106300@mail.tku.edu.

tw
ychang@math.tku.edu.tw


:
:
http://test.math.tku.edu.tw/

Meta-Analysis
:
http://www.math.tku.edu.tw/main.php

Meta-Analysis

What is meta-analysis?
The National Library of Medicine define meta-analysis as a
quantitative method of combining the results of
independent studies (usually drawn from the published
literature) and synthesizing summaries and conclusions
which may be used to evaluate therapeutic
effectiveness, plan new studies, etc., with application
chiefly in the areas of research and medicine.

Meta-analysis may be broadly defined as the quantitative
review and synthesis of the results of related but
independent studies.
Note:
Conducting a meta-analysis is conceptually no
different than conducting primary research.
It is multidisciplinary and therefore requires a
research team comprising several experts:
(a) A subject-matter specialist (e.g. psychiatrist,
cardiologist);
(b) A biostatistician to help in the design and analytic
aspects of the research;
(c) A group of subject-matter specialists to aid in
judging the relevance of the retrieved documents
The objectives of a meta-analysis include:
(1) increasing power to detect an overall treatment effect,
(2) estimation of the degree of benefit associated with a
particular study treatment, (NNT or NNH)
(3) assessment of the amount of variability between
studies,
(4) identification of study characteristics associated with
particularly effective treatments. (Meta-regression)
LANCET.pdf
LANCET.pdf
LANCET.pdf
LANCET.pdf
LANCET.pdf
Q: What is NNT (Number Needed to Treat) ?
or NNH (Number Needed to Harm) ?
95% Confidence Interval for NNT (or NNH)
95% Confidence Interval for :
1 2
1
NNT (or NNH)
P P
=

( )
( ) ( )
1 1 2 2
1 2
1 2
1 1 P P P P
Var P P
n n

= +
1 2
P P
( )
( ) ( )
( )
( ) ( )
1 1 2 2 1 1 2 2
1 2 1 2
1 2 1 2
1 1 1 1
1.96* , 1.96*
P P P P P P P P
P P P P
n n n n
| |

| + + +
|
\ .
( )
( ) ( )
( )
( ) ( )
1 1 2 2 1 1 2 2
1 2 1 2
1 2 1 2
1 1
,
1 1 1 1
1.96* 1.96*
P P P P P P P P
P P P P
n n n n
| |
|
|
|

|
+ + +
|
\ .
NNT&NNH
Figure 1-1
Figure1-1
LANCET.pdf
Figure1-2.excel
Figure1-2.dta
Forest Plot
?!
LANCET.pdf
Figure 2-1
Figure 2-1.dta
LANCET.pdf
Figure1.dta
Figure 2-2
Figure 2-2.dta
LANCET.pdf
The objectives of a meta-analysis include:
(1) increasing power to detect an overall treatment effect,
(2) estimation of the degree of benefit (Effect Size)
associated with a particular study treatment,
(3) assessment of the amount of variability between studies
(Homogeneity Test),
(4) identification of study characteristics associated with
particularly effective treatments. (Meta-regression)
Meta-Analyses:
(Binary Data)
(a) Relative Risk (RR, )
(b) Odds Ratio (OR, )
(c) Rate Difference (RD, )
(Normally Distributed Data)
Fixed Effect Method:
Random Effect Method:

Total

ai bi m
1i
=(ai+bi)

ci di m
2i
=(ci+di)
Total n
1i
=(ai+ci) n
2i
=(bi+di) Ni
Notations and Terminologies:
(Binary Data)
i 1, , K = (i.e. K)
Fixed Effect Method:
(Binary Data)
Pti = ai/(ai+ci) : Treatment Response Rate of i
th
Clinical Trial ;
Pci = bi/(bi+di) : Control Response Rate of i
th
Clinical Trial;
RRi = Pti / Pci ( i )
(a) Relative Risk (RR, )

Total

ai bi m
1i
=(ai+bi)

ci di m
2i
=(ci+di)
Total n
1i
=(ai+ci) n
2i
=(bi+di) Ni
Note: 0 RRi < <
(i.e. )
, RRi ,
i.e. RRi = Pti / Pci ()
ln RRi = ln(Pti) ln(Pci)
ln RRi ,
(Standard Error; SE) :



