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Titre original : Meta-Analysis of Prevalence

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1136/jech-2013-203104

Theory and methods

Meta-analysis of prevalence

Jan J Barendregt,1 Suhail A Doi,1 Yong Yi Lee,1 Rosana E Norman,2 Theo Vos3

1

University of Queensland,

School of Population Health

2

University of Queensland,

School of Population Health

and Queensland Children's

Medical Research Institute

3

University of Queensland,

School of Population Health

and University of Washington,

Institute of Health Metrics and

Evaluation

Correspondence to

Dr Jan J Barendregt, School of

Population Health, University of

Queensland, Herston Rd,

Herston, QLD 4006, Australia;

j.barendregt@sph.uq.edu.au

Received 12 July 2013

Revised 24 July 2013

Accepted 27 July 2013

ABSTRACT

Meta-analysis is a method to obtain a weighted average

of results from various studies. In addition to pooling

effect sizes, meta-analysis can also be used to estimate

disease frequencies, such as incidence and prevalence. In

this article we present methods for the meta-analysis of

prevalence. We discuss the logit and double arcsine

transformations to stabilise the variance. We note the

special situation of multiple category prevalence, and

propose solutions to the problems that arise. We

describe the implementation of these methods in the

MetaXL software, and present a simulation study and

the example of multiple sclerosis from the Global Burden

of Disease 2010 project. We conclude that the double

arcsine transformation is preferred over the logit, and

that the MetaXL implementation of multiple category

prevalence is an improvement in the methodology of the

meta-analysis of prevalence.

based on the inverse variance method (or modications thereof ), the binomial equation for variance

(expressed as a proportion) can be used to obtain

the individual study weights:

p(1 p)

1

N

where p is the prevalence proportion, and N the

population size.

Thus, the pooled prevalence estimate P then

becomes (according to the inverse variance

method):

Var(p)

pi

Var(pi )

P i

P 1

i Var(pi )

s

X 1

SE(P)

Var(pi )

i

with SE:

INTRODUCTION

The large majority of meta-analyses are devoted to

establishing the effects of interventions, and therefore aim to get a pooled estimate of effect size, be

that relative risk, odds ratio (OR), risk difference,

or weighted or standardised mean difference.

However, meta-analysis methods can be useful as

well to get a more precise estimate of disease frequency, such as disease incidence rates and prevalence proportions. For example, the Global Burden

of Disease 2010 project aimed to obtain disease frequency estimates of a large number of diseases and

conditions, often based on a limited number of

studies, of usually varying quality.

This article looks at the meta-analysis of prevalence, using a concrete example from the Global

Burden of Disease 2010 study: the distribution of

severity in the prevalence of multiple sclerosis

(MS). We rst discuss the specic properties of

prevalence as a variable and the options to deal

with these in the meta-analysis, next look at the

multiple category case, then discuss the implementation of these methods in the MetaXL software,

present the simulation study and the example, and

conclude.

PREVALENCE AS A VARIABLE

Doi SA, Lee YY, et al. J

Epidemiol Community Health

Published Online First:

[please include Day Month

Year] doi:10.1136/jech2013-203104

of prevalence rate, prevalence is dened as a proportion: the number of cases of a disease in a

population, divided by the population number.

This denition implies that (1) prevalence is always

between 0 and 1 (inclusive), and (2) the sum over

categories always equals 1.

The denition of prevalence is the same as the

denition of the binomial distribution (number of

successes in a sample), and therefore the standard

assumption is that prevalence follows a binomial

Barendregt

JJ, et al.Article

J Epidemiolauthor

Community(or

Health

2013;0:15.

doi:10.1136/jech-2013-203104

Copyright

their

employer)

2013. Produced

obtained by:

4

CIg (P) P + Za=2 SE(P)

where Za=2 denotes the appropriate factor from the

standard Normal distribution for the desired condence percentage (eg, Z0.025=1.96).

TRANSFORMATIONS

While this works ne for prevalence proportions

around 0.5, increasing problems arise when the

proportions get closer to the limits of the 0..1

range. The rst problem is mostly cosmetic: the

equation for the CI does not preclude condence

limits outside the 0..1 range. While this is annoying, the second problem is much more substantial:

when the proportion becomes small or big, the

variance of the study is squeezed towards 0 (see

equation (1)). As a consequence, in the inverse variance method, the study gets a large weight. A

meta-analysis of prevalence according to the

method described above therefore puts undue

weight on the studies at the extreme of the 0..1

range.

