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Study Design in Clinical Research
Ronald A Thisted, PhD
Department of Health Studies
The University of Chicago
The employment of a method
presupposes that in a proposed inquiry
the use of the method is advantageous
to the solution.
Alfred E Cohn (1924)
Purposes in Medical Research
Journal of Clinical Investigation
Components of Research
Broad objectives
Background and significance
Specific aims / hypotheses
Preliminary results
Methods / design
Dissemination
Social contract / human subjects protection
Components of Research
Broad objectives
Background and significance
Specific aims / hypotheses
Preliminary results
Methods / design
Dissemination
Social contract / human subjects protection
Methods
A detailed
1) plan of action,
2) that will achieve the specific aims
Note that there is an intimate
connection between the aims and the
methodsmake the connection clear!
Research Methods and
Journalism
The Methods answer basic questions:
Who?
What?
When?
Where?
Why?
How?
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Tying Methods to Aims
The methods to be employed are those
which are appropriate to illuminating the
specific problems in question.
Alfred E Cohn (1924)
Purposes in Medical Research
Journal of Clinical Investigation
Methods and W5H
Who will be studied?
Who will be excluded? Why? How will they be studied?
Observation or manipulation?
Measurements:
What will be measured?
How will they be done?
Who will take them? Why?
When, and how often?
Where? Why?
How will the measurements be
used to test the hypotheses?
What will subjects know?
What do different possible
outcomes imply for hypotheses?
What statistical methods will be
used, and why?
How will procedures/tests
accomplish the specific aims?
How many subjects will be
studied? Why?
What obstacles might prevent
complete success?
How can they be minimized?
What might limit conclusions?
Method vs Design
Pharmacokinetics Absorption
Distribution
Elimination
Bioequivalence
Immunogenicity
Dose-escalation
Toxicity / safety
Efficacy
Risk
Case-control
Cohort
Randomized control
trial (RCT)
Crossover
Meta-analysis
Repeated measures
There are packages of approaches:
Method vs Design
Pharmacokinetics Absorption
Distribution
Elimination
Bioequivalence
Immunogenicity
Dose-escalation
Toxicity / safety
Efficacy
Risk
Case-control
Cohort
Randomized control
trial (RCT)
Crossover
Meta-analysis
Repeated measures
There are packages of approaches:
Design = A + B + N
Testing hypotheses
Fundamental idea:Worthwhile research hinges on comparing A to B rigorously
All statistical tests involve comparison
The appropriate statistical analysis depends on the design
The design implies how a comparison will be accomplished,
which implies how the results can be interpreted
The best design depends on the hypothesis being tested
As methods are developed, aims may be refined
And vice versa
Investigator responsibility
Understanding what the methodsselected can accomplish
Understanding the limits of the method Selecting an appropriate design
This can be done with collaborators,including biostatisticians, epidemiolo-gists, and others with specific methods.
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Some Design Examples
Randomized clinical trial
Case-control study
Prospective cohort study
CAST Cardiac Arrhythmia Suppression Trial
Hypotheses:
E, F, M will reduce death from cardiac arrest
One of E, F, or M will do this job best
Design: Randomized, double-blind, placebo-controlled trial, juried adjudication of events, n=1727
Advantage: fairest possible comparison of effects ofprescribing agents on outcome
Strengths: prospective, bias-limiting
Limitations: generalizability to broad pt pops
Issues: compliance and intent-to-treat
Echt, et al (1991) NEJM
CAST Results DES and Vaginal Adenocarcinoma
Hypothesis: A specific risk factor accounts forsudden increase in rare Ca
Design: case-control studyof 8 cases with 32matched controls
Advantage: well-suited to rare disease withlengthy exposure-outcome latency
Limitations: weak bias control, retrospective
Issues: ascertainment, no incidence info,selection
Herbst (1971) NEJM
Maternal Risk Factor #1
Maternal Smoking
Yes No
Cases 7 1
Controls 21 11
p=0.50
Maternal Risk Factor #2
DES given this pregnancy
Yes No
Cases 7 1
Controls 0 32
p
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Natural Hx of Prostate Ca Conservative management of localized PCa
Hypothesis:
Prognosis is affected by specific risk factors
Design: Prospective cohorts, pooled data, n=828
Advantage: allows long follow-up, broad population
Strengths: prospective
Limitations: bias control limited
Issues: selection, loss to follow-up
Chodak, et al (1994) NEJM
Results
Also: age