1 The Future of Disease Ontology Barry Smith Department of Philosophy, University at Buffalo...

1

The Future of Disease Ontology

Barry SmithDepartment of Philosophy, University at Buffalo

National Center for Biomedical Ontology

http://ontology.buffalo.edu/smith

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Colors form a continuum

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colors form a prototyped continuum

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strategy of low hanging

fruit

focus on the foci

(cross-cultural,

lexicalized)

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Strategies for creating ontologies and terminologies

Ad hoc creation by each clinical or research community (à la UMLS)

versus

Coordinated creation of high quality reference ontologies in ways which serve reusability of clinical data and interoperability of with basic science

Ontologies as common railway gauge

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A simple rule

Use singular nouns

DiseaseDiseasesDisorderDisordersdisorderdisease

disordersdiseases

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Which strategy is more future proof?

Assumption: As time goes by the molecular/cellular basis of diseases will play an ever more important role in clinical medicine

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OBO Foundry

A subset of OBO ontologies whose developers agree in advance to accept a common set of principles designed to assure interoperability with basic science and support for logic-based reasoning

http://obofoundry.org

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OBO Foundry

– Gene Ontology– Cell Ontology– Sequence Ontology– RNA Ontology– PATO Phenotype Ontology– OBI Ontology of Biomedical Investigations

(née FuGO Functional Genomics Investigation Ontology)

– FMA– RO Relation Ontology

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GO’s three ontologies

molecular function

cellular component

biological process

continuant occurrent

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RELATION TO TIME

GRANULARITY

CONTINUANT OCCURRENT

INDEPENDENT DEPENDENT

ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

Anatomical Entity(FMA, CARO)

OrganFunction

(FMP, CPRO) Phenotypic

Quality(PaTO)

Biological Process

(GO)CELL AND CELLULAR

COMPONENT

Cell(CL)

Cellular Compone

nt(FMA, GO)

Cellular Function

(GO)

MOLECULEMolecule

(ChEBI, SO,RnaO, PrO)

Molecular Function(GO)

Molecular Process

(GO)

Building out fron the original GO

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The ontology is open and available to be used by all.

The developers of the ontology agree in advance to collaborate with developers of other OBO Foundry ontology where domains overlap.

The ontology is in, or can be instantiated in, a common formal language.

The ontology possesses a unique identifier space within OBO.

The ontology provider has procedures for identifying distinct successive versions.

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The ontology has a clearly specified and clearly delineated content.

The ontology includes textual definitions for all terms.

The ontology is well-documented.

The ontology has a plurality of independent users.

The ontology uses relations which are unambiguously defined following the pattern of definitions laid down in the OBO Relation Ontology.

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ORTHOGONALITY

The developers commit to working with other Foundry members to ensure community convergence on a single controlled vocabulary for each domain.

REASON: if we annotate a database or body of literature with one high-quality biomedical ontology, we should be able to add annotations from a second such ontology without conflicts

INTEGRATION PRESUPPOSES ADDITIVITY

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Goal: when we annotate disease-related data

the disease terms we use should yield annotations which are logically consistent with – and even inferable from – other annotations using other OBO Foundry ontologies

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Foundational Model of Anatomy (FMA)

ontology of structural human anatomy

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FMAorganized in a graph-theoretical structure involving two sorts of links or edges:

is-a (= is a subtype of )

(pleural sac is-a serous sac)

part-of

(cervical vertebra part-of vertebral column)

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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

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FMA follows formal rules for Aristotelian definitions

When A is_a B, the definition of ‘A ’ takes the form:

an A =Def. a B which C s...

a human being =Def. an animal which is rational

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Example

Cell =Def. an anatomical structure which consists of cytoplasm surrounded by a plasma membrane

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at every level of granularity

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The Gene Ontology

Cross-Species

Cross-Granularity

Impressive policies for maintenance

Has initiated logic-based reforms:relations to other ontologies

relations among GO’s 3 ontologies

Aristotelian definitions

enhanced treatment of granularity

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Multiple Inheritance

thing

car

blue thing

blue car

is_a is_a

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thing

car

blue thing

blue car

is_a1 is_a2

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is_a Overloading

Reasoning across ontologies demands that ontological relations (is_a, part_of, ...) have the same meanings in the different ontologies to be aligned.