,
1/ 2
1 2
1 1
(ln )
i i
Pti Pci
SE RRi
n Pti n Pci
(

= +
(

1 2
1 1
(ln )
i i
Pti Pci
Var RRi
n Pti n Pci

= +
ln( ) l ln ( ) n a b a b =
By -method
(1) RRi or ln(RRi)
RR (i.e. Pooled RR)?
Ans: (Weighted Average)
Q: Weight?
Guideline:
1. Weight
2. Weight
(1) RRi or ln(RRi)
RR (i.e. Pooled RR)?
( )
1
ln( ) ln
K
Pooled i j i
i
RR W W RR
=
=

1 1
exp ln
K K
Pooled i i i
i i
RR W RR W
= =
| |
=
|
\ .

Ans:
(Weight).
| |
2
1 (ln )
i i
W SE RR =
,ln(RR
Pooled
) (SE)
:
1/ 2
1
(ln ) 1
K
Pooled i
i
SE RR W
=
| |
=
|
\ .

RR.Excel
(2) RR
Pooled
95%(CI)?


RR
Pooled
95%(95% C.I.):




( ln (ln , (ln ))
Pooled Pooled
RR N RR Var RR
( ) | |
, ln 1.96* (ln )
L U Pooled Pooled
RR RR Exp RR SE RR =
( )
ln 1.96* (ln ) ln 1.96* (ln )
,
Pooled Pooled Pooled Pooled
RR SE RR RR SE RR
e e
+
=
1 1
ln ln
K K
Pooled i i i
i i
RR W RR W
= =
=

RR.Excel
(3) Testing H
*
0
: RR=1 vs. H
1
:
or H
*
0
: ln(RR)=0 vs. H
1
:





Reject H
*
0
if
( ln (ln , (ln ))
Pooled Pooled
RR N RR Var RR
RR 1( 1 or 1) = < >
ln(RR) 0( 0 or 0) = < >
ln (ln ) (0,1)
RR Pooled Pooled
Z RR SE RR N =
1.96
RR
Z >
Under H*
0
RR.Excel
(4) RR
i
(Test of Homogeneity)
i.e. Testing

KRR
i

, Q
RR
,:


Under H
0
, Q
RR
K-1

, Reject H
0
if Q
RR
>


0 1 2 K
H : RR =RR = =RR RR =
2
( 1,0.05) K
_

2
1
(ln ln )
K
RR i i Pooled
i
Q W RR RR
=
=

RR.Excel
Example: ChlorpheniramineDrowsiness
8
ai ci bi di Ni
Burns (1977) 2 14 2 43 61
Burns (1978) 2 13 2 43 60
Backhouse (1982) 11 33 2 43 89
Brandon (1982) 9 31 4 36 80
Brandon (1983) 6 35 3 36 80
Brostoff (1982) 5 12 1 14 32
Roman (1986) 8 4 1 11 24
Grant (1988) 10 24 2 18 54
RR.Excel
Results: 1. P(Z
RR
> 4.1482) < 0.00001, i.e. Chlorpheniramine
DrowsinessPlacebo;
2. 8 (RR).
RR.dta
Meta-Analyses:
(Binary Data)
(a) Relative Risk (RR, )
(b) Odds Ratio (OR, )
(c) Rate Difference (RD, )
(Normally Distributed Data)
Fixed Effect Method:
Random Effect Method:
(b) Odds Ratio (OR, )
(Odds) =





,

, (Odds Ratio), OR
i
=
( 1) (
( 0) (
P Y P
P Y P
=
=
=
)
)

Total

ai bi m
1i
=(ai+bi)

ci di m
2i
=(ci+di)
Total n
1i
=(ai+ci) n
2i
=(bi+di) Ni
ti
ai/(ai+ci) ai
Odds = =
ci/(ai+ci) ci
ci
bi/(bi+di) bi
Odds = =
di/(bi+di) di
ti
ci
Odds aidi
=
Odds bici
Y=1
Y=0
What is Odds (, , )?
Pr( 1)
1 Pr( 0)
p Y
Odds
p Y
=
= =
=
where Y=1 or 0 and p = Pr( Y=1).
( Y=1 , : , ,
. Odds ; Y=1
, : , , . Odds
or )
CHD Status White Black Hispanic Other
Present ( p
i
) 5 (0.2) 20 (0.67) 15 (0.6) 10 (0.5)
Absent ( 1-p
i
) 20 (0.8) 10 (0.33) 10 (0.4) 10 (0.5)
Total 25 30 25 20
Odds ( p
i
/ 1-p
i
)

