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<article article-type="research-article" dtd-version="2.3" xml:lang="EN" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Bioinform.</journal-id>
<journal-title>Frontiers in Bioinformatics</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Bioinform.</abbrev-journal-title>
<issn pub-type="epub">2673-7647</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="publisher-id">1305969</article-id>
<article-id pub-id-type="doi">10.3389/fbinf.2024.1305969</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Bioinformatics</subject>
<subj-group>
<subject>Technology and Code</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>MetaWin 3: open-source software for meta-analysis</article-title>
<alt-title alt-title-type="left-running-head">Rosenberg</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fbinf.2024.1305969">10.3389/fbinf.2024.1305969</ext-link>
</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Rosenberg</surname>
<given-names>Michael S.</given-names>
</name>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2532565/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/project-administration/"/>
<role content-type="https://credit.niso.org/contributor-roles/resources/"/>
<role content-type="https://credit.niso.org/contributor-roles/software/"/>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
</contrib-group>
<aff>
<institution>Center for Biological Data Science</institution>, <institution>Virginia Commonwealth University</institution>, <addr-line>Richmond</addr-line>, <addr-line>VA</addr-line>, <country>United States</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1218140/overview">Sankar Subramanian</ext-link>, University of the Sunshine Coast, Australia</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/2254760/overview">Marcel Van Tuinen</ext-link>, University of Groningen, Netherlands</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/2022701/overview">Michail Tsagris</ext-link>, University of Crete, Greece</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Michael S. Rosenberg, <email>msrosenberg@vcu.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="epub">
<day>08</day>
<month>02</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>4</volume>
<elocation-id>1305969</elocation-id>
<history>
<date date-type="received">
<day>02</day>
<month>10</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>08</day>
<month>01</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Rosenberg.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Rosenberg</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>The rise of research synthesis and systematic reviews over the last 25&#xa0;years has been aided by a series of software packages providing simple and accessible GUI interfaces which are intuitively easy to use by novice analysts and users. Development of many of these packages has been abandoned over time due to a variety of factors, leaving a gap in the software infrastructure available for meta-analysis. To fulfill the continued demand for a GUI-based meta-analytic system, we have now released MetaWin 3 as free, open-source, multi-platform software. MetaWin3 is written in Python and developed from scratch relative to earlier versions. The codebase is available on Github, with pre-compiled executables for both Windows and macOS available from the MetaWin website. MetaWin includes standardized effect size calculations, exploratory and publication bias analyses, and allows for both simple and complex explanatory models of variation within a meta-analytic framework, including meta-regression, using traditional least-squares/moments estimation.</p>
</abstract>
<kwd-group>
<kwd>effect sizes</kwd>
<kwd>meta-analysis</kwd>
<kwd>meta-regression</kwd>
<kwd>research synthesis</kwd>
<kwd>software</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Evolutionary Bioinformatics</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>Research synthesis is generally defined as a review of primary research with the intent to integrate findings; meta-analysis is a particular form of quantitative research synthesis with a focus on combining and comparing effect sizes across studies (<xref ref-type="bibr" rid="B13">Glass, 1976</xref>; <xref ref-type="bibr" rid="B16">Hedges and Olkin, 1985</xref>; <xref ref-type="bibr" rid="B19">Koricheva and Gurevitch, 2013</xref>). While meta-analytical studies have been particularly popular in the medical and social sciences, they have been performed for virtually every area of academic research.</p>
