CHAPTER 18
Using Systematic Reviews and the Appropriate Meta-analysis
Walter W. Rosser
Nature fits all her children with something to do.
He who would write and cant write, can surely
review.
James R. Lowell
LEARNING OBJECTIVES
On completion of this chapter, the reader should be
able to
1. Determine if the question asked by the review
article is appropriate
2. Determine if the process of producing the
review was adequately rigorous to consider
using the conclusions
3. Decide if the review is applicable to the patients
4. Determine if a meta-analysis is appropriate
5. Assess the quality of the meta-analysis to
determine if the conclusions are valid
6. Be confident that the results of the meta-
analysis are appropriate for his/her practice
Many review articles are written by an expert such
as an orthopedic surgeon giving views about low back
pain gained from personal experience over a 20-year
career. The most common form of review article finds
the author describing his/her approach to diagnosis
and management using a few selected references. From
an evidence-based perspective, this style of review arti-
cle has some value in providing an experts approach to
a common problem, but the methodology is not rigor-
ous enough to ensure that the conclusions represent an
objective and systematic review of the current litera-
ture. We now outline the approach to a review article
that is considered rigorous enough to use as evidence
to change your practice on the basis of the recommen-
dations.
Literature Search
The sources of data used in the search, including key
words, personal communications with researchers, dis-
cussions at scientific meetings, and other less formal
sources of information, should be described. The trans-
parent literature search techniques should use key
words that are relevant to the question(s). Studies have
been conducted that suggest that the literature tends to
be biased in favor of the publication of positive results.
Another documented bias is toward prominent authors
whose publications are accepted in preference to those
of unknown authors, despite similar rigor in design,
methodology, and outcome of studies. Thus, the pub-
lished literature may not always reflect all of the current
knowledge about a specific question. Investigators in a
research project supported by a pharmaceutical com-
pany who discover higher rates of side effects than have
been reported previously may never submit their find-
ings for publication, creating another form of publica-
tion bias.
It is not possible for the author of a review article
to overcome all of these obstacles, but identifying them
does illustrate the importance of a rigorous search
strategy and the deficiencies of even the most rigorous
search. The search description should show that a rea-
sonable effort was made to obtain all relevant literature
in an attempt to reduce bias as much as possible.
The author should then discuss the criteria for
inclusion or exclusion of literature and demonstrate
that the process of decision-making was as objective as
possible. The inclusion and exclusion criteria must be
stated so clearly that if other independent reviewers
applied the same search criteria, they would choose the
same primary articles. The author of a rigorous review
should report that an independent reviewer using the
same criteria and search strategy did indeed choose the
same articles.
Among the criteria for selecting an article should
be the studys population, the interventions, and the
outcomes that were considered for inclusion or exclu-
sion. It is important to determine if the outlined crite-
ria make sense in family and general practice. The
113
114 Information Mastery: Evidence-Based Family Medicine Second Edition
decision to include or exclude articles on the basis of
study methods used is also important. The stronger the
study methods demanded in the review, the greater
confidence there can be in the conclusions. Most rigor-
ous reviews include only randomized controlled trials
(RCTs) in their search; however, this strategy risks not
addressing important questions for family and general
practice.
When rigorous criteria are used, even if hundreds
or thousands of studies have been published on a sub-
ject, usually only 5 or 10 articles will meet the criteria.
Although it is rare to find a review article that is rigor-
ous about the literature selection, all reviews that do
not follow the prescribed level of rigor are at risk of
bias. An example of biased paper selection can be
drawn from the cholesterol debate, in which inclusion
