meta analysis for literature review

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Systematic reviews vs meta-analysis: what’s the difference?

Posted on 24th July 2023 by Verónica Tanco Tellechea

You may hear the terms ‘systematic review’ and ‘meta-analysis being used interchangeably’. Although they are related, they are distinctly different. Learn more in this blog for beginners.

What is a systematic review?

According to Cochrane (1), a systematic review attempts to identify, appraise and synthesize all the empirical evidence to answer a specific research question. Thus, a systematic review is where you might find the most relevant, adequate, and current information regarding a specific topic. In the levels of evidence pyramid , systematic reviews are only surpassed by meta-analyses. 

To conduct a systematic review, you will need, among other things: 

• A specific research question, usually in the form of a PICO question.
• Pre-specified eligibility criteria, to decide which articles will be included or discarded from the review. 
• To follow a systematic method that will minimize bias.

You can find protocols that will guide you from both Cochrane and the Equator Network , among other places, and if you are a beginner to the topic then have a read of an overview about systematic reviews.

What is a meta-analysis?

A meta-analysis is a quantitative, epidemiological study design used to systematically assess the results of previous research (2) . Usually, they are based on randomized controlled trials, though not always. This means that a meta-analysis is a mathematical tool that allows researchers to mathematically combine outcomes from multiple studies.

When can a meta-analysis be implemented?

There is always the possibility of conducting a meta-analysis, yet, for it to throw the best possible results it should be performed when the studies included in the systematic review are of good quality, similar designs, and have similar outcome measures.

Why are meta-analyses important?

Outcomes from a meta-analysis may provide more precise information regarding the estimate of the effect of what is being studied because it merges outcomes from multiple studies. In a meta-analysis, data from various trials are combined and generate an average result (1), which is portrayed in a forest plot diagram. Moreover, meta-analysis also include a funnel plot diagram to visually detect publication bias.

Conclusions

A systematic review is an article that synthesizes available evidence on a certain topic utilizing a specific research question, pre-specified eligibility criteria for including articles, and a systematic method for its production. Whereas a meta-analysis is a quantitative, epidemiological study design used to assess the results of articles included in a systematic-review. 

Remember: All meta-analyses involve a systematic review, but not all systematic reviews involve a meta-analysis.

If you would like some further reading on this topic, we suggest the following:

The systematic review – a S4BE blog article

Meta-analysis: what, why, and how – a S4BE blog article

The difference between a systematic review and a meta-analysis – a blog article via Covidence

Systematic review vs meta-analysis: what’s the difference? A 5-minute video from Research Masterminds:

• About Cochrane reviews [Internet]. Cochranelibrary.com. [cited 2023 Apr 30]. Available from: https://www.cochranelibrary.com/about/about-cochrane-reviews
• Haidich AB. Meta-analysis in medical research. Hippokratia. 2010;14(Suppl 1):29–37.

Verónica Tanco Tellechea

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• Open access
• Published: 01 August 2019

A step by step guide for conducting a systematic review and meta-analysis with simulation data

• Gehad Mohamed Tawfik 1 , 2 ,
• Kadek Agus Surya Dila 2 , 3 ,
• Muawia Yousif Fadlelmola Mohamed 2 , 4 ,
• Dao Ngoc Hien Tam 2 , 5 ,
• Nguyen Dang Kien 2 , 6 ,
• Ali Mahmoud Ahmed 2 , 7 &
• Nguyen Tien Huy 8 , 9 , 10  

Tropical Medicine and Health volume  47 , Article number:  46 ( 2019 ) Cite this article

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The massive abundance of studies relating to tropical medicine and health has increased strikingly over the last few decades. In the field of tropical medicine and health, a well-conducted systematic review and meta-analysis (SR/MA) is considered a feasible solution for keeping clinicians abreast of current evidence-based medicine. Understanding of SR/MA steps is of paramount importance for its conduction. It is not easy to be done as there are obstacles that could face the researcher. To solve those hindrances, this methodology study aimed to provide a step-by-step approach mainly for beginners and junior researchers, in the field of tropical medicine and other health care fields, on how to properly conduct a SR/MA, in which all the steps here depicts our experience and expertise combined with the already well-known and accepted international guidance.

We suggest that all steps of SR/MA should be done independently by 2–3 reviewers’ discussion, to ensure data quality and accuracy.

SR/MA steps include the development of research question, forming criteria, search strategy, searching databases, protocol registration, title, abstract, full-text screening, manual searching, extracting data, quality assessment, data checking, statistical analysis, double data checking, and manuscript writing.

Introduction

The amount of studies published in the biomedical literature, especially tropical medicine and health, has increased strikingly over the last few decades. This massive abundance of literature makes clinical medicine increasingly complex, and knowledge from various researches is often needed to inform a particular clinical decision. However, available studies are often heterogeneous with regard to their design, operational quality, and subjects under study and may handle the research question in a different way, which adds to the complexity of evidence and conclusion synthesis [ 1 ].

Systematic review and meta-analyses (SR/MAs) have a high level of evidence as represented by the evidence-based pyramid. Therefore, a well-conducted SR/MA is considered a feasible solution in keeping health clinicians ahead regarding contemporary evidence-based medicine.

Differing from a systematic review, unsystematic narrative review tends to be descriptive, in which the authors select frequently articles based on their point of view which leads to its poor quality. A systematic review, on the other hand, is defined as a review using a systematic method to summarize evidence on questions with a detailed and comprehensive plan of study. Furthermore, despite the increasing guidelines for effectively conducting a systematic review, we found that basic steps often start from framing question, then identifying relevant work which consists of criteria development and search for articles, appraise the quality of included studies, summarize the evidence, and interpret the results [ 2 , 3 ]. However, those simple steps are not easy to be reached in reality. There are many troubles that a researcher could be struggled with which has no detailed indication.

Conducting a SR/MA in tropical medicine and health may be difficult especially for young researchers; therefore, understanding of its essential steps is crucial. It is not easy to be done as there are obstacles that could face the researcher. To solve those hindrances, we recommend a flow diagram (Fig. 1 ) which illustrates a detailed and step-by-step the stages for SR/MA studies. This methodology study aimed to provide a step-by-step approach mainly for beginners and junior researchers, in the field of tropical medicine and other health care fields, on how to properly and succinctly conduct a SR/MA; all the steps here depicts our experience and expertise combined with the already well known and accepted international guidance.

Detailed flow diagram guideline for systematic review and meta-analysis steps. Note : Star icon refers to “2–3 reviewers screen independently”

Methods and results

Detailed steps for conducting any systematic review and meta-analysis.

We searched the methods reported in published SR/MA in tropical medicine and other healthcare fields besides the published guidelines like Cochrane guidelines {Higgins, 2011 #7} [ 4 ] to collect the best low-bias method for each step of SR/MA conduction steps. Furthermore, we used guidelines that we apply in studies for all SR/MA steps. We combined these methods in order to conclude and conduct a detailed flow diagram that shows the SR/MA steps how being conducted.

Any SR/MA must follow the widely accepted Preferred Reporting Items for Systematic Review and Meta-analysis statement (PRISMA checklist 2009) (Additional file 5 : Table S1) [ 5 ].

We proposed our methods according to a valid explanatory simulation example choosing the topic of “evaluating safety of Ebola vaccine,” as it is known that Ebola is a very rare tropical disease but fatal. All the explained methods feature the standards followed internationally, with our compiled experience in the conduct of SR beside it, which we think proved some validity. This is a SR under conduct by a couple of researchers teaming in a research group, moreover, as the outbreak of Ebola which took place (2013–2016) in Africa resulted in a significant mortality and morbidity. Furthermore, since there are many published and ongoing trials assessing the safety of Ebola vaccines, we thought this would provide a great opportunity to tackle this hotly debated issue. Moreover, Ebola started to fire again and new fatal outbreak appeared in the Democratic Republic of Congo since August 2018, which caused infection to more than 1000 people according to the World Health Organization, and 629 people have been killed till now. Hence, it is considered the second worst Ebola outbreak, after the first one in West Africa in 2014 , which infected more than 26,000 and killed about 11,300 people along outbreak course.

Research question and objectives

Like other study designs, the research question of SR/MA should be feasible, interesting, novel, ethical, and relevant. Therefore, a clear, logical, and well-defined research question should be formulated. Usually, two common tools are used: PICO or SPIDER. PICO (Population, Intervention, Comparison, Outcome) is used mostly in quantitative evidence synthesis. Authors demonstrated that PICO holds more sensitivity than the more specific SPIDER approach [ 6 ]. SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) was proposed as a method for qualitative and mixed methods search.

We here recommend a combined approach of using either one or both the SPIDER and PICO tools to retrieve a comprehensive search depending on time and resources limitations. When we apply this to our assumed research topic, being of qualitative nature, the use of SPIDER approach is more valid.

PICO is usually used for systematic review and meta-analysis of clinical trial study. For the observational study (without intervention or comparator), in many tropical and epidemiological questions, it is usually enough to use P (Patient) and O (outcome) only to formulate a research question. We must indicate clearly the population (P), then intervention (I) or exposure. Next, it is necessary to compare (C) the indicated intervention with other interventions, i.e., placebo. Finally, we need to clarify which are our relevant outcomes.

To facilitate comprehension, we choose the Ebola virus disease (EVD) as an example. Currently, the vaccine for EVD is being developed and under phase I, II, and III clinical trials; we want to know whether this vaccine is safe and can induce sufficient immunogenicity to the subjects.

An example of a research question for SR/MA based on PICO for this issue is as follows: How is the safety and immunogenicity of Ebola vaccine in human? (P: healthy subjects (human), I: vaccination, C: placebo, O: safety or adverse effects)

Preliminary research and idea validation

We recommend a preliminary search to identify relevant articles, ensure the validity of the proposed idea, avoid duplication of previously addressed questions, and assure that we have enough articles for conducting its analysis. Moreover, themes should focus on relevant and important health-care issues, consider global needs and values, reflect the current science, and be consistent with the adopted review methods. Gaining familiarity with a deep understanding of the study field through relevant videos and discussions is of paramount importance for better retrieval of results. If we ignore this step, our study could be canceled whenever we find out a similar study published before. This means we are wasting our time to deal with a problem that has been tackled for a long time.

To do this, we can start by doing a simple search in PubMed or Google Scholar with search terms Ebola AND vaccine. While doing this step, we identify a systematic review and meta-analysis of determinant factors influencing antibody response from vaccination of Ebola vaccine in non-human primate and human [ 7 ], which is a relevant paper to read to get a deeper insight and identify gaps for better formulation of our research question or purpose. We can still conduct systematic review and meta-analysis of Ebola vaccine because we evaluate safety as a different outcome and different population (only human).

Inclusion and exclusion criteria

Eligibility criteria are based on the PICO approach, study design, and date. Exclusion criteria mostly are unrelated, duplicated, unavailable full texts, or abstract-only papers. These exclusions should be stated in advance to refrain the researcher from bias. The inclusion criteria would be articles with the target patients, investigated interventions, or the comparison between two studied interventions. Briefly, it would be articles which contain information answering our research question. But the most important is that it should be clear and sufficient information, including positive or negative, to answer the question.

For the topic we have chosen, we can make inclusion criteria: (1) any clinical trial evaluating the safety of Ebola vaccine and (2) no restriction regarding country, patient age, race, gender, publication language, and date. Exclusion criteria are as follows: (1) study of Ebola vaccine in non-human subjects or in vitro studies; (2) study with data not reliably extracted, duplicate, or overlapping data; (3) abstract-only papers as preceding papers, conference, editorial, and author response theses and books; (4) articles without available full text available; and (5) case reports, case series, and systematic review studies. The PRISMA flow diagram template that is used in SR/MA studies can be found in Fig. 2 .

PRISMA flow diagram of studies’ screening and selection

Search strategy

A standard search strategy is used in PubMed, then later it is modified according to each specific database to get the best relevant results. The basic search strategy is built based on the research question formulation (i.e., PICO or PICOS). Search strategies are constructed to include free-text terms (e.g., in the title and abstract) and any appropriate subject indexing (e.g., MeSH) expected to retrieve eligible studies, with the help of an expert in the review topic field or an information specialist. Additionally, we advise not to use terms for the Outcomes as their inclusion might hinder the database being searched to retrieve eligible studies because the used outcome is not mentioned obviously in the articles.

The improvement of the search term is made while doing a trial search and looking for another relevant term within each concept from retrieved papers. To search for a clinical trial, we can use these descriptors in PubMed: “clinical trial”[Publication Type] OR “clinical trials as topic”[MeSH terms] OR “clinical trial”[All Fields]. After some rounds of trial and refinement of search term, we formulate the final search term for PubMed as follows: (ebola OR ebola virus OR ebola virus disease OR EVD) AND (vaccine OR vaccination OR vaccinated OR immunization) AND (“clinical trial”[Publication Type] OR “clinical trials as topic”[MeSH Terms] OR “clinical trial”[All Fields]). Because the study for this topic is limited, we do not include outcome term (safety and immunogenicity) in the search term to capture more studies.

Search databases, import all results to a library, and exporting to an excel sheet

According to the AMSTAR guidelines, at least two databases have to be searched in the SR/MA [ 8 ], but as you increase the number of searched databases, you get much yield and more accurate and comprehensive results. The ordering of the databases depends mostly on the review questions; being in a study of clinical trials, you will rely mostly on Cochrane, mRCTs, or International Clinical Trials Registry Platform (ICTRP). Here, we propose 12 databases (PubMed, Scopus, Web of Science, EMBASE, GHL, VHL, Cochrane, Google Scholar, Clinical trials.gov , mRCTs, POPLINE, and SIGLE), which help to cover almost all published articles in tropical medicine and other health-related fields. Among those databases, POPLINE focuses on reproductive health. Researchers should consider to choose relevant database according to the research topic. Some databases do not support the use of Boolean or quotation; otherwise, there are some databases that have special searching way. Therefore, we need to modify the initial search terms for each database to get appreciated results; therefore, manipulation guides for each online database searches are presented in Additional file 5 : Table S2. The detailed search strategy for each database is found in Additional file 5 : Table S3. The search term that we created in PubMed needs customization based on a specific characteristic of the database. An example for Google Scholar advanced search for our topic is as follows:

With all of the words: ebola virus

With at least one of the words: vaccine vaccination vaccinated immunization

Where my words occur: in the title of the article

With all of the words: EVD

Finally, all records are collected into one Endnote library in order to delete duplicates and then to it export into an excel sheet. Using remove duplicating function with two options is mandatory. All references which have (1) the same title and author, and published in the same year, and (2) the same title and author, and published in the same journal, would be deleted. References remaining after this step should be exported to an excel file with essential information for screening. These could be the authors’ names, publication year, journal, DOI, URL link, and abstract.

Protocol writing and registration

Protocol registration at an early stage guarantees transparency in the research process and protects from duplication problems. Besides, it is considered a documented proof of team plan of action, research question, eligibility criteria, intervention/exposure, quality assessment, and pre-analysis plan. It is recommended that researchers send it to the principal investigator (PI) to revise it, then upload it to registry sites. There are many registry sites available for SR/MA like those proposed by Cochrane and Campbell collaborations; however, we recommend registering the protocol into PROSPERO as it is easier. The layout of a protocol template, according to PROSPERO, can be found in Additional file 5 : File S1.

Title and abstract screening

Decisions to select retrieved articles for further assessment are based on eligibility criteria, to minimize the chance of including non-relevant articles. According to the Cochrane guidance, two reviewers are a must to do this step, but as for beginners and junior researchers, this might be tiresome; thus, we propose based on our experience that at least three reviewers should work independently to reduce the chance of error, particularly in teams with a large number of authors to add more scrutiny and ensure proper conduct. Mostly, the quality with three reviewers would be better than two, as two only would have different opinions from each other, so they cannot decide, while the third opinion is crucial. And here are some examples of systematic reviews which we conducted following the same strategy (by a different group of researchers in our research group) and published successfully, and they feature relevant ideas to tropical medicine and disease [ 9 , 10 , 11 ].

In this step, duplications will be removed manually whenever the reviewers find them out. When there is a doubt about an article decision, the team should be inclusive rather than exclusive, until the main leader or PI makes a decision after discussion and consensus. All excluded records should be given exclusion reasons.

Full text downloading and screening

Many search engines provide links for free to access full-text articles. In case not found, we can search in some research websites as ResearchGate, which offer an option of direct full-text request from authors. Additionally, exploring archives of wanted journals, or contacting PI to purchase it if available. Similarly, 2–3 reviewers work independently to decide about included full texts according to eligibility criteria, with reporting exclusion reasons of articles. In case any disagreement has occurred, the final decision has to be made by discussion.

Manual search

One has to exhaust all possibilities to reduce bias by performing an explicit hand-searching for retrieval of reports that may have been dropped from first search [ 12 ]. We apply five methods to make manual searching: searching references from included studies/reviews, contacting authors and experts, and looking at related articles/cited articles in PubMed and Google Scholar.

We describe here three consecutive methods to increase and refine the yield of manual searching: firstly, searching reference lists of included articles; secondly, performing what is known as citation tracking in which the reviewers track all the articles that cite each one of the included articles, and this might involve electronic searching of databases; and thirdly, similar to the citation tracking, we follow all “related to” or “similar” articles. Each of the abovementioned methods can be performed by 2–3 independent reviewers, and all the possible relevant article must undergo further scrutiny against the inclusion criteria, after following the same records yielded from electronic databases, i.e., title/abstract and full-text screening.

We propose an independent reviewing by assigning each member of the teams a “tag” and a distinct method, to compile all the results at the end for comparison of differences and discussion and to maximize the retrieval and minimize the bias. Similarly, the number of included articles has to be stated before addition to the overall included records.

Data extraction and quality assessment

This step entitles data collection from included full-texts in a structured extraction excel sheet, which is previously pilot-tested for extraction using some random studies. We recommend extracting both adjusted and non-adjusted data because it gives the most allowed confounding factor to be used in the analysis by pooling them later [ 13 ]. The process of extraction should be executed by 2–3 independent reviewers. Mostly, the sheet is classified into the study and patient characteristics, outcomes, and quality assessment (QA) tool.

Data presented in graphs should be extracted by software tools such as Web plot digitizer [ 14 ]. Most of the equations that can be used in extraction prior to analysis and estimation of standard deviation (SD) from other variables is found inside Additional file 5 : File S2 with their references as Hozo et al. [ 15 ], Xiang et al. [ 16 ], and Rijkom et al. [ 17 ]. A variety of tools are available for the QA, depending on the design: ROB-2 Cochrane tool for randomized controlled trials [ 18 ] which is presented as Additional file 1 : Figure S1 and Additional file 2 : Figure S2—from a previous published article data—[ 19 ], NIH tool for observational and cross-sectional studies [ 20 ], ROBINS-I tool for non-randomize trials [ 21 ], QUADAS-2 tool for diagnostic studies, QUIPS tool for prognostic studies, CARE tool for case reports, and ToxRtool for in vivo and in vitro studies. We recommend that 2–3 reviewers independently assess the quality of the studies and add to the data extraction form before the inclusion into the analysis to reduce the risk of bias. In the NIH tool for observational studies—cohort and cross-sectional—as in this EBOLA case, to evaluate the risk of bias, reviewers should rate each of the 14 items into dichotomous variables: yes, no, or not applicable. An overall score is calculated by adding all the items scores as yes equals one, while no and NA equals zero. A score will be given for every paper to classify them as poor, fair, or good conducted studies, where a score from 0–5 was considered poor, 6–9 as fair, and 10–14 as good.

In the EBOLA case example above, authors can extract the following information: name of authors, country of patients, year of publication, study design (case report, cohort study, or clinical trial or RCT), sample size, the infected point of time after EBOLA infection, follow-up interval after vaccination time, efficacy, safety, adverse effects after vaccinations, and QA sheet (Additional file 6 : Data S1).

Data checking

Due to the expected human error and bias, we recommend a data checking step, in which every included article is compared with its counterpart in an extraction sheet by evidence photos, to detect mistakes in data. We advise assigning articles to 2–3 independent reviewers, ideally not the ones who performed the extraction of those articles. When resources are limited, each reviewer is assigned a different article than the one he extracted in the previous stage.

Statistical analysis

Investigators use different methods for combining and summarizing findings of included studies. Before analysis, there is an important step called cleaning of data in the extraction sheet, where the analyst organizes extraction sheet data in a form that can be read by analytical software. The analysis consists of 2 types namely qualitative and quantitative analysis. Qualitative analysis mostly describes data in SR studies, while quantitative analysis consists of two main types: MA and network meta-analysis (NMA). Subgroup, sensitivity, cumulative analyses, and meta-regression are appropriate for testing whether the results are consistent or not and investigating the effect of certain confounders on the outcome and finding the best predictors. Publication bias should be assessed to investigate the presence of missing studies which can affect the summary.

To illustrate basic meta-analysis, we provide an imaginary data for the research question about Ebola vaccine safety (in terms of adverse events, 14 days after injection) and immunogenicity (Ebola virus antibodies rise in geometric mean titer, 6 months after injection). Assuming that from searching and data extraction, we decided to do an analysis to evaluate Ebola vaccine “A” safety and immunogenicity. Other Ebola vaccines were not meta-analyzed because of the limited number of studies (instead, it will be included for narrative review). The imaginary data for vaccine safety meta-analysis can be accessed in Additional file 7 : Data S2. To do the meta-analysis, we can use free software, such as RevMan [ 22 ] or R package meta [ 23 ]. In this example, we will use the R package meta. The tutorial of meta package can be accessed through “General Package for Meta-Analysis” tutorial pdf [ 23 ]. The R codes and its guidance for meta-analysis done can be found in Additional file 5 : File S3.

