BFO, SNOMED and Disease Barry Smith IHTSDO, Bethesda, October 8,

2 with acknowledgements to NLM: 1R21LM A1

3 infectious agent is_a navigational concept with acknowledgements to NLM: 1R21LM A1

4 infectious agent is_a navigational concept

5 with acknowledgements to NLM: 1R21LM A1

6 with acknowledgements to NLM: 1R21LM A1

7 with acknowledgements to NLM: 1R21LM A1

8 with acknowledgements to NLM: 1R21LM A1

9

10 with acknowledgements to NLM: 1R21LM A1

General comments Problems with ‘concept’ (no real coherence as to what SNOMED is representing) Mixing of singulars and plurals Confusion of disorder (continuants) with etiological and diagnostic processes (occurrents) and information entities (‘findings’) 11

Epistemology and Time (from Bill Hogan) According to SNOMED-CT User Guide (p. 42): Concepts in [the Clinical Finding] hierarchy represent the result of a clinical observation, assessment, or judgment, and include both normal and abnormal clinical states. So, does a date/time associated with a ‘finding’ refer to: –Date/time that the observation, assessment, or judgment occurred and thus the result was obtained –Date/time that the entity (that was found) began to exist –Date/time that entity (that was found) began to manifest in symptoms, signs, etc.

Epistemology and Combinatorial Explosion (from Bill Hogan) Epistaxis/nosebleed –Epistaxis (disorder) –Nosebleed/epistaxis symptom (finding) –On examination - epistaxis (disorder) –Has nosebleeds - epistaxis (disorder) –Evidence of recent epistaxis (finding)

Epistemology and Combinatorial Explosion Explosion (from Bill Hogan) Rash –Cutaneous eruption (morphologic abnormality), with synonym Rash –Eruption of skin (disorder), with synonym Rash –Complaining of a rash (finding) –On examination - a rash (finding) Dry skin –Dry skin (finding) –Complaining of dry skin (finding) –On examination - dry skin (finding) –Dry skin dermatitis (disorder)

Abscess (disorder) Abscess (morphologic abnormality) 15

BFO A simple top-level ontology to support information integration in scientific research No abstracta Nothing propositional No overlap with domain ontologies (for society, for information, …) – built by populating downwards 16

Basic Formal Ontology Continuant Occurrent (Process, Event) Independent Continuant Dependent Continuant 17

Benefits of coordination No need to reinvent the wheel Can profit from lessons learned through mistakes made by others Can more easily reuse what is made by others Can more easily inspect and criticize results of others’ work (PATO) Leads to innovations (e.g. Mireot) in strategies for combining ontologies 18

Users of BFO NCI BiomedGT SNOMED CT Ontology for General Medical Science (OGMS) ACGT Clinical Genomics Trials on Cancer – Master Ontology / Formbuilder (Case Report Forms for Cancer Clinical Trials) 19

Users of BFO MediCognos / Microsoft Healthvault Cleveland Clinic Semantic Database in Cardiothoracic Surgery Major Histocompatibility Complex (MHC) Ontology (NIAID) Neuroscience Information Framework Standard (NIFSTD) and Constituent Ontologies 20

Users of BFO Interdisciplinary Prostate Ontology (IPO) Nanoparticle Ontology (NPO): Ontology for Cancer Nanotechnology Research Neural Electromagnetic Ontologies (NEMO) ChemAxiom – Ontology for Chemistry Ontology for Risks Against Patient Safety (RAPS/REMINE) (EU FP7) IDO Infectious Disease Ontology (NIAID) 21

IDO 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 Case Western Reserve – Infective Endocarditis University of Michigan – Brucilosis 22

–GO Gene Ontology –CL Cell Ontology –SO Sequence Ontology –ChEBI Chemical Ontology –PATO Phenotype (Quality) Ontology –FMA Foundational Model of Anatomy –ChEBI Chemical Entities of Biological Interest –CARO Common Anatomy Reference Ontology –PRO Protein Ontology –Infectious Disease Ontology –Plant Ontology –Environment Ontology –Ontology for Biomedical Investigations –RNA Ontology The OBO Foundry 23