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thing

carblue

car #2947 is blue

is_a is_a

color

dark blue

is_a

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fracture

spiral fracturelimb

leg #29 has fracture #12

is_a is_a

anatomical structure

leg

is_a

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pharyngitis

infectious pharyngitis

heterogeneous cluster

disease instance #12 inheres in pharynx #29

is_a is_a

pharynx

is_a

anatomical structure

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is a source of errors

results are hard to maintain

serves as obstacle to integration with neighboring ontologies

hampers formulation of coherent definitions

contravenes orthogonality

no coherently defined levels

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can be easily dispensed with via normalization ???

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DO

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DO

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OBO Relation Ontology

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Three fundamental dichotomies

• types vs. instances

• continuants vs. occurrents

• dependent vs. independent

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Glossary

Instance: A particular entity in spatio-temporal reality.

Type: A general kind instantiated by an open-ended totality of instances which share certain qualities and propensities in common of the sort that can be documented in scientific literature

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Glossary

Biological process instance: A change or complex of changes on the level of granularity of the cell or organism, mediated by one or more gene products.

Biological process type: A type of biological process instance.

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Cellular component instance: A part of a cell, including cellular structures, macromolecular complexes and spatial locations identified in relation to the cell

Cellular component type: A type of cellular component.

Glossary

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Molecular function instance: The propensity of a gene product instance to perform actions, such as catalysis or binding, on the molecular level of granularity.

Molecular function type: A type of molecular function instance (type of propensity)

Glossary

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SCIENCE TEXTS AREREPRESENTATIONS OF

TYPES IN REALITY

= of what is general in reality

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CLINICAL GUIDELINES ARE REPRESENTATIONS OF TYPES

IN REALITY

diseases, therapies, diagnostic procedures (measurements) are

generals, with particular instances

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ONTOLOGIES AREREPRESENTATIONS OF

TYPES IN REALITY

aka kinds, universals, categories, species, genera, ...

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siamese

mammal

cat

organism

substancetypes

animal

instances

frog

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two kinds of parthood

1. between instances:Mary’s heart part_of Marythis nucleus part_of this cell

2. between typeshuman heart part_of humancell nucleus part_of cell

“Relations in Biomedical Ontologies”, Genome Biology, Apr 2005

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Continuants (aka endurants)– have continuous existence in time– preserve their identity through

change– exist in toto whenever they exist at

all

Occurrents (aka processes)– have temporal parts– unfold themselves in successive

phases– exist only in their phases

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You are a continuant

Your life is an occurrent

You are 3-dimensional

Your life is 4-dimensional

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Dependent entities

require independent continuants as their bearers

There is no grin without a catThere is no run without a runnerThere is no pumping without a pumpThere is no kiss without a kisser and a kissee

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Dependent vs. independent continuants

Independent continuants (organisms, cells, molecules, environments)

Dependent continuants (qualities, shapes, roles, dispositions, propensities, functions)

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All occurrents are dependent entities

They are dependent on those independent continuants which are their participants (agents, patients, media ...)

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types

Continuant Occurrent

IndependentContinuant

DependentContinuant

instances

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Top-Level Ontology

ContinuantOccurrent

(always dependent on one or more

independent continuants)


DependentContinuant

types

instances

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Top-Level Ontology

ContinuantOccurrent


DependentContinuant

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= A representation of top-level types



DependentContinuant

cell component

biological process

molecular function

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Continuant


anatomy

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“On Carcinomas and Other Pathological Entities”, Comparative and Functional Genomics, Apr. 2006

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Top-Level Ontology

ContinuantOccurrent


DependentContinuant

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= A representation of top-level types



DependentContinuant

cell component

biological process

molecular function

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molecular function

cellular component

biological process

continuant

occurrent

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Functions, etc.

Some dependent continuants are realizable

expression of a gene

application of a therapy

realization of a protocol

execution of a function

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The function of the heart is to pump blood

Not every activity (process) in an organism is the exercise of a function – there are – mal functionings

– side-effects (heart beating)

– accidents (external interference)

– background stochastic activity

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The FMA is a canonical representation

It is a computational representation of types and relations between types deduced from the qualitative observations of the normal human body

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The GO is a canonical representation

“The Gene Ontology is a computational representation of the ways in which gene products normally function in the biological realm”

Nucl. Acids Res. 2006: 34.

