neuroweb: modeling cerebrovascular phenotypes gianluca colombo daniele merico disco, università di...
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NEUROWEB:Modeling cerebrovascular phenotypes
Gianluca ColomboDaniele Merico
DISCo, Università di Milano-Bicocca
SSW09Signs, Symptoms and Findings:
Towards an Ontology for Clinical Phenotypes.
Milan, 4-5 September 2009
European CommissionSixth Framework Programme
Information Society Technologies project number 518513
NEUROWEB Project
Act IAssociation Studies
and Clinical Phenotypes
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
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
Clinical Phenotype(Association Studies)
• An aggregate of ‘bodily features’ (sensu OGMS) – directly observabledirectly observable (e.g. brain lesion)
or derived / inferablederived / 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: – StrengthStrength of association
– ParsimonyParsimony of associated factorsgenotype-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: AssociationNB: Association may (or may not) imply causationcausation
Etio-physiological relatednessof aggregated bodily features
Why association studies
• Association
Prognosis / improved diagnostics
• Causation
Part of the research elucidating the triads
disorder – disease – pathological process(es)– prevention
– treatment
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)
NEUROWEB Reference Ontology
+Query system
+Reasoner
Act IIThe NEUROWEB
Reference Ontology
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
PhysicalExamination
Symptoms
Degree
DiagnosticValue
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)
• 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 Phenotypesin the cerebrovascular domain
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
PhysicalExamination
Anatomy
SignLab test Symptoms
DiagnosticValue
Top Phenotype
Low Phenotype
Etiology
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
TopologicalEntity
AnatomicalComponents
Top Phenotype
Low Phenotype
Direct Evidences
Derived Evidences
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
TopologicalEntity
AnatomicalComponents
Top Phenotype
Low Phenotype
Direct Evidences
Durative Background
Traumatic Point Event
Derived Evidences
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-EventDiagnostic Evidence
DurativeDiagnostic Evidence
TopologicalEntity
AnatomicalComponents
Top Phenotype
Low Phenotype
Durative Background
Traumatic Point Event
Derived Evidences
Direct Evidences
Top-down CDS Building
CDS
Ischemic Stroke types
PhysicalExamination
Point-EventDiagnostic Evidence
DurativeDiagnostic Evidence
TopologicalEntity
AnatomicalComponents
SignLab test Symptoms
DiagnosticValue
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
Top-down CDS Building
CDS
Ischemic Stroke types
PhysicalExamination
Durative Background
Traumatic Point Event
Point-EventDiagnostic Evidence
DurativeDiagnostic Evidence
TopologicalEntity
AnatomicalComponents
SignLab test Symptoms
DiagnosticValue
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
Top-down CDS Building
CDS
Ischemic Stroke types
PhysicalExamination
Point-EventDiagnostic Evidence
DurativeDiagnostic Evidence
TopologicalEntity
AnatomicalComponents
SignLab test Symptoms
DiagnosticValue
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
BiologicalProcess
BiologicalProcessParticipant
Durative Background
Traumatic Point Event
Derived Evidences
Top-Down CDS Building
CDS
Atherosclerotic Ischemic Stroke
PhysicalExamination
Atherosclerosis
Ischemic Traumatic Event
RelevantIschemicLesion
SevereStenosis
Coagulation
PAI-1
Left
InternalCarotidArtery
SignLab test Symptoms
DiagnosticValue
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
Reasoner(Jena)
N2LConverter
N2LConverter
DB1
PhenotypeConverter
User2
NWInterface
User1
Mediator Mediator
Queries rewriter
OntologyT-Box
QueryEngine
DB2
QueryEngine
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.
