United States

&lt;p&gt;Noémie Aubert Bonn,&lt;sup&gt;1,2&lt;/sup&gt; Lukas Hughes-Noehrer&lt;sup&gt;1&lt;/sup&gt;&lt;/p&gt;
&lt;h4&gt;Objective &lt;/h4&gt;
&lt;p&gt;The impact that research environments have on the quality of research has gained heightened visibility in the past few years. The Research Excellence Framework (REF), a UK-wide funding exercise that assesses higher education institutions (HEIs) on the excellence of their research, includes research environment as part of the elements it assesses. Recently, the weight of research environment was increased to one-fourth of the total score, bringing it closer to the other elements of research outputs and impacts. However, measuring positive research environments is challenging and clear indicators are still hard to delineate.&lt;/p&gt;
&lt;h4&gt;Design &lt;/h4&gt;
&lt;p&gt;To identify indicators that may be associated with positive research environments, we conducted a qualitative analysis of environment statements submitted to REF 2021.&lt;sup&gt;1&lt;/sup&gt; We sampled 34 four-star statements drawn from different units of assessment (ie, academic disciplines) available openly on the REF website. Four-star scores are given to statements that describe “an environment that is conducive to producing research of world-leading quality and enabling outstanding impact, in terms of its vitality and sustainability.” Using these statements, 1 researcher conducted a mix of inductive (first 17 statements in NVivo 12) and deductive (last 17 statements) thematic analysis to extract the potential indicators of positive research environments. These indicators were organized in core themes, discussed with the research team, and compared with existing recommendations, policies, and literature on healthy research environments to build an exhaustive overview of possible indicators.&lt;/p&gt;
&lt;h4&gt;Results &lt;/h4&gt;
&lt;p&gt;The analysis  identified a vast array of elements, which were used to showcase positive research environments. We organized the elements extracted in indicators providing details on people, such as diversity metrics, staff and student characteristics, and measures to improve equity, diversity, and inclusion; indicators demonstrating positive research cultures, such as responsible leadership, collaborative culture, research integrity, and open research; and indicators demonstrating positive research environments, such as capacity-building measures, staff and financial support, employment security and progression, and responsible assessment practices (&lt;b&gt;Table 25-0889&lt;/b&gt;). The breadth of indicators identified showcased differences and similarities in how different institutions and units of assessment qualified their research environments.&lt;/p&gt;

![](https://assets.underline.io/markdown_image/1/image/8f8b88702af17ad7b2039178c62af22e.png)

&lt;h4&gt;Conclusions &lt;/h4&gt;
&lt;p&gt;Our analysis provided insights on the breadth of elements that can come into play in creating a positive research environment. Despite being drawn from the UK landscape, our findings could be relevant to a broad diversity of research settings. For example, our findings could help support more comprehensive research assessment or they could help inspire concrete actions to improve research environments in HEIs.&lt;/p&gt;
&lt;h4&gt;Reference&lt;/h4&gt;
&lt;p&gt;1. Research Excellence Framework. Results and submissions. May 12, 2022. Accessed June 24, 2025. &lt;a href=&quot;https://results2021.ref.ac.uk/&quot;&gt;https://results2021.ref.ac.uk/&lt;/a&gt;&lt;/p&gt;
&lt;sup&gt;1&lt;/sup&gt;The University of Manchester, Department of Computer Science, Faculty of Science and Engineering, Manchester, UK, noemie. aubertbonn@manchester.ac.uk; &lt;sup&gt;2&lt;/sup&gt;Hasselt University, Department of Healthcare &amp; Ethics, Faculty of Medicine, Hasselt, Belgium. 
&lt;h4&gt;Conflict of Interest Disclosures&lt;/h4&gt; Noémie Aubert Bonn was employed as a senior policy advisor with Research England from 2022 to 2023. 
&lt;h4&gt;Funding/Support&lt;/h4&gt; The conceptualization, design, and part of the analysis was carried out and supported during Noémie Aubert Bonn’s employment at Research England. The analysis software subscription was provided by Hasselt University, Belgium. &lt;h4&gt;Role of the Funder/Sponsor&lt;/h4&gt; The conclusions of the study are independent from Research England. 
&lt;h4&gt;Acknowledgment&lt;/h4&gt; We wish to thank all the members of the People, Culture and Environment team at Research England who provided feedback and discussion throughout this project, particularly Catriona Firth, Claire Fraser, Steven Hill, Myles Furr, Marie-Helene Nienaltowski, Duncan Shermer, and Nicole Dixon. We also wish to thank everyone within UK Research and Innovation and The University of Manchester who provided feedback and insights on this project.


The 10th Peer Review Congress

Extracting Research Environment Indicators From the UK Research Excellence Framework 2021 Statements

funding/grant peer review

diversity and inclusion

peer review

The Tenth Peer Review Congress featured 3 days for presentations of new research into peer review and all aspects of scientific publication, bias, quality of reporting, and information access and dissemination.

This year’s meeting was hybrid, and all plenary sessions were livestreamed with opportunities to view presentations and engage with participants in person and virtually during and after the meeting. All recordings are now available on Underline for viewing.

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The Tenth Peer Review Congress features 3 days for presentations of new research into peer review and all aspects of scientific publication, bias, quality of reporting, and information access and dissemination.

<p>Noémie Aubert Bonn,<sup>1,2</sup> Lukas Hughes-Noehrer<sup>1</sup></p>
<h4>Objective </h4>
<p>The impact that research environments have on the quality of research has gained heightened visibility in the past few years. The Research Excellence Framework (REF), a UK-wide funding exercise that assesses higher education institutions (HEIs) on the excellence of their research, includes research environment as part of the elements it assesses. Recently, the weight of research environment was increased to one-fourth of the total score, bringing it closer to the other elements of research outputs and impacts. However, measuring positive research environments is challenging and clear indicators are still hard to delineate.</p>
<h4>Design </h4>
<p>To identify indicators that may be associated with positive research environments, we conducted a qualitative analysis of environment statements submitted to REF 2021.<sup>1</sup> We sampled 34 four-star statements drawn from different units of assessment (ie, academic disciplines) available openly on the REF website. Four-star scores are given to statements that describe “an environment that is conducive to producing research of world-leading quality and enabling outstanding impact, in terms of its vitality and sustainability.” Using these statements, 1 researcher conducted a mix of inductive (first 17 statements in NVivo 12) and deductive (last 17 statements) thematic analysis to extract the potential indicators of positive research environments. These indicators were organized in core themes, discussed with the research team, and compared with existing recommendations, policies, and literature on healthy research environments to build an exhaustive overview of possible indicators.</p>
<h4>Results </h4>
<p>The analysis  identified a vast array of elements, which were used to showcase positive research environments. We organized the elements extracted in indicators providing details on people, such as diversity metrics, staff and student characteristics, and measures to improve equity, diversity, and inclusion; indicators demonstrating positive research cultures, such as responsible leadership, collaborative culture, research integrity, and open research; and indicators demonstrating positive research environments, such as capacity-building measures, staff and financial support, employment security and progression, and responsible assessment practices (<b>Table 25-0889</b>). The breadth of indicators identified showcased differences and similarities in how different institutions and units of assessment qualified their research environments.</p>

