systematic literature review x narrative review

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The Difference Between Narrative Review and Systematic Review

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Reviews in scientific research are tools that help synthesize literature on a topic of interest and describe its current state. Different types of reviews are conducted depending on the research question and the scope of the review. A systematic review is one such review that is robust, reproducible, and transparent. It involves collating evidence by using all of the eligible and critically appraised literature available on a certain topic. To know more about how to do a systematic review , you can check out our article at the link. The primary aim of a systematic review is to recommend best practices and inform policy development. Hence, there is a need for high-quality, focused, and precise methods and reporting. For more exploratory research questions, methods such as a scoping review are employed. Be sure you understand the difference between a systematic review and a scoping review , if you don’t, check out the link to learn more.

When the word “review” alone is used to describe a research paper, the first thing that should come to mind is that it is a literature review. Almost every researcher starts off their career with literature reviews. To know the difference between a systematic review and a literature review , read on here. Traditional literature reviews are also sometimes referred to as narrative reviews since they use narrative analysis to synthesize data. In this article, we will explore the differences between a systematic review and a narrative review, in further detail.

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Narrative Review vs Systematic Review

Both systematic and narrative reviews are classified as secondary research studies since they both use existing primary research studies e.g. case studies. Despite this similarity, there are key differences in their methodology and scope. The major differences between them lie in their objectives, methodology, and application areas.

Differences In Objective

The main objective of a systematic review is to formulate a well-defined research question and use qualitative and quantitative methods to analyze all the available evidence attempting to answer the question. In contrast, narrative reviews can address one or more questions with a much broader scope. The efficacy of narrative reviews is irreplaceable in tracking the development of a scientific principle, or a clinical concept. This ability to conduct a wider exploration could be lost in the restrictive framework of a systematic review.

Differences in Methodology

For systematic reviews, there are guidelines provided by the Cochrane Handbook, ROSES, and the PRISMA statement that can help determine the protocol, and methodology to be used. However, for narrative reviews, such standard guidelines do not exist. Although, there are recommendations available.

Systematic reviews comprise an explicit, transparent, and pre-specified methodology. The methodology followed in a systematic review is as follows,

Formulating the clinical research question to answer (PICO approach)
Developing a protocol (with strict inclusion and exclusion criteria for the selection of primary studies)
Performing a detailed and broad literature search
Critical appraisal of the selected studies
Data extraction from the primary studies included in the review
Data synthesis and analysis using qualitative or quantitative methods [3].
Reporting and discussing results of data synthesis.
Developing conclusions based on the findings.

A narrative review on the other hand does not have a strict protocol to be followed. The design of the review depends on its author and the objectives of the review. As yet, there is no consensus on the standard structure of a narrative review. The preferred approach is the IMRAD (Introduction, Methods, Results, and Discussion) [2]. Apart from the author’s preferences, a narrative review structure must respect the journal style and conventions followed in the respective field.

Differences in Application areas

Narrative reviews are aimed at identifying and summarizing what has previously been published. Their general applications include exploring existing debates, the appraisal of previous studies conducted on a certain topic, identifying knowledge gaps, and speculating on the latest interventions available. They are also used to track and report on changes that have occurred in an existing field of research. The main purpose is to deepen the understanding in a certain research area. The results of a systematic review provide the most valid evidence to guide clinical decision-making and inform policy development [1]. They have now become the gold standard in evidence-based medicine [1].

Although both types of reviews come with their own benefits and limitations, researchers should carefully consider the differences between them before making a decision on which review type to use.

Aromataris E, Pearson A. The systematic review: an overview. AJN. Am J Nurs. 2014;114(3):53–8.
Green BN, Johnson CD, Adams A. Writing narrative literature reviews for peer-reviewed journals: secrets of the trade. J Chiropratic Medicine 2006;5:101–117.
Linares-Espinós E, Hernández V, Domínguez-Escrig JL, Fernández-Pello S, Hevia V, Mayor J, et al. Metodología de una revisión sistemática. Actas Urol Esp. 2018;42:499–506.

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Annual Review of Psychology

Volume 70, 2019, review article, how to do a systematic review: a best practice guide for conducting and reporting narrative reviews, meta-analyses, and meta-syntheses.

Andy P. Siddaway 1 , Alex M. Wood 2 , and Larry V. Hedges 3
View Affiliations Hide Affiliations Affiliations: 1 Behavioural Science Centre, Stirling Management School, University of Stirling, Stirling FK9 4LA, United Kingdom; email: [email protected] 2 Department of Psychological and Behavioural Science, London School of Economics and Political Science, London WC2A 2AE, United Kingdom 3 Department of Statistics, Northwestern University, Evanston, Illinois 60208, USA; email: [email protected]
Vol. 70:747-770 (Volume publication date January 2019) https://doi.org/10.1146/annurev-psych-010418-102803
First published as a Review in Advance on August 08, 2018
Copyright © 2019 by Annual Reviews. All rights reserved

Systematic reviews are characterized by a methodical and replicable methodology and presentation. They involve a comprehensive search to locate all relevant published and unpublished work on a subject; a systematic integration of search results; and a critique of the extent, nature, and quality of evidence in relation to a particular research question. The best reviews synthesize studies to draw broad theoretical conclusions about what a literature means, linking theory to evidence and evidence to theory. This guide describes how to plan, conduct, organize, and present a systematic review of quantitative (meta-analysis) or qualitative (narrative review, meta-synthesis) information. We outline core standards and principles and describe commonly encountered problems. Although this guide targets psychological scientists, its high level of abstraction makes it potentially relevant to any subject area or discipline. We argue that systematic reviews are a key methodology for clarifying whether and how research findings replicate and for explaining possible inconsistencies, and we call for researchers to conduct systematic reviews to help elucidate whether there is a replication crisis.

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Article Type: Review Article

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How to Conduct a Systematic Review: A Narrative Literature Review

Affiliations.

1 Psychiatry, Mount Sinai Chicago.
2 Psychiatry, KVC Prairie Ridge Hospital.
3 Department of Psychiatry, Bronx Lebanon Hospital Icahn School of Medicine at Mount Sinai, Bronx, NY.
4 Psychiatry, Suny Upstate Medical University, Syracuse, NY.
PMID: 27924252
PMCID: PMC5137994
DOI: 10.7759/cureus.864

Systematic reviews are ranked very high in research and are considered the most valid form of medical evidence. They provide a complete summary of the current literature relevant to a research question and can be of immense use to medical professionals. Our goal with this paper is to conduct a narrative review of the literature about systematic reviews and outline the essential elements of a systematic review along with the limitations of such a review.

Keywords: meta-analysis; narrative literature review; prisma checklist; systematic reviews.

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The authors have declared that no competing interests exist.

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Acta Paulista de Enfermagem

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Acta paul enferm. 2007; 20(2): v-vi, issue cover.

Systematic literature review X narrative review

Edna Terezinha Rother

DOI: 10.1590/S0103-21002007000200001

How to cite this article

Rother E T . Systematic literature review X narrative review. Acta Paul Enferm. 2007;20(2):v-vi.

Rother, Edna Terezinha . Systematic literature review X narrative review. Acta Paul Enferm. , v. 20, n. 2, p. v-vi, Feb. 2007.

Rother, E. T. (2007). Systematic literature review X narrative review. Acta Paul Enferm., 20 (2), v-vi.

Rother, Edna Terezinha . Systematic literature review X narrative review. Acta Paul Enferm. [online]. 2007, vol. 20, n. 2, [cited 2024-09-10], pp.v-vi. Available from: <https://acta-ape.org/en/article/systematic-literature-review-x-narrative-review/>. ISSN 1982-0194.

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DOI: 10.1590/S0103-21002007000200001
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Systematic literature review X narrative review

E. T. Rother
Published 1 June 2007
Acta Paulista De Enfermagem

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Methodology
Open access
Published: 26 March 2019

SANRA—a scale for the quality assessment of narrative review articles

Christopher Baethge ORCID: orcid.org/0000-0001-6246-3674 1 , 2 ,
Sandra Goldbeck-Wood 1 , 3 &
Stephan Mertens 1

Research Integrity and Peer Review volume 4 , Article number: 5 ( 2019 ) Cite this article

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Narrative reviews are the commonest type of articles in the medical literature. However, unlike systematic reviews and randomized controlled trials (RCT) articles, for which formal instruments exist to evaluate quality, there is currently no instrument available to assess the quality of narrative reviews. In response to this gap, we developed SANRA, the Scale for the Assessment of Narrative Review Articles.

A team of three experienced journal editors modified or deleted items in an earlier SANRA version based on face validity, item-total correlations, and reliability scores from previous tests. We deleted an item which addressed a manuscript’s writing and accessibility due to poor inter-rater reliability. The six items which form the revised scale are rated from 0 (low standard) to 2 (high standard) and cover the following topics: explanation of (1) the importance and (2) the aims of the review, (3) literature search and (4) referencing and presentation of (5) evidence level and (6) relevant endpoint data. For all items, we developed anchor definitions and examples to guide users in filling out the form. The revised scale was tested by the same editors (blinded to each other’s ratings) in a group of 30 consecutive non-systematic review manuscripts submitted to a general medical journal.

Raters confirmed that completing the scale is feasible in everyday editorial work. The mean sum score across all 30 manuscripts was 6.0 out of 12 possible points (SD 2.6, range 1–12). Corrected item-total correlations ranged from 0.33 (item 3) to 0.58 (item 6), and Cronbach’s alpha was 0.68 (internal consistency). The intra-class correlation coefficient (average measure) was 0.77 [95% CI 0.57, 0.88] (inter-rater reliability). Raters often disagreed on items 1 and 4.

Conclusions

SANRA’s feasibility, inter-rater reliability, homogeneity of items, and internal consistency are sufficient for a scale of six items. Further field testing, particularly of validity, is desirable. We recommend rater training based on the “explanations and instructions” document provided with SANRA. In editorial decision-making, SANRA may complement journal-specific evaluation of manuscripts—pertaining to, e.g., audience, originality or difficulty—and may contribute to improving the standard of non-systematic reviews.

Peer Review reports

Narrative review articles are common in the medical literature. Bastian et al. found that they constitute the largest share of all text types in medicine and they concluded that they “remain the staple of medical literature” [ 1 ]. Narrative reviews also appear popular among both authors and readers, and it is plausible to assume that they exercise an enormous influence among doctors in clinical practice and research. However, because their quality varies widely, they have frequently been compared in blanket, negative terms with systematic reviews.

We use the term narrative review to refer to an attempt to summarize the literature in a way which is not explicitly systematic, where the minimum requirement for the term systematic relates to the method of the literature search, but in a wider sense includes a specific research question and a comprehensive summary of all studies [ 2 ].

