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

Olivia@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

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: <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...

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