![](https://assets.underline.io/markdown_image/1/image/8f8b88702af17ad7b2039178c62af22e.png)

<h4>Conclusions </h4>
<p>Our analysis provided insights on the breadth of elements that can come into play in creating a positive research environment. Despite being drawn from the UK landscape, our findings could be relevant to a broad diversity of research settings. For example, our findings could help support more comprehensive research assessment or they could help inspire concrete actions to improve research environments in HEIs.</p>
<h4>Reference</h4>
<p>1. Research Excellence Framework. Results and submissions. May 12, 2022. Accessed June 24, 2025. <a href="https://results2021.ref.ac.uk/">https://results2021.ref.ac.uk/</a></p>
<sup>1</sup>The University of Manchester, Department of Computer Science, Faculty of Science and Engineering, Manchester, UK, noemie. aubertbonn@manchester.ac.uk; <sup>2</sup>Hasselt University, Department of Healthcare & Ethics, Faculty of Medicine, Hasselt, Belgium. 
<h4>Conflict of Interest Disclosures</h4> Noémie Aubert Bonn was employed as a senior policy advisor with Research England from 2022 to 2023. 
<h4>Funding/Support</h4> The conceptualization, design, and part of the analysis was carried out and supported during Noémie Aubert Bonn’s employment at Research England. The analysis software subscription was provided by Hasselt University, Belgium. <h4>Role of the Funder/Sponsor</h4> The conclusions of the study are independent from Research England. 
<h4>Acknowledgment</h4> We wish to thank all the members of the People, Culture and Environment team at Research England who provided feedback and discussion throughout this project, particularly Catriona Firth, Claire Fraser, Steven Hill, Myles Furr, Marie-Helene Nienaltowski, Duncan Shermer, and Nicole Dixon. We also wish to thank everyone within UK Research and Innovation and The University of Manchester who provided feedback and insights on this project.


technical paper

<p>Ahmad Sofi-Mahmudi,<sup>1</sup> Hesam Salmabadi<sup>2</sup></p>
<h4>Objective</h4>
<p> To evaluate the association between countries’ democratic status and scientific article retraction rates while exploring potential factors influencing this association.</p>
<h4>Design</h4>
<p> This retrospective cohort study analyzed publication and retraction data from 2006 to 2023. Data sources included the Retraction Watch Database for retraction data (n = 64,264 retractions), the Economist Intelligence Unit’s Democracy Index for democratic status, and SCImago for country-specific publication outputs (n = 59,385,751 publications). Our primary outcome was retraction rate (retractions per 10,000 publications) rather than absolute retraction counts, to account for varying publication volumes across countries. Using bayesian hierarchical negative binomial regression models with multiple imputations for missing data, we examined the association between the democracy index and article retractions while controlling for key confounders, including gross domestic product (GDP) per capita, research investment as percentage of GDP, English language proficiency scores, corruption control, government effectiveness, regulatory quality, rule of law, press freedom, and international collaboration rates, across 167 countries.</p>
<h4>Results</h4>
<p> The analysis of 167 countries demonstrated a median democracy index score of 5.71 (range, 1.05-9.81) and a median scientific publication retraction rate of 5.3 per 10,000 publications (range, 0-214.8). Higher democracy scores were associated with lower retraction rates (adjusted coefficient, −0.46; 95% credible interval [CrI], −0.59 to −0.32) after controlling for confounders (<b>Figure 25-1106</b>). Among institutional factors, rule of law showed a positive association (0.40; 95% CrI, 0.17-0.63), whereas corruption control demonstrated a negative association (−0.54; 95% CrI, −0.72 to −0.36) with retraction rates. The association between democracy and retractions remained stable across periods (interaction coefficient, −0.03; 95% CrI, −0.46 to 0.39), although press freedom effects varied significantly between the 2006 to 2012 and 2013 to 2023 periods (interaction coefficient, −1.40; 95% CrI, −1.77 to −1.03). GDP per capita (0.09; 95% CrI, 0.01-0.17) and government effectiveness (0.21; 95% CrI, 0.01-0.41) were positively associated with retraction rates, suggesting better detection and correction mechanisms in wealthier, more effectively governed countries.</p>

![](https://assets.underline.io/markdown_image/1/image/7d8b6c98d8de5538c342378e51b17ad2.png)

<h4>Conclusions</h4>
<p> Democratic status shows a negative association with scientific article retraction rates, although this association is complex and mediated by institutional factors. The findings suggest that while democratic societies may have lower rates of problematic research requiring retraction, they also demonstrate stronger institutional capacity for detecting and addressing research misconduct.</p>
<h4>Affiliations</h4> <sup>1</sup>Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada, a.sofimahmudi@ gmail.com; <sup>2</sup>Department of Environmental Sciences, University of Quebec in Trois-Rivières, Trois-Rivières, Quebec, Canada. <h4>Conflict of Interest Disclosures</h4> Ahmad Sofi-Mahmudi is an employee of Cytel Canada Health Inc. <h4>Additional Information</h4> We used Claude, 3.5 Sonnet (claude-35-sonnet-20241022) through its website for refining the analysis codes. Also, it was used as a grammar and flow checker of the abstract.


