BFO and Ontology Design Principles Barry Smith 1

How is the OBO Foundry organized? Top-Level: Basic Formal Ontology (BFO) Mid-Level: IAO, OBI, OGMS... Domain-Level: Foundry Bio-Ontologies

Anatomy Ontology (FMA*, CARO) Environment Ontology (EnvO) Infectious Disease Ontology (IDO*) Biological Process Ontology (GO*) Cell Ontology (CL) Cellular Component Ontology (FMA*, GO*) Phenotypic Quality Ontology (PaTO) Subcellular Anatomy Ontology (SAO) Sequence Ontology (SO*) Molecular Function (GO*) Protein Ontology (PRO*) OBO Foundry Modular Organization 3 top level mid-level domain level Information Artifact Ontology (IAO) Ontology for Biomedical Investigations (OBI) Ontology of General Medical Science (OGMS) Basic Formal Ontology (BFO)

BFO: the very top Continuant Occurrent (Process, Event) Independent Continuant Dependent Continuant

5 RELATION TO TIME GRANULARITY CONTINUANTOCCURRENT INDEPENDENTDEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy) Anatomical Entity (FMA, CARO) Organ Function (FMP, CPRO) Phenotypic Quality (PaTO) Biological Process (GO) CELL AND CELLULAR COMPONENT Cell (CL) Cellular Component (FMA, GO) Cellular Function (GO) MOLECULE Molecule (ChEBI, SO, RnaO, PrO) Molecular Function (GO) Molecular Process (GO)

CONTINUANTOCCURRENT INDEPENDENTDEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy) Anatomical Entity (FMA, CARO) Organ Function (FMP, CPRO) Phenotypic Quality (PaTO) Organism-Level Process (GO) CELL AND CELLULAR COMPONENT Cell (CL) Cellular Component (FMA, GO) Cellular Function (GO) Cellular Process (GO) MOLECULE Molecule (ChEBI, SO, RnaO, PrO) Molecular Function (GO) Molecular Process (GO) obofoundry.org GRANULARITY RELATION TO TIME

BFO & GO continuant occurrent biological processes independent continuant cellular component dependent continuant molecular function

Basic Formal Ontology Continuant Occurrent process, event Independent Continuant thing Dependent Continuant quality types instances

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

Example: The Cell Ontology

11 How to build an ontology import BFO into ontology editor work with domain experts to create an initial mid- level 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)

The Road to Convergence All ontologies for each given domain (biology, physics, Army operations …) should be part of a single suite of interoperable ontologies should use a common top-level core should require acceptance of common, tested guidelines and common training and governance from all subscribing ontology developers 12

:. 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 13

:. 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 14

:. 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) 15

:. DOLCE, SUMO, Cyc DOLCE: (Largely) extends BFO, but built to support ‘linguistic and cognitive engineering’ SUMO: No dependent continuants (so: no diabetes, no temperature instances); SUMO has its own tiny biology (‘body- covering’, ‘fruit-Or-vegetable’) 16

:. Cyc:ConceivingSomething_BiologicalReproduct ionEvent =def a collection of events; a sub- collection of BiologicalReproductionEvent. In each conceivingSomething_BiologicalReproduction Event, someone becomes pregnant. Cyc:The immaculate conception =def. The ConceivingSomething_BiologicalReproductionEvent in which Mary_MotherOfJesus was conceived. Catholic dogma holds that Mary (unlike Jesus) was conceived by conventional biological means, but that GodOfAbrahamIsaacAndJacob interceded at the time of her conception to keep her free from the stain of original sin, or ‘immaculate’. 17

Basic Formal Ontology continuant occurrent independent continuant dependent continuant organism 18

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... 19

Occurrents processes, events, happenings –your life –this process of accelerated cell division 20

Qualities temperature blood pressure mass... are continuants they exist through time while undergoing changes 21

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 22

A Chart representing how John’s temperature changes 23

A Chart representing how John’s temperature changes 24

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 25

BFO: The Very Top continuant independent continuant dependent continuant quality occurrent temperature 26

