Disease, and Other Clinical      Natural Kinds               Barry Smith Gradualist Approaches to Health and Disease      ...
Natural KindSynonyms: universal, type= entities of the sorts which are referred to bygeneral terms of natural scienceInsta...
Old biology data                   3/
New biology dataMKVSDRRKFEKANFDEFESALNNKNDLVHCPSITLFESIPTEVRSFYEDEKSGLIKVVKFRTGAMDRKRSFEKVVISVMVGKNVKKFLTFVEDEPDFQGGPISKYL...
How to do biology across the genome?MKVSDRRKFEKANFDEFESALNNKNDLVHCPSITLFESIPTEVRSFYEDEKSGLIKVVKFRTGAMDRKRSFEKVVISVMVGKNVKK...
how to link the kinds ofphenomena represented here                              6/
or here          7
or here          8
MKVSDRRKFEKANFDEFESALNNKNDLVHCPSITLFESIPTEVRSFYEDEKSGLIKVVKFRTGAMDRK to this?RSFEKVVISVMVGKNVKKFLTFVEDEPDFQGGPIPSKYLIPKKIN...
or this?           10
answer: through annotation of data with terms  from a controlled vocabulary or ‘ontology’sphingolipid transporter activity...
this allows integration of databasesMouseEcotope                          GlyProt                  Holliday junction      ...
and supports logical reasoning over data                                           15
‘Ontology’ in PubMed                       16/24
GO, in particular, is tremendously successful                                            17
$100 million invested in literature and      data curation using GO  over 11 million annotations relating gene  products d...
Benefits of the GO1. rooted in basic experimental biology2. links people to data and to literature3. links data to data  •...
National Center for Biomedical Ontology(NIH Roadmap Center)   −      Stanford Biomedical Informatics Research   −      The...
25
26
GO supports only three types of annotationwhat cellular component?what molecular function?what biological process?        ...
28
CONTINUANT                     OCCURRENT    RELATION     TO TIME                 INDEPENDENT               DEPENDENTGRANUL...
http://obofoundry.org                  30
Current OBO Foundry Ontologies•   Biological process (GO)•   Cellular component (GO)•   Chemical entities of biological in...
Foundry ontologies under reviewCell Ontology (CL)Foundational Model of Anatomy (FMA)Infectious Disease Ontology (IDO)    S...
Ontologies under constructionAllergy OntologyEnvironment Ontology (EnvO)Immunology Ontology (IDO)Mental Functioning Ontolo...
Foundational Model of Anatomy OntologyFMA has 83281 types and 3 million relationsrepresenting canonical adult human anatom...
Anatomical             Anatomical Space                                                               Structure    Organ C...
An ontologyis a controlled structured vocabulary  that includes a backbone taxonomy  (nodes connected by the is_a [subtype...
Basic Formal Ontology (BFO) A simple top-level ontology to support information integration in scientific research Serves a...
Continuant             Occurrent       Basic Formal Ontology                                LifeIndependent       Dependen...
Example: The Cell Ontology
ContinuantIndependent       Dependent                 TYPESContinuant        Continuant                       Realizable N...
depends_on       Continuant                                       TYPES                           example:Independent   De...
Dependent              Continuant                     Realizable DependentQuality                   ContinuantDisposition ...
process of realization depends_on             realizable       Continuant           Occurrent              RealizableIndep...
Four distinct classificatory tasks1.   of people (patients, carriers, …)2.   of diseases (cases, instances, problems, …)3....
Four distinct BFO categories1. person (patient, carrier, …)   – independent continuant2. disease (case, instance, problem,...
Four distinct BFO categories1. people (patients, carriers, …)   – independent continuants2. disease (case, instance, probl...
Big Picture (Ontology for General Medical Science)                                                     55
Elucidation of Primitive Terms ‘extended organism’ = the organism and all  the material entities located within it ‘bodi...
Elucidation of Primitive Terms clinically   abnormal - some bodily feature that   (1) is not part of the life plan for a...
DisorderA material entity (fiat object part) which isclinically abnormal and part of an extendedorganismCompare:   Downtow...
