Toward an Ontological Treatment of Disease and Diagnosis

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


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



recognized_as


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


Symptoms - fatigue, anorexia Signs - jaundice, splenomegaly



Hypothesis - rule out cirrhosis suggests


Test results - elevated liver enzymes in serum used_in


Result - diagnosis that patient X has a disorder that bears the disease cirrhosis

Cirrhosis - environmental exposure

etiological process

produces

disorder

bears

disposition

realized_in



recognized_as


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


Symptoms - anxiety, depression Signs - difficulties in speaking and

swallowing



Hypothesis - rule out Huntington’s suggests


Test results - molecular detection of the HTT gene with >39CAG repeats used_in


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



Sta

te

Time

Acute Pathological Process

EtiologicalEvent


Sta

te

Time

Chronic Pathological Process

EtiologicalEvent


Sta

te

Time

AbnormalHomeostatic

Range

Progressive Pathological Process

EtiologicalEvent


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 [??].

Documents

Toward an Ontological Treatment of Disease and Diagnosis