continuant cellular component molecular function occurrent biological processes 27 Basic Formal Ontology continuant independent continuant occurrent dependent continuant organism 28 Basic Formal Ontology continuant independent continuant occurrent dependent continuant anatomical structure 29 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 ... 30 Qualities temperature blood pressure mass ... are continuants they exist through time while undergoing changes 31 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 32 A Chart representing how John’s temperature changes 34 John’s temperature the temperature he has throughout his entire life, cycles through different determinate temperatures from one time to the next John’s temperature is a physiology variable which, in thus changing, exerts an influence on other physiology variables through time 35 BFO: The Very Top continuant independent continuant occurrent dependent continuant quality temperature 36 Blinding Flash of the Obvious independent continuant dependent continuant quality organism John temperature John’s temperature types instances 37 Blinding Flash of the Obvious independent continuant dependent continuant quality organism John temperature John’s temperature types instances 38 Blinding Flash of the Obvious inheres_in organism John temperature John’s temperature types instances 39 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 40 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 41 • lower lever of types does not ‘carry identity’ in OntoClean terms • 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) 42 independent continuant dependent continuant quality organism John temperature types John’s temperature instances 43 independent continuant organism John dependent continuant occurrent quality process temperature John’s temperature course of temperature changes John’s temperature history 44 independent continuant organism John dependent continuant occurrent quality process temperature John’s temperature life of an organism John’s life 45 BFO/GO: The Very Top continuant independent continuant dependent continuant cellular component molecular function occurrent biological processes 46 BFO: The Very Top continuant independent continuant occurrent dependent continuant quality function role disposition 47 Function - of of of of of liver: to store glycogen birth canal: to enable transport eye: to see mitochondrion: to produce ATP liver: to store glycogen not optional; reflection of physical makeup of bearer; can malfunction 48 :. Role optional: exists because the bearer is in some special natural, social, or institutional set of circumstances in which the bearer does not have to be 49 :. Role - bearers can have more than one role person as student / as staff member - roles often form systems of mutual dependence husband / wife first in queue / last in queue doctor / patient host / pathogen :. 50 Role of some chemical compound: to serve as analyte in an experiment of a dose of penicillin in this human child: to treat a disease of this bacteria in a primary host: to cause infection 51 :. Qualities are categorical features of reality – you just have them Functions, roles and dispositions are potential featires of reality: they are realizable dependent continuants, realized in certain associated processes 52 :. independent continuant portion of chemical compound this portion of aspirin dependent continuant occurrent role process drug role process of drug adminstration role of this portion of aspirin John’s taking this portion of aspirin 53 independent continuant portion of chemical compound dependent continuant occurrent role process drug role process of drug adminstration inheres_in realized_in this portion of aspirin role of this portion of aspirin John’s taking this portion of aspirin 54 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) The Open Biomedical Ontologies (OBO) Foundry 55 • The Road to Convergence All ontologies for each given domain (anatomy, chemistry…) should be part of a single suite of interoperable ontologies should use a common top-level core for subdomains with many variants, should follow the strategy of canonical ontologies with extensions should require acceptance of common, tested guidelines on all subscribing ontology developers 56 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) initial OBO Foundry coverage, ontologies automatically semantically coupled 57 Disposition (InternallyGrounded Realizable Entity) disposition =def. a realizable entity which if it ceases to exist, then its bearer is physically changed, and whose realization occurs when this bearer is in some special physical circumstances, in virtue of the bearer’s physical make-up 58 Function • A Disposition (Internally-Grounded Realizable Entity) that is designed or selected for 59 OGMS • Ontology for General Medical Science http://code.google.com/p/ogms 60 Physical Disorder – independent continuant fiat object part 61 :. Big Picture 62 A disease is a disposition rooted in a physical disorder in the organism and realized in pathological processes. produces etiological process bears disorder realized_in disposition pathological process produces diagnosis interpretive process produces signs & symptoms used_in abnormal bodily features recognized_as 63 Elucidation of Primitive Terms • ‘bodily feature’ - an abbreviation for a physical component, a bodily quality, or a bodily process. • disposition - an attribute describing the propensity to initiate certain specific sorts of processes when certain conditions are satisfied. • clinically abnormal - some bodily feature that – (1) is not part of the life plan for an organism of the relevant type (unlike aging or pregnancy), – (2) is causally linked to an elevated risk either of pain or other feelings of illness, or of death or dysfunction, and – (3) is such that the elevated risk exceeds a certain threshold level.* *Compare: baldness 64 Definitions - Foundational Terms • Disorder =def. – A causally linked combination of physical components that is clinically abnormal. • Pathological Process =def. – A bodily process that is a manifestation of a disorder and is clinically abnormal. • Disease =def. – A disposition (i) to undergo pathological processes that (ii) exists in an organism because of one or more disorders in that organism. 