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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 OheDepartment of Medical Informatics, Graduate School of Medicine
The University of Tokyo
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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
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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.
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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 disposition4. a computational model of diseases to make our
proposals operational
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Some definitions1. A enacts B =def A is a continuant and B is an external process of A who/which partic
ipates 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 walkin
g 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)
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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?
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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
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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 processes2. Non-cumulative process: a process that proceeds by completing the
current process at every instant in time ⇒ causal chain of events
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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
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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
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Clinical imbalance modelas 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 bala
nce 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.
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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.
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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
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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
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The life of a river
overflow
minimal flow reaches the sea
branches
would reachanother lake
might dry up
extends and changesits route, etc.
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An example of causal chain of events
…
Causality (Causal relationship)
A person is injured by a car accident
A witness calls an ambulance
An ambulance arrives
…
t
Duration of events
t1 t2 t3 t4 t5 t6
Each event is caused by a completed previous event.
• The whole event corresponds to non-cumulative process
t0 t7
it arrives ata hospital
< <<
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An example of causal chainof a disease
…
A blood clot is growing .
The cross section of blood vessel is reducing.
Amount of oxygen supplied is reducing.
Cells are dying.
…
tt1 t2
Each process is not completed (keeps going) at every instant in time while the whole process is proceeding.
• It is a cumulative continuous process• So, the issue is how to derive a continuant from
a cumulative continuous process
Disorder
Causality (Causal relationship)
Duration of process
A continuous process
A continuous process
A blood clot grows
The cross section of blood vessel reduces
Amount of oxygen supplied reduces
Cells die
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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
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Types of diabetes constituted of causal chains
Disorder (nodes)
Causal Relationship
Causal chain of a disease(each color represents a disease)
Legend
loss of sight
Elevated level of glucose in the blood
Type I diabetesDiabetes-related Blindness
Steroid diabetes
Diabetes…
…
……
…
…
…
… … …
…
possible causes and effects
Destruction of pancreatic beta cells
Lack of insulin I in the blood
Long-term steroid treatment
Deficiency of insulin
Core causal chain of non-latent diabetes
Coloredregions
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A representation of the clinical imbalance model
…
……
…
… …
Clinical imbalance
imbalance
Performing amount of insulin operation(supply)
(possible)Maximal amount of insulin operation
Balance between supply and demand
Required amount of insulin operation (demand)
loss of sight
Elevated level of glucose in the blood
Type I diabetes
Diabetes-related Blindness
Steroid diabetes
DiabetesDestruction of pancreatic beta cells
Lack of insulin I in the blood
Long-term steroid treatment
Imbalanceoutcome
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Four qualitative values
Legends of values
balance
Performing amount of the operation (supply)
(a) Normal situation
balance
imbalance
(possible)Maximal amount of the operation
Balance between supply and demand
Required amount of the operation (demand)
Demand side Supply side
Very Large
Large
Middle
Small
Performing amount of the operation (supply)
(possible)Maximal amount of the operation
Balance between supply and demand
Required amount of the operation (demand)
Performing amount of the operation (supply)
(possible)Maximal amount of the operation
Balance between supply and demand
Required amount of the operation (demand)
(b) Hard or very active situation
(c) When demand increases up to very large
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defective insulin secretion
…
Clinical imbalance
insulin resistance
Medium
Medium
Medium