For the analysis, we assume that the study is heterogenous in nature; therefore, we choose a random effect model. We did an analysis on the safety of Ebola vaccine A. From the data table, we can see some adverse events occurring after intramuscular injection of vaccine A to the subject of the study. Suppose that we include six studies that fulfill our inclusion criteria. We can do a meta-analysis for each of the adverse events extracted from the studies, for example, arthralgia, from the results of random effect meta-analysis using the R meta package.

From the results shown in Additional file 3 : Figure S3, we can see that the odds ratio (OR) of arthralgia is 1.06 (0.79; 1.42), p value = 0.71, which means that there is no association between the intramuscular injection of Ebola vaccine A and arthralgia, as the OR is almost one, and besides, the P value is insignificant as it is > 0.05.

In the meta-analysis, we can also visualize the results in a forest plot. It is shown in Fig. 3 an example of a forest plot from the simulated analysis.

Random effect model forest plot for comparison of vaccine A versus placebo

From the forest plot, we can see six studies (A to F) and their respective OR (95% CI). The green box represents the effect size (in this case, OR) of each study. The bigger the box means the study weighted more (i.e., bigger sample size). The blue diamond shape represents the pooled OR of the six studies. We can see the blue diamond cross the vertical line OR = 1, which indicates no significance for the association as the diamond almost equalized in both sides. We can confirm this also from the 95% confidence interval that includes one and the p value > 0.05.

For heterogeneity, we see that I 2 = 0%, which means no heterogeneity is detected; the study is relatively homogenous (it is rare in the real study). To evaluate publication bias related to the meta-analysis of adverse events of arthralgia, we can use the metabias function from the R meta package (Additional file 4 : Figure S4) and visualization using a funnel plot. The results of publication bias are demonstrated in Fig. 4 . We see that the p value associated with this test is 0.74, indicating symmetry of the funnel plot. We can confirm it by looking at the funnel plot.

Publication bias funnel plot for comparison of vaccine A versus placebo

Looking at the funnel plot, the number of studies at the left and right side of the funnel plot is the same; therefore, the plot is symmetry, indicating no publication bias detected.

Sensitivity analysis is a procedure used to discover how different values of an independent variable will influence the significance of a particular dependent variable by removing one study from MA. If all included study p values are < 0.05, hence, removing any study will not change the significant association. It is only performed when there is a significant association, so if the p value of MA done is 0.7—more than one—the sensitivity analysis is not needed for this case study example. If there are 2 studies with p value > 0.05, removing any of the two studies will result in a loss of the significance.

Double data checking

For more assurance on the quality of results, the analyzed data should be rechecked from full-text data by evidence photos, to allow an obvious check for the PI of the study.

Manuscript writing, revision, and submission to a journal

Writing based on four scientific sections: introduction, methods, results, and discussion, mostly with a conclusion. Performing a characteristic table for study and patient characteristics is a mandatory step which can be found as a template in Additional file 5 : Table S3.

After finishing the manuscript writing, characteristics table, and PRISMA flow diagram, the team should send it to the PI to revise it well and reply to his comments and, finally, choose a suitable journal for the manuscript which fits with considerable impact factor and fitting field. We need to pay attention by reading the author guidelines of journals before submitting the manuscript.

The role of evidence-based medicine in biomedical research is rapidly growing. SR/MAs are also increasing in the medical literature. This paper has sought to provide a comprehensive approach to enable reviewers to produce high-quality SR/MAs. We hope that readers could gain general knowledge about how to conduct a SR/MA and have the confidence to perform one, although this kind of study requires complex steps compared to narrative reviews.

Having the basic steps for conduction of MA, there are many advanced steps that are applied for certain specific purposes. One of these steps is meta-regression which is performed to investigate the association of any confounder and the results of the MA. Furthermore, there are other types rather than the standard MA like NMA and MA. In NMA, we investigate the difference between several comparisons when there were not enough data to enable standard meta-analysis. It uses both direct and indirect comparisons to conclude what is the best between the competitors. On the other hand, mega MA or MA of patients tend to summarize the results of independent studies by using its individual subject data. As a more detailed analysis can be done, it is useful in conducting repeated measure analysis and time-to-event analysis. Moreover, it can perform analysis of variance and multiple regression analysis; however, it requires homogenous dataset and it is time-consuming in conduct [ 24 ].

Conclusions

Systematic review/meta-analysis steps include development of research question and its validation, forming criteria, search strategy, searching databases, importing all results to a library and exporting to an excel sheet, protocol writing and registration, title and abstract screening, full-text screening, manual searching, extracting data and assessing its quality, data checking, conducting statistical analysis, double data checking, manuscript writing, revising, and submitting to a journal.

Availability of data and materials

Not applicable.

Abbreviations

Network meta-analysis

Principal investigator

Population, Intervention, Comparison, Outcome

Preferred Reporting Items for Systematic Review and Meta-analysis statement

Quality assessment

Sample, Phenomenon of Interest, Design, Evaluation, Research type

Systematic review and meta-analyses

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Acknowledgements

This study was conducted (in part) at the Joint Usage/Research Center on Tropical Disease, Institute of Tropical Medicine, Nagasaki University, Japan.

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Gehad Mohamed Tawfik

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Gehad Mohamed Tawfik, Kadek Agus Surya Dila, Muawia Yousif Fadlelmola Mohamed, Dao Ngoc Hien Tam, Nguyen Dang Kien & Ali Mahmoud Ahmed

Pratama Giri Emas Hospital, Singaraja-Amlapura street, Giri Emas village, Sawan subdistrict, Singaraja City, Buleleng, Bali, 81171, Indonesia

Kadek Agus Surya Dila

Faculty of Medicine, University of Khartoum, Khartoum, Sudan

Muawia Yousif Fadlelmola Mohamed

Nanogen Pharmaceutical Biotechnology Joint Stock Company, Ho Chi Minh City, Vietnam

Dao Ngoc Hien Tam

Department of Obstetrics and Gynecology, Thai Binh University of Medicine and Pharmacy, Thai Binh, Vietnam

Nguyen Dang Kien

Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Ali Mahmoud Ahmed

Evidence Based Medicine Research Group & Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, 70000, Vietnam

Nguyen Tien Huy

Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, 70000, Vietnam

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Additional files

Additional file 1:.

Figure S1. Risk of bias assessment graph of included randomized controlled trials. (TIF 20 kb)

Additional file 2:

Figure S2. Risk of bias assessment summary. (TIF 69 kb)

Additional file 3:

Figure S3. Arthralgia results of random effect meta-analysis using R meta package. (TIF 20 kb)

Additional file 4:

Figure S4. Arthralgia linear regression test of funnel plot asymmetry using R meta package. (TIF 13 kb)

Additional file 5:

Table S1. PRISMA 2009 Checklist. Table S2. Manipulation guides for online database searches. Table S3. Detailed search strategy for twelve database searches. Table S4. Baseline characteristics of the patients in the included studies. File S1. PROSPERO protocol template file. File S2. Extraction equations that can be used prior to analysis to get missed variables. File S3. R codes and its guidance for meta-analysis done for comparison between EBOLA vaccine A and placebo. (DOCX 49 kb)

Additional file 6:

Data S1. Extraction and quality assessment data sheets for EBOLA case example. (XLSX 1368 kb)

Additional file 7:

Data S2. Imaginary data for EBOLA case example. (XLSX 10 kb)

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Tawfik, G.M., Dila, K.A.S., Mohamed, M.Y.F. et al. A step by step guide for conducting a systematic review and meta-analysis with simulation data. Trop Med Health 47 , 46 (2019). https://doi.org/10.1186/s41182-019-0165-6

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Systematic Reviews and Meta Analysis

• Getting Started
• Guides and Standards
• Review Protocols
• Databases and Sources
• Randomized Controlled Trials
• Controlled Clinical Trials
• Observational Designs
• Tests of Diagnostic Accuracy
• Software and Tools
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Cochrane Handbook

The Cochrane Handbook isn't set down to be a standard, but it has become the de facto standard for planning and carrying out a systematic review. Chapter 6, Searching for Studies, is most helpful in planning your review.

Scoping Reviews, JBI Manual for Evidence Synthesis

The Joanna Briggs Institute provides extensive guidance for their authors in producing both systematic and scoping reviews. Their chapter on scoping reviews provides a succinct overview of the scoping review process. JBI maintains a page with other materials for scoping reviewers.

Methods Guide for Effectiveness and Comparative Effectiveness Reviews

Very good chapters on conducting a review, most of which were published as articles in the Journal of Clincal Epidemiology.

Institutes of Medicine Standards for Systematic Reviews

The IOM standards promote objective, transparent, and scientifically valid systematic reviews. They address the entire systematic review process, from locating, screening, and selecting studies for the review, to synthesizing the findings (including meta-analysis) and assessing the overall quality of the body of evidence, to producing the final review report.

Systematic Reviews: CRD's Guidance for Undertaking Reviews in Health Care

Provides a succinct outline for carrying out systematic reviews and well as details about constructing a protocol, testing for bias, and other aspects of the review process. Includes examples.

Systematic reviews to support evidence-based medicine how to review and apply findings of healthcare research

Khan, K., & Royal Society of Medicine. 2nd ed,  2013. London [England]: Hodder Annold. [Harvard ID required]

Systematic reviews to answer health care questions

Nelson, H. (2014). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. [Harvard ID required]

Systematic Review Toolbox

Not a guide or standard but a clearinghouse for all things systematic review. Check here for templates, reporting standards, screening tools, risk of bias assessment, etc.

Reporting Standards: PRISMA and MOOSE

You will improve the quality of your review by adhering to the standards below. Using the approriate standard can reassure editors and reviewers that you have conscienciously carried out your review.

http://www.prisma-statement.org/ The Preferred Reporting Items for Systematic Reviews and Meta-Analyses is an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses. A 27-item checklist,  PRISMA  focuses on randomized trials but can also be used as a basis for reporting systematic reviews of other types of research, particularly evaluations of interventions. PRISMA may also be useful for critical appraisal of published systematic reviews, although it is not a quality assessment instrument to gauge the quality of a systematic review.

Consider using PRISMA-P when completing your protocol. PRISMA-P is a 17-item checklist for elements considered essential in protocol for a systematic review or meta-analysis. The documentation contains an excellent rationale for completing a protocol, too.

Use PRISMA-ScR, a 20-item checklist, for reporting scoping reviews. The documentation provides a clear overview of scoping reviews.

Further Reading:

Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009 Jul 21;6(7):e1000097. Epub 2009 Jul 21. PubMed PMID: 19621072 .  

Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting  systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009 Jul 21;6(7):e1000100. Epub 2009 Jul 21. PubMed PMID: 19621070 . 

Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA; PRISMA-P Group. Preferred reporting items for systematic review andmeta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349:g7647. doi: 10.1136/bmj.g7647. PubMed PMID: 25555855 .

Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA; PRISMA-P Group. Preferred reporting items for systematic review andmeta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015 Jan 1;4:1. doi: 10.1186/2046-4053-4-1. PubMed PMID: 25554246 .

Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, Moher D, Peters MDJ, Horsley T, Weeks L, Hempel S, Akl EA, Chang C, McGowan J, Stewart L, Hartling L, Aldcroft A, Wilson MG, Garritty C, Lewin S, Godfrey CM, Macdonald MT, Langlois EV, Soares-Weiser K, Moriarty J, Clifford T, Tunçalp Ö, Straus SE. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. 2018 Oct 2;169(7):467-473. doi: 10.7326/M18-0850. Epub 2018 Sep 4. PMID: 30178033 .

Also published in the Annals of Internal Medicine, BMJ, and the Journal of Clinical Epidemiology.

MOOSE Guidelines

http://www.consort-statement.org/Media/Default/Downloads/Other%20Instruments/MOOSE%20Statement%202000.pdf Meta-analysis of Observational Studies in Epidemiology checklist contains specifications for reporting of meta-analyses of observational studies in epidemiology. Editors will expect you to follow and cite this checklist.  It refers to the  Newcastle-Ottawa Scale for assessing the quality of non-randomized studies, a method of rating each observational study in your meta-analysis.

Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000 Apr 19;283(15):2008-12. PubMed PMID:  10789670 .

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Literature Review, Systematic Review and Meta-analysis

Literature reviews can be a good way to narrow down theoretical interests; refine a research question; understand contemporary debates; and orientate a particular research project. It is very common for PhD theses to contain some element of reviewing the literature around a particular topic. It’s typical to have an entire chapter devoted to reporting the result of this task, identifying gaps in the literature and framing the collection of additional data.

Systematic review is a type of literature review that uses systematic methods to collect secondary data, critically appraise research studies, and synthesise findings. Systematic reviews are designed to provide a comprehensive, exhaustive summary of current theories and/or evidence and published research (Siddaway, Wood & Hedges, 2019) and may be qualitative or qualitative. Relevant studies and literature are identified through a research question, summarised and synthesized into a discrete set of findings or a description of the state-of-the-art. This might result in a ‘literature review’ chapter in a doctoral thesis, but can also be the basis of an entire research project.

Meta-analysis is a specialised type of systematic review which is quantitative and rigorous, often comparing data and results across multiple similar studies. This is a common approach in medical research where several papers might report the results of trials of a particular treatment, for instance. The meta-analysis then statistical techniques to synthesize these into one summary. This can have a high statistical power but care must be taken not to introduce bias in the selection and filtering of evidence.

Whichever type of review is employed, the process is similarly linear. The first step is to frame a question which can guide the review. This is used to identify relevant literature, often through searching subject-specific scientific databases. From these results the most relevant will be identified. Filtering is important here as there will be time constraints that prevent the researcher considering every possible piece of evidence or theoretical viewpoint. Once a concrete evidence base has been identified, the researcher extracts relevant data before reporting the synthesized results in an extended piece of writing.

Literature Review: GO-GN Insights

Sarah Lambert used a systematic review of literature with both qualitative and quantitative phases to investigate the question “How can open education programs be reconceptualised as acts of social justice to improve the access, participation and success of those who are traditionally excluded from higher education knowledge and skills?”

“My PhD research used systematic review, qualitative synthesis, case study and discourse analysis techniques, each was underpinned and made coherent by a consistent critical inquiry methodology and an overarching research question. “Systematic reviews are becoming increasingly popular as a way to collect evidence of what works across multiple contexts and can be said to address some of the weaknesses of case study designs which provide detail about a particular context – but which is often not replicable in other socio-cultural contexts (such as other countries or states.) Publication of systematic reviews that are done according to well defined methods are quite likely to be published in high-ranking journals – my PhD supervisors were keen on this from the outset and I was encouraged along this path. “Previously I had explored social realist authors and a social realist approach to systematic reviews (Pawson on realist reviews) but they did not sufficiently embrace social relations, issues of power, inclusion/exclusion. My supervisors had pushed me to explain what kind of realist review I intended to undertake, and I found out there was a branch of critical realism which was briefly of interest. By getting deeply into theory and trying out ways of combining theory I also feel that I have developed a deeper understanding of conceptual working and the different ways theories can be used at all stagesof research and even how to come up with novel conceptual frameworks.”

Useful references for Systematic Review & Meta-Analysis: Finfgeld-Connett (2014); Lambert (2020); Siddaway, Wood & Hedges (2019)

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When is conducting a Meta-Analysis appropriate?

Methods and guidance, examples of meta-analyses, supplementary resources.

A meta-analysis is defined by Haidlich (2010) as "quantitative, formal, epidemiological study design used to systematically assess previous research studies to derive conclusions about that body of research. Outcomes from a meta-analysis may include a more precise estimate of the effect of treatment or risk factor for disease, or other outcomes , than any individual study contributing to the pooled analysis" (p.29).

According to Grant & Booth (2009) , a meta-analysis is defined as a "technique that statistically combines the results of quantitative studies to provide a more precise effect of the results" (p.94).

Characteristics

• A meta-analysis can only be conducted after the completion of a systematic review , as the meta-analysis statistically summarizes the findings from the studies synthesized in a particular systematic review. A meta-analysis cannot exist with a pre-existing systematic review . Grant & Booth (2009) state that "although many systematic reviews present their results without statistically combining data [in a meta-analysis], a good systematic review is essential to a meta-analysis of the literature" (p.98).
• Conducting a meta-analysis requires all studies that will be statistically summarized to be similar - i.e. that population, intervention, and comparison. Grant & Booth (2009) state that "more importantly, it requires that the same measure or outcome be measured in the same way at the same time intervals" (p.98).

When to Use It: According to the Cochrane Handbook , "an important step in a systematic review is the thoughtful consideration of whether it is appropriate to combine the numerical results of all, or perhaps some, of the studies. Such a meta-analysis yields an overall statistic (together with its confidence interval) that summarizes the effectiveness of an experimental intervention compared with a comparator intervention" (section 10.2).

Conducting meta-analyses can have the following benefits, according to Deeks et al. (2021, section 10.2) :

• To improve precision. Many studies are too small to provide convincing evidence about intervention effects in isolation. Estimation is usually improved when it is based on more information.
• To answer questions not posed by the individual studies. Primary studies often involve a specific type of participant and explicitly defined interventions. A selection of studies in which these characteristics differ can allow investigation of the consistency of effect across a wider range of populations and interventions. It may also, if relevant, allow reasons for differences in effect estimates to be investigated.
• To settle controversies arising from apparently conflicting studies or to generate new hypotheses. Statistical synthesis of findings allows the degree of conflict to be formally assessed, and reasons for different results to be explored and quantified.

The following resource provides further support on conducting a meta-analysis.

Methods & Guidance

• Cochrane Handbook for Systematic Reviews of Interventions. Chapter 10: Analysing data and undertaking meta-analyses

A comprehensive overview on meta-analyses within the Cochrane Handbook.

Reporting Guideline

• PRISMA 2020 checklist

PRISMA (2020) is a 27-item checklist that replaces the  PRISMA (2009) statement , which ensures proper and transparent reporting for each element in a systematic review and meta-analysis. "It is an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews."

• Marioni, R. E., Suderman, M., Chen, B. H., Horvath, S., Bandinelli, S., Morris, T., Beck, S., Ferrucci, L., Pedersen, N. L., Relton, C. L., Deary, I. J., & Hägg, S. (2019). Tracking the epigenetic clock across the human life course: a meta-analysis of longitudinal cohort data .  The journals of gerontology: Series A, Biological sciences and medical sciences ,  74 (1), 57–61. doi: 10.1093/gerona/gly060

Deeks, J.J., Higgins, J.P.T., & Altman, D.G. (Eds.). (2021).  Chapter 10: Analysing data and undertaking meta-analyses . In Higgins, J.P.T., Thomas J., Chandler, J., Cumpston, M., Li, T., Page, M.J., & Welch, V.A. (Eds.),  Cochrane Handbook for Systematic Reviews of Interventions  version 6.2. Cochrane. Available from www.training.cochrane.org/handbook

Grant, M. J., & Booth, A. (2009). A typology of reviews: an analysis of 14 review types and associated methodologies .  Health information and libraries journal ,  26 (2), 91–108. doi: 10.1111/j.1471-1842.2009.00848.x

Haidich A. B. (2010). Meta-analysis in medical research .  Hippokratia ,  14 (Suppl 1), 29–37.

Seidler, A.L., Hunter, K.E., Cheyne, S., Ghersi, D., Berlin, J.A., & Askie, L. (2019). A guide to prospective meta-analysis .  BMJ ,  367 , l5342. doi: 10.1136/bmj.l5342

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Limitations of a Meta-Analysis

The following challenges of conducting meta-analyses in systematic reviews are derived from Grant & Booth (2009) , Haidlich (2010) , and Deeks et al. (2021) .

• Can be challenging to ensure that studies used in a meta-analysis are similar enough, which is a crucial component
• Meta-analyses can perhaps be misleading due to biases such as those concerning specific study designs, reporting, and biases within studies

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• Getting Started with Systematic Reviews

What is a Systematic Review and Meta-Analysis

Differences between systematic and literature reviews.

• Finding and Evaluating Existing Systematic Reviews
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A systematic review collects and analyzes all evidence that answers a specific research question. In a systematic review, a question needs to be clearly defined and have inclusion and exclusion criteria. In general, specific and systematic methods selected are intended to minimize bias. This is followed by an extensive search of the literature and a critical analysis of the search results. The reason why a systematic review is conducted is to provide a current evidence-based answer to a specific question that in turn helps to inform decision making. Check out the Centers for Disease Control and Prevention and Cochrane Reviews links to learn more about Systematic Reviews.

A systematic review can be combined with a meta-analysis. A meta-analysis is the use of statistical methods to summarize the results of a systematic review. Not every systematic review contains a meta-analysis. A meta-analysis may not be appropriate if the designs of the studies are too different, if there are concerns about the quality of studies, if the outcomes measured are not sufficiently similar for the result across the studies to be meaningful.

Centers for Disease Control and Prevention. (n.d.).  Systematic Reviews . Retrieved from  https://www.cdc.gov/library/researchguides/sytemsaticreviews.html

Cochrane Library. (n.d.).  About Cochrane Reviews . Retrieved from  https://www.cochranelibrary.com/about/about-cochrane-reviews

Source: Kysh, Lynn (2013): Difference between a systematic review and a literature review. [figshare]. Available at:  https://figshare.com/articles/Difference_between_a_systematic_review_and_a_literature_review/766364

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Reproduced from Grant, M. J. and Booth, A. (2009), A typology of reviews: an analysis of 14 review types and associated methodologies. Health Information & Libraries Journal, 26: 91–108. doi:10.1111/j.1471-1842.2009.00848.x

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The Guide to Literature Reviews

• What is a Literature Review?
• The Purpose of Literature Reviews
• Guidelines for Writing a Literature Review
• How to Organize a Literature Review?
• Software for Literature Reviews
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• How to Conduct a Literature Review?
• Common Mistakes and Pitfalls in a Literature Review
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• What is a Systematic Literature Review?
• What is a Narrative Literature Review?
• What is a Descriptive Literature Review?
• What is a Scoping Literature Review?
• What is a Realist Literature Review?
• What is a Critical Literature Review?
• Introduction

What are the differences between a meta-analysis and a literature review?