Definitions - Foundational Terms   Pathological Process =def. – A bodily process that is    clinically abnormal.   Disea...
http://code.google.com/p/ogms/   61
Big Picture (Ontology for General Medical Science)                                                     62
http://code.google.com/p/ogms/   63
Disease Course=Def. The sum of processes through which agiven disease instance is realized.                               ...
independent   dependent                              occurrent continuant   continuant                                    ...
coronary heart  in nature, no sharp    disease    boundaries here CHD in phase                               CHD in phase ...
humanin nature, no sharp  boundaries hereembryo          fetus          neonate         infant         child          adul...
A disease is a disposition                      produces              bears                 realized_inetiological process...
Cirrhosis - environmental exposure   Etiological process - phenobarbitol-        Symptoms & Signs    induced hepatic cel...
Influenza - infectious   Etiological process - infection of          Symptoms & Signs    airway epithelial cells with in...
Huntington’s Disease - genetic   Etiological process - inheritance of    >39 CAG repeats in the HTT gene              Sy...
Dispositions and PredispositionsSome dispositions are predispositions toother dispositions.                               ...
HNPCC - genetic pre-disposition   Etiological process - inheritance of a mutant mismatch repair gene     produces   Dis...
Arterial AneurysmDisposition – atherosclerosis    realized inPathological process – fatty material collects within the wal...
Systemic arterial hypertension   Etiological process – abnormal               Symptoms & Signs    reabsorption of NaCl b...
Type 2 Diabetes Mellitus   Etiological process –                    Symptoms & Signs     produces                      ...
Type 1 hypersensitivity to penicillin   Etiological process – sensitizing of mast      Symptoms & Signs    cells and bas...
Early Onset Alzheimer’s DiseaseDisorder – mutations in APP, PSEN1 and PSEN2     bearsDisposition – impaired APP processing...
Arterial Aneurysm•   Disposition – atherosclerosis    –   realized in•   Pathological process – fatty material collects wi...
Hemorrhagic stroke•   Disorder – cerebral arterial aneurysm    – bears•   Disposition – of weakened artery to rupture    –...
Advantages of the Disposition TheoryOnly something like the dispositiontheory enables us to explain why afracture is not a...
PETER HUCKLENBROICHA disease entity is a set of possible alternativecoursesx has disease entity D ≡(x has course D1) or (x...
Think of all the different temporal extents ofthe disease courses association with anygiven disease  • for those who die i...
Think of all the different combination cases:of diseases with other diseasesof diseases with complicationsof diseases at d...
Think of all the different types of patient:     smoker     non-smoker     banana-leaf-smoker     Am-Sonntag-bei-Mutti-Ess...
93
humanin nature, no sharp  boundaries hereembryo          fetus          neonate         infant         child          adul...
portion of          Phrase                   water                                     transitionsportion of         porti...
temperaturein nature, no sharp  boundaries here37ºC            37.1ºC         37.2ºC           37.3ºC          37.4ºC     ...
