1. Toward an Ontological Treatment of Disease and Diagnosis
Supported by NIAID, NCRR, and NHGRI - N01AI40076, N01AI40041, U54RR and U54HG004928

2. Goal
To develop a consistent, logical and extensible framework (ontology) for the representation of
features of disease
clinical processes
results
Answer the following questions.

3. Motivation Clarity about: disease etiology and progression
disease and the diagnostic process
phenotype and signs/symptoms

4. 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
Answer the following questions.

5. abnormal bodily features
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.
produces
bears
realized_in
etiological process
disorder
disposition
pathological process
produces
diagnosis
interpretive process
signs & symptoms
abnormal bodily features
produces
recognized_as
representations
used_in

6. 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
Abnormal bodily features
recognized_as
Symptoms - weakness, dizziness
Signs - fever
Symptoms & Signs
used_in
Interpretive process
produces
Hypothesis - rule out influenza
suggests
Laboratory tests
Test results - elevated serum antibody titers
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).

7. Influenza – infection disorder
produces
bears
realized_in
etiological process
disorder
disposition
pathological process
infection of airway epithelial cells with influenza virus
cell w/virus
intracellular
flu
tissue destruction & acute inflammation
produces
serum Ab against
influenza type A
produces
laboratory test
test result
suggests
used_in
malaise, head ache,
weakness, fever
rule out influenza
inflammatory infiltrate
hypothesis
interpretive process
signs & symptoms
abnormal bodily features
produces
used_in
recognized_as
diagnosis
patient x has influenza

8. 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?
Answer the following questions.

9. Pathogen sterilization
Acute Influenza Infection Process
Immune response
Pathogen sterilization
Viral replication
& tissue destruction
State
Normal Homeostatic
Range
Etiological
Event
Time

10. 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.

11. Big Picture

12. Useful features
Evolution of the disorder
Variable expressivity
Dispositions and predispositions for other dispositions
Context dependence

13. 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
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
Test results - elevated liver enzymes in serum
Result - diagnosis that patient X has a disorder that bears the disease cirrhosis

14. 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
produces
suggests
used_in
splenomegaly, jaundice
fatigue, anorexia
portal vein hypertension,
increased bilirubin
rule out cirrhosis
hypothesis
interpretive process
signs & symptoms
abnormal bodily features
produces
used_in
recognized_as
diagnosis
patient x has disease cirrhosis

15. 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
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
Test results - molecular detection of the HTT gene with >39CAG repeats
Result - diagnosis that patient X has a disorder that bears the disease Huntington’s disease

16. 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
Disorder - mutations in proto-oncogenes and tumor suppressor genes with microsatellite repeats (e.g. TGF-beta R2)
Disposition (disease) - non-polyposis colon cancer

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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

24. 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

25. 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?
Answer the following questions.

26. 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.

27. An ontology-based approach for connecting disease pathogenesis with clinical/laboratory data
Richard Scheuermann

28. Motivation
Use of medical record information in support for clinical and translation research
Consistent, logical and extensible framework

29. progressive pathological process
Big Picture
What we observe
What we record
What we treat
disorder
etiological event
progressive pathological process
disorder
w/symptom
w/sign
clinical
phenotype
therapeutic response
person
homeostatic
profile
bodily
features
clinical
picture
interpretive
process
diagnosis
patient management
plan development
plan
treatment
self
assessment
physical
exam
specimen
isolation
lab
test
representation
of symptom
clinical
finding

30. 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

31. Definitions Document

32. Normal Adaptation State Time Etiological Event Normal Homeostatic
Range
Normal Homeostatic
Range
Time

33. Acute Pathological Process
Etiological
Event
State
Normal Homeostatic
Range
Time

34. Chronic Pathological Process
State
Abnormal
Homeostatic
Range
Etiological
Event
Normal Homeostatic
Range
Time

35. Progressive Pathological Process
State
Etiological
Event
Normal Homeostatic
Range
Time

36. 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 [??].