1. NEUROWEB: Modeling cerebrovascular phenotypes Gianluca Colombo Daniele Merico DISCo, Università di Milano-Bicocca SSW09 Signs, Symptoms and Findings: Towards an Ontology for Clinical Phenotypes. Milan, 4-5 September 2009 European Commission Sixth Framework Programme Information Society Technologies project number 518513 NEUROWEB Project

2. Act I Association Studies and Clinical Phenotypes

3. Association Studies 1.Identify patients with a common (clinical) phenotype 2.Determine the statistical significance of association for – Genotype (i.e. Single Nucleotide Polymorphisms) – Environmental / life style factors – Etc… Other patients Phenotype carriers (e.g. Severe Stenosis) SNP S1 SNP S2 SNP S3 Genotype Prosthetic Heart Valve Smoked Cigarettes Clinical Features and Risk Factors Blood Pressure

4. Clinical Phenotype (Association Studies) Of clinical interest, i.e. typically encountered as an intermediate or final stage of diagnosis, or treatment formulation, or prognosis Clinically abnormal sensu OGMS(?) –Not in the body plan –Potentially resulting in pain / malaise / dysfunction / death

5. Clinical Phenotype (Association Studies) An aggregate of ‘bodily features’ (sensu OGMS) –directly observable –directly observable (e.g. brain lesion) derived / inferable or derived / inferable (e.g Diabetes Mellitus Type-II) –which is likely to be strongly associated to A genotype, i.e. set of genomic positions with nucleotide value(s) A (set of) physiological parameter (e.g. blood pressure) A (set of) environmental or life style factor (e.g. cholesterol-rich diet) Aggregation rationale: –Strength –Strength of association –Parsimony –Parsimony of associated factors genotype-phenotype Mutation in a single gene (strictly mendelian) Multigenic (but maybe belonging to a certain functional category or pathway)  Hypothesis formulation and testing cycles NB: AssociationcausationNB: Association may (or may not) imply causation Etio-physiological relatedness of aggregated bodily features

6. Why association studies Association Prognosis / improved diagnostics Causation Part of the research elucidating the triads disorder – disease – pathological process(es) –prevention –treatment

7. NEUROWEB Project IT system supporting Association Studies Integrating the databases of four cerebrovascular excellence centers Semantic misalignments among local databases Granularity (what level of detail in the diagnostic assessment) Methodology (diagnostic process)

8. NEUROWEB Reference Ontology + Query system + Reasoner

9. Act II The NEUROWEB Reference Ontology

10. Bottom-Up CDS Building First Step: Dbs aggregation  Union of the existing clinical repositories; –Identify what is semantically equivalent but terminologically different Second Step: DBs collection cleaning: –Criterion: minimum granularity  DBs fields constituted of other DBs field have been removed from the CDS; The resulting fields corresponds to the minimal diagnostic assessment; –CDS elements can be: Signs Symptoms Lab Tests Physical Examination Third Step: Higher level concepts definition: –Clinical Phenotypes  aggregation of CDS elements; Results CDS Clinical Phenotypes Sign Lab test Methods Physical Examination Symptoms Degree Diagnostic Value

11. Top-Down Clinical Phenotype Building Design principles: –Represent the way clinicians classify stroke types and subtypes (Top Phenotype Layer) –Analytically deconstruct the stroke types to grant methodological consistency and resolve granularity discrepancies (Low Phenotype Layer) –Ground the stroke type definition on the clinical data via the CDS (Core Data Set Layer) –DB fields can be mapped both at the CDS and at the Low Phenotypes level (Local Database to Reference Ontology)

12. TOAST Classification System (Top Phenotypes) –The TOAST Classification System is adopted by the NEUROWEB clinical communities –and used by the international community to guide: Diagnosis Treatment Prevention Trials to identify best practices for these (Evidence Based Medicine) –The TOAST phenotypes need analytical deconstruction to grant methodological consistency and resolve granularity discrepancies among databases (Low Phenotypes, CDS Elements) Capital Clinical Phenotypes in the cerebrovascular domain