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Latent diabetes in daily life
Required amount of insulin operation (demand)
(Possible) maximal amount of insulin operation
Balance
Performing amount of insulin operation
Daily mean load
Balance between supply and demand
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Clinical Imbalanceovereating
Large
Medium
Medium
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Manifestation (Latent diabetes)
increased demand of insulin supply
(Possible) maximal amount of insulin operation
Performing amount of insulin operation
Required amount of insulin operation (demand)
Imbalance ImbalanceOutcome
Exceed the daily mean load level
defective insulin secretion
insulin resistance Elevated level o
f glucose in the bood
Balance between supply and demand
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break the biological defense
break the biological defense
proliferationproliferationInvasionInvasion
Invasion (Infection) stageInvasion (Infection) stage Onset stageOnset stage
colonizationcolonization
onsetonset
Infectious diseaseTwo-stage imbalance model for infectious diseases:① Invasion stage ②Onset stage
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Common coldCommon cold
No virus
virus invasion
Medium
Medium
No onset stageNo onset stage
OnsetOnset
virus invasion
virusExternalcause
t1
timet2
t3
virus infection Onset
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Required amount of defense against invasion (demand)
Performing amount of defense againstinvasion
(Possible) maximal amount of immune defense against invasion
no deficiency ofimmune defense
runny nose, throat pain
(Possible) maximal amount of defense against outcome
Performing amount of defense againstoutcome
deficiency of defense
balance
Invasion stageInvasion stage Onset stageOnset stage
Large
Medium
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imbalance of pathogen invasion defense imbalance of pathogen invasion defense
deficiency of immune defenseagainst invasion
Performing amount of defense againstinvasion(supply)
(Possible) maximal amount of immune defense against invasion
Pathogeninvasion
runny nose, throat pain
pathogenInfection
Required amount of defense against invasion (demand)
(Possible) maximal amount of defense against outcome
imbalance of onset imbalance of onset
Other attack
Onsetpathogen infection
OnsetOnset
pathogenInvasion
pathogenExternal cause
t1
timet2
t3
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ImbalanceOutcome
Performing amount of defense againstoutcome
Required amount of defense against outcome (demand)
ImbalanceOutcome
Imbalance Imbalance
deficiency of defense againstonset
Pathogen
hepatic fibrosis
Invasion stageInvasion stage Onset stageOnset stage
onset
Large
Large
Very large
Large
Very large
Large
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Hepatitis ( asymptomatic children )Hepatitis ( asymptomatic children )
Along with the development of immune system, symptom caused by excess immune defense appears.
VeryLarge
excess immune defense (supply)excess immune defense (supply)
destruction of hepatic cells
destruction of hepatic cells→ hepatic fibrosis→ cirrhosis
Adverse effect of immune defense
no deficiency of immune defense
Performing amount of immune defense againstvirus invasion (supply)
(Possible) maximal amount of immune defense against virus invasion
Hepatitis virusinvasion
Hepatitis virusInfection
Required amount of defense against invasion (demand)
Small
Small
VeryLarge
no deficiency of immune defense
balanceLarge
onset
In the childhood, due to immune system is immature, the maximal amount of immune defense was very small
demand
Performing amount of immune defense (supply)
ImbalanceVerysmall
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OsteoporosisOsteoporosis
deficiency of bone formation
Performing amount of bone formation (supply)
(Possible) maximal amount of bone formation
bone density loss
amount of bone resorption (demand)
(Possible) maximal amount of resist external pressure
fracturefracture
falling
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ImbalanceOutcome
Performing amount of resist external pressure (supply)
amount of external pressure(demand)
Imbalance
deficiency of resist external pressure
OsteoporosisOsteoporosis
fractureSmall
Small
Medium
steroidadministration
menopause
internal cause
external cause
Small
Small
osteoclastactivation
ImbalanceImbalanceOutcomeSmall
Large
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environmental factors(high-fat diet…)
Intolerable load on the lipid influx
Small
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Clinical imbalance
Lipid influx
(Possible) maximal amount of lipid efflux
Performing amount of lipid efflux
ImbalanceImbalanceOutcome
Elevated level of lipid in the blood (hyperlipidemia)
Balance between efflux and influx of lipids
genetic factors
HyperlipidemiaHyperlipidemia
Small
Large
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How can we correctly capture latent diabetes?
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II
Pancreaticβ cell
G
Insulin secretion
GG
G
blood
LiverMuscle …
IIIIII
IIII
Glucose uptakeregulation
G GG G
G
Overload!
Type 1 Diabetes : chronic severe elevated blood glucose by destruction of insulin-producing beta-cells
Latent diabetes : There is no symptom in the daily life, but will have problems with elevated blood glucose by some loading on insulin action.