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Basic Formal Ontology (BFO) and Disease

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  • http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=116006492 sequence of X chromosome in baker’s yeast
  • http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=116006492 sequence of X chromosome in baker’s yeast
  • http://ehealthadvice.info/what-is-crohns-disease/
  • http://www.topnews.in/health/why-schizophrenia-patients-may-have-trouble-reading-social-cues-212138
  • http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=116006492
  • http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=116006492
  • dir.niehs.nih.gov/ microarray/datamining/
  • http://www.yeastgenome.org/help/images/cytokinesisDAGrels.jpg
  • dir.niehs.nih.gov/ microarray/datamining/
  • Basic Formal Ontology (BFO) and Disease

    1. 1. Disease, and Other Clinical Natural Kinds Barry Smith Gradualist Approaches to Health and Disease Berlin, March 23, 2012 1
    2. 2. Natural KindSynonyms: universal, type= entities of the sorts which are referred to bygeneral terms of natural scienceInstances, particulars, individuals= entities of the sorts which can be observedin experiments of natural science 2/
    3. 3. Old biology data 3/
    4. 4. New biology dataMKVSDRRKFEKANFDEFESALNNKNDLVHCPSITLFESIPTEVRSFYEDEKSGLIKVVKFRTGAMDRKRSFEKVVISVMVGKNVKKFLTFVEDEPDFQGGPISKYLIPKKINLMVYTLFQVHTLKFNRKDYDTLSLFYLNRGYYNELSFRVLERCHEIASARPNDSSTMRTFTDFVSGAPIVRSLQKSTIRKYGYNLAPYMFLLLHVDELSIFSAYQASLPGEKKVDTERLKRDLCPRKPIEIKYFSQICNDMMNKKDRLGDILHIILRACALNFGAGPRGGAGDEEDRSITNEEPIIPSVDEHGLKVCKLRSPNTPRRLRKTLDAVKALLVSSCACTARDLDIFDDNNGVAMWKWIKILYHEVAQETTLKDSYRITLVPSSDGISLLAFAGPQRNVYVDDTTRRIQLYTDYNKNGSSEPRLKTLDGLTSDYVFYFVTVLRQMQICALGNSYDAFNHDPWMDVVGFEDPNQVTNRDISRIVLYSYMFLNTAKGCLVEYATFRQYMRELPKNAPQKLNFREMRQGLIALGRHCVGSRFETDLYESATSELMANHSVQTGRNIYGVDFSLTSVSGTTATLLQERASERWIQWLGLESDYHCSFSSTRNAEDVDISRIVLYSYMFLNTAKGCLVEYA 4TFRQYMRELPKNAPQKLNFREMRQGLIALGRHCVGSRFETDLYE
    5. 5. How to do biology across the genome?MKVSDRRKFEKANFDEFESALNNKNDLVHCPSITLFESIPTEVRSFYEDEKSGLIKVVKFRTGAMDRKRSFEKVVISVMVGKNVKKFLTFVEDEPDFQGGPISKYLIPKKINLMVYTLFQVHTLKFNRKDYDTLSLFYLNRGYYNELSFRVLERCHEIASARPNDSSTMRTFTDFVSGAPIVRSLQKSTIRKYGYNLAPYMFLLLHVDELSIFSAYQASLPGEKKVDTERLKRDLCPRKPIEIKYFSQICNDMMNKKDRLGDILHIILRACALNFGAGPRGGAGDEEDRSITNEEPIIPSVDEHGLKVCKLRSPNTPRRLRKTLDAVKALLVSSCACTARDLDIFDDNNGVAMWKWIKILYHEVAQETTLKDSYRITLVPSSDGISLLAFAGPQRNVYVDDTTRRIQLYTDYNKNGSSEPRLKTLDGLTSDYVFYFVTVLRQMQICALGNSYDAFNHDPWMDVVGFEDPNQVTNRDISRIVLYSYMFLNTAKGCLVEYATFRQYMRELPKNAPQKLNFREMRQGLIALGRHCVGSRFETDLYESATSELMANHSVQTGRNIYGVDFSLTSVSGTTATLLQERASERWIQWLGLESDYHCSFSSTRNAEDVMKVSDRRKFEKANFDEFESALNNKNDLVHCPSITLFESIPTEVRSFYEDEKSGLIKVVKFRTGAMDRKRSFEKVVISVMVGKNVKKFLTFVEDEPDFQGGPISKYLIPKKINLMVYTLFQVHTLKFNRKDYDTLSLFYLNRGYYNELSFRVLERCHEIASARPNDSSTMRTFTDFVSGAPIVRSLQKSTIRKYGYNLAPYMFLLLHVDELSIFSAYQASLPGEKKVDTERLKRDLCPRKPIEIKYFSQICNDMMNKKDRLGDILHIILRACALNFGAGPRGGAGDEEDRSITNEEPIIPSVDEHGLKVCKLRSPNTPRRLRKTLDAVKALLVSSCACTARDLDIFDDNNGVAMWKWIKILYHEVAQETTLKDSYRITLVPSSDGISLLAFAGPQRNVYVDDTTRRIQLYTDYNKNGSSEPRLKTLDGLTSDYVFYFVTVLRQMQICALGNSYDAFNHDPWMDVVGFEDPNQVTNRDISRIVLYSYMFLNTAKGCLVEYATFRQYMRELPKNAPQKLNFREMRQGLIALGRHCVGSRFETDLYESATSELMANHSVQTGRNIYGVDFSLTSVSGTTATLLQERASERWIQWLGLESDYHCSFSSTRNAEDVMKVSDRRKFEKANFDEFESALNNKNDLVHCPSITLFESIPTEVRSFYEDEKSGLIKVVKFRTGAMDRKRSFEKVVISVMVGKNVKKFLTFVEDEPDFQGGPISKYLIPKKINLMVYTLFQVHTLKFNRKDYDTLSLFYLNRGYYNELSFRVLERCHEIASARPNDSSTMRTFTDFVSGAPIVRSLQKSTIRKYGYNLAPYMFLLLHVDELSIFSAYQASLPGEKKVDTERLKRDLCPRKPIEIKYFSQICNDMMNKKDRLGDILHIILRACALNFGAGPRGGAGDEEDRSITNEEPIIPSVDEHGLKVCKLRSPNTPRRLRKTLDAVKALLVSSCACTARDLDIFDDNNGVAMWKWIKILYHEVAQETTLKDSYRITLVPSSDGISLLAFAGPQRNVYVDDTTRRIQLYTDYNKNGSSEPRLKTLDGLTSDYVFYFVTVLRQMQICALGNSYDAFNHDPWMDVVGFEDPNQVTNRDISRIVLYSYMFLNTAKGCLVEYATFRQYMRELPKNAPQKLNFREMRQGLIALGRHCVGSRFETDLYESATSELMANHSVQTGRNIYGVDFSLTSVSGTTATLLQERASERWIQWLGLESDYHCSFSSTRNAEDVMKVSDRRKFEKANFDEFESALNNKNDLVHCPSITLFESIPTEVRSFYEDEKSGLIKVVKFRTGAMDRKRSFEKVVISV5MVGKNVKKFLTFVEDEPDFQGGPISKYLIPKKINLMVYTLFQVHTLKFNRKDYDTLSLFYLNRGYYNELSFRVLERC
    6. 6. how to link the kinds ofphenomena represented here 6/
    7. 7. or here 7
    8. 8. or here 8
    9. 9. MKVSDRRKFEKANFDEFESALNNKNDLVHCPSITLFESIPTEVRSFYEDEKSGLIKVVKFRTGAMDRK to this?RSFEKVVISVMVGKNVKKFLTFVEDEPDFQGGPIPSKYLIPKKINLMVYTLFQVHTLKFNRKDYDTLSLFYLNRGYYNELSFRVLERCHEIASARPNDSSTMRTFTDFVSGAPIVRSLQKSTIRKYGYNLAPYMFLLLHVDELSIFSAYQASLPGEKKVDTERLKRDLCPRKPIEIKYFSQICNDMMNKKDRLGDILHIILRACALNFGAGPRGGAGDEEDRSITNEEPIIPSVDEHGLKVCKLRSPNTPRRLRKTLDAVKALLVSSCACTARDLDIFDDNNGVAMWKWIKILYHEVAQETTLKDSYRITLVPSSDGISLLAFAGPQRNVYVDDTTRRIQLYTDYNKNGSSEPRLKTLDGLTSDYVFYFVTVLRQMQICALGNSYDAFNHDPWMDVVGFEDPNQVTNRDISRIVLYSYMFLNTAKGCLVEYATFRQYMRELPKNAPQKLNFREMRQGLIALGRHCVGSRFETDLYESATSELMANHSVQTGRNIYGVDSFSLTSVSGTTATLLQERASERWIQWLGLESDYHCSFSSTRNAEDVVAGEAASSNHHQKISRVTRKRPREPKSTNDILVAGQKLFGSSFEFRDLHQLRLCYEIYMADTPSVAVQAPPGYGKTELFHLPLIALASKGDVEYVSFLFVPYTVLLANCMIRLGRRGCLNVAPVRNFIEEGYDGVTDLYVGIYDDLASTNFTDRIAAWENIVECTFRTNNVKLGYLIVDEFHNFETEVYRQSQFGGITNLDFDAFEKAIFLSGTAPEAVADAALQRIGLTGLAKKSMDINELKRSEDLSRGLSSYPTRMFNLIKEKSEVPLGHVHKIRKKVESQPEEALKLLLALFESEPESKAIVVASTTNEVEELACSWRKYFRVVWIHGKLGAAEKVSRTKEFVTDGSMQVLIGTKLVTEGIDIKQLMMVIMLDNRLNIIELIQGVGRLRDGGLCYLLSRKNSWAARNRKGELPPKEGCITEQVREFYGLESKKGKKGQHVGCCGSRTDLSADTVELIERMDRLAEKQATASMSIVALPSSFQESNSSDRYRKYCSSDEDSNTCIHGSANASTNASTNAITTASTNVRTNATTNASTNATTNASTNASTNATTNASTNATTNSSTNATTTASTNVRTSATTTASINVRTSATTTESTNSSTNATTTESTNSSTNATTTESTNSNTSATTTASINVRTSATTTESTNSSTSATTTASINVRTSATTTKSINSSTNATTTESTNSNTNATTTESTNSSTNATTTESTNSSTNATTTESTNSNTSAATTESTNSNTSATTTESTNASAKEDANKDGNAEDNRFHPVTDINKESYKRKGSQMVLLERKKLKAQFPNTSENMNVLQFLGFRSDEIKHLFLYGIDIYFCPEGVFTQYGLCKGCQKMFELCVCWAGQKVSYRRIAWEALAVERMLRNDEEYKEYLEDIEPYHGDPVGYLKYFSVKRREIYSQIQRNYAWYLAITRRRETISVLDSTRGKQGSQVFRMSGRQIKELYFKVWSNLRESKTEVLQYFLNWDEKKCQEEWEAKDDTVVVEALEKGGVFQRLRSMTSAGLQGPQYVKLQFSRHHRQLRSRYELSLGMHLRDQIALGVTPSKVPHWTAFLSMLIGLFYNKTFRQKLEYLLEQISEVWLLPHWLDLANVEVLAADDTRVPLYMLMVAVHKELDSDDVPDGRFDILLCRDSSREVGELIGLFYNKTFRQKLEYL 9LEQISEVWLLPHWLDLANVEVLAADDTRVPLYMLMVAVHKELDSDDVPDGRFDILLCRDSSREVGELI
    10. 10. or this? 10
    11. 11. answer: through annotation of data with terms from a controlled vocabulary or ‘ontology’sphingolipid transporter activityHolliday junction helicase complex 11
    12. 12. this allows integration of databasesMouseEcotope GlyProt Holliday junction helicase complex DiabetInGene GluChem 13
    13. 13. and supports logical reasoning over data 15
    14. 14. ‘Ontology’ in PubMed 16/24
    15. 15. GO, in particular, is tremendously successful 17
    16. 16. $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 terms experimental results reported in 52,000 scientific journal articles manually annoted by expert biologists using GO 18
