Study Design

1. Anatomy and Physiology of
Clinical Research
Srini Tridandapani, PhD MD
Department of Radiology and Imaging
Sciences
Emory University

2. Goal
• To understand the anatomy and physiology
of clinical research, i.e., understand the
principles of study design, analysis,
reporting and bias

3. Learning Objectives
At the end of this lecture you should be able
• To enumerate the various elements of a
research study
• To describe how the elements of the a
research study interact
• To name the two major classes of error in
research studies

4. Clinical Research
• Anatomy: What it’s
made of…
– Research question
– Design
– Subjects
– Measurements
– Sample size calculation
• Physiology: How it
works…
– Make valid inferences
– What happened in the
study sample
– How does it generalize
to the world outside
– How to  errors,
random and systematic

5. Anatomy of Research:
What it’s Made of

6. Anatomy: Outline of Study
Protocol
Element Purpose
Research Questions What questions will the study address?
Background and Significance Why are these questions important?
Design
(Time frame, epidemiologic approach)
How is the study structured?
Subjects
(Selection criteria, sampling design)
Who are the subjects and how will they
be selected?
Variables
(Predictor variables, confounding
variables, outcome variables)
What measurements will be made?
Statistical issues
(Hypotheses, sample size, analytic
approach)
How large is the study and how will it
be analyzed?

7. Anatomy: Outline of Study
Protocol
Element Purpose
Research Questions What questions will the study
address?
Background and Significance Why are these questions important?
Design
(Time frame, epidemiologic approach)
How is the study structured?
Subjects
(Selection criteria, sampling design)
Who are the subjects and how will they
be selected?
Variables
(Predictor variables, confounding
variables, outcome variables)
What measurements will be made?
Statistical issues
(Hypotheses, sample size, analytic
approach)
How large is the study and how will it
be analyzed?

8. Research Question
• Objective of the study
• Starts as a general question, but must be
narrowed down to a concrete, researchable
issue
• Example:
– Should people eat more fish?

9. Research Question
• Break this question into more specific
components:
– How often do Americans eat fish?
– Does eating fish  the risk of CV disease?
– Is there a risk of mercury toxicity from  fish
intake in older adults?
– Do fish oil supplements have the same effects
on CV disease as dietary fish?
– Which fish oil supplements don’t make people
smell like fish?

10. A well-formatted research question:
The four PICO elements
P patients
I intervention
(independent variable)
C comparison
O outcome
(dependent variable)
• S subjects
• E exposure
• C comparison
• O outcome

11. Using PICO to develop a question
Includes each of the following:
• Intended patients/subjects to study
• The independent variable of interest
– Intervention, exposure, pt characteristic
– The item of primary interest of the study
• Comparison group or procedure
• Outcome measure
Combines them together as a question

12. Question example
• Issues to address:
– Define CHD
– Define study population sample source
– Define fish intake
Final result:
Among a sample of patients seen in the investigator’s
clinic who have a previous CHD diagnosis and
respond to a mailed questionnaire, what proportion
report taking fish oil supplements?

13. PICO in practice
Essentially all proposed research
questions should include each of the
PICO elements

14. Research question comments
• It has been proposed that if your entire
question can be stated in one breath, it is too
short
• That is extreme. It need not include your entire
inclusion and exclusion criteria
• The research question is analogous to the pt
chief complaint. It is not the entire history and
exam.

15. Refine the Research Question:
Make it a FINER question
• Feasible = can it be done with the resources
that are available?
• Interesting = do you have passion for it?
• Novel = is it a new research idea?
• Ethical = does it comply with research ethics
and codes of conduct?
• Relevant = does it pass the “so what” test?

16. Applying the FINER criteria
• Carefully review your proposed research question
– Research in progress meetings can be helpful for this
• Consider how it meets each of the FINER
criteria……or not
Then decide:
• Do you still want to proceed with your proposed
project? Is it feasible, etc.?

17. The FINER review
This is where most good research
questions die an early death
(or should have died)

18. Anatomy: Outline of Study
Protocol
Element Purpose
Research Questions What questions will the study address?
Background and Significance Why are these questions important?
Design
(Time frame, epidemiologic approach)
How is the study structured?
Subjects
(Selection criteria, sampling design)
Who are the subjects and how will they
be selected?
Variables
(Predictor variables, confounding
variables, outcome variables)
What measurements will be made?
Statistical issues
(Hypotheses, sample size, analytic
approach)
How large is the study and how will it
be analyzed?

19. Background and Significance
• Provide context and Rationale
• References, including your own work (toot
your horn!...but not too loudly)
• Be succinct! Need to pare this down with
new NIH format

20. Anatomy: Outline of Study
Protocol
Element Purpose
Research Questions What questions will the study address?
Background and Significance Why are these questions important?
Design
(Time frame, epidemiologic
approach)
How is the study structured?
Subjects
(Selection criteria, sampling design)
Who are the subjects and how will they
be selected?
Variables
(Predictor variables, confounding
variables, outcome variables)
What measurements will be made?
Statistical issues
(Hypotheses, sample size, analytic
approach)
How large is the study and how will it
be analyzed?