Retractions and Democracy Index Scores Across 167 Countries

<p>João Phillipe Cardenuto,<sup>1</sup> Daniel Moreira,<sup>2</sup> Anderson Rocha<sup>1</sup></p>
<h4>Objective</h4>
<p> To quantitatively analyze the types, contexts, and manipulation methods of problematic images that lead to retractions of scientific articles.</p>
<h4>Design</h4>
<p> This cross-sectional study analyzed retracted articles flagged for problematic image manipulation (eg, image duplication) in the Retraction Watch Database<sup>1</sup> (56,716 entries as of October 4, 2024). We focused on entries containing the term <i>image</i> in the retraction reason (8002 entries) and further refined the dataset to those discussed on PubPeer<sup>2</sup> (2078 after duplicate removal) to gain more detailed insights into the image problems. Data extracted included figure types (eg, microscopy, gel blot), the context of image misuse (eg, within-article, between-article), and the type of manipulation (eg, duplication, splicing).</p>
<h4>Results</h4>
<p> The Table presents our results (<b>Table 25-0965</b>). Gel blots (eg, Western blots) were the most frequently cited image type in problematic retractions, appearing in 1074 articles (51.68%). Between-article image reuse, where an image and its associated data are duplicated across different publications, was the most common context of misuse, identified in 1241 cases (59.72%). Notably, 982 retractions (47.28%) were attributed to paper mills. Image duplication was the predominant cause of retraction, accounting for 1827 cases (87.92%). Only 1 retraction was attributed to computer- or artificial intelligence–generated manipulation. While our analysis did not filter by the biomedical area, most problematic images originated from the biomedical domain.</p>

![](https://assets.underline.io/markdown_image/1/image/0773fe066647557e1654c0bd3b16d9a9.png)

<h4>Conclusions</h4>
<p> This study highlights the prevalence of gel blot images and between-article image duplication in retracted articles, indicating a potential benefit from specialized tools to detect such issues. During our analysis, we noticed a frequent lack of detailed and standardized information in retraction notices, which hinders efforts to understand and prevent the presented problems. While PubPeer data offer valuable insights when the retraction notices fail to do so, PubPeer posts are not official documents and may exhibit biases from their authors, which could result in speculative claims about an article. Because of that, to facilitate research and improve the integrity of the scientific record, future research should focus on discussing and developing better guidelines for comprehensive retraction notices that may even support computer-aided solutions.</p>
<h4>References</h4>
<p>1. The Retraction Watch Database. Accessed January 31, 2025. <a href="http://retractiondatabase.org/">http://retractiondatabase.org/</a></p>
<p>2. PubPeer. Accessed January 31, 2025. <a href="https://pubpeer.com"><span class="CharOverride-10">https://pubpeer.com</span></a></p>
<p>
  <sup>1</sup>Artificial Intelligence Lab, Recod.ai, Institute of Computing, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil, phillipe.cardenuto@ic.unicamp.br; 
  <sup>2</sup>Department of Computer Science, Loyola University Chicago, Chicago, IL, US.
</p>

<h4>Conflict of Interest Disclosures</h4>
<p>None reported.</p>

<h4>Funding/Support</h4>
<p>This study was supported by the National Council for Scientific and Technological Development–CNPq (grant No. 442229/2024-0) and by the São Paulo Research Foundation–FAPESP (grant No. 2023/12865-8).</p>

<h4>Role of the Funder/Sponsor</h4>
<p>The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the abstract.</p>


Characterizing Problematic Images in Retracted Scientific Articles

<p>Reese A. K. Richardson,<sup>1,2</sup> Jeonghyun Moon,<sup>1</sup> Spencer S. Hong,<sup>1,3</sup> Luis A. Nunes Amaral<sup>1,2,4,5,6</sup></p>
<h4>Objective</h4>
<p> Materials science and engineering (MSE) research has, for the most part, escaped the doubts raised about the reliability of scientific literature by recent large-scale replication studies in psychology and cancer biology. However, users on postpublication peer review sites have recently identified dozens of articles where the make and model of the scanning electron microscope (SEM) listed in the text does not match the instrument’s metadata visible in the images in the published article.</p>
<h4>Design </h4>
<p>To systematically investigate this potential risk to the MSE literature, we developed a semiautomated approach using optical character recognition to scan published figures for instrumental metadata banners and check the information contained in these banners on instrument manufacturer and model against the SEM instrument identified in the text. We validated our approach by evaluating model performance on known instances of SEM misidentification and manual reevaluation of novel instances of SEM misidentification returned by the pipeline. This analysis was performed in January 2024.</p>
<h4>Results</h4>
<p> Starting from a set of 1,067,102 articles published since 2010 (as indexed by OpenAlex, downloaded on February 27, 2023) in 50 MSE journals (selected according to the publisher’s permissiveness of text and data mining and to represent a broad range of subdisciplines and impact factors), we identified 11,314 articles for which SEM make and model could be identified in an image’s metadata. For 2400 of those articles (21.2%), the image metadata did not match the SEM manufacturer or model listed in the text, and for another 2799 (24.7%), at least some of the instruments used in the study were not reported. We found that articles with SEM misidentification were more likely to have existing PubPeer comments than articles without (43 of 2400 [1.8%] vs 984 of 171,646 [0.5%]; <i>P</i> = 9.98 × 10<sup>-15</sup>) and that electrochemistry articles that featured SEM misidentification, compared with those that did not have SEM misidentification, were more likely to make a crucial error in their determination of optical band gap (41 of 154 [26.6%] vs 100 of 751 [13.3%]; <i>P</i> = 3.35 × 10<sup>-5</sup>).</p>
<h4>Conclusions</h4>
<p> Our results suggest that SEM misidentification can be a valuable indicator of irreproducibility in the results of extant scientific articles. We recommend that peer reviewers, before and after publication, remain attentive to the accurate reporting of instruments used in scientific articles. Our selection criteria for journals and the high false-negative rate of our pipeline limit the extent to which our findings are representative of the MSE literature at large. Unexplained textual similarities (eg, the same unlikely typo appearing in dozens of articles) common to many of these articles suggest the involvement of paper mills, organizations that mass produce, sell authorship on, and publish fraudulent scientific manuscripts at scale.</p>
<p>
  <sup>1</sup>Department of Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, IL US, richardsonr43@gmail.com; <sup>2</sup>Department of Molecular Biosciences, Northwestern University, Evanston, IL US; <sup>3</sup>Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL US; <sup>4</sup>Department of Physics and Astronomy, Northwestern University, Evanston, IL, US; <sup>5</sup>Northwestern Institute on Complex Systems, Northwestern University, Evanston, IL, US; <sup>6</sup>NSF-Simons National Institute for Theory and Mathematics in Biology, Chicago, IL, US.
</p>

<h4>Conflict of Interest Disclosures</h4>
<p>None reported.</p>

<h4>Funding/Support</h4>
<p>
  Reese A. K. Richardson was supported in part by the National Institutes of Health Training grant T32GM008449 through Northwestern University’s Biotechnology Training Program; Reese A. K. Richardson gratefully acknowledges funding from the Dr. John N. Nicholson fellowship from Northwestern University and Moderna Inc. Spencer S. Hong gratefully acknowledges support from the Ryan Fellowship and the International Institute for Nanotechnology at Northwestern University; Luis A. Nunes Amaral gratefully acknowledges funding from SCISIPBIO: a data-science approach to evaluating the likelihood of fraud and error in published studies (grant No. 1956338). 