• How to conduct a meta-analysis?

When to conduct meta-analyses?

• What is an Umbrella Literature Review?
• Differences Between Annotated Bibliographies and Literature Reviews
• Literature Review vs. Theoretical Framework
• How to Write a Literature Review?
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• How to Write the Body of a Literature Review?
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• How to Format a Literature Review?
• How Long Should a Literature Review Be?
• Examples of Literature Reviews
• How to Present a Literature Review?
• How to Publish a Literature Review?

Meta-Analysis vs. Literature Review

A meta-analysis is a statistical method used to combine data from multiple independent studies, often conducted as part of comprehensive literature reviews to provide more precise estimates and robust conclusions. Its purpose is to provide a more precise estimate of effect sizes by aggregating results from various studies. Meta-analyses are crucial in evidence-based medicine as they provide robust conclusions based on empirical evidence.

The primary purpose of a meta-analysis is to synthesize quantitative data from multiple studies to arrive at a single conclusion. By combining results, a meta-analysis can increase statistical power, making it possible to detect effects that may be missed in individual studies. It helps to resolve uncertainty when studies disagree and provides a comprehensive understanding of effect size across different contexts and conditions.

Meta-analyses are important because they offer a higher level of evidence than individual studies. They help researchers and practitioners make informed decisions by summarizing the best available evidence. In clinical settings, meta-analyses can guide treatment choices by comparing the effectiveness of different interventions. Meta-analyses help identify gaps in existing research, paving the way for future studies. They are also essential for developing guidelines and policies based on a thorough synthesis of the evidence.

Although meta-analyses are commonly associated with quantitative research , they can also be applied to qualitative research through a process known as meta-synthesis. Meta-synthesis involves systematically reviewing and integrating findings from multiple qualitative studies to draw broader conclusions. This approach allows researchers to combine qualitative data to develop new theories, understand complex phenomena, and gain insights into contextual factors.

Using meta-synthesis, qualitative meta-analyses can help provide a deeper understanding of a research topic by incorporating diverse perspectives and experiences from various studies. This method can reveal patterns and themes that might not be evident in individual qualitative studies, thereby enhancing the richness and depth of the analysis. By combining the strengths of both quantitative and qualitative research, meta-analyses can offer a more comprehensive view of the research landscape, supporting evidence-based practice and informed decision-making.

A meta-analysis literature review combines elements of both meta-analysis and traditional literature review methodologies. It is a comprehensive approach that includes both a qualitative summary and a quantitative synthesis of research findings. It is a hybrid approach that leverages the strengths of both meta-analysis and traditional literature reviews to provide a thorough and nuanced understanding of a research topic. Read this article to find out more about the differences, and when to use it.

A meta-analysis and literature reviews differ in purpose, methodology, and outcomes. The primary purpose of a meta-analysis is to provide a quantitative analysis of data from multiple studies, producing a precise estimate of the effect size through statistical methods. A literature review synthesizes findings to offer an overview of current knowledge, identify gaps, and suggest future research areas. Literature reviews can be systematic, scoping, or narrative reviews among others.

Meta-analyses use systematic methods, including defining inclusion and exclusion criteria, conducting a systematic search, extracting data, and applying statistical methods such as calculating the standardized mean difference or risk ratio. Other reviews, like systematic and scoping reviews, summarize relevant studies without combining results statistically. Narrative reviews provide qualitative summaries and interpretations.

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The outcome of a meta-analysis is a quantitative synthesis, offering more precise estimates of key variable effect sizes and identifying patterns through subgroup analysis and forest plots. Systematic reviews provide comprehensive literature summaries, highlighting research strengths and weaknesses. Scoping reviews map key concepts and evidence, while narrative reviews offer critical analysis.

Meta-analyses focus on combining quantitative data, often used in fields with substantial empirical evidence and similar research methods. Systematic and scoping reviews have a broader scope, and narrative reviews provide critical insights into theories and concepts. Each review type offers unique benefits, depending on the research goals.

Conducting a meta-analysis involves a systematic and rigorous process. By following established guidelines and best practices, such as those outlined in the Cochrane Handbook for Systematic Reviews of Interventions and the PRISMA statement, researchers can effectively combine data from multiple studies to derive more precise estimates of effect sizes. The following steps provide a structured approach to conducting a meta-analysis, ensuring a comprehensive and reproducible methodology (Higgins & Green, 2011; Moher et al., 2009).

Formulate a research question : Define a specific research question that the meta-analysis will address. This question guides the entire process.

Systematic search : Conduct a systematic search to identify relevant studies. Use scholarly databases to find studies on the same topic.

Inclusion and exclusion criteria : Establish clear inclusion and exclusion criteria to select studies. This ensures that only relevant studies are included.

Data extraction : Extract relevant data from the included studies. Key data points include effect sizes, sample sizes, and study characteristics.

Statistical methods : Use statistical methods to combine data from the studies. Common methods include calculating the standardized mean difference and risk ratio.

Subgroup analysis : Perform subgroup analyses to explore differences among studies. This can help identify factors that influence the overall estimate.

Forest plot : Create a forest plot to visualize the results of the meta-analysis. This plot shows the effect sizes and confidence intervals for each study.

Interpret results : Interpret the results in the context of the existing literature. Discuss the implications of the findings and their relevance to the research question.

Report findings : Write a comprehensive report detailing the methodology, findings, and conclusions. Ensure that the report is clear and reproducible.

Meta-analyses are conducted to achieve a quantitative analysis of data from multiple studies, providing more precise and robust conclusions. They are particularly useful when individual studies yield conflicting results, as combining data can help resolve discrepancies and offer a clearer understanding of the effect size. Meta-analyses enhance statistical power by aggregating data from studies with small sample sizes, making it possible to detect significant effects that individual studies might miss.

These analyses are crucial for generalizing findings across different populations, settings, or conditions, offering broader insights that are not limited to a single study's context. In evidence-based fields such as medicine, education, and psychology, meta-analyses often include data from randomized controlled trials and observational studies, providing a high level of evidence. This synthesis aids practitioners in making informed decisions and developing effective interventions.

Meta-analyses also help identify patterns, trends, and gaps in existing research. This is achieved through a systematic review attempt and critical analysis of previous studies, guiding future research directions. This supports informed decision-making and the creation of robust clinical practice recommendations. Conducting meta-analyses is essential for advancing knowledge, improving practices, and ensuring that decisions are based on the best available evidence.

Additionally, meta-analyses complement scoping reviews and literature reviews by providing a quantitative analysis of study findings, which literature reviews provide qualitatively. They form a crucial part of the research process , transforming diverse research papers into coherent, actionable insights.

Meta-analyses are powerful methods for synthesizing quantitative data from multiple studies, offering precise estimates and robust conclusions. By combining results, they enhance statistical power and resolve conflicting findings, providing a comprehensive understanding of research topics. Meta-analyses are essential in evidence-based fields, guiding informed decision-making and developing effective interventions. They complement literature reviews by adding a quantitative dimension to the analysis. Meta-synthesis extends the principles of meta-analysis to qualitative research, providing deeper insights and broader perspectives.

Higgins, J. P. T., & Green, S. (Eds.). (2011). Cochrane handbook for systematic reviews of interventions (Version 5.1.0). The Cochrane Collaboration. Available from: www.cochrane-handbook.org

Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & The PRISMA Group. (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med, 6(7), e1000097. https://doi.org/10.1371/journal.pmed.1000097

Borenstein, M., Hedges, L. V., Higgins, J. P. T., & Rothstein, H. R. (2009). Introduction to meta-analysis. John Wiley & Sons.

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Research Article

Knowledge and attitude towards mpox: Systematic review and meta-analysis

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Affiliation Facultad de Medicina Humana, Universidad de San Martín de Porres, Chiclayo, Peru

Roles Conceptualization, Data curation, Investigation, Methodology, Resources, Visualization, Writing – original draft, Writing – review & editing

Affiliation Facultad de Ciencias de la Salud, Escuela de Medicina, Universidad César Vallejo, Trujillo, Peru

Roles Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Visualization, Writing – original draft, Writing – review & editing

Affiliation Faculty of Pharmacy, Mansoura University, Mansoura, Egypt

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Writing – original draft, Writing – review & editing

Affiliations Department of Microbiology, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal, Department of Microbiology, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India, Department of Public Health Dentistry, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth, Pune, Maharashtra, India

* E-mail: [email protected]

Affiliations Universidad Continental, Lima, Peru, Oficina de Epidemiología, Hospital Regional Lambayeque, Chiclayo, Peru

Roles Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing – original draft, Writing – review & editing

Affiliations Master of Clinical Epidemiology and Biostatistics, Universidad Cientifica del Sur, Lima, Peru, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon

• Darwin A. León-Figueroa, 
• Joshuan J. Barboza, 
• Abdelmonem Siddiq, 
• Ranjit Sah, 
• Mario J. Valladares-Garrido, 
• Alfonso J. Rodriguez-Morales

• Published: August 9, 2024
• https://doi.org/10.1371/journal.pone.0308478
• Peer Review
• Reader Comments

The increase in mpox incidence underscores the crucial need to understand and effectively address prevention, early detection, and agile response to this disease. Therefore, the present study aims to determine the knowledge and attitude towards mpox.

A systematic review and comprehensive literature meta-analysis were conducted using prominent databases such as PubMed, Scopus, Web of Science, Embase, and ScienceDirect, with an updated search until June 25, 2023. The quality of the included observational studies was assessed using the Joanna Briggs Institute’s Statistical Meta-Analysis Review Instrument. The collected data were recorded in a Microsoft Excel spreadsheet, and analyses were conducted using R software version 4.2.3. Additionally, Cochran’s Q statistics were applied to assess the heterogeneity of the included studies.

A total of 299 articles were retrieved from 5 databases. This study included 27 cross-sectional articles with a total sample of 22,327 participants, of which 57.13% were women. The studies were conducted in 15 countries through an online survey. All studies had a moderate level of quality. The combined prevalence of a good level of knowledge about mpox was 33% (95% CI: 22%-45%; 22,327 participants; 27 studies; I 2 = 100%), and the combined prevalence of a positive attitude towards mpox was 40% (95% CI: 19%-62%; 2,979 participants; 6 studies; I 2 = 99%). Additionally, as a secondary outcome, the combined prevalence of the intention to vaccinate against mpox was 58% (95% CI: 37%-78%; 2,932 participants; 7 studies; I 2 = 99%).

Good knowledge and a positive attitude towards mpox were found to be low. The findings of this study highlight the need to identify gaps and focus on implementing educational programs on mpox.

Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI), Prospective International Registry of Systematic Reviews (PROSPERO), and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)

Citation: León-Figueroa DA, Barboza JJ, Siddiq A, Sah R, Valladares-Garrido MJ, Rodriguez-Morales AJ (2024) Knowledge and attitude towards mpox: Systematic review and meta-analysis. PLoS ONE 19(8): e0308478. https://doi.org/10.1371/journal.pone.0308478

Editor: Sirwan Khalid Ahmed, Ministry of Health, General Health Directorate of Raparin and University of Raparin, IRAQ

Received: March 6, 2024; Accepted: July 23, 2024; Published: August 9, 2024

Copyright: © 2024 León-Figueroa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: If the data are all contained within the manuscript and/or Supporting Information files, enter the following: All relevant data are within the manuscript and its Supporting Information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

1. Introduction

The spread of mpox in humans has raised significant concerns in various countries globally, extending beyond Africa, especially in a context marked by the COVID-19 pandemic [ 1 ]. As of June 30, 2024, 97,962 cases of mpox have been reported in 118 countries, 111 of which have not historically reported it [ 2 ].

Mpox is a reemerging zoonotic viral disease caused by the mpox virus, an Orthopoxvirus from the Poxviridae family [ 3 ]. Individuals affected by mpox experience a time interval of 7 to 21 days between exposure and the onset of distinctive clinical symptoms, which include fever, headache, muscle pain, back pain, chills, skin rash, and lymphadenopathy [ 4 ].

The spread of the mpox virus from one person to another extends beyond close direct contact [ 5 ]. Given the rapid development of the mpox virus, how it spreads includes skin wounds, genital lesions, throat secretions, seminal fluid, and blood [ 6 , 7 ]. The rapid expansion of the outbreak in 2022 has raised concerns, mainly because over 95% of the cases affected men who have sex with other men [ 8 , 9 ].

In the face of a public health emergency like the mpox outbreak in 2022, countries must have immediate action plans to prevent diseases promptly. Additionally, providing prevention equipment and disseminating clear information about the signs and symptoms of the disease among the general population is essential [ 10 , 11 ]. It is also vital to ensure that healthcare professionals receive ongoing training or participate in short-term emergency training programs related to mpox [ 10 , 12 ]. These measures will effectively contribute to mitigating the impact of mpox [ 11 ].

Despite efforts and thorough planning, several challenges persist that need to be overcome, including the deficiency in the level of education and the limited knowledge of citizens regarding the current health crisis [ 13 , 14 ]. Therefore, this study aims to determine the combined prevalence of knowledge and attitudes regarding mpox.

2. Materials and methods

2.1. protocol and registration.

This systematic review and meta-analysis were conducted following the guidelines of the PRISMA checklist [ 15 ] ( S1 Table ) . The protocol for this research has been appropriately registered in PROSPERO ( CRD42023439782 ), ensuring transparency and rigor in the process.

2.2. Eligibility criteria

Inclusion criteria..

All observational studies on the prevalence of knowledge, attitude, or both, regarding mpox were considered. No restrictions were imposed regarding gender, health status, language, time, quality, or geographic location. However, only those studies that were available in their entirety provided sample size information presented data related to any aspect of knowledge and attitude towards mpox or provided data from which the required results could be calculated, were included.

Exclusion criteria.

The following studies were excluded: those containing duplicate information, those whose research topics were unrelated to the objective of our study, as well as those using a design different from an observational study. Additionally, articles lacking full text were discarded due to insufficient data or not reporting the desired results.

2.3. Information sources and search strategy

Three expert researchers conducted exhaustive searches in various databases, including PubMed, Scopus, Embase, Web of Science, and ScienceDirect. Keywords such as "mpox," "knowledge," "awareness," and "attitude" were used as part of the search strategy. Specific search strategies for each database are detailed in S2 Table . The initial search was conducted on June 1, 2023, and subsequently updated on June 25, 2023.

2.4. Study selection

The search strategy results were stored and managed using the Endnote software. After eliminating duplicate articles, three experts independently conducted a preliminary selection of the remaining articles by reading the titles and abstracts, following predefined criteria. Subsequently, two other researchers thoroughly reviewed the complete reports to determine if they met the inclusion criteria. Any discrepancies would be resolved through discussions and consultations with a sixth investigator.

2.5. Main and secondary results of the study

This study addressed two main aspects related to knowledge and attitudes towards mpox.

Knowledge about mpox.

The knowledge base of the participants in this study relied on the reports of the included articles, which revealed either good general knowledge or a high level of specific knowledge about mpox. The criteria used to determine the combined prevalence of knowledge covered modes of transmission, clinical symptoms, treatment, prevention, and the diagnosis of mpox.

Attitude towards mpox.

The participants’ attitude in this study was based on the analysis of the included articles, which encouraged a positive attitude towards mpox. Positive attitudes toward mpox included confidence in the overall ability to control the epidemic, in the effectiveness of preventive and control measures, and in the perception that health actions are adequate to prevent its spread.

Intention to vaccinate against mpox.

The intention of the participants to vaccinate against mpox in this study was based on the analysis of the included articles, which reported the importance of getting vaccinated against mpox if the vaccine was available or as a preventive measure.

2.6. Quality assessment

Three independent authors evaluated the quality of the included studies using the "JBI-MAStARI" method for observational studies. In the event of any discrepancies among the evaluators, a fourth author intervened to address and resolve them. To perform this evaluation, a checklist composed of eight critical parameters was used to assess the responses as "yes," "no," "unclear," or "not applicable." The quality of the studies was classified based on their score as high (≥7 points), moderate (4 to 6 points), or low (<4 points) [ 16 ] ( S3 Table ).

2.7. Data collection process and data items

Two independent researchers meticulously collected relevant data from the selected articles. The following details were extracted and recorded in an Excel spreadsheet: first author’s name, publication year, country, sample size, study population, gender (male and female), the prevalence of mpox knowledge, prevalence of attitudes towards mpox, number of cases with knowledge of mpox, and number of cases with attitudes towards mpox. Finally, a third researcher verified the extracted data to ensure accuracy and eliminate incorrect information.

2.8. Data analysis

Firstly, the selected articles were entered into a Microsoft Excel spreadsheet to perform the analysis using R, version 4.2.3. Narrative tables and charts were used to present the research results. To estimate the joint prevalence of mpox knowledge and attitudes, an inverse variance-weighted random-effects model was used. This technique, commonly used in meta-analyses, allows the results of several independent studies to be combined. The model takes into account both within-study variability (within-study variance) and between-study variability (between-study variance) [ 17 ]. The Cochrane Q statistic was employed to assess heterogeneity among studies and quantified using the I 2 index, where 25%, 50%, and 75% indicated low, moderate, and high heterogeneity, respectively [ 18 ]. Funnel plots and Egger’s regression test were used to check for publication bias. Publication bias occurs when the results of published studies are not representative of all studies conducted, usually because studies with non-significant results are less likely to be published [ 19 ]. A possible publication bias was considered when the p-value was < 0.05 [ 20 ].

Subgroup analyses were performed according to study population and country. A forest plot was used to illustrate the combined prevalence of good knowledge and attitudes towards mpox, including 95% confidence intervals.

3.1. Study selection

A total of 299 articles were retrieved from 5 databases. After removing duplicates (n = 125), researchers analyzed 174 articles. Then, the titles and abstracts of these articles were reviewed, and 54 were selected for a thorough full-text review. Finally, 27 articles were included in the study [ 21 – 47 ]. The PRISMA flow diagram shows the study selection process ( Fig 1 ).

• PPT PowerPoint slide
• PNG larger image
• TIFF original image

https://doi.org/10.1371/journal.pone.0308478.g001

3.2. Characteristics of the included studies

This study included 27 cross-sectional articles with a total sample size of 22,327 participants ( Table 1 ). The sample composition consisted of 42.83% males, 57.13% females, and 0.04% others (undefined or unreported) [ 21 – 47 ]. The studies were conducted in 15 countries using an online survey, where questionnaires were sent via e-mail and other communication channels to those with Internet access. The articles cover the period between 2020 and 2023 in their publication year. The sample sizes ranged from 111 to 5,874. Regarding the prevalence of knowledge and attitude towards mpox, the ranges observed were from 0.6% to 65.46% and 12.2% to 84.83%, respectively [ 21 – 47 ].

https://doi.org/10.1371/journal.pone.0308478.t001

3.3. Quality of the included studies and publication bias

The studies were evaluated regarding quality using the JBI-MAStARI for observational research. It was determined that all studies had a moderate level of quality [ 21 – 47 ] ( S3 Table ). We examined the publication bias of articles that reported the level of good knowledge and positive attitude about mpox ( S1 Fig ). Egger’s test, applied to assess publication bias in studies related to the level of good knowledge about mpox, revealed a value of p = 0.0135 (t = 2.66, df = 25), leading to the rejection of the null hypothesis of symmetry. This finding suggests the possible presence of publication bias in the studies analyzed ( S1 Fig ) [ 21 – 47 ]. Articles reporting a positive attitude towards mpox were not assessed for publication bias, as there were fewer than ten studies.

3.4. Level of knowledge of and attitude towards mpox

The aggregated prevalence and 95% confidence interval of knowledge and attitudes towards mpox among study participants are presented in a forest plot ( Figs 2 and 3 ) [ 21 – 47 ]. The random-effects model showed that the combined level of good knowledge about mpox was 33% (95% CI: 22%–45%; 22,327 participants; 27 studies; I 2 = 100%; p < 0.01) ( Fig 2 ) [ 21 – 47 ]. The estimated overall positive attitude towards mpox was 40% (95% CI: 19%–62%; 2,979 participants; 6 studies; I 2 = 99%; p < 0.01) [ 21 , 29 , 32 , 33 , 37 , 43 ] ( Fig 3 ).

https://doi.org/10.1371/journal.pone.0308478.g002

https://doi.org/10.1371/journal.pone.0308478.g003

3.5. Secondary outcomes

The pooled prevalence of intention to vaccinate against mpox was 58% (95% CI: 37%–78%; 2,932 participants; 7 studies; I 2 = 99%; p < 0.01) [ 24 , 30 – 32 , 37 , 43 , 46 ] ( S2 Fig ).

3.6. Subgroup analysis

Subgroup analyses were performed based on the study region and study population [ 21 – 47 ].

3.6.1. Subgroup analysis by study region.

A subgroup analysis was performed based on country. The pooled prevalence of a high level of knowledge about mpox was found to be higher in Algeria (65%, 95% CI: 56%, 74%) [ 31 ] and lower in the Philippines (5%, 95% CI: 3%, 7%) [ 26 ] ( S3 Fig ). However, the pooled prevalence of a positive attitude towards mpox was higher in Bangladesh (85%, 95% CI: 81%, 89%) [ 21 ] and lower in Iraq (12%, 95% CI: 9%, 15%) [ 32 ] ( S4 Fig ).