<p>The rise of quantitative research synthesis and meta-analysis over the last 25&#xa0;years was aided by a series of software packages providing simple and accessible GUI interfaces which are intuitively easy to use for novice analysts and users. MetaWin (<xref ref-type="bibr" rid="B33">Rosenberg et al., 1997</xref>) was first published as a small, commercial software package that made meta-analytical calculations more accessible to the burgeoning research synthesis community, particularly in the ecological sciences, and helped introduce the use of resampling methods into the meta-analytic statistical repertoire (<xref ref-type="bibr" rid="B1">Adams et al., 1997</xref>). Version 2 of the software (<xref ref-type="bibr" rid="B34">Rosenberg et al., 2000</xref>) was substantially expanded over the original version, easier to use, and more flexible and powerful. These software have been cited thousands of times in fields including agriculture, anthropology, biology, business, chemistry, economics, education, engineering, forestry, geography, geology, medicine, physics, and psychology, among others.</p>
<p>Versions 1 and 2 of MetaWin were written in Pascal and Delphi and depended on several commercial licensed packages. These developmental environments and decisions combined to restrict the software to the Windows operating system and prevented any practical open-source release as the software was otherwise uncompilable without these components. These also served to restrict further development and updates as the developmental components and systems gradually became outdated and incompatible with newer operating systems.</p>
<p>Despite these limitations, MetaWin has continued to be regularly used and cited for over 20&#xa0;years after its original release; would-be users still regularly request copies of this relatively ancient software. The long-term popularity has likely been driven by the simple GUI-interface, which contrasts it with powerful, more difficult-to-use alternatives available in R. In an attempt to fill in the gap between MetaWin 2 and the R-based meta-analytic community, OpenMEE (<xref ref-type="bibr" rid="B38">Wallace et al., 2016</xref>) was created as open-source, cross-platform software with a GUI interface, but which used R computation on the backend. OpenMEE appeared to fill many of the needs that MetaWin served, but the software became quickly abandoned with development apparently halted in 2016. To fulfill the continued demand for a GUI-based meta-analytic system, we have now released MetaWin 3.</p>
</sec>
<sec sec-type="materials|methods" id="s2">
<title>2 Materials and methods</title>
<p>MetaWin 3 is free, open-source, and multi-platform, unlike its predecessors. It has been written from scratch relative to the earlier versions, entirely in Python, with the codebase openly available on Github and pre-compiled (using PyInstaller) executables for both Windows and macOS available from the MetaWin website. The code has minimal external dependencies, and relies on only four established, and heavily used Python packages: PyQt6, NumPy, SciPy, and Matplotlib.</p>
<p>The focus of MetaWin is to provide access to meta-analytic fundamentals with an easy-to-use GUI. Output includes citations and references to appropriate literature sources based on method choices made by the users; similarly, all graphical output includes auto-generated sample captions (including references, when appropriate) to ease in interpretation (see below). MetaWin imports and exports data from tables (row &#xd7; column) in standard text formats (<italic>e.g.</italic>, CSV). Textual output can be exported as plain text, HTML, or markdown. Figures can be exported in a variety of standard graphical formats, including both common vector (<italic>e.g.</italic>, SVG, EPS) and raster (<italic>e.g.</italic>, PNG, TIF, JPG) options.</p>
<p>The major functions in MetaWin are roughly divided into four primary categories: effect size calculations, publication bias exploration, meta-analytic computation, and additional graphical output.</p>
<p>Effect size calculations are for standardized effect measures well established in the meta-analytic literature (<xref ref-type="table" rid="T1">Table 1</xref>). Effect size calculation is optional within the MetaWin framework, as a user can always import a pre-calculated effect size and its variance for use in the general analytical computation.</p>
<table-wrap id="T1" position="float">
<label>TABLE 1</label>
<caption>
<p>Standardized effects size metrics included within MetaWin.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Data type</th>
<th align="left">Effect size</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Pairs of means</td>
<td align="left">Hedges&#x2019; <italic>d</italic> <xref ref-type="bibr" rid="B16">Hedges and Olkin (1985)</xref>
</td>
</tr>
<tr>
<td align="left"/>
<td align="left">ln response ratio <xref ref-type="bibr" rid="B15">Hedges et al. (1999)</xref>
</td>
</tr>
<tr>
<td align="left">Two &#xd7; Two contingency tables</td>
<td align="left">ln odds ratio <xref ref-type="bibr" rid="B24">Mantel and Haenszel (1959)</xref>; <xref ref-type="bibr" rid="B34">Rosenberg et al. (2000)</xref>
</td>
</tr>
<tr>
<td align="left"/>
<td align="left">ln relative rate <xref ref-type="bibr" rid="B14">Greenland (1987)</xref>; <xref ref-type="bibr" rid="B21">L&#x2019;Abb&#xe9; et al. (1987)</xref>; <xref ref-type="bibr" rid="B28">Normand (1999)</xref>
</td>
</tr>
<tr>
<td align="left"/>
<td align="left">Rate difference <xref ref-type="bibr" rid="B6">DerSimonian and Laird (1986)</xref>; <xref ref-type="bibr" rid="B21">L&#x2019;Abb&#xe9; et al. (1987)</xref>; <xref ref-type="bibr" rid="B4">Berlin et al. (1989)</xref>; <xref ref-type="bibr" rid="B28">Normand (1999)</xref>
