Disease, and Other Clinical Natural Kinds
Barry Smith
Gradualist Approaches to Health and DiseaseBerlin, March 23, 2012
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Natural Kind
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Synonyms: universal, type
= entities of the sorts which are referred to by general terms of natural science
Instances, particulars, individuals
= entities of the sorts which can be observed in experiments of natural science
Old biology data
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New biology data
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how to link the kinds of phenomena represented here
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or here
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or here
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MKVSDRRKFEKANFDEFESALNNKNDLVHCPSITLFESIPTEVRSFYEDEKSGLIKVVKFRTGAMDRKRSFEKVVISVMVGKNVKKFLTFVEDEPDFQGGPIPSKYLIPKKINLMVYTLFQVHTLKFNRKDYDTLSLFYLNRGYYNELSFRVLERCHEIASARPNDSSTMRTFTDFVSGAPIVRSLQKSTIRKYGYNLAPYMFLLLHVDELSIFSAYQASLPGEKKVDTERLKRDLCPRKPIEIKYFSQICNDMMNKKDRLGDILHIILRACALNFGAGPRGGAGDEEDRSITNEEPIIPSVDEHGLKVCKLRSPNTPRRLRKTLDAVKALLVSSCACTARDLDIFDDNNGVAMWKWIKILYHEVAQETTLKDSYRITLVPSSDGISLLAFAGPQRNVYVDDTTRRIQLYTDYNKNGSSEPRLKTLDGLTSDYVFYFVTVLRQMQICALGNSYDAFNHDPWMDVVGFEDPNQVTNRDISRIVLYSYMFLNTAKGCLVEYATFRQYMRELPKNAPQKLNFREMRQGLIALGRHCVGSRFETDLYESATSELMANHSVQTGRNIYGVDSFSLTSVSGTTATLLQERASERWIQWLGLESDYHCSFSSTRNAEDVVAGEAASSNHHQKISRVTRKRPREPKSTNDILVAGQKLFGSSFEFRDLHQLRLCYEIYMADTPSVAVQAPPGYGKTELFHLPLIALASKGDVEYVSFLFVPYTVLLANCMIRLGRRGCLNVAPVRNFIEEGYDGVTDLYVGIYDDLASTNFTDRIAAWENIVECTFRTNNVKLGYLIVDEFHNFETEVYRQSQFGGITNLDFDAFEKAIFLSGTAPEAVADAALQRIGLTGLAKKSMDINELKRSEDLSRGLSSYPTRMFNLIKEKSEVPLGHVHKIRKKVESQPEEALKLLLALFESEPESKAIVVASTTNEVEELACSWRKYFRVVWIHGKLGAAEKVSRTKEFVTDGSMQVLIGTKLVTEGIDIKQLMMVIMLDNRLNIIELIQGVGRLRDGGLCYLLSRKNSWAARNRKGELPPKEGCITEQVREFYGLESKKGKKGQHVGCCGSRTDLSADTVELIERMDRLAEKQATASMSIVALPSSFQESNSSDRYRKYCSSDEDSNTCIHGSANASTNASTNAITTASTNVRTNATTNASTNATTNASTNASTNATTNASTNATTNSSTNATTTASTNVRTSATTTASINVRTSATTTESTNSSTNATTTESTNSSTNATTTESTNSNTSATTTASINVRTSATTTESTNSSTSATTTASINVRTSATTTKSINSSTNATTTESTNSNTNATTTESTNSSTNATTTESTNSSTNATTTESTNSNTSAATTESTNSNTSATTTESTNASAKEDANKDGNAEDNRFHPVTDINKESYKRKGSQMVLLERKKLKAQFPNTSENMNVLQFLGFRSDEIKHLFLYGIDIYFCPEGVFTQYGLCKGCQKMFELCVCWAGQKVSYRRIAWEALAVERMLRNDEEYKEYLEDIEPYHGDPVGYLKYFSVKRREIYSQIQRNYAWYLAITRRRETISVLDSTRGKQGSQVFRMSGRQIKELYFKVWSNLRESKTEVLQYFLNWDEKKCQEEWEAKDDTVVVEALEKGGVFQRLRSMTSAGLQGPQYVKLQFSRHHRQLRSRYELSLGMHLRDQIALGVTPSKVPHWTAFLSMLIGLFYNKTFRQKLEYLLEQISEVWLLPHWLDLANVEVLAADDTRVPLYMLMVAVHKELDSDDVPDGRFDILLCRDSSREVGELIGLFYNKTFRQKLEYLLEQISEVWLLPHWLDLANVEVLAADDTRVPLYMLMVAVHKELDSDDVPDGRFDILLCRDSSREVGELIGLFYNKTFRQKLEYLLEQISEVWLLPHWLDLANVEVLAADDTRVPLYMLMVAVHKELDSDDVPDGRFDILLCRDSSREVGE
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to this?
