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ACCP Updates in Therapeutics 2012: The Pharmacotherapy Preparatory Review and Recertification Course
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Study Designs: Fundamentals of Design and Interpretation
Learning Objectives: were stratified on the basis of the duration of statin use
before the onset of myopathy.
1. Define, compare, and contrast the concepts of in-
ternal and external validity, bias, and confounding 1. To which one of the following types of bias is this
in clinical study design. study design most susceptible?
2. Identify potential sources of bias in clinical trials; A. Confounding by indication.
select strategies to eliminate or control for bias. B. Recall bias.
3. Outline the hierarchy of evidence generated by C. Diagnostic bias.
various study designs. D. Misclassification.
4. Compare and contrast the advantages and disad-
vantages of various study designs (e.g., prospec- 2. Which one of the following will be most affected
tive; retrospective; case-control; cohort; cross- by the type of bias likely to occur in this study?
sectional; randomized controlled clinical trials;
A. External validity.
systematic review; meta-analysis).
B. Internal validity.
5. Select from various biostatistical measures to ap-
C. Assessment of exposure.
propriately compare groups or their assessments
D. Number of patients needed for the study.
from various study designs and use their findings/
output to interpret results.
3. When describing the results of a randomized con-
6. Define and evaluate odds, odds ratio, risk/inci-
trolled clinical trial, the investigators report using
dence rate, risk ratio/relative risks, and other risk
an intention-to-treat analysis to analyze their data.
estimates. Compute and evaluate number needed
The results of their investigation comparing two
to treat and number needed to harm.
diuretics for heart failure show no difference in
7. Define and calculate terms such as true positive,
the number of hospitalizations for decompensated
false positive, true negative, false negative, sensi-
heart failure between the treatment groups. Given
tivity, specificity, positive predictive value, nega-
their method of data analysis, which one of the fol-
tive predictive value, positive likelihood ratio, and
lowing is most appropriate?
negative likelihood ratio.
8. Define and calculate terms such as point and peri- A. May be susceptible to issues regarding a lack
od prevalence, incidence rate, prevalence rate, ab- of power.
solute risk difference, and relative risk difference. B. Provides a good measure of effectiveness
9. Cite three key issues necessary for proper sample under usual clinical conditions.
size determination. C. Cannot provide an estimate of methods
10. Delineate the difference between parallel and effectiveness.
crossover study designs. D. May overestimate actual treatment effect.
ACCP Updates in Therapeutics 2012: The Pharmacotherapy Preparatory Review and Recertification Course
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Study Designs: Fundamentals of Design and Interpretation
1.5% to 4.5%. Which one of the following conclu- B. Margarine with ALA statistically
sions is most appropriate? significantly reduced the risk of
A. The difference in recurrence rates between cardiovascular events (p<0.01).
the two treatments is statistically significant. C. Margarine with ALA did not significantly
B. The difference in recurrence rates between reduce the risk of cardiovascular events
the two treatments is not statistically (p>0.05).
significant. D. Without a p-value, it is not possible to
C. Because twice-daily therapy causes determine whether margarine with ALA
fewer recurrences, clinicians should feel affected cardiovascular events.
comfortable using that dosing scheme for
their patients with VT. 7. When the study was being designed, which one
D. No conclusion can be drawn because p-values of the following choices describes the outcome
are unavailable. for which the study was most likely to have been
powered?
5. According to the data in the previous question, A. Differences in the rate of the composite
which one of the following best represents the outcome, cardiovascular events.
number of patients who would need to be treated B. Differences in the rate of percutaneous
with twice-daily enoxaparin to prevent the recur- coronary interventions.
rence of one VT? C. Differences in the rate of the composite
A. 7. outcome in women.
B. 23. D. No best answer because no statistical
C. 67. difference observed.
D. Number needed to treat (NNT) should not
be calculated because the result was not 8. In a meta-analysis of randomized controlled trials
statistically significant. examining the effects of several antihypertensive
drugs, the OR for treatment with low-dose diuret-
ics compared with calcium channel blockers for
Questions 6 and 7 pertain to the following case. prevention of cardiovascular disease events was
A multicenter, double-blind, placebo-controlled trial 0.84 (95% CI, 0.750.95). Which one of the follow-
randomly assigned 4837 patients to either treatment ing statements is the most appropriate interpreta-
with margarine supplemented with the omega-3 fatty tion of these findings?