While systematic reviews are not per se superior articles and while certain systematic reviews have been criticized lately [ 3 ], non-systematic reviews or narrative reviews have been widely criticized as unreliable [ 1 , 4 ]. Hence, the hierarchy of evidence-based medicine places systematic reviews much higher than non-systematic ones. However, it is likely—and even desirable—that good quality narrative reviews will continue to play an important role in medicine: while systematic reviews are superior to narrative reviews in answering specific questions (for example, whether it is advisable to switch an antidepressant among antidepressant non-responders in patients with major depressive disorder [ 5 ]), narrative reviews are better suited to addressing a topic in wider ways (for example, outlining the general principles of diagnosing and treating depression [ 6 ]).

Critical appraisal tools have been developed for systematic reviews (e.g., AMSTAR 2 [A MeaSurement Tool to Assess Systematic Reviews] [ 7 ]) and papers on RCTs (e.g., the CASP [Critical Appraisal Skills Program] checklist for randomized trials [ 8 ]) and other types of medical studies. For narrative reviews, in contrast, no critical appraisal, or quality assessment tool is available. Such a tool, however, if simple and brief enough for day-to-day use, may support editors in choosing or improving manuscripts, help reviewers and readers in assessing the quality of a paper, and aid authors in preparing narrative reviews. It may improve the general quality of narrative reviews.

As a consequence, we have developed SANRA, the Scale for the Assessment of Narrative Review Articles, a brief critical appraisal tool for the assessment of non-systematic articles. Here, we present the revised scale and the results of a field test regarding its feasibility, item-total correlation, internal consistency, reliability, and criterion validity.

SANRA was developed between 2010 and 2017 by three experienced editors (CB, SGW, and SM) working at a general medical journal, Deutsches Ärzteblatt , the journal of the German Medical Association and the National Association of Statutory Health Insurance Physicians . It is intended to be a simple and brief quality assessment instrument not only to assist editors in their decisions about manuscripts, but also to help reviewers and readers in their assessment of papers and authors in writing narrative reviews.

Two earlier, seven-item versions of SANRA have been developed and tested by the authors, the first in 10 narrative reviews from the field of neurology as retrieved through a PubMed search, the second among 12 consecutive narrative reviews submitted to Deutsches Ärzteblatt —both showing satisfactory internal consistency and inter-rater reliability [ 9 ].

The current version of SANRA [ 10 ] has been revised by the authors in 2014 in order to simplify the scale and make it more robust. We simplified the wording of the items, and we deleted an item addressing a manuscript’s writing and accessibility because ratings of that item differed considerably. The six items that form the revised scale are rated in integers from 0 (low standard) to 2 (high standard), with 1 as an intermediate score. The maximal sum score is 12.

The sum score of the scale is intended to measure the construct “quality of a narrative review article” and covers the following topics: explanation of the review’s importance (item 1) and statement of the aims (item 2) of the review, description of the literature search (item 3), referencing (item 4), scientific reasoning (item 5), and presentation of relevant and appropriate endpoint data (item 6) (Fig. 1 ). For all items, we developed anchor definitions and examples to guide users in filling out the instrument, provided in the document “explanations and instructions,” accompanying the scale. This document was also edited to improve clarity (Fig. 2 ).

SANRA - Scale

SANRA—explanations and instructions document

In 2015, one rater (CB) screened all submissions to Deutsches Ärzteblatt in 2015, and the first 30 consecutive review manuscripts without systematic literature searches were selected for inclusion in the present study. All three raters (CB, SGW, and SM) are editors, with, in 2015, at least 10 years of experience each. They scored the manuscripts independently and blinded to each other’s ratings.

Statistical analysis

Descriptive data are shown as means or medians, as appropriate, and as ranges, standard deviations, or confidence intervals. This study aimed at testing SANRA’s internal consistency (Cronbach’s alpha) and the item-total correlation—indicating whether the items measure the same phenomenon, here different aspects of review paper quality—as well as SANRA’s inter-rater reliability with regard to its sum score. Inter-rater reliability, as a measure of the consistency among different raters, was expressed as the average measure intra-class correlation, ICC, using a two-way random effects model (consistency definition). As an approximation of SANRA’s criterion validity (Is the score predictive of other indicators of paper quality, e.g., acceptance and rejection or citations?), we analyzed post hoc whether average sum scores of SANRA were associated with the decision to accept or reject the 30 manuscripts under study (point biserial correlation for the association between a dichotomous and a continuous variable). All calculations were carried out using SPSS. Where possible, the presentation follows the recommendations of the Guidelines for Reporting Reliability and Agreement Studies (GRRAS) [ 11 ].

All 90 ratings (3 raters × 30 manuscripts) were used for statistical analysis. The mean sum score across all 30 manuscripts ( N = 90) was 6.0 out of 12 possible points (SD 2.6, range 1–12, median 6). Highest scores were rated for item 4 (mean 1.25; SD 0.70), item 2 (mean 1.14; SD 0.84), and item 1 (mean 1.1; SD 0.69) whereas items 6, 5, and 3 had the lowest scores (means of 0.81 (SD 0.65), 0.83 (SD 0.67), and 0.84 (SD 0.60), respectively) (all single-item medians: 1).

The scale’s internal consistency, measured as Cronbach’s alpha, was 0.68. Corrected item-total correlations ranged from 0.33 to 0.58 (Table 1 ). Tentative deletions of each item to assess the effect of these on consistency showed reduced internal consistency with every deleted item (0.58–0.67) (as shown by the alpha values in Table 1 ).

Across 180 single-item ratings (6 items × 30 manuscripts), the maximum difference among the 3 raters was 2 in 12.8% ( n = 23; most often in items 1, 2, and 4), in 56.7% ( n = 102), the raters differed by no more than 1 point, and in 30.6% ( n = 55), they entirely agreed (most often in items 2 and 3). The intra-class correlation coefficient (average measure) amounted to 0.77 [95% CI 0.57, 0.88; F 4.3; df 29, 58]. Disagreements most often occurred with regard to items 1 and 4.

Average SANRA sum scores of the 30 manuscripts were modestly associated with the editorial decision of acceptance (mean score 6.6, SD 1.9; n = 17) or rejection (mean score 5.1, SD 2.1; n = 13): point biserial correlation of 0.37 ( t = 2.09, df 28; two-sided p = 0.046).

All raters confirmed that completing the scale is feasible in everyday editorial work.

This study yielded three important findings: (1) SANRA can be applied to manuscripts in everyday editorial work. (2) SANRA’s internal consistency and item-total correlation are sufficient. (3) SANRA’s inter-rater reliability is satisfactory.

Feasibility

It is our experience with the current and earlier SANRA versions that editors, once accustomed to the scale, can integrate the scale into their everyday routine. It is important, however, to learn how to fill out SANRA. To this end, together with SANRA, we provide definitions and examples in the explanations and instructions document, and we recommend that new users train filling out SANRA using this resource. Editorial teams or teams of scientists and/or clinicians may prefer to learn using SANRA in group sessions.

Consistency and homogeneity

With Cronbach’s alpha of 0.68 and corrected item-total correlations between 0.33 and 0.58, we consider the scale’s consistency and item homogeneity sufficient for widespread application. It should be noted that because coefficient alpha increases with the number of items [ 12 ], simplifying a scale by reducing the number of items—as we did—may decrease internal consistency. However, this needs to be balanced against the practical need for brevity. In fact, the earlier seven-item versions of SANRA had higher values of alpha: 0.80 and 0.84, respectively [ 9 ]. Still, the number of items is not necessarily the only explanation for differences in alpha values. For example, the manuscripts included in the two earlier studies may have been easier to rate.

Inter-rater reliability

The scale’s intra-class correlation (0.77 after 0.76 in [ 9 ]) indicates that SANRA can be used reliably by different raters—an important property of a scale that may be applied for manuscript preparation and review, in editorial decision-making, or even in research on narrative reviews. Like internal consistency, reliability increases with the number of items [ 12 ], and there is a trade-off between simplicity (e.g., a small number of items) and reliability. While the ICC suggests sufficient reliability, however, the lower confidence limit (0.57) does not preclude a level of reliability normally deemed unacceptable in most applications of critical appraisal tools. This finding underscores the importance of rater training. Raters more often disagreed on items 1 and 4. After the study, we have therefore slightly edited these items, along with items 5 and 6 which we edited for clarity. In the same vein, we revised our explanations and instructions document.

It is important to bear in mind that testing of a scale always relates only to the setting of a given study. Thus, in the strict sense, the results presented here are not a general feature of SANRA but of SANRA filled out by certain raters with regard to a particular sample of manuscripts. However, from our experience, we trust that our setting is similar to that of many journals, and our sample of manuscripts represents an average group of papers. As a consequence, we are confident SANRA can be applied by other editors, reviewers, readers, and authors.

In a post hoc analysis, we found a modest, but statistically significant correlation of SANRA sum scores with manuscript acceptance. We interpret this as a sign of criterion validity, but emphasize that this is both a post hoc result and only a weak correlation. The latter, however, points to the fact that, at the level of submitted papers, other aspects than quality alone influence editorial decision-making: for example, whether the topic has been covered in the journal recently or whether editors believe that authors or topics of manuscripts have potential, even with low initial SANRA scores. SANRA will therefore often be used as one, and not the only, decision aid. Also, the decision to accept a paper has been made after the papers had been revised.

Moreover, additional results on criterion validity are needed, as are results on SANRA’s construct validity. On the other hand, SANRA’s content validity, defined as a scale’s ability to completely cover all aspects of a construct, will be restricted because we decided to limit the scale to six items, too few to encompass all facets of review article quality—SANRA is a critical appraisal tool and not a reporting guideline. For example, we deleted an item on the accessibility of the manuscript. Other possible domains that are not part of SANRA are, for example, originality of the manuscript or quality of tables and figures. These features are important, but we believe the six items forming SANRA are a core set that sufficiently indicates the quality of a review manuscript and, at the same time, is short enough to be applied without too much time and effort. SANRA’s brevity is also in contrast to other tools to assess articles, such as AMSTAR 2, for systematic reviews, or, to a lesser extent, CASP for RCTs, with its 16 and 11 items, respectively.

Throughout this paper we have referred to the current version of SANRA as the revision of earlier forms. This is technically true. However, because it is normal that scales go through different versions before publication and because this paper is first widespread publication of SANRA, we propose to call the present version simpy SANRA.

