Ida Sim, MD, PhD Associate Professor of Medicine Associate Director for Medical Informatics

1. Analysis of HIV Trials cBIO Driving Biological Project Ida Sim, MD, PhD Associate Professor of Medicine Associate Director for Medical Informatics Program in Biological and Medical Informatics University of California, San Francisco, CA R01-LM-06780

2. Outline • Background • Trial Bank Project • DBP Goals

3. Death at 1 year Drug A Placebo Death at 1 year Domain Problem • Want to advance clinical science and practice evidence-based medicine • based on results from scientific experiments, e.g., from randomized controlled trials (RCTs) • randomization equalizes known and unknown confounders between intervention arms • any observed differences in outcome should be due only to the intervention

4. HIV Trials • Two controversial areas of HIV with conflicting RCT evidence • Prevention of mother-to-child-transmission (MTCT) • Structured Treatment Interruption • Very complex heterogenous trials • need computational support to visualize, analyze, apply these trials

5. Need Computational KBs of RCTs • RCT journal articles not ideal • key descriptors of experimental method not always reported • not easily computable • KB of information on RCT • design • execution • results • would allow for better computer support for advancing clinical science and practice

6. Outline • Background • Trial Bank Project • DBP Goals

7. Trial Bank Software • Bank-a-Trial • web-based program for entering trials into RCT Bank (annotation) • clinical descriptions of trial features (slot values) are in UMLS terms • RCT Presenter • web-based browser of RCT Bank entries • SecurePresenter for browsing restricted-access entries Bank-a-Trial RCT Presenter RCT Bank (SecurePresenter)

8. Ontology: RCT Schema • Models clinical trials • instantiated using UMLS terms to describe clinical concepts • Frame-based model (in Ocelot) • 7 levels deep • 188 frames, 601 unique slots • average 9.8 slots/frame • 13 frames (7%) have multiple parents • 187/601 slots (31%) take other frames as values • Available at http://rctbank.ucsf.edu/

9. RCT Presenter Demo • RCT Presenter is open access • http://rctbank.ucsf.edu/Presenter/

10. Bank-a-Trial Demo • http://rctbank.ucsf.edu/BaT/

11. Outline • Background • Trial Bank Project • DBP Goals

12. DBP Goals • Trial Bank instances • visualizing collections of related but heterogenous clinical trial instances • using sample HIV medical record to select “applicable” MTCT and STI trials in RCT Bank • meta-analysis • RCT Schema • towards a reference ontology for clinical trials

13. Interventions Outcomes 5 year survival XRT and tamoxifen 1 year local recurrence Stage III Breast CA tamoxifen only 5 year local recurrence 5 year metastatic dissemination XRT only 5 year quality of life Goal 1: Visualization

14. Interventions Outcomes 5 year survival XRT and tamoxifen RCT Bank OBD 1 year local recurrence Stage III Breast CA 5 year local recurrence tamoxifen only 5 year metastatic dissemination XRT only 5 year quality of life Visualization (cont.) Visualization meta-model Degree of Interest model Core 1 Bank-a-Trial Core 2 MTCT/STI trials WHO/ CDISC XML • interventions • conditions • outcomes • number of participants Presenter Visualizations!

15. Goal 2: Identifying Applicable Trials • Use case • I have an HIV patient, which STI trials are applicable? • patients in STI trials are “like” this patient • want to “drag and drop” EHR onto Trial Bank to pull out applicable trials • visualize these applicable trials, explore specific details of trials • Terminological matching required • sample EHR coded in SNOMED • RCT Bank trials coded in UMLS

16. Interventions Outcomes 5 year survival XRT and tamoxifen RCT Bank OBD EHR 1 year local recurrence Stage III Breast CA 5 year local recurrence tamoxifen only UMLS Applicability Engine LexGrid 5 year metastatic dissemination SNOMED XRT only 5 year quality of life Identifying Applicable Trials Visualization meta-model Degree of Interest model Core 1 Bank-a-Trial Core 2 STI trials WHO/ CDISC XML Presenter Visualizations! Core 1

17. Goal 3: Meta-Analysis • Given set of related trials, use statistical routines • explore statistical heterogeneity • perform quantitative meta-analysis

18. Interventions Outcomes 5 year survival Meta-analysis XRT and tamoxifen RCT Bank OBD EHR 1 year local recurrence Stage III Breast CA 5 year local recurrence tamoxifen only UMLS Applicability Engine LexGrid 5 year metastatic dissemination SNOMED XRT only 5 year quality of life Meta-Analysis Core 2? Bank-a-Trial STI trials Core 2 WHO/ CDISC XML Presenter Visualizations! Core 1 Core 1

19. RCT Reference Ontology? • Harmonize RCT Schema with CDISC, caBIG, WHO, etc. through BRIDG (outside cBIO) • Put into OWL • Deposit into OBO • Join the “OBO Collaboratory”

20. Timelines • Dec 2006 • Visualization • Year 2-3 • applicability • meta-analysis • moving towards OBO

21. Summary • Clinical trials are valuable source of biomedical knowledge • Trial Bank captures RCTs to support understanding, analyzing, applying RCT evidence • Drives cBIO on • Core 1: visualization, terminology mapping, Ocelot->OWL, RCT reference ontology • Core 2: OBD, data interchange standard, meta-analysis

22. Questions • To group