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 1, 2012

2. Outline • Anatomy and Physiology of Research • Research questions • Examples: jaundice in newborns

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

4. Highly Recommended

5. Highly Recommended

6. Highly Recommended

7. NIH Roadmap InitiativeTranslating Discoveries into Health What does work? How can we make sure they do? What might work? Who should get it? Westfall JM et al, JAMA 2007

8. Translational research and studies for Epi 150.03 • Not the best choice for this course • Animals, molecules without humans • Qualitative research • Data syntheses, e.g. decision analysis, cost-effectiveness analysis, meta-analysis – more feasible to complete, but not as good for learning the material

9. Translational research and studies for Epi 150.03 • Good choices for this course • A new observational study or clinical trial involving humans that you could at least imagine doing (or at least start) this year • Secondary data analysis?

10. What if you are planning a secondary data analysis? • Advantage: Easier to finish • Disadvantage: Not as good for learning DCR material • Choices: • Use it for your DCR project, rethinking decisions that were already made and getting thoughts and suggestions from colleagues • Design a new study you aren’t (currently) planning to do, but that interests you, to help you learn the material and maybe do some time in the future • Most important goal: learn the material

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

12. DCR Figure 1.3 CHD= Coronary Heart Disease

13. DCR Figure 1.4 CHD= Coronary Heart Disease

14. DCR Figure 1.5

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

16. Background about neonatal jaundice • 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

17. Background to question #1, cont’d • Phototherapy: shining light on the baby’s skin helps lower bilirubin levels • Very high bilirubin levels (“hyperbilirubinemia”) can cause kernicterus (brain damage) • More common in developing countries

18. Do I really have to do all of those laboratory tests before I can start phototherapy in jaundiced babies? My first grant: Laboratory Evaluation of Jaundice in Newborns (“LEJN”) Newman research question #1

19. Digression: the importance of a good acronym • Fun initial way to engage collaborators • Gives your study credibility and life • Useful for naming files and directories • Worth the effort!

20. The importance of a good acronym: Examples • A study of the effect of a combined intervention program to reduce blood pressure, cholesterol levels and smoking in middle-aged men • Multiple Risk Factor Intervention Trial • MRFIT

21. The importance of a good acronym: Examples • A follow-up study of the late effects of severe neonatal jaundice and its treatment with phototherapy • Late Impact of Getting Hyperbilirubinemia or photoTherapy • LIGHT

22. The importance of a good acronym: Examples • A study of the cost effectiveness of differerent protocols for treating gestational diabetes (James G. Kahn, MD, MPH) • Gestational Diabetes Formulas for Cost-Effectiveness GeDi FORCE

23. Background to Question #1, cont’d • A complete "hyperbilirubinemia work-up" used to be recommended for significant newborn 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 • 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

25. TN concerned about costs

26. 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

27. 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? • How often is treatment altered? • Diagnostic yield study (Chapter 12)

28. 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 laboratory methods for doing the tests

29. Is RQ /Study Plan FINER? Feasible Interesting Novel Ethical Relevant

30. Significance section of your protocol • Do a literature review! • Make sure no one has already done it • Writing the significance section is how you convince yourself and others that the developing the protocol is worth the effort • Writing and circulating the protocol is how you convince yourself and others that the study is worth doing

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

32. 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 • Not for significance section, but relevant for training grants

33. 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?

34. LEJN: Direct Bilirubin Results -1 • Test ordered 15 times as often per infant at UCSF as at Stanford • Results more than twice as high • Total N births • Stanford: 5,185 • UCSF: 5,778 1 2 3 4 mg/dL AJDC 1991;145:1305-1309

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

36. LEJN Conclusions • “Because of their low yield and poor specificity, direct bilirubin tests are seldom helpful in evaluating jaundice in term newborns.”* • Current guidelines: check direct bilirubin for unexplained rapid rise, babies needing phototherapy, persistence > 3 wks or sick baby *AJDC 1991;145:1305-1309

37. Background to TN RQ #2 • It is known that very high (> ~30 mg/dL) bilirubin levels can cause horrible brain damage (kernicterus) • Unclear how often kernicterus or more subtle abnormalities occur at lower bilirubin levels • Concern about this possibility leads to more treatment • Bilirubin levels  25 mg/dL are rare (~1/700)

38. Background to TN RQ#2, cont’d • During the 1990s hospital stays for newborns shortened dramatically • There were reports of increases in kernicterus and severe dehydration • We had already identified cases of bilirubin  25 mg/dL and dehydation from previous nested case-control studies • RQ: What are the effects of neonatal bilirubin levels 25 mg/dL and dehydration on neurodevelopmental outcomes?

39. Acronyms • Sequelae of Hyperbilirubinemia and Dehydration in Infants • “SHADI” • Jaundice and Infant FEEding Study • JIFee

40. Study Design • Triple Cohort Study • Hyperbilirubinemia group (TSB  25 mg/dL at < 30 days) • Dehydration group (readmitted for dehydration + either  12% weight loss or Na >= 150 mEq/L) • Randomly selected comparison group • Outcomes: blinded full neurodevelopmental evaluations at age ~5 by psychologists and child neurologists

41. Outcome Variables • Standard neurological examination by child neurologist* • IQ (WPPSI-R) and Visual-Motor Integration test (VMI) by psychologist* • Motor Performance Checklist (10 items like jumping, throwing, catching, putting beans in a bottle) by research associate* • Child Behavior Checklist (CBC-L) and Parent Evaluation of Developmental Status (PEDS) by parents *Blinded to study group

42. Compromises and challenge • Difficulty recruiting “controls” • Full exams on 82/140 (59%) hyperbili cases vs 168/419 (40%) of controls • Outcomes • Interobserver variability, subjectivity in examinations • Measurements at age 5 years may miss relevant school problems later • 5-year-olds get tired and have bad days • No hearing tests

43. Study Cohort (59%) (40%)

44. Results: continuous variables

45. Results: Adjusted OR and 95% CI for Dichotomized Outcomes

46. Publication • Submitted to JAMA • Rejected • Submitted to NEJM • Rejected • Lower participation rate in controls (40% vs 59%) • Questionable importance

47. Decision appealed! • Even if all unexamined controls normal, no change in results • Google search results and timely email

48. Google search results • "Jaundice baby” • Second hit: www.kernicterus.org • “Kernicterus” • First hi: PICK website • Bilirubin as a neurotoxin • Treatment advocated at lower levels than those recommended by the AAP

49. E-mail from a parent -1 To: <newman@itsa.ucsf.edu> Subject: my hyperbili son Date: Thu, 11 Aug 2005   Dear Dr Newman, I would like your input as to the prognosis with my son. He had a neonatal jaundice that was horribly mismanaged and I am now a hysterical mom.... My son was born [Wednesday] 4/13/2005 at 10am...On Sat night we had him tested, at 8pm TBR was 24, Coombs test positive. He was admitted under double lights and his TBR was 16 on Sun morn...

50. E-mail from a parent -2 He was breast fed throughout and had a strong suck. He is now 4 months old and milestones seem within developmental norms. Hearing seems ok. I am sleepless, hysterical and depressed. How concerned for the future do I have to be?  Please could you get back to me asap. Thanking you, Tracey P