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Tutorial On Meta-Analysis In R
R useR! Conference 2013
Stephanie Kovalchik
Research Fellow, National Cancer Institute
· Evaluating Heterogeneity
· Meta-Regression
· Publication Bias
· Comparing R Packages For Standard Meta-Analysis
· Some Advanced Topics
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O v e r v i ew
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W h at I s M e t a - A n a ly s i s ?
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W h at I s M e t a - A n a ly s i s ?
More formally...a meta-analysis is the synthesis of:
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Types Of Effects
An "effect" could be almost any aggregate statistic of interest:
· Correlation
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C o n d u c t i n g M e t a - A n a ly s e s i n R
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S e a rc h i n g T h e L i t e r a t u r e W i t h R
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Package RISmed
· Not many packages for helping with early stages of a systematic
review.
· Using this package, one can search, store, and easily mine
metadata on PubMed articles.
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Example: EUtilsSummary
library(RISmed) # Load Package
The following code performs a PubMed query of all BMJ articles with
"rofecoxib" in the title.
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## [1] "rofecoxib[ti] AND (\"Br Med J\"[Journal] OR \"Br Med J (Clin Res Ed)
\"[Journal] OR \"BMJ\"[Journal])"
## [1] 16
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Example: EUtilsGet
Now we can extract the metadata for the queried records.
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Year(fetch)
## [1] 2011 2008 2008 2007 2007 2006 2005 2005 2004 2004 2004 2004 2004 2003
## [15] 2002 2001
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## [1] 2001
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B a s i c M e t a - A n a ly s i s I n R
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R Pa c k a g e s F o r S t a n d a r d M e t a - A n a l y s i s
In no particular order...
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D a t a s e t s F o r Pa c k a g e E x a m p l e s
1. BCG vaccine trials (from metafor)
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- year published
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L o ad i n g B C G Dat a s e t
A version of the BCG dataset is provided by package metafor
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· Because of the CLT, this will holds for most ESs given large
enough samples.
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E x a m p l e : L o g O d d s Rat i o
Group A ai bi niA
Group B ci di niB
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E x a m p l e : L o g O d d s Rat i o
Effect Size
a∗d
LOR = log( )
b∗c
Variance
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C a lc u l at i n g : L o g O d d s Rat i o
Y <- with(dat.bcg, log(tpos * cneg/(tneg * cpos)))
V <- with(dat.bcg, 1/tpos + 1/cneg + 1/tneg + 1/cpos)
cbind(Y, V)
## Y V
## [1,] -0.93869 0.357125
## [2,] -1.66619 0.208132
## [3,] -1.38629 0.433413
## [4,] -1.45644 0.020314
## [5,] -0.21914 0.051952
## [6,] -0.95812 0.009905
## [7,] -1.63378 0.227010
## [8,] 0.01202 0.004007
## [9,] -0.47175 0.056977
## [10,] -1.40121 0.075422
## [11,] -0.34085 0.012525
## [12,] 0.44663 0.534162
## [13,] -0.01734 0.071635
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E f f e c t S i z e : L o g O d d s Rat i o
ES <- escalc(ai = tpos, bi = tneg, ci = cpos, di = cneg,
data = dat.bcg,
measure = "OR")
cbind(ES$yi, ES$vi)
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E f f e c t S i z e : L o g O d d s Rat i o
## [,1] [,2]
## [1,] -0.93869 0.357125
## [2,] -1.66619 0.208132
## [3,] -1.38629 0.433413
## [4,] -1.45644 0.020314
## [5,] -0.21914 0.051952
## [6,] -0.95812 0.009905
## [7,] -1.63378 0.227010
## [8,] 0.01202 0.004007
## [9,] -0.47175 0.056977
## [10,] -1.40121 0.075422
## [11,] -0.34085 0.012525
## [12,] 0.44663 0.534162
## [13,] -0.01734 0.071635
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F o r m u l a - B a s e d S p e c i f i c at i o n
· What if my data is in a "long" format?
· In that case, you may prefer specifying the variables for the ES
calculation using a formula.
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F o r m u l a - B a s e d S p e c i f i c at i o n
Syntax
Note: The exact syntax will vary a bit depending on the ES type.