1/4 2/1 3/2 1
Ex. CHD
CHD Status White Black Hispanic Other
Present 5 20 15 10
Absent 20 10 10 10
Total 25 30 25 20
Odds Ratio 1.0 8.0 6.0 4.0
log
e
(O.R.) 2.08 1.79 1.39
Note:ORi or ln(ORi)
OR (i.e. Pooled OR)?
Ans: (Weighted Average)
Q: Weight?
Guidelines:
1. Weight
2. Weight
(1) Woolf s Logit estimate of Odds Ratio
OR
i
= aidi/bici i
, . V(ln OR
i
)
ln OR
i
, i.e. .
,

OR
W
95% (95% C.I.):
1
(ln ) 1
K
W i
i
SE OR W
=
=

| |
( , ) exp ln 1.96 (ln )
WL WU W W
OR OR OR SE OR =
1 1
ln ln
K K
W i i i
i i
OR W OR W
= =
| |
=
|
\ .

1 (ln )
i i
W V OR =
(ln ) 1/ai+1/bi+1/ci+1/di
i
V OR =
| |
exp 1.96 (ln )
W W
OR SE OR =
OR.Excel
(2) OR
W
:
i.e. Testing H
0
: OR
W
= OR
0
(e.g. OR
0
=1)

,
Under H
0
,


,under H
0
,


i.e. Chi-Square with 1 degree of freedom.
( ) ( )
2 2 1
2 2
(ln )
1
(ln )
i i i i
W
i
i i
W Var OR W W
Var OR
W
W W

= = =

0
ln
ln ln
(0,1)
(ln )
W
W
OR
W
OR OR
Z N
Var OR

=
( )
( )
2
2
0 1
ln ln
W i W
U W OR OR _ =

OR.Excel
(3) OR
i
(Common OR):
i.e. Testing
K OR
i

, Q
W
,:


i.e. Under H
0
, Q
W
K-1

0 1 2 K
H : OR =OR = =OR OR =
( )
( )
( )
0
2
U
2
2
1
1
nder
ln ln
K
W i i i W
i
H
K
Q W OR W OR _

=
=

Test for Homogeneity!
OR.Excel
Example: ChlorpheniramineDrowsiness8

ai ci bi di Ni
Burns (1977) 2 14 2 43 61
Burns (1978) 2 13 2 43 60
Backhouse (1982) 11 33 2 43 89
Brandon (1982) 9 31 4 36 80
Brandon (1983) 6 35 3 36 80
Brostoff (1982) 5 12 1 14 32
Roman (1986) 8 4 1 11 24
Grant (1988) 10 24 2 18 54
OR.Excel
Results: 1. P(U
W
> 18.9842) < 0.00001, i.e.
, ChlorpheniramineDrowsiness ;
2. 8 .

OR70.dta
OR.dta
Meta-Analyses:
(Binary Data)
(a) Relative Risk (RR, )
(b) Odds Ratio (OR, )
(c) Rate Difference (RD, )
(Normally Distributed Data)
Fixed Effect Method:
Random Effect Method:
(c) Rate Difference (RD, )
(Risk Difference).






i 1, , K =

Total

ai bi m
1i
=(ai+bi)

ci di m
2i
=(ci+di)
Total n
1i
=(ai+ci) n
2i
=(bi+di) Ni
Pti = ai/(ai+ci) : Treatment Response Rate of i
th
Clinical Trial ;
Pci = bi/(bi+di) : Control Response Rate of i
th
Clinical Trial;
RDi = Pti Pci
1i 2i
Pti(1-Pti) Pci(1-Pci)
(RDi) +
n n
i
V Var = =
(i.e. K)
Note:RDi
RD (i.e. Pooled RD)?
1i 2i
Pti(1-Pti) Pci(1-Pci)
(RDi) +
n n
i
V Var = =
Ans: (Weighted Average)
Q: Weight?
Guidelines:
1. Weight
2. Weight
Note:
(1) RDi RD
(i.e. Pooled RD)?


