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River Flow Model of
Diseases
Riichiro Mizoguchi, Kouji Kozaki,
Hiroko Kou, Yuki Yamagata
ISIR, Osaka University
Takeshi Imai, Kayo Waki, Kazuhiko Ohe
Department of Medical Informatics, Graduate School of Medicine
The University of Tokyo
1
Agenda of my talk
Our goal
 Ontological discussion on a new definition of diseases

River flow model of diseases
 Ontology of causal chains
 Cumulative continuous processes


A new computational model of diseases
Core causal chain
 Clinical imbalance

2
OGMS:
Ontology for General Medical Science


supervised by Barry Smith
It includes fundamental clinical terms such as



Disorder, Pathological process, Disease, Etiological process,
Disease course, etc.
Pros: Sound and very carefully defined
Cons:
(a) Disease is defined as a disposition which is a potentiality for the
realization of chains of physical/physiological changes in the human
body.
(b) Although they mention “elevated level of glucose in the blood” to
talk about diabetes, there is no type it instantiates in OGMS.
3
Our goal

To augment OGMS by concretizing the definition of
diseases in it
To do that, we propose:
1. an clinician-friendly definition of diseases as causal
chains of clinical disorders
2. a new type for talking about so-called
“major pathological condition”
3. an idea of imbalance as a concretization of disposition
4. a computational model of diseases to make our
proposals operational
4
Some definitions
1. A enacts B =def A is a continuant and B is an external process of A who/which
participates in it as a whole in which it is maximal among participants who/which
play the same role in the process. Examples: when you walk, you (not your legs)
enact your walking, the motion of your legs is internal process of your walking
which you cannot enact.
2. Event =def a non-dissective unitary entity in the temporal space. Examples include a
conference, an arrival, etc. It must be dealt with as a whole in any case.
3. Process =def a dissective non-unitary entity in the temporal space like walking,
singing, etc.
An event is constituted of processes, except an instant event.
4. External process of A =def a process enacted by a continuant A.
5. Internal process of A =def a process enacted by a part of A. Examples: In a
walking process of A, leg motion is an internal process of A whose external process
is the walking.
6. Object =def anything which enacts a process [2]
[2] Antony Galton and Riichiro Mizoguchi: The water falls but the waterfall does not fall: New perspectives on
objects, processes and events, Applied Ontology 4(2), pp. 71-107 (2009)
5
Definition 1: Disease

A disease is a dependent continuant constituted of one or
more causal chains of clinical disorders appearing in a
human body and initiated by at least one disorder.


In OGMS: disposition (i) to undergo pathological processes that
(ii) exist in an organism because of one or more disorders in that
organism (excerpt from OGMS paper)
The main issue here is

How is a causal chain of clinical disorders a
continuant?
6
Informal account of our
river flow model of diseases





A river is similar to a disease as a causal chain
After it has been born as a river (as a disease), then it extends
further (causes some disorders) to another lake or to the sea. While
extending, it branches (the branching perhaps causes the
appearance of another disorder or symptom).
Finally, it may dry up because of climate change (cure).
Thus, the life of a river corresponds well to the life of a disease. Thus
– in concordance with OGMS – both a river and a disease are
continuants
Note here that a river is not a disposition
7
What is a causal chain
 Causal
chain =def a chain of entities linked by causality. There can be
a causal chain of disorders, causal chain of processes, causal chain
of events, etc.[1]
[1] What constitutes causality is outside the scope of our research.
Two kinds of processes:
1. Cumulative continuous process: a process that proceeds without
completing the current process/event at every instant in time
 ⇒ causal chain of processes
2. Non-cumulative process: a process that proceeds by completing the
current process at every instant in time
 ⇒ causal chain of events
8
Cumulative continuous process






Examples: a fall of water and a river flow
We know waterfall and river are a continuant associated with these two
processes. Following the definition of object in
, what we need is to
identify processes which each of these two enacts.
“The water falls, but the waterfall doesn’t fall”. That is, what a waterfall is
doing is not the water falling but migration upstream as it carves its way into
the rock
What a river enacts is not the water flow but change of the shape of its
course, and the water flow of the river is its internal process
Similarly, a causal chain as a flow of causality (propagation of causality) is
an internal process of the causal chain which is a continuant that enacts
branching, extension, and diminishing processes as its external
processes
Any disease has dynamic flows of the propagation of causality as its
internal processes, and is the enactor of processes such as branching
and extending its causal chain of disorders as its external processes
9
From Ontology
to a computational model
10
Computational model of diseases

Two kinds of diseases
(Type1) those whose etiological and pathological processes are well-understood and
(Type2) other diseases, and
 we mainly discuss type 1 diseases, but it also applies to type 2 diseases.

