Introduction to Clinical Research and Research Questions

1. Introduction to Clinical Research and Research Questions Thomas B. Newman, MD,MPH Professor of Epidemiology & Biostatistics and Pediatrics, UCSF Epi 150.03, August 2, 2009

2. Outline • Anatomy and Physiology of Research • Research questions • Examples

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

4. Highly Recommended

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

6. Translational Research and Studies for Epi 150.03 • Not the best choice for this course • Animals, molecules without humans • Data syntheses, e.g. decision analysis, cost-effectiveness analysis, meta-analysis • Qualitative research • Ideal • A new observational study or clinical trial involving humans that you could do (or at least start) this year

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

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

9. DCR Figure 1.3

10. DCR Figure 1.4

11. DCR Figure 1.5

12. Do I really have to do all of those laboratory tests before I can start phototherapy in jaundiced babies? LEJN = Laboratory Evaluation of Jaundice in Newborns Newman research question #1

13. Digression: the importance of a good acronym • Fun to create • Gives your study credibility and life • Favorite examples: • Multiple Risk Factor Intervention Trial = MRFIT • Jim Kahn’s study: Gestational Diabetes Formulas for Cost-Effectiveness GeDi FORCE

14. Background for Question #1 • Bilirubin: Yellow breakdown product of heme (from red blood cells) • Jaundice: Yellow color of whites of eyes and skin due to high bilirubin. Usually indicates liver or blood disease, but generally is normal in newborns

15. Background to Question #1, cont’d • Phototherapy: Shining light on the babies skin -- helps lower bilirubin levels • Very high bilirubin levels can cause kernicterus (brain damage)

16. Background to Question #1, cont’d • 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

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

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

19. More refined research question #1 (i.e., what we really want to know) • 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

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

21. Compromises • Just 2 S.F. Bay Area teaching hospitals • Surrogate outcome: • Discharge diagnosis of a significant disease • Diagnosed after an abnormal jaundice work-up • 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

22. Design and Implementation

23. Is RQ FINER? Feasible Interesting Novel Ethical Relevant

24. Can you put your FINGER on a good research question Feasible Interesting Novel Good for your career Ethical Relevant

25. Good for your career 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

26. Special considerations for Students and Residents • Are the people nice to work with? • Can you finish something? • Can you contribute enough to be a coauthor? • Do you understand and believe in the importance of the question you will address?

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

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

29. LEJN Conclusions • “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

30. August 6 is Hiroshima Day (65 years)

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

32. Background to Question #2 • 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 • Many practicing pediatricians were skeptical of this requirement • PROS (Pediatric Research in Office Settings) is the American Academy of Pediatrics research network

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

34. PROS FIS Design considerations • Subjects • Infants < 3 months old with T > 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

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

36. PROS FIS Design considerations -3 • Predictors • Physician characteristics, results of history, & physical examination, treatments • Both predictor and outcome • Whether or not urine tests done • How urine tests done • Outcome variables • Positive urine culture at initial visit (UTI) • Recovery from the acute febrile illness • Late diagnosis of UTI

37. The same study can answer multiple research questions • Designation of predictor and outcome variables depends on the research questions • Maintain clarity on the research question or it can get confusing

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

39. What happened to those not tested? • 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 (0.25%) were diagnosed with UTI the next day • Both received antibiotics and did well • N= 805 illnesses resolved without diagnosis of UTI

40. Why were there so few late diagnoses of UTI in those not initially tested? • Those not tested were at very low risk • Most UTIs in infants resolve spontaneously • Based on levels of risk factors in those not tested, 61 UTIs were expected in that group • 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

41. Alan Schroeder’s Research Questions: • What methods do practitioners use to obtain urine samples in young febrile infants? • What are predictors of using invasive methods (catheterization or bladder tap)? • How do different methods compare • Urine culture results • Correlation between UA and culture Schroeder AR, Newman TB, Wasserman RC, Finch SA, Pantell RH. Choice of urine collection methods for the diagnosis of urinary tract infection in young, febrile infants. Arch Pediatr Adolesc Med. 2005 Oct;159(10):915-22, 2005

42. Next …

43. One sentence describing anatomy of your study • Design • Variables • Predictor • Outcome • Subjects

44. Examples • 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. • 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

45. Do you have a FINERG research question? Feasible Interesting Novel Ethical Relevant Good for your career

46. Questions and comments