Meta-analysis of continuous outcome data
Calculation of fixed and random effects estimates for meta-analyses with continuous outcome data; inverse variance weighting is used for pooling.
metacont( n.e, mean.e, sd.e, n.c, mean.c, sd.c, studlab, data = NULL, subset = NULL, exclude = NULL, id = NULL, median.e, q1.e, q3.e, min.e, max.e, median.c, q1.c, q3.c, min.c, max.c, method.mean = "Luo", method.sd = "Shi", approx.mean.e, approx.mean.c = approx.mean.e, approx.sd.e, approx.sd.c = approx.sd.e, sm = gs("smcont"), pooledvar = gs("pooledvar"), method.smd = gs("method.smd"), sd.glass = gs("sd.glass"), exact.smd = gs("exact.smd"), method.ci = gs("method.ci.cont"), level = gs("level"), level.comb = gs("level.comb"), comb.fixed = gs("comb.fixed"), comb.random = gs("comb.random"), overall = comb.fixed | comb.random, overall.hetstat = comb.fixed | comb.random, hakn = gs("hakn"), adhoc.hakn = gs("adhoc.hakn"), method.tau = gs("method.tau"), method.tau.ci = gs("method.tau.ci"), tau.preset = NULL, TE.tau = NULL, tau.common = gs("tau.common"), prediction = gs("prediction"), level.predict = gs("level.predict"), method.bias = gs("method.bias"), backtransf = gs("backtransf"), text.fixed = gs("text.fixed"), text.random = gs("text.random"), text.predict = gs("text.predict"), text.w.fixed = gs("text.w.fixed"), text.w.random = gs("text.w.random"), title = gs("title"), complab = gs("complab"), outclab = "", label.e = gs("label.e"), label.c = gs("label.c"), label.left = gs("label.left"), label.right = gs("label.right"), byvar, bylab, print.byvar = gs("print.byvar"), byseparator = gs("byseparator"), keepdata = gs("keepdata"), warn = gs("warn"), control = NULL )
n.e |
Number of observations in experimental group. |
mean.e |
Estimated mean in experimental group. |
sd.e |
Standard deviation in experimental group. |
n.c |
Number of observations in control group. |
mean.c |
Estimated mean in control group. |
sd.c |
Standard deviation in control group. |
studlab |
An optional vector with study labels. |
data |
An optional data frame containing the study information. |
subset |
An optional vector specifying a subset of studies to be used. |
exclude |
An optional vector specifying studies to exclude from meta-analysis, however, to include in printouts and forest plots. |
id |
An optional vector specifying which estimates come from the same study resulting in the use of a three-level meta-analysis model. |
median.e |
Median in experimental group (used to estimate the mean and standard deviation). |
q1.e |
First quartile in experimental group (used to estimate the mean and standard deviation). |
q3.e |
Third quartile in experimental group (used to estimate the mean and standard deviation). |
min.e |
Minimum in experimental group (used to estimate the mean and standard deviation). |
max.e |
Maximum in experimental group (used to estimate the mean and standard deviation). |
median.c |
Median in control group (used to estimate the mean and standard deviation). |
q1.c |
First quartile in control group (used to estimate the mean and standard deviation). |
q3.c |
Third quartile in control group (used to estimate the mean and standard deviation). |
min.c |
Minimum in control group (used to estimate the mean and standard deviation). |
max.c |
Maximum in control group (used to estimate the mean and standard deviation). |
method.mean |
A character string indicating which method to use to approximate the mean from the median and other statistics (see Details). |
method.sd |
A character string indicating which method to use to approximate the standard deviation from sample size, median, interquartile range and range (see Details). |
approx.mean.e |
Approximation method to estimate means in experimental group (see Details). |
approx.mean.c |
Approximation method to estimate means in control group (see Details). |
approx.sd.e |
Approximation method to estimate standard deviations in experimental group (see Details). |
approx.sd.c |
Approximation method to estimate standard deviations in control group (see Details). |
sm |
A character string indicating which summary measure
( |
pooledvar |
A logical indicating if a pooled variance should
be used for the mean difference ( |
method.smd |
A character string indicating which method is
used to estimate the standardised mean difference
( |
sd.glass |
A character string indicating which standard
deviation is used in the denominator for Glass' method to
estimate the standardised mean difference. Either