acid ALA (margarine with ALA) or placebo margarine. A. Treatment of hypertension with low-
The primary end point was the rate of cardiovascular dose diuretics was 16% more effective in
events, defined as fatal and nonfatal cardiovascular preventing cardiovascular disease events than
events and percutaneous coronary interventions. Data treatment with calcium channel blockers.
were analyzed according to the intention-to-treat analy- B. Treatment of hypertension with calcium
sis with the use of a Cox proportional hazards model. channel blockers was 16% more effective in
The 95% hazard ratio and 95% CI for the margarine preventing cardiovascular disease events than
with ALA group was 0.91 (0.781.05). In the prespeci- treatment with low doses of diuretics.
fied subgroup of women, margarine with ALA was as- C. The difference observed between treatment
sociated with the following hazard ratio: 0.73 (95% CI, with calcium channel blockers and low doses
0.511.03; p=0.07). of diuretics is not statistically significant.
D. The odds of developing cardiovascular events
6. Which one of the following statements is most when treating hypertension with low doses
appropriate? of diuretics is lower than when using calcium
A. Margarine with ALA statistically channel blockers.
significantly reduced the risk of
cardiovascular events (p<0.05).
ACCP Updates in Therapeutics 2012: The Pharmacotherapy Preparatory Review and Recertification Course
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Study Designs: Fundamentals of Design and Interpretation
I. INTRODUCTION
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Study Designs: Fundamentals of Design and Interpretation
A. Document and Describe Experiences, Novel Treatments, and Unusual Events. Allows hypothesis
generation that can be tested with other study designs. Note that the title does not state study.
1. Possible adverse drug reactions in one or more patients: QT-interval prolongation associated with
fluoroquinolone antibiotics
2. Case report: One patient
3. Case series: More than one patient with a similar experience or many case reports combined into a
descriptive review
4. Reports should provide sufficient detail to allow readers to recognize same/similar cases at their center/
practice.
5. Is IRB (institutional review board) approval required?
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Study Designs: Fundamentals of Design and Interpretation
B. Advantages: Hypotheses are formed, which is perhaps the first step in describing an important clinical
problem. Easy to perform and inexpensive
C. Disadvantages: Does not provide explanation other than conjecture and does not establish causality or
association
A. Design Does Not Involve Investigator Intervention, Only Observation. It is essential to remember that
observational study designs investigate associations, not, in most cases, causes.
B. Case-control Study: Study Exposure in Those With and Without the Outcome of Interest
Risk
Factor
Present Cases
Subjects With
Risk Condition of Interest
Factor
Absent
Risk
Factor
Present Controls
Subjects Without
Condition of Interest
Risk
Factor
Absent
Past Present
1. Determine the association between exposures/risk factors and disease/condition. Classic example:
Aspirin use and Reye syndrome
2. Often referred to as retrospective studies
3. Useful method (and perhaps the only practical way) to study exposures in rare diseases or diseases that
take long periods to develop
4. Critical assumptions to minimize bias:
a. Cases are selected to be representative of those who have the disease.
b. Controls are representative of the general population that does not have the disease and are as
identical as possible to the cases, minus the presence of the disease.
c. Information is collected from cases and controls in the same way.
5. Examples
a. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction associated with
antihypertensive drug therapies. JAMA 1995;274:6205
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Study Designs: Fundamentals of Design and Interpretation
b. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine (PPA) and the risk of
hemorrhagic stroke. N Engl J Med 2000;343:182632. Purpose of phenylpropanolamine (PPA):
i. To estimate in women the association between hemorrhagic stroke and the use of appetite
suppressants containing PPA
ii. To estimate the association between any use of PPA (in appetite suppressant or cough or cold
remedy) and hemorrhagic stroke
iii. To estimate in men and women the association between hemorrhagic stroke and the type of
exposure to PPA
iv. Disease: Hemorrhagic stroke (several types). Exposure: PPA
v. Cases: Symptomatic subarachnoid or intracerebral hemorrhage (n=702). Controls: Matched
on telephone exchange, sex, race, and age (n=1376)
vi. Exposure assessed by structured questionnaire, product photographs, and ingredient
confirmation
6. Advantages
a. Inexpensive and can be conducted quickly
b. Allows investigation of several possible exposures or associations
7. Disadvantages
a. Confounding must be controlled for.
b. Observation and recall bias: Looking back to remember
c. Selection bias: Case selection and control matching are difficult.