While medicine has achieved a great deal in the formalization and improvement of the presentation of randomized trials and systematic review articles, and also a number of other text types in medicine, much less work have been done with regard to the most frequent form of medical publications, the narrative review. There are exceptions: Gasparyan et al. [ 13 ], for example, have provided guidance for writing narrative reviews, and Byrne [ 14 ] as well as Pautasso [ 15 ] has written, from different angles, thoughtful editorials on improving narrative reviews and presented lists of key features of writing a good review—lists that naturally overlap with SANRA items (e.g., on referencing). These lists, however, are not tested scales and not intended for comparing different manuscripts. SANRA can be used in comparisons of manuscripts the way we used it in our editorial office, that is, in one setting. At the present time, however, it seems unwise to compare manuscripts across different settings because, so far, there are no established cut-offs for different grades of quality (e.g., poor-fair-moderate-good-very good). Still, in our experience, a score of 4 or below indicates very poor quality.

Limitations

The main limitation of this study is its sample size. While, in our experience, a group of 30 is not unusual in testing scales, it represents a compromise between the aims of representativeness for our journal and adequate power and feasibility; it took us about 6 months to sample 30 consecutive narrative reviews. Also, in this study, the authors of the scale were also the test-raters, and it is possible that inter-rater reliability is lower in groups less familiar with the scale. As for most scales, this underscores the importance of using the instructions that belong to the scale, in the present case the explanations and instructions document. It is also advisable to train using the scale before applying SANRA for manuscript rating. In addition, by design, this is not a study of test-retest reliability, another important feature of a scale. Finally, as previously acknowledged, although we believe in the representativeness of our setting for medical journals, the present results refer to the setting of this study, and consistency and reliability measures are study-specific.

We present SANRA, a brief scale for the quality assessment of narrative review articles, the most widespread form of article in the medical literature. We suggest SANRA can be integrated into the work of editors, reviewers, and authors. We encourage readers to consider using SANRA as an aid to critically appraising articles, and authors to consider its use on preparing narrative reviews, with a view to improving the quality of submitted and published manuscripts.

SANRA and its explanations and instructions document are available (open access) at: https://www.aerzteblatt.de/down.asp?id=22862 , https://www.aerzteblatt.de/down.asp?id=22861 .

Abbreviations

A MeaSurement Tool to Assess Systematic Reviews

Critical Appraisal Skills Program

Guidelines for Reporting Reliability and Agreement Studies

Intra-class correlation

Randomized controlled trial

Scale for the Assessment of Narrative Review Articles

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Acknowledgements

This work has been presented at the Eighth International Congress on Peer Review and Scientific Publication in Chicago, Illinois, USA. (September 10-12, 2017) and at the 14th EASE Conference in Bucharest, Romania (June 8-10, 2018).

This work has not been externally funded.

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All authors (CB, SM, and SGW) made substantial contributions to the conception of the study and to the acquisition and interpretation of data. CB analyzed the data and drafted the manuscript. SM and SGW revised the draft critically for important intellectual content. All authors sufficiently participated in this work to take public responsibility for its content, all finally approved the manuscript, and all are accountable for every aspect of this project.

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Baethge, C., Goldbeck-Wood, S. & Mertens, S. SANRA—a scale for the quality assessment of narrative review articles. Res Integr Peer Rev 4 , 5 (2019). https://doi.org/10.1186/s41073-019-0064-8

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RAMESES publication standards: meta-narrative reviews

Geoff Wong 1 ,
Trish Greenhalgh 1 ,
Gill Westhorp 2 ,
Jeanette Buckingham 3 &
Ray Pawson 4

BMC Medicine volume 11 , Article number: 20 ( 2013 ) Cite this article

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Meta-narrative review is one of an emerging menu of new approaches to qualitative and mixed-method systematic review. A meta-narrative review seeks to illuminate a heterogeneous topic area by highlighting the contrasting and complementary ways in which researchers have studied the same or a similar topic. No previous publication standards exist for the reporting of meta-narrative reviews. This publication standard was developed as part of the RAMESES (Realist And MEta-narrative Evidence Syntheses: Evolving Standards) project. The project's aim is to produce preliminary publication standards for meta-narrative reviews.

We (a) collated and summarized existing literature on the principles of good practice in meta-narrative reviews; (b) considered the extent to which these principles had been followed by published reviews, thereby identifying how rigor may be lost and how existing methods could be improved; (c) used a three-round online Delphi method with an interdisciplinary panel of national and international experts in evidence synthesis, meta-narrative reviews, policy and/or publishing to produce and iteratively refine a draft set of methodological steps and publication standards; (d) provided real-time support to ongoing meta-narrative reviews and the open-access RAMESES online discussion list so as to capture problems and questions as they arose; and (e) synthesized expert input, evidence review and real-time problem analysis into a definitive set of standards.

We identified nine published meta-narrative reviews, provided real-time support to four ongoing reviews and captured questions raised in the RAMESES discussion list. Through analysis and discussion within the project team, we summarized the published literature, and common questions and challenges into briefing materials for the Delphi panel, comprising 33 members. Within three rounds this panel had reached consensus on 20 key publication standards, with an overall response rate of 90%.

This project used multiple sources to draw together evidence and expertise in meta-narrative reviews. For each item we have included an explanation for why it is important and guidance on how it might be reported. Meta-narrative review is a relatively new method for evidence synthesis and as experience and methodological developments occur, we anticipate that these standards will evolve to reflect further theoretical and methodological developments. We hope that these standards will act as a resource that will contribute to improving the reporting of meta-narrative reviews.

To encourage dissemination of the RAMESES publication standards, this article is co-published in the Journal of Advanced Nursing and is freely accessible on Wiley Online Library ( http://www.wileyonlinelibrary.com/journal/jan ). Please see related article http://www.biomedcentral.com/1741-7015/11/21 and http://www.biomedcentral.com/1741-7015/11/22

Peer Review reports

Academics and policymakers are increasingly interested in summarizsing the literature on complex questions that have been considered from different angles by different groups of researchers. The field of secondary research is expanding rapidly. A number of relatively new approaches are available to those seeking to undertake 'mixed method' literature reviews that combine qualitative and quantitative evidence, explore the nature and impact of complex interventions, and identify the mechanisms by which programs achieve their goals (or why they fail to do so) [ 1 – 3 ]. These approaches seek not only to address the questions 'what works?' and 'what is the effect size?' but to illuminate and clarify a complex topic area and highlight the strengths and limitations of different research approaches to that topic [ 4 ]. One such approach is meta-narrative review.

What is a meta-narrative review?

Meta-narrative review is a relatively new method of systematic review, designed for topics that have been differently conceptualized and studied by different groups of researchers. For example, many different groups have, for different reasons and in different ways, studied the building of dams in India. Some have conceptualized this dam-building as engineering; others as colonialism; others as a threat (or promise) to the local eco-system; others as inspiration for literature and drama, and so on. If we were to summarize this topic area in a way that was faithful to what each different group set out to do, we would have to start by asking how each of them approached the topic, what aspect of 'dams in India' they chose to study and how. In order to understand the many approaches, we would have to consciously and reflexively step out of our own world-view, learn some new vocabulary and methods, and try to view the topic of 'dams in India' through multiple different sets of eyes. When we had begun to understand the different perspectives, we could summarize them in an over-arching narrative, highlighting what the different research teams might learn from one another's approaches.

The methodology of meta-narrative review was developed by Greenhalgh et al. in 2004 as a pragmatic response to challenges that emerged in a review on diffusion of service-level innovations in healthcare [ 5 ]. A methods paper was published in early 2005 [ 6 ]. The inspiration for the method was Kuhn's 1962 book The Structure of Scientific Revolutions , which argued that science progresses in paradigms (that is, particular ways of viewing the world, including assumptions about how the world works) and that one scientific paradigm gives way to another as scientific progress renders yesterday's assumptions and practices obsolete [ 7 ]. Newton's theories and methods, for example, became less and less able to answer the emerging questions of particle physics, leading Einstein to develop his theory of relativity. Meta-narrative review looks historically at how particular research traditions have unfolded over time and shaped the kind of questions being asked and the methods used to answer them. According to Kuhn, a research tradition is a series of linked studies, each building on what has gone before and taking place within a coherent paradigm (that is, within a particular set of assumptions and preferred methodological approaches that are shared by a group of scientists at a particular point in time).

The meta-narrative approach has some parallels to what Paterson et al. call the 'meta-theoretical' method [ 8 ], but is more closely aligned to 'meta-triangulation', another Kuhnian approach which we came across when researching the background for the RAMESES project [ 9 ]. The similarities and differences between meta-narrative and meta-triangulation approaches are shown in Additional file 1 . In short, meta-triangulation review has a more theoretical focus and is not principally concerned with informing policy decisions. Meta-theoretical review focuses more narrowly on comparing the theoretical basis of empirical studies.

Why are publication standards needed?

Publication standards are common (and, increasingly, expected) in health services research - see for example, CONSORT for randomized controlled trials [ 10 ], AGREE for clinical guidelines [ 11 ], PRISMA for Cochrane-style systematic reviews [ 12 ] and SQUIRE for quality improvement studies [ 13 ]. For meta-narrative reviews, publication standards are urgently needed as this method is increasingly popular and we have encountered examples of inappropriate application of the methodology in papers, theses and grant applications, which we have been asked to review. Publication standards are needed to ensure that users of reviews are provided with relevant and necessary information to enable them to assess the quality and rigor of a review.

In our experience, there is considerable confusion among researchers, journal editors, peer reviewers and funders about what counts as a high quality meta-narrative review and what, conversely, counts as a flawed review. Even though experts still differ on detailed conceptual methodological issues, the increasing popularity of this method prompted a study to develop baseline standards from which, we anticipate, further developments in theory and methodology of this approach will occur.

The aim of this paper is to produce preliminary publication standards for meta-narrative reviews.

The methods we used to develop these reporting standards have already been published [ 14 ]. In brief, we purposively recruited an international group of experts to our online Delphi panel. Aiming to achieve maximum variety in the relevant sectors, disciplines and expert perspectives represented, we sought panel members working in meta-narrative reviews, evidence synthesis, publication, reviewer training and health policy. Prior to the start of our Delphi panel, with input from an expert informaticist (JB), we collated and summarized existing literature on the principles of good practice in meta-narrative reviews, created a database of such published reviews, and built relationships with teams who were undertaking ongoing reviews. Through discussion within the project team, we considered the extent to which the principles had been followed by published and in progress reviews, thereby identifying how rigor may be lost and how existing methods could be improved.

Our analysis of existing meta-narrative reviews formed the basis of the briefing materials for the first round of the Delphi panel. In addition, we drew on our collective experience in training and supporting meta-narrative review teams and an email discussion list on realist and meta-narrative methodology [ 15 ] to further inform the contents of our briefing document. Both the research team and panel members contributed draft items for the publication standards, and these were refined using the online Delphi process as previously described [ 14 ]. We ran the Delphi panels between September 2011 and March 2012.

