Automatic generation of MedDRA terms groupings using an ontology

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Automatic generation of MedDRA terms groupings using an ontology. Gunnar DECLERCK a , Cédric BOUSQUET a,b and Marie-Christine JAULENT a a INSERM, UMRS 872 EQ20, Université Paris Descartes, France. b Department of Public Health, CHU University of Saint Etienne, France. - PowerPoint PPT Presentation

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Automatic generation of MedDRA termsgroupings using an ontologyGunnar DECLERCKa, Cdric BOUSQUETa,b and Marie-Christine JAULENTa

a INSERM, UMRS 872 EQ20, Universit Paris Descartes, France.b Department of Public Health, CHU University of Saint Etienne, France.

MIE 2012, August 27th, Pisa

Context and Rationale MedDRA (Medical Dictionary for Drug Regulatory Activities) : standard terminology used to code adverse drug reactions (ADRs) in safety reports for postmarketing drug surveillance.

Used for Signal detection : Case reports coded with MedDRA stored in databases (i.e. FDA pharmacovigilance Database for the US, WHO Vigibase for Europe) Data mining algorithms used to find statistical correlations between ADRs (several MedDRA terms defining a unique medical condition) and drugs (a signal) Empirical studies to assess the causal relationship between the drug and ADR.

2MedDRA hierarchical structure

2WPWork Package title1Project management and administration2Framework for pharmacoepidemiological studies3Methods for signal detection 4New tools for data collection from consumers5Benefit-risk integration and representation6Validation studies involving an Extended Audience7Training and communication Main goal: To develop and evaluate semantic driven methods for grouping MedDRA terms to improve signal detection performances.

Hypothesis: Signal detection is improved when algorithms use groupings of MedDRA terms referring to the same ADR condition (rather than one single term). Need a way to assist human experts to build MedDRA groupings (currently made manually)

Method: Building an ADR ontology (OntoADR) providing MedDRA terms with formal machine-processable defintions to support automatic MedDRA terms grouping procedures (OWL queries selecting terms on the basis of their semantic properties).PROTECT WP3-SP6 Novel techniques for grouping ADRs to improve signal detection3PROTECT. Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium. IMI (Innovative Medicines Initiative) project (2009- 2014).

4 MedDRA terminology enriched with Snomed-CT concepts formal definitions

34994 concepts (20856 MedDRA 13.0 terms / others from Snomed-CT)

26 Snomed-CT relations used to express medical meaning of MedDRA conceptsOntoADR ontology

HASFINDINGSITEspecifies the body site affected by a condition

HASOCCURRENCErefers to the specific period of life during which a condition first occurs

Hierarchical relations from SOC level to PT (Preferred terms) level are converted to subsomption (subclass_of) relations

LLT (low level terms) are integrated as annotation labels of PT concepts

PT levelSOC levelHLT levelHLGT level

Ontologizing MedDRA5 When it is possible, MedDRA concepts are mapped with Snomed-CT concepts via UMLS metathesaurus

Semantic information describing Snomed-CT concepts used to build the formal definition of MedDRA concepts.

When mapping impossible, formal definition made manually (via collaboration between knowledge engineers and medical experts)

Formal definition of Dilatation intrahepatic duct congenital Meddra PT concept after Snomed-CT mapping (mapped with Congenital dilatation of lobar intrahepatic bile duct) Mapping process6

Snomed-CTMedDRASOCHLPTHLTPT

ONTOADR.owl 55.6 % of MedDRA 13.0 terms could be defined using (i) a direct mapping with a Snomed-CT concept (UMLS or other mappings methods) or (ii) a handmade definition. Those terms cover 97.02 % of MedDRA terms used in the FDA database (calculated for the period 2004-2010: 11 millions reports).

Mapping process Medical experts: Validation of mappingsManual enrichment of OntoADR= MEDDRA TERMS + FORMAL DEFINITIONSOntoADR generation: general schema77 Thanks to OntoADR, OWL queries can be built to select the MedDRA PTs whose formal definition fits some definitional criteria.

Example : Query to catch MedDRA terms related to Upper gastrointestinal bleeding

Will select from MedDRA hierarchy all PTs matching those two properties:

Duodenal ulcer haemorrhageGastric haemorrhageMallory-Weiss syndromePeptic ulcer haemorrhageetc.

hasAssociatedMorphology some Hemorrhage AND hasFindingSite some Upper gastrointestinal tract structure8Using OntoADR to perform automatic query-based MedDRA terms groupings Through the subsomption mechanism, MedDRA terms referring to hemorrhages of parts of the Upper gastrointestinal tract are also selected.

ex. Oesophageal ulcer haemorrhage, Gastric varices haemorrhage, etc.

9Using OntoADR to perform automatic query-based MedDRA terms groupings

Focus on 13 ADR safety topics identified by Trifir et al (2009) as first importance pharmacovigilance targets (EU-ADR project).