8. Measure of association: Odds ratio (OR): In some cases, this can be an estimate of the relative risk
(RR). The OR is interpreted as the odds (and its ratio) of exposure to a factor in those with a condition
or disease, compared with those who do not have the condition or disease.
C. Cohort Study
1. Determines the association between exposures/factors and disease/condition development. Allows an
estimation of the risk of outcome (and the RR between the exposure groups). Study outcome of interest
in those with and without the exposure of interest. Classic examples:
a. Framingham Study. A cohort of subjects from Framingham, Massachusetts, were (and are)
studied over time to evaluate the relationship between a variety of conditions (exposures) on the
development of cardiovascular disease.
b. Nurses Health Study: Investigates the potential long-term consequences of the use of oral
contraceptives
2. Describes the incidence or natural history of a disease/condition and measures it in time sequence
3. Retrospective: Begins and ends in the present but involves a major backward look to collect
information about events that occurred in the past
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Study Designs: Fundamentals of Design and Interpretation
Measure Outcomes
Begin Measure/Classify and Compare
Outcome
Present
Subjects With
Risk Factor
Outcome
Absent
Study Sample
Population Outcome
Present
Subjects Without
Risk Factor
Outcome
Absent
Subjects have Outcome
(EXCLUDED)
Past Present
Measure Outcomes
Begin Measure/Classify and Compare
Outcome
Present
Subjects With
Risk Factor
Outcome
Absent
Study Sample
Population Outcome
Present
Subjects Without
Risk Factor
Outcome
Absent
Subjects have Outcome
(EXCLUDED)
Present Future
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Study Designs: Fundamentals of Design and Interpretation
a. Example: Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary
prevention of coronary events in the nurses health study. A prospective, observational study. Ann
Intern Med 2001;135:18.
b. Advantages: Able to control for confounding factors to a greater extent, easier to plan for data
collection
c. Disadvantages: More expensive and time-intensive, loss of subject follow-up, difficult to study
rare diseases/conditions at a reasonable cost
5. Measure of association: Relative risk or risk ratio: The risk of an event or development of a condition
relative to exposure; the risk of developing a condition when exposed compared with someone who has
not been exposed
A. Incidence
1. Measure of the instantaneous rate of developing a disease so that it reflects the rate of disease
development
2. Divide the number of individuals who develop a disease by the total amount of time these individuals
were at risk of developing a disease.
B. Prevalence: Measure of the number of individuals who have a condition/disease at any given time
C. Interpreting RRs/ORs
1. Estimate the magnitude of association between exposure and disease. Key point: This is not cause and
effect but association.
2. The incidence of disease in the exposed group divided by the incidence of disease in the unexposed
group
3. The relative risk (a.k.a. risk ratio) cannot be directly calculated for most case-control studies; instead,
the OR is usually an estimate of the RR.
4. The RR and OR are interpreted on the basis of their difference from unity (1.0). If the 95% CI includes
unity, no statistical difference is indicated. The CI also gives us an idea of the spread within which the
true effect lies.
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b. Magnitude of risk
A / ( A + B)
a. RR=
C / (C + D)
A
b. OR = C
B
D
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Table 4. Contingency table from: Phenylpropanolamine (PPA) and the Risk of Hemorrhagic Stroke N. Engl J Med
2000;343:1826-32
Disease?