13. Top-down CDS Building Third Step: Higher level concepts definition: Clinical Phenotype: –Top Phenotype: Ischemic Stroke types  classified according to different criteria: –Etiology/Anatomy (Atherosclerotic, Cardioembolic, Lacunar). CDS Ischemic Stroke types Physical Examination Anatomy Sign Lab test Symptoms Diagnostic Value Top Phenotype Low Phenotype Etiology

14. Top-down CDS Building Third Step: Higher level concepts definition: Clinical Phenotype: –Top Phenotype –Low Phenotype Etiological Layer –Derived Evidences –Direct Evidences Anatomical Layer –Anatomical Components –Topological Entities Ischemic Stroke types Topological Entity Anatomical Components Top Phenotype Low Phenotype Direct Evidences Derived Evidences

15. Top-down CDS Building Third Step: Higher level concepts definition: Clinical Phenotype: –Top Phenotype –Low Phenotype Etiological Layer –Derived Evidences »Durative Background »Traumatic Point Event Direct Evidences Anatomical Layer –Anatomical Components –Topological Entities Ischemic Stroke types Topological Entity Anatomical Components Top Phenotype Low Phenotype Direct Evidences Durative Background Traumatic Point Event Derived Evidences

16. Top-down CDS Building Third Step: Higher level concepts definition: Clinical Phenotype: –Top Phenotype –Low Phenotype Etiological Layer –Derived Evidences »Durative Background »Traumatic Point Event –Direct Evidences »Durative Diagnostic Evidence »Point-event Diagnostic Evidence Anatomical Layer –Anatomical Components –Topological Entities Ischemic Stroke types Point-Event Diagnostic Evidence Durative Diagnostic Evidence Topological Entity Anatomical Components Top Phenotype Low Phenotype Durative Background Traumatic Point Event Derived Evidences Direct Evidences

17. Top-down CDS Building CDS Ischemic Stroke types Physical Examination Point-Event Diagnostic Evidence Durative Diagnostic Evidence Topological Entity Anatomical Components Sign Lab test Symptoms Diagnostic Value Top Phenotype Low Phenotype Third Step: Higher level concepts definition: Clinical Phenotype: –Top Phenotype –Low Phenotype Etiological Layer –Derived Evidences »Durative Background »Traumatic Point Event –Direct Evidences »Durative Diagnostic Evidence »Point-event Diagnostic Evidence Anatomical Layer –Anatomical Components –Topological Entities Durative Background Traumatic Point Event Derived Evidences Direct Evidences

18. Top-down CDS Building CDS Ischemic Stroke types Physical Examination Durative Background Traumatic Point Event Point-Event Diagnostic Evidence Durative Diagnostic Evidence Topological Entity Anatomical Components Sign Lab test Symptoms Diagnostic Value Top Phenotype Low Phenotype Third Step: Higher level concepts definition: Clinical Phenotype: –Top Phenotype –Low Phenotype Etiological Layer –Derived Evidences »Durative Background »Traumatic Point Event –Direct Evidences »Durative Diagnostic Evidence »Point-event Diagnostic Evidence Anatomical Layer –Anatomical Components –Topological Entities Direct-Composite Evidences Derived Evidences Atomic Evidences

19. Top-down CDS Building CDS Ischemic Stroke types Physical Examination Point-Event Diagnostic Evidence Durative Diagnostic Evidence Topological Entity Anatomical Components Sign Lab test Symptoms Diagnostic Value Top Phenotype Low Phenotype Third Step: Higher level concepts definition: Clinical Phenotype: –Top Phenotype –Low Phenotype Etiological Layer –Durative Background »Traumatic Point Event –Durative Diagnostic Evidence »Point event Evidence Anatomical Layer –Anatomical Components –Topological Entities Biological Process Biological Process Biological Process Participant Durative Background Traumatic Point Event Derived Evidences