The way to deal with these problems is to transform the prevalence to a variable that is not constrained to the 0..1 range, has an approximately

normal distribution, and by being unconstrained

avoids the squeezing of variance effect. The

meta-analysis can be carried out on the transformed proportions, using the inverse of the variance of the transformed proportion as study

weight. For nal presentation, the pooled transformed proportion and its CI are back transformed

to a proportion. We discuss two transformations that have been

used: the logit and the double arcsine.

Logit

The logit transformation is given by1:

p

l ln

1p

with variance:

Varl

1

1

+

Np N1 p

exp(l)

7

exp(l) 1

However, while the logit transformation solves the problem of

estimates falling outside the 0..1 limits, unfortunately, it does

not succeed in stabilising the variance. Rather, there is a reversal

of the variance instability of the non-transformed proportions:

studies with proportions close to 0 or 1 get their variance estimates grossly magnied, while the variance for proportions

around 0.5 is squeezed. So a large study with a small prevalence

gets completely outweighed by a small study with prevalence

around 0.5. The variance instability that plagues nontransformed proportions thus persists even after logit

transformation.

p

Double arcsine

The double arcsine transformation is given by2:

r

r

n

n1

sin1

8

N1

N1

with n the number of people in the category. The variance of t

is given by:

t sin1

1

N 0:5

The back transformation to a proportion is done using3:

Var(t)

8

2

12 30:5 9

0

>

>

>

>

1

>

>

>

>

sin

t

<

7

6

B

C 7 =

sin

t

6

B

C

p 0:5 1 sgn(cos t)61 @sin t

A 7

>

5 >

4

N

>

>

>

>

>

>

:

;

10

with sgn being the sign operator. A much simpler but less

accurate alternative back transformation is:

t 2

11

p sin

2

The double arcsine transformation addresses both the problem

of condence limits outside the 0..1 range and that of variance

instability, and it is therefore preferred over the logit

transformation.

MULTI-CATEGORY PREVALENCE

The discussion so far has implicitly been about single category

prevalence (those with the disease present which of course implies

2

k-category prevalences may be meta-analysed where k>2 (representing different health states associated with the disease such as

mild, moderate and severe), and this complicates matters.

The rst thing to mention is that a multi-category prevalence from

a study is a single (vector-valued) observation, which suggests that a

single study weight across all categories applies. This is no problem

in the case of the double arcsine transformation, because its variance

depends on the population size (N) only. But for the untransformed

and logit transformation options the variance of both p and logit(p)

depends on p itself, and this implies that the same study would get a

different weight in each category, which seems hard to justify.

A second issue is the calculation of the heterogeneity statistic

Cochrans Q. With multiple categories, the standard calculation

for Q will return a different value for each category, again something that is hard to justify. Moreover, Q is used for further calculations, in the random effects model for 2, and in the quality

effects model for the overdispersion correction (see below).

The third issue is that because of the non-linearities introduced by the logit and double arcsine transformations, the backtransformed pooled proportions from multiple categories will

not necessarily add up to 1. We discuss solutions to these three

issues in the next section.

MetaXL is a new, freely available, software program for

meta-analysis in Microsoft Excel, available from http://www.

epigear.com. It implements the standard xed effects (inverse

variance, MantelHaenszel, Peto) and random effects models.

MetaXL is unique in that it also implements a quality effects

model, which allows explicit accounting for study quality in the

meta-analysis.46

MetaXL implements three variants of meta-analysis of prevalence: untransformed, logit transformed and double arcsine

transformed prevalence, with the double arcsine transformation

as the default option. The user can specify as many categories as

desired, and can choose between xed effects (inverse variance

only), random effects and quality effects models.

The back-transformation in equation (10) can become numerically unstable when sin t is close to 0, and to avoid this, the double

arcsine back transformation is implemented as follows in MetaXL.