</td>
</tr>
<tr>
<td align="left">Correlations</td>
<td align="left">Fisher&#x2019;s Z-transform <xref ref-type="bibr" rid="B10">Fisher (1928)</xref>
</td>
</tr>
<tr>
<td align="left">Probabilities</td>
<td align="left">Logit <xref ref-type="bibr" rid="B25">Mengersen and Gurevitch (2013)</xref>
</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>Publication bias exploration (<xref ref-type="table" rid="T2">Table 2</xref>) includes both graphical approaches (<italic>e.g.,</italic> funnel plots) and analytical methods such as Egger&#x2019;s Regression, Rank Correlation Tests, and Trim-and-Fill Analysis. Fail-safe number calculation is included as a subcomponent of basic meta-analysis (see below).</p>
<table-wrap id="T2" position="float">
<label>TABLE 2</label>
<caption>
<p>Publication bias methods included in MetaWin.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Method</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Funnel plots <xref ref-type="bibr" rid="B23">Light and Pillemer (1984)</xref>
</td>
</tr>
<tr>
<td align="left">Pseudo-confidence intervals <xref ref-type="bibr" rid="B37">Sterne and Egger (2001)</xref>
</td>
</tr>
<tr>
<td align="left">Contour confidence intervals <xref ref-type="bibr" rid="B30">Peters et al. (2008)</xref>
</td>
</tr>
<tr>
<td align="left">Power-enhancement (Sunset) plot <xref ref-type="bibr" rid="B20">Kossmeier et al. (2020)</xref>
</td>
</tr>
<tr>
<td align="left">Egger regression <xref ref-type="bibr" rid="B9">Egger et al. (1997)</xref>
</td>
</tr>
<tr>
<td align="left">Rank correlation analysis <xref ref-type="bibr" rid="B2">Begg (1994)</xref>; <xref ref-type="bibr" rid="B3">Begg and Mazumdar (1994)</xref>
</td>
</tr>
<tr>
<td align="left">Trim and fill analysis <xref ref-type="bibr" rid="B8">Duval and Tweedie (2000b)</xref>; <xref ref-type="bibr" rid="B7">Duval and Tweedie (2000a)</xref>
</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>There are currently 8 primary analytical methods implemented within MetaWin 3, three of which represent simple and exploratory models, while the other five represent more complex explanatory structural models (<xref ref-type="table" rid="T3">Table 3</xref>), frequently referred to as meta-regression. These include a simple linear model or more complex multivariate models using a general linear model (GLM) regression framework. Most of the methods allow for both fixed- or random-effects variance model implementation; a mixed-effects model meta-analysis (<xref ref-type="bibr" rid="B27">Mengersen et al., 2013</xref>) is performed by using the grouped meta-analysis structure with random-effects variance chosen. Heterogeneity is estimated using both <italic>Q</italic>- and <italic>I</italic>
<sup>2</sup>-statistics (<xref ref-type="bibr" rid="B16">Hedges and Olkin, 1985</xref>; <xref ref-type="bibr" rid="B17">Higgins and Thompson, 2002</xref>; <xref ref-type="bibr" rid="B18">Huedo-Medina et al., 2006</xref>). Most analyses include one or more optional resampling tests for determining confidence intervals or significance testing (<xref ref-type="bibr" rid="B1">Adams et al., 1997</xref>). All of these methods currently implement traditional moments/least-squares estimators for meta-analysis (<xref ref-type="bibr" rid="B32">Rosenberg, 2013</xref>). The basic analysis also includes fail-safe number estimation (<xref ref-type="bibr" rid="B35">Rosenthal, 1979</xref>; <xref ref-type="bibr" rid="B29">Orwin, 1983</xref>; <xref ref-type="bibr" rid="B31">Rosenberg, 2005</xref>).</p>
<table-wrap id="T3" position="float">
<label>TABLE 3</label>
<caption>
<p>Primary meta-analytic methods included in MetaWin.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Simple and exploratory analyses</th>
<th align="left">Complex structural analyses</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Basic meta-analysis <xref ref-type="bibr" rid="B16">Hedges and Olkin (1985)</xref>
</td>
<td align="left">Grouped meta-analysis <xref ref-type="bibr" rid="B16">Hedges and Olkin (1985)</xref>
</td>
</tr>
<tr>
<td align="left">Jackknife meta-analysis</td>
<td align="left">Nested group meta-analysis <xref ref-type="bibr" rid="B32">Rosenberg (2013)</xref>
</td>
</tr>
<tr>
<td align="left">Cumulative meta-analysis <xref ref-type="bibr" rid="B5">Chalmers (1991)</xref>
</td>
<td align="left">Linear meta-regression analysis <xref ref-type="bibr" rid="B16">Hedges and Olkin (1985)</xref>; <xref ref-type="bibr" rid="B14">Greenland (1987)</xref>
</td>
</tr>
<tr>
<td align="left"/>
<td align="left">Complex/GLM meta-analysis <xref ref-type="bibr" rid="B16">Hedges and Olkin (1985)</xref>; <xref ref-type="bibr" rid="B34">Rosenberg et al. (2000)</xref>
</td>
</tr>
<tr>
<td align="left"/>
<td align="left">Phylogenetic GLM meta-analysis <xref ref-type="bibr" rid="B22">Lajeunesse et al. (2013)</xref>
