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 2, 2011

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Outline

• About this course
• Chapters 1 2
• Examples
• LEJN
• JIFee

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About This Course

• Began gt 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 8 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 recordings of lectures
• Forum

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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 usually won t be
  turned in
• Let us know your suggestions for improving the
  book! (Starting on DCR-4!)

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About the Reading -2

• Recommended reading this week (Saha et al.
  Survival guide) on the Epi 202 website
• Evidence-Based Diagnosis (EBD) text also
  recommended youll need it for Epi 204

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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 2- Lectures (910 1000)
• Sept 13 Selected issues from DCR 3 text
  and examples
• Sections (1010 1200)
• Protocol components
• More issues from the text
• Helping and getting to know your
  classmates
• Sept 19 5-page protocols due
• Oct 4, 11, tba Protocol review sessions (not
  Masters or ATCR Students)
• In pairs and trios, new faculty

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Grades, Attendance, Interruptions, etc.

• 5-page protocol must be turned in to pass
• Protocol review sessions encouraged but not reqd
• To get an A, in addition
• No unexcused absences
• No more than 1 missing or late HW
• Help your colleagues with their protocols
• Class time is sacred
• Do not answer cell phones or pages except
  emergencies
• If clinical responsibilities will interfere,
  arrange coverage or take this class another time

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Faculty for sections
Name Field
Christian Apfel Anesthesiology
Mary Beattie General Medicine
Michael Cabana General Pediatrics
Hillary Copp Pediatric Urology
Christine Dehlendorf Family Medicine
Valerie Flaherman General Pediatrics
Liz Goldman General Medicine
Jade Hiramoto Surgery
Kirsten Johansen Nephrology
Michael Kohn Emergency Medicine
Ann Lazar Biostatistics
Ed Murphy Laboratory Medicine
Mike Nevitt Epidemiology
Joel Simon General Medicine
John Takayama General Pediatrics
E-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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Questions?

• USE MICROPHONE OR REPEAT

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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
• Implementation, data management, quality control

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Highly Recommended
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Research Questions 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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Questions?

• USE MICROPHONE OR REPEAT

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Background for TNs Research Questions

• Bilirubin Yellow breakdown product of heme (from
  red blood cells)
• Jaundice Yellow color due to high bilirubin.
  Usually indicates liver disease, but generally is
  normal in newborns

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Background

• Phototherapy Shining light on the babys skin --
  helps lower bilirubin levels
• Very high bilirubin levels can cause kernicterus
  (brain damage)

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Background to TNs RQ 1

• 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
• High direct bilirubin suggests liver disease

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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
  before being allowed to start phototherapy

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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?
• LEJN Laboratory Evaluation of Jaundice in
  Newborns

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Digression the importance of a good acronym

• Fun to create
• Gives your study credibility and life
• Examples
• Multiple Risk Factor Intervention Trial MRFIT
• Jim Kahns study Gestational Diabetes Formulas
  for Cost-Effectiveness

GeDi FORCE
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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
  after an abnormal test result
• Retrospective study
• Limited to those in whom MD ordered the tests,
• No control over how tests were done

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Is RQ FINER?

• Feasible
• Interesting
• Novel
• Ethical
• Relevant

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Can you put your FINGER on a good research
question?

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

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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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Background to Toms RQ 2

• It is known that very high (gt 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)

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Background to Toms RQ2, contd

• 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?

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Acronyms

• SHADI Sequelae of Hyperbilirubinemia and
  Dehydration in Infants
• JIFee Jaundice and Infant FEEding Study

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Study Design

• Triple Cohort Study
• Hyperbilirubinemia group (TSB ? 25 mg/dL at lt 30
  days)
• (Dehydration group)
• Randomly selected comparison group
• Outcomes blinded full neurodevelopmental
  evaluations at age 5 by psychologists and child
  neurologists

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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, 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
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Compromises and challenge

• 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
• Difficulty recruiting controls
• Full exams on 82/140 (59) hyperbili cases vs
  168/419 (40) of controls

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Results continuous variables
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Results Adjusted Odds Ratios and 95 CI for
Dichotomized Outcomes
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Publication

• Rejected by JAMA
• Rejected by NEJM
• Lower participation rate in controls (40 vs 59)
• Questionable importance
• Decision appealed!
• Even if all unexamined controls were normal, no
  difference between groups
• Google results and timely email

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E-mail from a parent -1
To ltnewman_at_itsa.ucsf.edugt 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...
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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
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Questions and comments(use microphone or repeat)