Let:

s

t 2

sin

2

12

8

s

1s

>

>

s

if

,

2

or

,2

>

>

v

v

>

>

8

>

2

>

12 30:5 9

0

>

>

>

<

>

>

1

>

>

>

sin t

<

=

7 >

6

P

B

C

sin

t

7

6

>

B

C

>

0:5

1

sgn(cos

t)

1

sin

t

7

6

>

@

A 5 >

>

1

>

4

>

>

>

>

>

>

>

>

>

>

:

;

>

v

:

otherwise

13

Instead of the harmonic mean, as suggested by Miller,3 we use

1=v because our simulation studies suggest that this is a more

stable estimate for N than the harmonic mean. This works

because the variance of a double arcsine transformed proportion

is approximately 1/N.

The lower (LLC) and upper (ULC) limit are given by:

8

P

>

>

0

if , 2

>

>

>

v

>

8

>

2

12 30:5 9

>

0

>

>

< >

>

>

1

>

>

>

sin t

<

=

7 >

6

LLC

B

C

7

6

sin

t

>

C 7

>

1B

sin t

> 0:5>1 sgn(cos t)6

@

A

>

1

5 >

4

>

>

>

>

>

>

>

>

>

>

;

v

> :

:

otherwise

14

and

8

>

1P

>

>

,2

1

if

>

>

v

>

>

8

>

2

>

12 30:5 9

0

<

>

>

>

>

1

>

>

>

>

ULC

sint

<

7

6

B

C 7 =

>

6

sint

>

B

C

>

0:5

1

sgn(cost)

1

sint

6

>

@

A 7

>

1

>

5 >

4

>

>

>

>

>

>

>

>

>

>

:

;

:

v

otherwise

15

p

where t t + Za=2 v.

The three issues caused by generalising to more than two categories are dealt with as follows. To obtain a single study weight

across categories for the untransformed and logit transformed

prevalences, MetaXL uses the inverse of the average of the category variances.

For the second issue, to obtain a single estimate for Cochrans

Q, we have chosen to take the maximum category Q. This is

because if we believe that the effect size variations across studies

in one category of proportions is not independent of variations

in the other categories, the maximum category Q value would

be the best and most conservative estimate of a common Q.

For the random effects model, a single 2 is calculated in the

usual way from this common Q and this 2 is added to the previously computed average variance across categories. Inverting

this inated variance obtains the random effects weight for each

study. The pooled variance for each category is computed by

rst adding 2 to category variances, invert to a weight, and sum

the category weights over studies. The pooled category variance

is then obtained from the reciprocal of the summed category

weights.

In the quality effects model, the redistribution of inverse variance weights is done using a quality parameter between 0

(lowest quality) and 1 (highest quality), individualised to each

study rather than the common 2 parameter across studies as is

done with the random effects model.5 6 In addition to this, the

quality effects model applies an overdispersion correction based

on Cochrans Q 2 statistic, resulting in a more conservative CI

in the presence of heterogeneity.4 Note that, unlike in the

random effects model, this increase does not affect the study

weights. For the multi-category prevalence analysis, the overdispersion correction is applied to each of the categories separately,

thus boosting the CIs in case of heterogeneity.

The third and nal issue is that, due to the transformations,

the back transformed proportions may not sum to 1. The difference is usually small, and MetaXL deals with it by offering the

option to normalise the prevalences in each category after

pooling and back transformation. The CIs, however, are not

adjusted.

results are heterogeneous, we cannot assume that the same phenomenon has been measured in a sufciently similar way and

that differences in results are due to sampling error only. The

original random effects model assumed that the observed phenomenon follows a Normal distribution, and that individual

studies are random draws from this distribution.7

We have argued that, while the observed phenomenon may

well have a Normal distribution, the largest part of the heterogeneity is most likely due to differences in the way the studies

were carried out: differences in case denitions, biases, etc.46 8

The quality effects model was developed to take these differences explicitly into account by way of a study quality score,

thus giving lower weights to studies of lower quality.

In Burden of Disease studies, the aim is to get a best estimate

of disease frequency (in this case prevalence), based on available

data. When studies produce heterogeneous results, the rst

response is to look for covariates that may explain the heterogeneity, and stratify studies into more homogeneous subgroups

accordingly. But within those subgroups, the assumption is that

the studies have been measuring the same phenomenon, albeit

with varying quality. Therefore, the quality effects model is, in

our opinion, clearly the best choice for this purpose. However,

this will not be discussed further as the purpose of this paper is

to compare properties of various transformations of proportions, and not to compare meta-analysis models.

