Utility of an Effect Size Analysis for Communicating Treatment

Effectiveness: A Case Study of Cholinesterase Inhibitors for

Alzheimers Disease
Kevin R. Peters, PhD

OBJECTIVES: To highlight the utility of using an effect

size analysis to communicate the effectiveness of treatment
interventions.
DESIGN: Secondary analysis.
SETTING: Previously published systematic review on cholinesterase inhibitors (ChEIs) in Alzheimers disease.
PARTICIPANTS: Individuals with mild to moderate
Alzheimers disease.
INTERVENTION: Six-month randomized controlled trials involving a placebo group and a ChEI group (donepezil, galantamine, or rivastigmine).
MEASUREMENTS: Cognitive function was assessed
according to performance on the cognition subscale of the
Alzheimers Disease Assessment Scale (ADAS-Cog). Global
Function was quantified using the Clinicians InterviewBased Impression of ChangePlus (CIBIC-Plus). Harm
was defined as withdrawal from a trial because of an
adverse event. Several effect size indices were computed
based on these domains: the success rate difference (SRD),
the harm rate difference (HRD), the number needed to
treat (NNT) or harm (NNH), and the area under the curve
(AUC). Harm:benefit ratios were also computed to compare effect size indices across domains of function.
RESULTS: In terms of benefit, the NNT for cognition ranged from 4 to 14 (corresponding AUC values: 0.640.54),
and the NNT for global function ranged from 6 to 100 (corresponding AUC 0.590.51). In terms of harm, the NNH
ranged from 6 to 20 (corresponding AUC 0.580.53). Only
one of the four studies had favorable harm:benefit ratios in
both the cognition and global function domains.
CONCLUSION: Effect size indices should be reported in
clinical trials because they provide important insight into
the clinical meaningfulness of results. Additional benefit is
gained by comparing effect size indices across domains of

From the Department of Psychology, Trent University, Peterborough,

Ontario, Canada.
Address correspondence to Kevin R. Peters, Department of Psychology,
Trent University, 1600 West Bank Drive, Peterborough, Ontario K9J 7B8,
Canada. E-mail: kevinpeters@trentu.ca
DOI: 10.1111/jgs.12308

JAGS 61:11701174, 2013

2013, Copyright the Authors
Journal compilation 2013, The American Geriatrics Society

function to reveal harm:benefit ratios. J Am Geriatr Soc

61:11701174, 2013.

Key words: treatment; clinical meaningfulness; dementia

raditional measures of statistical significance

(P-values) estimate the probability of obtaining results
if the null hypothesis is true. In other words, they indicate
the probability that the results are simply due to chance.
Although important, this information falls short of revealing what one really wants to know about the results: the
magnitude of the effect and whether it is an important
effect.13 In contrast, effect size indices are better suited
for providing this information, and unlike measures of
statistical significance, they are largely unaffected by
sample size. Effect sizes indices are available for a wide
range of research contexts.13
Effect size indices are often used to help gauge the
practical or clinical meaningfulness of an obtained effect
(e.g., difference, relationship). With respect to treatment
interventions, statistically significant results are not always
clinically meaningful. Consider the following example; a
treatment group and a placebo group is each given a list of
20 words to remember. Imagine that the treatment group
remembers an average of 15.85 words and the control
group remembers an average of 15.01 words. With a sufficient number of subjects in each group this difference will
be statistically significant, but the clinical meaningfulness
of such a small difference is questionable. It is unlikely that
this treatment would help people remember more information in their day-to-day lives. Because effect size indices
help in assessing the clinical meaningfulness of a given
result, they complement traditional measures of statistical
significance and should be reported whenever possible.
Although the reporting of effect sizes is encouraged in
many disciplines, there are some that do not regularly follow
this practice. For example, in a systematic review of 57

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This study is a secondary analysis of a previously published Cochrane systematic review on ChEIs for AD.7
Although that review included 10 trials, only four of these
provided sufficient data to allow all of the effect size
indices of interest to be computed. For consistency, the
names of the trials used in that review have been kept:
DON-302,8 GAL-INT-Wilcock,9 GAL-USA-Raskind,10
and RIV-B303.11