Reasoner(Jena)
N2LConverter
N2LConverter
DB1
PhenotypeConverter
User2
NWInterface
User1
Mediator Mediator
Queries rewriter
OntologyT-Box
QueryEngine
DB2
QueryEngine
• 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)
SPQRLqueries
NWOntology engine
Mediator
NW Ontology Engine Services
NWGenomic engine
• 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
DerivedEvidences
DBsRecords
Reasoner(Jena)
N2LConverter
N2LConverter
DB1
PhenotypeConverter
User2
NWInterface
User1
Mediator Mediator
Queries rewriter
OntologyT-Box
QueryEngine
DB2
QueryEngine
• 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)
SPQRLqueries
NWOntology engine
Mediator
NW Ontology Engine Services
NWGenomic engine
• 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
DerivedEvidences
SNP
DBsRecords
BioProcesses
Act IIINEUROWEB meets OGMS
TOPPHENOTYPES
TOPPHENOTYPES
LOWPHENOTYPES
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
TOP PHENOTYPES(Ischemic Stroke types)
TOP PHENOTYPES(Ischemic Stroke types)
LOWPHENOTYPES
Durative Etiological Background
Traumatic Point Event
Has-Cause-PointEvent
Has-Cause-
Durative
Etiological /Pathological
ProcessDisorder Disposition
PathologicalProcesses
Diagnosis
Disposition
Atherosclerosis Atherogenesis AtheroscleroticPlaque(s)
Ath. Ischemic Stroke Risk
Ischemic Stroke (Point Event)
DisorderPathological
Process
TOP PHENOTYPES(Ischemic Stroke types)
TOP PHENOTYPES(Ischemic Stroke types)
LOWPHENOTYPES
Durative Etiological Background
Traumatic Point Event
Has-Cause-PointEvent
Has-Cause-
Durative
Etiological /Pathological
ProcessDisorder Disposition
PathologicalProcesses
Pathological Process Disorder Disposition
Diagnosis
Disposition
Atherosclerosis Atherogenesis AtheroscleroticPlaque(s)
Ath. Ischemic Stroke Risk
Ischemic Stroke (Point Event)
Plaque-based Thrombogenesis
TravelingThrombus
Cerebral Artery Occlusion
Ischemia
DisorderPathological
Process
TOP PHENOTYPES(Ischemic Stroke types)
TOP PHENOTYPES(Ischemic Stroke types)
LOWPHENOTYPES
Durative Etiological Background
Traumatic Point Event
Has-Cause-PointEvent
Has-Cause-
Durative
Etiological /Pathological
ProcessDisorder Disposition
PathologicalProcesses
Pathological Process Disorder Disposition
Diagnosis
Disposition
Atherosclerosis Atherogenesis AtheroscleroticPlaque(s)
Ath. Ischemic Stroke Risk
Ischemic Stroke (Point Event)
Plaque-based Thrombogenesis
TravelingThrombus
Cerebral Artery Occlusion
Occluded Vessel
TOPPHENOTYPES
TOPPHENOTYPES
LOWPHENOTYPES
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
ProcessDisorderDisposition
Atherosclerosis Atherogenesis AtheroscleroticPlaque(s)
Finding
Stenosis
Durative Etiological Background
TOPPHENOTYPES
TOPPHENOTYPES
LOWPHENOTYPES
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 tissuedeath
Traumatic Point Event
Disorder
Ischemicscar
Finding
Scan lesion
DisorderPathological
ProcessPathological
Process Disorder
TravelingThrombus
Cerebral Artery Occlusion
Ischemia
Pathological Process
Oxygen-deprivedBrain tissue
Plaque-based Thrombogenesis
Brain tissuedeath
Biomolecular Process
Coagulation
TOPPHENOTYPES
TOPPHENOTYPES
LOWPHENOTYPES
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-inducedApoptosis
DisorderPathological
ProcessPathological
Process Disorder
TravelingThrombus
Ischemia
Pathological Process
Oxygen-deprivedBrain tissue
Plaque-based Thrombogenesis
Brain tissuedeath
Biomolecular Process
Coagulation
TOPPHENOTYPES
TOPPHENOTYPES
LOWPHENOTYPES
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-inducedApoptosis
How to handle in OGMS the transition from physiology-level to biomolecular-
level processes?