|
exact.smd |
A logical indicating whether exact formulae should be used in estimation of the standardised mean difference and its standard error (see Details). |
method.ci |
A character string indicating which method is used to calculate confidence intervals for individual studies, see Details. |
level |
The level used to calculate confidence intervals for individual studies. |
level.comb |
The level used to calculate confidence intervals for pooled estimates. |
comb.fixed |
A logical indicating whether a fixed effect meta-analysis should be conducted. |
comb.random |
A logical indicating whether a random effects meta-analysis should be conducted. |
overall |
A logical indicating whether overall summaries should be reported. This argument is useful in a meta-analysis with subgroups if overall results should not be reported. |
overall.hetstat |
A logical value indicating whether to print heterogeneity measures for overall treatment comparisons. This argument is useful in a meta-analysis with subgroups if heterogeneity statistics should only be printed on subgroup level. |
hakn |
A logical indicating whether the method by Hartung and Knapp should be used to adjust test statistics and confidence intervals. |
adhoc.hakn |
A character string indicating whether an ad hoc variance correction should be applied in the case of an arbitrarily small Hartung-Knapp variance estimate, see Details. |
method.tau |
A character string indicating which method is
used to estimate the between-study variance τ^2 and its
square root τ. Either |
method.tau.ci |
A character string indicating which method is
used to estimate the confidence interval of τ^2 and
τ. Either |
tau.preset |
Prespecified value for the square root of the between-study variance τ^2. |
TE.tau |
Overall treatment effect used to estimate the between-study variance tau-squared. |
tau.common |
A logical indicating whether tau-squared should be the same across subgroups. |
prediction |
A logical indicating whether a prediction interval should be printed. |
level.predict |
The level used to calculate prediction interval for a new study. |
method.bias |
A character string indicating which test is to
be used. Either |
backtransf |
A logical indicating whether results for ratio of
means ( |
text.fixed |
A character string used in printouts and forest plot to label the pooled fixed effect estimate. |
text.random |
A character string used in printouts and forest plot to label the pooled random effects estimate. |
text.predict |
A character string used in printouts and forest plot to label the prediction interval. |
text.w.fixed |
A character string used to label weights of fixed effect model. |
text.w.random |
A character string used to label weights of random effects model. |
title |
Title of meta-analysis / systematic review. |
complab |
Comparison label. |
outclab |
Outcome label. |
label.e |
Label for experimental group. |
label.c |
Label for control group. |
label.left |
Graph label on left side of forest plot. |
label.right |
Graph label on right side of forest plot. |
byvar |
An optional vector containing grouping information
(must be of same length as |
bylab |
A character string with a label for the grouping variable. |
print.byvar |
A logical indicating whether the name of the grouping variable should be printed in front of the group labels. |
byseparator |
A character string defining the separator between label and levels of grouping variable. |
keepdata |
A logical indicating whether original data (set) should be kept in meta object. |
warn |
A logical indicating whether warnings should be printed (e.g., if studies are excluded from meta-analysis due to zero standard deviations). |
control |
An optional list to control the iterative process to
estimate the between-study variance τ^2. This argument
is passed on to |
Calculation of fixed and random effects estimates for meta-analyses with continuous outcome data; inverse variance weighting is used for pooling.
Three different types of summary measures are available for continuous outcomes:
mean difference (argument sm = "MD"
)
standardised mean difference (sm = "SMD"
)
ratio of means (sm = "ROM"
)
Default settings are utilised for several arguments (assignments
using gs
function). These defaults can be changed for
the current R session using the settings.meta
function.
Furthermore, R function update.meta
can be used to
rerun a meta-analysis with different settings.
