1. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Ida Sim, MD, PhD March 9, 2010 Division of General Internal Medicine, and Center for Clinical and Translational Informatics UCSF Informatics for Clinical Research Copyright Ida Sim, 2010. All federal and state rights reserved for all original material presented in this course through any medium, including lecture or print.

2. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Outline Clinical Research Systems Overview Clinical Research Informatics (CRI) –sharing research meaning UCSF clinical research information systems –MyResearch –Integrated Data Repository –REDCap –Epic Summary

3. Big Picture of Health Informatics Virtual Patient Transactions Raw data Medical knowledge Clinical research transactions Raw research data Decision support Medical logic PATIENT CARE / WELLNES RESEARCH Workflow modeling and support, usability, cognitive support, computer-supported cooperative work (CSCW), etc. CRMSs

4. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics IRBFunding Agency Study DB Data analysis Results reporting Contract Research Organization (CRO) Protocol Trial Design Sponsors Academic PIs ? Site 1Site 2 Site 3 Site Management Organization (SMO) Clinical Research Today >80% on paper

5. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics IT Systems for Clinical Research Electronic IRB systems –electronic system for submission and review of applications –e.g., ClickCommerce, home grown, iMedRIS (at UCSF) Clinical Trial Management System (CTMS) –web-based application to define variables, forms, sign-in authentication, data entry, data cleaning, data analysis and reporting, etc. –e.g, Velos, OnCore (at UCSF Cancer Center)

6. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics iMedRIS Just launched 2 weeks ago –http://research.ucsf.edu/chr/iMedRI S/Home.asp Each institution can customize what information is collected –mostly administrative data (e.g., PI name) –scientific info is all in text (e.g., design type = RCT)

7. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics IT Systems for Clinical Research Electronic IRB systems –electronic system for submission and review of applications –e.g., ClickCommerce, home grown, iMedRIS (at UCSF) Clinical Trial Management System (CTMS) –web-based application to define variables, forms, sign-in authentication, data entry, data cleaning, data analysis and reporting, etc. –e.g, Velos, OnCore (at UCSF Cancer Center)

8. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics CRMSs Clinical Research Management Systems are for running/managing a study –document management (protocol, case report forms) –finances, IRB –study calendar (what to do to whom when) and data entry –data management and analysis –reporting Most systems designed for supporting interventional clinical trials (CTMS)

9. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics EHR vs. CTMS Contents EHR Patient demographics Chart notes –problem list Visit and assessment Lab and other orders Lab and other results Clinical decision-making Discharge summary CTMS Title, NCT #, IRB # Protocol document –interventions, design, outcomes, etc. Study assessment Outcomes assessment Case report forms Data analysis Trial reporting/publication

10. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics CRMS Policy at UCSF Currently –Cancer Center on OnCore –rest of campus on smattering of other systems e.g., Quesgen, Immune Tolerance Network/Stanford Longer term –may extend OnCore to rest of campus In the meantime, have a few systems providing some support –REDCap, MyResearch, IDR, etc.

11. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Outline Clinical Research Systems Overview Clinical Research Informatics (CRI) –sharing research meaning UCSF clinical research information systems –REDCap –MyResearch –Integrated Data Repository –Epic Summary

12. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Why is CRI Important? Clinical trials are becoming very complex –avg 460 days (2002) to 780 days (2006) –avg # of participants: 1700 to 3400 over 30 yrs –# of study procedures: 70% increase to 85 procedures, from 2000 to 2005 Fragmented, global industry –estimated 1100 organizations involved in clinical research in 2009 in US (Sponsors, CROs, SMOs, AHCs...) –“43% big pharma FDA trials were conducted abroad... projecting as much as 65% within 3 years” [Tufts Outlook 2008] Can we afford to do this all in paper?? Tufts Center for the Study of Drug Development, “Growing Protocol Design Complexity Stresses Investigators, Volunteers,” Impact Report 10, no. 1 (January/February 2008).

13. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics IRB Trial Design Protocol Funding Agency Site 1Site 2 Site 3 Site Management Organization (SMO) Study DB Data analysis Results reporting Contract Research Organization (CRO) Sponsors Academic PIs ? Simplifying Clin Research Management

14. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Need to “Interoperate” Can achieve through one single standard system –one end-to-end CTMS from trial inception to end –used by all PIs, industry, CROs, worldwide –like everyone using Word for word processing...or through “plug and play” of multiple modular systems –define common terms, models, interchange protocols –provide software components for assembly –provide way to “certify” compatibility of systems

15. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Interoperation Ability of two or more systems or components to exchange information and to use the information that has been exchanged [IEEE Standard Computer Dictionary, 1990] –syntactic: grammar, composition of what is said e.g., using an exchange protocol over networks e.g., HL7, DICOM, XML Document Type Definition (DTD) –semantic: meaning of what is said e.g., using a controlled vocabulary aka dictionary e.g., SNOMED, ICD-9

16. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Biomedical IT “Stacks” AdministrativeClinical CareResearch ClinicalBilling Physical Networking Communications Protocols (e.g., HL-7) Standard Vocabulary Practice Management Systems Medical Business Data Model Electronic Medical Record Clinical Care Data Model Clinical Res. Management Systems Clinical Study Data Models

17. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Interoperation Over the Stack AdministrativeClinical CareResearch ClinicalBilling Physical Networking Communications Protocols (e.g., HL-7) Standard Vocabulary Practice Management Systems Medical Business Data Model Electronic Medical Record Clinical Care Data Model Clinical Res. Management Systems Clinical Study Data Models Syntactic Semantic and Workflow

18. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics MICU Finance Research QA Clinical / Research Data Repository Internet ADT ChemEHRXRayPBMClaims How do the machines “talk” to each other? Networking Basics

19. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Internet = Network of Networks itsa medicine ucsf.edu nci.nih.gov “the cloud” myhome.com Main Trunk Cables local trunk cable through Berkeley amazon.com at home dial-in to itsa.ucsf.edu via modem pacbell.net aol.com Internet Service Provider (ISP) via DSL or cable LAN

20. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Protocol = grammar for machines talking to each other –e.g., hypertext transfer protocol http for web http://www.epibiostat.ucsf.edu/courses/schedule/med_infor matics.htmlhttp://www.epibiostat.ucsf.edu/courses/schedule/med_infor matics.html –e.g., ftp file transfer protocol –all sit on top of basic networking protocol TCP/IP Health-specific protocols needed “on top of” http or TCP/IP –a “grammar” for how to exchange health-related data What Happens Over the Cables

21. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Health Data Interchange Protocols HL7, “containers” for data packages, e.g., lab DICOM, “containers” for radiology studies –machine used, type of study, # of images, etc. CCD (Continuity of Care Document) for the electronic chart –e.g., problem list, allergies, family history “Containers” do not address the data naming issue –e.g., Na, sodium, serum sodium -- need to standardize to a SNOMED code MSH|… message header PID|… patient identifier OBX|1|ST|84295^NA||150|mmol/l|136-148|H||A|F|19850301

22. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Sharing Research Meaning AdministrativeClinical CareResearch ClinicalBilling Physical Networking Communications Protocols (e.g., HL-7) Standard Vocabulary Practice Management Systems Medical Business Data Model Electronic Medical Record Clinical Care Data Model Clinical Res. Management Systems Clinical Study Data Models Syntactic Semantic and Workflow

23. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Computable Protocol Study protocol is core essence of a research study –the investigational plan, including the actions to be undertaken, the measurements, and the analysis procedures to be followed –is not the same as the study protocol document (i.e., the Word or PDF file) If this protocol is made computable, and standardized, then all clinical studies can be described in the same way so that clinical research systems can interoperate

24. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Components of a Study Protocol Who –participants: eligibility criteria, recruitment, followup –investigators: PI, sponsors, advisors, etc. What –interventions or exposures: experimental, control –study outcomes: primary, secondary, baseline When –dates of enrollment, timing of assessments Where –study sites Why –background, objective, hypothesis How –analytic approach, study monitoring, outcomes adjudication, etc.

25. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Computable Protocol AdministrativeClinical CareResearch ClinicalBilling Physical Networking Communications Protocols (e.g., HL-7) Standard Vocabulary Practice Management Systems Medical Business Data Model Electronic Medical Record Clinical Care Data Model Clinical Res. Management Systems Computable Protocol Syntactic Semantic and Workflow

26. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Need Standardization To... Common computable study protocol –the study plan: e.g., eligibility criteria, treatment, outcomes CTOM, SDTM, BRIDG, OCRe, etc. etc. Common variables –clinicallly-agreed upon data items for research e.g., “menopause” defined a certain way Terminologies/vocabularies –base terms used to describe biomedical concepts e.g., SNOMED, NCI Thesaurus Common interchange standards –e.g., CDISC (“HL7 for clinical research”)

27. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Scientific Case for Standardization Interventional studies fundamentally done to demonstrate differences between interventions, by types of patients [Clarke M, Trials 2007] –common eligibility criteria would facilitate cross-study comparisons and synthesis e.g., post-menopause, congestive heart failure –common study outcomes (phenotypes) necessary for pooling/meta-analysis e.g., 5-year cancer free survival, common asthma measures Similar argument for observational studies –e.g., comparative effectiveness research

28. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics NCI Approach in Cancer NCI caDSR (Data Standards Repository) –library of Common Data Elements (CDEs) that others have defined –you can define new CDEs using terms from NCI Thesaurus Let’s go search... –https://cdebrowser.nci.nih.gov/CDEBrowser/https://cdebrowser.nci.nih.gov/CDEBrowser/

29. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Case Report Forms (CRF) Why reinvent the wheel for common forms? NCI has a Forms Builder –“shop” for CDEs, put them into your cart –insert CDEs into your case report form can download as HTML, XML, Excel, Word, PDF NCI now building library of forms –e.g., Demographics Case Report Form built from CDEs PDF, Word, etc. or directly to CTMS for direct data entry Grant proposals to NCI are beginning to be reviewed on use of CDEs

30. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Summary: Interoperation of Research Data Interoperation = meaningful exchange of data among computers –syntactic: how things are said, the grammar – semantic: what is said, the meaning Semantic standardization a greater challenge in research than clinical care –need a common computable protocol model –need to be very precise, research needs change as knowledge grows, researchers very individualistic Moving towards standardized, coded variables

31. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Outline Clinical Research Systems Overview Clinical Research Informatics (CRI) –sharing research meaning UCSF clinical research information systems –REDCap –MyResearch –Integrated Data Repository –Epic Summary

32. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics IRBFunding Agency MyResearch Data analysis Results reporting Oncor CRMS? Protocol Trial Design Sponsors Academic PIs Site 1Site 2 Site 3 Site Management Organization (SMO) UCSF Research Info Systems Integrated Data Repository REDCap Epic

33. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics REDCap Web-based tool for building study databases and defining data entry forms –https://redcap.ucsfopenresearch.org/https://redcap.ucsfopenresearch.org/ –https://redcap.ucsfopenresearch.org/index.php?ac tion=traininghttps://redcap.ucsfopenresearch.org/index.php?ac tion=training –is HIPAA-compliant (unlike Survey Monkey) Example web-based survey –https://redcap.ucsfopenresearch.org/surveys/index.php?hash=c9f0f895fb98ab9159f51fd0297e236dhttps://redcap.ucsfopenresearch.org/surveys/index.php?hash=c9f0f895fb98ab9159f51fd0297e236d Now available to you for free

34. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics IRBFunding Agency MyResearch Data analysis Results reporting Oncor CRMS? Protocol Trial Design Sponsors Academic PIs Site 1Site 2 Site 3 Site Management Organization (SMO) Where Should REDCap Data Go? Integrated Data Repository REDCap Epic

35. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Risks of Data Security Breach PIs storing Protected Health Information (PHI) data on laptops, unsecured desktops –thefts, losses –VA, cancer registry New CA law: you can be fined up to $250,000 for PHI breach MyResearch is ultra- secure storage for your PHI data IRBFunding Agency MyResearch Data analysis Results reporting Oncor CRMS? Protocol Trial Design Sponsors Academic PIs Site 1Site 2 Site 3 Site Management Organization (SMO) REDCap

36. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics No More Lax Storage PI #2 PI #1 MyResearch Secure location with backup SAS, R Firewall Pixels only Secure Global Desktop

37. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics PHI stored in FISMA level secure database system Data never physically leaves MyResearch Your browser is a “dumb” window onto the MyResearch computer –SAS, etc. runs on data on MyResearch –you see pixels only, no local caching on your computer MyResearch Secure location with backup SAS, R Firewall Pixels only Secure Global Desktop

38. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Using MyResearch Satisfies soon-to-be required CHR criteria for secure data storage –if you don’t use MyResearch, must show you are as secure (i.e., FISMA level, very difficult) Works on PC, Mac with Leopard, Unix Is brand new, still has bugs Will cost ~$400/yr/PI starting ~July http://oaais.ucsf.edu/OAAIS/networking/research _data/1034-DSY.html

39. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics IRBFunding Agency MyResearch Data analysis Results reporting Oncor CRMS? Protocol Trial Design Sponsors Academic PIs Site 1Site 2 Site 3 Site Management Organization (SMO) UCSF Research Info Systems Integrated Data Repository REDCap Epic

40. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Retrospective cohort study of outpatients Compare 5 year rate for congestive heart failure for diabetics treated with a glitazone vs. not –find diabetics –find whether treated with a glitazone –for these patients, find all subsequent cases of congestive heart failure –analyze at 5 years adjust for age, sex, severity of diabetes, previous CHF, other meds, etc., etc. Outcomes Research Project

41. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Diabetes diagnosis –chart, HgbA1C, meds taken, problem list... Glitazone usage –orders, pharmacy Potential confounders –age, sex, severity, other meds, etc. Health System Minnesota: 50 paper, 50 computer 200,000 lives, 460 physicians Health System Minnesota: 50 paper, 50 computer 200,000 lives, 460 physicians Types of Data Needed

42. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics MICU Finance Research QA Integrated Data Repository Internet ADT ChemEHRXRayPBMClaims autofeed nightly, data stored securely with backup Data from UCare to IDR

43. The IDR Is Live! Complete UCare Data Set –2.7 Million patient records –5 Million encounter records –Currently inpatient data –Beginning to get billing data –Importing Dentistry (Axium system) Pilot Release to Select Investigators –Slow ramp up of customers will continue –Building full support for all users –Self Service interface 43

44. Typical Research Query A typical query: To do retrospective patient analyses using ICD-9 code searches/discharge diagnoses, e.g. a UCSF clinician is interested in looking at a patient population composed of children <21yo with heparin induced thrombocytopenia (ICD=289.84) in the last 5 years.

45. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics i2b2 Demo UCSF IDR built using the i2b2 software suite from Harvard Partners Demo of i2b2 query interface to over 5000 anonymized real records from Partners –http://services.i2b2.org/webclient/#

46. IDR User Interface

47. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Changing UCSF Research Culture Must keep all data/analyses in MyResearch environment Can search IDR for non-PHI and PHI-sensitive data Policies established on who owns what data when and when to share under what circumstances –e.g., what if you put data in then leave UCSF? In 2 years, UCSF will revisit policy on IDR use –may well require all PIs to deposit final research data into IDR for sharing Slow uptake, many reasons

48. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics IRBFunding Agency MyResearch Data analysis Results reporting Oncor CRMS? Protocol Trial Design Sponsors Academic PIs Site 1Site 2 Site 3 Site Management Organization (SMO) Epic Research Functionality? Integrated Data Repository REDCap Epic

49. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Summary Clinical research fragmented, global, essentially separate from clinical care Clinical research informatics ongoing in two worlds –most still paper, commercial CTMSs mostly document centered (PDFs) rather than data or concept-centered –moving towards modular component approach with standard data elements (CDEs) and case report forms (CRFs) common computable protocol models and interchange exchange standards (CDISC) UCSF offering web-based data entry and databases, secure data storage and access to UCare data via IDR Still very very early in design and use of clinical research information systems

50. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics

51. March 9, 2010: I. Sim EHRs and Research Epi 206 — Medical Informatics Market Facts In early 90s, 80% trials done in academia, now 20% –about 10% of UCSF studies are pharma-related Huge business –Big Pharma: $15.9 b on clinical trials [2006], out of $50.3 b total R&D [2009 PhRMA Industry Profile] –NIH budget $29.5 billion 2009 Fragmented, global industry –estimated 1100 organizations involved in clinical research in 2009 in US (Sponsors, CROs, SMOs, AHCs...) –CROs $15b market in 2007 –“43% big pharma FDA trials were conducted abroad... projecting as much as 65% within 3 years” [Tufts Outlook 2008]