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Grant Writing: Study design in clinical research

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Carefully address your study design, i.e. ... The subject matter (e.g. oncology, cardiology) Further reading on Clinical Epidemiology ... – PowerPoint PPT presentation

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Title: Grant Writing: Study design in clinical research


1
Grant WritingStudy design in clinical research
  • Huib Burger, MD, PhD
  • Department of Epidemiology
  • Department of Psychiatry
  • University Medical Center Groningen
  • June 14, 2007

2
Quiz
  • Most common reason for rejection is
  • A. uninteresting research question
  • B. methodological flaws in the design
  • C. unfeasible study
  • D. excessive budget

3
Prevention of methodological flaws
  • Carefully address your study design, i.e.
  • Theoretical design research question the type
    of study
  • Operational design

4
The study type
  • Etiologic study (aim is causal explanation)
  • Diagnostic or screening study (aim is prediction)
  • Prognostic study (aim is prediction)
  • Intervention study (aim is causal explanation)

5
Prognostic and diagnostic research is prediction
researchExamples
  • Prognosis is it possible to predict early
    relapse in early-stage Hodgkin disease from age,
    gender, erythrocyte sedimentation rate
  • Diagnosis can we accurately assess the
    probability of the presence of osteoarthritis
    from age, gender, joint stiffness and typical
    pain? 2. Is there added value of physical exam?

6
The research question
  • Be sure that you exactly write down the question
    you want to answer
  • Poor formulations ex
  • the role of estrogens in breast cancer
  • Better
  • Is the risk of breast concer increased by higher
    levels of endogenous estrogens?

7
The research question
  • Preferably define your research question in terms
    of
  • Determinants
  • Outcomes
  • Confounders (causal studies)
  • Effect modifiers
  • Mediating variables

8
Operational design
  • Observational / experimental
  • Cohort / case-control
  • Cross-sectional / longitudinal
  • Prospective/retrospective
  • Defend your choice!
  • 5. Research plan (study population, measurements,
    etc.)

9
Study Population
  • Be sure that you
  • sample from the domain, i.e. the abstract
    formulation of the target population
  • address representativeness of your sample for the
    target population, if relevant

10
Example
  • Aim
  • to predict mortality in preterm neonates admitted
    to neonatal intensive care units from birth
    weight, duration of gestation, congenital
    malformations, and several physiologic parameters
  • Should one exclude newborns with inevitably
    lethal conditions?

The International Neonatal Network. The CRIB
(clinical risk index for babies) score a tool
for assessing initial neonatal risk and comparing
performance of neonatal intensive care units.
Lancet 1993 324 193-8
11
Study Population
  • Describe clearly
  • the sampling frame (general population, primary
    care)
  • the methodology random, stratified, case-control
  • The practice of sampling (e.g. approaching
    consecutive patients by a research nurse)

12
Study Population
  • In- or exclusion criteria
  • Strict (intervention studies) or loose
    (diagnostic and prognostic)
  • Age or gender restrictions (males in CVD studies)
  • (Co) morbidity
  • Medication
  • Language skills
  • Provide motivation for your choices

13
Determinants
  • Describe measurement (as in practice or not)
  • Address precision (reproduceability) and validity
    of your instruments give key references
  • Describe the source of the data (medical charts,
    registrations, lab files etc)
  • Take care that among the determinants are the
    potential confounders (in causal research) and
    effect modifiers

14
Intervention
  • Describe the exact nature of the intervention
  • Single intervention e.g. medication, surgery,
    psychotherapy, placebo (explanatory RCTs)
  • Strategy e.g. care as usual, stepped care,
    psychotherapy with medication on demand
    (pragmatic RCTs)

15
Intervention
  • Motivate the choice and give argumentations why
    it would work
  • Is the intervention feasible PILOT!
  • Describe the process of randomisation (computer
    generated list, the use of internet, blinding,
    (stratified block randomisation, minimization)

16
Follow-up
  • Motivate frequency and time period of follow-up
  • What do you do to prevent lost to follow-up?
  • How do you optimize compliance (intervention
    studies), e.g. placebo run-in.
  • What is the procedure in case of unexpected
    adverse events, unexpected pathology, severe
    worsening of a condition, etc.

17
Outcomes
  • Define unambiguously primary and secondary
    outcomes (relevance)
  • Describe assessment carefully (clinical,
    registration data)
  • Multiple outcomes
  • Multiple testing problems
  • May provide essential information

18
Example multiple endpoints
19
Sample size calculation
  • Be realistic !
  • Underpin your estimates consider pilot
  • Ingredients alpha, beta, SD of outcome/base
    rate, clinically relevant effect size,
    non-response
  • Many computer programs available e.g.
  • PS from Vanderbilt University

http//biostat.mc.vanderbilt.edu/twiki/bin/view/Ma
in/PowerSampleSize
20
Data analysis
  • Provide a strategy for your data-analysis
  • Keep the study objectives in mind
    (explanation/prediction)
  • Dont use unnecessary technical terms
  • In principle all analyses must be specified
  • Trend of less freedom (subgroup analysis)

21
Most importantly
  • Make sure that you master
  • The methodological area (e.g. clinical
    epidemiology, public health, medical technology
    assessment)
  • The subject matter (e.g. oncology, cardiology)

22
Further reading on Clinical Epidemiology
  • Burger H, Hofman A. Klinische Epidemiologie. In
    Van der Meer J, CDA Stehouwer (red). Interne
    Geneeskunde. Houten Bohn, Stafleu, Van Loghum,
    20051-15.
  • Weiss NS. Clinical epidemiology. The study of the
    outcome of illness. New York Oxford University
    Press 1986.
  • Feinstein, A.R. Clinical Epidemiology The
    Architecture of Clinical Research. Philadelphia
    W. B. Saunders Co, 1985.
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