Definition 2: Is-a relation between diseases


Disease A is a super class of disease B if all of the causal chains at the class
level of disease A are included in those of disease B. The inclusion of nodes
(disorders) is judged by taking an is-a relation between the nodes into account,
as well as sameness of the nodes.
Definition 3: Core causal chain of a disease


The causal chain of a disease included in the chains of all its subclass diseases
is defined as the core causal chain of the disease. An example of the core causal
chain in the case of (non-latent) diabetes is:
deficiency of insulin  elevated level of glucose in the blood
11
Clinical imbalance model
as a concretization of disposition





From now on, I discuss only Type 1 diseases
In OGMS, a disposition to diabetes inheres in <deficiency of insulin>
The idea of disturbance of homeostasis to capture <deficiency of insulin>
For each parameter participating in homeostasis, there must be the notion of
balance and regulation functions
Definition 4: Clinical imbalance



Clinical imbalance is a local phenomenon of homeostasis in the human body and is
defined as a state where the difference between the amounts of supply and demand is
out of the range specified for the parameter under consideration.
In the case of diabetes, the supply is the performed amount of the insulin
operation and the demand is the required amount of the insulin operation.
In a normal case, the difference between the two amounts is within a certain range,
that is to say, “balanced”. In an abnormal case, on the other hand, an imbalance
(deficiency of insulin) occurs, which can be a disposition to the initiation of the
pathological process of diabetes.
12
Use cases of
the imbalance model


Four qualitative values
We applied the imbalance model to



Diabetes including latent one
Infectious diseases (including Hepatitis)
Osteoporosis




fracture caused by osteoporosis is modeled using medium value for
demand to resist the normal pressure given as an external cause and
small value for supply to resist external pressure
Hyperlipidemia
Ischemic heart diseases
Etc.
13
Concluding remarks





A new definition of diseases has been proposed within the
framework of OGMS
A disease is understood as a causal chain of clinical
disorders
OGMS’s disposition has been concretized as an
Imbalance model based on the OGMS’s notion of
homeostasis
We obtained a computational model of diseases
We are now building an ontology of about 6000 diseases of
12 different divisions
14
Thank you!
(Especially to Barry who kindly polished up
my poor English)
15
Definition of diseases in
OGMS

a disposition (i) to undergo pathological processes
that (ii) exist in an organism because of one or more
disorders in that organism (excerpt from OGMS paper)

This is a beautiful definition from a philosophical point of
view. At the same time, however, it is not very friendly to
clinicians because it lacks practicality
16
The life of a river
might dry up
branches
overflow
would reach
another lake
reaches the sea
minimal flow
extends and changes
its route, etc.
17
An example of causal chain of
events
Each event is caused by a completed previous event.
Duration
of events
t0
t1 < t2
t3 < t4
t5 < t6
t
t7
…
A person is
injured by a
car accident
…
A witness
calls an
ambulance
An
ambulance
arrives
it arrives at
a hospital
Nodes(Event/Process)
Causality
(Causal relationship)
• The whole event corresponds to non-cumulative process
18
An example of causal chain
of a disease
Each process is not completed (keeps going) at every instant in
time while the whole process is proceeding.
A continuous
process
Duration
of process
t1
t2
…
A blood
The cross
clot grows
is
section of
growing． blood vessel
reduces
is reducing.
t
…
Amount of Cells are
die
oxygen
dying.
supplied is
reduces
reducing.
Disorder
Causality
(Causal relationship)
• It is a cumulative continuous process
• So, the issue is how to derive a continuant from
a cumulative continuous process
19
20
Homeostasis in OGMS