Hemorrhagic Stroke in Women
Yes No
Exposure? Yes 6 377
Appetite suppression use No 1 749
a. OR = (6/1)/(377/749) = 12.
b. Data from the PPA study above related to appetite suppressant and development of hemorrhagic
stroke
Table 5. Use of PPA and appetite suppressants and the risk of developing hemorrhagic stroke
Cases Controls Adjusted OR
(+ Hemorrhagic stroke) ( Hemorrhagic stroke) (95% CI)
n=383 n=750
Appetite suppressant: Women 6 1 16.6 (1.51182)
Appetite suppressant: Men 0 0
Appetite suppressant: Either 6 1 15.9 (1.38184)
PPA: Women 21 20 1.98 (1.003.90)
PPA: Men 6 13 0.62 (0.201.92)
PPA: Either 27 33 1.49 (0.842.64)
CI = confidence interval; OR = odds ratio; PPA = phenylpropanolamine.
D. Causation
1. REMEMBER: In general, we do not prove or show causality with observation studies, but there is
some general guidance to consider when evaluating them. It is important to recognize that in many
situations, the conduct of studies to establish causality is not possible or practical.
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Study Designs: Fundamentals of Design and Interpretation
A. Characteristics
1. Whether study is experimental or interventional, investigator makes intervention and evaluates cause
and effect. Examine etiology, cause, efficacy, etc., using comparative groups.
2. Some previous background information or studies should exist to suggest that the intervention
employed will likely be beneficial.
3. Design allows assessment of causality.
4. Minimizes bias through randomization and/or stratification
5. May use parallel or crossover design
a. Crossover design provides practical and statistical efficiency.
b. Crossover design is not appropriate for certain types of treatment questions. Effect of treatment on
a disease that worsens quickly over time or worsens during the study period
6. Examples:
a. Clinical trial: Comparison of two drugs, comparison of two behavioral modifications, etc.
b. Educational intervention: Online course versus lecture class format
c. Health care intervention: Pharmacist-based health care team versus nonpharmacist-based health
care team
Measure Outcomes
Begin Randomized and Allocate and Compare
Outcome
Intervention #1
No
Outcome
Study Sample
Population Outcome
Intervention #2
(or Placebo, etc.)
No
Outcome
Present Future
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Study Designs: Fundamentals of Design and Interpretation
Washout
Intervention #1 Intervention #2
Study Sample
Present Future
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Study Designs: Fundamentals of Design and Interpretation
A. Subgroup Analysis
1. Important part of controlled clinical trials (if set a priori)
2. Many times, they are overused and over-interpreted, leading to unnecessary research, misinterpretation of
results, and/or suboptimal patient care.
3. Qualitative versus quantitative interactions or differences
a. Quantitative: Studied treatment is superior for both subgroups (ex. male and female).
b. Qualitative: Studied treatment is superior in only ONE of the subgroups (ex. male or female). These
types of differences should be viewed with caution.
4. Many potential pitfalls in identifying and interpreting:
a. Failure to account for several comparisons or to adjust p-values
b. Problems with sample size (power), classification, and lack of assessment of interaction
B. Composite End Points: Often, the Impression Is that This Practice Is Not a Good Practice.
1. The primary end point is one of the most important decisions to make in the design of a clinical study.
2. A composite end point combines several end points:
a. For example, cardiovascular death, nonfatal MI, and cardiac arrest with resuscitation
b. Usually combines measures of morbidity and mortality
c. What does the following statement mean?
Our findings show that ramiprilreduces the rate of death, MI, stroke, revascularization, cardiac
arrest, heart failure, complications related to diabetes, and new cases of diabetes in a broad spectrum
of high-risk patients. Treating 1000 patients with ramipril for 4 years prevents about 150 events in
around 70 patients.
i. Was there a reduction in all the end points or just some?
ii. Are all the outcomes just as likely to occur?
iii. Why would this trial have been interested in all of these outcomes?
3. What are the positives for using composite end points?
a. No single primary outcome
b. Alleviate problems of multiple testing
c. Increase number of events, which decreases sample size and cost
4. What are the problems?
a. Difficulties in interpreting composite end points; consider our example above
b. Misattribution of statistically beneficial effects of composite measure to each of its component end points
c. Dilution of effects, negative results for relatively common component of composite end point hide
real differences in other end points. Undue influence exerted on composite end point by softer
component end points
d. Averaging of overall effectproblems when component end points move in opposite directions
e. Should all end points be weighed the same, or should death weigh more?