or exclusion of articles greatly influences the con-
clusion of a review. If the end point considered in a
review is cholesterol lowering, then a number of well-
controlled randomized trials demonstrated success for
a number of widely prescribed drugs (disease-oriented
evidence [DOE] rather than patient-oriented evidence
that matters [POEM]).
Assessment of the Quality of the Literature
Once the primary studies to be included in the review
have been selected, the author must then review the
quality of the studies. An assessment of this process will
use all of the skills acquired from understanding Chap-
ters 14 to 20. The review should include a brief com-
mentary on the strengths and weaknesses of each
primary study. The commentary on each selected arti-
cle should include the numbers and characteristics of
the population, the duration of the study, and the out-
comes and how they were measured. These brief
descriptions give the reader a sense of the strength,
quality, and relevance of the studies from which the
review has drawn its conclusions. There should be evi-
dence that the critique of the primary studies was
objective. Objective and unbiased reviews are best
achieved by having two or three individuals review and
critique each article independently and then share their
opinions. If the results of the studies chosen by the
author for inclusion are inconsistent, then the possible
causes of the inconsistency should be discussed. There
are five components of a clinical study in which minor
differences can result in different outcomes:
1. Study design
2. Chance (small sample size)
3. Population used
4. Intervention used and its duration and
strength
5. Methods used to measure outcomes
If the review uses RCTs, cohort studies, and case-
control studies, the potential for bias in the method-
ologically weaker studies is likely to provide some
explanation for variability of outcome. If the sample
sizes in the studies are small, chance may play a major
role in the variability of results. The Students t-test and
measurement of confidence limits are the common
ways to assess the risk of chance alone accounting for
the results. The smaller the sample size, the less likeli-
hood there is of a difference being statistically signifi-
cant and the more likely it is that a difference can be
explained by chance alone. Chance may explain minor
differences between studies, but large differences in
outcome are more likely to be explained by the popu-
lation sample. Often factors such as the severity of ill-
ness of patients in two samples will explain a difference.
Difference in the age or sex distribution of the study
samples or racial differences in the two populations are
factors that might explain differences. Study outcomes
may differ because of dosage differences or different
rates of compliance. Outcome measures may vary from
one study to another, especially in those measuring
quality of life as an outcome, in which both the instru-
ments and the methods by which the information are
gathered may vary.
Combining Data in a Review
After any rigorous review is completed, consideration
should be given to combining the key articles to create
a meta-analysis. If, after proper assessment, the results
cannot be combined, there should be a commentary as
to why and also discussion of the strengths or weak-
nesses of the best studies that have been found in the
review. The conclusions may be weakened if the qual-
ity or variability of the results from the literature raises
concerns.
Conclusions in a Review Article
Conclusions from a review should be based on findings
from the review. This seems to be an obvious statement,
but there are some examples of rigorously conducted
reviews that draw conclusions that are not linked to the
findings of the review.2
Review articles are an important source of infor-
mation for all primary care providers. Historically,
most review articles have been opinion articles. In the
twenty-first century, opinion is no longer a sound
enough basis on which to practice medicine. Primary
care providers must demand rigorously constructed
review articles to trust them as sources of information
for evidence-based practice. This demand must be
repeatedly expressed to the editors of journals designed
to assist family and general practitioners so that the
quality of review articles will continue to improve.
Why Do a Meta-analysis?
After assessing a review of the literature, it may be
appropriate to merge several good-quality studies
 Using Systematic Reviews and the Appropriate Meta-analysis 115

