1. OGMS Ontology for General Medical Science http://code.google.com/p/ogms 1

2. Basic Formal Ontology continuant occurrent independent continuant dependent continuant organism 2 http://www.ifomis.org/bfo

3. :. 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 3

4. :. Users of BFO Ontology for Risks Against Patient Safety (RAPS/REMINE) 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) National Cancer Institute Biomedical Grid Terminology (BiomedGT) US Army Biometrics Ontology US Army Command and Control Ontology 4

5. Basic Formal Ontology continuant occurrent independent continuant dependent continuant organism 5

6. 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... 6

7. Occurrents processes, events, happenings –your life –this process of accelerated cell division 7

8. Qualities temperature blood pressure mass... are continuants they exist through time while undergoing changes 8

9. 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 9

10. A Chart representing how John’s temperature changes 10

11. A Chart representing how John’s temperature changes 11

12. 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 12

13. BFO: The Very Top continuant independent continuant dependent continuant quality occurrent temperature 13

14. clear division of types and instances independent continuant dependent continuant quality temperature types instances organism John John’s temperature 14

15. Blinding Flash of the Obvious temperature types instances organism John John’s temperature. 15 inheres_in

16. temperature types instances John’s temperature 16 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

17. human types instances John 17 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

18. human phase types instances John 18 embryo stage fetus stage adult stage neonate stage infant stage child stage has at t 1 has at t 2 has at t 3 has at t 4 has at t 5 has at t 6

19. Canonical whole (human) organism stages 19 whole human development stage post-natal development stage aging stage reproductive stage maturation stage growth stage P life of whole human pre-natal development stage morula stage embryo stage zygote stage P blastula stage gastrula stage

20. coronary heart disease John’s coronary heart disease 20 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

21. hand John’s hand 21 fist unclenched hand instantiates at t 1 instantiates at t 2 instantiates at t 3 time folding hand, folding protein

22. 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) 22

23. independent continuant dependent continuant quality temperature types instances organism John John’s temperature 23

24. independent continuant dependent continuant quality temperature organism John John’s temperature occurrent process course of temperature changes John’s temperature history 24

25. independent continuant dependent continuant quality temperature organism John John’s temperature occurrent process life of an organism John’s life 25

26. BFO: The Very Top continuantoccurrent independent continuant dependent continuant qualitydisposition 26

27. Disposition - of a glass vase, to shatter if dropped - of a human, to eat - of a banana, to ripen - of John, to lose hair 27

28. Disposition if it ceases to exist, then its bearer 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 28

29. :. Function - of liver: to store glycogen - of birth canal: to enable transport - of eye: to see - of mitochondrion: to produce ATP functions are dispositions which are designed or selected for 29

30. 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 30

31. 31 Physical Disorder

32. :. Physical Disorder – independent continuant (part of the extended organism) A causally linked combination of physical components that is clinically abnormal. 32

33. 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 33

34. Big Picture 34

35. 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. 35

36. 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 36

37. 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 37

38. 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. 38

39. Huntington’s Disease – genetic (sure-fire) 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 39

40. 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) 40

41. 41

42. 42

43. http://code.google.com/p/ogms 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. 43

44. 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 44

45. OGMS Applied OGMS is the Ontology for General Medical Science, which provides definitions for all the terms (such as ‘disorder’, ‘symptom’, and so forth) See: http://code.google.com/p/ogms/ Axes where PRO can make contributions are, I think, as follows: Etiological Process Disorder Pathological Process Laboratory Test Result (Drug) Treatment Examples of the first 4 are given in slides 3ff.

46. Big Picture 46

47. 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).

48. 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

49. 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

50. 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

51. 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

52. Type 2 Diabetes Mellitus Etiological process – – produces Disorder – abnormal pancreatic beta cells or 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

53. 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

54. Early Onset Alzheimer’s Disease Disorder – mutations in APP, PSEN1 and PSEN2 bears Disposition – impaired APP processing realized in Pathological process – accumulation of intra- and extracellular protein in the brain produces Disorder – amyloid plaque and neurofibrillary tangles bears Disposition – of neurons to die realized in Pathological process – neuronal loss produces Disorder – cognitive brain regions damaged and reduced in size bears Disposition (disease) – Alzheimer’s dementia realized in Symptoms – episodic memory loss and other cognitive domain impairment 54

55. 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 55

56. 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 56

57. Ontology of Aging and Death

58. Ontology axioms (dying) dying part_of life of organism life of organism occupies temporal interval dying has_participant organism dying occupies temporal interval 58

59. Ontology axioms – universal truths 1. dying occupies temporal interval 2. every dying instance_of process 3. every process occupies some temporal interval 1.is an assertion about types or universals* 2.is an assertion about a relation between types and instances 3. is an assertion about instances *what ontology graphs represent 59

60. 60

61. We know when dying ends 61 Death Process boundaries Instants of Time occupy Dying

62. When does dying begin? 62 Death Process boundaries Instants of Time occupy Dying

63. When does balding begin? 63

64. An ontological question: what is aging? 64 The Aging Process Death Processes in the Organism Regions of Time occupy The Dying Process Life of Organism

65. Orthomereology 65 The Aging Process Death Processes in the Organism Regions of Time occupy The Dying Process (Normal) life of (normal) multicellular organism

66. Aging part_of life of organism 66 – Every instance of aging part_of life of some organism NOT: aging has_part dying – given progeria NOT: Life of organism has_part aging (a)a life may be cut short by early death (b)rejuvenation

67. NOT: dying part_of aging (not even of normal [non- premature] aging) 67

68. http://www.sens.org/ 68

69. We focus in what follows on ‘normal aging’? = non-premature aging which is not cut short by early death There are certain processes which are normally part of the aging process 69