5. The results for each individual end point should be reported together with the results for the composite.
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8. Significant time trend: More CHD events in the treatment group than in placebo in year 1 and fewer in
years 4 and 5
9. Conclusions
A. Intention-to-Treat Analysis
1. Compares outcomes on the basis of initial group assignment or as randomized. The allocation
to groups was how they were intended to be treated, even though they may not have taken the
medication for the full duration of the study or they dropped out, etc.
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2. Determines effect of treatment under usual conditions of use. Analogous to routine clinical practice in
which a patient receives a prescription but may not adhere to the drug
3. Gives a conservative estimate of differences in treatments; may underestimate treatment benefits
4. Most common approach to assessing clinical trial results
B. Per-Protocol Analysis
1. Subjects who do not adhere to allocated treatment are not included in the final analysis; only those who
completed the trial and adhered to the protocol (based on some predetermined definition [e.g., 80%
adherence])
2. Provides additional information about treatment effectiveness and provides more generous estimates of
differences between treatments
3. Subject to several issues because of factors such as lower sample size and definitions of adherence.
Results are more difficult to interpret.
C. As-Treated Analysis
1. Subjects are analyzed by the actual intervention received. If subjects were in the active treatment group
but did not take active treatment, the data would be analyzed as if they were in the placebo group.
2. This analysis essentially ignores the randomization process for those who did not adhere to the study
design.
X. SYSTEMATIC REVIEW/META-ANALYSIS
A. Introduction
1. Dramatic increase in the number of these types of papers
2. First meta-analysis probably published in 1904: Assessment of typhoid vaccine effectiveness
B. Systematic Review
1. Summary that uses explicit methods to perform a comprehensive literature search, critically appraise it,
and synthesize the world literature on a specific topic. Instead of the subjects being human subjects, the
individual studies are the study subjects (i.e., the subjects are studies).
2. Differs from a standard literature review: The study results are more comprehensively synthesized and
reviewed.
3. As with a controlled clinical trial (or other studies), the key is a well-documented and described
systematic review.
4. Some systematic reviews will attempt to statistically combine results from many studies.
5. Differs from other reviews, which combine evaluation with opinions
C. Meta-analysis
1. Systematic review that uses mathematical/statistical techniques to summarize the results of the
evaluated studies
2. These techniques may improve on:
a. Calculation of effect size
b. Increase in statistical power
c. Interpretation of disparate results
d. Reduction in bias
e. Answers to questions that may not be addressable with individual studies
3. Issues related to meta-analysis
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a. Reliant on criteria for inclusion of previous studies and statistical methods to ensure validity.
Details of included studies are essential.
b. Assessment of trial methodology
i. Is there a focused research question?
ii. What types of studies were included?
iii. How was the literature search conducted, and how were trials included or excluded?
iv. How was quality assessed, and how many reviewers were there?
v. How was heterogeneity assessed?
(a) Statistical heterogeneity
(b) 2 and Cochran Q are common tests for heterogeneity.
c. Sensitivity analysis
d. Assessment of risk
4. Forest plots
5. Application: Koshman SL, et al. Pharmacist care of patients with heart failure. A systematic review of
randomized trials. Arch Intern Med 2008;168:68794
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A. Cost-minimization Analysis
1. Outcome: Equal, only cost is addressed
2. Determines the lowest cost alternative
B. Cost-benefit Analysis
1. Outcome: Monetary; is a treatment worth the cost?
2. Determines the greatest net benefit alternative
C. Cost-effectiveness Analysis
1. Clinical units
2. Determines the most cost-effective alternative
D. Cost-utility Analysis
1. Utility
2. Determines the greatest benefit alternative
C. Positive Predictive Value: Proportion of Patients with a Positive Test Who Are Given a Correct Diagnosis
D. Negative Predictive Value: Proportion of Patients with a Negative Test Who Are Given a Correct Diagnosis
E. Example: Relationship Between Test and Correct Diagnosis Identified by Disease (data from: J Nucl Med
1972;13:90815)
Acknowledgement: The contributions of the previous author/contributor, Dr. G. Robert DeYoung, to this topic are acknowledged.
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