For the standardised mean difference three methods are implemented:
Hedges' g (default, method.smd = "Hedges"
) - see
Hedges (1981)
Cohen's d (method.smd = "Cohen"
) - see Cohen (1988)
Glass' delta (method.smd = "Glass"
) - see Glass (1976)
Hedges (1981) calculated the exact bias in Cohen's d which is a
ratio of gamma distributions with the degrees of freedom,
i.e. total sample size minus two, as argument. By default (argument
exact.smd = FALSE
), an accurate approximation of this bias
provided in Hedges (1981) is utilised for Hedges' g as well as its
standard error; these approximations are also used in RevMan
5. Following Borenstein et al. (2009) these approximations are not
used in the estimation of Cohen's d. White and Thomas (2005) argued
that approximations are unnecessary with modern software and
accordingly promote to use the exact formulae; this is possible
using argument exact.smd = TRUE
. For Hedges' g the exact
formulae are used to calculate the standardised mean difference as
well as the standard error; for Cohen's d the exact formula is only
used to calculate the standard error. In typical applications (with
sample sizes above 10), the differences between using the exact
formulae and the approximation will be minimal.
For Glass' delta, by default (argument sd.glass =
"control"
), the standard deviation in the control group
(sd.c
) is used in the denominator of the standard mean
difference. The standard deviation in the experimental group
(sd.e
) can be used by specifying sd.glass =
"experimental"
.
Meta-analysis of ratio of means – also called response ratios –
is described in Hedges et al. (1999) and Friedrich et al. (2008).
Calculations are conducted on the log scale and list elements
TE
, TE.fixed
, and TE.random
contain the
logarithm of the ratio of means. In printouts and plots these
values are back transformed if argument backtransf = TRUE
.
Missing means in the experimental group (analogously for the control group) can be derived from
sample size, median, interquartile range and range (arguments
n.e
, median.e
, q1.e
, q3.e
,
min.e
, and max.e
),
sample size, median and interquartile range (arguments
n.e
, median.e
, q1.e
, and q3.e
), or
sample size, median and range (arguments n.e
,
median.e
, min.e
, and max.e
).
By default, methods described in Luo et al. (2018) are utilized
(argument method.mean = "Luo"
):
equation (15) if sample size, median, interquartile range and range are available,
equation (11) if sample size, median and interquartile range are available,
equation (7) if sample size, median and range are available.
Instead the methods described in Wan et al. (2014) are used if
argument method.mean = "Wan"
):
equation (10) if sample size, median, interquartile range and range are available,
equation (14) if sample size, median and interquartile range are available,
equation (2) if sample size, median and range are available.
By default, missing means are replaced successively using
interquartile ranges and ranges (if available), interquartile
ranges (if available) and finally ranges. Arguments
approx.mean.e
and approx.mean.c
can be used to
overwrite this behaviour for each individual study and treatment
arm:
use means directly (entry ""
in argument
approx.mean.e
or approx.mean.c
);
median, interquartile range and range ("iqr.range"
);
median and interquartile range ("iqr"
);
median and range ("range"
).
Missing standard deviations in the experimental group (analogously for the control group) can be derived from
sample size, median, interquartile range and range (arguments
n.e
, median.e
, q1.e
, q3.e
,
min.e
, and max.e
),
sample size, median and interquartile range (arguments
n.e
, median.e
, q1.e
and q3.e
), or
sample size, median and range (arguments n.e
,
median.e
, min.e
and max.e
).
Wan et al. (2014) describe methods to estimate the standard
deviation from the sample size, median and additional
statistics. Shi et al. (2020) provide an improved estimate of the
standard deviation if the interquartile range and range are
available in addition to the sample size and median. Accordingly,
equation (11) in Shi et al. (2020) is the default (argument
method.sd = "Shi"
), if the median, interquartile range and
range are provided. The method by Wan et al. (2014) is used if
argument method.sd = "Wan"
and, depending on the sample
size, either equation (12) or (13) is used. If only the
interquartile range or range is available, equations (15) / (16)
and (7) / (9) in Wan et al. (2014) are used, respectively.