95% confidence intervals (CIs) for each trial. Two effect

size indices were then calculated using these SRD values.
First, the number needed to treat (NNT13), which estimates the number of individuals that need to be treated
with a given intervention (e.g., ChEI) to obtain one more
successful outcome than would have been obtained if
they had been treated with a different intervention (e.g.,
placebo), was computed. The formula for the NNT is
1/(success rate difference); this formula was used to compute the point estimates and the 95% CIs. Lower NNT
values are favorable. The 95% CIs of the SRD were calculated using the prop.test function in the R software
package.14
Second, the AUC,3 which estimates the probability of
a participant in the drug group having a better outcome
than a participant in the placebo group if one were to randomly sample participants from each group, was computed. This index is referred to as AUC-positive, and it is
computed as 0.5 (success rate difference + 1). This formula
was used to compute the point estimates and 95% CIs
based on the SRD values described above. An AUC value
of 0.50 indicates no group difference; higher AUC values
are favorable.
Global Function was assessed using the Clinician
Interview-Based Impression of ChangePlus (CIBIC-Plus),
which is based on the Alzheimers Disease Cooperative
StudyClinical Global Impression of Change scale.15
Without access to laboratory or psychometric testing
results, the clinician forms an impression of change that is
based on separate interviews with the individual and the
caregiver. The interview covers the domains of general,
cognitive, behavior, and activities of daily living and uses
a 7-point Likert scale (1, marked improvement; 4, no
change; 7, marked worsening). Responders were individuals who showed improvement on the CIBIC-Plus (scores of
13) over the trial. As with the cognition domain, point
estimates and 95% CIs were computed for the SRD, then
these values were used to compute the NNT and AUCpositive for each trial.
Harm was assessed by comparing the number of participants who dropped out of each RCT because of an
adverse event from each group. It was felt that this was a
more-conservative measure of harm than if the total number of dropouts in each group had simply been used,
because there are various reasons why participants drop
out of a study. The same effect size indices computed for
the cognition and global function domains were also
computed here, but they were called the harm rate
difference (HRD), number needed to harm (NNH), and
AUC-negative to reflect their negative nature.

Individual Domains of Function

Multidimensional Analysis

Cognition was assessed using the cognition subscale of

the Alzheimers Disease Assessment Scale (ADAS-Cog).
This scale ranges from 0 to 70, with higher scores indicating greater impairment.12 For each study, the number
of responders on the ADAS-Cog (those who improved by
 4 points) in each group was obtained from the individual studies, because this is a commonly used criterion in
the field. The success rate difference (SRD; also known as
the absolute difference) was then computed along with

To illustrate the utility of comparing effect size indices

across domains of function, two harm:benefit ratio scores
were computed: the harm:cognition score and the harm:global function score. For each of these ratio scores, the NNH
value was divided by the respective NNT for each trial.
Ratios of 1.0 indicate no difference (harm = benefit), ratios
greater than 1.0 indicate more benefit than harm, and ratios
less than 1.0 indicate more harm than benefit. This
approach was based on a method previously developed16

randomized control trials of pharmacological interventions

for dementia, the clinical meaningfulness of results was discussed in fewer than half of these trials (46%).4 When clinical meaningfulness was mentioned, the majority of authors
used opinion-based assessments. Measures of effect size
were not reported in any of the 57 studies.
At the aggregate level, the most commonly reported
effect size indices in meta-analyses are the standardized
mean difference (e.g., Cohens) for continuous measures
and the odds ratio for binary measures. It has been argued
that other effect size indices provide better estimates of
clinical meaningfulness,3 including number needed to treat
(NNT), area under the curve (AUC), and success rate difference (SRD). In the area of dementia research at least,
few individual trials or meta-analyses compute these indices, although some have.5,6 In addition, effect size indices
are typically reported in a unidimensional sense; they are
considered individually for each scale or outcome, and
authors rarely compare and contrast these indices across
different outcome domains.
The purpose of this study is to highlight the utility
of an effect size analysis for communicating the effectiveness of treatment interventions. To achieve this goal, this
study examines a subset of randomized clinical trials that
were included in a published Cochrane systematic review
on the effectiveness of cholinesterase inhibitors (ChEIs)
for Alzheimers disease (AD).7 In addition to computing
effect size indices for individual domains of function
(cognition, global function, and harm), harm:benefit
ratios were also systematically generated and compared
across these domains of function. The goal of this
secondary analysis is not to comment directly on the
effectiveness of the ChEIs for AD but rather to showcase
how such an approach can be beneficial for communicating the clinical meaningfulness of treatment interventions
in the future. The intended audience is not only authors
of clinical trial reports, but also journal editors, healthcare policy-makers, and the more general audience of
readers.