For each safety topic:

Groupings of MedDRA PTs have been realized with OntoADR queries.ST 1 Bullous eruptionsST 2 Acute renal failureST 3 Anaphylactic shockST 4 RhabdomyolysisST 5 Aplastic anaemia/pancytopeniaST 6 NeutropeniaST 7 Cardiac valve fibrosisST 8 Extrapyramidal disordersST 9 Confusional stateST 10 ThrombocytopeniaST 11 Upper gastrointestinal bleedingST 12 Peripheral neuropathyST 13 Maculo-papular erythematous eruptionsADR topics identified by Trifir et al (2009) 10Evaluation of the OntoADR-based grouping methodTrifir G, Pariente A, Coloma PM, Kors JA, Polimeni G, Miremont-Salam G, Catania MA, Salvo F, David A, Moore N, Caputi AP, Sturkenboom M, Molokhia M, Hippisley-Cox J, Acedo CD, van der Lei J, Fourrier-Reglat A. Data mining on electronic health record databases for signal detection in pharmacovigilance: which events to monitor? Pharmacoepidemiol Drug Saf. 2009; 18(12):1176-84.The content of those groupings has been evaluated by comparison with existing handmade MedDRA groupings of PTs targeting same or close conditions:

Original MedDRA hierarchy groupings (HLTs or HLGTs)

SMQs (Standard Medical Queries): collections of MedDRA PTs developed manually by the MSS0 (Maintenance and Support Services Organization) to describe a common clinical conditionNeutropenia Safety TopicType (for SMQ)LabelId MeddraAgranulocytosis10001507Autoimmune neutropenia10055128Cyclic neutropenia10053176Febrile neutropenia10016288Felty's syndrome10016386Granulocytopenia10018687Granulocytopenia neonatal10018688Idiopathic neutropenia10051645Infantile genetic agranulocytosis10052210Neutropenia10029354Neutropenia neonatal10029358Neutropenic colitis10062959Neutropenic infection10059482Neutropenic sepsis10049151NarrowAgranulocytosis10001507NarrowBand neutrophil count decreased10057950NarrowBand neutrophil percentage decreased10059130NarrowCyclic neutropenia10053176NarrowFebrile neutropenia10016288NarrowIdiopathic neutropenia10051645NarrowNeutropenia10029354NarrowNeutropenic infection10059482NarrowNeutropenic sepsis10049151NarrowNeutrophil count decreased10029366BroadMyelocyte percentage decreased10052227BroadNeutropenia neonatal10029358BroadNeutrophil count abnormal10061313BroadNeutrophil percentage decreased10052223 Leukopenia Sometimes used as synonym of Neutropenia

But stricly speaking Leukopenia semantically broader (refers to a deficit in the number of all types of white blood cells)

To enable comparison with query-based neutropenia grouping, only neutropenia relevant PTs were selected in the SMQHLT NeutropeniasSMQ Leukopenia Generally defined as an abnormally low number of neutrophils (*), which are the most abundant type of white blood cells (leukocytes) in mammals.

(*) http://www.nlm.nih.gov/medlineplus/ency/article/007230.htmhasDefinitionalManifestation some Neutropenia

OR interprets some (hasComponent some 'Segmented neutrophil' OR hasComponent some 'Myelocyte' OR hasComponent some 'Stab form')

AND (hasInterpretation some 'Below reference range' OR hasInterpretation some 'Decreased' OR hasInterpretation some 'Abnormal')Neutropenia: Building the OWL querySemantic relations used by the queryDescriptioninterpretsRefers to the entity being evaluated or interpreted, when an evaluation, interpretation or judgment is intrinsic to the meaning of a concept.hasInterpretationThis attribute is grouped with the attribute Interprets, and designates the judgment aspect being evaluated or interpreted for a concept (e.g., presence, absence, degree, normality, abnormality, etc.).hasComponentRefers to what is being observed or measured by a procedure.hasDefinitionalManifestationLinks disorders to the manifestations (observations) that define them.(*) http://en.wikipedia.org/wiki/Neutrophil_granulocytehasDefinitionalManifestation some Neutropenia

OR interprets some (hasComponent some 'Segmented neutrophil' OR hasComponent some 'Myelocyte' OR hasComponent some 'Stab form')

AND (hasInterpretation some 'Below reference range' OR hasInterpretation some 'Decreased' OR hasInterpretation some 'Abnormal')Neutropenia: Building the OWL querySemantic relations used by the queryDescriptioninterpretsRefers to the entity being evaluated or interpreted, when an evaluation, interpretation or judgment is intrinsic to the meaning of a concept.hasInterpretationThis attribute is grouped with the attribute Interprets, and designates the judgment aspect being evaluated or interpreted for a concept (e.g., presence, absence, degree, normality, abnormality, etc.).hasComponentRefers to what is being observed or measured by a procedure.hasDefinitionalManifestationLinks disorders to the manifestations (observations) that define them.(*) http://en.wikipedia.org/wiki/Neutrophil_granulocyteSelecting disorders defined by an abnormally low number of neutrophils (ex. autoimmune neutropenia, cyclical neutropenia, etc.)hasDefinitionalManifestation some Neutropenia

OR interprets some (hasComp