.




,
1 1
K K
i i i
i i
RD WRD W
= =
| |
=
|
\ .

1
i i
W V =
2
2
1
1
2 2
1
1 1
1
(RDi)
1
(RD)
K
K
i
i
i
i i
K
K K
i
i i
i
i i
W
W Var
W
Var
W
W W
=
=
=
= =
= = =
| |
| | | |
|
| |
\ .
\ . \ .

(RD) 1
i
SE W =

RD.Excel
Note: RD 95% (95% C.I.):
(2) RD, i.e. Testing H
0
: RD = 0
Under H
0
, ,
i.e. Reject H
0
if .

( )
, 1.96* (RD)
L U
RD RD RD SE =
( ) (0,1)
RD
Z RD SE RD N =
1.96
RD
Z >
RD.Excel
(3) RD (Homogeneity) ,
i.e. Testing H
0
:
K RD
i

, Q
RD
,:


or

i.e. , under H
0
,
Q
RD
K-1 .
( )
( )
( )
0
2 2
2
1
1
Under
K
RD i i K
H
i
i
Q W RD W RD _

=
=

1 2 K
RD RD RD = = =
( )
2
2
1
1
K
RD i i K
i
Q W RD RD _

=
=

RD.Excel
Example: ChlorpheniramineDrowsiness8

ai ci bi di Ni
Burns (1977) 2 14 2 43 61
Burns (1978) 2 13 2 43 60
Backhouse (1982) 11 33 2 43 89
Brandon (1982) 9 31 4 36 80
Brandon (1983) 6 35 3 36 80
Brostoff (1982) 5 12 1 14 32
Roman (1986) 8 4 1 11 24
Grant (1988) 10 24 2 18 54
RD.Excel
Results:
1. P(Z
RD
>4.737) < 0.00001, i.e. , Chlorpheniramine
Drowsiness ;
2. P(Q
RD
>11.169) =0.134 i.e. 8 .
RD.dta
Example:
Thrombolytic therapy in acute myocardial infarction
(meta-analysis)
References Year ai ci NoTr bi di NoCo Ni
Fletcher 1959 1 11 12 4 7 11 23
Dewar 1963 4 17 21 7 14 21 42
Lippschutz 1965 6 37 43 7 34 41 84
European 1 1969 20 63 83 15 69 84 167
European 2 1971 69 304 373 94 263 357 730
Heikinhermo 1971 22 197 219 17 190 207 426
Italian 1971 19 145 164 18 139 157 321
Australian 1 1973 26 238 264 32 221 253 517
Frankfurt 2 1973 13 89 102 29 75 104 206
Gonnsen 1973 2 12 14 3 11 14 28
NHLBI SMIT 1974 7 46 53 3 51 54 107
Brochier 1975 2 58 60 8 52 60 120
Euro Collab 1975 29 143 172 24 145 169 341
Frank 1975 6 49 55 6 47 53 108
Valere 1975 11 38 49 9 33 42 91
Klein 1976 4 10 14 1 8 9 23
UK-Collab 1976 38 264 302 40 253 293 595
Australian 1977 37 315 352 65 311 376 728
Australian 2 1977 25 98 123 31 76 107 230
OR70.dta
labbe ai ci bi di, xlabel(0, 0.1, 0.2, 0.3, 0.4, 0.5) ylabel(0, 0.1, 0.2, 0.3, 0.4, 0.5) psize(50)
For binary data, a LAbbe plot (LAbbe et al. 1987) plots the event rates in control and
experimental groups by study.
OR70.dta
TumorResponse.dta
OR70.dta
OR70.dta
OR70.dta
Note:
For rare events, rate ratio or odds ratio is unstable.
Therefore, rate difference is recommended.
NSCLC.pdf
Grade34PLT.dta
Grade34HB.dta
(Normally Distributed Data)


K,
(T)(C),


(Effect Size)


(Standardized difference between two means)


