Transcript OGMS - University at Buffalo

OGMS
Ontology for General Medical
Science
http://code.google.com/p/ogms
1
Basic Formal Ontology
continuant
independent
continuant
occurrent
dependent
continuant
organism
http://www.ifomis.org/bfo
2
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)
3
ChemAxiom – Ontology for Chemistry
:.
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
4
US Army Command and Control Ontology :.
Basic Formal Ontology
continuant
independent
continuant
occurrent
dependent
continuant
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
Qualities
temperature
blood pressure
mass
...
are continuants
they exist through time while
undergoing changes
8
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
A Chart representing how
John’s temperature changes
10
A Chart representing how
John’s temperature changes
11
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
independent
continuant
occurrent
dependent
continuant
quality
temperature
13
clear division of types and instances
independent
continuant
dependent
continuant
quality
organism
John
temperature
John’s
temperature
types
instances
14
Blinding Flash of the Obvious
inheres_in
organism
John
temperature
John’s
temperature
types
instances
15
types
temperature
37ºC
instantiates
at t1
37.1ºC
instantiates
at t2
37.2ºC
instantiates
at t3
37.3ºC
instantiates
at t4
37.4ºC
instantiates
at t5
37.5ºC
instantiates
at t6
John’s temperature
instances
16
types
human
embryo
instantiates
at t1
fetus
instantiates
at t2
neonate
instantiates
at t3
infant
child
instantiates
at t4
instantiates
at t5
adult
instantiates
at t6
John
instances
17
human phase
embryo
stage
has at t1
fetus
stage
has at t2
types
neonate
stage
infant
stage
child
stage
adult
stage
has at t3
has at t4
has at t5
has at t6
John
instances
18
Canonical whole (human) organism stages
whole human development
stage
life of whole human
pre-natal
development
stage
P
P
post-natal
development
stage
aging stage
zygote
stage
gastrula
stage
embryo
stage
blastula
stage
morula stage
growth stage
reproductive
stage
maturation stage
19
coronary heart
disease
early lesions
and small
fibrous plaques
instantiates
at t1
asymptomatic
(‘silent’)
infarction
instantiates
at t2
surface
disruption of
plaque
instantiates
at t3
unstable
angina
instantiates
at t4
stable
angina
instantiates
at t5
John’s coronary heart disease
time
20
folding hand, folding protein
hand
unclenched
hand
instantiates
at t1
fist
instantiates
at t2
unclenched
hand
instantiates
at t3
John’s hand
time
21
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
independent
continuant
dependent
continuant
quality
organism
John
temperature
types
John’s
temperature
instances
23
independent
continuant
organism
John
dependent
continuant
occurrent
quality
process
temperature
John’s
temperature
course of
temperature
changes
John’s
temperature history
24
independent
continuant
organism
John
dependent
continuant
occurrent
quality
process
temperature
John’s
temperature
life of an
organism
John’s
life
25
BFO: The Very Top
continuant
independent
continuant
occurrent
dependent
continuant
quality
disposition
26
Disposition
-
of
of
of
of
a glass vase, to shatter if dropped
a human, to eat
a banana, to ripen
John, to lose hair
27
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
Function
-
of
of
of
of
liver: to store glycogen
birth canal: to enable transport
eye: to see
mitochondrion: to produce ATP
functions are dispositions which are
designed or selected for
29
:.
independent
continuant
eye
John’s eye
dependent
continuant
occurrent
function
process
to see
process of
seeing
function of John’s
eye: to see
John seeing
30
Physical Disorder
31
Physical Disorder
– independent continuant
(part of the extended
organism)
A causally linked combination
of physical components that is
clinically abnormal.
32
:.
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
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
36
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.
38
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
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
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.
43
independent
continuant
disorder
John’s
disordered
heart
dependent
continuant
occurrent
disposition
process
disease
course of
disease
John’s
coronary heart
disease
course of John’s
disease
44
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 - phenobarbitolinduced 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 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
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
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
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 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
We know when dying ends
Process
boundaries
occupy
Dying
Death
Instants of Time
61
When does dying begin?
Process
boundaries
occupy
Dying
Death
Instants of Time
62
When does balding begin?
63
An ontological question: what is aging?
Life of
Organism
Processes in
the Organism
The Aging
Process
The Dying
Process
Death
occupy
Regions of Time
64
Orthomereology
(Normal) life of
(normal) multicellular
organism
Processes in
the Organism
The Aging
Process
The Dying
Process
Death
occupy
Regions of Time
65
Aging part_of life of organism
– 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
66
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
process
69
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
71
What does ‘normal’ mean?
For anatomy we have an answer to
this question
72
Foundational Model of Anatomy
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’
73
Foundational Model of Anatomy Ontology
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)
74
Anatomical
Structure
Anatomical Space
Organ Cavity
Subdivision
Organ
Cavity
Organ
Serous Sac
Cavity
Subdivision
Serous Sac
Cavity
Serous Sac
Organ
Component
Organ
Subdivision
Pleural Sac
Pleural
Cavity
Parietal
Pleura
Interlobar
recess
Organ Part
Mediastinal
Pleura
Tissue
Pleura(Wall
of Sac)
Visceral
Pleura
Mesothelium
of Pleura
75
Foundational Model of Anatomy (FMA)
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
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
Life plan (human, first 9 days)
78
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
Where do we find a good
ontology of stages?
80
whole plant
development stage
PO:0007033
life of whole plant
PO:0025337
gametophyte
development stage
PO:0028003
P
P
sporophyte
development stage
PO:0028002
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
81
which the gametophyte arises.
Life cycle of Selaginella apoda (Felsen Moosfarn)
82
whole plant
development
stage
PO:0007033
gametophyte
development
stage
PO:0028003
plant spore
stage
PO:0025375
life of whole
plant
PO:0025337
P
gametophyte
senescent stage
PO:0025343
gametophyte
vegetative stage
PO:0025340
gametophyte
dormant stage
PO:0025342
gametophyte
reproductive
stage
PO:0025341
P
sporophyte
development
stage
PO:0028002
sporophyte
senescent
stage
PO:0007017
plant zygote
stage
PO:0028002
sporophyte
vegetative stage
PO:0007134
sporophyte
dormant stage
PO:0007132
sporophyte
reproductive
stage
PO:0007130
Plant Life Cycle (principal whole
plant development stages)
is_a
part_
of
83
sporophyte senescent stage
PO:0007017
http://blog.botanybill.info/?p=1225
84
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
http://bioportal.bioontology.org
86
Canonical whole (human) organism stages
whole human development
stage
life of whole human
pre-natal
development
stage
P
P
post-natal
development
stage
aging stage
zygote
stage
gastrula
stage
embryo
stage
blastula
stage
morula stage
growth stage
reproductive
stage
maturation stage
87
From birth
to death
whole human
development stage
life of whole human
P
post-natal
development stage
growth stage
maturation stage
aging stage
reproductive
stage
88
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
92
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
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