70. Carlos Lopez-Otin, et al., “The Hallmarks of Aging”, Cell 153, 2013 70

71. Of the roughly 150,000 people who die each day across the globe, about two thirds die of age-related causes (senescence) Hypothesis: age-related causes =def. processes of a sort which (i) are part of the normal aging process and (ii) occur at the stage in life that is normal for aging 71

72. What does ‘normal’ mean? For anatomy we have an answer to this question 72

73. Foundational Model of Anatomy 73 Canonically (normally) human beings have 32 teeth This is part of the Bauplan of human beings US adults have an average of 24.92 teeth Thus ‘normal’  ‘statistically normal’

74. 74 represents canonical adult human anatomy = the Bauplan generated by the coordinated expression of the human organism’s own structural genes* *thus there is still a statistical dimension here, but not at the level of patient phenotypes (teeth lost in bar fights) Foundational Model of Anatomy Ontology

75. 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) Visceral Pleura Visceral Pleura Pleural Sac Parietal Pleura Parietal Pleura Anatomical Space Organ Cavity Organ Cavity Serous Sac Cavity Serous Sac Cavity Anatomical Structure Anatomical Structure Organ Serous Sac Mediastinal Pleura Mediastinal Pleura Tissue Organ Part Organ Subdivision Organ Subdivision Organ Component Organ Component Organ Cavity Subdivision Organ Cavity Subdivision Serous Sac Cavity Subdivision Serous Sac Cavity Subdivision part_of is_a 75

76. Canonically (normally) human beings have 2 lungs This is part of the Bauplan of human beings Canonically (normally) death is the terminal boundary of a process of aging This is part of the life plan of human beings 76

77. What makes premature aging non-normal? Answer: that it does not fit in the right way into the life plan for an organism of the relevant type It does not fit into the canonical cycle of stages generated by the coordinated expression of the organism’s own developmental genes 77

78. 78 Life plan (human, first 9 days)

79. From anatomy to development Canonical Bauplan = no amputation stumps, no effects of steroids, no webbed fingers … Canonical life plan = canonical sequence of life processes for an organism of this species (no early death through injury or famine, no life-changing childhood disease, no excessive studying of philosophy …) - 79

80. Where do we find a good ontology of stages? 80

81. In the life cycle of plants we have alternating generations gametophyte = whole plant in haploid stage; male and female gametes fuse to produce the zygote from which the sporophyte arises sporophyte = whole plant in diploid stage (the dominant form in vascular plants such as ferns); produces spores from which the gametophyte arises. whole plant development stage PO:0007033 gametophyte development stage PO:0028003 sporophyte development stage PO:0028002 life of whole plant PO:0025337 P P 81

82. Life cycle of Selaginella apoda (Felsen Moosfarn) 82

83. whole plant development stage PO:0007033 gametophyte development stage PO:0028003 sporophyte development stage PO:0028002 life of whole plant PO:0025337 plant spore stage PO:0025375 gametophyte vegetative stage PO:0025340 gametophyte dormant stage PO:0025342 gametophyte reproductive stage PO:0025341 gametophyte senescent stage PO:0025343 sporophyte senescent stage PO:0007017 sporophyte dormant stage PO:0007132 sporophyte reproductive stage PO:0007130 sporophyte vegetative stage PO:0007134 plant zygote stage PO:0028002 PP is_a part_ of 83 Plant Life Cycle (principal whole plant development stages)

84. 84 http://blog.botanybill.info/?p=1225 sporophyte senescent stage PO:0007017

85. Senescence for whole plants does not imply senescence for plant parts often fruit development on a whole plant is happening simultaneously with senescence of the plant in some cases, fruit doesn’t ripen until after the vegetative parts of the plant are dead 85

86. 86 http://bioportal.bioontology.org

87. Canonical whole (human) organism stages 87 whole human development stage post-natal development stage aging stage reproductive stage maturation stage growth stage P life of whole human pre-natal development stage morula stage embryo stage zygote stage P blastula stage gastrula stage

88. From birth to death 88 whole human development stage post-natal development stage life of whole human aging stage reproductive stage maturation stage growth stage P

89. How to understand the aging stage Aging not part of the life plan for multicellular organisms like us aging is a disease; it is a deviation (or set of deviations) from this life plan, which can in principle be rectified by treatment or engineering (SENS) – thus it is not a stage at all aging is a post-reproductive pseudo-stage: (some) organisms manage to survive after the (last genuine) stage where they can reproduce; to be alive in this pseudo-stage is a lucky accidentc Aging is part of the life plan; it is a genuine stage in the life of the organism, a reflection of its evolutionary program, and thus it must be in some sense adaptive what is programmed for by the genome cannot be a disease characteristic disease-like correlates of aging are not diseases 89

90. How to deal with the Boorsean problems raised by ‘typical diseases of old age’ (benign prostatic hypertrophy)? old Boorse: they are not diseases because they are statistically typical for the age group formed by aged people (they are like menopause …) new Boorse: they are diseases, because typicality is to be determined by the reference class formed by healthy young adults this seems ad hoc See C. Boorse, “Replies to recent critics”, August 2012 90

91. Boorse (Replies to critics) – it is not ad hoc: “biologists, though they catalogue immature stages, do not usually catalogue stages of senescence” 91

92. old Boorse A disease [later, pathological condition] is a type of internal state which impairs health, i.e., reduces one or more functional abilities below typical efficiency in a way that is detrimental to their individual survival [or] reproduction 92

93. new (pseudo-)Boorse A disease [later, pathological condition] in the aged is a type of internal state which impairs health, i.e., reduces one or more functional abilities below typical efficiency for young adults in a way that is detrimental to their individual survival [or] reproduction “All functional declines with age to far below the young-adult mean would be pathological. “ So menopause is a disease 93