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molecular function

cellular component

biological process

continuant occurrent

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GO’s three+ ontologies

biological functions at

different levels of granularity

biological continuants =

cellular components +

FMA

biological processes (including molecular processes

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Top-Level Ontology



DependentContinuant

Functioning Side-Effect,

Accident,Background Stochastic Process,

...Function

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Disease vs. Event

Myocardial infarction is not a disease

A disease is something realizable

Disease ≠ Realization

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Disease vs. Course of disease

Symptom-suppressant drugs demonstrate that a disease is not identical with any specific sequence or pattern of symptoms

Diseases are continuants that may exist even when their observable manifestations are not present

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Top-Level Ontology



DependentContinuant

Functioning Course or history

of disease,mal-

functioningsFunction Disease

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Disease vs. symptom

Psoriasis as disease vs. psoriasis as manifestation (skin rash ...)

Cancer as disease vs. cancer as tumor

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Disease vs. Bearer of disease

A mushy brain is not a disease

A broken leg is not a disease

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types



DependentContinuant

Function Disease

Functioning Side-Effect, Stochastic Process, ...

instances

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types



DependentContinuant

Function Disease

Functioning Side-Effect, Stochastic Process, ...

Mary’s pneumonia Mary’s coughing

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Functions are continuant instances

The function of your heart begins to exist with the beginning to exist of your heart, and continues to exist, self-identically, until (roughly) your heart ceases to be able to respond if stimulated by your sympathetic and parasympathetic nervous systems

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Functions vs Functionings

the function of your heart = to pump blood in your body

this function is realized in processes of pumping blood

not all functions are realized (consider the function of this sperm ...)

not all functions are realized normally

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The Abnormality Theory of Disease

Disease is a state of a person which issues in abnormal behavior; something is an abnormal bodily or mental process if it does standard members of the human species some harm in standard circumstances;something does a person harm if it makes the person less able to live a good or worthwhile life.(Lawrie Reznek)

What are standard circumstances?What are states and how do they issue in consequences?

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"Defining Disease in the Genomics Era“, Larissa et al.

A disease is:

a state that places individuals at increased risk of adverse consequences.

genetic variations with no adverse consequences (like Gilbert's syndrome) will be interesting but inconsequential polymorphisms

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"Defining Disease in the Genomics Era“, Larissa et al.

A disease is:

a state that places individuals at increased risk of adverse consequences.

Where is the threshold for ‘adverse’ consequences (a) along the intensity dimension; (b) along the time dimension?

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A function is a disposition of a continuant to act in such a way as to contribute to the organism’s survival

states issue in consequences = continuants (e.g. cellular networks) have functions which are executed as patterns of functionings

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The function of the kidney is to clean blood

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Nephron

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Functional Segments

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Functions

functions based on shapes

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Low hanging fruit

Why we should not just talk about conditions

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What clinical medicine is for

to eliminate malfunctioning by fixing broken body parts

or to prevent the appearance of malfunctioning by intervening

or to alleviate the harmful consequences of this malfunctioning

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molecule cellular component

molecular function

cellularfunction

organism-level

biological function

organism

molecular process

cellularprocess

organism-level

process

functioningsfunctionings functionings

molecularlocation

cellular location

organism-level

location

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cell (types)

molecular function

(GO)

species

molecular process

cellular anatom

y

anatomy(fly, fish, human...)

cellularphysiology

organism-levelphysiology

ChEBI,Sequence,

RNA ...

normal(functionings)

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pathophysiology

pathoanatomy(fly, fish, human ...)

pathological(malfunctionings)

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pathophysiology

pathoanatomy(fly, fish, human ...)

pathological(dispositional

malfunctionings)

disease

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Pathoanatomy

not: disease of anatomical structure

but: disease of pathonatomical structure

Types of pathoanatomical structures:

malshapen limbs

pathological formations (tumors)

disturbed networks

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Some pathoanatomical structures are not associated with a risk of adverse consequences (‘disorders’)

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Fiat vs. bona fide boundaries

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Fiat vs. Bona Fide Boundaries