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E x a m p l e : F o r m u l a - B a s e d S p e c i f i c at i o n
library(reshape2) # Load package for data reshaping
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E x a m p l e : F o r m u l a - B a s e d S p e c i f i c at i o n
escalc(factor(pos) ~ factor(group) | factor(trial),
weights = value,
data = bcg.long,
measure = "OR")
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E x a m p l e : F o r m u l a - B a s e d S p e c i f i c at i o n
## yi vi
## 1 -0.9387 0.3571
## 2 -1.6662 0.2081
## 3 -1.3863 0.4334
## 4 -1.4564 0.0203
## 5 -0.2191 0.0520
## 6 -0.9581 0.0099
## 7 -1.6338 0.2270
## 8 0.0120 0.0040
## 9 -0.4717 0.0570
## 10 -1.4012 0.0754
## 11 -0.3408 0.0125
## 12 0.4466 0.5342
## 13 -0.0173 0.0716
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· rma is also a wrapper for escalc, and will compute ESs before
modeling (if you like).
· But if you want the ESs (yi) and variances (vi) without modeling,
use escalc.
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S u m m a r i z i n g E f f e c t s : B a s i c Fr a m e w o r k
Normal Assumption
Yi ∼ N(θ, Vi )
θ̂ = ∑ Yi Wi / ∑ Wi , Var(θ̂ ) = 1/ ∑ Wi
i i i
λi = W i / ∑ W i
i
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M o d e l i n g A p p r o ac h e s
· Fixed
· Random
· Mixed
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F ix e d E f f e c t s M o d e l
· Same mean ES, known variance
Yi = θ + ei ,
ei ∼ N(0, Vi ).
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Ra n d o m E f f e c t s M o d e l
· Different mean ES, between-study variance
Yi = θ + θi + ei ,
θi ∼ N(0, τ 2 ),
ei ∼ N(0, Vi ).
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M ix e d E f f e c t s M o d e l ( M e t a - R e g r e s s i o n )
· Study-level regression for mean ES
Yi = β′ xi + θi + ei ,
θi ∼ N(0, τ 2 ),
ei ∼ N(0, Vi ).
xi = Study-level covariates
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F ix e d V e r s u s Ra n d o m E f f e c t s
· The FE model is a description of the K studies.
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F ix e d E f f e c t s
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Ra n d o m E f f e c t s
Summary ES has more uncertainty because of between-study variance.
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· yi effect size
· vi variances
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· "DL" = DerSimonian-Laird
· "REML" = Restricted ML
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F it t i n g T h e F ix e d E f f e c t s M o d e l
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E xa m p l e : B C G F E M o d e l
result.or <- rma(yi = Y, vi = V, method = "FE") # Log Odds Ratio
summary(result.or)
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## function (yi, vi, sei, weights, ai, bi, ci, di, n1i, n2i, x1i,
## x2i, t1i, t2i, m1i, m2i, sd1i, sd2i, xi, mi, ri, ti, sdi,
## ni, mods, measure = "GEN", intercept = TRUE, data, slab,
## subset, add = 1/2, to = "only0", drop00 = FALSE, vtype = "LS",
## method = "REML", weighted = TRUE, knha = FALSE, level = 95,
## digits = 4, btt, tau2, verbose = FALSE, control)
## NULL
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E xa m p l e : M e a n D if f e r e n c e
result.md <- rma(m1 = mean.amlo, m2 = mean.plac,
sd1 = sqrt(var.amlo), sd2 = sqrt(var.plac),
n1 = n.amlo, n2 = n.plac,
method = "FE", measure = "MD",
data = amlodipine)
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-> You can use the function names to see available elements.
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Components Of rma
names(result.md)
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b Summary effect
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## [,1]
## intrcpt 0.1619
c(result.md$ci.lb, result.md$ci.ub)
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cbind(contributions)
## contributions
## [1,] 21.219
## [2,] 11.355
## [3,] 10.923
## [4,] 6.667
## [5,] 17.943
## [6,] 10.848
## [7,] 1.661
## [8,] 19.385
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## [1] 21.22
amlodipine$study[which(contributions == max(contributions))]
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## Fixed-Effects Model (k = 8)
##
## logLik deviance AIC BIC
## 4.7834 12.3311 -7.5669 -7.4874
##
## Test for Heterogeneity:
## Q(df = 7) = 12.3311, p-val = 0.0902
##
## Model Results:
##
## estimate se zval pval ci.lb ci.ub
## 0.1619 0.0323 5.0134 <.0001 0.0986 0.2252 ***
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## intrcpt
## 0.1619
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##
## estimate ci.lb ci.ub
## tau^2 NA 0.0000 0.1667
## tau NA 0.0000 0.4082
## I^2(%) NA 0.0000 95.0658
## H^2 NA 1.0000 20.2667
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F it t i n g T h e Ra n d o m E f f e c t s M o d e l
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Ra n d o m E f f e c t s M o d e l
· Suppose between-study variance (τ 2 ) is non-zero.