a disposition of the whole organism (or of some causally
relatively isolated part of the organism, such as a single
cell) to regulate its bodily processes in such a way as
(1) to maintain bodily qualities within a certain range or
profile and
(2) to respond successfully to departures from this range
caused by internal influences or environmental
influences such as poisoning
21
Types of diabetes constituted
of causal chains
possible causes and effects
…
…
Type I diabetes
…
Destruction of
Lack of insulin I
pancreatic
in the blood
beta cells
…
…
…
Diabetes
Deficiency
of insulin
Elevated level
of glucose in
the blood
Diabetes-related
Blindness
loss of sight
…
Core causal chain of
non-latent diabetes
Long-term steroid
treatment
Legend
…
Disorder (nodes)
…
Steroid diabetes
…
…
Causal Relationship
Colored
regions
Causal chain of a disease
(each color represents a disease)
22
A representation of the
clinical imbalance model
(possible)Maximal Performing
amount of insulin amount of insulin Diabetes
Destruction of
operation
operation(supply)
pancreatic Lack of insulin I
Elevated level
beta cells
in the blood
of glucose in
imbalance the blood
Type I diabetes
…
Steroid diabetes
Diabetes-related
Blindness
Imbalance
outcome
…
Long-term steroid
treatment
…
Balance between
supply and demand
Clinical imbalance
…
loss of sight
…
Required amount
of insulin operation
(demand)
…
23
Four qualitative values
(possible)
Performing
Max imal amount amount of the
of the operation operation (supply)
balance
Balance between
supply and demand
(possible)
Performing
Max imal amount amount of the
of the operation operation (supply)
balance
Balance between
supply and demand
Required amount of
the operation (demand)
Required amount of
the operation (demand)
(a) Normal situation
(b) Hard or very active situation
Legends of values
(possible)
Performing
Max imal amount amount of the
of the operation operation (supply)
imbalance
Demand side Supply side
Very Large
Large
Balance between
supply and demand
Required amount of
the operation (demand)
(c) When demand increases
up to very large
Middle
Small
24
Latent diabetes in daily life
defective
insulin secretion
(Possible) maximal
amount of insulin
operation
Performing amount
of insulin operation
Balance
Medium
Medium
insulin
resistance
Medium
…
Balance between
supply and demand
Required amount of insulin
operation (demand)
Daily mean
load
Clinical imbalance
25
increased demand of
Manifestation
(Latent diabetes) insulin supply
defective
insulin secretion
(Possible) maximal
amount of insulin
operation
Imbalance
Medium
insulin
resistance
Performing amount
of insulin operation
Imbalance
Outcome
Medium
Large
Balance between
supply and demand
Required amount of insulin
operation (demand)
overeating
Elevated level
of glucose in
the bood
Exceed the
daily mean
load level
Clinical Imbalance
26
Infectious disease
Two-stage imbalance model for infectious
diseases:
① Invasion stage
②Onset stage
Invasion (Infection) stage
Onset stage
break the
biological
defense
onset
Invasion
colonization
proliferation
27
Common cold
Invasion stage
Onset stage
t1
t2
External
cause
virus
virus invasion
virus infection
runny nose,
throat pain
(Possible) maximal amount
of immune defense against
invasion
Performing amount
of defense against
Large
No virus
Medium
no deficiency of
immune defense
virus
invasion
time
Onset
Onset
(Possible) maximal amount
of defense against outcome
Performing amount
of defense against
outcome
invasion
Medium
t3
No onset stage
deficiency of
defense
balance
Required
amount
Medium
of defense
against invasion (demand)
28
28
Invasion stage
t1
Onset stage
t2
pathogen
External
cause
pathogen
Invasion
runny nose,
throat pain
(Possible) maximal amount
of immune defense against
Performing amount
of defense against
invasion(supply)
Imbalance
Outcome
Imbalance
imbalance of onset
pathogen
deficiency of
immune defense Infection
against invasion
Required amount