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or this?
answer: through annotation of data with terms from a controlled vocabulary or ‘ontology’
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sphingolipid transporter activity
Holliday junction helicase complex
this allows integration of databases
MouseEcotope GlyProt
DiabetInGene
GluChem
Holliday junction helicase complex
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and supports logical reasoning over data
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‘Ontology’ in PubMed
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GO, in particular, is tremendously successful
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$100 million invested in literature and data curation using GO
over 11 million annotations relating gene products described in the UniProt, Ensembl and other databases to GO termsexperimental results reported in 52,000 scientific journal articles manually annoted by expert biologists using GO
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1. rooted in basic experimental biology
2. links people to data and to literature
3. links data to data
• across species (human, mouse, yeast, fly ...)
• across granularities (molecule, cell, organ, organism, population)
4. links medicine to biological science
5. promotes cumulation of scientific knowledge in algorithmically tractable form
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Benefits of the GO
National Center for Biomedical Ontology (NIH Roadmap Center)
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− Stanford Biomedical Informatics Research− The Mayo Clinic− University at Buffalo Department of
Philosophy
http://bioportal.bioontology.org
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GO supports only three types of annotation
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what cellular component?
what molecular function?
what biological process?
no diseases in GO
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RELATION TO TIME
GRANULARITY
CONTINUANT OCCURRENT
INDEPENDENT DEPENDENT
ORGAN ANDORGANISM
Organism(NCBI
Taxonomy)
Anatomical Entity(FMA, CARO)
OrganFunction
(FMP, CPRO) Phenotypic
Quality(PaTO)
Biological Process
(GO)CELL AND CELLULAR
COMPONENT
Cell(CL)
Cellular Compone
nt(FMA, GO)
Cellular Function
(GO)
MOLECULEMolecule
(ChEBI, SO,RnaO, PrO)
Molecular Function(GO)
Molecular Process
(GO)
OBO Foundry (first version, 2006)Yellow = Gene Ontology
Current OBO Foundry Ontologies
• Biological process (GO)• Cellular component (GO)• Chemical entities of biological interest• Molecular function (GO)• Phenotypic quality• PRotein Ontology (PRO)• Xenopus Anatomy and Development• Zebrafish Anatomy and Development
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Foundry ontologies under review
Cell Ontology (CL)Foundational Model of Anatomy (FMA)Infectious Disease Ontology (IDO)
Staph. aureus Ontology (IDO Sa)
Malaria Ontology (IDO MAL)
Influenza Ontology (IDO Flu)
HIV Ontology (IDO HIV)
Ontology for Biomedical Investigations (OBI)Ontology for General Medical Sciences (OGMS)Plant Ontology (PO)
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Ontologies under construction
Allergy OntologyEnvironment Ontology (EnvO) Immunology Ontology (IDO)Mental Functioning Ontology (MFO)
Emotion Ontology (MFO-EM)Pain Ontology
Mental Disease Ontology (MDO)Neurological Disease Ontology (ND)Vaccine Ontology (VO)
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FMA has 83281 types and 3 million relations representing canonical adult human anatomy= the anatomy generated by the coordinated expression of the organism’s own structural genes.