Fiat boundary Physical boundary

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Colorado exists

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Tumors exist

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everything here is an independent continuant

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structure vs. formation = bona fide vs. fiat boundaries

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malgrowths

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disease and anatomical damage

prokaryotic organisms do not have diseases

eukaryotic cells have a high number of different types of dispositions and form complex networks (such as the human brain) which can be damaged in ways which give rise to adverse effects

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(Lou)

polio, ALS, myasthenia gravis, muscular distrophy begin with changes in the structures of certain cells (this we know)

if these changes lead to distortions in the network which compromise the viability of the organism, then the organism has a disease

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Action item

Add molecular and cellular networks to the domain anatomy

Create a new discipline of network pathoanatomy

extend anatomy to networksextend pathoanatomy to types of disturbed

networks

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pathoanatomy

There are malshaped networks and malshaped things (deformities)

and also genetic malmutations

which give rise to malfunctionings, behavioral abnormalities

The networks function

The malshaped network malfunctions

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Boorse

Health is conformity to normal species design (as statistically determined).

(Biostatistical Theory)

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Boorse

disease =def. an impairment of normal functional ability

What Is Disease? J. M. Humber, R. F. Almeder, Eds., Humana Press, Totowa, NJ, 1997.

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from Larissa, et al. Science 2001

To be considered a DISEASE, the genotypic or phenotypic state of the patient must have the potential for adverse consequences. In Gilbert's syndrome, there is an asymptomatic elevation of liver enzymes in response to stress, but this condition is not considered a DISEASE because it does not lead to adverse consequences. The World Health Organization's valuable classification of adverse consequences includes physical or psychological impairment, activity restrictions, and/or role limitations. The inclusion of role limitations is particularly important because it acknowledges the sociological consequences of DISEASE in terms of shortening the quantity of life or disturbing its quality. When determining states that are associated with DISEASE, the challenge is to describe potential adverse outcomes comprehensively and explicitly. Because an adverse consequence in one culture may not be viewed as such in another, this consideration must take into account different ethnic and cultural beliefs. For example, whereas menopause is considered a medical condition in North America, in other cultures it is viewed as a normal aspect of aging.

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from Larissa, et al. Science 2001

The human genome sequence is likely to reveal many harmless genetic variations that will turn out not to be associated with DISEASE. Until we resolve questions about polymorphisms, incomplete penetrance of genetic mutations, and the contribution of environmental factors to DISEASE etiology, we will not be able to assess the probability of adverse consequences associated with a particular gene abnormality. There is little doubt that many genetic variations will have no consequences and, like those in individuals with Gilbert's syndrome, will be interesting but inconsequential polymorphisms. Until a mutation is shown to demonstrate a defined risk of developing adverse consequences, individuals carrying that mutation should not be considered DISEASEd. Defining adverse consequences and determining the risk of myriad small genetic variations is a mammoth task. But it is only with this information that clinicians can accurately define the term DISEASE in the genomics era, and in so doing, be able to advise their patients appropriately.

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Enc Brit 1an impairment of the normal state of an organism that interrupts or modifies its vital functions. A brief discussion of disease follows. The subject is treated in a variety of articles. For a general discussion of human, animal, and plant diseases, see disease. For a discussion

of diseases categorized according to their cause or transmission, see infection; nutritional disease; occupational disease. For a discussion of diseases associated with particular stages of human development, see childhood disease and disorder; growth; development. For a discussion of malignancy, which may affect any organ or tissue in the body, see cancer. For a discussion of disease-causing organisms such as viruses, bacteria, and parasites, see bacteria; virus. For a discussion of bodily defenses against disease, see immune system. For a discussion of the diagnosis and treatment of disease, see diagnosis; therapeutics; drug; medicine, history of. For a discussion of diseases affecting particular organs, tissues, or processes, see blood disease; cardiovascular disease; digestive system disease; endocrine system, human; renal system disease; skin disease; metabolic disease; muscle disease; nervous system disease; reproductive system disease; respiratory disease; eye disease and ear disease; connective tissue disease. For a discussion of neuroses and psychoses, see mental disorder. For a discussion of alcoholism and other drug addictions, see alcohol consumption.