Pathogen of defense
invasion against invasion (demand)
hepatic fibrosis
Performing amount
of defense against
Large
Pathogen
Large
Very
large
Onset
(Possible) maximal amount
of defense against outcome
invasion
time
Onset
pathogen infection
imbalance of pathogen invasion defense
Large
t3
outcome
Imbalance
Outcome
Imbalance
Large
Very
large
deficiency of
defense against onset
onset
Required amount
of defense
Other attack against outcome (demand)
29
Hepatitis（ asymptomatic children）
(Possible) maximal amount
of immune defense against virus
invasion
Performing amount of
immune defense against
Very
virus invasion (supply)
small
Imbalance
In the childhood, due to immune system is
immature, the maximal amount of immune
defense was very small
no deficiency of Hepatitis virus
immune defense Infection
Small
Hepatitis virus
invasion
Small
Required amount
of defense
against invasion (demand)
Along with the development of
immune system, symptom caused by
excess immune defense appears.
excess immune defense (supply)
destruction of hepatic cells→ hepatic fibrosis→ cirrhosis
Very
Large
Performing amount of
immune defense
(supply)
Very
Large
no deficiency of onset
immune defense
Large
Adverse effect of immune defense
destruction
of hepatic
cells
balance
demand
30
Osteoporosis
Osteoporosis
fracture
(Possible)
Performing amount
maximal
of bone formation
amount of
(supply)
bone formation
menopause
Small
Small
Imbalance
Imbalance
Outcome
internal cause
Small
Large
osteoclast
activation
external cause
Performing amount
of resist external pressure
(supply)
(Possible) maximal
amount of resist
Imbalance
external pressure
Imbalance
Outcome
bone
deficiency of
bone formation density
loss
Small
Small
Medium
deficiency of
fracture
resist external
pressure
amount of
external pressure
(demand)
amount
of bone resorption
(demand)
falling
steroid
administration
31
31
Hyperlipidemia
genetic
factors
(Possible) maximal
amount of lipid
efflux
Performing amount
of lipid efflux
Imbalance
Small
Small
Large
environmental
factors
(high-fat diet…)
Imbalance
Outcome
Balance between
efflux and influx of
lipids
Lipid influx
Elevated level of
lipid in the blood
(hyperlipidemia)
Intolerable load on the
lipid influx
Clinical imbalance
32
33
How can we correctly capture
latent diabetes?
Glucose uptake
regulation
Insulin
secretion I
I
Pancreatic
β cell
I
I
I
I
G G
G G
G
G
Liver
Overload!
Muscle …
GG G
blood
LatentType
diabetes：There
1 Diabetes： is
chronic
no symptom
severe elevated
in the daily
life, but
blood
will glucose
have problems
by destruction
with elevated
of insulinblood
glucose
producing
by somebeta-cells
loading on insulin action. 34
34
Malaria
Invasion stage
Onset stage
t1
t2
t3
Plasmodium
External
cause
plasmodium
invasion
(Possible) maximal amount
of immune defense action
Onset
plasmodium infection
Performing amount
of defense action
Large (supply)
Imbalance
time
Onset of disease
Imbalance
Outcome
brain damage
（Cerebral Malaria）
Plasmodium
Large
External
cause
Infection
deficiency of
Very
immune defense (liver cell)
Large
action
Required amount
of defense action (demand)
plasmodium
invasion
via a mosquito bite
destruction of
red blood cells
anemia
35
Imbalance model
•Ischemic heart disease myocardial infarction
Imbalance: O2 demand ｖｓ． O2 supply
Imbalance outcome： ischemic necrosis
•Osteoporosis
Imbalance: bone resorption ｖｓ．bone formation
Imbalance outcome： bone density loss
•Fracture
Imbalance: external pressure ｖｓ． Resistance to external pressure
–Fracture caused by osteoporosis
Imbalance: external pressure
medium
–Fracture caused by traffic accident
Imbalance: external pressure
very large
ｖｓ． Resistance to external pressure
Imbalance Outcome
small
Fracture
ｖｓ． Resistance to external pressure
Imbalance Outcome
medium
Fracture
•Hyperlipidemia
Imbalance: lipid influx ｖｓ． lipid efflux in the blood
Imbalance outcome： hyperlipidemia (elevated levels of lipids in the blood)
36
Supplement