</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>While most of the analytical methods can optionally produce an associated graph or figure, additional figures which have proven useful for meta-analysis can be created outside of the main methods (examples are shown in the panels of <xref ref-type="fig" rid="F1">Figure 1</xref>). These include scatter plots, weighted histograms, forest plots, normal quantile plots (<xref ref-type="bibr" rid="B39">Wang and Bushman, 1998</xref>), and Galbraith radial plots (<xref ref-type="bibr" rid="B11">Galbraith, 1988</xref>; <xref ref-type="bibr" rid="B12">1994</xref>). Figures are customizable and exportable. Additionally, the underlying data can be exported for re-creation in a user&#x2019;s preferred plotting software. All figures include automatically generated captions to aid in interpretation and communication (<xref ref-type="fig" rid="F2">Figure 2</xref>).</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption>
<p>Examples of graphical output from MetaWin. <bold>(A)</bold> Funnel plot with contour confidence intervals. <bold>(B)</bold> A power enhancement funnel plot. <bold>(C)</bold> A forest plot of individual effect sizes and the overall mean and median, including confidence intervals based on both an assumption of a normal distribution and bootstrapping. <bold>(D)</bold> A forest plot of a cumulative meta-analysis.</p>
</caption>
<graphic xlink:href="fbinf-04-1305969-g001.tif"/>
</fig>
<fig id="F2" position="float">
<label>FIGURE 2</label>
<caption>
<p>Example of the graphical output from a Trim-and-Fill Analysis. The following caption is automatically generated by MetaWin as part of the figure creation, including the associated reference information: &#x201C;Funnel plot of effect vs. precision, showing the results of a Trim and Fill Analysis (<xref ref-type="bibr" rid="B7">Duval and Tweedie, 2000a</xref>; <xref ref-type="bibr" rid="B8">Duval and Tweedie, 2000b</xref>). Original data are represented by black circles, inferred &#x201c;missing&#x201d; data by open circles with a fire engine red border. The dashed silver line represents the mean effect size of the original data, the dashed fire engine red line the mean effect size including the inferred data.&#x201D;</p>
</caption>
<graphic xlink:href="fbinf-04-1305969-g002.tif"/>
</fig>
</sec>
<sec sec-type="results|discussion" id="s3">
<title>3 Results and discussion</title>
<p>The immediate goal of the current release of MetaWin was to minimally replicate what older versions of the software could do in a modern package, along with adding some obvious enhancements reflecting methodological advancement from the past 20&#xa0;years. Over half of the analyses listed in <xref ref-type="table" rid="T2">Tables 2</xref>, <xref ref-type="table" rid="T3">3</xref> were not available in earlier versions of the software. This package now forms a platform to add additional features and analytical methods, for example, potentially including maximum likelihood (<xref ref-type="bibr" rid="B26">Mengersen and Schmid, 2013</xref>) and/or Bayesian inference (<xref ref-type="bibr" rid="B36">Schmid and Mengersen, 2013</xref>) solutions, which would allow greater flexibility in model specification and distributional assumptions then the currently implemented least-squares approach. Many additional analytical ideas and approaches in meta-analysis have been developed across a broad research synthesis community and could be added to MetaWin in the future, depending on demand, fit, and computational complexity, including additional effect size metrics, analysis models, plots, publication-bias and outlier estimators, etc.</p>
</sec>
<sec id="s4">
<title>4 Availability</title>
<p>MetaWin is free and released under a GPL-3.0 license. Pre-compiled versions of MetaWin for both Windows and macOS can be downloaded directly from <ext-link ext-link-type="uri" xlink:href="https://www.metawinsoft.com">https://www.metawinsoft.com</ext-link>. The entire codebase is open-source and available on Github at <ext-link ext-link-type="uri" xlink:href="https://www.github.com/msrosenberg/MetaWin">https://www.github.com/msrosenberg/MetaWin</ext-link>. The help manual can be found on the MetaWin website and is also accessible offline bundled within the pre-compiled executables.</p>
</sec>
</body>
<back>
<sec sec-type="data-availability" id="s5">
<title>Data availability statement</title>
<p>Publicly available datasets were analyzed in this study. This data can be found here: <ext-link ext-link-type="uri" xlink:href="https://www.github.com/msrosenberg/MetaWin">https://www.github.com/msrosenberg/MetaWin</ext-link>.</p>
</sec>
<sec id="s6">
<title>Author contributions</title>
<p>MR: Conceptualization, Methodology, Project administration, Resources, Software, Validation, Writing&#x2013;original draft.</p>
</sec>
<sec sec-type="funding-information" id="s7">
<title>Funding</title>
<p>The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported in part by Virginia Commonwealth University.</p>
</sec>
<sec sec-type="COI-statement" id="s8">
<title>Conflict of interest</title>
<p>The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="s9">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
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