2
2
~ ( , ), 1, 2, , , 1, 2, ,
~ ( , ), 1, 2, , , 1, 2, ,
T T T
ij i i i
C C C
ij i i i
Y N j n i K
Y N j n i K
o
o
= =
= =
( )
, 1, 2, ,
T C
i i i i
i K o o = =
Hedges (1981):



Hedges & Olkin (1985)
(Unbiased Estimator) :




.
( )
2 2
, 1, 2, ,
( 1)( ) ( 1)( )
where
2
T C
i i i i
T T C C
i i i i
i
T C
i i
ES Y Y S i K
n S n S
S
n n
= =
+
=
+
( ) ( )
( )
2
( )
2
T C U
i i i
U
i i
T C
T C
i i
i i
n n ES
V Var ES
n n
n n
+
= = +
+
U
i
ES
ES.Excel
3
( ) , where 2 and ( ) 1
4 1
U T C
i i i i
ES C M ES M n n C M
M
= = + ~

Example: 8Flouride Varnishes (Duraphat)

(Permanent Teeth)?(,
Caries Increment)
ES.Excel
References N
T
Y
T
S
T
N
C
Y
C
S
C
Si
Maiwald(1973) 82 1.38 1.75 110 1.29 1.47 1.595389
Maiwald(1973) 97 1.31 1.44 64 2.41 2.22 1.790181
Koch (1975) 60 0.9 3.8 61 4 3.75 3.774873
Koch (1979) 98 0.4 0.78 99 0.7 0.91 0.847829
Schoth (1981) 47 4.8 4.11 46 6.7 6.99 5.718431
Tewari (1984) 326 0.31 2.35 319 1.12 1.82 2.104633
Kirkeqaard (1986) 156 2.96 2.69 163 2.77 3.33 3.033981
Seppa (1987) 61 6.38 5 62 10.4 7.56 6.419476
(1) Pooled ES (SE):





(2) ES95%(95% C.I.):

1 1
, where 1 .
K K
U
i i i i i
i i
ES WES W W V
= =
| | | |
= =
| |
\ . \ .

1
( ) 1
K
i
i
SE ES W
=
=

( )
, 1.96 ( )
L U
ES ES ES SE ES =
ES.Excel
(3) ES,
i.e. Testing H
0
: Effect Size = 0

Under H
0
, ,


i.e. Reject H
0
if


2
2
1
1 1
~
K K
U
ES i i i
i i
U WES W _
= =
| | | |
=
| |
\ . \ .

2
1
(0.05) 3.8415
ES
U _ > ~
ES.Excel
(4) ES,
i.e. Testing H
0
:

Under H
0
, ,


i.e. Reject H
0
if .


1 2 K
o o o = = =
( )
2
2
1
1
~
K
U
ES i i K
i
Q W ES ES _

=
=

2
1
(0.05)
ES K
Q _

>
ES.Excel
Example: 8Flouride Varnishes (Duraphat)
(Permanent Teeth)?(,
Caries Increment)
References N
T
Y
T
S
T
N
C
Y
C
S
C
Maiwald(1973) 82 1.38 1.75 110 1.29 1.47
Maiwald(1973) 97 1.31 1.44 64 2.41 2.22
Koch (1975) 60 0.9 3.8 61 4 3.75
Koch (1979) 98 0.4 0.78 99 0.7 0.91
Schoth (1981) 47 4.8 4.11 46 6.7 6.99
Tewari (1984) 326 0.31 2.35 319 1.12 1.82
Kirkeqaard (1986) 156 2.96 2.69 163 2.77 3.33
Seppa (1987) 61 6.38 5 62 10.4 7.56
Results: 1. ES < 0;
2. 95% C.I. (ESL, ESU)=(-0.4064, -0.2217) ;
3. U
ES
=44.4414 (p-value < 0.0001)
4. , P(Q
ES
> 31.6839) ~0.000046 , i.e. ESis (Heterogeneity).
ES.Excel
ES.dta
ES.dta
Overall (I-squared = 78.1%, p = 0.000)
ID
6
7
3
Study
2
8
4
1
5
-0.32 (-0.41, -0.22)
SMD (95% CI)
-0.38 (-0.54, -0.23)
0.06 (-0.16, 0.28)
-0.82 (-1.19, -0.45)
-0.61 (-0.94, -0.29)
-0.63 (-0.99, -0.26)
-0.35 (-0.64, -0.07)
0.06 (-0.23, 0.34)
-0.33 (-0.74, 0.08)
100.00
Weight
35.15
17.69
6.19
%
8.19
6.50
10.77
10.43
5.09
-0.32 (-0.41, -0.22)
SMD (95% CI)
-0.38 (-0.54, -0.23)
0.06 (-0.16, 0.28)
-0.82 (-1.19, -0.45)
-0.61 (-0.94, -0.29)
-0.63 (-0.99, -0.26)
-0.35 (-0.64, -0.07)
0.06 (-0.23, 0.34)
-0.33 (-0.74, 0.08)
100.00
Weight
35.15
17.69
6.19
%
8.19
6.50
10.77
10.43
5.09