METHODS

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for interpreting the clinical meaningfulness of results of

weight loss intervention trials.

RESULTS
Individual Domains of Function
The effect size indices for the four RCTs are reported in
Table 1. For the cognition domain, SRD values ranged
from 0.07 to 0.27, NNT values ranged from 14 to 4, and
AUC-positive values ranged from 0.54 to 0.64. The 95%
CI for the SRD in the RIV-B303 trial crossed 0 ( 0.01 to
0.15), indicating a statistically nonsignificant benefit of the
drug for cognition. The corresponding NNT for this effect
is 14, and the 95% CI ( 100 to 7) does not contain this
point estimate. This is a known limitation of the NNT for
effects that are not statistically significant, which complicates its interpretation.17,18 In addition, the AUC-positive
value for the RIV-B303 trial was 0.54, and the 95% CI
included 0.50, which is the value of this statistic when
there is no difference between the two groups. Accordingly, in this case, a SRD of 0.07, a NNT of 14, and an
AUC-positive value of 0.54 are all associated with statistically nonsignificant differences between the two groups.
The SRD values in the global function domain ranged
from 0.01 to 0.17 and were generally lower than those
reported for the cognition domain (the drugs benefitted
cognition more than global function). The CIs for the two
galantamine trials crossed 0, indicating no statistically

JAGS

significant benefit of the drug over placebo. The NNT

values ranged from 100 to 6, and the AUC-positive values
ranged from 0.51 to 0.59.
For the harm domain, the HRD values ranged from
0.05 to 0.16. The HRD CI crossed 0 in the GAL-INTWilcock trial, indicating that the two groups did not differ
significantly with respect to the number of withdrawals
due to an adverse event, but the number of such withdrawals was significantly greater in the drug group than in
the placebo group for the other three trials. The NNH
ranged from 20 to 6, and the AUC-negative values ranged
from 0.53 to 0.58.

Multidimensional Analysis
Figure 1 shows the harm:cognition and the harm:global
function ratio scores for each of the four trials. The best
pair of outcomes is observed for the DON-302 trial, both
of the ratios are greater than 1.0. The ratio of 2.5 for
harm:cognition indicates that the NNH (10) is 2.5 times
as great as the NNT (4), and in this trial, the drug benefitted cognition more than global function. The results for
the GAL-INT-Wilcock trial are inconsistent: Although
there is a positive outcome for cognition (the NNH is 2.86
times as great as the NNT), there is more harm than benefit for global function (the NNT is 5 times as great as the
NNH). The other two studies, GAL-USA-Raskind and
RIV-B303, show no net benefit at all or some degree of
harm.

Table 1. Responder Data and Effect Size Indices

Study
Domain or Index

Cognition
Drug responders, n/N
Placebo responders, n/N
SRD (95% CI)
NNT (95% CI)
AUC-positive (95% CI)
Global Function
Drug responders, n/N
Placebo responders, n/N
SRD (95% CI)
NNT (95% CI)
AUC-positive (95% CI)
Harm
Drug withdrawals due to
adverse events, n/N
Placebo withdrawals due
to adverse events, n/N
Harm rate difference (95% CI)
NNH (95% CI)
AUC-negative (95% CI)

DON-302

80/150
41/153
0.27 (0.15 to 0.38)
4 (7 to 3)
0.64 (0.58 to 0.69)
37/149
17/152
0.14 (0.04 to 0.23)
7 (25 to 4)
0.57 (0.52 to 0.62)

GAL-INT-Wilcock

64/220
32/215
0.14 (0.06 to 0.22)
7 (17 to 5)
0.57 (0.53 to 0.61)
36/206
33/203
0.01 ( 0.07 to 0.09)a
100 ( 14 to 11)b
0.51 (0.47 to 0.55)