<h4>Role of the Funder/Sponsor</h4> The funders had no role in the design or execution of this study.



Misidentification of Scanning Electron Microscope Instruments in the Peer-Reviewed Materials Science and Engineering Literature

<p>Iakovos Evdaimon,<sup>1</sup> John P. A. Ioannidis,<sup>2</sup> Giannis Nikolentzos,<sup>3</sup> Michail Chatzianastasis,<sup>1</sup> George Panagopoulos,<sup>4</sup> Michalis Vazirgiannis<sup>1,5</sup></p>
<h4>Objective</h4>
<p> Citation counts are widely used to evaluate research influence.<sup>1</sup> The h-index, while popular, does not account for how citations are distributed across articles or authors. This is critical when citations are strategically concentrated to boost perceived influence. We studied extreme citation concentration patterns that may distort bibliometric evaluations and merit further scrutiny.<sup>2</sup></p>
<h4>Design</h4>
We analyzed Scopus data up to March 2023, focusing on 1,496,680 authors with more than 5 full articles and at least 1000 citations. We used Scopus-calculated h-indices and citation counts and introduced 3 indicators of extreme citation concentration: C/h2 ratio, A<i><sub>50%C</sub></i> , and A<i><sub>50</sub></i> . For C/h2 ratio, a small value (first percentile, 2.45) indicates that the citations of the author may have been strategically placed to increase the h-index. This metric normalizes citation volume by what would be expected if the h-index reflected broad citation distribution. A<i><sub>50%C</sub></i> measured the number of distinct citing authors contributing at least 50% of an author’s total citations. Extremely low values (first percentile, 5) suggest reliance on few citing sources, possibly from self-citation or closed groups. A<i><sub>50</sub></i> measured the number of coauthors with whom an author has published more than 50 articles. Extremely high values (99th percentile, more than 7) may indicate large-scale collaborations and dense citation clusters. Thresholds were based on the 1% extremes of each metric’s distribution. Authors in physics and astronomy were excluded from A<i><sub>50</sub></i> and A<sub>50%C</sub> analyses due to the influence of nuclear and particle physics. Field definitions followed the ScienceMetrix classification.
<h4>Results</h4>
<p> In the C/h<sup>2</sup> analysis, 14,967 authors (1%) fell below 2.45. These authors had a median of 63 articles, all with h-indices exceeding 21. Fields such as chemistry and earth and environmental sciences showed 1.5-fold higher representation of authors with extremely low C/h<sup>2</sup> scores (<b>Table 25-0974</b>). In the A<i><sub>50%C</sub></i> analysis, 11,277 authors (1%) had 5 or fewer citing authors accounting for 50% of their citations. The median number of articles was 104, and most authors had an h-index greater than 20. Fields with the highest enrichment included chemistry and mathematics and statistics. In the A<i><sub>50</sub></i> analysis, 12,015 authors (1%) had more than 7 highly recurrent coauthors (50 or more shared publications). These authors were exceptionally prolific (median, 596 articles) and had very high h-indices (median, 56; 12.8% with an h-index greater than 100). A total of 73.3% were in clinical medicine. Co-occurrence analysis revealed a strong association between low C/h<sup>2</sup> and low A<i><sub>50%C</sub></i> values (odds ratio, 6.4; 95% CI, 5.9-6.9). There was modest coexistence for extremely low A<i><sub>50%C</sub></i> and extremely high A<i><sub>50</sub></i> values (odds ratio, 1.5; 95% CI, 1.3-1.7). Extremely low C/h<sup>2</sup> very rarely co-occurred with extremely high A<i><sub>50</sub></i> values (odds ratio, 0.09; 95% CI, 0.05-0.16).</p>

![](https://assets.underline.io/markdown_image/1/image/74d68afd39138897dab9923e970655c4.png)

<h4>Conclusions</h4>
<p> Extreme patterns of citation concentration can substantially distort citation-based metrics, especially the h-index. While not implying misconduct, these metrics highlight outliers where citation behavior diverges from norms. Such metrics may serve as red flags for further analysis.</p>
<h4>References</h4>
<p>1. Bornmann L. How are excellent (highly cited) papers defined in bibliometrics? a quantitative analysis of the literature. <i>Res Eval</i>. 2014;23(2):166-173. doi:10.1093/reseval/rvu002</p>
<p>2. Waltman L, van Eck NJ, van Leeuwen TN, Visser MS, van Raan AFJ. Towards a new crown indicator: some theoretical considerations. <i>J Informetrics</i>. 2011;5(1):37-47. doi:10.1016/j.joi.2010.08.001</p>
<sup>1</sup>LIX, École Polytechnique, Institut Polytechnique de Paris, Palaiseau, France; <sup>2</sup>Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA, US, jioannid@stanford.edu; <sup>3</sup>Department of Informatics and Telecommunications, University of Peloponnese, Tripoli, Greece; <sup>4</sup>Department of Computer Science, University of Luxembourg, Esch-sur-Alzette, Luxembourg; <sup>5</sup>Mohamed bin Zayed University of Artificial Intelligence, Masdar City, Abu Dhabi, United Arab Emirates.
<h4>Conflict of Interest Disclosures</h4> John P. A. Ioannidis is a member of the Peer Review Congress Advisory Board but was not involved in the review or decision for this abstract. No other disclosures were reported. 
<h4>Additional Information</h4> Iakovos Evdaimon is a cocorresponding author (ievdaimon7@gmail.com).