3.6.2. Subgroup analysis by study population.

A subgroup analysis based on the study population was conducted and divided into two groups: healthcare personnel (doctors, medical students, dental health professionals, and healthcare employees) and the general population (hotel workers, sex workers, university students from different health-related disciplines, and participants from the public). The overall prevalence of a high level of knowledge about mpox was higher in the general population (34%; 95% CI: 23%–46%; 10,505 participants; 12 studies; I 2 = 99%; p < 0.01) [ 23 , 24 , 26 – 28 , 30 , 32 , 34 , 35 , 39 , 41 , 43 ] and lower among healthcare personnel (32%; 95% CI: 17%– 49%; 11,822 participants; 15 studies; I 2 = 100%; p < 0.01) [ 21 , 22 , 25 , 29 , 31 , 33 , 36 – 38 , 40 , 43 – 47 ] ( S5 Fig ). The overall prevalence of a positive attitude towards mpox was higher among healthcare personnel (53%; 95% CI: 26%– 79%; 1,523 participants; 4 studies; I 2 = 99%; p < 0.01) [ 21 , 29 , 33 , 37 ] and lower in the general population (16%; 95% CI: 9%– 25%;1,456 participants; 2 studies; I 2 = 94%; p < 0.01) [ 32 , 43 ] ( S6 Fig ).

4. Discussion

Mpox is not currently considered a public health emergency of international concern; however, it continues to be transmitted in several countries. A thorough understanding of prevention and control measures for this disease is essential.

Given the diversity of research on mpox, multiple studies have been conducted to assess the knowledge of different population targets about mpox to understand the gap of knowledge that can be covered by appropriate educational tools to increase the knowledge score about this disease and to curb its transmission by following the infection control measures [ 21 , 22 , 24 , 48 ]. So we have conducted a systematic review and meta-analysis to gain a more comprehensive understanding of the prevalence of good knowledge levels and attitudes of the general population towards mpox. All relevant studies found through various online search engines were considered to achieve this. Additionally, a subgroup analysis was performed to examine the prevalence of individuals with positive attitudes and a good level of knowledge about mpox based on the region of study and the population analyzed.

The findings of this study revealed that the combined prevalence of good knowledge about mpox was 33%, and the subgroup analysis revealed a total prevalence of good knowledge among the general population and healthcare personnel equal to 34% and 32%, respectively. A meta-analysis by Jahromi AS et al., which included 22 studies involving 27,731 health care workers, revealed that 26% of them had a good knowledge of mpox [ 49 ]. To improve knowledge about mpox, it is crucial to identify reliable and up-to-date sources of information that provide accurate data on its transmission, symptoms, prevention, and treatment. This is essential to effectively understanding and addressing this disease, with a strong emphasis on online sources such as social networks (59%) and the Internet (61%) [ 50 ].

Another result of this study was the combined prevalence of positive attitudes towards mpox, which was 40%. The subgroup analysis results indicated that the combined proportion of positive attitudes towards mpox among healthcare workers was 53%, and the general population was 16%. Different research has assessed this positive attitude towards mpox, ranging from 12% to 85% [ 21 , 29 , 32 , 33 , 37 , 43 ]. A meta-analysis by Jahromi AS et al., which included six studies with 14,388 health care workers, revealed that 34.6% of them had a positive attitude toward mpox [ 49 ]. That could be explained by the disparity in how different populations respond to disease severity and adopt protective measures, which may be attributed to socioeconomic, cultural, information access, and distrust in the healthcare system or government policies. It is essential to address these factors to ensure a more equitable and effective response to any disease and promote the adoption of public health measures to benefit the entire population [ 51 , 52 ].

The difference in the prevalence estimates of the knowledge and the attitude score between our findings and other individual papers may be justified by the difference in the culture of the population from one country to another, the difference in the target group (general population, medical students and healthcare workers), the difference in the timeline at which each study was conducted, the difference in the survey methods used in the assessment of the knowledge and the attitude, and other factors that should be taken into our consideration.

The secondary outcome revealed that the prevalence of the intention to vaccinate against mpox was 58%, consistent with a meta-analysis conducted by Ulloque-Badaracco et al., which reported that the prevalence of mpox vaccine acceptance equals 56% [ 53 ]. Another meta-analysis proposed by León-Figueroa DA et al., which included 29 articles with a total sample of 52,658 participants, determined that the combined prevalence of intention to be vaccinated against mpox was 61% [ 54 ]. It was recommended by the World Health Organization (WHO) and The Center for Disease Control and Prevention (CDC) to vaccinate certain groups of the population who are at risk of developing mpox in terms of pre-exposure and postexposure prophylaxis using JYNNEOS, ACAM2000, and LC16m8 vaccines [ 55 – 57 ]. However, there is variation in the prevalence of intention to vaccinate against mpox reported in the individual studies; this variation could be due to fear of unknown adverse reactions and doubts about the efficacy and safety of the mpox vaccine [ 54 , 58 ].

We recommend that further research is needed to cover the knowledge of the different population groups, including the general public, healthcare professionals, and students, regarding mpox disease, especially in countries with missing data. Further research is needed in countries with many mpox-infected patients at different intervals to track the change in the people’s knowledge, attitude, intention to get vaccinated, and their maintenance on tracking the infection control measures.

This research has several limitations. First, the use of self-reported questionnaires could introduce biases, as participants could provide socially acceptable answers or exaggerate their knowledge about mpox, thus affecting the validity of the data. To mitigate this problem, it is crucial to recommend the use of proxy questions, ensure the anonymity of responses, and perform consistency analysis. Second, the high heterogeneity among the included studies (I 2 > 75%) indicates diversity in the methodologies and populations investigated, which could limit the generalizability of the findings. Our study addressed this issue through subgroup analysis, clear inclusion criteria, and the use of random-effects models, thus providing more accurate and robust data. Third, we found evidence of publication bias, which we addressed using tests such as Egger’s test and funnel plots. Fourth, variations in questionnaire design, distribution methods, and participant demographics could introduce confounding factors into the analysis. Despite these differences, the studies presented similar general criteria regarding transmission, clinical symptoms, diagnosis, treatment, and prevention of mpox. Finally, variability in outcomes could be attributed to sociodemographic, economic, and cultural factors, as well as access to education and trust in the health system or government policies of each country.

Nevertheless, this research has strengths. First, an exhaustive search was carried out in multiple databases without language restrictions, which increased the completeness of the review. Second, robust tools were used to assess quality, and statistical analysis was performed, which reinforced the validity of the results (JBI-MAStARI, PRISMA, Egger’s test, funnel plots, and R software). Third, article selection and data extraction were performed independently by more than three investigators. Finally, this study represents the first systematic review and meta-analysis assessing the prevalence of good knowledge and positive attitudes toward mpox, providing reliable data that can be used by policymakers to improve knowledge and attitudes toward mpox.

5. Conclusions

In conclusion, this systematic review and meta-analysis reported a significant gap in good knowledge and positive attitudes towards mpox. Furthermore, the combined prevalence of good knowledge and positive attitudes differed across study populations, regions, and publication years. A holistic and multisectoral approach is necessary for the successful understanding of mpox. Additional healthcare education and communication are crucial for improving knowledge and attitudes regarding mpox.

Supporting information

S1 table. prisma checklist (prisma 2020 main checklist and primsa abstract checklist)..

https://doi.org/10.1371/journal.pone.0308478.s001

S2 Table. The adjusted search terms as per searched electronic databases.

https://doi.org/10.1371/journal.pone.0308478.s002

S3 Table. Quality of the included studies.

https://doi.org/10.1371/journal.pone.0308478.s003

S1 Fig. Funnel plot and Egger’s test illustrate the publication bias of the included studies.

https://doi.org/10.1371/journal.pone.0308478.s004

S2 Fig. Forest plot showing prevalence of intention to vaccinate against mpox among study participants.

https://doi.org/10.1371/journal.pone.0308478.s005

S3 Fig. Subgroup analysis by country on good knowledge of mpox.

https://doi.org/10.1371/journal.pone.0308478.s006

S4 Fig. Subgroup analysis by country on positive attitude toward mpox.

https://doi.org/10.1371/journal.pone.0308478.s007

S5 Fig. Subgroup analysis by study subjects on good knowledge of mpox.

https://doi.org/10.1371/journal.pone.0308478.s008

S6 Fig. Subgroup analysis by study subjects on positive attitude toward mpox.

https://doi.org/10.1371/journal.pone.0308478.s009

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• Kamlesh Khunti 2 &
• Pankaj Gupta   ORCID: orcid.org/0000-0001-9481-6067 4 , 5  

Journal of Human Hypertension ( 2024 ) Cite this article

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• Health care
• Hypertension

Hypertension is the leading modifiable risk factor for cardiovascular disease, but less than 50% have their blood pressure controlled. A possible avenue to support hypertension management is a holistic approach, using non-pharmacological interventions. Since hypertension is mediated in part by dysregulation of the autonomic nervous system (ANS), biofeedback may help improve hypertension management by targeted self-regulation and self-awareness of parameters that regulate the ANS. This systematic review aimed to assess the effectiveness of biofeedback on blood pressure in hypertensive patients. The review was pre-registered on PROSPERO and followed the PICO strategy. A total of 1782 articles were retrieved, 20 met the inclusion criteria. Sample sizes ranged from 15 to 301 participants; with a median age of 49.3 (43.3–55.0) years and 45% were female. There was a significant effect of biofeedback on systolic (−4.52, Z = 2.31, P  = 0.02, CI [−8.35, −0.69]) and diastolic blood pressure (−5.19, Z = 3.54, P  = 0.0004, CI [−8.07, −2.32]). Six different biofeedback modalities were used, with biofeedback delivered by psychologists, trained therapists and research assistants. There was no publication bias, heterogeneity was rated as substantial and data quality was rated to be poor. This review demonstrated that biofeedback had a significant effect on blood pressure. However, this should be viewed in the context of included studies being limited by heterogeneity and dated literature, meaning the research does not reflect the current biofeedback technology such as wearable devices. Future research should incorporate these technologies with robust methodology to fully understand the effect of biofeedback on hypertension.

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Introduction.

Hypertension is the leading modifiable risk factor for cardiovascular disease, stroke and premature death [ 1 ]. Globally, 1.2 billion people have hypertension, a figure that doubled between 1990 and 2019 [ 1 ]. Worldwide hypertension control remains poor with only 21% of men and 18% of women achieving blood pressure targets [ 1 ]. This is despite the availability of cheap and effective medications. Hence it would be useful to consider non-pharmacological therapies that, in conjunction with medications, may help improve blood pressure in a more holistic manner.

It is accepted that hypertension is in part due to a derangement in the regulation of the autonomic nervous system (ANS). The sympathetic nervous system leads to increase in heart rate and blood pressure, whereas the parasympathetic nervous system relaxes the body and decreases blood pressure [ 2 ]. Hypertension is also linked to impaired baroreceptor regulation with interrelationships between baroreflex sensitivity and autonomic dysfunction [ 3 ]. There is evidence that non-pharmacological treatments such as lifestyle interventions and weight loss have a positive impact on the ANS [ 2 ]. Therefore, improved regulation in the ANS, especially an increase in parasympathetic activity, can improve blood pressure and biofeedback may help to achieve this [ 4 ].

Biofeedback improves ANS control as it promotes self-regulation, induces a ‘relaxation response’ and reduces cognitive avoidance (i.e., avoiding thoughts of undesirable situations through distraction, thought suppression or worry [ 5 ]) through increasing awareness of physiological processes [ 6 ]. Biofeedback uses instruments to measure physiological responses such as heart rate variability, sharing this with the user in real time with the aim to increase awareness and health [ 7 ]. Biofeedback is often paired with interventions that address behaviour, emotion and thoughts, which can benefit physiological processes [ 7 ]. Frank et al. [ 8 ] described biofeedback as “training not treatment” highlighting the level of motivation and practice required by the user to achieve the benefits of biofeedback. Ultimately, the goal is that these learned processes become automatic and individuals do not require device feedback to achieve the desired outcomes.

Over the years, the field of biofeedback has progressed with advances in technology. Available devices are user friendly and wearable [ 9 , 10 , 11 , 12 ], making biofeedback a more accessible intervention. Additionally, using a wearable device gives insight into an individual’s physiology and response to stress and daily life on a continuous basis. This is more representative than data provided by a static clinic blood pressure measurement. With the improvement of technology, accessibility to biofeedback and progressions in artificial intelligence (AI), it is important to understand the existing literature and how we can progress knowledge and implementation of biofeedback to improve health and wellbeing. This review aimed to assess the effectiveness of biofeedback in patients with hypertension. The main outcome assessed was a change in blood pressure.

Eligibility criteria

This review was pre-registered on PROSPERO (ID: CRD42021285875) and follows PRISMA 2020 reporting guidelines [ 13 ]. Inclusion criteria were as follows: assessment of biofeedback (all modalities e.g., neurological, cardiovascular, physical) on systolic and/or diastolic blood pressure, randomised control trial, published in English, adult participants aged 18 and over, with a diagnosis of hypertension (office reading of systolic blood pressure (SBP) ≥ 140 and/or diastolic blood pressure (DBP) ≥ 90 mmHg or home blood pressure readings of SBP ≥ 135 and/or DBP ≥ 85 mmHg) [ 14 ]. There was no specification for patients to be on specific types of hypertension treatment. Systematic reviews, editorial letters and conference abstracts were excluded.

Study selection

The following electronic bibliographic databases were searched: PubMed, MEDLINE, PsycINFO, Embase, CINAHL and Cochrane Central Register of Trials. There was no date limit and all sources were last searched on January 16th, 2024. The search strategy followed the PICO criteria and was adjusted according to each database. The MEDLINE search strategy can be viewed in the Supplementary Material. Mendeley Desktop Reference Manager was used to store retrieved results and remove duplicates. Abstracts were reviewed in the first stage screening, which was completed by one review (S.J.), with a random 10% of abstracts screened by a second reviewer (A.C.). Disagreements were resolved after discussion between the two reviewers. The second stage screening reviewed the full text of articles and was completed by one reviewer (S.J.).

Data extraction

Extracted data was retrieved and collated into an Excel spreadsheet by one reviewer (S.J.). Outcomes retrieved included participant characteristics, intervention design, study design, pre/post intervention measurements and conclusions. Please see the Supplementary Material for the list of outcomes and variables retrieved. The effect measure for all main outcomes was mean (±standard deviation).

Synthesis methods

Studies were included in the meta-analysis if the mean and standard deviation was reported for a change in SBP and/or DBP. If reported, raw data and standard errors were converted to standard deviations and included. Authors were emailed for missing data and if there was no response, papers were excluded from the meta-analysis and assessed narratively.

The meta-analysis and forest plot diagrams were completed in Review Manager (version 5.4). A random effects model was used to assess systolic and diastolic blood pressure. Publication bias and Egger’s test was conducted in RStudio (version 2023.12.0 + 369).

A meta-regression was conducted on age and sex to explore possible causes of heterogeneity. However, there was insufficient data to conduct a reliable meta-regression for biofeedback modality. The meta-regression was a mixed effects model conducted in RStudio (version 2023.12.0 + 369).

Data quality assessment

Papers were assessed for bias with the Cochrane Risk of Bias assessment [ 15 ], assessing for selection, reporting, performance, detection, attrition, and other sources of bias. The Risk of Bias 2 Tool [ 16 ] was used to input assessment, calculate summary data and figures, and to check inter-rater agreement.

The overall quality of evidence from reviewed studies was assessed with the GRADE assessment [ 17 ], which reviewed individual study limitations, inconsistency of results, indirectness of evidence, imprecision, and publication bias. The quality of evidence was rated from high to very low.

Figure  1 details the PRISMA flowchart. The search generated 1782 articles, with 244 potentially eligible articles identified during the title and abstract screening. The full text screen identified 20 articles that met the inclusion criteria for the review. Of these articles, 18 were from peer-reviewed journals and two were PhD theses. The main reasons for exclusion were study design not meeting the inclusion criteria (31%), articles not in English (18%), or outcomes outside of the inclusion criteria (14%).

Flowchart in line with PRISMA guidelines indicating the number of articles originally identified, screened, excluded and included within the systematic review.

Participant characteristics

The overall characteristics of the 20 included studies are summarised in Table  1 . The mean demographics are reported in Table  2 . The studies were published between 1975 and 2013, from 10 different countries. There was a total of 988 participants and sample sizes ranged from 15 to 301 participants. The age ranged from 28 to 70 years, with 45% female participants. Ethnicity was reported in 3 articles, of these, 96% were Caucasian. The mean baseline SBP was 149.3 ± 7.8 mmHg and the mean DBP 93.0 ± 6.9 mmHg. Five studies [ 18 , 19 , 20 , 21 , 22 ] did not report data such as sex or age and were omitted from the above summary but were included in the main analysis as they reported key outcomes.

Types of biofeedback modalities

There were six different biofeedback modalities used across the 20 studies (Table  3 ). The type of biofeedback device used varied across studies and modalities, including finger or forehead electrodes [ 22 , 23 , 24 , 25 ], sphygmomanometer [ 18 , 26 , 27 ], finger blood pressure machines [ 28 , 29 ] and compact disk (CD) players [ 30 , 31 ]. No studies used a wearable device.

Blood pressure biofeedback was used by six studies and was measured with either a non-invasive beat to beat finger arterial pressure measurement [ 29 ] or an automated blood pressure device [ 18 , 20 , 26 , 27 , 32 ]. Blood pressure biofeedback was typically received by the participant visually (e.g., a screen) [ 18 , 26 , 28 , 29 , 32 ] and/or auditorily (e.g., a beep) [ 22 , 23 ]. For example, participants in the study by Tsai et al. [ 29 ] performed self-regulation techniques, such as deep breathing, and observed their blood pressure on a display.

Electromyographic (EMG) biofeedback detects changes or contractions in muscle. All six studies using EMG biofeedback gave auditory feedback, with some using the tone pitch and frequency to indicate EMG changes [ 19 , 20 , 22 , 24 , 33 ].

Galvanic skin response (GSR) biofeedback focuses on sweat gland activity and was used by five studies. As an example: Patel et al. [ 25 ] delivered the GSR feedback tone in one headphone and played a relaxation tape through the other headphone. The tone grew fainter as the participant relaxed and GSR activity reduced.

Thermal biofeedback was used in four studies. The intervention by Blanchard et al. [ 34 ] aimed to teach participants to increase temperature of their hands or feet, therefore strengthening deep-muscle relaxation.

RESPeRATE, a branded auditory based biofeedback device, was used in two studies [ 30 , 31 ]. It involves listening and breathing in time with a melody to guide slow breathing [ 30 ].

Achmon et al. [ 35 ] was the only study to use heart rate biofeedback. It used ear lobe capillary pulsations to guide heart rate reductions in normal and tension-provoking situations.

Intervention characteristics

Table  3 details the biofeedback intervention characteristics of the included studies. Biofeedback was mostly delivered one-to-one, with four studies delivering biofeedback to groups of 3–13 participants [ 19 , 28 , 33 , 34 ]. Studies varied in the biofeedback session length (12–75 min) and number of sessions (4–48 sessions). The post-study follow up ranged from 2 weeks to 12 months, with ten studies not reporting any follow up. Biofeedback training was delivered by psychologists in four studies [ 27 , 34 , 36 , 37 ] and by a trained nurse or therapist in two studies [ 32 , 35 ]. Three studies used an experimenter or research assistant to deliver biofeedback [ 18 , 20 , 24 ], with the remaining eleven not detailing who delivered biofeedback training.

There were eight different control conditions used across studies, the most common were self-recorded blood pressure measurements and placebo. Six studies [ 22 , 24 , 26 , 34 , 35 , 38 ] had multiple comparison groups (i.e., biofeedback and treatment as usual, placebo biofeedback, normotensive comparators). For data extraction, the treatment as usual group was prioritised as a comparator, followed by placebo biofeedback.

There was large variation across intervention design making it difficult to compare different designs and understand the most effective biofeedback intervention.

In terms of measuring how intervention delivery corresponded to the protocol, only two studies [ 29 , 34 ] detailed methods that suggested fidelity checks, including a therapist remaining with the group throughout the intervention and a trained nurse implementing biofeedback under supervision of a qualified biofeedback practitioner. Only five studies [ 18 , 25 , 28 , 31 , 36 ] reported the use of power calculations to inform the sample size.

The methods used for blood pressure measurements varied across studies; seventeen [ 18 , 19 , 20 , 22 , 23 , 24 , 25 , 27 , 28 , 29 , 30 , 31 , 33 , 35 , 36 , 37 , 38 ] used clinic readings, and three [ 26 , 32 , 34 ] used home measurements. In the ten studies [ 19 , 20 , 23 , 24 , 27 , 30 , 31 , 32 , 35 , 36 ] reporting medication use, 55% of participants were on anti-hypertensive medications. Medication status was not reported in three studies [ 25 , 33 , 37 ], whilst seven [ 18 , 22 , 26 , 28 , 29 , 34 , 38 ] studies reported participants were not taking any medications.

A total of seventeen studies detailed information regarding participant withdrawal or exclusion, with the remaining three studies [ 22 , 26 , 38 ] not reporting if any participants withdrew from the study. Overall, 111 participants withdrew, 44 were excluded and 2 participants died during the study time period. Reasons or details of participant withdrawal was limited, with 4 studies [ 19 , 27 , 33 , 36 ] detailing if participants withdrew from the control or biofeedback group, and six studies detailing the specific stage participants withdrew at i.e., before or after baseline measurements [ 27 , 37 ], after randomisation [ 30 , 33 , 35 ] or “within 2 weeks” [ 32 ]. Nine studies [ 18 , 19 , 20 , 23 , 24 , 28 , 29 , 34 , 36 ] did not detail at what stage participants withdrew. Reasons for participant exclusion included overly high blood pressure [ 28 , 34 ], medication changes [ 23 , 36 ], hypertrophy [ 18 ], failure in randomisation [ 25 ] and Olsson et al. [ 37 ] reported issues with biofeedback installation, commuting for the study and blood pressure not meeting hypertension criteria.

