Maintainer: | Michael Dewey |

Contact: | lists at dewey.myzen.co.uk |

Version: | 2015-12-18 |

This task view covers packages which include facilities for meta-analysis of summary statistics from primary studies. The task view does not consider the meta-analysis of individual participant data (IPD) which can be handled by any of the standard linear modelling functions but does include some packages which offer special facilities for IPD.

The standard meta-analysis model is a form of weighted least squares and so any of the wide range of R packages providing weighted least squares would in principle be able to fit the model. The advantage of using a specialised package is that (a) it takes care of the small tweaks necessary (b) it provides a range of ancillary functions for displaying and investigating the model. Where the model is referred to below it is this model which is meant.

Where summary statistics are not available a meta-analysis of significance levels is possible. This is not completely unconnected with the problem of adjustment for multiple comparisons but the packages below which offer this, chiefly in the context of genetic data, also offer additional functionality.

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Preparing for meta-analysis
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- The primary studies often use a range of statistics to present their results. Convenience functions to convert these onto a common metric are presented by: compute.es which converts from various statistics to d, g, r, z and the log odds ratio, MAc which converts to correlation coefficients, MAd which converts to mean differences, and metafor which converts to effect sizes an extensive set of measures for comparative studies (such as binary data, person years, mean differences and ratios and so on), for studies of association (a wide range of correlation types), for non-comparative studies (proportions, incidence rates, and mean change). It also provides for a measure used in psychometrics (Cronbach's alpha).
- meta provides functions to read and work with files output by RevMan 4 and 5.
- metagear provides an extensive range of facilities to support the systematic review process, ease data extraction, and generate effect sizes.

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Fitting the model
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- Four packages provide the inverse variance weighted, Mantel-Haenszel, and Peto methods: epiR, meta, metafor, and rmeta.
- For binary data metafor provides the binomial-normal model.
- For sparse binary data exactmeta provides an exact method which does not involve continuity corrections.
- Packages which work with specific effect sizes may be more congenial to workers in some areas of science MAc and metacor which provide meta-analysis of correlation coefficients and MAd which provides meta-analysis of mean differences. MAc and MAd provide a range of graphics. psychometric provides an extensive range of functions for the meta-analysis of psychometric studies.
- Bayesian approaches are contained in various packages. bspmma which provides two different models: a non-parametric and a semi-parametric. Graphical display of the results is provided. metamisc provides a method with priors suggested by Higgins. mmeta provides meta-analysis using beta-binomial prior distributions. A Bayesian approach is also provided by bmeta which provides forest plots via forestplot and diagnostic graphical output. bayesmeta also provides a Bayesian approach with forest plots via metafor and diagnostic graphical output.
- Some packages concentrate on providing a specialised version of the core meta-analysis function without providing the range of ancillary functions. These are: metaLik which uses a more sophisticated approach to the likelihood, metamisc which as well as the method of moments provides two likelihood-based methods, and metatest which provides another improved method of obtaining confidence intervals.
- metagen provides a range of methods for random effects models and also facilities for extensive simulation studies of the properties of those methods.
- metaplus fits random effects models relaxing the usual assumption that the random effects have a normal distribution. Also provides some diagnostics.

An extensive range of graphical procedures is available.

- Forest plots are provided in forestplot, meta, metafor and rmeta. Although the most basic plot can be produced by any of them they each provide their own choice of enhancements.
- Funnel plots are provided in meta, metafor and rmeta. In addition to the standard funnel plots an enhanced funnel plot to assess the impact of extra evidence is available in extfunnel, and a funnel plot for limit meta-analysis in metasens,
- Radial (Galbraith) plots are provided in metafor,
- L'Abbe plots are provided in meta and metafor,
- Baujat plots are provided in meta and metafor
- An extensive series of plots of diagnostic statistics is provided in metafor.

Confidence intervals for the heterogeneity parameter are provided in metafor and metagen.