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E s t i m at o r s o f τ 2
The rma function offers the following estimators:
Method Estimator
HE Hedges
HS Hunter-Schmidt
SJ Sidik-Jonkman
ML Maximum-likelihood
EB Empirical Bayes
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Method Estimator
HE Hedges
HS Hunter-Schmidt
SJ Sidik-Jonkman
ML Maximum-likelihood
EB Empirical Bayes
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E xa m p l e : R E M o d e l , M e a n D if f e r e n c e
result.md <- rma(m1 = mean.amlo, m2 = mean.plac,
sd1 = sqrt(var.amlo), sd2 = sqrt(var.plac),
n1 = n.amlo, n2 = n.plac,
method = "REML", measure = "MD",
data = amlodipine)
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E xa m p l e : R E M o d e l , M e a n D if f e r e n c e
summary(result.md)
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## [1] 0.0001353
result.md$se.tau2
## [1] 0.004239
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H ow M u c h C a n E s t i m at e s O f τ 2 D i f f e r ?
estimators <- c("DL", "REML", "HE", "HS", "SJ", "ML", "EB")
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P l ot O f τ 2 E s t i m at e s
plot(y = taus, x = 1:length(taus),
type = "h", pch = 19,
axes = FALSE, xlab = "Estimators")
axis(2, las = 1)
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P l ot O f τ 2 E s t i m at e s
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D e r S i m o n i a n - L a i rd
Q = ∑ Wi (Yi − Yˉ)2
i
YˉW = ∑ Wi Yi / ∑ Wi
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REML
∑i W̃ i [ K−1 (Yi − θ̂ )2 − Vi ]
2 K
τˆ2 = 2
∑i W̃ i
K = Number of trials
θ̂ = Effect size
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Maximum-Likelihood
∑i Wi2 [(Yi − θ̂ )2 − Vi ]
τˆ2 =
∑i Wi2
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Hedges
2 ∑i (Yi − Yˉ)2 ∑i Vi
τˆ = −
(K − 1) K
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Sidik-Jonkman
θ̂ = (∑ W̃ i )−1 ∑ W̃ i Yi
i i
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1 0 - m i n u t e Br e a k
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Ev a l u a t i n g H e t e r o g e n e i t y
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Q = ∑ Wi (Yi − θ̂ )2
i
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E xa m p l e : Q - t e s t , M e a n D if f e r e n c e s
MD <- with(amlodipine, mean.amlo - mean.plac)
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E xa m p l e : Q - t e s t , M e a n D if f e r e n c e s
Q
## [1] 12.33
df <- length(MD) - 1
pchisq(Q, df = df, lower = FALSE) # HOW LIKELY UNDER NULL?
## [1] 0.09018
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E xa m p l e : Q - t e s t , M e a n D if f e r e n c e s
curve(1 - pchisq(x, df = df), 0, 20)
abline(v = Q, col = "red", lwd = 2)
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## [1] 12.33
result.md$QEp
## [1] 0.09018
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1. Obtain the Q-test for the meta-analysis of log odds ratios with
the BCG Vaccine Trials.
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result.or$QE
## [1] 163.2
result.or$QEp
## [1] 1.189e-28
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Remarks On Q-test
· The chi-squared approximation is valid when study sample sizes
are large.
· Q-test has low power (<0.80) when the number of studies and/or
sample sizes is small.