20. Top-Down CDS Building CDS Atherosclerotic Ischemic Stroke Physical Examination Atherosclerosis Ischemic Traumatic Event Relevant Ischemic Lesion Severe Stenosis Coagulation PAI-1 Left Internal Carotid Artery Sign Lab test Symptoms Diagnostic Value Top Phenotype Low Phenotype Third Step: Higher level concepts definition: Clinical Phenotype: –Top Phenotype –Low Phenotype Etiological Layer –Durative Background »Traumatic Point Event –Durative Diagnostic Evidence »Point event Evidence Anatomical Layer –Anatomical Components –Topological Entities Biological Process

21. Reasoner (Jena) N2L Converter N2L Converter DB1 Phenotype Converter User2 NW Interface User1 Mediator Queries rewriter Ontology T-Box Query Engine DB2 Query Engine Computational Issues Generating queries and accessing local repositories requires two tasks: –The elements of the local repository need to be mapped into the ones in the Reference Ontology and the CDS (N2L); –The NEUROWEB phenotypes need to be transformed in queries in terms of the reference ontology elements that map to the local repository (Phenotype Converter). The net effect is the translation of high-level concepts into regular SQL queries.

22. Reasoner (Jena) N2L Converter N2L Converter DB1 Phenotype Converter User2 NW Interface User1 Mediator Queries rewriter Ontology T-Box Query Engine DB2 Query Engine Querying the Ontology (Top Phenotypes) the NW Ontology engine returns portions of the Ontology graph of interest for clinicians w.r.t.: –DBs Analysis (NW Ontology Engine) SPQRL queries NW Ontology engine Mediator NW Ontology Engine Services NW Genomic engine

23. Querying the Ontology the NW Ontology engine returns portions of the Ontology graph of interest for clinicians w.r.t.: –DBs Analysis: Evaluation of the methodological coherence of the federated data bases according to their compliancy to the NW Ontology (exploiting the Low Phenotype layer, i.e. the Composite Evidences Sub-Layer); NW Ontology Engine Services CDS Top Phenotype Composite Evidences Low Phenotype Atomic Evidences Derived Evidences DBs Records

24. Reasoner (Jena) N2L Converter N2L Converter DB1 Phenotype Converter User2 NW Interface User1 Mediator Queries rewriter Ontology T-Box Query Engine DB2 Query Engine Querying the Ontology the NW Ontology engine returns portions of the Ontology graph of interest for clinicians w.r.t.: –Genomic Analysis (NW Genomic Engine) SPQRL queries NW Ontology engine Mediator NW Ontology Engine Services NW Genomic engine

25. Querying the Ontology (built-in queries) the NW Ontology engine returns portions of the Ontology graph of interest for clinicians w.r.t.: –Genomic Analysis: Evaluating two different phenotypes associated with a common SNP, which may have a direct causative role in phenotype determination; NW Ontology Engine Services CDS Top Phenotype Composite Evidences Low Phenotype Atomic Evidences Derived Evidences SNP DBs Records Bio Processes

26. Act III NEUROWEB meets OGMS

27. TOP PHENOTYPES TOP PHENOTYPES LOW PHENOTYPES Durative Etiological Background Traumatic Point Event Point-event Diagnostic Evidence TOPO-ANATOMICAL ENTITIES Topological Concepts Anatomical Parts BIOMOLECULAR ENTITIES Biological Process Biological Process Participant Diagnostic Values CDS Indicators Has- Diagnostic -Evidence Has- Cause- PointEvent Has- Cause- Durative By- Means-Of Has-Value Has- Side Has- Location Involves Has- Participant Durative Diagnostic Evidence

