1. Epi 202:Designing Clinical Research Session 1: Introduction to the Course and to Clinical Research Thomas B. Newman, MD,MPH Professor of Epidemiology & Biostatistics and Pediatrics, UCSF August 4, 2009

2. Outline n About this course n Chapters 1 & 2 n Examples

3. About This Course n Began ~30 years ago n Also known as the "Hulley Course" n Steve was the leader for the text (DCR) and designed the course, homework, and instructions to section leaders n Michael Kohn co-director last 6 years Steve Hulley

4. Website n Google “Epi 202” or find from TICR home page n Course roster, schedule, rooms, readings, PowerPoint files (when available) n Links to videos of lectures (we hope)

5. About the Reading -1 n DCR-3 includes exercises and answers at the end of the book –We recommend jotting down answers before reading ours –Can discuss in section but no need to turn in n Let us know your suggestions for improving the book!

6. About the Reading -2 n Recommended reading this week (Saha et al. Survival guide…) on the Epi 202 website n Recommended for next week: an Articulate® Presentation on Marketing of Medicines with Research n Evidence-Based Diagnosis (EBD) text also recommended

7. Course Objectives 1. Learn about how to design and do clinical research 2. Produce a protocol for a study 3. Help others in the workshop 4. Provide feedback on the workshop 5. Have a multiplier effect

8. Course Ingredients August 4- Lectures (9:10 – 10:00) Sept 15 * Selected issues from DCR 3 text Sections (10:10 – 12:00) * Protocol components * More issues from the text * Helping and getting to know your classmates Sept 225-page protocols due Oct 6, 13(8:15 – 9:30) Protocol review sessions (not Masters or ATCR Students) * In pairs, new faculty

9. Computer skills n You need to know how to –Word process, attach documents –Use PubMed –Use citation management software such as Endnote® or RefWorks® n You can learn by –Getting a mentor or friend to show you –Taking a course in the UCSF Library (last EndNote course 2:00 PM today!) –Learning on your own

10. Epi 202 Credit or DCR 2009 Certificate* n For satisfactory performance including: –Showing up for class, doing homework and helping your colleagues (60%) Let your section leader know if you will miss any sessions –Your 5-page clinical research protocol (must be turned in on time; 40%) *Electronic; available upon request

11. Faculty for sections

13. Course Coordinator Olivia De Leon Olivia@epi.ucsf.edu 514-8231 (tel) 514-8150 (fax) (Please let her know if your email address changes by sending her an email from the new address) Olivia De Leon

14. Anatomy of research: What it’s made of n Research question, significance n Study design n Study subjects and how they will be sampled n Variables and how they will be measured –Predictor –Outcome n Analysis plan, sample size calculation

15. NIH Roadmap Initiative -translating discoveries into health Westfall JM et al, JAMA 2007

16. Translational Research and Studies for Epi 202 n Not the best choice for this course –Animals, molecules without humans –Data syntheses, e.g. decision analysis, cost-effectiveness analysis, meta- analysis –Qualitative research n Ideal –A new observational study or clinical trial involving humans that you could do (or at least start) this year

17. What if I am doing a secondary data analysis? You can: n Use it for your DCR project, rethinking decisions that were already made and getting thoughts and suggestions for colleagues n Design a new study you aren’t (currently) planning to do

18. Physiology of research: How it works Using measurements in a sample to draw inferences about phenomena in a population

19. DCR Figure 1.3

20. DCR Figure 1.4

21. DCR Figure 1.5

22. n Do I really have to do all of those laboratory tests before I can start phototherapy in jaundiced babies? Newman research question #1

23. Background to Question #1 n Most babies get a little jaundiced in the first few days after birth n A complete "hyperbilirubinemia work- up" used to be recommended for significant jaundice: –Total and direct bilirubin –Direct and indirect Coombs’ tests –Complete Blood Count –Blood smear for red cell morphology –Reticulocyte count –Urine reducing substance

24. Background to Question #1, cont’d n In TN’s experience reference ranges were poorly defined and results rarely if ever affected management n As a pediatric resident TN did not like having to get out of bed to draw blood for these tests

25. Background: International Comparison of Spending on Health, 1980–2006 Average spending on health per capita ($US PPP) Total expenditures on health as percent of GDP Data: OECD Health Data 2008 (June 2008). From Commonwealth fund TN concerned about costs

26. More refined research question #1 (i.e., what we really want to know) n Do the expected health benefits of the recommended tests justify their costs? –Subjects: Jaundiced newborns (candidates for phototherapy) –Predictor variable: obtaining the tests –Outcome variable: measurements of health and costs

