Toward an Ontological Treatment of
Disease and Diagnosis
Supported by NIAID, NCRR, and NHGRI - N01AI40076, N01AI40041, U54RR023468 and U54HG004928
Goal
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To develop a consistent, logical and
extensible framework (ontology) for the
representation of
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features of disease
clinical processes
results
Motivation
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Clarity about:
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disease etiology and progression
disease and the diagnostic process
phenotype and signs/symptoms
Approach
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Propose terms and provide definitions for a representational
framework drawing on best practices in ontology
development as promulgated within the OBO Foundry for:
 Etiological process
 Disorder
 Disease
 Pathological process
 Sign
 Symptom
 Laboratory finding
 Diagnosis
 Pre-disposition
 Clinically abnormal
Foundation
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The approach we recommend rests on an account of disease
as a disposition rooted in a physical disorder in the organism
and realized in pathological processes.
produces
etiological process
bears
disorder
realized_in
disposition
pathological process
produces
diagnosis
interpretive process
produces
signs & symptoms
representations
used_in
abnormal bodily features
recognized_as
Influenza - infectious
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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 – tissue
destruction & acute inflammation
 produces
Abnormal bodily features
 recognized_as
Symptoms - weakness, dizziness
Signs - fever
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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).
Influenza – infection disorder
produces
etiological process
infection of airway epithelial
cells with influenza virus
bears
disorder
disposition
pathological process
cell w/virus
intracellular
flu
tissue destruction &
acute inflammation
produces
laboratory test
serum Ab against
produces
test result influenza type A
used_in
suggests
malaise, head ache,
weakness, fever
inflammatory infiltrate
signs & symptoms
abnormal bodily features
rule out influenza
hypothesis
realized_in
interpretive process
produces
diagnosis patient x has influenza
used_in
recognized_as
Questions
How does one deal with the ever changing
nature of the physical disorder?
 How does one deal with the evolution of the
disposition?
 Is an infection disorder still an infection
disorder even after the pathogenic organism
has been sterilized?
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Acute Influenza Infection Process
Pathogen sterilization
State
Immune response
Viral replication
& tissue destruction
Normal Homeostatic
Range
Etiological
Event
Time
Elucidation of Primitive Terms
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‘bodily feature’ - an abbreviation for a physical
component, a bodily quality, or a bodily process.
disposition - an attribute describing the propensity to
initiate certain specific sorts of processes when certain
conditions are satisfied.
clinically abnormal - some bodily feature that
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(1) is not part of the life plan for an organism of the relevant type
(unlike aging or pregnancy),
(2) is causally linked to an elevated risk either of pain or other
feelings of illness, or of death or dysfunction, and
(3) is such that the elevated risk exceeds a certain threshold level.
Big Picture
Useful features
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Evolution of the disorder
Variable expressivity
Dispositions and predispositions for other
dispositions
Context dependence
Cirrhosis - environmental exposure
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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
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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
Cirrhosis - environmental exposure
produces
bears
realized_in
etiological process
disorder
disposition
pathological process
phenobarbitol-induced
hepatic cell death
necrotic liver
cirrhosis
abnormal tissue
repair - fibrosis &
hypoxia
produces
laboratory test
test result elevated LFT’s
used_in
suggests
splenomegaly, jaundice
fatigue, anorexia
rule out cirrhosis
hypothesis
interpretive process
produces
produces
signs & symptoms
used_in
diagnosis patient x has disease cirrhosis
portal vein hypertension,
increased bilirubin
abnormal bodily features
recognized_as
Huntington’s Disease - genetic
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Etiological process - inheritance of
>39 CAG repeats in the HTT gene
 produces
Disorder - chromosome 4 with
abnormal mHTT
 bears
Disposition (disease) - Huntington’s
disease
 realized_in
Pathological process - accumulation of
mHTT protein fragments, abnormal
transcription regulation, neuronal cell
death in striatum
 produces
Abnormal bodily features
 recognized_as
Symptoms - anxiety, depression
Signs - difficulties in speaking and
swallowing
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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
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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
Definitions - Foundational Terms
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Disorder =def. – A causally linked combination of physical
components that is (a) clinically abnormal and (b) maximal, in
the sense that it is not a part of some larger such combination.
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Pathological Process =def. – A bodily process that is a
manifestation of a disorder and is clinically abnormal.
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Disease =def. – A disposition (i) to undergo pathological
processes that (ii) exists in an organism because of one or
more disorders in that organism.
Dispositions and Predispositions
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All diseases are dispositions; not all dispositions are diseases.
A predisposition is a disposition.
Predisposition to Disease of Type X =def. – A disposition in an organism
that constitutes an increased risk of the organism’s subsequently
developing the disease X.
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HNPCC is caused by a
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disorder (mutation) in a DNA mismatch repair gene that
disposes to the acquisition of additional mutations from defective DNA repair
processes, and thus
predisposition to the development of colon cancer.
Etiology
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Etiological Process =def. – A process in an organism that
leads to a subsequent disorder.
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Example: toxic chemical exposure resulting in a mutation in
the genomic DNA of a cell; infection of a human with a
pathogenic virus; inheritance of two defective copies of a
metabolic gene
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The etiological process creates the physical basis of that
disposition to pathological processes which is the disease.
Definitions - Clinical Evaluation Terms
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Sign =def. – A bodily feature of a patient that is observed in a physical
examination and is deemed by the clinician to be of clinical significance.
(Objectively observable features)
Symptom =def. – A bodily feature of a patient that is observed by the
patient and is hypothesized by the patient to be a realization of a disease. (a
restricted family of phenomena (including pain, nausea, anger,
drowsiness), which are of their nature experienced in the first person)
Laboratory Test =def. – A measurement assay that has as input a patientderived specimen, and as output a result representing a quality of the
specimen.