Disease most commonly is caused by the invasion of an organism by one or more outside agents. Typically the infectious organisms are microorganisms (e.g., bacteria, viruses, and fungi), but they also can include larger organisms such as parasitic worms or nonliving but harmful substances such as toxins or ionizing radiation. Disease also may result from changes within the organism—an anatomical fault (congenital or acquired) or a physiological malfunction (e.g., diabetes mellitus, in which the body fails to secrete or adequately utilize insulin, a hormone that regulates blood-sugar levels). Other diseases are a combination of external and internal factors. An organism's failure to adapt to changes in its environment can produce damaging changes within it. Physiological malfunctions and disturbances of normal growth can be induced by changes of diet or by invasion of microorganisms or other agents.

Nearly all organisms are able to defend themselves against most diseases. Humans and other vertebrates have developed two strategies of resistance, called immunity, to invading agents: nonspecific immunity, which is present in all vertebrates at birth; and specific immunity, which is acquired only after stimulation by the presence of a certain microbe or its products (e.g., the virus that causes chicken pox). Immunity also can be stimulated artificially in humans or other animals by inoculating them with microorganisms that have been killed (as in typhoid vaccine) or weakened (attenuated) ones (as in measles vaccine), which produce the defensive immune reaction without causing the disease.

Sometimes an organism's defensive reaction to invasion by an outside agent can become part of the disease. The crippling of the lungs produced by tuberculosis is caused partly by the destruction of lung tissue by the invading microorganism (in humans, usually Mycobacterium tuberculosis) and partly by the fibrous tissue that the body lays around the infection in a defensive reaction. Disorders of the immune response itself can produce autoimmune disease (e.g., rheumatoid arthritis) in which the immune response is triggered not by an outside invader but by the body's own tissues, which some cells fight against and try to reject. The immune system also can be disabled by an invading microorganism, as is the case with the disease AIDS.

Not all organisms that invade another produce disease. Some can establish a mutually beneficial relationship with their host without impairing its vital systems; for example, the bacteria that live in the gastrointestinal tracts of humans and other vertebrates make possible the digestive processes of their hosts. In addition, organisms that are pathogenic to one species may be harmless to another.

A disease that becomes established in an organism usually requires some form of treatment. In most cases, treatment consists of administering drugs that kill the causative agent, restore any physiological or biochemical imbalances that have occurred, or control the symptoms caused by the agent so that the affected organism can continue to function. Other forms of treatment include moving the diseased organism to another environment or removing the diseased parts from the organism.

The most effective way to control disease is by preemptory prevention. The best method is to eliminate a disease-causing organism from the environment, such as by killing pathogens or parasites contaminating a water supply. Also effective is the disruption of a pathogen's transmission from one organism to another, either by avoiding contact with body tissues or fluids that harbour a pathogen or by eliminating an intermediary vector (e.g., killing the mosquitoes that transmit malaria to humans). Disease also may be prevented by removing a susceptible organism from an unhealthful environment, strengthening the organism's defenses by making it healthier, or vaccination.

http://www.search.eb.com.gate.lib.buffalo.edu/eb/article-9110618












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everything here is an independent continuant

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Functions are beneficial

those processes which are the realizations of a biological function Z are (in normal circumstances) beneficial to the organism

( such as to sustain the organism in existence)

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Functions

This is a screwdriver

This is a good screwdriver

This is a broken screwdriver

This is a heart

This is a healthy heart

This is an unhealthy heart

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Prototypes

good functioning (sound anatomy)

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Departures from Prototypes

reasonable functioning

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Poor functioning

poor functioning

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Malfunctioning

malfunctioning

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Death?

not functioning at all

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Not functioning at all

leads to death modulo internal factors:

plasticity

redundancy (2 kidneys)

criticality of the system involved

external factors:

prosthesis (dialysis machines, oxygen tent)

special environments

assistance from other organisms

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Disease = remoteness from prototypical functioning

disease

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Ontology of Disease

Diseases are, like functions, dependent continuants

They are states or conditions which endure for a certain time and have a course or history, which is an occurrent

Disease instances = Mary’s pneumonia

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Need to take time into account

a forty year old man with rapidly dividing, highly invasive, cancerous prostate cells has the disease prostate cancer

a ninety year old man with slowly dividing cancerous prostate cells does not have the disease prostate cancer