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) The Open Biomedical Ontologies (OBO) Foundry 24

RELATION TO TIME GRANULARITY CONTINUANTOCCURRENT INDEPENDENTDEPENDENT COMPLEX OF ORGANISMS Family, Community, Deme, Population Organ Function (FMP, CPRO) Population Phenotype Population Process ORGAN AND ORGANISM Organism (NCBI Taxonomy) (FMA, CARO) Phenotypic Quality (PaTO) Biological Process (GO) CELL AND CELLULAR COMPONENT Cell (CL) Cell Com- ponent (FMA, GO) Cellular Function (GO) MOLECULE Molecule (ChEBI, SO, RnaO, PrO) Molecular Function (GO) Molecular Process (GO) E N V I R O N M E N T 25

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) rationale of OBO Foundry coverage (homesteading principle) GRANULARITY RELATION TO TIME 26

BFO and the 3 Gene Ontologies (GO) Continuant Occurrent Independent Continuant Dependent Continuant cell component biological process molecular function Kumar A., Smith B, Borgelt C. Dependence relationships between Gene Ontology terms based on TIGR gene product annotations. CompuTerm 2004, Bada M, Hunter L. Enrichment of OBO Ontologies. J Biomed Inform Jul 26 27

OBO Foundry organized in terms of Basic Formal Ontology Each Foundry ontology can be seen as an extension of a single upper level ontology (BFO) either post hoc, as in the case of the GO or in virtue of creation ab initio via downward population from BFO 28

Example: The Cell Ontology

Continuant Independent Continuant Dependent Continuant Non-realizable Dependent Continuant (quality) Realizable Dependent Continuant (function, role, disposition) 30

Realizable dependent continuants plan function role disposition capability tendency continuants 31

Their realizations execution expression exercise realization application course occurrents 32

Continuant Independent Continuant Dependent Continuant Non-realizable Dependent Continuant (quality) Realizable Dependent Continuant (function, role, disposition) 33

realization depends_on realizable Continuant Occurrent Independent Continuant bearer Dependent Continuant disposition Process of realization

Specific Dependence on the instance level a depends_on b =def. a is necessarily such that if b ceases to exist than a ceases to exist on the type level A specifically_depends_on B =def. for every instance a of A, there is some instance b of B such that a depends_on b. 35

depends_on Continuant Occurrent process, event Independent Continuant thing Dependent Continuant quality temperature depends on bearer 36

Specifically dependent continuants the quality of whiteness of this cheese your role as lecturer the disposition of this patient to experience diarrhea 37

the particular case of redness (of a particular fly eye) the universal red instantiates an instance of an eye (in a particular fly) the universal eye instantiates depends_on 38

the particular case of redness (of a particular fly eye) red instantiates an instance of an eye (in a particular fly) eye instantiates depends on coloranatomical structure is_a 39

depends_on Continuant Occurrent process Independent Continuant thing Dependent Continuant quality temperature depends on bearer 40

Specifically Dependent Continuants Specifically Dependent Continuant Quality, Pattern Realizable Dependent Continuant if the bearer ceases to exist, then its quality, function, role ceases to exist the color of my skin the function of my heart to pump blood my weight 41

Generically Dependent Continuants Generically Dependent Continuant Information Object Gene Sequence if one bearer ceases to exist, then the entity can survive, because there are other bearers (copyability) the pdf file on my laptop the DNA (sequence) in this chromosome 42

Continuant Occurrent Independent Continuant Specifically Dependent Continuant Quality Disposition Functioning Function Generically Dependent Continuant Realizable Role Information Artifact Sequence…

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Realizable dependent continuants Role: nurse role, pathogen role, food role Disposition: fragility, virulence, susceptibility, genetic disposition to disease X Function: to pump (of the heart), to unlock (of the key) 46

Role (Externally-Grounded Realizable Entity) role =def. a realizable entity which exists because the bearer is in some special physical, social, or institutional set of circumstances in which the bearer does not have to be, and is not such that, if it ceases to exist, then the physical make-up of the bearer is thereby changed. 47