Description of panel and items

In all, we recruited 33 individuals from 25 organizations in six countries. These comprised researchers in public or population health researchers (5); evidence synthesis (5); health services research (8); international development (2); education (2); and also research methodologists (6), publishing (1), nursing (2) and policy and decision making (2). In round 1, 22 panel members provided suggestions of items that should be included in the publication standards. In rounds 2 and 3, our panel members were asked to rate each potential item for relevance and clarity. The response rates across all items for round 2 and 3 were 93% and 87%, respectively. Consensus was reached within three rounds on both the content and wording of 20 items within the publication standards. Table 1 provides an overview of these items.

Scope of the publication standards

These publication standards are intended to help researchers, authors, journal editors and policy and decision makers to know and understand what should be reported in the write-up of a meta-narrative review. They are not intended to provide detailed guidance on how to conduct such a review; for this we direct interested readers to other publications [ 5 , 6 ]. This publication standard applies only to meta-narrative reviews. A list of publication guidelines for other review methods can be found on the EQUATOR Network's website [ 16 ], but at present none of these relate specifically to meta-narrative reviews. As part of the RAM-ESES project we are also developing quality standards and training materials for meta-narrative review, which will be submitted as a separate publication. Publication standards for realist syntheses (also covered in the RAMESES project) have been addressed in a separate article.

How to use these publication standards

The layout of this document has drawn on previous methodological publications and in particular on the 'Explanations and Elaborations' document of the PRISMA statement [ 12 ]. Each item is followed by an example drawn from published reviews and a rationale for its inclusion. The purpose of the example text is to illustrate how an item might be reported in a write-up. However, potentially relevant contextual information may have been omitted, so it may be necessary to consult the original paper from which the example text was drawn. The standards set out what might be expected for each item, but authors will still need to exercise judgement about how much information to include. The purpose of the detail reported should be to ensure that the description and explanation provided is coherent and plausible, both against the guidance set out within an item and for the overall purpose of the meta-narrative review.

While this publication standard is modeled on the PRISMA statement, the items within are not identical. This publication standard, developed to apply only to meta-narrative reviews, has some overlap with the PRISMA statement. Items 1 to 3, 16, 17 and 20 in this statement broadly match the purpose of items 1 to 3, 24, 25 and 27 in the PRISMA statement. For items 4 to 15, while there is some overlap in purpose with some PRISMA statement items, different or additional reporting is needed due to the nature of meta-narrative reviews. Other items (5, 12, 13, 15, 16, 19 and 23) in the PRIMSA statement have no equivalent in the RAMESES publication standards for realist reviews.

The order in which items are reported may vary. Meta-narrative reviews are not 'linear' reviews. Some of the processes that are listed may legitimately take place in parallel or have to be revisited at a later date as a review progresses. As a general rule, if a recommended item is excluded from the write-up of a meta-narrative review, a justification should be provided.

The RAMESES publication standards for meta-narrative reviews

Item 1: title.

In the title, identify the document as a meta-narrative review or synthesis.

"Tensions and Paradoxes in Electronic Patient Record Research: A Systematic Literature Review Using the Meta-narrative Method." [ 17 ]

Explanation

Some meta-narrative reviews are not flagged as such in the title and/or are inconsistently indexed and, hence, are difficult to locate in searches. Most authors currently use the term 'meta-narrative review'. No consensus was reached by our Delphi panel on whether 'review' or 'synthesis' should be the preferred term, and there seemed no good reason to impose one or the other term.

Item 2: Abstract

While acknowledging that requirements and house style may differ between journals, abstracts should ideally contain brief details of the study's background, review question or objectives; search strategy; methods of selection, appraisal, analysis and synthesis of sources; main results; and implications for practice.

"Background: The therapeutic relationship is complex. Any attempt to capture its quality in a score or metric must involve an element of reductionism. But policy-makers increasingly ignore the unmeasured.

Aim: To review the different concepts, theoretical models and empirical approaches which researchers have used to capture the relationship between practitioner and patient in terms of scales, categories and other objective metrics.

Method: Drawing on the principles of meta-narrative systematic review (but without seeking an exhaustive inventory of every paper ever published), we considered different research traditions in terms of their respective philosophical assumptions, methodological strengths and limitations and empirical findings. We applied published quality criteria from each tradition to papers within that tradition.

Results: Three main research approaches were oriented to producing objective data about the therapeutic relation-ship. These appeared to have emerged in different research traditions: patient satisfaction surveys (health services research), rate-your-relationship surveys (social psychology) and interaction analysis (cognitive psychology). Each emphasised a different dimension and produced a different perspective on quality.

Conclusions: Objective metrics, when well designed, offer important insights into the therapeutic relation-ship, but its elusive essence remains imperfectly captured by the best of them." [ 18 ]

Apart from the title, an abstract is the only source of information accessible to searchers unless the full paper is obtained. The information in it must allow reviewers and/or users to decide if the review is relevant to their needs.

Introduction section

The following items should be reported in the introduction section.

Item 3: Rationale for review

Explain why the review is needed and what it is likely to contribute to existing understanding of the topic area.

"A number of researchers have documented a tremendous gap between knowledge and policy action to tackle social gradients in health (References x8). Yet, the roles and capacities of urban municipalities to address population health inequities, as perceived by both researchers and urban municipal policy-makers themselves, have been particularly neglected areas of study. While the Healthy Cities movement has been active in prescribing avenues for municipal activity (primarily in non-academic/grey literature (References x4)), it remains to be empirically demonstrated how other health inequities literatures have implicated municipalities, the precise nature of these implications, and the manner in which these implications are taken up by relevant municipal actors and institutions." [ 19 ]

As with all research, a background section explaining what is already known and what the researchers considered the 'knowledge gaps' to be is a helpful orientation.

Item 4: Objectives and focus of review

State the objective(s) of the review and/or the review question(s). Define and provide a rationale for the focus of the review.

...."our review is focused on the collective level of analysis in order to understand deliberate interventions aimed at influencing behaviors or opinions though the communication of information." [ 20 ]

A meta-narrative review asks some or all of the following questions:

Which research (or epistemic) traditions have considered this broad topic area?; (2) How has each tradition conceptualized the topic (for example, including assumptions about the nature of reality, preferred study designs and ways of knowing)?; (3) What theoretical approaches and methods did they use?; (4) What are the main empirical findings?; and (5) What insights can be drawn by combining and comparing findings from different traditions?'

Because a meta-narrative review may generate a large number of avenues that might be explored and explained, and because resources and timescale are invariably finite, the expectation is that the review must be 'contained' by progressively focusing both its breadth (how wide an area?) and depth (how much detail?). This important process may involve discussion and negotiation with (for example) content experts, funders and/or users. It is typical and legitimate for the review's objectives, question and/or the breadth and depth of the review to evolve as the review progresses. How and why it evolved is usually worth reporting.

Methods section

The following items should be reported in the methods section.

Item 5: Changes in the review process

Any changes made to the review that were initially planned should be briefly described and justified.

"But as the review unfolded, two things became clear: first, in many areas, the evidence meeting all these criteria was sparse, and second, we could gain critical insights from beyond the parameters we had set. We therefore extended our criteria to a wider range of literature. In particular, we added both overview articles and "landmark" empirical studies from outside the health sector if they had important methodological or theoretical lessons for our research question." [ 5 ]

A meta-narrative review can (and, in general, should) evolve over the course of the review. For example, changes to the research question or its scope are likely to have an impact on many of the review's subsequent processes. However, this does not mean the review can meander uncontained. An accessible summary of what was originally planned (for example, as described in an initial protocol) and how and why this differed from what was done should be provided as this may assist interpretation.

Item 6: Rationale for using the meta-narrative approach

Explain why meta-narrative review was considered the most appropriate method to use.

"We used an adaptation of meta-narrative review, based on Kuhn's notion of the scientific paradigm (a coherent body of work that shares a common set of concepts, theories, methods and instruments).(references x2) This qualitative approach seeks to tease out the over-arching storylines of different research traditions by asking four key questions: how is the topic conceptualised in each separate tradition?; what are the key theory(ies)?; what are the preferred study designs and ways of knowing? and what are the main empirical findings? Meta-narrative review is pluralistic rather than normative (ie, it asks not 'what is the best approach to researching this topic?' but 'what can we learn from the range of different approaches?'). It is particularly suited to exploring tensions and paradoxes between different research traditions and making sense of 'conflicting' findings." [ 18 ]

Meta-narrative review, (which is rooted in a constructivist philosophy of science), is inspired by the work of Thomas Kuhn, who observed that science progresses in paradigms (see definition below). Meta-narrative reviews often look historically at how particular research traditions or epistemic traditions have unfolded over time and shaped the 'normal science' of a topic area.

Some definitions:

A paradigm is a particular way of viewing the world, including assumptions about how the world works, what are the important questions in a particular topic area, and what study designs and methods are best for adding to the knowledge base.

A research tradition comprises studies building on what has gone before, each building on what has gone before, usually situated within a coherent paradigm, though an interdisciplinary tradition may bridge more than one paradigm.

An epistemic tradition is the unfolding of the underpinning set of philosophical assumptions which drive the development of theory and method; scholarship may progress via debate around these assumptions even in the absence of new empirical studies.

Normal science is a paradigm along with the practices and empirical approaches which are taken for granted by scientists within a particular tradition.

Meta-narrative review is, therefore, best suited to studying topic areas that have been differently conceptualized and studied by different groups. The review seeks first to identify and understand as many as possible of the potentially important different research traditions which have a bearing on the topic, and then to synthesize them by means of an over-arching narrative. The goal of meta-narrative review is sensemaking of a complex (and perhaps contested) topic area.

Item 7: Evidence of adherence to guiding principles of meta-narrative review

Where appropriate, show how each of the six guiding principles (pragmatism, pluralism, historicity, contestation, reflexivity and peer review) have been followed.

"We identified 13 research areas that had, largely independently of one another, provided evidence relevant to the diffusion of innovations in health service organizations (Table 1 ). Four of these traditions can be classified as "early diffusion research":

.... One important weakness of the literature on structural determinants of innovativeness is the assumption that they can be treated as variables whose impact can be isolated and independently quantified. For example, the empirical studies of organizational size implicitly assume that there is a "size effect" that is worth measuring and that is to some extent generalizable. An alternative theoretical approach (Reference x1), supported by a number of recent detailed qualitative studies (References x2), is that the determinants of organizational innovativeness interact in a complex, un-predictable, and nongeneralizable way with one another." [ 5 ]

Currently meta-narrative review is based on six guiding principles [ 6 ]:

Principle of pragmatism: what to include is not self-evident. The reviewer must be guided by what will be most useful to the intended audience(s), for example, what is likely to promote sense making;

Principle of pluralism: the topic should be illuminated from multiple angles and perspectives, using the established quality criteria appropriate to each. For example, reviewers should avoid beginning with a single 'preferred' perspective or methodological hierarchy and proceed to judge work in other traditions using these external benchmarks. Research that lacks rigor must be rejected, but the grounds for rejection should be intrinsic to the relevant tradition, not imposed on it;

Principle of historicity: research traditions are often best described as they unfolded over time, highlighting significant individual scientists, events and discoveries which shaped the tradition;

Principle of contestation: 'conflicting data' from different research traditions should be examined to generate higher-order insights (for example, about how different research teams framed the issue differently or made different assumptions about the nature of reality);

Principle of reflexivity: throughout the review, reviewers must continually reflect, individually and as a team, on the emerging findings;

Principle of peer review: emerging findings should ideally be presented to an external audience and their feedback used to guide further reflection and analysis.