The issue of whether small studies give different results from large studies has been addressed by visual examination of the funnel plots mentioned above. In addition:

- meta and metafor provide both the non-parametric method suggested by Begg and Mazumdar and a range of regression tests modelled after the approach of Egger.
- xmeta provides a method in the context of multivariate meta-analysis.
- An exploratory technique for detecting an excess of statistically significant studies is provided by PubBias.

A recurrent issue in meta-analysis has been the problem of unobserved studies.

- Rosenthal's fail safe n is provided by MAc and MAd. metafor provides it as well as two more recent methods by Orwin and Rosenberg.
- Duval's trim and fill method is provided by meta and metafor.
- metasens provides Copas's selection model and also the method of limit meta-analysis (a regression based approach for dealing with small study effects) due to R??cker et al.
- selectMeta provides various selection models: the parametric model of Iyengar and Greenhouse, the non-parametric model of Dear and Begg, and proposes a new non-parametric method imposing a monotonicity constraint.
- SAMURAI performs a sensitivity analysis assuming the number of unobserved studies is known, perhaps from a trial registry, but not their outcome.
- The metansue package allows the inclusion by multiple imputation of studies known only to have a non-significant result

metap provides some facilities for meta-analysis of significance values. Some of these methods are also provided in some of the genetics packages mentioned below.

Standard methods outlined above assume that the effect sizes are independent. This assumption may be violated in a number of ways: within each primary study multiple treatments may be compared to the same control, each primary study may report multiple endpoints, or primary studies may be clustered for instance because they come from the same country or the same research team. In these situations where the outcome is multivariate:

- mvmeta assumes the within study covariances are known and as well as fixed effects provides a variety of options for fitting random effects. metafor provides fixed effects and likelihood based random effects model fitting procedures. Both these packages include meta-regression, metafor also provides for clustered and hierarchical models
- mvtmeta provides multivariate meta-analysis using the method of moments for random effects although not meta-regression,
- metaSEM provides multivariate (and univariate) meta-analysis and meta-regression by embedding it in the structural equation framework and using OpenMx for the structural equation modelling. It can provide a three-level meta-analysis taking account of clustering and allowing for level 2 and level 3 heterogeneity. It also provides via a two-stage approach meta-analysis of correlation or covariance matrices.
- xmeta provides various functions for multivariate meta-analysis and also for detecting publication bias.
- dosresmeta concentrates on the situation where individual studies have information on the dose-response relationship.
- robumeta provides robust variance estimation for clustered and hierarchical estimates.

A special case of multivariate meta-analysis is the case of summarising studies of diagnostic tests. This gives rise to a bivariate, binary meta-analysis with the within-study correlation assumed zero although the between-study correlation is estimated. This is an active area of research and a variety of methods are available including what is referred to here called Reitsma's method, and the heirarchical summary receiver operating characteristic (HSROC) method. In many situations these are equivalent.

- mada provides various descriptive statistics and univariate methods (diagnostic odds ratio and Lehman model) as well as the bivariate method due to Reitsma. In addition meta-regression is provided. A range of graphical methods is also available.
- HSROC provides HSROC with estimation in a Bayesian framework. Graphical methods are provided. The case of imperfect reference standards is catered for.
- Metatron provides a method for the Reitsma model incuding the case of an imperfect reference standard
- metamisc provides the method of Riley which estimates a common within and between correlation. Graphical output is also provided.
- bamdit provides Bayesian meta-analysis with a bivariate random effects model (using JAGS to implement the MCMC method).
- meta4diag provides Bayesian inference analysis for bivariate meta-analysis of diagnostic test studies and an extensive range of graphical methods.
- CopulaREMADA uses a copula based mixed model

Where suitable moderator variables are available they may be included using meta-regression. All these packages are mentioned above, this just draws that information together.

- metafor provides meta-regression (multiple moderators are catered for). Various packages rely on metafor to provide meta-regression (meta, MAc, and MAd) and all three of these provide bubble plots.
- bmeta, metagen, metaLik, metaSEM, and metatest also provide meta-regression.
- mvmeta provides meta-regression for multivariate meta-analysis as do metafor and metaSEM.
- mada provides for the meta-regression of diagnostic test studies.