0 -1.19 0 1.19
Effect of Flouride Varnishes (Duraphat) on Child's Permanent Teeth
ES.dta
NOTE: Weights are from random effects analysis
Overall (I-squared = 78.1%, p = 0.000)
7
1
3
2
8
5
ID
6
4
Study
-0.36 (-0.57, -0.15)
0.06 (-0.16, 0.28)
0.06 (-0.23, 0.34)
-0.82 (-1.19, -0.45)
-0.61 (-0.94, -0.29)
-0.63 (-0.99, -0.26)
-0.33 (-0.74, 0.08)
SMD (95% CI)
-0.38 (-0.54, -0.23)
-0.35 (-0.64, -0.07)
100.00
14.21
12.84
11.05
12.06
11.23
10.29
Weight
15.39
12.93
%
-0.36 (-0.57, -0.15)
0.06 (-0.16, 0.28)
0.06 (-0.23, 0.34)
-0.82 (-1.19, -0.45)
-0.61 (-0.94, -0.29)
-0.63 (-0.99, -0.26)
-0.33 (-0.74, 0.08)
SMD (95% CI)
-0.38 (-0.54, -0.23)
-0.35 (-0.64, -0.07)
100.00
14.21
12.84
11.05
12.06
11.23
10.29
Weight
15.39
12.93
%

0 -1.19 0 1.19
Effect of Flouride Varnishes (Duraphat) on Child's Permanent Teeth
Note:
(Fixed Effect Method)
, e.g. RRs, ORs, RDs, ESs,
(Heterogeneity)
Within-study Variance Between-study
Variance, : Pooled RR, Pooled
OR, Pooled ES

Q:
i.e. Reject the hypothesis of homogeneity
?

Ans.:
(A) Random Effect Model when the potential
different characteristics of the study were unknown
or (not available)
(B) Meta-regression Model -- when the potential
different characteristics of the study were known
and available
(A) Random Effect Model
u
i
, i = 1, , K, i
: RD
i
, OR
i
u
i
~ N (
2
)

i

(Ethnic Differences)
Follow-up
2


Reference: DerSimonian R, Larid N., Meta-analysis in clinical trials,
Controlled Clinical Trials 1986; V 7; p. 177- 188.
2
, ~ (0 , )
i i i
N u o o t = +
Q W
i

Among-study Variance,
2
:
| |
2 2
1 1 1
max 0 , ( 1)
K K K
i i i
i i i
Q K W W W t
= = =

(
| |
=
`
( |
\ .

)


( )
* 2
1
i i
W V t = +

( )
i i
V Var u =
Pooledu
*
:
* * *
1 1
K K
i i i
i i
W W u u
= =
=


( )
* *
1
1
K
i
i
SE W u
=
=

Figure 2-1
u
*
95%:
( )
* * * *
, 1.96 ( )
L U
SE u u u u =

u
*
:
2
* * * 2
1
1 1
K K
i i i
i i
U W W
u
u _
= =
| |
=
|
\ .

*
0
: 0 H u =
i.e. Reject H
0
if
* 2
1
(0.05) 3.8415 U
u
_ > ~
or
* * * * *
1 1
( )
K K
i i i
i i
Z SE W W
u
u u u
= =
= =

i.e. Reject H
0
if
*
1.96 Z
u
>
Figure 2-1
Note:
( )
* *
1 1
1 1 ( )
K K
i i
i i
SE W W SE u u
= =
= > =

1.
2. ()
3.

