Epi 202:Designing Clinical Research Session 1: Introduction to the Course and to Clinical Research

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Epi 202Designing Clinical ResearchSession 1
Introduction to the Course and to Clinical
Research

• Thomas B. Newman, MD,MPH
• Professor of Epidemiology Biostatistics and
  Pediatrics, UCSF
• August 4, 2009

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Outline

• About this course
• Chapters 1 2
• Examples

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About This Course

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

Steve Hulley
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Website

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

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About the Reading -1

• 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
• Let us know your suggestions for improving the
  book!

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About the Reading -2

• Recommended reading this week (Saha et al.
  Survival guide) on the Epi 202 website
• Recommended for next week an Articulate
  Presentation on Marketing of Medicines with
  Research
• Evidence-Based Diagnosis (EBD) text also
  recommended

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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

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Course Ingredients

• August 4- Lectures (910 1000)
• Sept 15 Selected issues from DCR 3 text
• Sections (1010 1200)
• Protocol components
• More issues from the text
• Helping and getting to know your
  classmates
• Sept 22 5-page protocols due
• Oct 6, 13 (815 930) Protocol review sessions
  (not Masters or ATCR Students)
• In pairs, new faculty

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Computer skills

• You need to know how to
• Word process, attach documents
• Use PubMed
• Use citation management software such as Endnote
  or RefWorks
• You can learn by
• Getting a mentor or friend to show you
• Taking a course in the UCSF Library (last EndNote
  course 200 PM today!)
• Learning on your own

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Epi 202 Credit or DCR 2009 Certificate

• 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
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Faculty for sections
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Faculty for sections
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Course Coordinator

• Olivia De Leon
• Olivia_at_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
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Anatomy of research What its 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

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NIH Roadmap Initiative-translating discoveries
into health
Westfall JM et al, JAMA 2007
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Translational Research and Studies for Epi 202

• 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

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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 arent (currently)
  planning to do

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Physiology of research How it works

• Using measurements in a sample to draw inferences
  about phenomena in a population

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DCR Figure 1.3
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DCR Figure 1.4
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DCR Figure 1.5
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Newman research question 1

• Do I really have to do all of those laboratory
  tests before I can start phototherapy in
  jaundiced babies?

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Background to Question 1

• Most babies get a little jaundiced in the first
  few days after birth
• 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

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Background to Question 1, contd

• In TNs 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

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Background International Comparison of Spending
on Health, 19802006
Average spending on healthper capita (US PPP)
Total expenditures on healthas percent of GDP
TN concerned about costs
Data OECD Health Data 2008 (June 2008). From
Commonwealth fund
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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

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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)

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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

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Design and Implementation
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Is RQ FINER?

• Feasible
• Interesting
• Novel
• Ethical
• Relevant

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Is RQ FINERG?

• Feasible
• Interesting
• Novel
• Ethical
• Relevant
• Good for your career

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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

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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 19911451305-1309
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LEJN Results Direct Bilirubin Results -2
AJDC 19911451305-09
Spontaneous resolution in all 4 infants
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LEJN Conclusions

• Because of their low yield and poor specificity,
  direct bilirubin tests are seldom helpful in
  evaluating jaundice in term newborns.

AJDC 19911451305-1309
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August 6 is Hiroshima Day
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Newman research question 2

• Do I really have to do all of those laboratory
  tests and admit infants lt 3 months old with
  fevers?

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Background to Question 2

• A complete sepsis work-up and IV antibiotics used
  to be required for all infants lt 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

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Study questions for the PROS Febrile Infant Study
(FIS)

• How do practicing pediatricians in manage young
  febrile infants?
• What variables predict testing and positive
  tests?
• What is the outcome of infants not initially
  tested?
• TN piece urine tests

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PROS FIS Design considerations

• Subjects
• Infants lt 3 months old with T gt 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

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PROS FIS Design considerations -2

• Cross-sectional study
• Prevalence predictors of urine testing at first
  visit
• Prevalence predictors of 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

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PROS FIS Design considerations -3

• Predictor variables
• Whether or not urine tests done
• Other variables results of history, physical
  examination, treatments
• Outcomes
• Positive urine culture at initial visit (UTI)
• Recovery from the acute febrile illness
• Late diagnosis of UTI

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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 gt10 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

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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 (0.025) were diagnosed with UTI the next day
• Both received antibiotics and did well
• N 805 illnesses resolved without diagnosis of UTI

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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

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Next
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One sentence describing anatomy of your study

• Design
• Variables
• Predictor
• Outcome
• Subjects

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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

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Do you have a FINERG research question?
Feasible Interesting Novel Ethical Relevant Good
for your career
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Questions and comments