28. TOP PHENOTYPES (Ischemic Stroke types) TOP PHENOTYPES (Ischemic Stroke types) LOW PHENOTYPES Durative Etiological Background Traumatic Point Event Has- Cause- PointEvent Has- Cause- Durative Etiological / Pathological Process DisorderDisposition Pathological Processes Diagnosis Disposition AtherosclerosisAtherogenesisAtherosclerotic Plaque(s) Ath. Ischemic Stroke Risk Ischemic Stroke (Point Event)

29. Disorder Pathological Process TOP PHENOTYPES (Ischemic Stroke types) TOP PHENOTYPES (Ischemic Stroke types) LOW PHENOTYPES Durative Etiological Background Traumatic Point Event Has- Cause- PointEvent Has- Cause- Durative Etiological / Pathological Process DisorderDisposition Pathological Processes Pathological ProcessDisorderDisposition Diagnosis Disposition AtherosclerosisAtherogenesisAtherosclerotic Plaque(s) Ath. Ischemic Stroke Risk Ischemic Stroke (Point Event) Plaque-based Thrombogenesis Traveling Thrombus Cerebral Artery Occlusion Ischemia

30. Disorder Pathological Process TOP PHENOTYPES (Ischemic Stroke types) TOP PHENOTYPES (Ischemic Stroke types) LOW PHENOTYPES Durative Etiological Background Traumatic Point Event Has- Cause- PointEvent Has- Cause- Durative Etiological / Pathological Process DisorderDisposition Pathological Processes Pathological ProcessDisorderDisposition Diagnosis Disposition AtherosclerosisAtherogenesisAtherosclerotic Plaque(s) Ath. Ischemic Stroke Risk Ischemic Stroke (Point Event) Plaque-based Thrombogenesis Traveling Thrombus Cerebral Artery Occlusion Occluded Vessel

31. TOP PHENOTYPES TOP PHENOTYPES LOW PHENOTYPES Traumatic Point Event Point-event Diagnostic Evidence Diagnostic Values CDS Indicators Has- Diagnostic -Evidence Has- Cause- PointEvent Has- Cause- Durative By- Means-Of Has- Value Durative Diagnostic Evidence Etiological / Pathological Process DisorderDisposition AtherosclerosisAtherogenesisAtherosclerotic Plaque(s) Finding Stenosis Durative Etiological Background

32. TOP PHENOTYPES TOP PHENOTYPES LOW PHENOTYPES Durative Etiological Background Point-event Diagnostic Evidence Diagnostic Values CDS Indicators Has- Diagnostic -Evidence Has- Cause- PointEvent Has- Cause- Durative By- Means-Of Has- Value Durative Diagnostic Evidence Pathological Process Ischemia Pathological Process Brain tissue death Traumatic Point Event Disorder Ischemic scar Finding Scan lesion

33. Disorder Pathological Process Pathological ProcessDisorder Traveling Thrombus Cerebral Artery Occlusion Ischemia Pathological Process Oxygen-deprived Brain tissue Plaque-based Thrombogenesis Brain tissue death Biomolecular Process Coagulation TOP PHENOTYPES TOP PHENOTYPES LOW PHENOTYPES Durative Etiological Background Traumatic Point Event BIOMOLECULAR ENTITIES Biological Process Biological Process Participant Has- Cause- PointEvent Has- Cause- Durative Involves Has- Participant Biomolecular Process Hypoxia-induced Apoptosis

34. Disorder Pathological Process Pathological ProcessDisorder Traveling Thrombus Ischemia Pathological Process Oxygen-deprived Brain tissue Plaque-based Thrombogenesis Brain tissue death Biomolecular Process Coagulation TOP PHENOTYPES TOP PHENOTYPES LOW PHENOTYPES Durative Etiological Background Traumatic Point Event BIOMOLECULAR ENTITIES Biological Process Biological Process Participant Has- Cause- PointEvent Has- Cause- Durative Involves Has- Participant Biomolecular Process Hypoxia-induced Apoptosis How to handle in OGMS the transition from physiology-level to biomolecular- level processes?