Toward an Ontological Treatment of Disease and Diagnosis

1. Toward an Ontological Treatment of Disease and Diagnosis Supported by NIAID, NCRR, and NHGRI - N01AI40076, N01AI40041, U54RR023468 and U54HG004928

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

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

5. 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. But the disorder also induces normal physiological processes (immune response) that can results in the elimination of the disorder (transient disease course). Influenza - infectious • 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 • 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

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 used_in suggests malaise, head ache, weakness, fever inflammatory infiltrate rule out influenza hypothesis interpretive process signs & symptoms abnormal bodily features used_in recognized_as produces patient x has influenza diagnosis

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?

9. Acute Influenza Infection Process Pathogen sterilization Immune response 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 • 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 • 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

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

15. Huntington’s Disease - genetic • 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 • 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

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 • 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

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?

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

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 Etiological Event Normal Homeostatic Range Normal Homeostatic Range Time

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

34. Chronic Pathological Process Abnormal Homeostatic Range State 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 [??].