Indicators of Small-Scale and Large-Scale Citation Concentration Patterns

<p>Reese A. K. Richardson,<sup>1,2</sup> Spencer S. Hong,<sup>1,3</sup> Jennifer A. Byrne,<sup>4,5</sup> Thomas Stoeger,<sup>6,7,8</sup> Luís A. Nunes Amaral<sup>1,2,9,10,11</sup></p>
<h4>Objective </h4>
<p>Some suggest that the ease of communication provided by the internet and open access publishing has created the conditions for the emergence of entities (including paper mills, brokers, and predatory publishers) that facilitate systematic scientific fraud. However, little is understood about the organization of these entities as well as how they react to and evade science integrity measures. Here, we sought to demonstrate that large networks that produce scientific fraud at scale can be identified by the footprints they have left in the published scientific literature. These footprints can be analyzed to glean insights about their organizational structure and operations.</p>
<h4>Design </h4>
<p>Our work consisted of observational case studies making use of article metadata from OpenAlex and the complete corpora of <i>PLOS One </i>and Hindawi articles; all PubPeer comments made before January 2024; historical indexing data from MEDLINE, Scopus, and Web of Science; and archived webpages obtained with the Internet Archive’s Wayback Machine. Our case studies addressed networks of compromised editors at large mega-journals, analysis of article provenance through observations of interarticle image duplication, a longitudinal study of the operations of a large broker organization, a comparison of revision and retraction rates in closely related biomedical subfields, and an overall assessment of growth rates of systematic scientific fraud. This analysis was performed from June to September 2024.</p>
<h4>Results </h4>
<p>We identified 45 editors at <i>PLOS One</i>, 53 editors at 10 Hindawi journals, and 205 Institute of Electrical and Electronics Engineers (IEEE) conferences that handled articles that were eventually retracted, articles with PubPeer comments, or articles featuring tortured phrases far more often than expected by chance (1-sided Poisson binomial test, Benjamini-Hochberg false discovery rate, &lt;0.05). We characterized a network of image duplication spanning 2213 articles. We catalogued the involvement of a broker organization with an evolving portfolio spanning 188 journals over 7 years. We found similar rates of revision in subfields of RNA biology but retraction rates orders of magnitude apart. We found that while publication rates of scientific articles doubled approximately every 15 years and the publication rates of eventually retracted articles every 3 years, articles of likely paper mill provenance were published at a rate that doubled less than every 2 years.</p>
<h4>Conclusions </h4>
<p>Here, we demonstrated through case studies that (1) individuals have colluded to publish problematic papers in a number of journals; (2) brokers can ensure publication in infiltrated journals at scale; and (3) within a field of science, not all subfields are equally targeted for scientific fraud. Our results revealed some of the strategies that enable entities promoting scientific fraud to evade interventions. Our final analysis suggested that this ability to evade interventions is enabling the number of fraudulent publications to grow at a rate far outpacing that of legitimate science.</p>
<h4>Author Affiliations</h4>
<sup>1</sup>Department of Engineering Sciences & Applied Mathematics, Northwestern University, Evanston, IL, US, richardsonr43@gmail.com; <sup>2</sup>Department of Molecular Biosciences, Northwestern University, Evanston, IL, US; <sup>3</sup>Department of Chemical & Biological Engineering, Northwestern University, Evanston, IL, US; <sup>4</sup>School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, NSW, Australia; <sup>5</sup>NSW Health Statewide Biobank, NSW Health Pathology, Camperdown, NSW, Australia; <sup>6</sup>The Potocsnak Longevity Institute, Northwestern University, Chicago, IL, US; <sup>7</sup>Simpson Querrey Lung Institute for Translational Science, Northwestern University, Chicago, IL, US; <sup>8</sup>Division of Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL, US; <sup>9</sup>Department of Physics and Astronomy, Northwestern University, Evanston, IL, US; <sup>10</sup>Northwestern Institute on Complex Systems, Northwestern University, Evanston, IL, US; <sup>11</sup>NSF-Simons National Institute for Theory and Mathematics in Biology, Chicago, IL, US.
<h4>Conflict of Interest Disclosures</h4>
Luís A. Nunes Amaral is a member of the Peer Review Congress Advisory Board but was not involved in the review or decision for this abstract.

<h4>Funding/Support</h4>
Reese A. K. Richardson was supported in part by a National Institutes of Health Training Grant (T32GM008449) through Northwestern University’s Biotechnology Training Program and receives funding from the Dr John N. Nicholson Fellowship from Northwestern University and Moderna. Spencer S. Hong receives support from the Ryan Fellowship and the International Institute for Nanotechnology at Northwestern University. Jennifer A. Byrne receives funding from a National Health and Medical Research Council of Australia Ideas grant (APP1184263) and Rewarding Research Success funding from the Faculty of Medicine and Health at The University of Sydney. Thomas Stoeger receives funding from the National Institute on Aging, Integrative Multi-Scale Systems Analysis of Gene-Expression-Driven Aging Morbidity (R00AG068544), National Institute of Allergy and Infectious Diseases (AI135964), and Successful Clinical Response In Pneumonia Therapy (SCRIPT) Systems Biology Center. Luís A. Nunes Amaral and Thomas Stoeger receive funding from SCISIPBIO: a data-science approach to evaluating the likelihood of fraud and error in published studies (1956338).
<h4>Role of the Funder/Sponsor</h4>
The funders had no role in the design or execution of this study.



Scale and Resilience in Organizations Enabling Systematic Scientific Fraud

<p>Anna Abalkina,<sup>1</sup> Svetlana Kleiner<sup>2</sup></p>
<h4>Objective </h4>
<p>Paper mills pose a significant challenge to the scientific community, yet knowledge of paper mills remains fragmented. An estimated 400,000 studies originate from paper mills,<sup>1</sup> although only 56,000 have been retracted or corrected. This study investigated the patterns of paper-mill articles and the challenges of their retraction, using a sample from Tanu.pro,<sup>2</sup> one of Europe’s largest paper mills.</p>
<h4>Design</h4>
<p> Tanu.pro creates unique emails to submit papers, often leading to discrepancies between the country domains and authors’ affiliations. Employing a snowball method, the study identified more than 60 suspicious email domains, such as tanu.pro (which gave the paper mill its title in the literature). To retrieve Tanu.pro articles, we conducted a full-text search in Scopus on these domains on December 14, 2024. Combining both outsider and insider perspectives, we analyzed the retraction challenges, focusing on Tanu.pro papers published in Springer journals. A sample of 77 Springer articles was used to examine scholars’ positions and compare the results with a control group of 77 randomly selected articles without paper-mill hallmarks but with the matching indicators (year, journal, number of coauthors). The ranks and positions of all authors in both groups were examined, where possible, at the time of submission.</p>
<h4>Results </h4>
<p>The study detected 1517 papers published between 2017 and 2025 in 380 journals and coauthored by more than 4500 scholars from 46 countries and over 460 universities. While a problematic email was not definitive proof of malpractice, there was evidence that some Tanu.pro papers were associated with an author number anomaly (<b>Figure 25-1113</b>), poor empirical analysis, irrelevant citations, data fabrication, errors, fake reviewer suggestions, compromised special issues, and translated plagiarism. The Springer articles were initially identified by authors’ emails; an additional selection criterion was the presence of suggested reviewers. Tanu.pro papers had a higher proportion of scholars occupying top university positions, such as professors or department heads, than in the control group (44% vs 30%). A problematic email as the only evidence posed challenges for action by journals when other issues are absent: 20 of the 77 Tanu.pro articles (26%) could not be retracted under current Committee on Publication Ethics (COPE) guidelines. Editors also felt more reluctant to retract when the only red flags were emails and unused suggested reviewers.</p>