The published literature on meta-narrative review indicates that some review teams have deliberately adapted the method as first described by Greenhalgh et al. [ 6 ].

While evolution and/or adaptation of the method is to be welcomed in principle, the description and rationale for any adaptations made should be provided to allow readers to judge their appropriateness.

Item 8: Scoping the literature

Describe and justify the initial process of exploratory scoping of the literature.

...."we undertook an initial 'territory mapping' exercise. We each explored a different area of possibly relevant research using informal and unstructured methods. We asked colleagues, sent emails to academic lists, browsed libraries and the Internet, and built on our own prior knowledge. One of us began, for example, with the literature on evidence-based medicine (EBM) and guideline implementation (Reference x1), which led serendipitously to another literature on health promotion campaigns (Reference x1) (the spread of 'innovative messages' about healthy lifestyles). One of us was directed by a colleague towards work on technology transfer to developing countries (Reference x1), and discovered a huge 'grey literature' in the databases of international development agencies. Another had previously completed a PhD that involved exploring social network theory in relation to the spread of medical technologies (Reference x1). By exploring all these (and more) avenues, we gained a feel of the overall literature." [ 6 ]

One of the main challenges in meta-narrative review is to identify a sufficiently broad range of sources so as to be able to build as comprehensive a map as possible of research undertaken on the topic. This scoping step is used to identify in broad terms the different research traditions, situated in different literatures, which have addressed the topic of interest. Initial attempts to make sense of a topic area may involve not just informal 'browsing' of the literature but also consulting with experts and stakeholders.

Item 9: Searching process

While considering specific requirements of the journal or other publication outlet, state and provide a rationale for how the iterative searching was done. Provide details on all the sources accessed for information in the review. For example, where electronic databases have been searched, details should include, for example, names of databases, search terms, dates of coverage, and dates last searched. If individuals familiar with the relevant literature and/or topic area were contacted, indicate how they were identified and selected.

"Inspired in a large part by the work of Greenhalgh and colleagues (Reference x2), we relied instead on a non-keyword-based reviewing process that we dubbed double-sided systematic snowball .

Our goal was to identify documents that made a core contribution, either conceptually or empirically, to the understanding of the phenomenon. Our starting point was to identify, through team consensus, some seminal papers ( n = 33) that were considered to have shaped the evolution of the field. We started by identifying a heuristic list of seven "traditions":....

Each tradition was exemplified by one or more publications. The definition of "traditions" and the identification of specific publications were interdependent processes conducted on a consensus basis. At the end of the process, we had produced a list of thirty-three "seminal" sources (see the appendix). ....

We then used the ISI Web of Science Citation Index to identify all documents (n = 4,201) that cited those seminal papers. The snowball process here was prospective, since it exclusively targeted documents published after the selected seminal paper. We then triaged the results using the titles and (if present) the abstracts, using a decision grid based on the definition of the phenomenon under review, as discussed in the previous section. ....

Next we used the bibliographies of those 102 documents as a basis for retrospective systematic snowball sampling. We entered each document's complete bibliography in a database ( n = 5,622) and used algorithms to identify all articles cited five times or more and all books cited seven times or more. ....

Among the articles, we excluded fourteen based on relevance criteria and twelve that were already among the 102 identified in the first step. Finally, we included forty-nine other documents either through deliberate selection during the first step of analysis because of their empirical or conceptual contribution, or through nonsystematic sampling of the field." [ 20 ]

Searching should be guided by the objectives and focus of the review, and revised iteratively in the light of emerging data. By definition, a meta-narrative review seeks to identify and combine different research traditions, hence different search strategies will need to be developed as appropriate to the different literatures. This stage is likely to involve searching for different kinds of data in different ways.

Search methods using forward and backward citation tracking may be particularly valuable in finding key documents. In particular, potential seminal sources (conceptual, theoretical or empirical studies, which have defined the tradition and inspired later work) may be identified from judicious searching of the reference lists of later studies. Once identified, seminal sources should be citation-tracked to identify further sources which drew on these.

Meta-narrative reviews do not approach the literature with a pre-defined 'preferred' study design. Rather, any preferred study design(s) should be identified from quality standards developed within a particular research tradition. 'Methodological filters' (for example, to identify randomized controlled trials) should be used only when these have been designated as a quality feature by the scientists within that tradition.

Searching is necessarily iterative, since the reviewer must move between the seminal source(s) and papers which subsequently cited that source, so as to build a picture of how research unfolded in each tradition. The process used for any such additional searches should be clearly documented. A single pre-defined search is unlikely to be sufficient and may suggest insufficient reflection on emerging findings.

Sufficient detail should be given to enable the reader to judge whether searching was likely to have located sources needed for elucidating all the key research traditions.

Item 10: Selection and appraisal of documents

Explain how judgements were made about including and excluding data from documents, and justify these.

"Abstracts had to mention, in some capacity, differences in health outcomes or well-being, and/or the SDOH [social determinants of health]. Abstracts that discussed policy implications were also of distinct interest for review, but this was not an explicit inclusion criterion. Abstracts that described health differences in a strictly clinical scope were excluded, as were abstracts that referred to inequalities or disparities in a different context (e.g., measurement disparities). Highly technical pieces that discussed new clinical technologies, or issues related to healthcare systems and/or delivery, were excluded. Abstracts were also excluded if they contained the words "National Population Health Survey" or "Ottawa Charter for Health Promotion", but lacked any other information relevant to the review." [ 19 ]

Meta-narrative review is not a technical process - that is, following a set protocol will not guarantee that a review will be robust. Rather, it is a process of sense-making of the literature, selecting and combining data from primary sources to produce an account of how a research tradition unfolded and why, and then (in a second phase) comparing and contrasting findings from these different traditions to build a rich picture of the topic area from multiple angles. This process requires a series of judgements about the unfolding of research in particular traditions, and about the relevance and robustness of particular data within that tradition.

Meta-narrative review takes its quality criteria from the traditions included in the review, and in particular from seminal papers which have been accepted by others within that tradition as authoritative. A meta-narrative review might, for example, include a meta-narrative from clinical epidemiology in which randomized controlled trials and meta-analyses of these are greatly valued; it might also include a meta-narrative from critical sociology in which theory-driven qualitative studies are greatly valued. Studies in these separate traditions should be appraised using the quality criteria that a competent peer-reviewer in that tradition would choose to use.

The description of the selection and appraisal process should be sufficiently detailed to enable a reader to judge how likely it is that researchers inadvertently excluded data that may have significantly altered the findings of the review.

Item 11: Data extraction

Describe and explain which data or information were extracted from the included documents and justify this selection.

"Bibliographic characteristics of interest were body of literature .... from which the abstract was retrieved; journal name; publication year; geographical region of focus (or origin); type of study described in the abstract; and population investigated by the study or target audience. Abstract contents were captured using two variables: article themes and SDOH [social determinants of health] profile. Article theme codes were developed through an inductive process of immersion with the article abstracts and saturation of article themes; codes were based not on any one particular keyword or phrase in the abstracts, but on the content area as conveyed by the abstract as a whole." [ 19 ]

The type of data collected in meta-narrative review can be very diverse. The analysis and synthesis phases are influenced by the amount and type of data extracted. Reporting on what was extracted and why can add to the transparency of the review process.

In a meta-narrative review the data elements extracted would go to constructing a story of how research on a topic unfolded over time in a particular tradition. This may include (where relevant), for example:

upstream (antecedent) traditions from which these emerged; background philosophical assumptions;

research questions and how they were framed; conceptual and theoretical issues;

preferred methodologies, study designs and quality criteria;

key actors (for example, leading scientists or commentators) and events (for example, conferences) in the unfolding of the tradition;

landmark empirical or theoretical studies;

significant findings and how these shaped subsequent work; and

key debates and areas of dispute within the tradition, including links with or breaches from other traditions.

Meta-narrative review is used for a wide range of research questions, so it is impossible to be prescriptive about which data should be extracted. However, the link between the research question and the type of data extracted should be clear.

Item 12: Analysis and synthesis processes

Describe the analysis and synthesis processes in detail. This section should include information on the process by which the account of each meta-narrative (that is, the story of each unfolding research tradition) was built up and how the separate meta-narratives were compared and contrasted. Document and justify any changes in this process as the study unfolded.

"We mapped the meta-narratives (i.e., we traced the historical development of concepts, theory, and methods in each research tradition) by identifying the seminal theoretical and overview papers and books and analyzing the conceptual and theoretical models proposed by recognized experts in each field. ....

Because different researchers in different traditions generally conceptualized their topic differently; used different language and metaphors for diffusion, dissemination, and implementation; asked different questions; privileged different methods; and used different criteria to judge "quality" and "success," we used narrative, rather than statistical, synthesis techniques. ....

We highlighted the similarities and differences of the findings from different research traditions and considered the reasons for the differences. In this way, the heterogeneity of approaches and "contradictions" in findings could be turned into data and analyzed systematically." [ 5 ]

If exploration of a range of research traditions on the topic is not deemed to be appropriate, the work is probably not a meta-narrative review.

A meta-narrative review should include two specific stages, though these will usually overlap as they will necessarily influence one another iteratively.

In the analysis stage, reviewers should seek to identify and map out specific meta-narratives (that is, unfolding stories of research traditions over time), focusing in particular on the concepts, theories, methods and instruments which have characterized the tradition, major findings in that tradition and foci of dissent and disagreement.

The process of building this unfolding storyline is essentially interpretive and, hence, follows the principles of interpretivist analysis, including immersion in the data by repeated reading and/or analysis of quantitative data; reflexivity and discussion among researchers; consideration of how each new data item fits with an emerging picture of the whole; and checking where appropriate that the account is considered valid by experts within the designated research tradition. Both quantitative and qualitative traditions and data may need to be incorporated in the storyline. Explanation and justification for any analytic methods used to combine and summarize data within a particular tradition should be provided.

The synthesis stage involves comparing and contrasting the meta-narratives so as to identify and compare how the different groups have conceptualized the topic (including differences in philosophical position), how they have theorized it, and the methodological approaches and study designs used. Differences in findings between meta-narratives are higher-order data and should be analyzed interpretively to produce further insights (for example, about differences in underlying assumptions or methodological approaches between different research traditions).