found through the review process. Merging the results 25% increase in
1.0 event rate
of several RCTs may provide information that cannot
be obtained from each study independently. Small tri- 0.9 no change in
K event rate
als, although less difficult and less expensive to carry

Event rate in those receiving treatment

0.8
out, are subject to Type II error (ie, false-negative
results occurring by chance). Pooling of the results 0.7 H
J 25% reduction
from several similar RCTs reduces the risk of Type II 0.6 L in event rate
error and strengthens confidence in the conclusions. A G
0.5
further benefit can be derived from pooling results
I
from analyses of subsets from larger trials. In the past 0.4 D
F
few years, subsets of persons representing specific age E
0.3
or sex groups or a group with unique characteristics C
have been derived from very large trials to answer spe- 0.2
A
cific questions applicable to these smaller groups. The 0.1 B
numbers in these subset analyses are small. Pooling the
0
results strengthens the statistical power of the analysis. 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3
The risk of a Type I error (ie, false-positive results Event rate in those not receiving treatment
occurring by chance) also exists in small trials. Pooling
data from all of the trials reduces this risk. Another Figure 18-1 An example of heterogeneity of a number of studies (not suitable for
meta-analysis).
advantage to pooling several small trials, compared
with the results from one large trial, is that the sam-
pling bias of the large trial is minimized by the differ- tions in the results of the studies should correspond to Meta-analysis
ences in the population samples from several small differences in the characteristics of the studies. An eye- is the
studies. The meta-analysis of a number of small trials ball estimate made by the reader should correspond to biostatisticians
should be more generalizable to primary care practice an estimate of the magnitude of difference between the playpen from
which statistical
populations than results from a single large trial. intervention and the control when the trials are com-
missiles can
bined.
be thrown at
ASSESSING THE QUALITY OF META-ANALYSIS Homogeneity confused
physicians.
The Question If the combined studies are comparable, variation in
As in a review article, the question being asked by the their outcomes should be accounted for by sampling
meta-analysis must be clear. Trials to be included in a variation or chance. The results can be demonstrated
meta-analysis are usually determined after all of the graphically by plotting the control groups along the
preliminary steps in a systematic review are completed horizontal axis and the intervention groups along the
and the question as to whether similar trials can or can- vertical axis.
not have their results combined. Many meta-analyses Significant variation suggests a lack of homogene-
pay little attention to the assessment of the literature as ity in the studies being merged, indicating that com-
outlined in the first part of this chapter and then com- bining their results is inappropriate (see Figure 18-1).
bine studies that should not be combined from a clin- Although a number of statistical tools are available to
ical perspective. analyze homogeneity (Mantel and Haenszel equation),
Reasons for conducting a meta-analysis might your own judgment about homogeneity from the plot
include the impracticality of conducting a large enough is a simple way to determine if combining the studies
single trial to answer the question, the presence of small is appropriate. A lack of homogeneity may reflect dif-
trials or subset analysis and the absence of a large trial, ferent doses of the intervention or different age or sex
and the importance of the question in health care deliv- composition of the study populations. Table 18-1
ery. Often a series of small trials have results that are demonstrates a homogeneous set of trials that can be
inconsistent, and by combining them, a more definitive appropriately combined. A good meta-analysis gives
conclusion is possible. The pharmaceutical industry you a table like this and explains any differences.
tends to carry out short trials with a few patients when
testing out new drugs and their effects. Combining sev- Sensitivity Analysis
eral of these studies into a meta-analysis can increase or Sensitivity analysis responds to the question, Are the
decrease confidence in the new drug (Figure 18-1). results of the meta-analysis sensitive to changes in the
way in which the analysis is done? An example would
Merging the Results of Trials be to conduct a meta-analysis using only RCTs and
Trials can be merged only when the outcome measures then to add cohort studies that otherwise meet the
used in each trial are the same or very similar. Varia- same criteria to see if the outcome changes.
116 Information Mastery: Evidence-Based Family Medicine Second Edition

Table 18-1 Trials on the Effect of Lipid-Lowering Strategies (the Effect of Cholesterol Lowering on Cause-Specific and
All-Cause Death Rates)

Drug Trials

Trial Cardiac Noncardiac Cancer Violence Total

LRC 0.78 1.34 1.06 2.75 0.96

HHS 0.84 1.30 0.99 2.48 0.96

WHO 1.05 1.74 1.66 1.19 1.47

UCS 0.59 1.60 1.00 5.00 0.62

Total 0.88 1.54 1.32 1.77 1.14

Diet Trials

LAUDS 0.80 1.06 1.70 9.04 0.96

MCS 1.39 1.00 1.34 1.50 1.00

Total 0.90 1.02 1.55 1.79 1.00

Adapted from the Canadian Task Force on Periodic Health Examination, 1993 update. Lowering the total blood cholesterol to prevent coro-
nary heart disease. Can Med Assoc J 1993;148:52137.

A similar outcome after combining studies using
different methodologies adds confidence to the meta-
analysis results. Age or sex groups might be excluded
from combined data as a strategy to measure their
influence in determining outcomes. The results of this
type of sensitivity analysis may strengthen confidence
in the meta-analysis if the results make clinical sense
and confirm clinical observations.
After reviewing a meta-analysis and determining
that the analysis has been carefully conducted and
meets the outlined criteria, one can be confident that
the results are relevant and useful for patients.
Although statisticians may lose our attention in areas
within the process of meta-analysis (the actual mathe-
matical process of pooling the data), the general prin-
ciples of good meta-analysis can be judged by any
clinician. Many meta-analyses in the literature do not
meet the above criteria, so the mathematical wizardry
becomes irrelevant.
QUESTIONS TO ASK WHEN ASSESSING THE VALUE
OF A REVIEW ARTICLE AND/OR A META-ANALYSIS
1. Is the question a POEM or a DOE?
2. Is the question clearly stated?
3. Is the literature search strategy described in a
transparent fashion?
4. Are there explicit inclusion and exclusion cri-
teria and an appropriate explanation for the
studies that were included?
5. Is the homogeneity of the studies appropri-
ately evaluated?
6. Are appropriate statistics used? Is sensitivity
analysis used?
7. Does the pooled analysis demonstrate signifi-
cant differences between the trial and control
groups?
8. Are appropriate conclusions drawn from the
analysis?
9. Would you incorporate the recommendations
into your practice?
RELEVANT CAPRE TOPICS
Diagnosing deep vein thrombosis (DVT)
Cost-effective management of dyspepsia
<http://www.meds.queensu.ca/ce/capre>