Blinding Flash of the Obvious independent continuant dependent continuant quality temperature types instances organism John John’s temperature 27

Blinding Flash of the Obvious independent continuant dependent continuant quality temperature types instances organism John John’s temperature 28

Blinding Flash of the Obvious temperature types instances organism John John’s temperature. 29 inheres_in

temperature types instances John’s temperature 30 37ºC37.1ºC37.5ºC37.2ºC37.3ºC37.4ºC instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 instantiates at t 6

human types instances John 31 embryofetusadultneonateinfantchild instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 instantiates at t 6

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) 32

independent continuant dependent continuant quality temperature types instances organism John John’s temperature 33

independent continuant dependent continuant quality temperature organism John John’s temperature occurrent process course of temperature changes John’s temperature history 34

independent continuant dependent continuant quality temperature organism John John’s temperature occurrent process life of an organism John’s life 35

BFO: The Very Top continuantoccurrent independent continuant dependent continuant qualitydisposition 36

BFO: The Very Top continuant independent continuant dependent continuant quality function role disposition occurrent

disposition - of a glass vase, to shatter if dropped - of a human, to eat - of a banana, to ripen - of John, to lose hair 38

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 39

function - of liver: to store glycogen - of birth canal: to enable transport - of eye: to see - of mitochondrion: to produce ATP not optional; reflection of physical makeup of bearer

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

role - bearers can have more than one role person as student and staff member - roles often form systems of mutual dependence husband / wife first in queue / last in queue doctor / patient host / pathogen

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

independent continuant dependent continuant function to see eye John’s eye function of John’s eye: to see occurrent process process of seeing John seeing 44

New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U Particulars and Universals methis walking my left leg this leg moving to make me walk human being living creature walkingleg moving leg function process Instance-of at t Instance-of at t Instance-of at t Instance-of 1

New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U instanceOf at t 2 instanceOf at t 1 instanceOf at t 2 The importance of temporal indexing #1’s stomach benign tumor instanceOf at t 1 #4 malignant tumor partOf at t 1 stomach partOf at t 2

New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U Continuants and Occurrents methis walking my left leg this leg moving to make me walk human being living creature walkingleg moving leg function process Instance-of at t Instance-of at t Instance-of at t Instance-of 2

New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U Independent versus dependent Independent entities Do not require any other entity to exist to enable their own existence Dependent entities Require the existence of some other entity for their existence methis walking my left leg this leg moving to make me walk Independent continuants Dependent continuants Occurrents (are all dependent) 3

New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U Dependent continuants Realized –Quality:redness (of blood) Realizable –Function:to flex (of knee joint) –Role:student –Power:boss –Disposition:brittleness (of a bone) Realizations flexing studying ordering breaking continuantsoccurrents 3

New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U Relation Ontology Continuant Occurrent process, event Independent Continuant ~ thing Dependent Continuant universals particulars has_participant inheres_in instance_of (at t) isa

New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U tt t instanceOf The essential pieces material object spacetime region me some temporal region my life my 4D STR some spatial region course spatial region temporal region dependent continuant some quality located-in at t at t participantOf at toccupies projectsOn projectsOn at t

OGMS Ontology for General Medical Science 52

New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U 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 Ontology of General Medical Science (OGMS)

New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U Motivation Clarity about: –disease etiology and progression –disease and the diagnostic process –phenotype and signs/symptoms –entities in reality and observations of sucn entities

55 Physical Disorder

:. Physical Disorder – independent continuant fiat object part A causally linked combination of physical components of the extended organism that is clinically abnormal. 56

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 57

Big Picture 58

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. 59

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 60

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 61

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. 62

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) 63

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 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

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

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, 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

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

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

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

71

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. 72

coronary heart disease John’s coronary heart disease 73 asymptomatic (‘silent’) infarction early lesions and small fibrous plaques stable angina surface disruption of plaque unstable angina instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 time

independent continuant dependent continuant disposition disease disorder John’s disordered heart John’s coronary heart disease occurrent process course of disease course of John’s disease 74