    17. 17. Benefits of the GO1. rooted in basic experimental biology2. links people to data and to literature3. links data to data • across species (human, mouse, yeast, fly ...) • across granularities (molecule, cell, organ, organism, population)1. links medicine to biological science2. promotes cumulation of scientific knowledge in algorithmically tractable form 19
    18. 18. National Center for Biomedical Ontology(NIH Roadmap Center) − Stanford Biomedical Informatics Research − The Mayo Clinic − University at Buffalo Department of Philosophy http://bioportal.bioontology.org 24
    19. 19. 25
    20. 20. 26
    21. 21. GO supports only three types of annotationwhat cellular component?what molecular function?what biological process? no diseases in GO 27
    22. 22. 28
    23. 23. CONTINUANT OCCURRENT RELATION TO TIME INDEPENDENT DEPENDENTGRANULARITY Anatomical Organism Organ ORGAN AND Entity (NCBI Function ORGANISM (FMA, Taxonomy) (FMP, CPRO) Phenotypic Biological CARO) Quality Process (PaTO) (GO) CELL AND Cellular Cellular Cell CELLULAR Component Function (CL) COMPONENT (FMA, GO) (GO) Molecule Molecular Function Molecular Process MOLECULE (ChEBI, SO, (GO) (GO) RnaO, PrO) OBO Foundry (first version, 2006) Yellow = Gene Ontology 29
    24. 24. http://obofoundry.org 30
    25. 25. 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 31
    26. 26. Foundry ontologies under reviewCell 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) 32
    27. 27. Ontologies under constructionAllergy OntologyEnvironment Ontology (EnvO)Immunology Ontology (IDO)Mental Functioning Ontology (MFO) Emotion Ontology (MFO-EM) Pain OntologyMental Disease Ontology (MDO)Neurological Disease Ontology (ND)Vaccine Ontology (VO) 33
    28. 28. Foundational Model of Anatomy OntologyFMA has 83281 types and 3 million relationsrepresenting canonical adult human anatomy= the anatomy generated by the coordinatedexpression of the organism’s own structuralgenes. 32 teeth one nose two arms two nostrils two legs two kidneys, …Canonical ≠ statistically normal 34
    29. 29. Anatomical Anatomical Space Structure Organ Cavity Organ Organ Organ Part Subdivision Cavity Serous Sac Serous Sac Organ Organ Cavity Cavity Serous Sac Component Subdivision Tissue Subdivision is_a Pleural Sac Pleural Sac Pleura(Wall Pleural Pleura(Wall Pleural of Sac) of Sac) Cavity of Cavity Parietal Parietal Pleura t_ Pleura Visceral Visceral Interlobar Pleura Pleura Interlobar r recess recess Mediastinal pa Mediastinal Pleura Pleura Mesothelium Mesothelium of Pleura of Pleura 35dational Model of Anatomy (FMA)
    30. 30. An ontologyis 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 36
    31. 31. 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 38
    32. 32. Continuant Occurrent Basic Formal Ontology LifeIndependent Dependent http://www.ifomis.org/bfo/ Continuant ContinuantOrganism Temperature 39
    33. 33. Example: The Cell Ontology
    34. 34. ContinuantIndependent Dependent TYPESContinuant Continuant Realizable Non-realizable Dependent Dependent Continuant Continuant (function, role, ..... ..... (quality) disposition) INSTANCE
    35. 35. depends_on Continuant TYPES example:Independent Dependent temperature depends Continuant Continuant on bearer thing quality.... ..... INSTANCE
    36. 36. Dependent Continuant Realizable DependentQuality ContinuantDisposition Function Roleof banana, of heart, of employee,to ripen to pump blood to work for pay 46