Synthesis across traditions may occur at a high level of abstraction (that is, at the level of concepts and theories) and may involve one or more of the following:

paradigm bridging (seeking commonalities in underlying conceptual and theoretical assumptions),

paradigm bracketing (highlighting differences in these assumptions),

interplay (exploring tensions);

meta-theorizing (exploring patterns that span conflicting understandings)

Synthesis may also occur at a more concrete level and summarize empirical findings, using techniques including statistical aggregation, qualitative aggregation and narrative summary.

A description should be provided of how the all the individuals involved in the review have been involved in the analysis and synthesis processes, and input (if any) from external advisors/peer reviewers from included traditions.

Results section

The following items should be reported in the Results section.

Item 13: Document flow diagram

Provide details on the number of documents assessed for eligibility and included in the review with reasons for exclusion at each stage as well as an indication of their source of origin (for example, from searching databases, reference lists and so on). You may consider using the example provided (which is likely to need modification to suit the data) in Figure 1 .

Flow chart of search from Greenhalgh et al . [ 5 ].

"The breakdown of sources that contributed to the final report is shown in Figure 1 ." [ 5 ]

A flow diagram provides an accessible summary of the sequence of steps and gives an indication of the volume of data included and excluded at each step.

Item 14: Document characteristics

Provide information on the characteristics of the documents included in the review.

"The 94 primary studies (described in 129 papers) outside the health informatics literature were philosophically pluralist, with 14% positivist, 19% interpretivist, 22% critical and 55% recursive. As Table 3 shows, they also were methodologically diverse, most with different types of case studies." [ 17 ]

A clear summary of the characteristics of included sources can add to the transparency of the review and some characteristics may help readers judge the coherence and plausibility of inferences. Examples of possibly relevant characteristics of documents that may be worth reporting include, where applicable: full citation, country of origin, study design, summary of key main findings, use made of documents in the review and relationship of documents to each other (for example, there may be more than one document reporting on an intervention). While considering the specific requirements of any particular publication, reviewers may wish to tabulate key characteristics.

Item 15: Main findings

Present the key findings with a specific focus on the key meta-narratives that have a bearing on the topic area, and the commonalities and differences between them.

"Exploratory searches suggested that approaches could be divided into two broad schools ('objective' and 'subjective'). In reality there is much overlap between them for example, many 'objective' numerical scales are designed to capture and quantify respondents' subjective perceptions. The objective school defines research rigour in positivistic terms (accuracy, precision, reproducibility, inter-rater reliability and distancing from the data) while the subjective school defines rigour in interpretivist terms (strength of underpinning theory, coherence of concepts and explanations, reflexivity and immersion in the data).

The objective school .... is oriented to producing verifiable and reproducible facts (such as scores, estimates of frequencies or lists of commonly occurring themes). ....

The subjective school, oriented to generating interpretations rather than facts, includes psychodynamic analysis (e.g. Balint method), narrative analysis, critical consultation analysis and socio-technical analysis." [ 18 ]

The defining feature of a meta-narrative review is illumination of a complex topic area from multiple angles. In general, this will be achieved by first presenting each meta-narrative as a coherent individual account which conveys the underpinning 'normal science' of the relevant research tradition (concepts, theories, preferred methods) and the key empirical findings in that tradition. Findings and inferences from the synthesis across the different meta-narratives may then be presented as an over-arching narrative which retains the integrity of the separate research traditions but draws out what might be learned from the commonalities and differences between them.

The outputs of paradigm bridging, paradigm bracketing, interplay and meta-theorizing should be presented as appropriate to summarize the conceptual and theoretical basis of the meta-narratives. The outputs of statistical aggregation, qualitative aggregation and narrative summary of disaggregated data should be presented as appropriate to summarize the empirical findings. In each case, data from the primary documents should be presented and sourced to illustrate how inferences have been made and justify these. The more detail that is given, the more readers will be able to judge the validity of the inferences.

Discussion section

The following Items should be reported in the discussion section.

Item 16: Summary of findings

Summarize the main findings, taking into account the review's objective(s), research question(s), focus and intended audience(s).

"The UK NPfIT [National Programme for Information Technology] appeared to be built on six assumptions, that the EPR [Electronic Patient Record] (1) is primarily a container for information about the patient; (2) can be integrated seamlessly and unproblematically into clinical work; (3) will increase the effectiveness and efficiency of clinical work; (4) will drive changes in how staff interact with the patient and one another; (5) should replace most, if not all, forms of paper record, which are old-fashioned and limited; and (6) the more comprehensive and widely distributed it is, the more value it will add.

.... Much of the literature covered in this review suggests, conversely, that (1) the EPR may be alternatively conceptualized as an "itinerary," "organizer," or "actor"; (2) seamless integration of different EPR systems is unlikely because human work will always be needed to bridge the model-reality gap and recontextualize knowledge for different uses; (3) while secondary work (audit, research, billing) may be made more efficient by the EPR, primary clinical work is often made less efficient; (4) the EPR may support, but will not drive, changes in the social order of the workplace; (5) paper will not necessarily disappear, as it offers a unique level of ecological flexibility (although workable paperless systems have been developed in one or two centers); and (6) smaller, more local EPR systems may often (though perhaps not always) be more efficient and effective than larger ones." [ 17 ]

In order to place the findings in the context of the wider literature and any specific policy need, it is necessary to summarize briefly what has been found. This section should be succinct and balanced, highlighting the key meta-narratives that emerged from the analysis and the key points of commonality and contestation between them. This should be done with careful attention to the needs of the main users of the review.

Item 17: Strengths, limitations and future research directions

Discuss both the strengths of the review and its limitations. These should include (but need not be restricted to) (a) consideration of all the steps in the review process and (b comment on the overall strength of evidence supporting the explanatory insights that emerged.

The limitations identified may point to areas where further work is needed.

"The most important limitation of our study is in attempting to make generalizations about the applicability of potential municipal government interventions across diverse governmental forms and functions, and geographical jurisdictions. ....

Another limitation of this study was in restricting our analysis to the four bodies of literature chosen. As discussed, our decision not to include the policy sciences and social epidemiology, for instance, may have led our findings to under-represent dimensions of the health inequities knowledge base that focus on broader social welfare policies or more technically-oriented epidemiological studies documenting the scope of health inequities at the local level." [ 19 ]

Meta-narrative reviews may be constrained by time and resources, by the skill mix and collective experience of the research team, by the scope of the review's questions or objectives and/or by anticipated or unanticipated challenges in the data. These should be made explicit so that readers can interpret the findings in light of them. A common challenge in meta-narrative reviews is that in order to focus the review, some material is omitted at each successive stage. Some aspects of the topic area, therefore, end up being reviewed in detail and rich explanatory insights produced for these. Other aspects are neglected (relatively or absolutely). It is thus inevitable that in generating illumination, the review will also cast shadows. These should be highlighted in the discussion so as to indicate areas where other reviews might focus.

Strengths and/or limitations associated with any modifications made to the review process should also be reported and justified.

Item 18: Comparison with existing literature

Where applicable, compare and contrast the review's findings with the existing literature (for example, other reviews) on the same topic.

"Our review affirmed many well-described themes in the literature, such as the useful list of innovation attributes that predict (but do not guarantee) successful adoption; the importance of social influence and the networks through which it operates; the complex and contingent nature of the adoption process; the characteristics (both "hard" and "soft") of organizations that encourage and inhibit innovation; and the messy, stop-start, and difficult-to-research process of assimilation and routinization. We also exposed some demons in this literature, such as the lack of empirical evidence for the widely cited "adopter traits"; the focus on innovations that arise centrally and are disseminated through official channels at the expense of those that arise peripherally and spread informally; the limited generalizability of the empirical work on product-based innovation in companies to process innovation in service organizations; and the near absence of studies focusing primarily on the sustainability of complex service innovations." [ 5 ]

A meta-narrative review will typically cover a broad and diverse literature. In particular, it is likely to have uncovered findings from outside the healthcare literature (for example, sociology, cognitive or social psychology, economics, education) that may supplement and extend (and in some cases challenge) the findings of previous, more narrowly focused, systematic reviews on the topic. In general, meta-narrative reviews should make explicit where and how the review extends the knowledge base.

Item 19: Conclusion and recommendations

List the main implications of the findings and place these in the context of other relevant literature. If appropriate, offer recommendations for policy and practice.

"Overall, the health inequities knowledge base offered insufficient guidance to municipal governments in developing healthy public policy at the local level. Health was conceptualized in primarily 'behavioural' and 'biomedical' terms, providing little incentive for municipalities to consider, and act on, the full range of the SDOHs [social determinants of health]. If researchers, who have at their disposal voluminous evidence on the social determinants of health inequities, overwhelmingly defer to healthy lifestyles and healthcare services as the levers for improving health, then how can busy, and often uninformed, policy-makers be expected to conceptualize health any differently? The minimal attention paid to municipal governments in the health inequities knowledge base urges critical reflection on the subject areas and types of health research that funding agencies privilege, and highlights the need for increased funding and translation of interdisciplinary health inequities research that is relevant to policy-makers, especially at the municipal level where human resources devoted to exchange with research communities are in short supply." [ 19 ]

A clear line of reasoning is needed to link the findings (results section) with the implications (discussion and/or conclusion). If the review is small and preliminary, or if the coherence and plausibility of evidence behind the inferences is weak or moderate, statements about implications for practice and policy should be appropriately guarded.

Item 20: Funding

Provide details of funding source (if any) for the review, the role played by the funder (if any) and any conflicts of interests of the reviewers.

"This review had multiple funding streams, including the National Institute for Health Research Service Delivery and Organisation Programme (project numbers 08/1602/131 and 08/TA252), the Medical Research Council (project number 07/133), and the UK Department of Health via the Connecting for Health Evaluation Programme (project numbers CFHEP 002 and 007)." [ 17 ]

The source of funding for a review and/or personal conflicts of interests may influence the research question, methods, data analysis and conclusions. No review is a 'view from nowhere', and readers will be better able to interpret the review if they know why it was done and for which sponsor.

If a review is published, the process for reporting funding and conflicts of interest as set out by the publication concerned should be followed.

We have developed these publication standards for meta-narrative review (which we view as synonymous with meta-narrative synthesis) by drawing together a range of sources - namely existing published evidence, a Delphi panel and comment, discussion and feedback from a mailing list, training sessions and workshops. We hope these standards will lead to greater consistency and rigor of reporting and, thereby, make the outputs of meta-narrative reviews more accessible, usable and helpful to different stakeholders.

This publication standard is not a detailed guide of how to undertake a meta-narrative review. Other resources, both published (see Introduction) and in preparation, are better suited for this purpose. These standards have been developed as a guide to assist the quality of reporting of meta-narrative reviews and the work of publishers, editors and reviewers. As part of the RAMESES project, we will be developing and disseminating both training materials and quality standards for meta-narrative reviews [ 14 ].