By default, missing standard deviations are replaced successively
using these method, i.e., interquartile ranges and ranges are used
before interquartile ranges before ranges. Arguments
approx.sd.e
and approx.sd.c
can be used to overwrite
this default for each individual study and treatment arms:
sample size, median, interquartile range and range
("iqr.range"
);
sample size, median and interquartile range ("iqr"
);
sample size, median and range ("range"
).
For the mean difference (argument sm = "MD"
), the confidence
interval for individual studies can be based on the
standard normal distribution (method.ci = "z"
, default), or
t-distribution (method.ci = "t"
).
Note, this choice does not affect the results of the fixed effect and random effects meta-analysis.
The following methods to estimate the between-study variance τ^2 are available:
DerSimonian-Laird estimator (method.tau = "DL"
)
Paule-Mandel estimator (method.tau = "PM"
)
Restricted maximum-likelihood estimator (method.tau =
"REML"
)
Maximum-likelihood estimator (method.tau = "ML"
)
Hunter-Schmidt estimator (method.tau = "HS"
)
Sidik-Jonkman estimator (method.tau = "SJ"
)
Hedges estimator (method.tau = "HE"
)
Empirical Bayes estimator (method.tau = "EB"
)
See metagen
for more information on these
estimators.
The following methods to calculate a confidence interval for τ^2 and τ are available.
Argument | Method |
method.tau.ci = "J"
|
Method by Jackson (2013) |
method.tau.ci = "BJ"
|
Method by Biggerstaff and Jackson (2008) |
method.tau.ci = "QP"
|
Q-Profile method (Viechtbauer, 2007) |
method.tau.ci = "PL"
|
Profile-Likelihood method for three-level meta-analysis model |
(Van den Noortgate et al., 2013) |
See metagen
for more information on these methods. No
confidence intervals for τ^2 and τ are calculated
if method.tau.ci = ""
.
Hartung and Knapp (2001) proposed an alternative method for random effects meta-analysis based on a refined variance estimator for the treatment estimate. Simulation studies (Hartung and Knapp, 2001; IntHout et al., 2014; Langan et al., 2019) show improved coverage probabilities compared to the classic random effects method.
In rare settings with very homogeneous treatment estimates, the Hartung-Knapp variance estimate can be arbitrarily small resulting in a very narrow confidence interval (Knapp and Hartung, 2003; Wiksten et al., 2016). In such cases, an ad hoc variance correction has been proposed by utilising the variance estimate from the classic random effects model with the HK method (Knapp and Hartung, 2003; IQWiQ, 2020). An alternative approach is to use the wider confidence interval of classic fixed or random effects meta-analysis and the HK method (Wiksten et al., 2016; Jackson et al., 2017).
Argument adhoc.hakn
can be used to choose the ad hoc
method:
Argument | Ad hoc method |
adhoc.hakn = ""
|
not used |
adhoc.hakn = "se"
|
use variance correction if HK standard error is smaller |
than standard error from classic random effects | |
meta-analysis (Knapp and Hartung, 2003) | |
adhoc.hakn = "iqwig6"
|
use variance correction if HK confidence interval |
is narrower than CI from classic random effects model | |
with DerSimonian-Laird estimator (IQWiG, 2020) | |
adhoc.hakn = "ci"
|
use wider confidence interval of classic random effects |
and HK meta-analysis | |
(Hybrid method 2 in Jackson et al., 2017) |
A prediction interval for the proportion in a new study (Higgins et
al., 2009) is calculated if arguments prediction
and
comb.random
are TRUE
. Note, the definition of
prediction intervals varies in the literature. This function
implements equation (12) of Higgins et al., (2009) which proposed a
t distribution with K-2 degrees of freedom where
K corresponds to the number of studies in the meta-analysis.
Argument byvar
can be used to conduct subgroup analysis for
a categorical covariate. The metareg
function can be
used instead for more than one categorical covariate or continuous
covariates.
Arguments subset
and exclude
can be used to exclude
studies from the meta-analysis. Studies are removed completely from
the meta-analysis using argument subset
, while excluded
studies are shown in printouts and forest plots using argument
exclude
(see Examples in metagen
).
Meta-analysis results are the same for both arguments.
