ogms ontology for general medical science 1

OGMSOntology for General Medical

Science

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

1

Basic Formal Ontology

continuant occurrent

independentcontinuant

dependentcontinuant

organism

2http://www.ifomis.org/bfo

:.

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

:.

Users of BFOOntology 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

Basic Formal Ontology

continuant occurrent

independentcontinuant

dependentcontinuant

organism

5

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

Occurrents

• processes, events, happenings– your life– this process of accelerated cell

division

7

Qualitiestemperatureblood pressuremass...

are continuantsthey exist through time while undergoing changes

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Qualitiestemperature / blood pressure /

mass ...are dimensions of variation within the structure of the entitya quality is something which can change while its bearer remains one and the same

9

A Chart representing how John’s temperature

changes

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A Chart representing how John’s temperature

changes

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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

BFO: The Very Top

continuant

independentcontinuant

dependentcontinuant

quality

occurrent

temperature 13

clear division of types and instances

independentcontinuant

dependentcontinuant

quality

temperature types

instances

organism

John John’s

temperature 14

Blinding Flash of the Obvious

temperature types

instances

organism

John John’s

temperature .

15

inheres_in

temperature types

instances

John’s temperature

16

37ºC37.1º

C37.5º

C37.2º

C37.3º

C37.4º

C

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

instantiates at t5

instantiates at t6

human types

instances

John

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embryo

fetus adultneonat

einfant child

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

instantiates at t5

instantiates at t6

human phase types

instances

John

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embryo

stage

fetusstage

adultstage

neonate

stage

infantstage

childstage

has at t1 has at t2 has at t3 has at t4 has at t5 has at t6

Canonical whole (human) organism stages

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blastula stage

gastrula stage

coronary heart disease

John’s coronary heart disease

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asymptomatic (‘silent’) infarction

early lesions and small

fibrous plaques

stable angina

surface disruption of plaque

unstable angina

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

instantiates at t5

time

hand

John’s hand

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fistunclenche

d hand unclenche

d hand

instantiates at t1

instantiates at t2

instantiates at t3

time

folding hand, folding protein

Temperature subtypesDevelopment-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)

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independentcontinuant

dependentcontinuant

quality

temperature types

instances

organism

John John’s

temperature

23

independentcontinuant

dependentcontinuant

quality

temperature

organism

John John’s

temperature

occurrent

process

course of temperature

changes

John’s temperature history

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independentcontinuant

dependentcontinuant

quality

temperature

organism

John John’s

temperature

occurrent

process

life of an organism

John’s life

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BFO: The Very Top

continuant occurrent

independentcontinuant

dependentcontinuant

quality disposition

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

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Dispositionif it ceases to exist, then its bearer is physically changedits realization occurs when its bearer is in some special physical circumstancesits realization is what it is in virtue of the bearer’s physical make-up

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:.

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

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independentcontinuant

dependentcontinuant

function

to seeeye

John’s eye function of John’s eye: to see

occurrent

process

process of seeing

John seeing

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Physical Disorder

:.

Physical Disorder

– independent continuant (part of the extended organism)

A causally linked combination of physical components that is clinically abnormal.

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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: baldness33

Big Picture

34

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

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

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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 37

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.

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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

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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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41

42

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.

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independentcontinuant

dependentcontinuant

disposition

diseasedisorder

John’s disordered

heart

John’s coronary heart

disease

occurrent

process

course of disease

course of John’s disease

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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.

Big Picture

46

Influenza - infectious

• Etiological process - infection of airway epithelial cells with influenza virus

– produces

• Disorder - viable cells with influenza virus

– bears

• Disposition (disease) - flu

– realized_in

• Pathological process - acute inflammation

– produces

• Abnormal bodily features

– recognized_as

• Symptoms - weakness, dizziness

• Signs - fever

Symptoms & Signs used_in

Interpretive process produces

Hypothesis - rule out influenza suggests

Laboratory tests produces

Test results - elevated serum antibody titers used_in

Interpretive process produces

Result - diagnosis that patient X has a disorder that bears the disease flu

But the disorder also induces normal physiological processes (immune response) that can results in the elimination of the disorder (transient disease course).