Canonical ≠ statistically normal
32 teethtwo arms two legs
one nosetwo nostrilstwo kidneys, …
Foundational Model of Anatomy Ontology
Foundational Model of Anatomy (FMA)
Pleural Cavity
Pleural Cavity
Interlobar recess
Interlobar recess
Mesothelium of Pleura
Mesothelium of Pleura
Pleura(Wall of Sac)
Pleura(Wall of Sac)
VisceralPleura
VisceralPleura
Pleural SacPleural Sac
Parietal Pleura
Parietal Pleura
Anatomical SpaceAnatomical Space
OrganCavityOrganCavity
Serous SacCavity
Serous SacCavity
AnatomicalStructure
AnatomicalStructure
OrganOrgan
Serous SacSerous Sac
MediastinalPleura
MediastinalPleura
TissueTissue
Organ PartOrgan Part
Organ Subdivision
Organ Subdivision
Organ Component
Organ Component
Organ CavitySubdivision
Organ CavitySubdivision
Serous SacCavity
Subdivision
Serous SacCavity
Subdivision
part
_of
is_a
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An ontology
is a controlled structured vocabulary
that includes a backbone taxonomy (nodes connected by the is_a [subtype] relation)
together with further logically defined relations such as part_of, regulated_by
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Basic Formal Ontology (BFO)
A simple top-level ontology to support information integration in scientific research
Serves as starting point for OBO Foundry ontologies
Domain ontologies built by downward population
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Basic Formal Ontology
http://www.ifomis.org/bfo/
Continuant Occurrent
IndependentContinuant
DependentContinuant
Organism
Life
Temperature
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Example: The Cell Ontology
Continuant
IndependentContinuant
DependentContinuant
..... .....
Non-realizableDependentContinuant(quality)
Realizable DependentContinuant(function, role, disposition)
TYPES
INSTANCES
depends_on
Continuant
IndependentContinuant
thing
DependentContinuant
quality
.... .....
example: temperature dependson bearer
TYPES
INSTANCES
DependentContinuant
QualityRealizable Dependent
Continuant
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Disposition Function Role
of banana, to ripen
of heart, to pump blood
of employee, to work for pay
process of realization depends_on realizable
Continuant Occurrent
IndependentContinuant
bearer
Realizable DependentContinuant
disposition
.... ..... .......47
Process of realization
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.
Most standard terminologies confuse 2. and 4
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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
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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
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Big Picture (Ontology for General Medical Science)
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Elucidation of Primitive Terms
‘extended organism’ = the organism and all the material entities located within it
‘bodily feature’ = either a physical part of the extended organism, a bodily quality, or a bodily process.
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Elucidation of Primitive Terms
clinically abnormal - some bodily feature that (1) is not part of the life plan for an organism of the
relevant type (unlike loss of milk teeth, 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
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DisorderA material entity (fiat object part) which is clinically abnormal and part of an extended organism
Compare:
Downtown Santa Barbara
Mount Everest
Peter Hucklenbroich’s pate
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Definitions - Foundational Terms
Pathological Process =def. – A bodily process that 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.
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61http://code.google.com/p/ogms/
Big Picture (Ontology for General Medical Science)
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63http://code.google.com/p/ogms/
Disease Course=Def. The sum of processes through which a given disease instance is realized.
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independentcontinuant
dependentcontinuant
disposition
diseaseorganism
John John’s disease
occurrent
process
course of disease
course of John’s disease
TY
PES
INS
TA
NC
ES
coronary heart disease
John’s coronary heart disease
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CHD in phase of asymptomatic
(‘silent’) infarction
CHD in phase of early lesions
and small fibrous plaques
stable angina
CHD in phase of surface
disruption of plaque
unstable angina
instantiates at t1
instantiates at t2
instantiates at t3
instantiates at t4
instantiates at t5
in nature, no sharp boundaries here
human
John
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embryo fetus adultneonate infant child
instantiates at t1
instantiates at t2
instantiates at t3
instantiates at t4
instantiates at t5
instantiates at t6
in nature, no sharp boundaries here
A disease is a disposition
etiological process
produces
disorder
bears
disposition
realized_in
pathological process
produces
abnormal bodily features
recognized_as
signs & symptomsinterpretive process
produces
diagnosis
used_in71
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
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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
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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
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Dispositions and Predispositions
Some dispositions are predispositions to other dispositions.