Internally, both fixed effect and random effects models are
calculated regardless of values choosen for arguments
comb.fixed
and comb.random
. Accordingly, the estimate
for the random effects model can be extracted from component
TE.random
of an object of class "meta"
even if
argument comb.random = FALSE
. However, all functions in R
package meta will adequately consider the values for
comb.fixed
and comb.random
. E.g. function
print.meta
will not print results for the random
effects model if comb.random = FALSE
.
An object of class c("metacont", "meta")
with corresponding
print
, summary
, and forest
functions. The
object is a list containing the following components:
n.e, mean.e, sd.e, |
As defined above. |
n.c, mean.c, sd.c, |
As defined above. |
studlab, exclude, sm, method.ci, |
As defined above. |
median.e, q1.e, q3.e, min.e, max.e, |
As defined above. |
median.c, q1.c, q3.c, min.c, max.c, |
As defined above. |
method.mean, method.sd, |
As defined above. |
approx.mean.e, approx.sd.e, approx.mean.c, approx.sd.c, |
As defined above. |
level, level.comb, |
As defined above. |
comb.fixed, comb.random, |
As defined above. |
overall, overall.hetstat, |
As defined above. |
pooledvar, method.smd, sd.glass, |
As defined above. |
hakn, adhoc.hakn, method.tau, method.tau.ci, |
As defined above. |
tau.preset, TE.tau, method.bias, |
As defined above. |
tau.common, title, complab, outclab, |
As defined above. |
label.e, label.c, label.left, label.right, |
As defined above. |
byvar, bylab, print.byvar, byseparator |
As defined above. |
TE, seTE |
Estimated treatment effect and standard error of individual studies. |
lower, upper |
Lower and upper confidence interval limits for individual studies. |
statistic, pval |
Statistic and p-value for test of treatment effect for individual studies. |
w.fixed, w.random |
Weight of individual studies (in fixed and random effects model). |
TE.fixed, seTE.fixed |
Estimated overall treatment effect and standard error (fixed effect model). |
lower.fixed, upper.fixed |
Lower and upper confidence interval limits (fixed effect model). |
statistic.fixed, pval.fixed |
Statistic and p-value for test of overall treatment effect (fixed effect model). |
TE.random, seTE.random |
Estimated overall treatment effect and standard error (random effects model). |
lower.random, upper.random |
Lower and upper confidence interval limits (random effects model). |
statistic.random, pval.random |
Statistic and p-value for test of overall treatment effect (random effects model). |
prediction, level.predict |
As defined above. |
seTE.predict |
Standard error utilised for prediction interval. |
lower.predict, upper.predict |
Lower and upper limits of prediction interval. |
k |
Number of studies combined in meta-analysis. |
Q |
Heterogeneity statistic Q. |
df.Q |
Degrees of freedom for heterogeneity statistic. |
pval.Q |
P-value of heterogeneity test. |
tau2 |
Between-study variance τ^2. |
se.tau2 |
Standard error of τ^2. |
lower.tau2, upper.tau2 |
Lower and upper limit of confidence interval for τ^2. |
tau |
Square-root of between-study variance τ. |
lower.tau, upper.tau |
Lower and upper limit of confidence interval for τ. |
H |
Heterogeneity statistic H. |
lower.H, upper.H |
Lower and upper confidence limit for heterogeneity statistic H. |
I2 |
Heterogeneity statistic I^2. |
lower.I2, upper.I2 |
Lower and upper confidence limit for heterogeneity statistic I^2. |
Rb |
Heterogeneity statistic R_b. |
lower.Rb, upper.Rb |
Lower and upper confidence limit for heterogeneity statistic R_b. |
df.hakn |
Degrees of freedom for test of treatment effect for
Hartung-Knapp method (only if |
method |
Pooling method: |
bylevs |
Levels of grouping variable - if |
TE.fixed.w, seTE.fixed.w |
Estimated treatment effect and
standard error in subgroups (fixed effect model) - if
|
lower.fixed.w, upper.fixed.w |
Lower and upper confidence
interval limits in subgroups (fixed effect model) - if