    37. 37. process of realization depends_on realizable Continuant Occurrent RealizableIndependent Dependent Continuant Continuant Process of bearer realization.... ..... ....... disposition 47
    38. 38. Four distinct classificatory tasks1. 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 51
    39. 39. Four distinct BFO categories1. person (patient, carrier, …) – independent continuant2. disease (case, instance, problem, …) – specifically dependent continuant3. course of disease (symptom, treatment…) – occurrent4. representation (record, datum, diagnosis…) – generically dependent continuant 52
    40. 40. Four distinct BFO categories1. people (patients, carriers, …) – independent continuants2. disease (case, instance, problem, condition …) – disposition3. course of disease (symptom, episode, outbreak …) – realization of dispositions4. representations (records, data, diagnoses…) – generically dependent continuants 53
    41. 41. Big Picture (Ontology for General Medical Science) 55
    42. 42. 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. 56
    43. 43. 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 57
    44. 44. DisorderA material entity (fiat object part) which isclinically abnormal and part of an extendedorganismCompare: Downtown Santa Barbara Mount Everest Peter Hucklenbroich’s pate 58
    45. 45. 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. 60
    46. 46. http://code.google.com/p/ogms/ 61
    47. 47. Big Picture (Ontology for General Medical Science) 62
    48. 48. http://code.google.com/p/ogms/ 63
    49. 49. Disease Course=Def. The sum of processes through which agiven disease instance is realized. 65
    50. 50. independent dependent occurrent continuant continuant TYPES disposition processorganism disease course of disease INSTANCE course of John John’s John’s disease disease
    51. 51. coronary heart in nature, no sharp disease boundaries here CHD in phase CHD in phase CHD in phase ofof early lesions of surface unstable stable asymptomatic and small disruption of angina angina (‘silent’) infarctionfibrous plaques plaque instantiates instantiates instantiates instantiates instantiates at t1 at t2 at t3 at t4 at t5 John’s coronary heart disease 67
    52. 52. humanin nature, no sharp boundaries hereembryo fetus neonate infant child adult instantiates instantiates instantiates instantiates instantiates instantiates at t1 at t2 at t3 at t4 at t5 at t6 John 68
    53. 53. A disease is a disposition produces bears realized_inetiological process disorder disposition pathological process producesdiagnosis interpretive process signs & symptoms abnormal bodily features produces used_in recognized_as 71
    54. 54. Cirrhosis - environmental exposure Etiological process - phenobarbitol-  Symptoms & Signs induced hepatic cell death  used_in  produces  Interpretive process  produces Disorder - necrotic liver  bears  Hypothesis - rule out cirrhosis  suggests Disposition (disease) - cirrhosis  realized_in  Laboratory tests  produces Pathological process - abnormal tissue  Test results - elevated liver enzymes repair with cell proliferation and in serum fibrosis that exceed a certain  used_in threshold; hypoxia-induced cell death  Interpretive process  produces  produces Abnormal bodily features  Result - diagnosis that patient X has a  recognized_as disorder that bears the disease Symptoms - fatigue, anorexia cirrhosis Signs - jaundice, splenomegaly 72