GAL-USA-Raskind

RIV-B303

67/202
34/207
0.17 (0.08 to 0.26)
6 (13 to 4)
0.59 (0.54 to 0.63)

57/242
39/238
0.07 ( 0.01 to 0.15)a
14 ( 100 to 7)b
0.54 (0.50 to 0.58)

37/186
27/196
0.06 ( 0.02 to 0.14)a
17 ( 50 to 7)b
0.53 (0.49 to 0.57)

80/219
46/230
0.17 (0.08 to 0.25)
6 (13 to 4)
0.59 (0.54 to 0.63)

26/157

31/220

49/212

55/242

11/162

19/215

16/213

16/239

0.10 (0.02 to 0.17)

10 (50 to 6)
0.55 (0.51 to 0.59)

0.05 ( 0.01 to 0.12)a

20 ( 100 to 8)b
0.53 (0.50 to 0.56)

0.16 (0.08 to 0.23)

6 (13 to 4)
0.58 (0.54 to 0.62)

0.16 (0.10 to 0.23)

6 (10 to 4)
0.58 (0.55 to 0.62)

SRD, success rate difference; AUC, area under the curve.

a
95% confidence intervals (CIs) that cross 0 indicate that the group difference is not statistically significant.
b
Negative number needed to treat (NNT) indicate that participants in the placebo group are doing better than those in the drug group, and number
needed to harm (NNH) indicate that participants in the placebo group are doing worse. For example, a NNT of 100 indicates that 100 participants
would need to be treated with placebo to obtain one additional successful outcome than would have been obtained they had been treated with the
drug. The CI here does not actually contain the point estimate because the effect is not statistically significant; this is a well-known limitation of NNT
and NNH.

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Figure 1. Cognition and global function harm:benefit ratios for each study. Ratios equal to 1.00 indicate no difference between
the amount of harm and benefit. Values greater than 1.00 indicate more benefit than harm; values less than 1.00 indicate more
harm than benefit. The x-axis is a logarithmic scale to reflect equal spacing of values above and below 1.00. NNH, number
needed to harm; NNT, number needed to treat.

DISCUSSION
This investigation highlights two important points. First,
effect size indices help to interpret the clinical meaningfulness of RCT results. For example, consider the AUC-positive values reported here; the highest was 0.64. Although in
this trial, the number of responders on the ADAS-Cog in
the drug group was significantly greater than in the placebo
group (SRD = 0.27, 95% CI = 0.150.38), this AUC is not
large considering that a value of 0.50 indicates an equal
probability of success if one were to sample a participant
from each group. The information from the effect size indices provide a meaningful context for interpreting trial
results and therefore complement the traditional approach
of relying on measures of statistical significance alone.
Second, there is value in comparing effect size indices
across outcome domains. Harm:benefit ratios were computed for the cognition and global function domains. This
analysis revealed that only one of the four RCTs showed
consistent evidence of more benefit than harm in these two
domains. In addition, the GAL-USA-Raskind and the RIVB303 studies nicely illustrate the limitations of looking at
one index in isolation. The NNT values in these two studies
ranged from 6 to 17, which would be considered very good
considering that the azidothymidine drug trial for AIDS
was halted early with a NNT of 919 and the Physicians
Health Study examining the benefit of aspirin was also
halted early with a NNT of 130.20 However, in the GALUSA-Raskind and the RIV-B303 studies, the interpretation
of these NNT values changes considerably when one takes
into account the fact that the NNH in these two trials is 6,
and the harm:benefit ratios illustrate this point. This
approach of directly comparing the harm and benefit of a
treatment intervention is more consistent with what physicians do when treating patients; they compare the potential
harm and potential benefit of a medication to inform their
therapeutic decision-making. Rarely do physicians ponder
the probability of whether the results of a given trial were