SIMULATION

We carried out a simulation study to compare bias and coverage

between the transformation methods, based on a hypothetical

dataset. We dened nine studies of increasing size, with the

smallest comprising 20 subjects, and each subsequent study

having 20 more subjects, resulting in 180 subjects for the largest

study. We assumed the number of cases in each study to have a

binomial distribution, with study size and prevalence proportion

as the parameters.

For the xed effects model, we assumed a prevalence of 0.05,

and for the random effects model we assumed the prevalence to

have a Normal distribution with parameters 0.05 and 0.005, for

mean and SD, respectively. For the quality effects model, we

assumed that quality associated deviations from the true prevalence would also follow a Normal distribution with parameters

0.05 and 0.005. From the deviation we calculated a quality

score between 0 and 1 using a quadratic function. (Note that

the quality effects model does not require that the quality score

is a function of the difference between the true effect and the

study estimate, but for this simulation this provides a convenient

way to calculate a quality score.)

We implemented the numbers and functions in Excel, using

the Ersatz Monte Carlo simulation add-in, and drew randomly

from the distributions 1000 times.9 Each time we recalculated

the meta-analysis for the three transformation options for each

model. We calculated the mean of the central estimates, the bias

in this mean and the mean squared error, and determined the

coverage proportion, given the pooled CIs.

Results of the simulation study are presented in table 1.

Without transformation, the effect of the squeezed variance for

a prevalence of this size can clearly be seen: the mean pooled

prevalences are much lower than the true prevalence of 0.05,

dragged down by the large weights applied to the samples with

low prevalence. For the logit transformation, a reverse (but

much smaller) effect can be seen: the lowest sampled

Table 1 Results from the simulation study: mean, bias, mean

squared error (MSE) and coverage, by transformation option and

model

Transformation

Model

Variable

None

Logit

Double arcsine

Fixed effects

Mean

Bias

MSE

Coverage

Mean

Bias

MSE

Coverage

Mean

Bias

MSE

Coverage

0.02810

0.02190

0.00077

0.39400

0.04215

0.00785

0.00014

0.82200

0.03111

0.01889

0.00064

0.63200

0.05428

0.00428

0.00007

0.92500

0.05373

0.00373

0.00007

0.94700

0.05263

0.00263

0.00006

0.95500

0.05206

0.00206

0.00006

0.94300

0.05162

0.00162

0.00006

0.96100

0.05145

0.00145

0.00006

0.95800

Random effects

Quality effects

is overestimated. Both logit and double arcsine do much better

than the no transformation option across all variables, with the

double arcsine doing slightly better than the logit for most variables, but much better for bias.

For prevalences close to 0.5, there is hardly any difference

between the results from the three transformation options (data

not shown).

found to contain usable data on the distribution of MS severity.

A quality score was given to each study based on the method of

measuring functional impairment, with higher preference given

to studies that assessed impairment using both a physician and a

standardised scale. Kurtzkes Expanded Disability Status Scale

(EDSS) is considered by experts to be the gold standard for

measuring MS functional impairment and studies using this

were given the highest quality score of 1. The majority of

studies in table 2 used EDSS, as demonstrated by the frequent

score of 1. Three studies assessed MS severity with no emphasis

on scores or scales used and were given a nal quality score

of 0.6.

Table 2 shows the studies in this analysis, their distribution

over the three categories, their quality and population size

scores. From the table, it is clear that substantial heterogeneity

exists, and the I2 for these studies is 95.2% (95% CI 93.6% to

96.4%).

Table 3 shows the pooled results, with the normalisation option

of MetaXL switched on. The pooled estimates do not differ much

between models and transformation methods, with the random

effects and to a lesser extent the quality effects model producing a

bit larger proportion for the mild category at the expense of the

severe one. In the transformed analyses the CIs of the random

effects model are the widest: because the quality scores are mostly

1, the quality effects model CIs are not as wide.