![](https://assets.underline.io/markdown_image/1/image/05c9b5fc3034d8ef288f41a58baaaf9c.png)

<h4>Conclusions </h4>
<p>The study has shown that specific paper mill patterns are useful when investigating problematic articles. However, some red flags are insufficient grounds for paper retraction due to limited clarity of COPE guidelines that place some articles in the gray zone if they do not feature strong grounds for retraction. More retractable categories are necessary so that COPE members can mark dubious research more easily, eg, undisclosed third-party submission. Although our recommendations are limited by the analysis of one paper mill, COPE guidelines need regular updating considering patterns of other paper mills.</p>
<h4>References</h4>
<p>1. Van Noorden R. How big is science’s fake-paper problem? <i>Nature</i>. 2023;623(7987):466-467. doi:10.1038/d41586-023-03464-x</p>
<p>2. Bishop D, Abalkina A. Paper mills: a novel form of publishing malpractice affecting psychology. <i>Meta-Psy</i>. March 17, 2024. <a href="https://open.lnu.se/index.php/metapsychology/article/view/3422">https://open.lnu.se/index.php/metapsychology/article/view/3422</a></p>
<h4>Affiliations</h4> <sup>1</sup>Freie Universität Berlin, Berlin, Germany, abalkina@gmail.com; <sup>2</sup>Springer Nature, Dordrecht, the Netherlands. <h4>Conflict of Interest Disclosures</h4> None reported.


Patterns of Paper Mill Papers and Retraction Challenges

<p>Renee V. Hoch,<sup>1</sup> Emily J. Chenette<sup>1</sup></p>
<h4>Objective </h4>
<p><i>PLOS One </i>has experienced a sharp rise in paper mills and poor-quality submissions since 2021 and has taken an agile, multifaceted preventive approach to address these issues at scale. This quality improvement study evaluated trends in large-scale integrity issues (ie, megacases) at <i>PLOS One</i> between 2021 and 2024 and the impacts of preventive initiatives on the journal’s ability to address megacase concerns prior to publication.</p>
<h4>Design</h4>
<p> We analyzed temporal and geographic trends, issue types, and research areas for megacases detected at <i>PLOS One</i> between 2021 and 2024. We then evaluated changes to desk reject rates following specific interventions as well as changes to the pre- vs postpublication impacts of megacases over time.</p>
<h4>Results</h4>
<p> Between 2021 and 2024, <i>PLOS One</i> detected 50 megacases that cumulatively involved more than 7000 submissions and publications, with concerns including paper mills (42%; 21 of 50), authorship (22%; 11 of 50), peer review (52%; 26 of 50), and policy compliance (12%; 6 of 50). Megacases spanned multiple research areas, with the highest representation in the physical sciences and engineering (42%; 21 of 50) and medicine and public health (18%; 9 of 50). Most megacases involved submissions from geographically clustered author groups; megacases were received from 19 countries, with the highest representation from Pakistan (20%; 10 of 50), China (18%; 9 of 50), and India (10%; 5 of 50). The number of megacases detected by PLOS increased from 2 (214 articles) in 2021 to 25 (4310 articles) in 2024, and during this time the journal’s desk reject rate more than doubled, from 13% (5188 of 40,548) in 2021 to 27% (16,160 of 59,425) in 2024. In 2024 alone, we rejected more than 3000 submissions flagged for megacase concerns. Desk reject data in periods before and after specific preventive interventions indicated that each of these efforts increased the journal’s ability to detect and/or reject concerning content (<b>Table 25-0967</b>
	). We quantified pre- vs postpublication megacase impacts using a preventive efficacy metric, defined as the number of submissions flagged for megacase concerns (ie, prepublication impact) divided by the number of affected publications (ie, postpublication impact). <i>PLOS One</i>’s preventive efficacy increased from 0.70 in 2022 to 9.09 in 2024; the cumulative number of affected articles increased substantially during this time, but articles of concern were increasingly rejected prepublication, and the postpublication impact actually decreased (530 affected publications in 2022 vs 427 affected publications in 2024).</p>
	
![](https://assets.underline.io/markdown_image/1/image/b1311984a7ead8b037c781f0545fc4ac.png)

<h4>Conclusions</h4>
<p> Large-scale integrity issues have risen considerably in recent years, affecting a broad array of subject areas and geographies. Through varied approaches, <i>PLOS One</i> has improved prepublication detection and rejection of content linked to megacases. This reduces the volume of unreliable publications, the resources required to address these integrity issues, and the impacts of megacases on peer review. Such scalable preventive approaches are crucial to the long-term sustainability of integrity work in an era of increasing paper mill activity.</p>
<h4>Affiliations</h4> <sup>1</sup>PLOS (Public Library of Science), Cambridge, UK, and San Francisco, CA, US, rhoch@plos.org. <h4>Conflict of Interest Disclosures</h4> Renee V. Hoch is an employee of PLOS; the head of the PLOS Publication Ethics team; a member of the Committee on Publication Ethics (COPE) Council, a United2Act Working Group, and an STM Task & Finish Working Group that developed guidance pertaining to large-scale integrity cases; a former member of the COPE Paper Mills Working Group; and a coauthor of COPE guidance on addressing large-scale paper mill issues. Emily J. Chenette is an employee of PLOS and is the editor in chief of <i>PLOS One</i> and head of PLOS editorial board services. <h4>Acknowledgment</h4> We thank the <i>PLOS One</i> Editorial and Publication Ethics teams for their work identifying and addressing large-scale cases, the PLOS editorial board management team for their help investigating and offboarding editorial board members of concern, and the PLOS Digital team for their help developing data analytics and technology tools needed for this work. Thanks also to Suzanne Farley, Rebecca Kirk, Zena Nyakoojo, and Dena Emmerson for their input on this abstract. <h4>Additional Information</h4> PLOS data and resources were used for this study, and others within PLOS Editorial provided input and contributed to the work underlying the datasets. PLOS was not otherwise involved in the reported study.