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Remarks On Q-test
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Indices Of Heterogeneit y
· τ2
· Higgins' I 2
· H 2 , H Index
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Higgins' I 2
I 2 = (Q − df)/Q × 100
df = Degrees of Freedom
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T h r e s h o ld s F o r I 2
Judging the severity of measured heterogeneity is subjective,
however Higgins suggests these rules of thumb:
· 0% to 30% → Low
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E xa m p l e : I 2 , M e a n D if f e r e n c e s
(Q - df)/Q * 100
## [1] 43.23
## [1] 43.23
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H2
Is the ratio of Q to the Q-test's degrees of freedom,
Q
H2 = ,
df
2 I2
1/H = 1 − .
100
−−
−
H index is the √H 2 .
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E xa m p l e : H 2
Q/df
## [1] 1.762
1/(1 - I2/100)
## [1] 1.762
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I n t r a - C l a s s C o r r e l at i o n
After fitting RMA and getting measure of τ 2 , we can compute the
intra-class correlation (ICC)
τ2
ICC =
τ 2 + S2
∑ Wi (K − 1)
S2 =
(∑ Wi )2 − ∑ Wi2
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E x a m p l e : I n t r a - C l a s s C o r r e l at i o n
S2 <- sum(W * (length(W) - 1))/(sum(W)^2 - sum(W^2))
result.md$tau2/(result.md$tau2 + S2)
## [1] 0.0154
result.md$I2
## [1] 1.54
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R e l at i o n s h i p B e t w e e n I C C , I 2 , H 2
· What happened in the previous example?
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I 2 & H 2 In metafor
I 2 = ICC × 100
H 2 = (τ 2 + σ 2 )/σ 2
−1
σ 2 = [(K − 1)(∑ Wi − ∑ Wi2 / ∑ Wi )]
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Example: I 2 In metafor
result.md$tau2/(result.md$tau2 + S2) * 100
## [1] 1.54
result.md$I2
## [1] 1.54
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Example: H 2 In metafor
sigma2 <- (length(Y) - 1) * (sum(W) - sum(W^2)/sum(W))^(-1)
result.md$tau2/sigma2 + 1 #H2
## [1] 1.009
result.md$H2
## [1] 1.016
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E x a m p l e : I 2 & H 2 C o n v e n t i o n a l E s t i m at e s
result.md <- rma(m1 = mean.amlo, m2 = mean.plac,
sd1 = sqrt(var.amlo), sd2 = sqrt(var.plac),
n1 = n.amlo, n2 = n.plac,
method = "DL", measure = "MD", data = amlodipine)
result.md$I2
## [1] 43.23
result.md$H2
## [1] 1.762
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E xa m p l e : C o n f i d e n c e I n t e r v a l s F o r I n di c e s
confint(result.md)
##
## estimate ci.lb ci.ub
## tau^2 0.0066 0.0000 0.1667
## tau 0.0812 0.0000 0.4082
## I^2(%) 43.2328 0.0000 95.0658
## H^2 1.7616 1.0000 20.2667
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1. Use the confint method to obtain a 95% CI for the ICC of the
mean difference DL meta-analysis.
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I2CI/100
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Visualizing Heterogeneit y
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T h e F o r e s t P l ot
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Arguments Of forest
args(forest.rma)
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C u s t o m i z i n g F o r e s t P l ot
Some typical modifications:
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E xa m p l e : C u s t o m i z i n g F o r e s t P l ot
In the following, we modify the study labels and add the (fake) year
of publication.
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E xa m p l e : C u s t o m i z i n g F o r e s t P l ot
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E xa m p l e : C u s t o m i z i n g F o r e s t P l ot
In the following, we plot the ORs of the BCG trials and order the
studies by precision.
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E xa m p l e : C u s t o m i z i n g F o r e s t P l ot
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Ad j u s t i n g L i m it s
· You can change the min and max of the drawn region with the
argument alim.
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E xa m p l e : Ad j u s t i n g L i m it s
forest(result.or, order = "prec",
ilab = dat.bcg[, c("n", "year")],
ilab.xpos = exp(result.or$b) - c(4, 2),
transf = exp, refline = 1,
alim = c(0, 4))
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E xa m p l e : Ad j u s t i n g L i m it s
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S e n s i t iv i t y A n a ly s e s
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Ca s e D i a g n o s t i c s
· A single outlying trial could be the source of substantial
heterogeneity.
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E xa m p l e : Ca s e D i a g n o s t i c s
leave1out(result.md)
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3. Does the removal of any trial change the main conclusion about
the efficacy of BCG?
