1. Translational Research and Patient Safety in Europe TRANSFoRm: Vision of a learning healthcare system

2. Translational Research and Patient Safety in Europe TRANSFoRm Consortium

3. Translational Research and Patient Safety in Europe Specific research knowledge Actionable knowledge Routinely collected knowledge Knowledge in healthcare 3 Clinical trials Controlled populations Well-defined questions EHR systems Wide coverage Vast quantity May lack in detail and quality Distilled scientific findings Usable in clinical practice Decision support

4. Translational Research and Patient Safety in Europe Aims of TRANSFoRm To develop the infrastructure in primary care to support: Epidemiological research using GP records, including genotype- phenotype studies and other record linkages Research workflow embedded in the EHR Decision support for diagnosis Infrastructure components: Implementation methods Models for data and process organization Services Architectures Demonstrations with industry 3

5. Translational Research and Patient Safety in Europe TRANSFoRm Use Cases 5 Research Question: Effectiveness of continuous versus on demand PPI use? Electronic CRF embedded in the eHR RCT with event-initiated patient-related outcome measures: Trigger within EHR Semantic Mediator eCRF tool (embedded in EHR) GORD Research Question: Are well selected SNPs in T2D patients associated with variations in drug response to oral antidiabetics? Genotype-Phenotype record linkage study: Privacy model Record linkage (browsing, selecting, extracting) Data quality tool Provenance tool Type 2 Diabetes Experimental Study: Comparing approaches to diagnostic support Alerting versus suggesting Clinical Prediction rule web service (with underlying ontology) Prototype DSS integrated into EHR system Domains: chest pain abdominal pain shortness of breath Decision Support

6. Translational Research and Patient Safety in Europe Overall Architecture (1) Distributed Nodes Middleware (Distributed Infrastructure) End User Tools and Services Support Services

7. Translational Research and Patient Safety in Europe Support Services (e.g. rule based security, authentication) Overall Architecture (2) End User Tools and Services Data Mining and Analysis Clinical Evidence Extraction Tool Visual model explorer Data Mining Analysis Toolkit Data Provenance Provenance Capture Service Study Design Protocol Designer Query Workbench Eligibility Criteria Designer Query formulation and execution tool Study Management eCRF Designer Identify/Recruit Eligible Patients Study eCRF Data Collector Patient-reported outcome Manager CDE Designer Distributed Nodes Middleware (Distributed Infrastructure) Semantic Mediation Vocabulary Service Timeline Designer Consent Data Manager Data quality tool Provenance Audit Tool GP Decision Support Interactive Consultation Decision Support Tool Event-based trigger tool Clinical Evidence Content Manager Clinical Evidence Service

8. Translational Research and Patient Safety in Europe Models in TRANSFoRm Clinical Data Integration Model (CDIM) Mapping clinical data from EHRs and aggregated data repositories Clinical Research Information Model (CRIM) Research process information Evolution of Primary Care Research Information Model (PCROM). 9

9. Translational Research and Patient Safety in Europe Provenance Processing history of a data item –Actors involved –Data sources used –Operations performed –Data movements –Authorizations Supports: –Reliability –Accountability –Auditability Related research areas: –Workflows standardizing representation of data processing –Information systems tracking data evolution

10. Translational Research and Patient Safety in Europe Provenance benefits System monitoring –Entity oriented, rather than raw logs –Exploratory investigations possible User accountability –Data items and actions directly connect back to the user Traceability –Every step in the evolution of a result becomes easily accessible Reuse and repurposing –Storing previous queries for use by recommendation engines and the users directly Data warehouse –Large-scale statistics about resource usage, organisational performance and user activity

11. Translational Research and Patient Safety in Europe Architecture MD DB CP DB Centralized Zone Provenance API Prov. Query Service SQL SPARQL Capture Represen- tation Storage Metadata Registry Reasoner LP DB Local Servic e DB 1 DB n Local Zone Provenance API Prov. Query Service SQL SPARQL Capture Represen- tation Storage Reas. & DM