Meta-analysis of suitable studies

A meta-analysis was conducted for SBP with twelve studies and DBP with eleven studies, since the remainder did not have adequate data as detailed in the methods section. The studies included in the meta-analysis had six different control conditions (please see Table  3 ).

The meta-analysis showed that biofeedback had a significant effect on SBP −4.52 (Z = 2.31, P  = 0.02, CI [−8.35, −0.69]) and a significant effect on DBP −5.19 (Z = 3.54, P  = 0.0004, CI [−8.07, −2.32] (Fig.  2 ). The forest plot shows heterogeneity was high for SBP I 2  = 75% (Tau 2  = 27.80; Chi 2  = 43.15; P  < 0.0001). The DBP forest plot can be seen in Fig.  3 , also highlighting the high heterogeneity I 2  = 76% (Tau 2  = 15.46; Chi 2  = 41.46; P  < 0.00001).

The forest plot demonstrates a significant effect of biofeedback on systolic blood pressure.

The forest plot demonstrates a significant effect of biofeedback on diastolic blood pressure.

Notably, Nakao et al. [ 32 ] and Achmon et al. [ 35 ] had substantial mean differences between the biofeedback and control group, with a mean difference in SBP of −23.00 mmHg in Nakao et al. [ 32 ] and −23.93 mmHg in Achmon et al. [ 35 ] studies. Within the papers there were limited reasons for the large decreases. Despite the large mean difference, neither paper was given a heavier weighting within the forest plot compared to other studies, with Nakao et al. [ 32 ] allocated 5.6% and 9.4% and Achmon et al. [ 35 ] allocated 6.7% and 10.0% for systolic and diastolic blood pressure respectively.

Additionally, it is noticeable that Pandic et al. [ 30 ] had a SBP mean difference of 7.68 mmHg in favour of the control group. The control group had a larger reduction in blood pressure compared to the RESPeRATE intervention group. The authors reflected on previous literature that showed relaxing music played to the control group can decrease blood pressure. Publication bias was assessed with Egger’s test and was non-significant for both SBP (−0.34, 95% CI [−2.22–1.54], P  = 0.73) and DBP (−1.1, 95% CI [−3–0.75], P  = 0.27). Corresponding funnel plots can be found in the Supplementary Material (Supplementary Figs.  S1 and S2 ).

Of the eight studies excluded from the meta-analysis, only two showed significant findings in favour of biofeedback [ 19 , 33 ] (Supplementary Tables  S1 and S2 ). Across the 20 included studies, the pooled blood pressure difference in biofeedback groups was −9.5 mmHg SBP and −6.7 mmHg DBP, compared to −3.4 mmHg SBP and −1.9 mmHg DBP in control groups (Supplementary Table  S3 ).

Meta-regression

A meta-regression was conducted for age and sex on systolic and diastolic blood pressure. There was no significant association between participant age and effect of biofeedback on systolic (β = 0.49, SE = 0.40, 95% CI [−0.29, 1.26], p  < 0.22) or diastolic (β = 0.44, SE = 0.26, 95% CI [−0.07, 0.96], p  < 0.09) blood pressure (Supplementary Figs.  S3 and S4 ).

There was no significant effect of sex on biofeedback outcomes, with no effect of participants being male on systolic (β = 0.00, SE = 0.05, 95% CI [-0.10, 0.11], p  < 0.97) or diastolic (β = 0.01, SE = 0.04, 95% CI [−0.06, 0.07], p  < 0.87) blood pressure, or being female on systolic (β = 0.01, SE = 0.07, 95% CI [−0.12, 0.15], p  < 0.87) or diastolic (β = 0.01, SE = 0.05, 95% CI [−0.08, 0.10], p  < 0.80) blood pressure (Supplementary Figs.  S5 – 8 ).

Quality assessments

The Cochrane risk of bias assessment identified there were “some concerns” (Supplementary Table  S4 ). This was affected by 65% of papers not specifying randomisation allocation sequences or blinding of researchers or participants. All papers were raised to “some concerns” due to lack of pre-specified analysis plans.

The GRADE assessment showed data to have a “low certainty” of evidence, meaning further research is likely to change the estimate and have an important impact on confidence in the effect estimate. The certainty was downgraded from “high” to “low” due to inconsistency in evidence identified by heterogeneity and the risk of bias score. See Supplementary Material (Supplementary Table  S5 ) for assessment ratings.

This was the first systematic review since 2009 to assess the effect of biofeedback in patients with hypertension (≥140/90 mmHg). The review and meta-analysis demonstrated that biofeedback significantly improved SBP and DBP. However, these results should be interpreted with caution given the limitations of included studies, such as heterogeneity, low study quality and limited details regarding randomisation, blinding and intervention delivery. The meta-regression analyses demonstrated that participant age or sex did not account for the heterogeneity seen within the meta-analysis.

The heterogeneity across biofeedback rendered it difficult to conduct modality specific analysis. Follow up ranged from 2 weeks to 12 months, with 10 studies not reporting if a follow up was conducted. Given the requirement of continued practice to benefit from biofeedback it is important to understand the longevity of the intervention [ 8 ].

Studies included in this review reporting using different instructors to deliver biofeedback to participants, including a psychologist, a trained therapist or nurse, a research assistant or experimenter. Eleven studies did not detail who delivered biofeedback. Although this review was unable to statistically compare delivery personnel and biofeedback outcomes, both studies which used nurse delivered biofeedback demonstrated a significant effect on blood pressure [ 32 , 35 ]. For biofeedback to be a feasible and affordable intervention, the method and personnel delivering the intervention need to be considered. For services such as the NHS in the United Kingdom, it may benefit from biofeedback that is formulated to be delivered by a healthcare assistant or another allied health professional as this would be cheaper and scalable. More innovative solutions for delivery of biofeedback such as the use apps or videos need to be considered.

The results of this review are partly supported by the meta-analysis from Vital et al. [ 39 ] who included nine studies and found a significant reduction in DBP only. The current review differed from Vital et al. [ 39 ] as they included pre-hypertensive patients (SBP measuring 130–139 mmHg). The current review only included patients with SBP ≥ 140/90 mmHg because inclusion of patients with low-mild hypertension can lead to floor effects, with only small reductions possible [ 40 ]. An earlier review by Greenhalgh et al. [ 40 ] found no consistent evidence that demonstrated the benefits of biofeedback. However, they included thirty-six studies, some of which were excluded from the current systematic review based on low blood pressure readings (<140/90 mmHg), and missing or unclear outcomes. The inclusion of more studies, some of which did not meet the criteria for this review, may explain the higher heterogeneity and lack of consistent evidence in comparison to the present review.

This review is limited by heterogeneity and the number of studies included. This made it difficult to identify the most effective intervention design including, number of sessions, intervention length, and biofeedback modality. Despite the meta-analysis demonstrating a significant effect of biofeedback on SBP and DBP, the quality of data was low, especially relating to limited details on randomisation, blinding, missing pre-analysis statistical plans, and whether patients were on antihypertensive medications. The missing details regarding randomisation, blinding and key demographic data is a limitation that if submitted for publication in the current day, papers would not meet research guidelines. Limited details reported about interventions meant it was difficult to understand why some interventions worked, whilst others did not. Additionally, the lack of details regarding at what stage participants withdrew from the study make it difficult to understand if withdrawal was due to the requirements of biofeedback, or for another reason. Similarly, the wide variation in control conditions add difficulty to understanding the effect of biofeedback. This poor quality of data is similar to the findings of by previous reviews, highlighting the need for improved methods and reporting in future studies.

The included studies have several limitations that may affect the reliability of outcomes. These include wide variations in sample size, which may result in findings that do not reflect real patients. In line with representation, the mean age of the included participants was 51.7 ± 8.7 years, which does not reflect the mean age of patients with hypertension, which largely affects patients aged over 65 [ 41 ]. Only 25% of articles reported any power calculations. No studies reported measurements of medication adherence, which can significantly affect blood pressure control [ 42 , 43 ]. Furthermore, ten studies used participant populations that were either partly, or not on any medication. Similarly, intervention adherence was reported in only four studies, and two studies reported the use of fidelity checks. Consequently, it is difficult to ensure the biofeedback intervention was implemented as planned in the majority of studies.

A significant issue in this review is that the dated studies do not represent the availability of current technologies. The majority of studies were published between 1970 and 1999, with only one study published after 2010. Since then, biofeedback technology has improved dramatically and is more user friendly, with the ability to practice independently at home. This has been further supported by the progression with AI, which can further support the development and integration of biofeedback in the healthcare field. It has already been incorporated in biofeedback research in virtual reality exposure therapy for anxiety [ 44 ] and eXtended Reality training scenarios [ 45 ]. The use of machine learning in biofeedback can support tailored feedback and identify scenarios and stimuli that increase physiological responses, which can increase user awareness of their health. Biofeedback devices now include wearables, such as a wristband that continuously records blood pressure and displays results in an app on the user’s phone [ 11 ]. This contrasts with examples from included studies where biofeedback was conducted in the clinic in the presence of researchers [ 29 , 34 ] and using techniques not suitable for home use, such as a researcher manually plotting blood pressure biofeedback on a graph [ 20 ]. The dated technology is reflected in methods of blood pressure measurement.

We believe that biofeedback has a potential role to play in the management of hypertension. New research should incorporate robust methodology, updated biofeedback technology such as wearable devices, and incorporate the use of innovative techniques to support large scale delivery of biofeedback.

To conclude, this meta-analysis showed that biofeedback significantly reduces systolic (-4.52 mmHg, P  = 0.02) and diastolic blood pressure (−5.19 mmHg, P  = 0.0004), with the pooled blood pressure decrease in biofeedback groups reaching clinical significance. However, the low quality of evidence and heterogeneity across studies mean results should be interpreted with caution. Importantly, the dated nature of existing studies means they do not represent the current climate of biofeedback and the availability of current technologies. But future research especially featuring wearable devices using robust methodology are needed to provide evidence of a practical and scalable approach to biofeedback that is clinically deliverable and acceptable to patients.

What is known about the topic

Hypertension is a leading modifiable risk factor for cardiovascular disease. However, despite the availability of medication, hypertension control remains suboptimal in approximately 50% of patients.

Autonomic nervous system dysregulation in part mediates hypertension, highlighting a possible target for interventions aiming to improve blood pressure.

Biofeedback can increase self-regulation and self-awareness of parameters that regulate the autonomic nervous system, suggesting a suitable intervention to support patients with hypertension

What this study adds

The meta-analysis demonstrated that biofeedback had a significant effect on blood pressure, with a reduction in both systolic (−4.52, Z = 2.31, P  = 0.02, CI [−8.35, −0.69]) and diastolic blood pressure (−5.19, Z = 3.54, P  = 0.0004, CI [−8.07, −2.32]).

The weaknesses of the study not only make it difficult to determine the most effective intervention but also affect the ability to draw conclusions about the effect of biofeedback on blood pressure.

Future studies need to incorporate robust methodology and updated technology such as wearable devices, to improve understanding of the role of biofeedback in hypertension.

Data availability

All data generated or analysed during this review are included in this published article [and its supplementary information files].

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Acknowledgements

This study is funded by the National Institute for Health Research (NIHR) Applied Research Collaboration East Midlands (ARC EM). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. HO is funded by Servier Affaires Medicale. The views expressed are those of the author(s) and not necessarily those of Servier Affaires Medicale. KK is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration East Midlands (ARC EM) and the NIHR Leicester Biomedical Research Centre (BRC). DL is supported by the John and Lucille van Geest Foundation and the NIHR Leicester Biomedical Research Centre (BRC).

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Farah Salim, Dan Lane, Dennis Bernieh & Pankaj Gupta

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SJ led the systematic review, analysis and drafted the manuscript; AC screened articles, co-conceived the work that led to the manuscript and reviewed the manuscript; HO conducted data quality assessments and reviewed the manuscript; FS conducted data quality assessments and reviewed the manuscript; DL contributed to data analysis and conception and reviewed the manuscript; DB reviewed the manuscript; KK contributed to data analysis and conception and reviewed the manuscript; PG conceived and designed the work that led to the manuscript, played an important role in data analysis, results interpretation and the manuscript.

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Jenkins, S., Cross, A., Osman, H. et al. Effectiveness of biofeedback on blood pressure in patients with hypertension: systematic review and meta-analysis. J Hum Hypertens (2024). https://doi.org/10.1038/s41371-024-00937-y

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The role of circular RNAs (circRNAs) as a prognostic factor in lung cancer: a meta-analysis

• Sanabil Ahsan 1 , 2 ,
• Thin Thin Win 3 ,
• Saint Nway Aye 3 &
• Nan Nitra Than 4  

BMC Cancer volume  24 , Article number:  988 ( 2024 ) Cite this article

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Lung cancer is a leading cause of cancer-related death worldwide. Among various histological types of lung cancer, majority are non-small cell lung cancer (NSCLC) which account for > 80%. Circular RNAs (circRNAs) are widely expressed in various cancers including lung cancer and implicated in tumourigenesis and cancer progression. This study aimed to systematically evaluate the prognostic values of circRNAs in lung cancer.

A systematic literature search was done in PubMed, Embase, and MEDLINE databases to select the eligible studies which reported the association between the expression of circRNAs and overall survival (OS) or disease-free survival (DFS) in histopathologically diagnosed lung cancer patients. The pooled hazard ratio (HR) and 95% confidence interval (CI) were assessed to determine the prognostic significance of circRNAs.

A total of 43 studies were eligible for this meta-analysis (MA). 39 different types of circRNAs were reported: 28 showing upregulating and 11 showing downregulating action in lung cancer. High expression of circRNAs with upregulating action in lung cancer was associated with worse prognosis and poor OS (HR 1.93, 95% CI [1.61–2.33], p  < 0.00001). High expression of circRNAs with downregulating action in lung cancer was associated with favorable OS and prognosis (HR 0.73, 95% CI [0.58–0.94], p  = 0.01). However, there was no statistically significant association between high and low expression of both upregulating and downregulating circRNAs and DFS (HR 1.44, 95% CI [0.92–2.24], p  = 0.11).

Conclusions

This MA confirmed the pivotal role of circRNAs as important prognostic biomarkers for lung cancer, especially NSCLC. High expression of upregulating circRNAs is associated with poor prognosis; however, high expression of downregulating circRNAs is associated with favorable prognosis. Therefore, downregulatory action of circRNAs should be considered a promising treatment in the management of lung cancer, especially NSCLC.

Peer Review reports

Introduction

Lung cancer is a leading cause of cancer-related death in both men and women [ 1 ]. >80% of lung cancers are non-small cell lung cancer (NSCLC) and only 13% are small cell lung cancer (SCLC) [ 2 ]. Generally, the prognosis of lung cancer especially NSCLC is mainly based on the tumor-node-metastasis (TNM) staging [ 2 ], histopathological types [ 2 ], and predictive biomarker analyses, such as epidermal growth factor (EGFR) mutation [ 3 ], anaplastic lymphoma kinase (ALK) translocations [ 4 ] and BRAF mutation [ 5 ]. However, the prognosis varies significantly even among the patients with the same TNM staging, histomorphological characteristics, and mutation status [ 6 ].

In cancer management, diagnostic and prognostic biomarkers with high sensitivity and specificity play a crucial role in preventing or treating cancer. Circular RNAs (circRNAs) which are abundant in serum, plasma, and other body fluids with stable property and high specificity has been described as molecular marker in the initiation and development of cancer [ 7 , 8 ].

In recent years, circRNAs have been recognized as a new sensitive, non-invasive biomarker for diagnosis, prognosis and even prediction to therapeutic responses in many types of cancer including lung cancer [ 9 ]. Few meta-analyses (MAs) were done to assess the role of circRNAs in lung cancer. However, they were only focused on NSCLC and not on different histopathological types of lung cancer [ 10 , 11 ]. Therefore, we aimed to conduct this updated MA which includes the latest primary studies to synthesize the evidence on the role of circRNAs as a prognostic factor in all histopathological types of lung cancer.

Materials and methods

The systematic review (SR) and MA were done according to the updated guideline of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement [ 12 ].

Identification of eligible studies

The systematic literature search was carried out in health-related electronic databases such as PubMed, Embase and MEDLINE. The search terms used were “circular RNAs/circRNAs, lung cancer, non-small cell lung cancer, small cell lung cancer and prognosis”. The search was limited to original articles published in the English language up to July 2023. To find additional studies, reference lists of the original articles were also screened.

Inclusion and exclusion criteria

Studies selection was based on criteria of PICOTS format: (1) Participants (P): All patients who have been histopathologically diagnosed with non-small cell and small cell lung cancer; (2) Index prognostic factor (I): circRNAs; (3) Comparisons (C): Not applicable to this review; (4) Outcomes (O): Outcomes were overall survival (OS) which is defined as the length of time that patients remained alive after diagnosis of cancer; and disease progression-free survival (DFS) which is defined as the length of time that patients remained disease‐free/cancer-free; (5) Setting (S): Hospital/Pathology laboratory [ 13 ]. Review articles, case reports, editorials, letters, commentaries, and articles in non-English languages were excluded from this MA.

Literature search and study selection

Two researchers (TTW, SA) conducted an independent literature search in healthcare electronic databases (PubMed, Embase and MEDLINE). Any disagreements between both researchers were initially discussed between two researchers. If an agreement was not reached, two researchers discussed with a third researcher (SNA) to finalize. The articles were screened according to the PRISMA flowchart as displayed in Fig.  1 . The articles that did not fit the inclusion criteria based on abstract and title alone were excluded. Finally, full-text articles were examined to obtain the included studies required for MA.

PRISMA flowchart summarizing the process to identify the eligible studies

Assessment of study quality

The quality of eligible studies was assessed by the Newcastle-Ottawa Quality Assessment Scale (NOS) [ 14 ]. Studies were assessed using three categories, selection of study groups (0–4 points), comparability (0–2 points), and exposure (0–3 points). A total score ≤ of 3 was considered low quality, scores between 4 and 6 were moderate quality and scores ≥ 7 were high quality. These scores were used only to facilitate the interpretation of the MA results, but not used as a criterion for inclusion or exclusion of the studies. During these processes, any discrepancy or disagreement was resolved by discussion among authors to arrive at a consensus.

Data extraction

Two researchers (TTW, SA) independently extracted the relevant data from the included studies using a piloted data extraction sheet. Discrepancies were discussed thoroughly and finalized with a third researcher (SNA). The data that were extracted included study title, first author with year of publication, country of publication, histopathological type of lung cancer, type of circRNA, OS and DFS with hazard ratio (HR), [95% confidence interval (CI)], and p-value.

Statistical analysis

The outcome analyses of OS and PFS were estimated as HR for the prognostic value of circRNAs in patients with lung cancers. From the statistical analysis, heterogeneities were assessed using I 2 statistics. To avoid heterogeneity, if the I 2 statistic is more than 50%, a random effects model was used; and if the I 2 statistic is less than 50%, a fixed effect model was used. A two-tailed p-value of less than 0.05 was considered statistically significant. The corresponding 95% CI was used to quantify the precision of the estimated HR. MA was performed with Review Manager (RevMan 5.4) software.

Literature search results

A total of 2137 potential studies were identified using the preliminary search strategy; 804 were from PubMed, 731 were from EMBASE, and 603 were from MEDLINE. A total of 1873 studies which included duplicates, review articles and irrelevant studies were removed in the screening stage. Based on the title and abstracts, 202 studies were removed. After that, the full texts of 63 studies were reviewed. 20 studies were excluded due to wrong outcomes, wrong study design, or no reported HR and 95% CI. Finally, 43 studies were included for SR and MA. A three-phase flow chart of the study selection process based on the updated PRISMA statement 2020 is illustrated in Fig.  1 .

Characteristics of the included studies

The characteristics of the 43 included studies are shown in Table  1 . All the included studies were carried out in China. There were 39 different types of circRNAs. Among them, Cirs-7 was reported by 3 studies [ 34 , 39 , 41 ], Circ_0020123 was reported by 2 studies [ 33 , 35 ] and Circ_0067934 was reported by 2 studies [ 36 , 46 ]. 28 different types of cirRNAs (Circ_0003645, CircUSP7, Circ_001569, Circ_0128332, Circ_0074027, Circ-BANP, Circ-RAD23B, CircATXN7, CircRARS, Circ_000984, Circ_0016760, Circ-FOXM1, CircRNA_103809, CircSWT1, Circ_0001715, Circ_0007534, CircPVT1, CircPRKCI, Circ_0020123, CiRS-7, Circ_0067934, CircVANGL1, Circ-PRMT5, Circ_0001946, Circ_0023179, Circ_101237, CircFADS2 and Circ_102231) showed upregulating action in the lung cancer and 11 different types of circRNAs (Circ_100395, Circ_0065214, CESRP1, Circ-ITCH, Circ_0001649, Circ_11780, Circ-SMARCA5, CircCRIM1, Circ_0046264, Circ_0006427 and Circ_007230) showed downregulating action in the lung cancer. 32 studies [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ] reported that high expression of circRNAs was associated with unfavorable prognosis and facilitated the tumour progression (upregulation). The remaining 11 studies [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ] reported that high expression of circRNAs was associated with favorable prognosis by inhibiting tumour progression (downregulation) in lung cancer. Among 43 studies, a majority of the studies reported on NSCLC; 32 studies [ 15 , 16 , 17 , 19 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 30 , 31 , 33 , 34 , 35 , 36 , 38 , 39 , 41 , 42 , 43 , 44 , 46 , 47 , 48 , 50 , 51 , 52 , 53 , 57 ] on NSCLC, 2 studies [ 20 , 55 ] on just lung cancer without specific histopathological types, 8 studies on adenocarcinoma [ 18 , 29 , 32 , 37 , 40 , 45 , 54 , 56 ], and only one study on SCLC [ 49 ]. All 43 studies reported OS with HR and 95% CI. Only 5 studies [ 24 , 28 , 39 , 43 , 53 ] reported DFS with HR and 95% CI.