    55. 55. Influenza - infectious Etiological process - infection of  Symptoms & Signs airway epithelial cells with influenza  used_in virus  Interpretive process  produces  produces Disorder - viable cells with influenza  Hypothesis - rule out influenza virus  suggests  bears  Laboratory tests  produces Disposition (disease) - flu  realized_in  Test results - elevated serum antibody titers  used_in Pathological process - acute inflammation  Interpretive process  produces  produces  Result - diagnosis that patient X has a Abnormal bodily features disorder that bears the disease flu  recognized_as Symptoms - weakness, dizziness Signs - fever 73
    56. 56. Huntington’s Disease - genetic Etiological process - inheritance of >39 CAG repeats in the HTT gene  Symptoms & Signs  produces  used_in Disorder - chromosome 4 with  Interpretive process abnormal mHTT  produces  bears  Hypothesis - rule out Huntington’s Disposition (disease) - Huntington’s  suggests disease  Laboratory tests  realized_in  produces Pathological process - accumulation of  Test results - molecular detection of mHTT protein fragments, abnormal the HTT gene with >39CAG repeats transcription regulation, neuronal cell  used_in death in striatum  produces  Interpretive process  produces Abnormal bodily features  recognized_as  Result - diagnosis that patient X has a disorder that bears the disease Symptoms - anxiety, depression Huntington’s disease Signs - difficulties in speaking and swallowing 74
    57. 57. Dispositions and PredispositionsSome dispositions are predispositions toother dispositions. 75
    58. 58. 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) 76
    59. 59. 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 produces 77Death
    60. 60. Systemic arterial hypertension Etiological process – abnormal  Symptoms & Signs reabsorption of NaCl by the kidney  used_in  produces  Interpretive process  produces Disorder – abnormally large scattered molecular aggregate of salt in the  Hypothesis - rule out hypertension blood  suggests  bears  Laboratory tests  produces Disposition (disease) - hypertension  realized_in  Test results -  used_in Pathological process – exertion of abnormal pressure against arterial wall  Interpretive process  produces  produces  Result - diagnosis that patient X has a Abnormal bodily features disorder that bears the disease hypertension  recognized_as Symptoms - Signs – elevated blood pressure 82
    61. 61. Type 2 Diabetes Mellitus Etiological process –  Symptoms & Signs  produces  used_in Disorder – abnormal pancreatic beta  Interpretive process  produces cells and abnormal muscle/fat cells  bears  Hypothesis - rule out diabetes mellitus  suggests Disposition (disease) – diabetes mellitus  Laboratory tests – fasting serum blood glucose, oral glucose challenge test, and/or  realized_in blood hemoglobin A1c Pathological processes – diminished  produces insulin production , diminished  Test results - muscle/fat uptake of glucose  used_in  produces  Interpretive process Abnormal bodily features  produces  recognized_as  Result - diagnosis that patient X has a Symptoms – polydipsia, polyuria, disorder that bears the disease type 2 polyphagia, blurred vision diabetes mellitus Signs – elevated blood glucose and 83 hemoglobin A1c