Sustainable Approaches to Upholding High Integrity Standards in the Face of Large-Scale Threats: Insights From PLOS One

<p>Malcolm Macleod<sup>1</sup></p>
<h4>Importance </h4>
<p>From the perspective of the researcher, there seems to be too much research, of often questionable quality, in too many journals, published following too little scrutiny.</p>
<h4>Observations </h4>
<p>It has become more difficult to distinguish between intrusive email solicitations from “proper” publishers and those from predatory publishers. While many employed in publishing have the most noble of intentions, the profits of publishing houses—profit drawn largely from our research budgets—continue to soar. At the same time, alternative routes of dissemination, such as preprint servers, now allow research findings to be made public, if not published, at minimal cost. Loud protestations from journals that preprints are of inferior quality because they have not been peer reviewed would carry more weight if the process of peer review was a reliable guarantee of quality and the provenance of the data presented. Despite several decades of opportunity to increase the value of journal articles by investing in these processes, most publishers have not done so. Many in my own community have been complicit in the generation of “research for publication” rather than “research for the advancement of knowledge” (where publication is a part of the process, but not the primary objective). Drivers for these behaviors come from across the research ecosystem, and the focus on journal publication as the cardinal researcher output for evaluation serves as the major enabler of exploitative publisher behaviors.</p>
<h4>Conclusions </h4>
<p>If the journal article is to have a future, this extractive behavior must stop. The added value of peer review needs to be clear and apparent, and the quality of published work must be such that research users can trust the provenance of what is reported; with sufficient information, data, and code provided so that they can check that provenance if they wish. The quality of published work is improving, in some respects, at some journals, and those who have driven these changes, often in the face of internal opposition, should be celebrated. I will close by outlining some further avenues for improvement.</p>
<sup>1</sup>Edinburgh Neuroscience, University of Edinburgh, Edinburgh, Scotland, malcolm.macleod@ed.ac.uk. <h4>Conflict of Interest Disclosures</h4> Malcom Macleod is a member of the Peer Review Congress Advisory Board but was not involved in the review or decision for this abstract.



Does the Journal Article Have a Future?

<p>Jae Il Shin,<sup>1,2,3</sup> Min Seo Kim,<sup>4,5,6,7</sup> Dong Keon Yon,<sup>8</sup> Seung Won Lee,<sup>9</sup> Masoud Rahmati,<sup>10</sup> Marco Solmi,<sup>11,12,13,14,15</sup> Andre F. Carvalho,<sup>16</sup> Ai Koyanagi,<sup>17,18,19</sup> Lee Smith,<sup>20</sup> John P. A. Ioannidis<sup>21,22,23,24,25</sup></p>
<h4>Objective</h4>
<p> Immortal time bias (ITB) is the error in estimating the association between the exposure and the outcome that results from misclassification or exclusion of time intervals. The aim of our study was to estimate the prevalence of ITB in systematic reviews and meta-analyses and to assess the degree to which it contributes to effect size estimates and evidence reversal.</p>
<h4>Design</h4>
<p> We performed a systematic review of systematic reviews with meta-analyses (SRMA) that only underwent detailed analysis based on ITB. We only included SRMA of observational studies including cohort and case-control studies and excluded those without meta-analysis or SRMA of randomized control trials. We searched PubMed/MEDLINE, Embase, and Cochrane Database of Systematic Reviews from database inception to July 31, 2024. Two authors independently extracted data and evaluated the methodological quality of the systematic reviews. Information on ITB judgment and effect sizes with 95% CIs for individual studies in forest plots were extracted to run reanalysis using generic inverse variance fixed- and random-effects methods. After extracting data, we conducted subgroup analyses by the presence of ITB for all available topics and assessed the influence of ITB on the heterogeneity (<i>I</i><sup>2</sup>), changes of evidence, statistical significance of the finding, and altering effect size in favor of intervention/exposure.</p>
<h4>Results</h4>
<p> Among the 12 systematic reviews with relevant data, there were 25 eligible topics (only 21 could be divided by ITB, as 4 included only studies without ITB). The median (IQR) number of studies included for a topic was 6 (4-10). Among 182 studies among 25 topics, 44.0% (80 studies) were affected by ITB. Among the 21 topics where both studies with ITB and studies without ITB were available, 57.1% (12/21) demonstrated discordant results between ITB subgroups (<b>Figure 25-0976</b>). Evidence reversal occurred in 23.8% (5/21), where overall summary results changed from statistically significant to non–statistically significant or vice versa after excluding studies with ITB. The ratio of effect size (effect sizes pooled from studies with ITB relative to those pooled from studies without ITB) was 0.71 (95% CI, 0.66-0.78), suggesting that the effect sizes from studies with ITB were exaggerated by an average of 29% in favor of the intervention/exposure. Excluding studies involving ITB reduced the heterogeneity (<i>I</i><sup>2</sup>) of overall pooled results by 21.4% on average.</p>

![](https://assets.underline.io/markdown_image/1/image/f4e85eb7af8587aaffcff8858c101115.png)

![](https://assets.underline.io/markdown_image/1/image/1a8b75ac4280c10ed9e7883e7ed371a3.png)