21. Design of Study
Observational Study
• Cohort study
– Retrospective
– Prospective
• Cross-sectional study
• Case-control study
Clinical Trial
• Randomized blinded trial
– Can also have nonrandomized
or un-blinded designs

22. Anatomy: Observational Designs
Study Design Key Feature Example
Cohort Study A group followed over
time
Measure fish intake at
baseline and periodically
examine subjects at fu
visits to see if eating more
fish  CHD events
Cross sectional study A group examined at one
point in time
Interview subjects about
current and past history of
fish intake and correlate
with h/o CHD and current
coronary calcium score
Case-control study Two groups selected
based on the presence or
absence of an outcome
Examine a group of
patient w/ CHD (“cases”)
and compare them with
group who did not have
CHD (“controls”), asking
about past fish intake

23. Anatomy: Clinical Trial Design
Study Design Key Feature Example
Randomized Blinded
Trial
Two groups created by a
random process, and a
blinded intervention
Randomly assign subjects
to receive fish oil
supplements or placebo,
then follow both
treatment groups for
several years to observe
the incidence of CHD

24. Anatomy: Outline of Study
Protocol
Element Purpose
Research Questions What questions will the study address?
Background and Significance Why are these questions important?
Design
(Time frame, epidemiologic approach)
How is the study structured?
Subjects
(Selection criteria, sampling design)
Who are the subjects and how will
they be selected?
Variables
(Predictor variables, confounding
variables, outcome variables)
What measurements will be made?
Statistical issues
(Hypotheses, sample size, analytic
approach)
How large is the study and how will it
be analyzed?

25. Anatomy: Study Subjects
• Inclusion and Exclusion Criteria defining
target population
• How best to recruit

26. Anatomy: Study Subjects
• In the Fish Study example, how is CHD
defined?
– Could be subjects seen in the clinic with
diagnosis codes for MI, angioplasty, or CABG
in their EMR
• Recruitment Trade-off
– Using random sample of CHD patients in the
entire country would enhance generalizability
but more expensive

27. Anatomy: Outline of Study
Protocol
Element Purpose
Research Questions What questions will the study address?
Background and Significance Why are these questions important?
Design
(Time frame, epidemiologic approach)
How is the study structured?
Subjects
(Selection criteria, sampling design)
Who are the subjects and how will they
be selected?
Variables
(Predictor variables, confounding
variables, outcome variables)
What measurements will be made?
Statistical issues
(Hypotheses, sample size, analytic
approach)
How large is the study and how will it
be analyzed?

28. Variables
• Predictor variables
– Age, race, sex, smoking history, fish and fish
oil supplement intake
• Outcome variables
– Heart attacks, strokes, quality of life,
unpleasant odor
• Confounder variables
– Other predictors of outcome such as intake of
red meat or income level that could be related
to dietary fish and confuse interpretation

29. Anatomy: Outline of Study
Protocol
Element Purpose
Research Questions What questions will the study address?
Background and Significance Why are these questions important?
Design
(Time frame, epidemiologic approach)
How is the study structured?
Subjects
(Selection criteria, sampling design)
Who are the subjects and how will they
be selected?
Variables
(Predictor variables, confounding
variables, outcome variables)
What measurements will be made?
Statistical issues
(Hypotheses, sample size, analytic
approach)
How large is the study and how will it
be analyzed?

30. Anatomy: Statistical Issues
• Consult a Statistician
• Develop a sound statistical hypothesis
(different from a scientific hypothesis)
• Reframe research question to test for
statistical significance of findings
• Hypothesis allows calculation of sample
size

31. Anatomy: Statistical Issues
• Reframe scientific into a statistical
hypothesis
• Hypothesis: 50- to 69-year-old women with
CHD who take fish oil supplements will
have a lower risk of myocardial infarction
than those who do not

32. Physiology of Research:
How it Works

33. Inferences
Findings in
the Study
Truth in the
Universe
INFER

34. Inferences
Truth in the
Study
Study
Plan
Truth in the
Universe
Research
Question
Infer Findings in the
Study
Actual
Study
Infer
Design Implement
EXTERNAL
VALIDITY
INTERNAL
VALIDITY
DESIGNING AND IMPLEMENTING
DRAWING CONCLUSIONS

35. Designing the Study
• What is the prevalence of regular use of fish
oil supplements among people with CHD?
• Among a sample of patients seen in the
investigator’s clinic who have a previous
CHD diagnosis and respond to a mailed
questionnaire, what proportion report taking
fish oil supplements?

36. Design Errors
Truth in the Study
Study Plan
Truth in the Universe
Research Question
EXTERNAL
VALIDITY
Infer
Design
Errors

37. Implementation Errors
Findings in the Study
Actual study
Truth in the Study
Study plan
Infer
Implement
INTERNAL
VALIDITY
Errors

38. Types of Errors
• Systematic Errors (Bias)
• Random Errors (Chance) – this can be
reduced by increasing the sample size

39. Summary of the Physiology of
Clinical Research: How it Works
Truth in the
Universe
Research
question
Infer
Design
INTERNAL
VALIDITY
Truth in the
Study
Study
Plan
Findings in the
Study
Actual
Plan
Infer
Design
EXTERNAL
VALIDITY
Random
and
Systematic
Errors
Random
and
Systematic
Errors

40. Summary
• Anatomy of research: what it’s
made of
• Physiology of research: how it
works
• Research ?  study plan  actual
study

41. Thank You