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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)
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Arterial AneurysmDisposition – atherosclerosis
realized inPathological process – fatty material collects within the walls of arteries
producesDisorder – artery with weakened wall
bearsDisposition – of artery to become distended
realized_inPathological process – process of distending
producesDisorder – arterial aneurysm
bearsDisposition – of artery to rupture
realized inPathological process – (catastrophic event) of rupturing
producesDisorder – ruptured artery, arterial system with dangerously low blood pressure
bearsDisposition – circulatory failure
realized inPathological process – exsanguination, failure of homeostasis
producesDeath
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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 - 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
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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
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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
84
Early Onset Alzheimer’s Disease
Disorder – mutations in APP, PSEN1 and PSEN2bears
Disposition – impaired APP processingrealized in
Pathological process – accumulation of intra- and extracellular protein in the brainproduces
Disorder – amyloid plaque and neurofibrillary tanglesbearsDisposition – of neurons to dierealized in Pathological process – neuronal loss
producesDisorder – cognitive brain regions damaged and reduced in size
bearsDisposition (disease) – Alzheimer’s dementia
realized inSymptoms – episodic memory loss and other cognitive domain impairment
85
Arterial Aneurysm• Disposition – atherosclerosis
– realized in• Pathological process – fatty material collects within the walls of arteries
– produces• Disorder – artery with weakened wall
– bears• Disposition – of artery to become distended
– realized_in• Pathological process – process of distending
– produces• Disorder – arterial aneurysm
– bears• Disposition – of artery to rupture
– realized in• Pathological process – (catastrophic event) of rupturing
– produces• Disorder – ruptured artery, arterial system with dangerously low blood pressure
– bears• Disposition – circulatory failure
– realized in• Pathological process – exsanguination, failure of homeostasis
– produces• Death
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Hemorrhagic stroke• Disorder – cerebral arterial aneurysm
– bears• Disposition – of weakened artery to rupture
– realized in• Pathological process – rupturing of weakened blood vessel
– produces• Disorder – Intraparenchymal cerebral hemorrhage
– bears• Disposition (disease) – to increased intra-cranial pressure
– realized in• Pathological process – increasing intra-cranial pressure, compression of brain
structures– produces
• Disorder – Cerebral ischemia, Cerebral neuronal death– bears
• Disposition (disease) – stroke– realized in
• Symptoms – weakness/paralysis, loss of sensation, etc
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Only something like the disposition theory enables us to explain why a fracture is not a disease
PETER HUCKLENBROICH−Radius fracture loco classico “ is a disease”
Advantages of the Disposition Theory
89
PETER HUCKLENBROICH
A disease entity is a set of possible alternative courses
x has disease entity D ≡ (x has course D1) or (x has course D2) or … or (x has course Dn)
Only something like the disposition theory can allow us to determine what does and what does not belong to this list.
90
Think of all the different temporal extents of the disease courses association with any given disease
• for those who die in an accident 5 seconds after catching the disease
• for those who have no treatment
• for those who have truly excellent treatment
• …
91
Think of all the different combination cases:
of diseases with other diseases of diseases with complicationsof diseases at different stages of lifeof diseases with different environments
in igloosin Ost-Thüringenin sub-Saharan Africain space-ships…
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Think of all the different types of patient:
smokernon-smokerbanana-leaf-smokerAm-Sonntag-bei-Mutti-EsserAspirin-vor-dem-Schlafen-Gehen-NehmerAuf-dem-Schiessplatz-Ohrstöpsel-TrägerAuf-Weihnachtsmarkt-Lebkuchenherz-KäuferAuto-in-Waschstrasse-Abschliesser
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human
John
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embryo fetus adultneonate infant child
instantiates at t1
instantiates at t2
instantiates at t3
instantiates at t4
instantiates at t5
instantiates at t6
in nature, no sharp boundaries here
portion of water
this portion of H20
95
portion of ice
portion of liquid water
portion of gas
instantiates at t1
instantiates at t2
instantiates at t3
Phrase transitions
temperature
John’s temperature
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37ºC 37.1ºC 37.5ºC37.2ºC 37.3ºC 37.4ºC
instantiates at t1
instantiates at t2
instantiates at t3
instantiates at t4
instantiates at t5
instantiates at t6
in nature, no sharp boundaries here
in nature, no sharp boundaries here
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