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which(cases$I2 == min(cases$I2))
## [1] 8
## [1] 0
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## [,1] [,2]
## [1,] 0.4784 1
## [2,] 0.5047 1
## [3,] 0.4885 1
## [4,] 0.5173 1
## [5,] 0.4493 1
## [6,] 0.4835 1
## [7,] 0.5025 1
## [8,] 0.4379 1
## [9,] 0.4605 1
## [10,] 0.5033 1
## [11,] 0.4510 1
## [12,] 0.4499 1
## [13,] 0.4424 1
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Explaining Heterogeneit y:
Meta-Regression
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C h a n g e I n E s t i m at e & H e t e r o g e n e i t y
exp(c(result.or$b, result.ormr$b[1]))
c(result.or$I2, result.ormr$I2)
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C h a n g e I n E s t i m at e & H e t e r o g e n e i t y
· What happened?
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## [1] 35.13
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Pu b l i c at i o n B i a s
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` T h e F i l e - D r a w e r ' Pr o b l e m
· It is possible that studies showing a significant intervention effect
are more often published than studies with null results.
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funnel(result.md)
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S e n s i t iv i t y A n a ly s e s F o r Pu b l i c at i o n B i a s
· Judging asymmetry in the funnel plot can be difficult.
· Sensitivity Analyses:
- Trim-and-Fill
- Fail Safe N
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Tr im-and-Fill Method
· The trim and fill method estimates the number of missing NULL
studies from the meta-analysis.
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Fail-Safe N
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value
##
## Fail-safe N Calculation Using the Rosenthal Approach
##
## Observed Significance Level: <.0001
## Target Significance Level: 0.05
##
## Fail-safe N: 65
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## [1] 65
## [1] 0.05
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O t h e r R Pa c k a g e s f o r M e t a - A n a l y s i s
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· The package rmeta only has DSL random effects modeling and
no meta-regression modeling functions, which might be fine for
some purposes
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Main Functions:
· metareg: Meta-regression
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Example Of metabin
dat.bcg$tn <- dat.bcg$tpos + dat.bcg$tneg
dat.bcg$cn <- dat.bcg$cpos + dat.bcg$cneg
result.or.meta <- metabin(event.e = tpos, n.e = tn, event.c = cpos, n.c = cn,
data = dat.bcg,
sm = "OR",
method = "Inverse",
method.tau = "REML")
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K ey C o m p o n e n t s
· w.fixed, w.random: Weight of individual studies
· k: Number of studies
· Q: Heterogeneity statistic
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Example Of metabin
summary(result.or.meta)
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##
## Rank correlation test of funnel plot asymmetry
##
## data: result.or.meta
## z = 0.122, p-value = 0.9029
## alternative hypothesis: asymmetry in funnel plot
## sample estimates:
## ks se.ks
## 2.00 16.39
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Key Functions:
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M a n t e l- H a e n s z e l O R
· rmeta has the fewest features of the packages we have
discussed.
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Example: meta.MH
dat.bcg$tn <- with(dat.bcg, tpos + tneg)
dat.bcg$cn <- with(dat.bcg, cpos + cneg)
dat.bcg$tp <- with(dat.bcg, tpos/tn)
dat.bcg$cp <- with(dat.bcg, cpos/cn)
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K ey C o m p o n e n t s
· logOR: Log odds ratio
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Example: meta.MH
summary(result.mh)
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Example: meta.MH
c(exp(result.or$b), exp(result.mh$logMH)) # Compare with RE model
result.mh$MHtest
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O v e ra ll
Feature metafor rmeta meta
Publication-ready graphics ✓ ✓
Provides tools to assess threat of publication bias ✓ ✓ ✓
Provides tools to perform sensitivity analyses ✓
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C a lc u l at e d E f f e c t S i z e s
Effect Size metafor rmeta meta
Relative Risk ✓ ✓
Odds Ratio ✓ ✓ ✓
Risk Difference ✓ ✓
Mean Difference ✓ ✓
Standardized Mean Difference ✓ ✓
Correlation Coefficient ✓ ✓
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Sy n t h e s i s M e t h o d s
Method metafor rmeta meta
Peto's OR ✓ ✓
Mantel-Haenszel OR ✓ ✓
DerSimonian-Laird RE ✓ ✓
REML RE ✓ ✓
Hedges ✓ ✓
Sidik-Jonkman ✓ ✓
Meta-Regression ✓ ✓
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C o m p u t e d & Acc e s i b l e H e t e r o g e n e it y
Measures
τ2 ✓ ✓ ✓
I2 ✓
H 2
✓
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C o m p u t e d & Acc e s i b l e C o n f i d e n c e
Inter vals
Study Effects ✓
Summary Effect ✓ ✓ ✓
τ 2
✓
I 2
✓
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G ra p h i c s
Forest Plot ✓ ✓ ✓
Funnel Plot ✓ ✓ ✓
Galbraith (Radial) Plot ✓ ✓
L'Abbe Plot ✓ ✓
Trim-and-Fill Plot ✓ ✓
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S o m e Ad va n c e d T o p i c s
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Zero Counts
· No events in one or both treatment groups can create
computational problems in standard meta-analytic approaches.