    62. 62. Type 1 hypersensitivity to penicillin Etiological process – sensitizing of mast  Symptoms & Signs cells and basophils during exposure to  used_in penicillin-class substance  Interpretive process  produces  produces Disorder – mast cells and basophils with  Hypothesis - epitope-specific IgE bound to Fc epsilon  suggests receptor I  Laboratory tests –  bears  produces Disposition (disease) – type I  Test results – occasionally, skin testing hypersensitivity  used_in  realized_in  Interpretive process  produces Pathological process – type I hypersensitivity reaction  Result - diagnosis that patient X has a  produces disorder that bears the disease type 1 hypersensitivity to penicillin Abnormal bodily features  recognized_as Symptoms – pruritis, shortness of breath 84 Signs – rash, urticaria, anaphylaxis
    63. 63. Early Onset Alzheimer’s DiseaseDisorder – mutations in APP, PSEN1 and PSEN2 bearsDisposition – impaired APP processing realized inPathological process – accumulation of intra- and extracellular protein in thebrainproduces Disorder – amyloid plaque and neurofibrillary tanglesbearsDisposition – of neurons to dierealized inPathological 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
    64. 64. 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 86• Death
    65. 65. 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 87
    66. 66. Advantages of the Disposition TheoryOnly something like the dispositiontheory enables us to explain why afracture is not a diseasePETER HUCKLENBROICH−Radius fracture loco classico “ is a disease” 88
    67. 67. PETER HUCKLENBROICHA disease entity is a set of possible alternativecoursesx has disease entity D ≡(x has course D1) or (x has course D2) or … or (xhas course Dn)Only something like the disposition theory canallow us to determine what does and what doesnot belong to this list. 89
    68. 68. Think of all the different temporal extents ofthe disease courses association with anygiven 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 • … 90
    69. 69. Think of all the different combination cases:of diseases with other diseasesof diseases with complicationsof diseases at different stages of lifeof diseases with different environments in igloos in Ost-Thüringen in sub-Saharan Africa in space-ships … 91
    70. 70. Think of all the different types of patient: smoker non-smoker banana-leaf-smoker Am-Sonntag-bei-Mutti-Esser Aspirin-vor-dem-Schlafen-Gehen-Nehmer Auf-dem-Schiessplatz-Ohrstöpsel-Träger Auf-Weihnachtsmarkt-Lebkuchenherz-Käufer Auto-in-Waschstrasse-Abschliesser 92
    71. 71. 93
    72. 72. humanin nature, no sharp boundaries hereembryo fetus neonate infant child adult instantiates instantiates instantiates instantiates instantiates instantiates at t1 at t2 at t3 at t4 at t5 at t6 John 94
    73. 73. portion of Phrase water transitionsportion of portion of portion of ice liquid water gasinstantiates instantiates instantiates at t1 at t2 at t3 this portion of H20 95
    74. 74. temperaturein nature, no sharp boundaries here37ºC 37.1ºC 37.2ºC 37.3ºC 37.4ºC 37.5ºC instantiates instantiates instantiates instantiates instantiates instantiates at t1 at t2 at t3 at t4 at t5 at t6 John’s temperature 96

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