Where all studies can provide individual participant data then software for analysis of multi--centre trials or multi-centre cohort studies should prove adequate and is outside the scope of this task view. Other packages which provide facilities related to IPD are:

- ipdmeta which uses information on aggregate summary statistics and a covariate of interest to assess whether a full IPD analysis would have more power.
- ecoreg which is designed for ecological studies enables estimation of an individual level logistic regression from aggregate data or individual data.

Also known as multiple treatment comparison. This is a very active area of research and development. Note that some of the packages mentioned above under multivariate meta-analysis can also be used for network meta-analysis with appropriate setup.

This is provided in a Bayesian framework by gemtc, which acts as a front-end to BUGS or JAGS, and pcnetmeta, which uses JAGS. netmeta works in a frequentist framework. Both pcnetmeta and netmeta provide network graphs and netmeta provides a heatmap for displaying inconsistency and heterogeneity

There are a number of packages specialising in genetic data: EasyStrata for startified GWAS meta-analysis with graphics, etma proposes a new statistical method to detect epistasis, gap combines p-values, MAMA provides meta-analysis of microarray data, MetABEL provides meta-analysis of genome wide SNP association results, MetaDE provides microarray meta-analysis of differentially expressed dene detection, metaMA provides meta-analysis of p-values or moderated effect sizes to find differentially expressed genes, MetaPath performs meta-analysis for pathway enrichment, MetaPCA provides meta-analysis in the dimension reduction of genomic data, MetaQC provides objective quality control and inclusion/exclusion criteria for genomic meta-analysis, metaRNASeq meta-analysis from multiple RNA sequencing experiments, MultiMeta for meta-analysis of multivariate GWAS results with graphics, designed to accept GEMMA format, MetaSKAT, seqMeta, and skatMeta provide meta-analysis for the SKAT test.

SCMA provides single case meta-analysis. It is part of a suite of packages dedicated to single-case designs.

joint.Cox provides facilities for the meta-analysis of studies of joint time-to-event and disease progression.

CRTSize provides meta-analysis as part of a package primarily dedicated to the determination of sample size in cluster randomised trials in particular by simulating adding a new study to the meta-analysis.

CAMAN offers the possibility of using finite semiparametric mixtures as an alternative to the random effects model where there is heterogeneity. Covariates can be included to provide meta-regression.

RcmdrPlugin.EZR provides an interface via the Rcmdr GUI using meta and metatest to do the heavy lifting, RcmdrPlugin.RMTCJags provides an interface for network meta-analysis using BUGS code, and MAVIS provides a shiny interface using metafor, MAc and MAd.

- bamdit
- bayesmeta
- bmeta
- bspmma
- CAMAN
- compute.es
- CopulaREMADA
- CRTSize
- dosresmeta
- EasyStrata
- ecoreg
- epiR
- etma
- exactmeta
- extfunnel
- forestplot
- gap
- gemtc
- HSROC
- ipdmeta
- joint.Cox
- MAc
- MAd
- mada
- MAMA
- MAVIS
- meta (core)
- meta4diag
- MetABEL
- metacor
- MetaDE
- metafor (core)
- metagear
- metagen
- metaLik
- metaMA
- metamisc
- metansue
- metap
- MetaPath
- MetaPCA
- metaplus
- MetaQC
- metaRNASeq
- metaSEM
- metasens
- MetaSKAT
- metatest
- Metatron
- mmeta
- MultiMeta
- mvmeta
- mvtmeta
- netmeta
- pcnetmeta
- psychometric
- PubBias
- RcmdrPlugin.EZR
- RcmdrPlugin.RMTCJags
- rmeta
- robumeta
- SAMURAI
- SCMA
- selectMeta
- seqMeta
- skatMeta
- xmeta

- CRAN Task View: Genetics
- CRAN Task View: ClinicalTrials