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A 90 year old man with Alzheimers probably had Alzheimers undiagnosed at the age of 40

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The FMA is a canonical representation

but it recognizes also variant anatomical structures (e.g. coronary arteries or bronchopulmonary segments which deviate from the canonical anatomical pattern of organization)

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canonical life Gestalten

+ variant life Gestalten (vegetarians)

+ pathological life Gestalten (serial murderers)

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Model organisms

you can buy a mouse with the prototypical mouse Bauplan according to a precise specification

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Just as there are 2 x n canonical Baupläne for human beings (male

and female at n successive stages)

so there may be different canonical life plans for different types of human beings (in different types of contexts)

what are the different types?

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What is a canonical environment?

What is a canonical family?

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From Embryontology to GerontologyConceptionDevelopmentBirthInfancyToddlerdomEarly ChildhoodChildhoodAdolescenceEarly AdulthoodMiddle ageOld age Death

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What does every human canonical life involve?

9 months of development (here the plan is very determinate)

birthinfancytoddlerdomlater: acquisition of consciousness, languagecycles of waking, sleeping; eating and not

eatingdeath

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The organizing principle of complex living systems

a life-like system =def. any compact system containing an order and distribution of sustaining nonlinear limit cycle oscillators, and a related system of algorithmic guide mechanisms, that is capable of regulating its interior conditions for a considerable range of ambient environmental conditions so as to permit its own satisfactory preservative operation

Iberall, A. S. and McCulloch, W. S. The organizing principle of complex living systems. Journal of Basic Engineering. 290-294. June 1969.

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Iberall and McCulloch

An essential characteristic of a living system is its marginal instability. Its principal dynamic properties are that it hungers, feeds, and can move or creep so that it can continue to hunger, feed, and move or creep.

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Iberall and McCulloch 20 action modes:Action Modes % of timeSleeps 30Eats 5Drinks 1Voids 1Sexes 3Works 25Rests (no motor activity, indifferent internal sensory flux) 3Talks 5Attends (indifferent motor activity, involved sensory activity) 4Motor practices (runs, walks, plays, etc.) 4Angers 1Escapes (negligible motor and sensory input) 1“Anxioius-es” 2”Euphorics” 2Laughs 1Aggresses 1Fears, fights, flights 1Interpersonally attends (body, verbal or sensory contact) 8Envies 1Greeds 1 Total: 100% +/- 20% of time involvement

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Functions

an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to the organism’s survival

doesn’t apply to sperm

doesn’t apply to carcinomatous lung

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Revised formulation

an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to the organism’s realization of the canonical life plan for an organism of the relevant species

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What clinical medicine is for

to bring the patient back in the direction of the canonical life for an organism of his stage of development

cure = pulling you all the way back

life extension (can take you beyond the canonical life)

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Disease (Some Hypotheses)

• an anatomical structure in an organism has a certain function

• this structure has become pathological– growths, pathogens, genetically determined

deformations

• and so malfunctions in ways which fall outside the species-typical range for an organism in this stage of development (= outside the canonical life)

• and brings a high risk of adverse consequences

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Disease = remoteness from prototypical functioning modulo stage

of development and environment

disease

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A new proposed definition

X has a disease =def.

i. X departs from the canonical life plan appropriate for X‘s stage of development and environment

ii. this departure brings (causally) risk of adverse consequences for X

iii. this departure is rooted in an enduring pathoanatomical distortion

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To apply this definition

we do not need to know the nature of the pathoanatomical distortion in every type of case

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Implications for disease ontology

Focus on specific focal families of diseases* where we can specify relevant pathoanatomical entities (including cellular networks ...) and relevant types of disturbances

A classification of diseases is a classification of those patterns of pathoanatomical disturbance which give rise to adverse consequences

*Ignore the common cold; ignore syndromes

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Implications for disease ontology

Follow the principle of low-hanging fruit

Have these specifications created and validated by human experts

Take the structure and work with SNOMED for importing further content

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United States

Colorado

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Abnormality rooted in generalized pathoanatomy

disease

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Abnormality rooted in generalized pathoanatomy

disease

Enduring phenotypic abnormality

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DO

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