( )
( )
* 2
1 1
i i i i
V V W W t s = + =
Example: 8Flouride Varnishes (Duraphat)
(Permanent Teeth)?(,
Caries Increment)
References N
T
Y
T
S
T
N
C
Y
C
S
C
Maiwald(1973) 82 1.38 1.75 110 1.29 1.47
Maiwald(1973) 97 1.31 1.44 64 2.41 2.22
Koch (1975) 60 0.9 3.8 61 4 3.75
Koch (1979) 98 0.4 0.78 99 0.7 0.91
Schoth (1981) 47 4.8 4.11 46 6.7 6.99
Tewari (1984) 326 0.31 2.35 319 1.12 1.82
Kirkeqaard (1986) 156 2.96 2.69 163 2.77 3.33
Seppa (1987) 61 6.38 5 62 10.4 7.56
Results: 1. ES < 0;
2. 95% C.I. (ESL, ESU)=(-0.4064, -0.2217) ;
3. U
ES
=44.4414 (p-value < 0.0001)
4. , P(Q
ES
> 31.6839) ~0.000046 , i.e. ESis (Heterogeneity).
ES.Excel
ES.dta
ES.dta
Example: Efficacy analysis: number of patients with
no clinically significant response (Figure 2)
P(Q
RD
>37.22042) =0.000206, i.e. 13
(RDi) , i.e.Heterogeneity.
,
2
, : Figure 2-1
| |
| | ( )
{ }
{ }
2 2
1 1 1
max 0 , ( 1)
max 0 , 37.22042 (13 1) 1611.74 293522.08 1611.74
max 0 , 0.0176413 0.0176413
K K K
i i i
i i i
Q K W W W t
= = =

(
| |
=
`
( |
\ .

)
= (

= =

Figure 2-1.dta
Q: ?
Ans: Yes! STATA
Random Effect
ES.Excel ES.dta
ES.Excel ES.dta
0
.
0
5
.
1
.
1
5
.
2
s
e
(
S
M
D
)
-.8 -.6 -.4 -.2 0 .2
SMD
Funnel plot with pseudo 95% confidence limits
ES.dta
Note:
1. There are a variety of potential problems such as
publication and selection bias. It is well-recognized
that negative results are not often published.
2. Outside funded studies yield stronger positive results
than non-funded studies.
3. Blinded randomized results are generally less positive
than unblinded randomized results, which it turn are
less positive than non-randomized results.
4. Soft endpoints generally yield stronger results than
hard endpoints. Soft endpoints permit more flexibility
and subjectivity in the reporting of results.
Funnel plots are simple graphical displays of a
measure of study size on the vertical axis against
intervention or treatment effect on the horizontal axis.
The name "funnel plot" is based on the fact that the
precision in the estimation of the underlying
intervention or treatment effect will increase as the
size of component studies increases. Results from
small studies will therefore scatter more widely, with
the spread narrowing among larger studies. In the
absence of bias, the plot will resemble a symmetrical
inverted funnel.
If there is bias, for example, because smaller studies
showing no statistically significant effects remain
unpublished, then such publication bias will lead to an
asymmetrical appearance of the funnel plot. It should be
noted that although funnel plots have traditionally been used
to examine evidence for publication bias, funnel-plot
asymmetry may reflect other types of bias or even result from
the true intervention or treatment effect differing between
small and large studies. They should, thus, be seen as
displaying the evidence for "small study effects" in general
rather than publication bias in particular. These issues are
discussed by Egger et al. (1997) and Sterne, Egger, and
Davey Smith (2001).
(B) Meta-Regression
Meta-regressions are similar in essence to simple
regressions, in which an outcome variable is predicted
according to the values of one or more explanatory
variables.
In meta-regression, the outcome variable is the
effect estimate (for example, a mean difference, a risk
difference, a log odds ratio or a log risk ratio). The
explanatory variables are characteristics of studies that
might influence the size of intervention effect. These are
often called potential effect modifiers or covariates.