Huntington’s Disease - genetic

• Etiological process - inheritance of >39 CAG repeats in the HTT gene– produces

• Disorder - chromosome 4 with abnormal mHTT– bears

• Disposition (disease) - Huntington’s disease– realized_in

• Pathological process - accumulation of mHTT protein fragments, abnormal transcription regulation, neuronal cell death in striatum– produces

• Abnormal bodily features– recognized_as

• Symptoms - anxiety, depression• Signs - difficulties in speaking and

swallowing

Symptoms & Signs used_in

Interpretive process produces

Hypothesis - rule out Huntington’s suggests

Laboratory tests produces

Test results - molecular detection of the HTT gene with >39CAG repeats used_in

Interpretive process produces

Result - diagnosis that patient X has a disorder that bears the disease Huntington’s disease

HNPCC - genetic pre-disposition

• Etiological process - inheritance of a mutant mismatch repair gene– produces

• Disorder - chromosome 3 with abnormal hMLH1– bears

• Disposition (disease) - Lynch syndrome– realized_in

• Pathological process - abnormal repair of DNA mismatches– produces

• Disorder - mutations in proto-oncogenes and tumor suppressor genes with microsatellite repeats (e.g. TGF-beta R2)– bears

• Disposition (disease) - non-polyposis colon cancer

Cirrhosis - environmental exposure

• Etiological process - phenobarbitol-induced hepatic cell death

– produces

• Disorder - necrotic liver

– bears

• Disposition (disease) - cirrhosis

– realized_in

• Pathological process - abnormal tissue repair with cell proliferation and fibrosis that exceed a certain threshold; hypoxia-induced cell death

– produces

• Abnormal bodily features

– recognized_as

• Symptoms - fatigue, anorexia

• Signs - jaundice, splenomegaly

Symptoms & Signs used_in

Interpretive process produces

Hypothesis - rule out cirrhosis suggests

Laboratory tests produces

Test results - elevated liver enzymes in serum used_in

Interpretive process produces

Result - diagnosis that patient X has a disorder that bears the disease cirrhosis

Systemic arterial hypertension

• Etiological process – abnormal reabsorption of NaCl by the kidney

– produces

• Disorder – abnormally large scattered molecular aggregate of salt in the blood

– bears

• Disposition (disease) - hypertension

– realized_in

• Pathological process – exertion of abnormal pressure against arterial wall

– produces

• Abnormal bodily features

– recognized_as

• Symptoms -

• Signs – elevated blood pressure

Symptoms & Signs used_in

Interpretive process produces

Hypothesis - rule out hypertension suggests

Laboratory tests produces

Test results - used_in

Interpretive process produces

Result - diagnosis that patient X has a disorder that bears the disease hypertension

Type 2 Diabetes Mellitus

• Etiological process –

– produces

• Disorder – abnormal pancreatic beta cells 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

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

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

54

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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Ontology of Aging and Death

Ontology axioms (dying)

• dying part_of life of organism

• life of organism occupies temporal interval

• dying has_participant organism

• dying occupies temporal interval

58

Ontology axioms – universal truths1. dying occupies temporal interval 2. every dying instance_of process3. every process occupies some temporal interval

1.is an assertion about types or universals*2.is an assertion about a relation between types and instances3. is an assertion about instances

*what ontology graphs represent59

60

We know when dying ends

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Death

Process boundaries

Instants of Time

occupy

Dying

When does dying begin?

62

Death

Process boundaries

Instants of Time

occupy

Dying

When does balding begin?

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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

Orthomereology

65

The Aging Process

Death

Processes in the Organism

Regions of Time

occupy

The Dying Process

(Normal) life of (normal) multicellular

organism

Aging part_of life of organism

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– 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

http://www.sens.org/ 68

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

process69

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

70

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

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

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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’

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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

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

75

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

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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 typeIt does not fit into the canonical cycle of stages generated by the coordinated expression of the organism’s own developmental genes

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Life plan (human, first 9 days)

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 …) -

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Where do we find a good ontology of stages?

80

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 plantPO:0025337

PP

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Life cycle of Selaginella apoda (Felsen Moosfarn)

82

whole plant development

stagePO:0007033

gametophyte development

stagePO:0028003

sporophyte development

stagePO:0028002

life of whole plant

PO:0025337

plant spore stage

PO:0025375

gametophyte vegetative stage

PO:0025340

gametophyte dormant stagePO:0025342

gametophyte reproductive

stagePO:0025341

gametophyte senescent stage

PO:0025343

sporophyte senescent

stagePO:0007017

sporophyte dormant stagePO:0007132

sporophyte reproductive

stagePO:0007130

sporophyte vegetative stage

PO:0007134

plant zygote stage

PO:0028002

PP

is_apart_

of

83

Plant Life Cycle (principal whole plant development stages)

84http://blog.botanybill.info/?p=1225

sporophyte senescent stagePO:0007017

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

http://bioportal.bioontology.org

Canonical whole (human) organism stages

87

blastula stage

gastrula stage

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

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

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

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

91

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

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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