|
statistic.fixed.w, pval.fixed.w |
Statistics and p-values for
test of treatment effect in subgroups (fixed effect model) - if
|
TE.random.w, seTE.random.w |
Estimated treatment effect and
standard error in subgroups (random effects model) - if
|
lower.random.w, upper.random.w |
Lower and upper confidence
interval limits in subgroups (random effects model) - if
|
statistic.random.w, pval.random.w |
Statistics and p-values
for test of treatment effect in subgroups (random effects model)
- if |
w.fixed.w, w.random.w |
Weight of subgroups (in fixed and
random effects model) - if |
df.hakn.w |
Degrees of freedom for test of treatment effect
for Hartung-Knapp method in subgroups - if |
n.e.w |
Number of observations in experimental group in
subgroups - if |
n.c.w |
Number of observations in control group in subgroups -
if |
k.w |
Number of studies combined within subgroups - if
|
k.all.w |
Number of all studies in subgroups - if |
Q.w.fixed |
Overall within subgroups heterogeneity statistic Q
(based on fixed effect model) - if |
Q.w.random |
Overall within subgroups heterogeneity statistic
Q (based on random effects model) - if |
df.Q.w |
Degrees of freedom for test of overall within
subgroups heterogeneity - if |
pval.Q.w.fixed |
P-value of within subgroups heterogeneity
statistic Q (based on fixed effect model) - if |
pval.Q.w.random |
P-value of within subgroups heterogeneity
statistic Q (based on random effects model) - if |
Q.b.fixed |
Overall between subgroups heterogeneity statistic
Q (based on fixed effect model) - if |
Q.b.random |
Overall between subgroups heterogeneity statistic
Q (based on random effects model) - if |
df.Q.b |
Degrees of freedom for test of overall between
subgroups heterogeneity - if |
pval.Q.b.fixed |
P-value of between subgroups heterogeneity
statistic Q (based on fixed effect model) - if |
pval.Q.b.random |
P-value of between subgroups heterogeneity
statistic Q (based on random effects model) - if |
tau.w |
Square-root of between-study variance within subgroups
- if |
H.w |
Heterogeneity statistic H within subgroups - if
|
lower.H.w, upper.H.w |
Lower and upper confidence limit for
heterogeneity statistic H within subgroups - if |
I2.w |
Heterogeneity statistic I^2 within subgroups - if
|
lower.I2.w, upper.I2.w |
Lower and upper confidence limit for
heterogeneity statistic I^2 within subgroups - if |
keepdata |
As defined above. |
data |
Original data (set) used in function call (if
|
subset |
Information on subset of original data used in
meta-analysis (if |
call |
Function call. |
version |
Version of R package meta used to create object. |
The function metagen
is called internally to
calculate individual and overall treatment estimates and standard
errors.
Guido Schwarzer sc@imbi.uni-freiburg.de
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data(Fleiss1993cont) # Meta-analysis with Hedges' g as effect measure # m1 <- metacont(n.psyc, mean.psyc, sd.psyc, n.cont, mean.cont, sd.cont, data = Fleiss1993cont, sm = "SMD") m1 forest(m1) # Use Cohen's d instead of Hedges' g as effect measure # update(m1, method.smd = "Cohen") # Use Glass' delta instead of Hedges' g as effect measure # update(m1, method.smd = "Glass") # Use Glass' delta based on the standard deviation in the experimental group # update(m1, method.smd = "Glass", sd.glass = "experimental") # Calculate Hedges' g based on exact formulae # update(m1, exact.smd = TRUE) data(amlodipine) m2 <- metacont(n.amlo, mean.amlo, sqrt(var.amlo), n.plac, mean.plac, sqrt(var.plac), data = amlodipine, studlab = study) summary(m2) # Use pooled variance # summary(update(m2, pooledvar = TRUE)) # Meta-analysis of response ratios (Hedges et al., 1999) # data(woodyplants) m3 <- metacont(n.elev, mean.elev, sd.elev, n.amb, mean.amb, sd.amb, data = woodyplants, sm = "ROM") summary(m3) summary(m3, backtransf = FALSE)
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