12. Translational Research and Patient Safety in Europe Example: Provenance of a query

13. Translational Research and Patient Safety in Europe Example: Linkage process

14. Translational Research and Patient Safety in Europe Example: Decision support 14

15. Translational Research and Patient Safety in Europe The challenge of representing knowledge in an interoperable computable form Developing a user understandable, computable and extensible knowledge representation scheme for capturing clinical trials’ concepts and information (knowledge) – including patient safety (medical errors) – with a multilingual support The foundation of interoperability lies with a shared understanding of concepts and data representation between systems: both syntactic (model-based) semantic interoperability – it is necessary to establish both syntactic (model-based) and semantic interoperability to represent knowledge in a computable form TRANSFoRm provides this through an Integrated Vocabulary Service (TRANSFoRm VS) 15

16. Translational Research and Patient Safety in Europe Challenges for EU TRANSFoRm Vocabulary Services have been traditionally provided by the NCI Cross Mapping of Vocabularies –The case of Primary Care in Europe: the difficulty with using the NCI EVS in European Primary Care is that neither Read codes nor ICPC2 are part of the service –some mapping exists with UMLS (but many concepts missing) –EVS can be augmented by referencing Read codes to UMLS codes via SNOMED CT (where a cross-mapping exists) and by adding the ICPC-2 mapping through ICD-10 Evolving technologies and APIs for EVS –LexEVSAPI – various versions from 3.0 to 5.0 16

17. Translational Research and Patient Safety in Europe Application Architecture The TRANSFoRm Integrated Vocabulary Service is designed to allow end users to search and retrieve clinical vocabulary concepts and associated content –a web interface and a web service API –the service uses the LexEVS (version 5.1) technology to access a backend UMLS vocabulary database –the service uses direct Java Database Connectivity (JDBC) to access other vocabulary databases (e.g. Read Codes V2, ICPC2) 17

18. Translational Research and Patient Safety in Europe TRANSFoRm Integrated VS Server Architecture 18

19. Translational Research and Patient Safety in Europe A screenshot of the web-based interface 19

20. Translational Research and Patient Safety in Europe RCD v2/ICPC2 Read Codes (RCDv2) and International Classification of Primary Care (ICPC2) corpus of terms and their associated mappings –created to cater for the initial need of the existence of specific primary care oriented terminologies. The UK NHS Connecting for Health Terminology Centre - mappings from Read Codes version 2 to SNOMED CT. The Read Codes v2 database in Transform VS is set up based on this mapping so that Read Codes 2 concepts can be linked to a UMLS search. Similar approach for ICPC2. ICPC2-ICD10 Thesaurus and mappings - Transition Project @ University of Amsterdam The TRANSFoRm team is updating the ICPC-ICD 10 mapping and Thesaurus –to eventually incorporate the new Thesaurus into UMLS. 20 UMLS Metathesaurus Read Codes v2 Codes SNOMED CT Codes ICPC2 Codes ICD-10 Thesaurus/Codes UMLS Metathesaurus

21. Translational Research and Patient Safety in Europe Demonstration of integrating a current prototype of the Study Designer and TRANSFoRm Integrated Vocabulary Service 21

22. Translational Research and Patient Safety in Europe ePCRN Study Designer and TRANSFoRM VS integration 22

23. Translational Research and Patient Safety in Europe eCRF Introduction  eCRF is electronic version of case report form (CRF)  CRF are forms designed by clinical study investigators to collect data about each subject during the whole study process  CRFs are usually filled in by research staff, but can also be filled in by practice staff if CRFs are ‘integrated’ into practice system  Collected data are saved and analysed afterwards 23

24. Translational Research and Patient Safety in Europe eCRF Workflow 24 Design Study Collect Data Analyse Data Protocol Timeline CRFs Study Database The following provide some example screenshots of the eCRF technology on a current prototype