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Pa t i e n t - L e v e l M e t a - A n a l y s i s
· Always preferred but are rarely possible to undertake.
· More often only some studies have IPD and focusing only on
these can introduce selection bias.
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M e t a - A n a ly s e s O f O b s e r v at i o n a l S t u d i e s
· Great care is needed in assessing compatibility of effects when
considering meta-analysis of non-randomized studies.
· The reason for this is that outcomes will be more sensitive to the
sample characteristics and adjustment methods a study has used.
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M e t a - A n a ly s i s O f G e n o m i c Dat a
· Standard FE or RE methodology can be applied to perform
meta-analyses of genomic data (e.g., GWAS, microarray, etc.).
- Missing data
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M u lt i v a r i a t e M e t a - A n a l y s i s
· There may be multiple endpoints of interest.
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N e t w o r k M e t a - A n a ly s i s
· A disease may have multiple trial-tested treatments.
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B ay e s i a n M e t a - A n a ly s i s
· Bayesian meta-analysis focuses on estimating a posterior
distribution of effect rather than a summary effect estimate.
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Pa c k a g e s F o r A d v a n c e d M e t a - A n a l y s e s
HSROC, metamisc
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K ey M e s s a g e s
Remember...
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R e s o u r c e s F o r Sy s t e m a t i c R e v i e w s
· Cochrane Collaboration Handbook
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· Cochrane Handbook
· Chen D-G, Peace KE. Applied meta-analysis with R. Boca Raton, Florida: Taylor & Francis Group; 2013.
· Ellis PD. The essential guide to effect sizes : statistical power, meta-analysis, and the interpretation of
· Hartung J, Knapp G, Sinha BK. Statistical meta-analysis with applications. Hoboken, N.J.: Wiley; 2008.
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Overview (2)
· Hartung J, Knapp G. On tests of the overall treatment effect in meta-analysis with normally distributed
· Hedges LV, Olkin I. Statistical methods for meta-analysis. Orlando: Academic Press; 1985.
· Hunter JE, Schmidt FL. Methods of meta-analysis : correcting error and bias in research findings. 2nd ed.
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Heterogeneity
· Hardy RJ, et al. Detecting and describing heterogeneity in meta-analysis. Stat Med 1998;17:841-56.
· Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-58.
· Viechtbauer W. Hypothesis tests for population heterogeneity in meta-analysis. Br J Math Stat Psychol
2007;60:29-60.
· Viechtbauer W. Confidence intervals for the amount of heterogeneity in meta-analysis. Stat Med
2007;26:37-52.
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· Cai T, Parast L, Ryan L. Meta-analysis for rare events. Stat Med 2010;29:2078-89.
· Dukic V, Gatsonis C. Meta-analysis of diagnostic test accuracy assessment studies with varying number of
· Gasparrini A, Armstrong B, Kenward MG. Multivariate meta-analysis for non-linear and other multi-
· Kovalchik SA. Aggregate-data estimation of an individual patient data linear random effects meta-analysis
· Kovalchik SA, Cumberland WG. Using aggregate data to estimate the standard error of a treatment-
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· Lin DY, Zeng D. On the relative efficiency of using summary statistics versus individual-level data in
· Singh K, Xie M, Strawdermann. Combining information from independent sources through confidence
· Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat
Med 2002;21:1559-73.
· van Houwelingen HC, Arends LR, Stijnen T. Advanced methods in meta-analysis: multivariate approach
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Applications
· Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis.
· Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from
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