Note: Meta-regression should generally not be considered
when there are fewer than ten studies in a meta-analysis.
2
0
0
0
2
5
0
0
3
0
0
0
3
5
0
0
34 36 38 40 42
Gestat
95% CI Fitted values
Weight
Gestation, Smoking (n > 2)
Q: ()
0 1
2
, 1, 2,
where ~ . . . (0 , )
i i i
i
Y X i n
i i d N
| | c
c o
= + + =
0 1

i i
Y X | | = +
Y: Dependent Variable
X: Independent Variable(s)
Predicted (fitted) values
0 1
2
, 1, 2,
where ~ . . . (0 , )
i i i
i
Y X i n
i i d N
| | c
c o
= + + =
(B) Meta-Regression
Meta-regressions usually differ from simple regressions in
two ways:
(1)larger studies have more influence on the relationship
than smaller studies, since studies are weighted by the
precision of their respective effect estimate.
(2)Sometimes we should allow for the residual
heterogeneity among intervention effects not modelled by
the explanatory variables. This gives rise to the term
random-effects meta-regression, since the extra
variability is incorporated in the same way as in a random-
effects meta-analysis.

(B) Meta-Regression
The regression coefficient obtained from a meta-
regression analysis will describe how the outcome variable
(the intervention effect) changes with a unit increase in the
explanatory variable (the potential effect modifier).
The statistical significance of the regression coefficient is
a test of whether there is a linear relationship between
intervention effect and the explanatory variable.
If the intervention effect is a ratio measure, the log-
transformed value of the intervention effect should always
be used in the regression model, and the exponential of the
regression coefficient will give an estimate of the relative
change in intervention effect with a unit increase in the
explanatory variable.
(B) Meta-Regression
Meta-regression can also be used to investigate differences for
categorical explanatory. If there are J categories of a particular
explanatory, we usually use J 1 dummy variables (which can
only take values of 0 or 1) and use them simultaneously enter
into/remove from the model in the meta-regression model (as in
standard linear regression modelling).
The regression coefficients will estimate how the intervention
effect in each subcategory differs from a nominated reference
subcategory.
The p-value of each regression coefficient will indicate
whether this difference is statistically significant.
Note: Meta-regression may be performed using the metareg
macro available for the STATA statistical package.
(B) Meta-Regression
Generally, three types of models can
be distinguished in the literature on meta-
regression:
1.simple regression,
2.fixed effect meta-regression and
3.random effects meta-regression.


(1)Simple regression:
The model can be specified as
Where Y
i
is the effect size in study i and |
0
is the
overall effect size. The variable X
ji
specify different
characteristics of the study, j=1,,p and i=1,,K.
c specifies the between study variation. Note that
this model does not allow specification of within
study variation.

0 1 1 2 2 i i i p pi
Y X X X | | | | c = + + + + +
(2) Fixed-effect meta-regression
Fixed-effect meta-regression assumes that:


Here is the variance of the effect size in study j.
Fixed effect meta-regression ignores between
study variation, i.e. test for homogeneity is not
significant. As a result, parameter estimates are
biased if between study variation can not be
ignored. Furthermore, generalizations to the
population are not possible.
0 1 1 2 2 j j j p pj j
Y X X X | | | | q = + + + + +
2
j
q
o
(3) Random effects meta-regression
Random effects meta-regression rests on the
assumption that :


Here is the variance of the effect size in study j.
Between study variance estimated using
common estimation procedures for random effects
models (restricted maximum likelihood (REML)
estimators).
0 1 1 2 2 j j j p pj j
Y X X X | | | | q c = + + + + + +
2
j
c
o
2
q
o
Example:
a meta-analysis of 28 randomized controlled trials
of cholesterol-lowering interventions for reducing
risk of ischemic heart disease (IHD). The outcome
event was death from IHD or nonfatal myocardial
infarction. The measure of effect size is the odds
ratio. With the following known potential different
characteristics:
1.Intervention methods (different drugs and dietary)
2.Different eligibility criteria
3.Reduction in cholesterol varied among trials
cholesterol.dta
Example

STATA 11.0


RNFLMetaRegression.dta

logOR4metareg.dta

cholesterol.dta
.
4
.
6
.
8
1
R
O
C
i
.5 .6 .7 .8 .9 1
Linear prediction
Thanks for Your Attention