Methodological quality of the included studies and publication bias

Based on the NOS assessment of the methodological quality of the included studies, the scores of all 43 included studies ranged from 6 to 9. Therefore, all included studies in this MA showed high quality. Publication bias was assessed for all included studies. Funnel plots of Begg’s and Egger’s tests for the publication bias of upregulated and downregulated circRNAs are shown in Figures S1 and S2 .

Prognostic value of circRNAs on OS and DFS in lung cancers

As 32 studies [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] reported circRNAs that were upregulating in lung cancer and only 11 studies [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ] reported circRNAs that were downregulating in lung cancer, we meta-analyzed these two groups of circRNAs separately. MA of upregulating circRNAs showed a favorable OS with low expression compared to high expression (HR 1.93, 95% CI [1.61–2.33], p  < 0.00001); and heterogeneity I 2 was 76% (Fig.  2 ). MA of downregulating circRNAs showed a favorable OS with high expression compared to low expression (HR 0.73, 95% CI [0.58–0.94], p  = 0.01); and heterogeneity I 2 was 54% (Fig.  3 ).

Forest plot of the association between high and low expression of upregulating CircRNAs and overall survival of lung cancer

Forest plot of the association between high and low expression of downregulating CircRNAs and overall survival of lung cancer

As only 4 studies [ 24 , 28 , 39 , 43 ] reported DFS in association with expression of upregulating and only one study [ 53 ] reported downregulating cirRNAs respectively, MA was done all together for those 5 studies. There was no significant association between DFS and expression of circRNAs (HR 1.44, 95% CI [0.92–2.24], p  = 0.11); heterogeneity I 2 was 90% (Fig.  4 ).

Forest plot of the association between high and low expression of CircRNAs and disease-free survival of NSCLC

CircRNAs are known to have a diverse array of functions. They act as miRNA sponges, interact with RNA-binding proteins (RBPs), regulate alternative splicing and transcription, facilitate translation, generate pseudogenes, transport molecules, and mediate cell-to-cell communication [ 58 , 59 ]. Characterized by their unique covalently closed loop structures, circRNAs are involved in the regulation of gene expression and are emerging as key players in the oncogenic process [ 60 ]. They have also emerged as a large class of primarily non-coding RNA molecules, many of which have key roles in cancer development and progression through diverse mechanisms of action [ 61 ]. Thus, they were reported as promising biomarkers for cancer diagnosis and prognostication as well as for early cancer detection and therapeutic targets or agents to inhibit oncogenic microRNAs or proteins [ 59 , 62 ]. In recent years, an increasing number of studies have shown that some circRNAs have a significant association with the prognosis and progression of cancer; and they are aberrantly expressed in lung cancer, especially NSCLC [ 63 , 64 ]. In the oncogenic process of NSCLC, circRNAs contribute to cancer proliferation and invasion by sponging specific miRNAs, impacting crucial oncogenic pathways [ 63 , 65 ].

Upregulating circRNAs play roles in proliferation, migration, invasion, apoptosis, cell cycle, stemness of lung cancer stem cells, chemotherapy resistance, tumor metabolism, tumor microenvironment (TME), and immune evasion of lung cancer cells [ 66 ]. Most of the upregulating circRNAs promoted the activation of nuclear factor kappa-B (NF-kB) regulatory signaling, epidermal growth factor receptor (EGFR), cyclin E1 (CCNE1) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD); and thus, exerted remarkable effects through sponging miR-7 [ 34 , 39 , 41 ]. Therefore, cancers that highly express those upregulating circRNAs are associated with a poor prognosis due to rapid tumour invasion, tumour proliferation and chemoresistance.

Some researchers have reported MA on the prognosis of NSCLC in association with various types of circRNAs. The first MA was done in 2019 and it was found that both upregulating and downregulating circRNAs are associated with a poor prognosis of lung cancer [ 67 ]. Later, another MA reported that expression of upregulating circRNAs was significantly associated with a poor prognosis for NSCLC [ 68 ].

In our MA, we collected 43 primary studies that reported an association between the expression of 39 different types of circRNAs and the survival outcomes of lung cancer. Based on our best literature search, our MA included the highest number of prognostic factor studies, and it included primary studies published in 2023. All the studies were conducted in China, and all the participants in the studies are Chinese. Among them, 40 (32 NSCLC + 8 Adenocarcinoma) studies reported on NSCLC, 2 were just lung cancer and only one study reported on SCLC. Regarding the actions of circRNAs on lung cancer, 32 studies reported an association between upregulating circRNAs and lung tumours; and 11 studies reported an association between downregulating circRNAs and lung tumours. In those 32 studies, it was reported that high expression of circRNAs was associated with an unfavorable prognosis by facilitating tumour progression, inducing resistance to immune checkpoint inhibitor therapy, enhancing metastasis etc. 11 studies reported that high expression of circRNAs was associated with a favorable prognosis, as those cirRNAs have downregulating action on cancer cells by inhibiting cancer cell proliferation and enhancing chemosensitivity.

Although we planned to conduct a MA on the association of circRNAs and prognosis in both NSCLC and SCLC, we can only conduct it for NSCLC as only one study reported prognosis for SCLC. This study reported that circRNA cESRP1 expression had downregulating effect in SCLC tissues, playing a crucial role in chemosensitivity by sponging miR-93-5p to inhibit the TGF-β pathway, and it was associated with survival [ 49 ].

The results of our MA were comparable with other published MAs. A MA on the association of expression of downregulating circRNAs and OS in NSCLC showed that high expression of downregulating circRNAs was correlated with favorable OS in both NSCLC and SCLC. Pooled results of those MAs indicated that the expression of upregulating circRNAs was significantly associated with the worse prognosis in NSCLC [ 67 , 68 ]. A MA on the diagnostic and prognostic value of circRNAs in lung cancer also reported a significant association between circRNAs expression and diagnostic and prognostic values in lung cancer patients [ 69 ]. Many types of circRNAs are also correlated with tumour size, lymph node metastasis, distant metastasis, TNM staging, and differentiation, by promoting lung cancer invasion and migration [ 11 ]. Most of the prognostic role of circRNAs was based on the mechanism of microRNA (miRNA) molecular sponge by adsorbing miRNA, regulating the transcription of parental genes, interacting with RNA-binding proteins to play biological roles, and translating proteins [ 70 , 71 , 72 ].

In our MA, three studies reported on ciRS-7 and they reported that high expression of ciRS-7 was associated with a poor prognosis of NSCLC [ 34 , 39 , 41 ]. CiRS-7 was described as associated not only with the poor prognosis of NSCLC, but also with the poor prognosis of other malignancies such as hepatocellular carcinoma and renal cell carcinoma [ 73 , 74 ]. Previously, ciRS-7 was reported to act as a tumour promoter by regulating the miR-139-3p/TAGLN axis and activating the PI3K/AKT signaling pathway to promote tumour progression and metastasis [ 74 ]. A study on lung adenocarcinoma reported that high expression of this circRNA was associated with TNM staging and lymphatic metastasis [ 75 ].

In our MA, circ-100,395, circ-0065214, cESRP1, circ-ITCH, circ-0001649, circ-11,780, circSMARCA5, circCRIM1, circ-0046264, circ-0006427 and circ-0072309 had downregulating effect in NSCLC by playing an important role in NSCLC cell proliferation, cell migration, and apoptosis. Regarding the downregulating action of circRNAs in lung cancer, those circRNAs inhibit the growth and invasion of lung cancer cells for example through the miR-558/TNFAIP1 and TPM1 pathways [ 76 ]. Considering the effect of individual circRNAs, cESRP1 circRNA acted on the chemoresistant cells and augmented chemosensitivity by sponging miR-93-5p in SCLC to inhibit the TGF-β pathway [ 49 ]. Circ-0065214 (circSCAP) directly binds to the SF3A3 protein, facilitating the reduction of SF3A3 by promoting its ubiquitin–proteasome-mediated degradation, which enhances the expression of MDM4-S to finally activate its downstream p53 signaling [ 48 ]. Circ_100395 inhibits the malignancy of NSCLC by targeting miR-141-3p and upregulating LATS2; these can in turn increase phosphorylation of YAP and inactivate the Hippo/YAP pathway [ 47 ]. Moreover, it significantly decreases the tumour volume and weight in vivo [ 77 ]. These downregulating actions of enhancing chemosensitivity and inhibiting tumour invasion can be considered in the management of lung cancer. Accumulated evidence to date highlights the multifaceted role of circRNAs in cancer, especially their regulatory functions across various signaling pathways underscore their potential as biomarkers and therapeutic targets in the field of oncology [ 59 ]. Therefore, regulating the expression level of circRNAs is of great significance to the malignant biological behavior of lung cancer [ 63 ].

There were a few limitations in conducting this MA. Although we aimed to conduct MA on both NSCLC and SCLC, this MA was mainly on NSCLC as only one study on SCLC was included. Although we planned to conduct subgroup analysis on different types of circRNAs, all 43 included studies reported different diverse types of circRNAs and it was not possible to perform subgroup analysis. Subgroup analysis on histopathological types was not able to perform, as most of the studies reported on NSCLC or lung cancer. Subgroup analysis on prognostic association in different treatment regimens was also not performed, as most of the included studies did not report the types of treatment. Another limitation was that all 43 included studies are from China with a Chinese population. If primary studies from other parts of the world could be included, it would be an epidemiologically more informative report.

Our MA confirmed that circRNAs serve as important biomarkers for the prognostic value of lung cancer, especially NSCLC. The findings supported that high expression of upregulating circRNAs is associated with poor OS and poor prognosis; on the other hand, downregulating action of circRNAs are associated with favorable OS and better prognosis. CircRNAs act as tumour-promoting or tumour-suppressing factors to regulate the biological behaviours of lung cancer, such as proliferation, metastasis, and apoptosis, regulate the sensitivity of chemotherapy or targeted drugs and the efficacy of immunotherapy, and provide a preliminary theoretical basis for adjuvant clinical treatment. Moreover, circRNA can be considered a promising novel biomarker for the prognosis of lung cancer, especially NSCLC. The downregulatory action of circRNAs should be considered a promising treatment in the management of lung cancer, especially NSCLC. More translational research should be explored to understand the downregulatory action of circRNAs to be used as a promising treatment in the management of lung cancer.

Data availability

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. The data used to support the findings of this study are included within the manuscript and supplementary files.

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Acknowledgements

The authors are grateful to the participants and researchers of the primary studies in this meta-analysis; and to the IMU University (Formerly known as International Medical University), Malaysia for allowing us to perform this study [ID: BMS I/2022 (04)].

This research work was supported by a Grant from the IMU University, Kuala Lumpur, Malaysia (Project ID: BMS I/2022(04).

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Sanabil Ahsan

Warwick Medical School, The University of Warwick, Coventry, CV4 7AL, UK

Department of Pathology and Pharmacology, School of Medicine, IMU University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur, 57000, Malaysia

Thin Thin Win & Saint Nway Aye

Department of Community Medicine, Faculty of Medicine, Manipal University College Malaysia, Melaka, Malaysia

Nan Nitra Than

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Research design: TTW, SNA; Data collection and extraction: TTW, SA, SNA; Statistical analysis: TTW, SA; Drafting manuscript: SA, TTW, SNA, NNT; Final approval of manuscript: SA, TTW, SNA, NNT.

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Ahsan, S., Win, T.T., Aye, S.N. et al. The role of circular RNAs (circRNAs) as a prognostic factor in lung cancer: a meta-analysis. BMC Cancer 24 , 988 (2024). https://doi.org/10.1186/s12885-024-12704-w

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• Circular RNA
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Identifying the primary tumour in patients with cancer of unknown primary (CUP) using [ 18 F]FDG PET/CT: a systematic review and individual patient data meta-analysis

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• Published: 14 August 2024

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• Jeroen R. J. Willemse 1 , 2 ,
• Doenja M. J. Lambregts 1 , 2 ,
• Sara Balduzzi 3 ,
• Winnie Schats 4 ,
• Petur Snaebjornsson 5 , 6 ,
• Serena Marchetti 7 ,
• Marieke A. Vollebergh 8 ,
• Larissa W. van Golen 9 ,
• Zing Cheung 9 ,
• Wouter V. Vogel 9 , 10 ,
• Zuhir Bodalal 1 , 2 ,
• Sajjad Rostami 1 , 2 ,
• Oke Gerke 11 , 12 ,
• Tharani Sivakumaran 13 , 14 ,
• Regina G.H. Beets-Tan 1 , 2 , 15 &
• Max J. Lahaye   ORCID: orcid.org/0000-0002-8444-202X 1 , 2  

In this systematic review and individual patient data (IPD) meta-analysis, we analysed the diagnostic performance of [ 18 F]FDG PET/CT in detecting primary tumours in patients with CUP and evaluated whether the location of the predominant metastatic site influences the diagnostic performance.

A systematic literature search from January 2005 to February 2024 was performed to identify articles describing the diagnostic performance of [ 18 F]FDG PET/CT for primary tumour detection in CUP. Individual patient data retrieved from original articles or obtained from corresponding authors were grouped by the predominant metastatic site. The diagnostic performance of [ 18 F]FDG PET/CT in detecting the underlying primary tumour was compared between predominant metastatic sites.

A total of 1865 patients from 32 studies were included. The largest subgroup included patients with predominant bone metastases ( n  = 622), followed by liver ( n  = 369), lymph node ( n  = 358), brain ( n  = 316), peritoneal ( n  = 70), lung ( n  = 67), and soft tissue ( n  = 23) metastases, leaving a small group of other/undefined metastases ( n  = 40). [ 18 F]FDG PET/CT resulted in pooled detection rates to identify the primary tumour of 0.74 (for patients with predominant brain metastases), 0.54 (liver-predominant), 0.49 (bone-predominant), 0.46 (lung-predominant), 0.38 (peritoneal-predominant), 0.37 (lymph node-predominant), and 0.35 (soft-tissue-predominant).

This individual patient data meta-analysis suggests that the ability of [ 18 F]FDG PET/CT to identify the primary tumour in CUP depends on the distribution of metastatic sites. This finding emphasises the need for more tailored diagnostic approaches in different patient populations. In addition, alternative diagnostic tools, such as new PET tracers or whole-body (PET/)MRI, should be investigated.

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Introduction

Cancer of unknown primary (CUP) can be defined as histologically confirmed metastatic cancer in which standard diagnostic methods do not identify a primary tumour [ 1 ]. Approximately 2–5% of cancer cases worldwide are estimated to be CUP [ 2 ]. Because patients with CUP have metastatic disease, survival rates are abysmal, with a median survival of 2–12 months [ 3 ]. Adenocarcinomas account for approximately 70–80% of CUP, whereas the rest are undifferentiated, squamous, and neuroendocrine carcinomas [ 4 ]. Autopsy studies conducted before 2010 have shown that CUP mainly originates from lung cancer (27%) and pancreatic or hepatobiliary cancer (24% and 8%, respectively) [ 5 ]. However, the available diagnostic armamentarium per time period will affect such data.

Identifying the primary tumour allows for standard-of-care treatment options, potential inclusion in trials for identified primary tumours, and possibly other targeted therapies with a consequent positive impact on survival [ 6 , 7 ]. Establishing guidelines for the diagnostic work-up remains challenging given the heterogeneous nature of CUP patients. Guidelines from the European Society of Medical Oncology (ESMO) state that the minimal mandatory clinical work-up should consist of a thorough history and physical examination, basic blood analyses, and either computed tomography (CT) with an intravenous contrast agent or MRI scans of the head & neck, chest, abdomen and pelvis. Additional mammography is advised in women. Tissue sampling is required to allow histological and immunohistochemical analyses to guide the search for the underlying primary tumour [ 8 ]. If the routine diagnostic work-up fails to detect a primary tumour, tailored diagnostic strategies can be used, depending on patient characteristics, location of the metastases, and genetic profiling.

Whole-body 2-deoxy-2-[ 18 F]fluoro-D-glucose Positron Emission Tomography/ Computed Tomography ( [ 18 F]FDG PET/CT) is a frequently used second-line imaging technique after CT in CUP patients, as it can aid in identifying the primary tumour and depicting the true extent of the disease. The ESMO guidelines currently recommend the use of [ 18 F]FDG PET/CT to rule out additional manifestations in patients with single-site/oligometastatic CUP or in patients with cervical metastases that are likely to originate from head and neck cancers, mostly squamous cell carcinomas, which are highly hypermetabolic [ 8 ]. In the latter group, a recent systematic review found that [ 18 F]FDG PET/CT had a pooled detection rate of primary tumours of 40% [ 9 ].

Due to the heterogeneous nature of CUP, other studies investigating the potential additional role of [ 18 F]FDG PET/CT have mainly included mixed patient cohorts with various metastatic locations, histopathological features, and primary tumours. Using aggregate data from heterogeneous study populations typically limits the applicability of conventional systematic reviews and meta-analyses, as these do not account for the large heterogeneity in included cohorts. At the same time, large numbers of heterogeneous study populations provide a unique opportunity to group individual patients from individual cohorts into larger subgroups. This allows for more specific analyses of the role of [ 18 F]FDG PET/CT in different subgroups of CUP patients.

This study aimed to perform a retrospective individual patient data (IPD) meta-analysis of CUP patients to analyse the diagnostic performance of [ 18 F]FDG PET/CT for primary tumour detection rate in relation to the most predominant metastatic site and to map the distribution of underlying primary tumours for each subgroup.

This IPD systematic review and meta-analysis was conducted according to the Preferred Items for Systematic Reviews and Meta-Analyses of Individual Participant Data (PRISMA-IPD) [ 10 ] guidelines and was registered in the prospective systematic review database PROSPERO under registration number CRD42023401409.

Literature search and inclusion criteria

A comprehensive search was conducted across multiple electronic databases (MEDLINE, EMBASE, SCOPUS) from 1 January 2005 to 14 February 2024 to identify all randomised controlled trials and retrospective cohort studies describing the diagnostic value of [ 18 F]FDG PET/CT in CUP. The search strategy included the terms [ 18 F]Fluorodeoxyglucose, cancer of unknown primary and relevant synonyms or abbreviations. The entire search strategy is shown in Online Resource 1 .

The titles, abstracts, and complete text reports of the retrieved studies were screened for eligibility. We considered studies eligible for inclusion if CUP was defined as histologically or radiologically confirmed solid or mucinous metastatic cancer and standard diagnostic methods (including CT) did not identify a primary tumour. Studies focusing solely on cervical lymph node metastases to identify occult head and neck tumours were excluded as this subgroup has already been addressed in a recent meta-analysis by Huasong et al. [ 9 ]. The reference lists of all included papers were cross-checked for additional relevant studies. Authors of papers that did not report individual patient data and authors of conference proceedings were contacted with a data request. In the case of no response, a reminder was sent three weeks after the initial attempt. Studies were excluded if individual patient data could not be retrieved. If a study assessed both PET only and PET/CT, patients with PET only (without CT) were excluded.

Quality assessment

The quality of all included published papers was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [ 11 ]. The signalling questions tailored to this review are shown in Online Resource 2 A.

Individual patient data analysis

Metastatic locations, primary tumour sites suggested by [ 18 F]FDG PET/CT, and available reference standards were collected at the patient level. Individual patients were excluded from further analyses based on the following exclusion criteria: (a) patients with primarily cervical metastases; (b) patients not conforming to the definition of CUP as described in the previous section; and (c) patients who underwent PET only (without CT). The primary tumour diagnosis (if any) as established by [ 18 F]FDG PET/CT was matched with the reference standard (established as described in the final column of Table  1 ) and classified as true positive (TP), false positive (FP), false negative (FN), or Confirmed CUP (no diagnosis), using the following definitions:

TP : [ 18 F]FDG PET/CT diagnosis of the primary tumour matched the final reference standard.

FP : [ 18 F]FDG PET/CT diagnosis of the primary tumour did not match the final reference standard.

FN : no primary tumour was found on [ 18 F]FDG PET/CT, but a primary tumour diagnosis was established using another method (e.g. colonoscopy, genomic profiling, etc.).

Confirmed CUP : no primary tumour was found on [ 18 F]FDG PET/CT nor using any other methods, or during further follow-up(no diagnosis).

We divided the patients into eight subgroups based on the predominant metastatic site: bone, brain, liver, lung, lymph nodes, peritoneal, soft tissue, and ‘other’ metastases. To measure the diagnostic accuracy of [ 18 F]FDG PET/CT, we considered the primary tumour detection rates (DRs), defined as the number of TP out of the number of subjects included, per study. For each subgroup, pooled DRs, corresponding 95% confidence intervals (CI), and prediction intervals were calculated. The random effects model considering the inverse variance method and logit transformed proportions was applied. The I 2 -statistic and τ 2 were used to assess heterogeneity. A Sankey diagram was used to visualise the relationship between metastatic sites and primary tumours. Data analysis was performed using R Studio (version 6.2) and meta-analyses were conducted using the meta package.

A total of 2285 unique studies were identified after searching Medline, Embase, and Scopus. Following title and abstract screening, 153 studies were assessed for full-text availability and eligibility for inclusion. Figure  1 shows the inclusion process, resulting in individual patient data of 1865 patients from 31 original studies and one conference proceeding. Table  1 shows the characteristics of the included studies. Two studies had partially overlapping study populations, which were corrected by excluding overlapping patients from one study [ 12 , 13 ].