the cases of resistant peripheral receptors which are also covered by
our model.
The model except the imbalance model is applicable to either type of
diseases thanks to the flexibility of the granularity and the degree of
“well-understood”-ness by putting “unknown” node of cause
37
An example of causal chain of
processes
Continuous
processes
Duration
of process
t1
…
The engine is The shaft is
generating transmitting
torque
the torque
to wheels.
t
t2
…
Wheels are
The car is
transforming moving
the torque to forward
forward-going
force
Nodes(Event/Process)
Causality
(Causal relationship)
Each process is not completed (keeps going) at every instant in
time while the whole process is proceeding.
• A causal chain as a flow of causality (propagation of causality) is internal
process (=cumulative continuous process) of the causal chain.
- The flow corresponds to a flow of the water in a river.
38
Causal chain
1.
Causal chain =def a chain of entities linked by causality. There can
be a causal chain of disorders, causal chain of processes, causal
chain of events, etc.[1]
[1] What constitutes causality is outside the scope of our research.
39
Types of diabetes constituted
of causal chains
possible causes and effects
…
…
Type I diabetes
…
Destruction of
Lack of insulin I
pancreatic
in the blood
beta cells
…
…
Diabetes
…
Elevated level
Deficiency of glucose in
of insulin the blood
Diabetes-related
Blindness
loss of sight
…
…
Legends
Long-term steroid
treatment
…
…
Disorder (nodes)
Causal Relationship
Steroid diabetes
…
Core causal chain of a disease
(each color represents a disease)
40
41
Healthy person
Invasion stage
Onset stage
t1
t2
External
cause
virus
virus invasion
virus infection
runny nose,
throat pain
(Possible) maximal amount
of imumne defense against
invasion
Small
Performing amount
of defense against
invasion
Small
Small
virus
invasion
t3
time
Onset
Onset
(Possible) maximal amount
of defense against outcome
Performing amount
of defense against
outcome
No virus
No onset stage
deficiency of
defense
no deficiency of
immune defense
balance
Required amount
of defense
against invasion (demand)
42
42
Computational disease model
…
…
Causal
Relationship
clinical
disorder
…
clinical
disorder
causal chain
…
43
43
Types of diabetes constituted of causal chains
possible causes and effects
…
…
Type I diabetes
…
Destruction of
Lack of insulin I
pancreatic
in the blood
beta cells
…
…
…
Diabetes
Deficiency
of insulin
Elevated level
of glucose in
the blood
Diabetes-related
Blindness
loss of sight
…
Core causal chain of
diabetes
Long-term steroid
treatment
Legend
…
…
Steroid diabetes
…
…
Disorder (nodes)
Causal Relationship
Causal chain of a disease
(each color represents a disease)
44
Diabetes
Clinical imbalance model
(possible)Maximal Performing
amount of insulin amount of insulin
operation
operation(supply) Diabetes
Destruction of
Lack of insulin
pancreatic
Elevated level
in the blood
beta cell
of glucose in
imbalance the bood
…
Diabetes related
Blindness
Type I diabetes
loss of sight
…
Long term steroid
treatment
…
Steroid diabetes
Balance between
supply and demand
Clinical imbalance
…
…
Required amount of
insulin operation
(demand)
…
45
Demand
Side
Supply
Side
Very Large
Cause
(Possible)Maxima
l amount of the
operation
Large
Performing
amount of the
operation(supply)
Medium
Imbalance
Outcome
Imbalance
Small
internal cause
Balance between
supply and demand
Required amount of the
operation(demand)
external cause
Clinical Imbalance
46
46
Type I (non-latent) diabetes
Intolerable load on the
demand side
(Possible) maximal
amount of insulin
operation
Performing amount
of insulin operation
Imbalance
Small
Imbalance
Outcome
Small
defective
insulin secretion
Medium
Balance between
supply and demand
Required amount of insulin
operation (demand)
Elevated level
of glucose in
the blood
Daily mean
load
Clinical imbalance
47
Informal account of diseases





After it begins to exist, it undergoes extending, branching, and
disappearing processes before the patient is cured, not always though
Such an entity (a disease) can change according to its phase while
keeping its identity, and hence it seems to be a continuant
It could be something related directly to a manifestation process
of the disease rather than a disposition itself
At the same time, a disease should not be a process (occurrent)
This is why defining a disease is difficult
Although the introduction of the notion of disposition is one way to
solve this problem, disposition is a bit too far from what its
manifestation process implies/suggests
48