toward an ontological treatment of disease and diagnosis
DESCRIPTION
Toward an Ontological Treatment of Disease and Diagnosis. Supported by NIAID, NCRR, and NHGRI - N01AI40076, N01AI40041, U54RR023468 and U54HG004928. Goal. To develop a consistent, logical and extensible framework (ontology) for the representation of features of disease clinical processes - PowerPoint PPT PresentationTRANSCRIPT
Toward an Ontological Treatment of Disease and Diagnosis
Supported by NIAID, NCRR, and NHGRI - N01AI40076, N01AI40041, U54RR023468 and U54HG004928
Goal
To develop a consistent, logical and extensible framework (ontology) for the representation of features of disease clinical processes results
Motivation
Clarity about: disease etiology and progression disease and the diagnostic process phenotype and signs/symptoms
Approach
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
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.
etiological process
produces
disorder
bears
disposition
realized_in
pathological process
produces
abnormal bodily features
recognized_as
signs & symptomsinterpretive process
produces
diagnosis
used_in
representations
Influenza - infectious Etiological process - infection of
airway epithelial cells with influenza virus produces
Disorder - viable cells with influenza virus bears
Disposition (disease) - flu realized_in
Pathological process – tissue destruction & acute inflammation produces
Abnormal bodily features recognized_as
Symptoms - weakness, dizziness Signs - fever
Symptoms & Signs used_in
Interpretive process produces
Hypothesis - rule out influenza suggests
Laboratory tests produces
Test results - elevated serum antibody titers used_in
Interpretive process produces
Result - diagnosis that patient X has a disorder that bears the disease flu
But the disorder also induces normal physiological processes (immune response) that can results in the elimination of the disorder (transient disease course).
Influenza – infection disorder
etiological process
produces
disorder
bears
disposition
realized_in
pathological process
abnormal bodily features
recognized_as
signs & symptomsinterpretive process
produces
hypothesis
used_in
infection of airway epithelial cells with influenza virus
cell w/virusintracellular
flu tissue destruction & acute inflammation
malaise, head ache,weakness, fever
patient x has influenzadiagnosis
rule out influenza
laboratory test test result
produces
serum Ab againstinfluenza type A
used_in
produces
suggestsinflammatory infiltrate
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?
Acute Influenza Infection Process
EtiologicalEvent
Normal HomeostaticRange
Sta
te
Time
Viral replication& tissue destruction
Immune response Pathogen sterilization
Elucidation of Primitive Terms
‘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 (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
Evolution of the disorder Variable expressivity Dispositions and predispositions for other
dispositions Context dependence
Cirrhosis - environmental exposure Etiological process - phenobarbitol-
induced hepatic cell death produces
Disorder - necrotic liver bears
Disposition (disease) - cirrhosis realized_in
Pathological process - abnormal tissue repair with cell proliferation and fibrosis that exceed a certain threshold; hypoxia-induced cell death produces
Abnormal bodily features recognized_as
Symptoms - fatigue, anorexia Signs - jaundice, splenomegaly
Symptoms & Signs used_in
Interpretive process produces
Hypothesis - rule out cirrhosis suggests
Laboratory tests produces
Test results - elevated liver enzymes in serum used_in
Interpretive process produces
Result - diagnosis that patient X has a disorder that bears the disease cirrhosis
Cirrhosis - environmental exposure
etiological process
produces
disorder
bears
disposition
realized_in
pathological process
abnormal bodily features
recognized_as
signs & symptomsinterpretive process
produces
hypothesis
used_in
phenobarbitol-inducedhepatic cell death
necrotic liver cirrhosis abnormal tissuerepair - fibrosis &
hypoxia
splenomegaly, jaundicefatigue, anorexia
patient x has disease cirrhosisdiagnosis
rule out cirrhosis
laboratory test test result
produces
elevated LFT’s
used_in
produces
suggests portal vein hypertension, increased bilirubin
Huntington’s Disease - genetic Etiological process - inheritance of
>39 CAG repeats in the HTT gene produces
Disorder - chromosome 4 with abnormal mHTT bears
Disposition (disease) - Huntington’s disease realized_in
Pathological process - accumulation of mHTT protein fragments, abnormal transcription regulation, neuronal cell death in striatum produces
Abnormal bodily features recognized_as
Symptoms - anxiety, depression Signs - difficulties in speaking and
swallowing
Symptoms & Signs used_in
Interpretive process produces
Hypothesis - rule out Huntington’s suggests
Laboratory tests produces
Test results - molecular detection of the HTT gene with >39CAG repeats used_in
Interpretive process produces
Result - diagnosis that patient X has a disorder that bears the disease Huntington’s disease
HNPCC - genetic pre-disposition
Etiological process - inheritance of a mutant mismatch repair gene produces
Disorder - chromosome 3 with abnormal hMLH1 bears
Disposition (disease) - Lynch syndrome realized_in
Pathological process - abnormal repair of DNA mismatches produces
Disorder - mutations in proto-oncogenes and tumor suppressor genes with microsatellite repeats (e.g. TGF-beta R2) bears
Disposition (disease) - non-polyposis colon cancer
Definitions - Foundational Terms
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.
Pathological Process =def. – A bodily process that is a manifestation of a disorder and is clinically abnormal.
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
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.
HNPCC is caused by a 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
Etiological Process =def. – A process in an organism that leads to a subsequent disorder.
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
The etiological process creates the physical basis of that disposition to pathological processes which is the disease.
Definitions - Clinical Evaluation Terms
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 patient-derived 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
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. 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
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.
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
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
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
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
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
Use of medical record information in support for clinical and translation research
Consistent, logical and extensible framework
personhomeostatic
profile
bodilyfeatures
Big Picture
selfassessment
selfassessment
physicalexam
specimenisolation
labtest
representationof symptom
clinicalfinding
labfinding
clinicalpicture
interpretive
processdiagnosis
patient managementplan development
plan
treatment
disorder
etiological event therapeutic responseprogressive pathological process
disorderw/symptom
disorderw/sign
clinicalphenotype
What we observe
What we record
What we treat
Key concepts
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
Normal Adaptation
EtiologicalEvent
Normal HomeostaticRange
Normal HomeostaticRange
Sta
te
Time
Acute Pathological Process
EtiologicalEvent
Normal HomeostaticRange
Sta
te
Time
Chronic Pathological Process
EtiologicalEvent
Normal HomeostaticRange
Sta
te
Time
AbnormalHomeostatic
Range
Progressive Pathological Process
EtiologicalEvent
Normal HomeostaticRange
Sta
te
Time
Feasibility Use Case 1. Find all patients who are
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 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
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].
4. Find all normal volunteer adult subject with 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 a diagnosis of asthma or asthma symptoms [diagnosis] for at least 1 year,
and who are able to perform spirometry (breathing test) [?normal disposition], and
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
have some form of insurance which covers costs of medications [??].