Laboratory Finding =def. – A representation of a quality of a specimen
that is the output of a laboratory test and that can support an inference to an
assertion about some quality of the patient.
Definitions - Qualities
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Manifestation of a Disease =def. – A bodily feature of a patient that is (a) a
deviation from clinical normality that exists in virtue of the realization of a disease
and (b) is observable.
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Observability includes observable through elicitation of response or through the use of
special instruments.
Preclinical Manifestation of a Disease =def. – A manifestation of a disease that
exists prior to its becoming detectable in a clinical history taking or physical
examination.
Clinical Manifestation of a Disease =def. – A manifestation of a disease that is
detectable in a clinical history taking or physical examination.
Phenotype =def. – A (combination of) bodily feature(s) of an organism determined
by the interaction of its genetic make-up and environment.
Clinical Phenotype =def. – A clinically abnormal phenotype.
Definitions - Diagnosis
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Clinical Picture =def. – A representation of a clinical
phenotype that is inferred from the combination of
laboratory, image and clinical findings about a given
patient.
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Diagnosis =def. – A conclusion of an interpretive process
that has as input a clinical picture of a given patient and
as output an assertion to the effect that the patient has a
disease of such and such a type.
Motivation
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Better clarity to how the relevant information relates to each other
Better support for use in the context of patient care, clinical research
and translational research
Extensibility
Constraints
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We need to be accurate
We need to be practical (reproducibility vs dogma)
 What can we expect the clinicians to understand and provide?
 Is the distinction between chronic and progressive easily determined?
We need to leverage and harmonize existing and emerging standards
Goals
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What are the fundamental types of things for which we need ontological
categories (what’s the domain)?
 disease initiation, progression, pathogenesis, signs, symptoms, assessments,
clinical and laboratory findings, disease diagnosis, treatment, treatment
response and outcome
 normal phenotype, homeostatic (normal) profile
What are the fundamental relationships between the types of things?
 between the process of observing, the results of the observation and what is
being observed
 between signs/symptoms and disease (no absolutes?)
 between clinical and pre-clinical pathological processes, their manifestations
and their representations in the EHR
How should ontologies be developed - intelligent design or natural selection
(evolution)?
What is the relationship between the ontologies/terminologies and the
information models?
Outcome Assessment
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What are the criteria by which we can judge whether we have good categories
and good definitions?
 The degree to which ordinary clinicians can understand and reproducibly
apply the definitions.
 The degree to which entities can be easily mapped between humans and
animal models.
 The degree to which the categories can accommodate new diagnostic
technologies (e.g. proteomics).
 The degree to which electronic medical record data can be integrated with
clinical and translational research data.
An ontology-based approach for
connecting disease pathogenesis with
clinical/laboratory data
Richard Scheuermann
Motivation
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Use of medical record information in support for clinical and
translation research
Consistent, logical and extensible framework
Big Picture
etiological event
bodily
features
person
homeostatic
profile
What we observe
progressive pathological process
clinical
phenotype
What we treat
disorder
self
assessment
disorder
w/symptom
self
assessment
representation
of symptom
therapeutic response
disorder
w/sign
physical
exam
clinical
finding
specimen
isolation
treatment
lab
test
lab
finding
clinical
picture
diagnosis
What we record
plan
patient management
plan development
Key concepts
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Bodily features
Normal/Abnormal
Homeostasis
Types of disorders
Types of pathological processes (dynamics)
Signs and symptoms
Assessments and laboratory tests
Representations of signs, symptoms and test results
Diagnosis
Definitions Document
State
Normal Adaptation
Etiological
Event
Normal Homeostatic
Range
Normal Homeostatic
Range
Time
State
Acute Pathological Process
Etiological
Event
Normal Homeostatic
Range
Time
State
Chronic Pathological Process
Abnormal
Homeostatic
Range
Etiological
Event
Normal Homeostatic
Range
Time
State
Progressive Pathological Process
Etiological
Event
Normal Homeostatic
Range
Time
Feasibility Use Case
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1. Find all patients who are
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at average risk for colorectal cancer [?normal disposition],
undergoing colon cancer screening by colonoscopy [physical exam], and
age 50 and older [bodily feature].
2. Find all SLE [disorder => diagnosis] patients with stable, mildly active disease
[chronic pathological process] and up-to-date immunization history [bodily features].
3. Find all patients with diagnosis of active rheumatoid arthritis [diagnosis] that have
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failed to respond positively to at least 1 disease modifying anti-rheumatic drug due to toxicity or lack
of efficacy [type of disorder],
and have either
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4. Find all normal volunteer adult subject with
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C-reactive Protein (CRP) >2.0 mg/dL [laboratory finding],
or Erythrocyte Sedimentation rate (ESR) ≥28 mm/hour [laboratory finding],
or morning stiffness for ≥45 minutes [clinical finding].
BMI of ≥22 kg/m2 [bodily feature], and
a desire to lose weight [?normal disposition].
5. Find all males and females [bodily feature] with
ages 6 to 20 years [bodily feature], and
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a diagnosis of asthma or asthma symptoms [diagnosis] for at least 1 year,
and who are
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able to perform spirometry (breathing test) [?normal disposition], and
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are either themselves willing to sign the written Informed Consent or assent prior to initiation of any
study procedure [disposition], or whose parent or legal guardian is willing to sign the written
Informed Consent prior to initiation of any study procedure, and
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have some form of insurance which covers costs of medications [??].
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