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Epi 202: Designing Clinical Research
Introduction to the Course, Clinical Research and Research Questions
Thomas B. Newman, MD, MPH
Professor of Epidemiology & Biostatistics and Pediatrics, UCSF
July 31, 2012
Outline About this course Anatomy and Physiology of
Research Research questions Examples: jaundice in newborns
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
Steve Hulley
About This Course Michael Kohn
–Co-director, 2004 – 2011
Joel Simon –Section leader,
1991– –Course co-
director, 2012
Website Google “Epi 202” or find
from TICR home page Course roster, schedule,
rooms, readings, PowerPoint files (when available)
Links to recordings of lectures– This class– Epi 150.03/CTSI site
Forum
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! (Now working on DCR-4!)
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; you’ll need it for Epi 204
Course Objectives1. 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
Course Ingredients
July 31- Lectures (9:10 – 10:00)
Sept 11 * Selected issues from DCR 3 text and examples
Sections (10:10 – 12:00)
* Protocol components
* More issues from the text
* Helping and getting to know your classmates
Sept 18 5-page protocols due
Oct 2, 9, tba Protocol review sessions (not Masters or ATCR Students)
* In pairs and trios, new faculty
Prefer 9:00 start?
Grades, Attendance, Interruptions, etc.
5-page protocol must be turned in to pass– Protocol review sessions encouraged but not req’d
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, please
arrange coverage or take this class another time
Faculty for sectionsName Field
Naomi Bardach General PediatricsHal Barron Cardiology
Michael Cabana General PediatricsCarlos Iribarren EpidemiologyBruce Gaynor Ophthalmology
Hannah Glass Child Neurology
Mary Haan EpidemiologyAnthony Kim* Neurology
Conan MacDougal Clinical PharmacyJoel Simon General Medicine
John Takayama* General Pediatrics
Jess Waldura Family MedicineJanet Wojcicki Pediatrics/GI
*E-sections
Course CoordinatorOlivia De Leon
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
Questions?
USE MICROPHONE OR REPEAT
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 Implementation, data management, quality
control
Required Viewing for Next Week
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
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 may not be planning to do
Physiology of research: How it works
Using measurements in a sample to draw inferences about phenomena in a population
DCR Figure 1.3
DCR Figure 1.4
DCR Figure 1.5
Questions?
USE MICROPHONE OR REPEAT
Do I really have to do all of those laboratory tests before I can start phototherapy in jaundiced babies?
Newman research question #1
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
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
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
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!
The importance of a good acronym: Examples Multiple Risk Factor Intervention Trial = MRFIT Late Impact of Getting
Hyperbilirubinemia or photoTherapy = LIGHT
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
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
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
TN concerned about costs
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
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);
primarily descriptive
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
Is RQ /Study Plan FINER?
Feasible
Interesting
Novel
Ethical
Relevant
Can you put your FINGER on a good research question?
Feasible
Interesting
Novel
Good for your career
Ethical
Relevant
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
LEJN: Direct Bilirubin Results -1 Test ordered 15 times as often per infant at
UCSF as at Stanford Results more than twice as high
AJDC 1991;145:1305-1309
Total N births
•Stanford: 5,185
•UCSF: 5,778
mg/dL
1 2 3 4
LEJN Results: Direct Bilirubin Results -2AJDC 1991;145:1305-09
Spontaneous resolution in all 4 infants
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
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)
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?
Acronyms Sequelae of Hyperbilirubinemia and
Dehydration in Infants “SHADI” Jaundice and Infant FEEding Study JIFee
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
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
Results: continuous variables
Control (N=168)
Hyperbili
(N=82)Adjusted
difference PWPPSI-R
Verbal IQ 101.1 103.52.5 (-1.1 to
6.1) 0.18
Performance IQ 106.0 107.00.5 (−2.9 to
4.0) 0.29
Full Scale IQ 104.0 105.91.4 (−2.1 to
5.0) 0.42 VMI-4
VMI 102.1 103.30.6 (−2.8 to
3.9) 0.74Visual
perception 105.9 107.51.2 (−3.5 to
6.0) 0.6Motor
coordination 100.4 101.3−1.3 (−5.6 to
2.9) 0.54
Results: Adjusted OR and 95% CI for Dichotomized Outcomes
PublicationPublication
Submitted to JAMA Rejected Submitted to NEJM Rejected
– Lower participation rate in controls (40% vs 59%)
– Questionable importance
Decision appealed!
Even if all unexamined controls normal, no change in results
Google search Timely e-mail
Google search results "Jaundice baby”
– Second hit: www.kernicterus.org “Kernicterus”
– First hit: PICK website• Bilirubin as a neurotoxin• Treatment advocated at lower levels than those
recommended by the AAP
E-mail from a parent -1
To: <[email protected]>
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...
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
Today in section: one sentence describing anatomy of your study
Design Variables
– Predictor– Outcome
Subjects
Questions and comments
Extra slides
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
Example
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.
Example
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