simply due to sampling error (the information provided by

a P-value), and rarely do they consider the harms and benefits of a medication in isolation from one another.
Placing the current approach into a larger context, the
CONSORT guidelines21 for the reporting of statistics in
parallel-group randomized trials recommends reporting the
absolute and relative effect sizes for binary outcomes (Item
17b), and they state that reporting the NNT and NNH
can be helpful (Items 17a and 21). These guidelines serve
well their intended goal as being minimal requirements for
reporting of clinical trials, but the NNT, the NNH, the
AUC estimates, and the harm:benefit ratios presented here
should be reported. These effect sizes and ratios are useful
in conveying the clinical meaningfulness of trial results and
will appeal to a much wider audience.
There are several notable limitations with this secondary analysis. First, effect size indices were computed based
on binary outcomes only (e.g., improved or not, withdrew
from RCT due to an adverse event or not). Although the
effect size indices reported here have been shown to demonstrate clinical meaningfulness,3 future research should
consider expanding such an approach to include effect size
indices based on continuous outcome measures.
A second limitation is that in computing harm:benefit
ratios, the severity of the measures of harm and benefit
were implicitly equated, but it is difficult to say whether
one can consider the act of withdrawing from an RCT due
to an adverse event as being of the same magnitude as
showing an improvement of 4 or more points on the
ADAS-Cog. Part of the problem is that this field lacks
what has been referred to as a language of benefit for
AD treatments.22 Is it fair to state that a 4-point improvement on the ADAS-Cog is a clinically meaningful benefit?
To make this approach more successful, agreement on
what constitutes benefit and what constitutes harm is
needed. Such clarification would make it easier for clinicians to take into account their patients preferences in a
shared, or informed, decision-making model.23,24 For

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example, some people may place more importance on any

degree of improvement regardless of the adverse events
typically associated with ChEIs; in contrast, other people
may feel that the degree of benefit typically achieved by
taking these drugs does not outweigh the risks for adverse
events. The approach illustrated here is useful for communicating benefits and harms to individuals, policy-makers,
and the lay public, but there should also be more discussion of how to define these terms better.
Although the task of developing more clinically meaningful measures of benefit and harm will be challenging, it
would allow a much more-nuanced effect size analysis
approach to be adopted. For example, an approach has
been outlined in which individuals baseline risks (the risks
associated with not being treated as well as risks due to
adverse events) and preferences regarding their assessment
of the benefits and harms factor in the calculation of a
NNT:NNH ratio.25 This metric is called the likelihood of
being helped or harmed. It is not feasible to apply this
analysis here, because it would be difficult to ask people to
comment on how important a 4-point improvement on the
ADS-Cog would be to them as opposed to how important
it would be to avoid adverse events associated with ChEIs.
Thus, the simpler approach adopted here is a useful first
step in developing more-useful methods for communicating
the benefit and harm of treatments.
Finally, more work is needed to determine how large
these harm:benefit ratios need to be to signify clinical
meaningfulness. In other words, how much larger does the
NNH need to be than the NNT: 2, 3, or 4 times greater?
Again, these decisions will be dependent upon definitions
of benefit and harm and the preferences of individuals. For
example, the NNH will need to be considerably higher
than the NNT if the definition of harm is a serious event
(e.g., stroke) than if it is a less-serious event (e.g., nausea).
The cost and ease of use of treatments will also factor into
these equations. As indicated previously,3 although the
NNT to prevent one additional heart attack in the aspirin
group of the Physicians Health Study was 130, this treatment is cheap and easy to administer.
In the future, researchers conducting clinical trials
ought to have a clear understanding a priori of what will
constitute clinically meaningful benefit and harm rather
than relying simply on the statistical significance of the
results obtained. The goals of this secondary analysis were
to offer a useful approach to communicating the effectiveness of treatment interventions and to initiate a larger
discourse around these issues. Consensus among clinicians
and researchers on these issues will be crucial to identifying
safe and effective treatment interventions for dementia.

ACKNOWLEDGMENTS
A poster based on this work was presented at the 2012 Alzheimer Association International Conference held in Vancouver, British Columbia, Canada. The author gratefully
acknowledges the assistance of Ms. Jaclyn Orsetto for her
help in preparing the manuscript, and Dr. Peter Whitehouse for helpful comments on an earlier draft of this manuscript.
Conflict of Interest: This study was supported by an
operating grant from the Canadian Institutes of Health

JULY 2013VOL. 61, NO. 7

JAGS

Research. The author has no financial conflicts to disclose.

Author Contributions: KRP designed the study, conducted all analyses, and wrote the manuscript.
Sponsors Role: None.

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