27. Laboratory Evaluation of Jaundice in Newborns (LEJN) study questions (i.e., questions our study can answer) n How often are each of these tests done in newborns at UCSF and Stanford? n How often are they abnormal? n When they are abnormal what diagnoses are made as a result of the test? n In what proportion is treatment altered? n Diagnostic yield study (Chapter 12)

28. Compromises n Just 2 S.F. Bay Area teaching hospitals n Surrogate outcome: –Discharge diagnosis of a significant disease –Diagnosed after an abnormal jaundice work-up n Retrospective study –Limited to those in whom MD ordered the tests, rather than those with a certain level of jaundice or meeting other inclusion criteria –No control over how tests were done

29. Design and Implementation

30. Is RQ FINER? F easible I nteresting N ovel E thical R elevant

31. Is RQ FINERG? F easible I nteresting N ovel E thical R elevant G ood for your career

32. Try to identify a research question that will allow you to –Learn more about an area of potential long-term interest – Acquire new skills you could use on other projects –Work with people and/or organizations with whom you want to develop a long term relationship –Build on the project for future work

33. LEJN: Direct Bilirubin Results -1 n Test ordered 15 times as often per infant at UCSF as at Stanford n Results more than twice as high 1 2 3 4 5 6 7 ≥ 8 mg/dL AJDC 1991;145:1305-1309

34. LEJN Results: Direct Bilirubin Results -2 AJDC 1991;145: 1305-09 Spontaneous resolution in all 4 infants

35. LEJN Conclusions n “Because of their low yield and poor specificity, direct bilirubin tests are seldom helpful in evaluating jaundice in term newborns.” AJDC 1991;145:1305-1309

36. August 6 is Hiroshima Day

37. n Do I really have to do all of those laboratory tests and admit infants < 3 months old with fevers? Newman research question #2

38. Background to Question #2 n A complete sepsis work-up and IV antibiotics used to be “required” for all infants < 3 months old with fevers at academic medical centers –Complete Blood Count and blood culture –Urinalysis and urine culture –Lumbar puncture and CSF culture –Hospital admission for 2-3 days of IV antibiotics n Many practicing pediatricians were skeptical of this requirement n PROS (Pediatric Research in Office Settings) is the American Academy of Pediatrics research network

39. Study questions for the PROS Febrile Infant Study (FIS) n How do practicing pediatricians in manage young febrile infants? n What variables predict testing and positive tests? n What is the outcome of infants not initially tested? n TN piece: urine tests

40. PROS FIS Design considerations n Subjects –Infants 38.0 seen by a Pediatric Research in Office Settings (PROS) practitioner –Issues Different from infants presenting to inner city emergency rooms PROS practitioners may not be representative Not all eligible infants enrolled

41. PROS FIS Design considerations -2 n Cross-sectional study –Prevalence & predictors of urine testing at first visit –Prevalence & predictors of UTI among those tested n Cohort study –Begin with measurements made at baseline –Follow the infants to see what happens to them, especially those not initially treated

42. PROS FIS Design considerations -3 n Predictor variables –Whether or not urine tests done –Other variables: results of history, physical examination, treatments n Outcomes –Positive urine culture at initial visit (UTI) –Recovery from the acute febrile illness –Late diagnosis of UTI

43. PROS FIS Selected Results n Only 54% of infants had urine tested at the initial visit n 10% of those tested at the initial visit had a urinary tract infection (UTI) n Uncircumcised boys were >10 times as likely to have a UTI but no more likely to have urine tested n Other risk factors for UTI also predicted testing, e.g., –Height of fever –Lack of viral symptoms –Lack of sick family members

44. What happened to those not tested? n N= 1400 who had no urine test first visit –N = 1324 followed-up through end of illness N= 807 not initially treated with antibiotics –2 (0.025%) were diagnosed with UTI the next day –Both received antibiotics and did well N= 805 illnesses resolved without diagnosis of UTI

45. Why were there so few late diagnoses of UTI in those not initially tested? n Those not tested were at very low risk n Most UTIs in infants resolve spontaneously n Based on levels of risk factors in those not tested, 61 UTIs were expected in that group n Since only 2 were observed, either most UTIs resolve spontaneously or the PROS practitioners were using some secret extremely effective method for selecting infants for urine testing

46. Next …

47. One sentence describing anatomy of your study n Design n Variables –Predictor –Outcome n Subjects

48. Examples n This is a randomized double-blind trial to see whether low doses of oral diphenydramine reduce self-reported severity of motion sickness among elderly passengers on a cruise ship. n This is a prospective cohort study to estimate the effects of various medical treatments for osteoarthritis on the risk of intensive care unit admission for H1N1 influenza among members of the Northern California Kaiser Permanente Medical Care Program

49. Do you have a FINERG research question? F easible I nteresting N ovel E thical R elevant G ood for your career

50. Questions and comments