Epi 202:Designing Clinical Research

Session 1: Introduction to the Course and to Clinical Research

Thomas B. Newman, MD,MPH

Professor of Epidemiology & Biostatistics and Pediatrics, UCSF

August 4, 2009

Outline

About this course Chapters 1 & 2 Examples

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

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)

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!

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

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

August 4- Lectures (9:10 – 10:00)

Sept 15 * Selected issues from DCR 3 text

Sections (10:10 – 12:00)

* Protocol components

* More issues from the text

* Helping and getting to know your classmates

Sept 22 5-page protocols due

Oct 6, 13 (8:15 – 9:30) Protocol review sessions (not Masters or ATCR Students)

* In pairs, new faculty

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 2:00 PM today!)– Learning on your own

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

Faculty for sections

Name FieldChristian Apfel AnesthesiologyAlison Bryant Obstetrics/GynecologyCaroline Calfee Pulmonary MedicineChristine Dehlendorf Family medicineKirsten Greene UrologyMichael Kohn Emergency MedicineKirby Lee Clinical PharmacyTom Newman General PediatricsDavid Rehkoff EpidemiologyJulie Schmittdiel Health Services ResearchJoel Simon General MedicineMax Wintermark Radiology

Faculty for sections

Name FieldChristian Apfel Clinical ResearchAlison Bryant Clinical ResearchCaroline Calfee Clinical ResearchChristine Dehlendorf Clinical ResearchKirsten Greene Clinical ResearchMichael Kohn Clinical ResearchKirby Lee Clinical ResearchTom Newman Clinical ResearchDavid Rehkoff Clinical ResearchJulie Schmittdiel Clinical ResearchJoel Simon Clinical ResearchMax Wintermark Clinical Research

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

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

NIH Roadmap Initiative-translating discoveries into health

Westfall JM et al, JAMA 2007

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

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 aren’t (currently) 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

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

Newman research question #1

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

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

Background: International Comparison of Spending on Health, 1980–2006

0

1000

2000

3000

4000

5000

6000

7000

1980 1984 1988 1992 1996 2000 2004

AustraliaCanadaDenmarkFranceGermanyNetherlandsNew ZealandSwedenSwitzerlandUnited KingdomUnited States

Average spending on healthper capita ($US PPP)

0

2

4

6

8

10

12

14

16

1980 1984 1988 1992 1996 2000 2004

AustraliaCanadaDenmarkFranceGermanyNetherlandsNew ZealandSwedenSwitzerlandUnited KingdomUnited States

Total expenditures on healthas percent of GDP

Data: OECD Health Data 2008 (June 2008). From Commonwealth fund

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?

In what proportion is treatment altered? Diagnostic yield study (Chapter 12)

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

Design and ImplementationTRUTH IN THE UNIVERSE TRUTH IN THE STUDY FINDINGS IN THE STUDY

Research Question Study Plan Actual studyShould I do test? What is yield of test? What does yield look like

from my database and chart review?

Jaundiced term newborns Jaundiced newborns ≥ 37 weeks (by obstetrician estimate) born at UCSF and Stanford 1986-7

Newborns ≥ 37 weeks who had the test and have test results included in the COPE database

Health benefit of testing Yield of testing Discharge diagnoses of signficant diseases made after an abnormal test result (based on electronic discharge abstracts and chart review)

Is RQ FINER?

Feasible

Interesting

Novel

Ethical

Relevant

Is RQ FINERG?

Feasible

Interesting

Novel

Ethical

Relevant

Good for your career

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

1 2 3 4 5 6 7 ≥ 8mg/dL

AJDC 1991;145:1305-1309

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.”

AJDC 1991;145:1305-1309

August 6 is Hiroshima Day

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

Newman research question #2

Background to Question #2 A complete sepsis work-up and IV antibiotics

used to be “required” for all infants < 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

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

PROS FIS Design considerations Subjects

– Infants < 3 months old with T > 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

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

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

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 >10 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

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

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

Next …

One sentence describing anatomy of your study

Design Variables

– Predictor– Outcome

Subjects

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

Do you have a FINERG research question?

Feasible

Interesting

Novel

Ethical

Relevant

Good for your career

Questions and comments