Because meta-narrative review is used for a broad range of topics and questions, and because it involves making judgements and inferences rather then checking against or following a technical checklist, it is impossible to be prescriptive about what exactly must be done in a review. The guiding principle is that transparency is important, as this will help readers to decide for themselves if the arguments for the judgements made were reasonable, both for the chosen topic and from a methodological perspective. While we have encouraged review authors to provide detail on what they have done and how, we emphasize that these standards are intended to supplement rather than replace the exercise of judgement by editors, reviewers, readers and users of meta-narrative reviews. We have tried to indicate in each item where judgement needs to be exercised.

The sense-making focus of meta-narrative reviews means that detailed data may need to be reported in order to provide enough support for inferences and/or judgments made. While developing these publication standards, it became apparent that in some cases the word count limitations imposed by journals did not enable review teams to fully explain aspects of their review - such as how judgments were made or inferences arrived at. Alternative ways of providing the necessary detail may need to be found, such as online appendices or additional files available from authors on request.

Previous efforts to develop publication standards have sometimes been criticized for being too 'ivory-tower' and failing to take account of real-world problems faced by reviewers. In an effort to redress this problem in the RAMESES project, we sought from the outset to engage not just senior academics but also junior and mid-career researchers, practitioners, policymakers and publishers in the development of the standards and to capture real-life challenges of ongoing meta-narrative reviews as these emerged.

Conclusions

We have developed these publication standards for meta-narrative review by drawing on a range of sources. Our hope is that these standards will lead to greater consistency and rigor of reporting and make the outputs of meta-narrative reviews more accessible, usable and helpful to different stakeholders. Meta-narrative review is a relatively new approach to evidence synthesis and with increasing use and methodological development, changes are likely to be needed to any publication standards. We hope to continue capturing and improving these publication standards, through our email list [ 15 ] and wider links and discussions with researchers and those who commission, sponsor, publish and use meta-narrative reviews.

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Pre-publication history

The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1741-7015/11/20/prepub

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Acknowledgements

This project was funded by the National Institute for Health Research Health Services and Delivery Research Programme (NIHR HS&DR) - project number 10/1008/07.

We thank the following individuals for their participation in the RAMESES Group and contributions to the Delphi panel:

Dave Baker, Sinai Hospital of Baltimore (Baltimore, USA); Marcello Bertotti, University of East London (London, UK); Allan Best, InSource (Vancouver, Canada); Margaret Cargo, University of South Australia (Adelaide, Australia); Simon Carroll, University of Victoria (Victoria, Canada); Colleen Davison, Queens University, (Kingston, Canada); Marjolein Dieleman, Royal Tropical Institute (Amsterdam, Netherlands); Tim Dornan, Maastricht University (Maastricht, Netherlands); Ruth Garside, Peninsula College of Medicine and Dentistry (Exeter, UK); Bradford Gray, Milbank Quarterly (New York, USA); Joanne Greenhalgh, University of Leeds (Leeds, UK); Lois Jackson, Dalhousie University (Halifax, Canada); Justin Jagosh, McGill University (Montreal, Canada); Monika Kastner, University of Toronto (Toronto, Canada); James Lamerton, Sunshine Coast Division of General Practice (Cotton Tree, Australia); Fraser MacFarlane, Queen Mary, University of London (London, UK); Bruno Marchal, Institute of Tropical Medicine (Antwerp, Belgium); Tracey McConnell, Queen's University (Belfast, UK); Gemma Moss, Institute of Education (London, UK); Douglas Noble, Queen Mary, University of London (London, UK); Patricia O'Campo, University of Toronto (Toronto, Canada); Mark Pearson, Peninsula College of Medicine and Dentistry (Exeter, UK); Pierre Pluye McGill University (Montreal, Canada); Henry Potts, University College London (London, UK); Barbara Riley, University of Waterloo, (Waterloo, Canada); Glenn Robert, Kings College London (London, UK); Jessie Saul, North American Research & Analysis, Inc (Faribault, USA); Paul Shekelle, RAND Corporation (Santa Monica, USA); Neale Smith, University of British Columbia (Vancouver, Canada); Sanjeev Sridharan, University of Toronto (Toronto, Canada); Deborah Swinglehurst, Queen Mary, University of London (London, UK); Nick Tilley, University College London (London, UK); Kieran Walshe, University of Manchester (Manchester, UK).

All the authors (except JB) were also members of the Delphi panel.

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GWo carried out the literature review. JB searched the literature for meta-narrative reviews. GWo, TG, GWe and RP analyzed the findings from the review and produced the materials for the Delphi panel. They also analyzed the results of the Delphi panel. GWo, TG, GWe and RP conceived of the study, and participated in its design. GWo coordinated the study and ran the Delphi panel. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HS&DR program, NIHR, NHS or the Department of Health.

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Additional file 1: A Comparison between meta-triangulation and meta-narrative review. This table compares the differences between meta-triangulation and meta-narrative review along nine dimensions. (DOC 40 KB)

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Wong, G., Greenhalgh, T., Westhorp, G. et al. RAMESES publication standards: meta-narrative reviews. BMC Med 11 , 20 (2013). https://doi.org/10.1186/1741-7015-11-20

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A systematic literature review of the clinical and socioeconomic burden of bronchiectasis

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Background The overall burden of bronchiectasis on patients and healthcare systems has not been comprehensively described. Here, we present the findings of a systematic literature review that assessed the clinical and socioeconomic burden of bronchiectasis with subanalyses by aetiology (PROSPERO registration: CRD42023404162).

Methods Embase, MEDLINE and the Cochrane Library were searched for publications relating to bronchiectasis disease burden (December 2017–December 2022). Journal articles and congress abstracts reporting on observational studies, randomised controlled trials and registry studies were included. Editorials, narrative reviews and systematic literature reviews were included to identify primary studies. PRISMA guidelines were followed.

Results 1585 unique publications were identified, of which 587 full texts were screened and 149 were included. A further 189 citations were included from reference lists of editorials and reviews, resulting in 338 total publications. Commonly reported symptoms and complications included dyspnoea, cough, wheezing, sputum production, haemoptysis and exacerbations. Disease severity across several indices and increased mortality compared with the general population was reported. Bronchiectasis impacted quality of life across several patient-reported outcomes, with patients experiencing fatigue, anxiety and depression. Healthcare resource utilisation was considerable and substantial medical costs related to hospitalisations, treatments and emergency department and outpatient visits were accrued. Indirect costs included sick pay and lost income.

Conclusions Bronchiectasis causes significant clinical and socioeconomic burden. Disease-modifying therapies that reduce symptoms, improve quality of life and reduce both healthcare resource utilisation and overall costs are needed. Further systematic analyses of specific aetiologies and paediatric disease may provide more insight into unmet therapeutic needs.

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Bronchiectasis imposes a significant clinical and socioeconomic burden on patients, their families and employers, and on healthcare systems. Therapies that reduce symptoms, improve quality of life and reduce resource use and overall costs are needed. https://bit.ly/4bPCHlp

Introduction

Bronchiectasis is a heterogeneous chronic respiratory disease clinically characterised by chronic cough, excessive sputum production and recurrent pulmonary exacerbations [ 1 ], and radiologically characterised by the abnormal widening of the bronchi [ 2 ]. Bronchiectasis is associated with several genetic, autoimmune, airway and infectious disorders [ 3 ]. Regardless of the underlying cause, the defining features of bronchiectasis are chronic airway inflammation and infection, regionally impaired mucociliary clearance, mucus hypersecretion and mucus obstruction, as well as progressive structural lung damage [ 4 , 5 ]. These features perpetuate one another in a “vicious vortex” leading to a decline in lung function, pulmonary exacerbations and associated morbidity, mortality and worsened quality of life [ 4 , 5 ]. Bronchiectasis can be further categorised into several infective and inflammatory endotypes and is associated with multiple comorbidities and underlying aetiologies [ 6 ].

Bronchiectasis has been described as an emerging global epidemic [ 7 ], with prevalence and incidence rates increasing worldwide [ 8 – 12 ]. The prevalence of bronchiectasis, as well as of the individual aetiologies, varies widely across geographic regions [ 13 ]. In Europe, the reported prevalence ranges from 39.1 (females) and 33.3 (males) cases per 100 000 inhabitants in Spain and 68 (females) and 65 (males) cases per 100 000 inhabitants in Germany, to as high as 566 cases (females) and 486 cases (males) per 100 000 inhabitants in the UK [ 10 – 12 ]. In the US, the average overall prevalence was reported to be 139 cases per 100 000 [ 14 ], in Israel, the prevalence was reported to be 234 cases per 100 000 [ 15 ], and in China the prevalence was reported to be 174 per 100 000 [ 8 ]. Studies show that bronchiectasis prevalence increases with age [ 14 ]. This may increase the socioeconomic impact of bronchiectasis on countries with disproportionately higher number of older citizens. Large registry studies in patients with bronchiectasis have been published from the US (Bronchiectasis Research Registry) [ 16 ], Europe and Israel (European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC)); the largest and most comprehensive report available to date) [ 17 ], India (EMBARC-India) [ 18 , 19 ], Korea (Korean Multicentre Bronchiectasis Audit and Research Collaboration) [ 20 ] and Australia (Australian Bronchiectasis Registry) [ 21 ].

Although there are currently no approved disease-modifying therapies for bronchiectasis [ 4 ], comprehensive clinical care recommendations for the management of patients with bronchiectasis have been published [ 22 , 23 ]. However, the burden that bronchiectasis imposes on patients and their families, as well as on healthcare systems, payers and employers, remains poorly understood. No review to date has used a systematic method to evaluate the overall disease burden of bronchiectasis. This is the first systematic literature review aimed at investigating and synthesising the clinical and socioeconomic burden of bronchiectasis. A better understanding of the overarching burden of bronchiectasis, both overall and by individual aetiologies and associated diseases, will highlight the need for new therapies and assist healthcare systems in planning care and required resources.

The protocol of this systematic review was registered on PROSPERO (reference number: CRD42023404162).

Search strategy

This systematic literature review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [ 24 ]. Embase, MEDLINE and the Cochrane Library were searched for studies related to the clinical and socioeconomic burden of bronchiectasis (noncystic fibrosis bronchiectasis (NCFBE) and cystic fibrosis bronchiectasis (CFBE)) using the search terms available in supplementary table S1 . Articles written in English and published over a 5-year period (December 2017–December 2022) were included.