<h4>Conclusions</h4>
<p> We quantitatively captured how far ITB has influenced our knowledge and clinical practices. Given the projected high prevalence and nontrivial influence of ITB, ITB should be considered in studies with survival analyses, and improving reporting standards by researchers as well as collective surveillance from readers, reviewers, and editors is warranted. Future studies should address how ITS may also interact with other trial characteristics and biases in affecting treatment effect estimates.</p>
<h4>Affiliations</h4> <sup>1</sup>Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea, shinji@yuhs.ac; <sup>2</sup>Severance Underwood Meta-Research Center, Institute of Convergence Science, Yonsei University, Seoul, Republic of Korea; <sup>3</sup>Affiliate in Meta-Research Innovation Center at Stanford, Stanford University, Stanford, CA, US; <sup>4</sup>Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea; <sup>5</sup>Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, US; <sup>6</sup>Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, US; <sup>7</sup>Department of Medicine, Harvard Medical School, Boston, MA, US; <sup>8</sup>Center for Digital Health, Medical Science Research Institute, Kyung Hee University College of Medicine, Seoul, Republic of Korea; <sup>9</sup>Department of Data Science, Sejong University College of Software Convergence, Seoul, Republic of Korea; <sup>10</sup>Department of Physical Education and Sport Sciences, Faculty of Literature and Human Sciences, Lorestan University, Khoramabad, Iran; <sup>11</sup>Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada; <sup>12</sup>Department of Mental Health, The Ottawa Hospital, Ottawa, Ontario, Canada; <sup>13</sup>Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program University of Ottawa, Ottawa, Ontario, Canada; <sup>14</sup>School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; <sup>15</sup>Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany; <sup>16</sup>Innovation in Mental and Physical Health and Clinical Treatment, Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia; <sup>17</sup>Research and Development Unit, Parc Sanitari Sant Joan de Déu, Universitat de Barcelona, Fundació Sant Joan de Déu, CIBERSAM, Barcelona, Spain; <sup>18</sup>ICREA, Pg. Lluis Companys 23, Barcelona, Spain; <sup>19</sup>Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain; <sup>20</sup>The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, United Kingdom; <sup>21</sup>Department of Medicine, Stanford University, Stanford, CA, US; <sup>22</sup>Department of Epidemiology and Population Health, Stanford University, Stanford, CA, US; <sup>23</sup>Department of Biomedical Data Science, Stanford University, Stanford, CA, US; <sup>24</sup>Department of Statistics, Stanford University, Stanford, CA, US; <sup>25</sup>Meta-Research Innovation Center at Stanford, Stanford University, Stanford, CA, US. <h4>Conflict of Interest Disclosures</h4> John P. A. Ioannidis is a member of the Peer Review Congress Advisory Board but was not involved in the review or decision for this abstract. <h4>Funding/Support</h4> The work of John P. A. Ioannidis is supported by an unrestricted gift from Sue and Bob O’Donnell to Stanford University. Jae Il Shin is supported by the Yonsei Faculty Fellowship, funded by Lee Youn Jae. <h4>Role of the Funder/Sponsor</h4> The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. <h4>Additional Information</h4> John P. A. Ioannidis is a cocorresponding author (jioannid@stanford.edu).



Immortal Time Bias Prevalence and Influence on Estimates in Systematic Reviews and Meta-Analyses

<p>Yuanxi Jia,<sup>1</sup> Yiwen Jiang,<sup>2</sup> Karen A. Robinson,<sup>3</sup> Jinling Tang<sup>4</sup></p>
<h4>Objective</h4>
<p> Researchers conducting randomized clinical trials (RCTs) might focus more on primary outcomes than secondary outcomes. Therefore, when the design and conduct of an RCT were manipulated for positive results, the effect size of the primary outcome may be overestimated more than that of the secondary outcomes. Among RCTs with similar design, the discrepant effect estimates of the same outcome between those designating it as a primary outcome (PO-RCTs) and others designating it as a secondary outcome (SO-RCTs) may indicate the impact of bias. This study aimed to compare the effect estimates of the same outcomes between PO-RCTs and SO-RCTs. PO-RCTs were hypothesized to produce higher effect estimates than SO-RCTs.</p>
<h4>Design</h4>
<p> This meta-research study using a matched cohort design included 153 meta-analyses assessing the efficacy/effectiveness of health interventions published in the Cochrane Database of Systematic Reviews between 2021 and 2023. A total of 1073 RCTs with parallel design, individual randomization, superiority tests, recruitment in or after 2006, and negative control (placebo, sham, no intervention, waiting list, minimal intervention, attention control, or standard care) were included. Within each meta-analysis, RCTs designating the meta-analyzed outcome as primary outcome were classified as PO-RCTs (553 RCTs), while those designating the meta-analyzed outcome as secondary outcome were classified as SO-RCTs (520 RCTs). RCTs that did not define a primary outcome were excluded. The PO-RCTs were compared with the SO-RCTs using 2-stage random-effect meta-analyses: the effect estimates from RCTs were transformed into odds ratios (ORs); within each meta-analysis, the ORs from PO-RCTs and SO-RCTs were compared as a ratio of ORs (ROR); and the RORs across meta-analyses were combined. The primary analyses were conducted among all RCTs and prospectively registered RCTs. The risk of bias for blinding was assessed using the Cochrane Risk of Bias Tool.</p>
<h4>Results </h4>
<p>Among 1073 RCTs from 153 meta-analyses, PO-RCTs produced ORs 1.27 (95% CI, 1.14-1.42; <i>I</i><sup>2</sup> = 43.6%) times higher than SO-RCTs. Among 372 prospectively registered RCTs from 122 meta-analyses, PO-RCTs produced ORs 1.21 (95% CI, 1.03-1.41; <i>I</i><sup>2</sup> = 22.3%) times higher than SO-RCTs. When restricted to RCTs with high/unclear risk in performance bias, detection bias, or both types of bias, PO-RCTs produced ORs 1.48 (95% CI, 1.26-1.75), 1.44 (95% CI, 1.21-1.71), and 1.60 (95% CI, 1.30-1.96) times higher than SO-RCTs, respectively. When restricted to RCTs with low risk in performance bias, detection bias, or both types of bias, PO-RCTs produced ORs 1.08 (95% CI, 0.90-1.28), 1.04 (95% CI, 0.87-1.24), and 1.06 (95% CI, 0.90-1.26) times higher than SO-RCTs, respectively.</p>
<h4>Conclusions</h4>
<p> The effect estimate for an outcome could be 27% larger when designated as a primary outcome than a secondary outcome in RCTs, which may be partially attributed to bias. Researchers conducting systematic reviews may need to note whether an outcome was designated as primary or secondary in RCTs, perform sensitivity analyses, and interpret results considering the impact of potential bias.</p>
<sup>1</sup>Yong Loo Lin School of Medicine, National University of Singapore, Singapore, yx.jia@nus.edu.sg; <sup>2</sup>Shenzhen Institute of Advanced Technology, Shenzhen, China; <sup>3</sup>School of Medicine, Johns Hopkins University, Baltimore, US; <sup>4</sup>Shenzhen University of Advanced Technology, Shenzhen, China. <h4>Conflict of Interest Disclosures</h4> None reported. <h4>Funding/Support</h4> This study was supported by the Shenzhen Science and Technology Program (grant KQTD20190929172835662) from the Shenzhen Municipal Government, Guangdong Province, China, and the Outstanding Youth Innovation Fund from the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (grant E2G019). <h4>Role of the Funder/Sponsor</h4> The funders had no roles in the design, conduct, or reporting of this study.



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