PRISMA flowchart depicting the process of identifying relevant studies and inclusion of patients. a Excluding conference proceedings for which no full text is available by default

Thirty-one of thirty-two studies had full-text availability. One conference proceeding was included and could not be assessed using the QUADAS-2 checklist [ 11 ]. The results are shown in Fig.  2 . The full QUADAS-2 assessment on a per-study basis is shown in Online Resource 2 B.

QUADAS-2 results: an overview of 31 studies with full-text availability

In total, 1865 patients from 32 studies were included in this analysis. The number of patients included in each study ranged from 10 to 143, with a median of 50 patients. In one study, only a part of the population underwent PET/CT, whereas the remaining participants were excluded because they underwent PET only [ 31 ]. The characteristics of the included patients are shown in Table  2 . The diagnostic workup that patients underwent prior to PET/CT was poorly documented in the majority of patients. In nine studies (460 patients), it was explicitly reported that patients had undergone an extensive diagnostic workup prior to [ 18 F]FDG PET/CT, consisting of at least a CT scan, laboratory, and physical examinations. In the remaining studies, the extent of the pre-PET/CT diagnostic work-up was either not well defined or not reported (1405 patients).

In most studies, the reference standard for determining the primary tumour was established by histopathology and/or clinical follow-up. In the case of positive findings, discovered lesions were typically biopsied to obtain histological confirmation, while in the case of negative findings, clinical follow-up was implemented as the main standard of reference to establish a definitive negative (CUP) diagnosis.

Detection rates of the primary tumour in relation to the predominant metastatic site

The pooled DRs of primary tumours varied between 0.74 (for patients with predominant brain metastases) and 0.35 (for patients with soft tissue metastases). Figure  3 shows a forest plot of the pooled DRs for each subgroup. Overall, a pooled detection rate of 0.54 (CI: [0.45; 0.64]) was found.

Forest plot of pooled detection rates of [ 18 F]FDG PET/CT across different patient subgroups according to the most predominant metastatic site. LN lymph nodes; TP true positives

Table  3 provides an overview of the [ 18 F]FDG PET/CT results per predominant metastatic site group, including a specification of the types of primary tumour diagnoses. Overall (in 6/10 subgroups) lung cancer was the most frequently detected primary tumour, diagnosed in 29% of our total study population. The second and third most common primary tumour types were colorectal cancer ( n  = 101; 5%) and oesophageal and gastric cancers ( n  = 77; 4%). In the final columns, the heterogeneity of the results across the different studies is shown for each subgroup. A more detailed table of all primary tumours and corresponding classifications (TP/FP/FN/Confirmed CUP) is shown in in Online Resource 3 .

Primary tumours

Overall, [ 18 F]FDG PET/CT and follow-up revealed a primary tumour in 1258 out of 1865 patients (67%). In 1037 of these cases, the primary tumour was correctly identified by [ 18 F]FDG PET/CT (pooled DR: 0.54), while in the remainder, follow-up revealed the primary tumour. Six hundred and seven (33%) patients were classified as having a confirmed CUP. Figure  4 presents a Sankey diagram visualising the corresponding primary tumours for each subgroup.

Sankey diagram: patients were grouped by metastatic sites on the left side. Flows and their relative sizes represent connections to the final diagnosis after [ 18 F]FDG PET/CT and follow-up (true primary tumours or confirmed CUP). a Thoracic lymph nodes; b lymph nodes (not specified); c abdominopelvic lymph nodes. Figure created using https://sankeymatic.com/

This review and meta-analysis of 1865 individual patient cases found an overall detection rate of 0.54 for [ 18 F]FDG PET/CT in identifying primary tumours in patients with CUP. Interestingly detection rates varied considerably depending on the most predominant metastatic site, ranging from only 0.35–0.38 in patients with predominant soft tissue, lymph node and peritoneal metastases to as high as 0.74 in patients with predominant brain metastases. Detection rates for patients presenting primarily with bone, liver and lung metastases were in the intermediate range (0.46–0.54).

In 2017, a systematic review on the diagnostic performance of [ 18 F]FDG PET/CT in CUP by Burglin et al. [ 44 ] found a lower detection rate (0.41) than the pooled overall detection rate (0.54) we found in our current review. This discrepancy might be caused by the included studies: three out of four studies with the lowest detection rates in the previous review were not included in our current study, as these studies did not provide sufficient data for the per-metastasis analysis performed in our review [ 45 , 46 , 47 ].

Lung tumours constituted the largest subgroup of primary tumour diagnoses by far, comprising 29% of the cohort. It is known from literature that primary lung cancers are the leading cause of CUP, accounting for an estimated 27% of primary tumours [ 48 ].

Interestingly, our cohort had a significantly smaller number of primary pancreatic or hepatobiliary primary tumours than expected based on autopsy and genetic profiling studies [ 48 ]. Although it is difficult to draw firm conclusions, one hypothesis could be that [ 18 F]FDG PET/CT has a relatively limited performance in detecting abdominal primary tumours. For instance, in peritoneal metastases, which are generally likely to originate from abdominal primary tumours, [ 18 F]FDG PET/CT could be a suboptimal imaging modality given its relatively low detection rate of primary tumours in this subgroup [ 49 ]. The limited soft-tissue contrast of low-dose CT could limit its ability to distinguish peritoneal disease from the adjacent abdominal organs from which the cancer is disseminated. Similarly, abdominal (low-volume) primary cancers might be easily missed by [ 18 F]FDG PET/CT because of low spatial resolution and partial volume effects or get lost in physiological FDG-uptake as observed in the colon or urological system. In addition, primary tumours with low FDG avidity, such as mucinous, signet ring cell, or low grade neuroendocrine cancers, can be missed more easily by [ 18 F]FDG PET/CT, as these are not hypermetabolic [ 50 , 51 , 52 ]. In other patients with non-hypermetabolic metastases, identification of the primary tumour through [ 18 F]FDG PET/CT may also pose a challenge, as this is an indication of primary tumours with slower metabolism. In addition, high glucose levels decrease the sensitivity of [ 18 F]FDG PET/CT in general and should be taken into account when considering [ 18 F]FDG PET/CT.

Current ESMO guidelines state the use of MRI as an alternative modality to CT in searching for a primary tumour, even though research on MRI in the setting of CUP is limited [ 8 ]. Therefore, in addition to identifying CUP patients that might benefit from [ 18 F]FDG PET/CT, the potential role of MRI should also be investigated in future research. For instance, whole-body diffusion-weighted MRI (WB-DWI/MRI) has shown promising diagnostic accuracy in different types of gastrointestinal cancer and could be considered a diagnostic imaging modality for patients with metastases that are likely to originate from the abdomen or pelvis [ 53 , 54 , 55 , 56 ].

By categorising patients according to the predominant metastatic site, we aimed to provide insight into which patients with CUP might benefit the most from [ 18 F]FDG PET/CT. The differences in detection rates observed across subgroups further highlight the heterogeneity of CUP patients and oppose the idea of a ‘one-size-fits-all’ diagnostic approach. As outlined above, our results suggest that [ 18 F]FDG PET/CT might not be the most suitable imaging technique for each CUP patient, and that further tailoring of imaging according to the pattern of disease could be beneficial.

Novel imaging strategies should also be considered as potential diagnostic tools for CUP. As newer, whole-body PET/CT systems are now available, which will result in a better image quality and higher diagnostic accuracy (when not compensating for the better quality by decreasing the injected activity), while imaging the whole body including the legs, in only five minutes [ 57 ]. In addition, novel tracers, e.g. radiolabeled FAPI (Fibroblast Activation Protein Inhibitor), might be superior to [ 18 F]FDG in the detection of primary non-hypermetabolic tumours, like gastric, colorectal, biliary, hepatic and pancreatic cancer [ 58 ].

Apart from imaging, molecular(genetic) profiling techniques are emerging that could be of additional value in identifying the primary tumour in CUP patients. Over the past few years, whole-genome sequencing (WGS) has gained popularity in clinical practice. Using an algorithm to generate profiles indicative of specific tumour types by genetic profiling of tissue samples taken from biopsies, WGS can point to a specific primary tumour [ 59 ]. The integration of different new diagnostic modalities, such as whole-body MRI and WGS algorithms, combined with a structural multidisciplinary approach, might further improve the diagnostic work-up of CUP patients.

This study has some limitations. First, as is common in CUP research, establishing consistent and valid reference standards is a major challenge, and it is difficult to evaluate the validity of the reference standards used in the individual studies included in this review. Likewise, it was difficult to determine the risk of bias in the included studies. Since CUP is not a clearly defined diagnosis but rather a diagnosis per exclusionem, patients who eventually enrol in studies such as those included in this review have experienced different diagnostic investigations and time paths during their disease course. Other variations between the included studies that limit the generalisability of our results include differences in the pre-[ 18 F]FDG PET/CT diagnostic workup and therefore the availability of clinicopathological information at the time of PET/CT evaluation, as well as varying [ 18 F]FDG PET/CT procedures (including patient preparation, blood glucose levels at the time of acquisition and field of view) and improvements in scanner systems, in terms of hardware and software throughout the years. Additionally, there was limited information available on the definition of predominant metastatic disease and the possible presence of metastatic sites in addition to the single site presented in the included articles, restricting this review to containing analyses of single site metastatic disease only. Finally, some subgroups in our study were relatively small, limiting the applicability of these results.

This individual patient data meta-analysis demonstrated that the detection rate of [ 18 F]FDG PET/CT to identify the primary tumour in patients with CUP depends on the distribution of metastatic sites. Future studies should focus on exploring the potential of new diagnostic tools, including novel PET tracers, whole-body (PET/)MRI, and on further tailoring diagnostic strategies based on the predominant pattern of disease.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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All authors agreed to the published version of the manuscript. Conceptualization & Methodology: Jeroen Willemse, Max Lahaye, Doenja Lambregts; Literature search, Data Synthesis & Analysis: Jeroen Willemse, Sara Balduzzi, Winnie Schats, Max Lahaye; Writing - original draft preparation: Jeroen Willemse, Max Lahaye, Doenja Lambregts; Writing; Review, critical revision: Petur Snaebjornsson, Serena Marchetti, Marieke Vollebergh, Larissa van Golen, Zing Cheung, Wouter Vogel, Zuhir Bodalal, Sajjad Rostami, Oke Gerke, Tharani Sivakumaran, Regina Beets-Tan.

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Willemse, J.R., Lambregts, D.J., Balduzzi, S. et al. Identifying the primary tumour in patients with cancer of unknown primary (CUP) using [ 18 F]FDG PET/CT: a systematic review and individual patient data meta-analysis. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06860-1

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Morphology and root canal configuration of maxillary canines: a systematic review and meta-analysis

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This study assessed the internal morphology of maxillary canines (MxC) through a systematic review of existing literature.

Research articles up to June 2024 were retrieved from five electronic databases (MEDLINE via PubMed, Embase, Scopus, LILACS, and Cochrane). Predefined search terms and keywords were used, and potential studies were identified by cross-referencing and bibliographies of the selected articles reviewed.

Two hundred studies were identified, 73 duplicates were removed, 127 records were screened, and 113 were removed after consultation of title and abstract. After full-text consultation and hand searching, finally 22 studies were included. Using the method for describing the root canal configuration (RCC) of Briseño Marroquín et al. (2015) and Vertucci (Ve) (1984), the most frequently reported RCC of MxC were 1–1-1/1 (Ve I, 75.4–100%), 2–2-1/1 (Ve II, 0.1–20%), 1–2-1/1 (Ve III, 0.1–11.6%), 2–2-2/2 (Ve IV, 0.1–0.4%), 1–1-2/2 (Ve V, 0.1–2.4%), 2–1-2/2 (Ve VI, 0.5–1.2%), and 1–2-1/2 (Ve VII, 0.1–0.2%). The meta-analysis of six studies (Europe/Asia) showed that a significantly higher number of RCC of 2–2-1/1 (Ve II) (OR [95%CI] = 1.34 [0.53, 3.41]), 1–2-1/1 (Ve III) (OR [95%CI] = 2.07 [1.01, 4.26]), and 1–1-2/2 (Ve V) (OR [95%CI] = 2.93 [1.07, 8.07]), were observed in males, and 2–2-2/2 (Ve IV) (OR [95%CI] = 0.08 [0.00, 4.00]) in females. No sex differences in the RCC of 1–1-1/1 (Ve I) and 1–2-1/2 (Ve VII) were observed.

Conclusions

Cone beam computed tomography is the most frequently used method for research on the RCC of MxC. Despite the high prevalence of type 1–1-1/1 (Ve I) RCC in MxC, clinicians should remain vigilant for more complex and sex-differentiated patterns in up to 25% of cases to prevent endodontic treatment complications or failures.

Peer Review reports

Introduction

Detailed knowledge and comprehensive understanding of the three-dimensional internal morphology and root canal configuration are crucial for the success of endodontic treatment [ 1 , 2 , 3 ]. Awareness of the complexity of root canal anatomy simplifies the planning of endodontic therapy and the respective treatment steps, furthermore, diminishes the possibility of iatrogenic errors [ 1 , 2 , 3 , 4 ]. The existence of numerous morphological differences emphasizes the importance of diagnosing and evaluating each case individually. Numerous studies show that the most frequent root canal configuration (RCC) of single-rooted maxillary canines is a single root canal from the pulp chamber to the apex (1–1-1/1, Vertucci I) [ 5 , 6 , 7 , 8 , 9 ]. However, different populations studied using modern 3D imaging examination methods show that up to a quarter of the teeth have anatomical variations [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ], which can offer problems and additional challenges for the different steps of root canal treatment that could lead to failure. In the past, various ex vivo methods have been used to study the morphology of root canal systems such as clearing technique, scanning electron microscopy, and light microscopy [ 1 , 2 , 5 , 6 , 14 , 15 ]. Cone beam computed tomography (CBCT) has proven to be a modern and particularly effective tool for such in vivo examinations, as it offers a superior level of detail compared to previous methods [ 16 , 17 ], even if CBCT is inferior to micro-computed tomography regarding imaging of fine structures and details [ 18 ]. The combination of three-dimensional imaging and software analysis allows a non-destructive clinical examination of complex internal morphological structures of the root canal system without compromising the integrity of the tooth [ 16 , 17 ]. The classifications of RCC proposed by Vertucci [ 1 ] and Weine et al. [ 2 ] et al. describe possible root canal system variations; unfortunately, they cannot respond to the morphological intricacies of some root canals in comparison to more modern classifications describing root canal anatomy or root canal configuration [ 3 , 4 ]. The current study aimed to systematically review the literature on the internal morphology and in particular root canal configuration of maxillary canines (MxC) and to identify sex influence on variation in root canal morphology.

Materials and methods

A systematic review was undertaken with the aim to examine the published literature on the internal morphology and root canal configuration (RCC) of MxC up to June 2024. The following five databases were searched: MEDLINE via PubMed, Embase, Cochrane Database, LILACS, and Scopus as well as grey literature. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed by the current systematic review [ 19 ]. Furthermore, the review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) system (CRD42023394478). In the review protocol inclusion criteria were defined as follows: randomized controlled trials, cross-sectional studies, comparative, validation, and evaluation studies of the internal morphology and RCC of MxC without any restrictions. Case reports and reviews were excluded. A standardized comprehensive search strategy was used, including a combination of MeSH terms and keywords: (“root canal configuration” OR “root canal system” OR “root canal morphology”) AND (“maxillary canine” OR “maxillary anterior teeth”) AND (“morphology” OR “anatomy”). Cross-referencing and hand-search were performed by using the bibliographies of full-text articles. Studies addressing morphological anatomies other than the internal morphology and root canal configuration of maxillary canines were excluded. Duplicates or repeated articles were removed, and the remaining ones were evaluated based on their title and abstract by two independent reviewers (T.R., A.L.W.). Papers not relevant to the topic were discarded again at this stage. The remaining papers underwent a full-text review and were examined again by the same two independent reviewers. All the included articles were summarized in a table, referring to the following details: authors, publication year, quality assessment, place of origin, number of samples, methodology, sex (if mentioned), and root canal configuration using the classifications of Vertucci [ 1 ], Weine et al. [ 2 ], and Briseño Marroquín et al. [ 3 ]. The risk of bias was evaluated using the Anatomical QUality Assessment (AQUA) tool [ 20 ], specifically designed for assessing the quality of anatomical studies included in meta-analyses and systematic reviews. Two independent reviewers (T.R., A.L.W.) screened the articles for bias assessment. In case of disagreement, a third reviewer (T.G.W.) was consulted to achieve consensus. The quality of the included studies was assessed by two independent reviewers (A.L.W., T.G.W.) following the customized quality assessment tool developed by the National Heart, Lung, and Blood Institute ( www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools ).

The statistical analysis of the included studies for the meta-analyses was performed using Review Manager software (RevMan version 5.4, Cochrane Collaboration, Copenhagen, Denmark, 2014). The odds ratio (OR) was used to determine the effect size. The I 2 statistic was used to quantify the degree of variability between studies, which was due to heterogeneity rather than chance [ 21 ]. Based on the degree of heterogeneity (I2 < 35% for low heterogeneity, fixed-effects meta-analysis; I 2  > 35% for substantial heterogeneity, random-effects meta-analysis), the appropriate meta-analysis model was selected [ 22 , 23 ]. The primary outcome measures comparing different root canal configurations, patient sex, and geographical factors were presented as odds ratios with 95% confidence intervals (95% CI) for studies with binary outcomes. A p -value of 0.05 or less was considered statistically significant.

The literature search through five databases resulted in 200 articles. The 127 remaining articles after removing all duplicates were screened by title and abstract. 14 articles were consulted in full text and four articles were excluded. Twelve articles were added to this investigation after a hand search, resulting in a total of 22 reviewed articles. The selection process is shown in a PRISMA flowchart diagram [ 19 ] (Fig.  1 ). Data of the risk of bias assessment using the Anatomical QUality Assessment (AQUA) tool can be found in Supplementary Materials. The included investigations were conducted in various regions and populations around the world, utilizing different methodologies, encompassing both sexes and without age limitations.

PRISMA flow diagram

Table 1 shows a summary of the included studies regarding the RCC of MxC until December 2023. The table is divided into detailed information on the author(s), publication year, quality assessment, population, sample number, research method, and RCC according to the classification proposed by Vertucci [ 1 ], and Weine et al. [ 2 ], and Briseño Marroquín et al. [ 3 ]. The most frequently observed RCC of MxC, regardless of the research methodology or the sample number, is 1–1-1/1 (Vertucci’s I or Weine et al. I) with a frequency of 75.4 – 100% [ 1 , 5 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. The second most common RCC in MxC is Briseño Marroquín et al.’s 2–2-1/1 (also known as Vertucci’s II; Weine’s II) with 0.1–20% [ 12 , 15 , 23 , 24 , 25 , 27 , 28 ], and the following common RCC with frequency up to 11.6% is Briseño Marroquín et al.’s type 1–2-1/1 (Vertucci’s III) [ 6 , 7 , 9 , 11 , 12 , 14 , 15 , 24 , 25 , 26 , 27 , 28 , 29 , 32 , 33 ], whereas the Weine et al. classification does not include this RCC type. Among the summarized studies in Table  1 , other RCCs such as 2–2-2/2 (Vertucci IV or Weine et al. III), 1–1-2/2 (Vertucci V), 2–1-2/2 (Vertucci VI) and 1–2-1/2 have been also observed less frequently. The CBCT analysis is reported as the most used research method [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 25 , 26 , 28 , 29 , 30 , 31 , 32 , 33 ], with the radiographic [ 5 ], staining and clearing [ 1 , 14 , 15 , 24 ], or micro-computed tomography [ 27 ] methods less frequently reported. Six studies reported sex-specific differences [ 8 , 11 , 13 , 28 , 29 , 32 ]; data from the meta-analysis of these studies differed by origin (Europe/Asia) are shown in Figs. 2 and 3 .

Root canal configuration 1–1-1/1 (Vertucci I), 2–2-1/1 (Vertucci II), and 1–2-1/1 (Vertucci III)

Root canal configuration 2–2-2/2 (Vertucci IV), 1–1-2/2 (Vertucci V), and -2–1/2 (Vertucci VII)

This study aims to systematically review the literature regarding the internal morphology and root canal configuration (RCC) of maxillary canines (MxC) to provide the clinician with an overview that should lead to better understanding to make better treatment decisions leading to a better outcome in root canal treatments.

The present systematic review shows that the Briseño Marroquín et al.’s type 1–1-1/1 RCC of maxillary canines is the most frequently observed root canal configuration across all studies, with the lowest frequencies of this RCC type reported by Weng et al. [ 15 ] and Somalinga Amardeep et al. [ 25 ] at 75.4% and 81.6%, respectively. In half of the 22 studies analyzed, a Briseño Marroquín et al.’s 2–2-1/1 RCC (type II according to Vertucci and Weine) was reported as the second most common RCC with a frequency between 0.1 and 20% [ 12 , 15 , 24 , 25 , 26 , 28 , 29 ]. Nearly all studies examined reported an Briseño Marroquín et al.’s RCC of 1–2-1/1 (Vertucci's III, while the Weine et al. classification does not include this RCC type) as the third most common RCC with a frequency between 0.1 and 11.6% [ 7 , 8 , 12 , 13 , 26 , 28 , 29 , 33 ]. In all studies, other Briseño Marroquín et al.’s RCCs such as 2–2-2/2, 1–1-2/2, 2–1-2/2, 1–2-1/2, and 1–1-3/3 (Vertucci types IV, V, VI, VII, VIII) were reported less frequently. However, one of the twenty-two included studies were published before the existence of Vertucci’s classification [ 5 ], reporting only a single root with RCC type 1–1-1/1 (Ve I).