Disposition (Internally-Grounded 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 48

Function (A Disposition Designed or Selected For) function =def. a disposition that exists in virtue of the bearer’s physical make-up,, and this physical make-up is something the bearer possesses because it came into being, either through evolution (in the case of natural biological entities) or through intentional design (in the case of artifacts), in order to realize processes of a certain kind. 49

Four distinct classificatory tasks 1.of people (patients, carriers, …) 2.of diseases (cases, instances, problems, …) 3.of courses of disease (symptoms, treatments…) 4.of representations (records, observations, data, diagnoses…) ICD confuses 1. & 2. HL7, most standard terminologies, confuse 2. and 4 50

Four distinct BFO categories 1.person (patient, carrier, …) – independent continuant 2.disease (case, instance, problem, …) – specifically dependent continuant 3.course of disease (symptom, treatment…) – occurrent 4.representation (record, datum, diagnosis…) – generically dependent continuant 51

Four distinct BFO categories 1.people (patients, carriers, …) – independent continuants 2.disease (case, instance, problem, condition …) – disposition 3.course of disease (symptom, episode, outbreak …) – realization of dispositions 4.representations (records, data, diagnoses…) – generically dependent continuants 52

Disposition Internally-Grounded Realizable Entity A disposition is a realizable entity which is such that, if it ceases to exist, then its bearer is physically changed, whose realization occurs, in virtue of the bearer’s physical make-up, when this bearer is in some special physical circumstances 53

Disorder 1.person – independent continuant objects fiat object part object aggregate 54

Disorder A fiat object part of an organism which serves as the bearer of a disposition of a certain sort This fiat object may have no determinate boundaries (compare: Downtown Santa Barbara) 55

Where does Mount Everest begin and end? Cf. Barry Smith and David M. Mark, “Do Mountains Exist?”, Environment and Planning B, 30,

Big Picture (with thanks to Richard Scheuermann) 57

A disease is a disposition rooted in a physical disorder in the organism and realized in pathological processes. etiological process produces disorder bears disposition realized_in pathological process produces abnormal bodily features recognized_as signs & symptomsinterpretive process produces diagnosis used_in 58

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 59

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. 60

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. 61

Definitions - Clinical Evaluation Terms Sign =def. – A bodily feature of a patient that is observed in a physical examination and is deemed by the clinician to be of clinical significance. (Objectively observable features) Symptom =def. – A experienced bodily feature of a patient that is observed by and observable only by the patient and is of the type that can be hypothesized by a patient to be a realization of a disease. (A restricted family of phenomena including pain, nausea, anger, drowsiness, which are of their nature experienced in the first person) Symptoms are subjective. But this does not mean that there is no objective fact of the matter whether a given symptom exists 62

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 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). 64

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 65

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) 66

Definition: Etiology Etiological Process =def. – A process in an organism that leads to a subsequent disorder. Example: toxic chemical exposure resulting in a mutation in the genomic DNA of a cell; infection of a human with a pathogenic virus; inheritance of two defective copies of a metabolic gene The etiological process creates the physical basis of that disposition to pathological processes which is the disease. 67

Definitions - Diagnosis Clinical Picture =def. – A representation of a clinical phenotype that is inferred from the combination of laboratory, image and clinical findings about a given patient. Diagnosis =def. – A conclusion of an interpretive process that has as input a clinical picture of a given patient and as output an assertion to the effect that the patient has a disease of such and such a type. 68

Definitions - Qualities Manifestation of a Disease =def. – A bodily feature of a patient that is (a) a deviation from clinical normality that exists in virtue of the realization of a disease and (b) is observable. Observability includes observable through elicitation of response or through the use of special instruments. Preclinical Manifestation of a Disease =def. – A manifestation of a disease that exists prior to its becoming detectable in a clinical history taking or physical examination. Clinical Manifestation of a Disease =def. – A manifestation of a disease that is detectable in a clinical history taking or physical examination. Phenotype =def. – A (combination of) bodily feature(s) of an organism determined by the interaction of its genetic make-up and environment. Clinical Phenotype =def. – A clinically abnormal phenotype. 69