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MalariaMalaria
deficiency of immune defenseaction
Performing amount of defense action (supply)
(Possible) maximal amount of immune defense action
Externalcause
plasmodiuminvasionvia a mosquito bite
Infection (liver cell)
Required amount of defense action (demand)
Large
Very Large
ImbalanceOutcomeLarge
Imbalance brain damage( Cerebral Malaria )
destruction of red blood cells
plasmodium infection
anemia
OnsetOnset
plasmodiuminvasion
Externalcause
t1
timet2
t3
Onset of disease
Invasion stageInvasion stage Onset stageOnset stage
Plasmodium
Plasmodium
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Imbalance model•Ischemic heart disease myocardial infarction
Imbalance: O2 demand vs. O2 supplyImbalance outcome : ischemic necrosis
•OsteoporosisImbalance: bone resorption vs. bone formationImbalance outcome : bone density loss
•Fracture Imbalance: external pressure vs. Resistance to external pressure–Fracture caused by osteoporosis
Imbalance: external pressure vs. Resistance to external pressure
–Fracture caused by traffic accidentImbalance: external pressure vs. Resistance to external pressure
•HyperlipidemiaImbalance: lipid influx vs. lipid efflux in the blood Imbalance outcome : hyperlipidemia (elevated levels of lipids in the blood)
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smallsmallmediummedium
Imbalance OutcomeFracture
very largevery large mediummediumImbalance Outcome
Fracture
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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
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An example of causal chain of processes
…
The engine isgeneratingtorque
The shaft is transmitting the torque to wheels.
Wheels are transforming the torque toforward-going force
The car is movingforward
…
t
Duration of process
t1 t2
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.
Causality (Causal relationship)
Continuous processes
Continuous processes
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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.
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Types of diabetes constituted of causal chains
Disorder (nodes)
Causal Relationship
Core causal chain of a disease(each color represents a disease)
Legends
loss of sight
Elevated level of glucose in the blood
Type I diabetesDiabetes-related Blindness
Steroid diabetes
Diabetes…
…
……
…
…
…
… … …
…
possible causes and effects
Destruction of pancreatic beta cells
Lack of insulin I in the blood
Long-term steroid treatment
Deficiency of insulin
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No virus
virus invasion
Small
Small
Required amount of defense against invasion (demand)
Performing amount of defense againstinvasion
(Possible) maximal amount of imumne defense against invasion
runny nose, throat pain
balance
Healthy personHealthy person
no deficiency ofimmune defense
OnsetOnset
virus invasion
virusExternalcause
t1
timet2
t3
virus infection Onset
Invasion stageInvasion stage Onset stageOnset stage
No onset stageNo onset stage
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(Possible) maximal amount of defense against outcome
Performing amount of defense againstoutcome
deficiency of defense
Small
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Computational disease model
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…
……
…
causal chaincausal chain
clinicaldisorder
clinicaldisorder
CausalRelationship
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Types of diabetes constituted of causal chains
Disorder (nodes)
Causal Relationship
Causal chain of a disease(each color represents a disease)
Legend
loss of sight
Elevated level of glucose in the blood
Type I diabetesDiabetes-related Blindness
Steroid diabetes
Diabetes…
…
……
…
…
…
… … …
…
possible causes and effects
Destruction of pancreatic beta cells
Lack of insulin I in the blood
Long-term steroid treatment
Deficiency of insulin
Core causal chain of diabetes
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DiabetesClinical imbalance model
…
……
…
… …
Clinical imbalance
imbalance
Performing amount of insulin operation(supply)
(possible)Maximal amount of insulin operation
Balance between supply and demand
Required amount of insulin operation (demand)
loss of sightType I diabetes
Diabetes related Blindness
Steroid diabetes
DiabetesDestruction of pancreatic beta cell
Lack of insulin in the blood
Long term steroid treatment
Elevated level of glucose in the bood
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Required amount of the operation(demand)
Cause
internal cause
external cause
ImbalanceOutcomeImbalance
Performing amount of the operation(supply)
Clinical Imbalance
(Possible)Maximal amount of the operation
Balance between supply and demand
Very Large
Large
Medium
Small
SupplySide
DemandSide
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defective insulin secretion
Intolerable load on the demand side
Daily mean load
Type I (non-latent) diabetes
Small
Small
Medium
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Clinical imbalance
Required amount of insulin operation (demand)
(Possible) maximal amount of insulin operation
Performing amount of insulin operation
ImbalanceImbalanceOutcome
Elevated level of glucose in the blood
Balance between supply and demand
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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