There are plenty of research methods that have been used to examine the internal root canal morphology [ 1 , 5 , 6 , 8 , 27 ]. However, nowadays, micro-computed tomography (micro-CT) imaging is widely accepted as the gold standard for ex vivo research for internal tooth morphology and root canal configuration [ 18 ]. Advances in non-destructive digital three-dimensional imaging systems such as cone beam computed tomography (CBCT) and micro-CT imaging can provide data that simplify the analytical process for describing internal morphology [ 34 ]. These methods offer the possibility of obtaining both quantitative and qualitative information about the samples noninvasively and without destroying them, and of reusing the samples for future examinations, if necessary, in contrast to alternative techniques that were frequently used in the past, such as staining and clearing [ 35 , 36 ]. Although CBCT enables less detailed visualization of fine structures than micro-CT, it allows clinical use in vivo, which is currently not possible with either staining and clearing techniques or with humans using micro-CT due to the high radiation exposure.

Various classification systems for root canal configuration are given in the literature [ 1 , 2 , 3 , 4 ], whereby the systems of Vertucci [ 1 ] and Weine et al. [ 2 ] were the most used systems for many years. In the meantime, more modern systems are used to describe the root canal configuration, which allows additional information about the entire root [ 3 , 4 ].

Six of the twenty-two included studies compared sex differences [ 8 , 11 , 13 , 14 , 28 , 32 ], whereby all studies were examined by CBCT, except for one study using the staining and clearing method [ 14 ]. All authors reported that Briseño Marroquín et al.’s RCC of 1–1-1/1 was most observed in both sexes, with up to 99.5% in men and up to 100% in women. It was also observed that there were sex-specific differences in the comparison of studies from Europe and Asia, resulting in increased frequencies regarding different root canal configurations. Furthermore, differences in the studies can be explained by the research methodologies used or ethnic origin. While sex differences were still documented in various studies, the age of the subjects or patients was reported in some studies, but not included in the analysis of the respective studies.

Although the most common Briseño Marroquín et al.’s RCC for MxC is 1–1-1/1 (Ve I), the clinician should always be aware of the complex internal root canal morphology in up to 25% of cases. These could include connecting canals or even accessory root canals that cannot be prepared mechanically, emphasizing the importance of chemical root canal irrigation. The application of an adequate irrigation protocol and a careful obturation technique therefore has an important impact on reducing complications or errors that could compromise the outcome of root canal treatment.

Various limitations should be mentioned, such as possible distortions in the selected studies due to the methodology used or possible artifacts, especially in the digital imaging of CBCT and micro-CT, but also limitations of the selected subjective evaluation criteria and description methodology for root canal configuration. Although it is known that aging, caries or even tooth wear can cause a narrowing of the root canal system due to secondary dentin deposits [ 24 ], it has also been reported that they have only a minimal effect on the morphology of the main root canal [ 24 , 37 ]. Unfortunately, some studies explicitly stated that no information on sex and age was available [ 25 , 27 ]. Although the age of the patients examined by CBCT may have been available in several included studies, this was unfortunately not included in the analysis regarding the change in root canal configuration. A comparison with ethnic groups of similar mean age would be interesting, with few studies in molars and none for maxillary canines suggesting that age may influence the configuration of the root canal system in certain tooth types [ 29 , 38 ] or that the frequency of complex root canal configurations as well as the presence of second mesial root canals in molars may decrease with age [ 39 ].

Within the limitations of the current systematic review and meta-analysis, the following conclusions can be drawn:

The most frequently observed RCC of MxC is the 1–1-1/1 (Vertucci’s and Weine’s et al. type I), followed by a 2–2-1/1 (Vertucci’s and Weine’s et al. type II) and 1–2-1/1 (Vertucci’s type III).

25% of cases harbor the possibility of a more complicated RCC, which should always be taken into consideration by the clinician.

The most frequently used method for in vivo research on the root canal morphology of MxC, nowadays, is CBCT.

A significantly higher number of RCC of 2–2-1/1 (Ve II), 1–2-1/1 (Ve III), and 1–1-2/2 (Ve V) were observed in males and 2–2-2/2 (Ve IV) in females. No sex differences in the RCCs of 1–1-1/1 (Ve I) and 1–2-1/2 (Ve VII) were observed.

Availability of data and materials

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

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Open Access funding enabled and organized by Projekt DEAL. This study was funded partially by the Swiss Society of Endodontology (SSE) and by the institutions of the authors.

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T.G.W., T.R., and A.L.W., contributed to conception, design, data acquisition, analysis, and interpretation, R.J.W. carried out the meta-analysis and contributed to interpretation. T.G.W., T.R., and A.L.W. drafted the manuscript; all authors read and critically revised the manuscript. All authors gave final approval and agreed to be accountable for all aspects of the work. All authors read and approved the final manuscript.

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Wolf, T.G., Rempapi, T., Wierichs, R.J. et al. Morphology and root canal configuration of maxillary canines: a systematic review and meta-analysis. BMC Oral Health 24 , 944 (2024). https://doi.org/10.1186/s12903-024-04682-z

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DOI : https://doi.org/10.1186/s12903-024-04682-z

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• Internal morphology
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Graphical Abstract

1. Introduction

2. literature review, 2.1. architectural components influencing attention in order to foster mindfulness, 2.2. architectural concept enhancing attention in order to foster mindfulness, 3. methodology, 3.1. the systematic review, 3.2. the content analysis, 3.3. the meta-analysis, 3.3.1. word frequency analysis, 3.3.2. word association analysis, 4.1. the result of a systematic review, 4.2. the result of content analysis, 4.3. the result of meta-analysis, 4.3.1. the result from word frequency analysis, 4.3.2. the result from word association analysis, 5. discussion, 5.1. the discussion from the systematic review, 5.2. the discussion from the content analysis, 5.3. the discussion from the meta-analysis, 6. conclusions, author contributions, data availability statement, acknowledgments, conflicts of interest.

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Thampanichwat, C.; Wongvorachan, T.; Bunyarittikit, S.; Chunhajinda, P.; Phaibulputhipong, P.; Wongmahasiri, R. The Architectural Design Strategies That Promote Attention to Foster Mindfulness: A Systematic Review, Content Analysis and Meta-Analysis. Buildings 2024 , 14 , 2508. https://doi.org/10.3390/buildings14082508

Thampanichwat C, Wongvorachan T, Bunyarittikit S, Chunhajinda P, Phaibulputhipong P, Wongmahasiri R. The Architectural Design Strategies That Promote Attention to Foster Mindfulness: A Systematic Review, Content Analysis and Meta-Analysis. Buildings . 2024; 14(8):2508. https://doi.org/10.3390/buildings14082508

Thampanichwat, Chaniporn, Tarid Wongvorachan, Suphat Bunyarittikit, Pornteera Chunhajinda, Prima Phaibulputhipong, and Rungroj Wongmahasiri. 2024. "The Architectural Design Strategies That Promote Attention to Foster Mindfulness: A Systematic Review, Content Analysis and Meta-Analysis" Buildings 14, no. 8: 2508. https://doi.org/10.3390/buildings14082508

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• Indian J Dermatol
• v.59(2); Mar-Apr 2014

Understanding and Evaluating Systematic Reviews and Meta-analyses

Michael bigby.

From the Department of Dermatology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA

A systematic review is a summary of existing evidence that answers a specific clinical question, contains a thorough, unbiased search of the relevant literature, explicit criteria for assessing studies and structured presentation of the results. A systematic review that incorporates quantitative pooling of similar studies to produce an overall summary of treatment effects is a meta-analysis. A systematic review should have clear, focused clinical objectives containing four elements expressed through the acronym PICO (Patient, group of patients, or problem, an Intervention, a Comparison intervention and specific Outcomes). Explicit and thorough search of the literature is a pre-requisite of any good systematic review. Reviews should have pre-defined explicit criteria for what studies would be included and the analysis should include only those studies that fit the inclusion criteria. The quality (risk of bias) of the primary studies should be critically appraised. Particularly the role of publication and language bias should be acknowledged and addressed by the review, whenever possible. Structured reporting of the results with quantitative pooling of the data must be attempted, whenever appropriate. The review should include interpretation of the data, including implications for clinical practice and further research. Overall, the current quality of reporting of systematic reviews remains highly variable.

Introduction

A systematic review is a summary of existing evidence that answers a specific clinical question, contains a thorough, unbiased search of the relevant literature, explicit criteria for assessing studies and structured presentation of the results. A systematic review can be distinguished from a narrative review because it will have explicitly stated objectives (the focused clinical question), materials (the relevant medical literature) and methods (the way in which studies are assessed and summarized).[ 1 , 2 ] A systematic review that incorporates quantitative pooling of similar studies to produce an overall summary of treatment effects is a meta-analysis.[ 1 , 2 ] Meta-analysis may allow recognition of important treatment effects by combining the results of small trials that individually might lack the power to consistently demonstrate differences among treatments.[ 1 ]

With over 200 speciality dermatology journals being published, the amount of data published just in the dermatologic literature exceeds our ability to read it.[ 3 ] Therefore, keeping up with the literature by reading journals is an impossible task. Systematic reviews provide a solution to handle information overload for practicing physicians.

Criteria for reporting systematic reviews have been developed by a consensus panel first published as Quality of Reporting of Meta-analyses (QUOROM) and later refined as Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).[ 4 , 5 ] This detailed, 27-item checklist contains items that should be included and reported in high quality systematic reviews and meta-analyses. The methods for understanding and appraising systematic reviews and meta-analyses presented in this paper are a subset of the PRISMA criteria.

The items that are the essential features of a systematic review include having clear objectives, explicit criteria for study selection, an assessment of the quality of included studies, criteria for which studies can be combined, appropriate analysis and presentation of results and practical conclusions that are based on the evidence evaluated [ Table 1 ]. Meta-analysis is only appropriate if the included studies are conceptually similar. Meta-analyses should only be conducted after a systematic review.[ 1 , 6 ]

Criteria for evaluating a systematic review or the meta-analysis

A Systematic Review Should Have Clear, Focused Clinical Objectives

A focused clinical question for a systematic review should contain the same four elements used to formulate well-built clinical questions for individual studies, namely a Patient, group of patients, or problem, an Intervention, a Comparison intervention and specific Outcomes.[ 7 ] These features can be remembered by the acronym PICO. The interventions and comparison interventions should be adequately described so that what was done can be reproduced in future studies and in practice. For diseases with established effective treatments, comparisons of new treatments or regimens to established treatments provide the most useful information. The outcomes reported should be those that are most relevant to physicians and patients.[ 1 ]

Explicit and Thorough Search of the Literature

A key question to ask of a systematic review is: “Is it unlikely that important, relevant studies were missed?” A sound systematic review can be performed only if most or all of the available data are examined. An explicit and thorough search of the literature should be performed. It should include searching several electronic bibliographic databases including the Cochrane Controlled Trials Registry, which is part of the Cochrane Library, Medline, Embase and Literatura Latino Americana em Ciências da Saúde. Bibliographies of retrieved studies, review articles and textbooks should be examined for studies fitting inclusion criteria. There should be no language restrictions. Additional sources of data include scrutiny of citation lists in retrieved articles, hand-searching for conference reports, prospective trial registers (e.g., clinical trials.gov for the USA and clinical trialsregister.eu for the European union) and contacting key researchers, authors and drug companies.[ 1 , 8 ]

Reviews should have Pre-defined Explicit Criteria for what Studies would be Included and the Analysis should Include Only those Studies that Fit the Inclusion Criteria

The overwhelming majority of systematic reviews involve therapy. Randomized, controlled clinical trials should therefore be used for systematic reviews of therapy if they are available, because they are generally less susceptible to selection and information bias in comparison with other study designs.[ 1 , 9 ]

Systematic reviews of diagnostic studies and harmful effects of interventions are increasingly being performed and published. Ideally, diagnostic studies included in systematic reviews should be cohort studies of representative populations. The studies should include a criterion (gold) standard test used to establish a diagnosis that is applied uniformly and blinded to the results of the test(s) being studied.[ 1 , 9 ]

Randomized controlled trials can be included in systematic reviews of studies of adverse effects of interventions if the events are common. For rare adverse effects, case-control studies, post-marketing surveillance studies and case reports are more appropriate.[ 1 , 9 ]

The Quality (Risk of Bias) of the Primary Studies should be Critically Appraised

The risk of bias of included therapeutic trials is assessed using the criteria that are used to evaluate individual randomized controlled clinical trials. The quality criteria commonly used include concealed, random allocation; groups similar in terms of known prognostic factors; equal treatment of groups; blinding of patients, researchers and analyzers of the data to treatment allocation and accounting for all patients entered into the trial when analyzing the results (intention-to-treat design).[ 1 ] Absence of these items has been demonstrated to increase the risk of bias of systematic reviews and to exaggerate the treatment effects in individual studies.[ 10 ]

Structured Reporting of the Results with Quantitative Pooling of the Data, if Appropriate

Systematic reviews that contain studies that have results that are similar in magnitude and direction provide results that are most likely to be true and useful. It may be impossible to draw firm conclusions from systematic reviews in which studies have results of widely different magnitude and direction.[ 1 , 9 ]

Meta-analysis should only be performed to synthesize results from different trials if the trials have conceptual homogeneity.[ 1 , 6 , 9 ] The trials must involve similar patient populations, have used similar treatments and have measured results in a similar fashion at a similar point in time.

Once conceptual homogeneity is established and the decision to combine results is made, there are two main statistical methods by which results are combined: random-effects models (e.g., DerSimonian and Laird) and fixed-effects models (e.g., Peto or Mantel-Haenszel).[ 11 ] Random-effects models assume that the results of the different studies may come from different populations with varying responses to treatment. Fixed-effects models assume that each trial represents a random sample of a single population with a single response to treatment [ Figure 1 ]. In general, random-effects models are more conservative (i.e., random-effects models are less likely to show statistically significant results than fixed-effects models). When the combined studies have statistical homogeneity (i.e., when the studies are reasonably similar in direction, magnitude and variability), random-effects and fixed-effects models give similar results.

Fixed-effects models (a) assume that each trial represents a random sample (colored curves) of a single population with a single response to treatment. Random-effects models (b) assume that the different trials’ results (colored curves) may come from different populations with varying responses to treatment.

The point estimates and confidence intervals of the individual trials and the synthesis of all trials in meta-analysis are typically displayed graphically in a forest plot [ Figure 2 ].[ 12 ] Results are most commonly expressed as the odds ratio (OR) of the treatment effect (i.e., the odds of achieving a good outcome in the treated group divided by the odds of achieving a good result in the control group) but can be expressed as risk differences (i.e., difference in response rate) or relative risk (probability of achieving a good outcome in the treated group divided by the probability in the control group). An OR of 1 (null) indicates no difference between treatment and control and is usually represented by a vertical line passing through 1 on the x-axis. An OR of greater or less than 1 implies that the treatment is superior or inferior to the control respectively.

Annotated results of a meta-analysis of six studies, using random effects models reported as odd ratios using MIX version 1.7 (Bax L, Yu LM, Ikeda N, Tsuruta H, Moons KGM. Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Med Res Methodol http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1626481/ ). The central graph is a typical Forest Plot

The point estimate of individual trials is indicated by a square whose size is proportional to the size of the trial (i.e., number of patients analyzed). The precision of the trial is represented by the 95% confidence interval that appears in Forest Plots as the brackets surrounding point estimate. If the 95% confidence interval (brackets) does not cross null (OR of 1), then the individual trial is statistically significant at the P = 0.05 level.[ 12 ] The summary value for all trials is shown graphically as a parallelogram whose size is proportional to the total number of patients analyzed from all trials. The lateral tips of the parallelogram represent the 95% confidence interval and if they do not cross null (OR of 1), then the summary value of the meta-analysis is statistically significant at the P = 0.05 level. ORs can be converted to risk differences and numbers needed to treat (NNTs) if the event rate in the control group is known [ Table 2 ].[ 13 , 14 ]

Deriving numbers needed to treat from a treatment's odds ratio and the observed or expected event rates of untreated groups or individuals

The difference in response rate and its reciprocal, the NNT, are the most easily understood measures of the magnitude of the treatment effect.[ 1 , 9 ] The NNT represents the number of patients one would need to treat in order to achieve one additional cure. Whereas the interpretation of NNT might be straightforward within one trial, interpretation of NNT requires some caution within a systematic review, as this statistic is highly sensitive to baseline event rates.[ 1 ]

For example, if a treatment A is 30% more effective than treatment B for clearing psoriasis and 50% of people on treatment B are cleared with therapy, then 65% will clear with treatment A. These results correspond to a rate difference of 15% (65-50) and an NNT of 7 (1/0.15). This difference sounds quite worthwhile clinically. However if the baseline clearance rate for treatment B in another trial or setting is only 30%, the rate difference will be only 9% and the NNT now becomes 11 and if the baseline clearance rate is 10%, then the NNT for treatment A will be 33, which is perhaps less worthwhile.[ 1 ]

Therefore, NNT summary measures within a systematic review should be interpreted with caution because “control” or baseline event rates usually differ considerably between studies.[ 1 , 15 ] Instead, a range of NNTs for a range of plausible control event rates that occur in different clinical settings should be given, along with their 95% confidence intervals.[ 1 , 16 ]

The data used in a meta-analysis can be tested for statistical heterogeneity. Methods to tests for statistical heterogeneity include the χ 2 and I.[ 2 , 11 , 17 ] Tests for statistical heterogeneity are typically of low power and hence detecting statistical homogeneity does not mean clinical homogeneity. When there is evidence of heterogeneity, reasons for heterogeneity between studies – such as different disease subgroups, intervention dosage, or study quality – should be sought.[ 11 , 17 ] Detecting the source of heterogeneity generally requires sub-group analysis, which is only possible when data from many or large trials are available.[ 1 , 9 ]

In some systematic reviews in which a large number of trials have been performed, it is possible to evaluate whether certain subgroups (e.g. children versus adults) are more likely to benefit than others. Subgroup analysis is rarely possible in dermatology, because few trials are available. Subgroup analyses should always be pre-specified in a systematic review protocol in order to avoid spurious post hoc claims.[ 1 , 9 ]

The Importance of Publication Bias

Publication bias is the tendency that studies that show positive effects are more likely to be published and are easier to find.[ 1 , 18 ] It results from allowing factors other than the quality of the study to influence its acceptability for publication. Factors such as the sample size, the direction and statistical significance of findings, or the investigators’ perception of whether the findings are “interesting,” are related to the likelihood of publication.[ 1 , 19 , 20 ] Negative studies with small sample size are less likely to be published.[ 1 , 19 , 20 ] Studies published are often dominated by the pharmaceutical company sponsored trials of new, expensive treatments often compared with the placebo.

For many diseases, the studies published are dominated by drug company-sponsored trials of new, expensive treatments. Such studies are almost always “positive.”[ 1 , 21 , 22 ] This bias in publication can result in data-driven systematic reviews that draw more attention to those medicines. Systematic reviews that have been sponsored directly or indirectly by industry are also prone to bias through over-inclusion of unpublished “positive” studies that are kept “on file” by that company and by not including or not finishing registered trials whose results are negative.[ 1 , 23 ] The creation of study registers (e.g. http://clinicaltrials.gov ) and advance publication of research designs have been proposed as ways to prevent publication bias.[ 1 , 24 , 25 ] Many dermatology journals now require all their published trials to have been registered beforehand, but this policy is not well policed.[ 1 ]

Language bias is the tendency for studies that are “positive” to be published in an English-language journal and be more quickly found than inconclusive or negative studies.[ 1 , 26 ] A thorough systematic review should therefore not restrict itself to journals published in English.[ 1 ]

Publication bias can be detected by using a simple graphic test (funnel plot), by calculating the fail-safe N, Begg's rank correlation method, Egger regression method and others.[ 1 , 9 , 11 , 27 , 28 ] These techniques are of limited value when less than 10 randomized controlled trials are included. Testing for publication bias is often not possible in systematic reviews of skin diseases, due to the limited number and sizes of trials.[ 1 , 9 ]

Question-driven systematic reviews answer the clinical questions of most concern to practitioners. In many cases, studies that are of most relevance to doctors and patients have not been done in the field of dermatology, due to inadequate sources of independent funding.[ 1 , 9 ]

The Quality of Reporting of Systematic Reviews

The quality of reporting of systematic reviews is highly variable.[ 1 ] One cross-sectional study of 300 systematic reviews published in Medline showed that over 90% were reported in specialty journals. Funding sources were not reported in 40% of reviews. Only two-thirds reported the range of years that the literature was searched for trials. Around a third of reviews failed to provide a quality assessment of the included studies and only half of the reviews included the term “systematic review” or “meta-analysis” in the title.[ 1 , 29 ]

The Review should Include Interpretation of the Data, Including Implications for Clinical Practice and Further Research

The conclusions in the discussion section of a systematic review should closely reflect the data that have been presented within that review. Clinical recommendations can be made when conclusive evidence is found, analyzed and presented. The authors should make it clear which of the treatment recommendations are based on the review data and which reflect their own judgments.[ 1 , 9 ]

Many reviews in dermatology, however, find little evidence to address the questions posed. The review may still be of value even if it lacks conclusive evidence, especially if the question addressed is an important one.[ 1 , 30 ] For example, the systematic review may provide the authors with the opportunity to call for primary research in an area and to make recommendations on study design and outcomes that might help future researchers.[ 1 , 31 ]

Source of Support: Nil

Conflict of Interest: Nil.