25. Translational Research and Patient Safety in Europe Protocol Design 25

26. Translational Research and Patient Safety in Europe Timeline Design 26

27. Translational Research and Patient Safety in Europe CRF Design 27

28. Translational Research and Patient Safety in Europe Decision Support Tool Decision Support Tool Characteristics: Embedded within the eHR Triggered by a ‘reason for encounter’ Presents diagnostic prompts based on ontology service for clinical prediction rules Collects ontologically controlled diagnostic cue data Alerts/suggests for potential missed diagnoses The Decision Support Tool will provide patient-specific advice at the moment of consultation so that clinicians are able to access and quantify likely differential diagnoses framed in terms of diagnostic probability and alternative diagnostic possibilities. 28

29. Translational Research and Patient Safety in Europe Decision support objectives Develop a model of clinical evidence upon which diagnostic decision support is provided Formulating and quantifying potential differential diagnoses based on presenting patient cues from primary care EHRs Linked to primary care EHRs and based on clinical knowledge derived from electronic sources of research data

30. Translational Research and Patient Safety in Europe Method Ontological approach - define an ontology of clinical evidence to represent what we know about defined clinical scenarios Provides for top down and bottom up reasoning to formulate potential diagnoses Clinical Prediction Rule – used as one possible mechanism to interpret that evidence by applying some quantification of the importance of the constituent diagnostic cues

31. Translational Research and Patient Safety in Europe General model of evidence

32. Translational Research and Patient Safety in Europe Development Tools Protégé – Ontology Development Sesame Triple Store – provides persistent representation enabling dynamic update of knowledge Sesame API – provides for programmatic update/manipulation and provision of clinical evidence web service for decision support

33. Translational Research and Patient Safety in Europe Protégé – defining concepts and relations

34. Translational Research and Patient Safety in Europe Protégé – defining instances of knowledge

35. Translational Research and Patient Safety in Europe Sesame query platform

36. Translational Research and Patient Safety in Europe Future DSS work Focus moving to defining query and update interfaces as part of a defined evidence service Allow for generation and update of knowledge from data mining done on electronic sources of primary care data Working with EHR vendors to define user interface requirements

37. Translational Research and Patient Safety in Europe TRANSFoRm Tools & Services TRANSFoRm Vision TRANSFoRm will drive the integration of clinical research and clinical practice by developing tools & services to facilitate greater system interoperability. 37 eHR System Clinical Repositories CTDMS Pharmaceutical Companies eHR Vendors Clinical Research Networks CTDMS: Clinical Trial Data Management Software e.g. Oracle Clinical eHR: Electronic Heath Record e,g, EMIS Web Clinical Repositories e.g. GO-DARTs Tayside

38. Translational Research and Patient Safety in Europe TRANSFoRm Anticipated Benefits 38 Support quicker and more economic recruitment and follow-up of Randomised Clinical Trials... Improve patient safety... Support large scale phenotype- genotype association studies and follow-up on trials... Drive the integration and re-use of clinical data stored in different eHR systems... Enhance uptake of eHR systems that offer support for clinical care and research......with an integrated eHR interface that enables the rich capture of clinical data, including symptoms and signs...by providing not only a diagnosis support tool but also a query workbench that supports the identification of patient eligible to participate in clinical trials... through distributed interoperability of eHR data and clinical data repositories that maintain provenance, confidentiality and security... with software tools and web-services that support clinical research by enabling use of controlled vocabulary and standardised data elements... by adopting an open-source business model, allowing eHR vendors and data integrators direct cost savings and the ability to reach more customers through improved pricing flexibility

39. Translational Research and Patient Safety in Europe Contact details www.transformproject.eu –1 st year deliverables publicly available eCRF – EHR integration –Theo Arvanitis, University of Birmingham Decision Support System –Derek Corrigan, Royal College of Surgeons Ireland Provenance, general queries –Vasa Curcin, Imperial College London 39