65 Dispositions and Predispositions • All diseases are dispositions; not all dispositions are diseases. • A predisposition is a disposition. • Predisposition to Disease of Type X =def. – A disposition in an organism that constitutes an increased risk of the organism’s subsequently developing the disease X. • HNPCC is caused by a – disorder (mutation) in a DNA mismatch repair gene that – disposes to the acquisition of additional mutations from defective DNA repair processes, and thus is a – predisposition to the development of colon cancer. 66 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 67 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 Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out influenza suggests Laboratory tests produces Test results - elevated serum antibody titers used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease flu But the disorder also induces normal physiological processes (immune response) that can results in the elimination of the 68 disorder (transient disease course). 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 69 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) 70 The OBO Foundry Initiative 71 A good solution to the data integration problem must be: • modular • incremental • bottom-up • evidence-based • revisable • incorporate a strategy for motivating potential developers and users 72 GO is amazingly successful – but covers only three sorts of biological entities: – cellular components – molecular functions – biological processes and does not provide representations of disease-related phenomena 73 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) The Open Biomedical Ontologies (OBO) Foundry 74 OBO Foundry provides • tested guidelines enabling new groups to develop the ontologies they need in ways which counteract forking and dispersion of effort • an incremental bottoms-up approach to evidence-based terminology practices in medicine that is rooted in basic biology • automatic web-based linkage between medical terminologies and biological knowledge resources • traffic laws and traffic police 75 the strategy establish common rules governing best practices for creating ontologies in coordinated fashion, with an evidencebased pathway to incremental improvement 76 The methodology of cross-products compound terms in ontologies to be defined as cross-products of simpler terms: E.g elevated blood glucose is a cross-product of PATO: increased concentration with FMA: blood and CheBI: glucose. = factoring out of ontologies into disciplinespecific modules (orthogonality) 77 The methodology of cross-products enforcing use of common relations in linking terms drawn from Foundry ontologies serves • to ensure that the ontologies are maintained and revised in tandem • logically defined relations serve to bind terms in different ontologies together to create a network 78 CRITERIA CRITERIA opennness common formal language. collaborative development evidence-based maintenance identifiers versioning textual and formal definitions 79 Orthogonality = modularity • one ontology for each domain • no need for mappings (which are in any case too expensive, too fragile, too difficult to keep up-to-date as mapped ontologies change) • everyone knows where to look to find out how to annotate each kind of data 80 Ontologies and research groups using BFO and RO – OBO Foundry (60 biomedical ontologies, including GO, OBI, Protein Ontology, Cell Ontology, IDO … – National Cancer Institute (BiomedGT) – NIF (NIH Neuroscience Information Framework) – Cleveland Clinic Semantic Database – Siemens – AstraZeneca – EU (ACGT Cancer Ontology, RAPS, …) 81 Because the ontologies in the Foundry are built as orthogonal modules which form an incrementally evolving network • scientists are motivated to commit to developing ontologies because they will need in their own work ontologies that fit into this network • users are motivated by the assurance that the ontologies they turn to are maintained by experts 82 More benefits of orthogonality • helps those new to ontology to find what they need • to find models of good practice • ensures mutual consistency of ontologies (trivially) • and thereby ensures additivity of annotations 83 More benefits of orthogonality • it rules out the sorts of simplification and partiality which may be acceptable under more pluralistic regimes • thereby brings an obligation on the part of ontology developers to commit to scientific accuracy and domain-completeness 84 More criteria of a successful standard 1. intelligibility to users, consistent use of terms like ‘term’, ‘class’, ‘entity’, ‘object’ …) 2. track record of lessons learned (GO has 10 years of hard user testing) 3. lots of existing users (ontologies are like telephone networks) 85 COMMON ARCHITECTURE The ontology uses relations which are unambiguously defined following the pattern of definitions laid down in the Basic Formal Ontology (BFO) including the Relation Ontology (RO) http://ifomis.org/bfo http://www.obofoundry.org/ro/ 86 top level mid-level Basic Formal Ontology (BFO) Anatomy Ontology (FMA*, CARO) Cell Ontology (CL) domain level Ontology for Biomedical Investigations (OBI) Information Artifact Ontology (IAO) Cellular Component Ontology (FMA*, GO*) Environment Ontology (EnvO) Subcellular Anatomy Ontology (SAO) Sequence Ontology (SO*) Protein Ontology (PRO*) Spatial Ontology (BSPO) Infectious Disease Ontology (IDO*) Phenotypic Quality Ontology (PaTO) Biological Process Ontology (GO*) Molecular Function (GO*) OBO Foundry Modular Organization 87 BFO:continuant continuant independent continuant portion of material object fiat object part object aggregate object boundary dependent continuant site generically dependent continuant information artifact spatial region specifically dependent continuant quality realizable entity 0D-region 1D-region 2D-region function 3D-region role disposition BFO:occurrent occurrent processual entity process spatiotemporal region scattered spatiotemporal region connected spatiotemporal region temporal region scattered temporal region connected temporal region fiat process part spatiotemporal instant temporal instant process aggregate spatiotemporal interval temporal interval process boundary processual context Example: The Cell Ontology top level mid-level Basic Formal Ontology (BFO) Anatomy Ontology (FMA*, CARO) Cell Ontology (CL) domain level Ontology for Biomedical Investigations (OBI) Information Artifact Ontology (IAO) Cellular Component Ontology (FMA*, GO*) Environment Ontology (EnvO) Subcellular Anatomy Ontology (SAO) Sequence Ontology (SO*) Protein Ontology (PRO*) Spatial Ontology (BSPO) Infectious Disease Ontology (IDO*) Phenotypic Quality Ontology (PaTO) Biological Process Ontology (GO*) Molecular Function (GO*) OBO Foundry Modular Organization 91