transformation method and model

In this section we present an example from the Global Burden

of Disease 2010 Study where systematic reviews of the scientic

literature and quantitative meta-analyses were conducted in

order to estimate the severity distribution of various disorders at

the global level. We look at the distribution of cases of MS over

Model

HCI

Range

Inverse variance

None

Logit

Arcsine

multiple sclerosis studies

Study name

Country

Casetta 199810

Balasa 200711

Tsai 200412

Houzen 200313

Chancellor 200314

Cabre 200115

Bencsik 199816

Lobinska 200417

Bencsik 200118

Benedikz 200219

Alvarez 199220

Arruda 200121

Al-Araji 200522

Pittock 2004 (1)23

Pittock 2004 (2)23

Modrego Pardo 199724

McDonnell 199825

Tola 199926

Italy

Romania

Taiwan

Japan

New Zealand

Caribbean

Hungary

Poland

Hungary

Iceland

Chile

Brazil

Iraq

USA

USA

Spain

Ireland

Spain

394

152

43

31

86

62

130

204

248

290

100

200

300

162

201

46

258

54

0.561

0.441

0.651

0.645

0.512

0.645

0.785

0.632

0.149

0.710

0.550

0.610

0.400

0.525

0.627

0.609

0.322

0.574

0.175

0.250

0.233

0.129

0.337

0.306

0.162

0.260

0.540

0.179

0.330

0.225

0.373

0.296

0.224

0.217

0.477

0.296

0.264

0.309

0.116

0.226

0.151

0.048

0.054

0.108

0.310

0.110

0.120

0.165

0.227

0.179

0.149

0.174

0.202

0.130

1.00

1.00

0.60

1.00

1.00

1.00

1.00

1.00

0.60

1.00

0.60

1.00

1.00

1.00

1.00

1.00

1.00

1.00

Random effects

None

Logit

Arcsine

Quality effects

None

Logit

Arcsine

Mild

Moderate

Severe

Mild

Moderate

Severe

Mild

Moderate

Severe

0.539

0.281

0.179

0.511

0.297

0.192

0.525

0.289

0.185

0.523

0.266

0.167

0.477

0.271

0.173

0.502

0.270

0.170

0.556

0.297

0.192

0.515

0.305

0.201

0.537

0.302

0.198

0.033

0.031

0.026

0.038

0.034

0.029

0.036

0.033

0.028

Mild

Moderate

Severe

Mild

Moderate

Severe

Mild

Moderate

Severe

0.551

0.280

0.169

0.560

0.278

0.162

0.555

0.279

0.166

0.470

0.199

0.090

0.458

0.207

0.115

0.464

0.204

0.106

0.632

0.360

0.249

0.630

0.346

0.212

0.632

0.355

0.232

0.162

0.161

0.160

0.172

0.139

0.097

0.168

0.151

0.126

Mild

Moderate

Severe

Mild

Moderate

Severe

Mild

Moderate

Severe

0.552

0.272

0.176

0.527

0.286

0.187

0.540

0.279

0.181

0.441

0.192

0.129

0.464

0.244

0.156

0.461

0.224

0.143

0.663

0.352

0.223

0.562

0.317

0.212

0.607

0.331

0.219

0.223

0.160

0.094

0.097

0.073

0.056

0.145

0.107

0.076

CONCLUSION

We discussed the meta-analysis of prevalence, and two transformation options used: logit and double arcsine transformed

proportions. We signalled issues with the meta-analysis of multiple categories, and proposed solutions for these issues.

We discussed the implementation of these methods in

MetaXL, including a normalisation option for multiple category

prevalence, and presented results from a simulation study and

an example. We conclude that the double arcsine is the preferred transformation and that the MetaXL implementation of

multiple category prevalence is an improvement in the methodology of the meta-analysis of prevalence.

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1

2

3

4

5

6

7

8

Meta-analysis of prevalence using inverse variance methods

has the problem that the variance becomes very small when

the prevalence is small or large, with the consequence that

such studies get a large weight in the meta-analysis.

Transformation methods can be used to avoid an undue

large weight for studies with small or large prevalence.

9

10

11

12

13

14

15

16

The double arcsine transformation is discussed and we show

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The generalisation of the methods to multiple category

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We conclude that the resulting MetaXL software is an

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17

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22

Contributors JJB and SAD developed the methods, YYL, RN and TV did the

meta-analyses, all authors contributed to writing.

Competing interests JJB owns Epigear International Pty Ltd, which sells the

Ersatz software used in the analysis.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement The data are available from the Epigear website, and

are part of the MetaXL download.

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