Selection criteria

The following article types reporting on prospective and retrospective observational studies, registry studies and randomised controlled trials (only baseline data extracted) were included: journal articles, preprints, research letters, conference proceedings, conference papers, conference abstracts, meeting abstracts and meeting posters. Reviews, literature reviews, systematic reviews and meta-analyses, as well as editorials, commentaries, letters and letters to the editor, were included for the purpose of identifying primary studies. A manual search of references cited in selected articles was performed and references were only included if they were published within the 5 years prior to the primary article being published.

Screening and data extraction

A reviewer screened all titles and abstracts to identify publications for full-text review. These publications then underwent full-text screening by the same reviewer for potential inclusion. A second reviewer independently verified the results of both the title/abstract screen and the full-text screen. Any discrepancies were resolved by a third independent reviewer. Data relating to aetiology, symptoms, disease severity, exacerbations, lung function, infection, comorbidities, patient-reported outcomes (PROs), exercise capacity, mortality, impact on family and caregivers, healthcare resource utilisation (HCRU), treatment burden, medical costs, and indirect impacts and costs, as well as data relating to the patient population, study design, sample size and country/countries of origin, were extracted from the final set of publications into a standardised Excel spreadsheet by one reviewer. Studies were grouped based on the burden measure, and aggregate data (range of reported values) were summarised in table or figure format. For the economic burden section, costs extracted from studies reporting in currencies other than the euros were converted to euros based on the average exchange rate for the year in which the study was conducted.

Data from patients with specific bronchiectasis aetiologies and in children (age limits varied from study to study and included upper age limits of 15, 18, 19 and 20 years) were reported separately, where available. As literature relating to NCFBE and CFBE is generally distinct, any data related to CFBE are reported separately in the tables and text. We conducted subanalyses of key disease burden indicators, in which we extracted data from multicentre studies or those with a sample size >1000 subjects, to try to identify estimates from the most representative datasets. These data from larger and multicentre studies are reported in square brackets in tables 1 – 3 and supplementary tables S2–S7 , where available.

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Prevalence and severity of bronchiectasis symptoms overall, in children, during exacerbations and in individual bronchiectasis aetiologies

Patient-reported outcome scores in patients with bronchiectasis overall and in individual bronchiectasis aetiologies

Healthcare resource utilisation (HCRU) in patients with bronchiectasis overall and in individual bronchiectasis aetiologies

Given the nature of the data included in this systematic literature review (that is, a broad range of patient clinical and socioeconomic characteristics rather than the outcome(s) of an intervention), in addition to the broad range of study types included, meta-analyses to statistically combine data of similar studies were not deemed appropriate and therefore not performed.

Summary of included studies

A total of 1834 citations were retrieved from the Embase, MEDLINE and Cochrane Library databases, of which 1585 unique citations were identified. Abstract/title screening led to the inclusion of 587 citations for full-text screening. Following full-text screening, 149 primary citations and 110 literature reviews, systematic reviews and meta-analyses as well as editorials and letters to the editor remained. From the reference lists of these 110 citations, a further 189 primary citations were identified. These articles were only included if 1) the primary articles contained data relating to the burden of bronchiectasis and 2) the primary articles were published within the 5 years prior to the original article's publication date. In total, 338 publications were considered eligible and included in this review ( supplementary figure S1 ). This included 279 journal articles, 46 congress abstracts and 13 letters to the editor or scientific/research letters. The results are summarised in the sections below. For the results from individual studies, including a description of the patient population, study design, sample size and country/countries of origin, please see the supplemental Excel file .

The most frequently reported aetiologies included post-infectious, genetic (primary ciliary dyskinesia (PCD), alpha-1 antitrypsin deficiency (AATD) and cystic fibrosis (CF)), airway diseases (COPD and asthma), allergic bronchopulmonary aspergillosis (ABPA), aspiration and reflux-related, immunodeficiency and autoimmune aetiologies ( supplementary figure S2 ). However, in up to 80.7% of adult cases and 53.3% of paediatric cases, the aetiology was not determined (referred to as “idiopathic bronchiectasis”) ( supplementary figure S2 ). When limited to larger or multicentre studies, the frequency of idiopathic bronchiectasis ranged from 11.5 to 66.0% in adults and from 16.5 to 29.4% in children. Further details and additional aetiologies can be seen in the supplemental Excel file .

Clinical burden

Symptom burden and severity.

Commonly reported symptoms in patients with bronchiectasis included cough, sputum production, dyspnoea, wheezing and haemoptysis, with these symptoms more prevalent in adults compared with children ( table 1 ). Other reported symptoms included chest discomfort, pain or tightness (both generally and during an exacerbation), fever and weight loss in both adults and children, and fatigue, tiredness or asthenia, appetite loss, and sweating in adults. In children, respiratory distress, hypoxia during an exacerbation, sneezing, nasal and ear discharge, thriving poorly including poor growth and weight loss, exercise intolerance, malaise, night sweats, abdominal pain, recurrent vomiting, and diarrhoea were reported ( supplemental Excel file ). Classic bronchiectasis symptoms such as sputum production (range of patients reporting sputum production across all studies: 22.0–92.7%) and cough (range of patients reporting cough across all studies: 24.0–98.5%) were not universally reported ( table 1 ).

In a study comparing bronchiectasis (excluding CFBE) in different age groups (younger adults (18–65 years), older adults (66–75 years) and elderly adults (≥76 years) [ 63 ]), no significant differences across age groups were reported for the presence of cough (younger adults: 73.9%; older adults: 72.8%; elderly adults: 72.9%; p=0.90), sputum production (younger adults: 57.8%; older adults: 63.8%; elderly adults: 6.0%; p=0.16) or haemoptysis (younger adults: 16.5%; older adults: 19.3%; elderly adults: 16.3%; p=0.47).

Disease severity

Disease severity was reported according to several measures including the bronchiectasis severity index (BSI), the forced expiratory volume in 1 s (FEV 1 ), Age, Chronic Colonisation, Extension, Dyspnoea (FACED) score and the Exacerbations-FACED (E-FACED) score, all of which are known to be associated with future exacerbations, hospitalisations and mortality ( supplementary table S2 and the supplemental Excel file ). Up to 78.7, 41.8 and 40.8% of patients with bronchiectasis reported severe disease according to the BSI, FACED score and E-FACED score, respectively ( supplementary table S2 ). In most studies, severity scores were greater among people with bronchiectasis secondary to COPD or post-tuberculosis (TB) than idiopathic bronchiectasis ( supplementary table S2 ). No data relating to disease severity were reported for CFBE specifically.

Exacerbations

The number of exacerbations experienced by patients with bronchiectasis in the previous year, per year and during follow-up are presented in figure 1 . For further details, please see the supplemental Excel file . Two studies reported exacerbation length in patients with bronchiectasis; this ranged from 11 to 16 days (both small studies; sample sizes of 191 and 32, respectively) [ 25 , 64 ]. A study in children with NCFBE reported a median of one exacerbation in the previous year. Additionally, the same study reported that 31.1% of children with bronchiectasis experienced ≥3 exacerbations per year [ 65 ].

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Range of bronchiectasis exacerbations in the previous year, per year and in the first and second years of follow-up. # : Two studies reported significant differences in the number of exacerbations experienced in the previous year across individual aetiologies. Study 1 [ 90 ]: Patients with idiopathic bronchiectasis had significantly fewer exacerbations in the previous year compared with other aetiologies (primary ciliary dyskinesia (PCD), COPD and post-infectious) (p<0.021). Study 2 [ 33 ]: significant difference between post-tuberculosis (TB) bronchiectasis (mean: 2.8) and other aetiologies excluding idiopathic bronchiectasis (mean: 1.7) (p<0.05).

Lung function

Reduced lung function was reported across several different measures in adults and children with bronchiectasis overall, including FEV 1 (absolute values and % predicted), forced vital capacity (FVC; absolute values and % pred) and lung clearance index (adults only) ( supplementary table S3 and the supplemental Excel file ). In most studies, lung function was lowest among people with post-TB bronchiectasis and bronchiectasis secondary to COPD or PCD ( supplementary table S2 ). Additional measures of lung function are detailed in the supplemental Excel file . Lung clearance index, considered more sensitive than spirometry to early airway damage, was elevated in two studies in adults with bronchiectasis, with a range of 9.0–12.8 (normal: 6–7 or less) [ 66 , 67 ].

In a study comparing bronchiectasis (people with CFBE excluded) in different age groups, elderly adults (≥76 years) had significantly lower FEV 1 % pred (median: 67) compared with both younger (18–65 years; median: 78) and older adults (66–75 years; median: 75) (p<0.017 for both comparisons) [ 63 ]. FVC % pred was found to be significantly lower in elderly adults (mean: 65) compared with both younger adults (median: 78) and older adults (median: 75) (p<0.017 for both comparisons) [ 63 ].

Chronic infection with at least one pathogen was reported in 22.3–79.6% of patients with bronchiectasis, although each study defined chronic infection differently (number of studies: 20). When limited to larger or multicentre studies, chronic infection with at least one pathogen was reported in 10.7–54.5% of patients with bronchiectasis (number of studies: 12). In two studies in NCFBE, significant differences in the proportion of patients chronically infected with at least one pathogen were reported across aetiologies (p<0.001 for both studies) [ 68 , 69 ]. Patients with post-infectious (other than TB) bronchiectasis (34.9%) [ 68 ] and patients with PCD-related bronchiectasis (68.3%) [ 69 ] had the highest prevalence of chronic infection.

The most commonly reported bacterial and fungal pathogens are shown in supplementary table S4 . The two most common bacterial pathogens were Pseudomonas ( P .) aeruginosa and Haemophilus ( H. ) influenzae . In several studies, more patients with PCD, TB and COPD as the aetiology of their bronchiectasis reported infection with P. aeruginosa . Additionally, in one study, significantly more children with CFBE had P. aeruginosa infection compared with children with NCFBE [ 70 ]. Further details and additional pathogens are reported in the supplemental Excel file .

Diversity of the sputum microbiome was assessed in two studies. In the first study in people with bronchiectasis (people with CFBE excluded), reduced microbiome alpha diversity (defined as the relative abundance of microbial species within a sample), particularly associated with Pseudomonas or Proteobacteria dominance, was associated with greater disease severity, increased frequency and severity of exacerbations, and a higher risk of mortality [ 71 ]. In the second study (unknown whether people with CFBE were excluded), a lower Shannon–Wiener diversity index (a measure of species diversity, with lower scores indicating lower diversity) score was associated with multiple markers of disease severity, including a higher BSI score (p=0.0003) and more frequent exacerbations (p=0.008) [ 72 ].

In a study comparing bronchiectasis (people with CFBE excluded) in different age groups (younger adults: 18–65 years; older adults: 66–75 years; elderly adults: ≥76 years) [ 63 ], chronic infection with H. influenzae was reported in 18.3% of younger adults, 12.8% of older adults and 8.8% of elderly adults, and chronic infection with Streptococcus ( Str. ) pneumoniae was reported in 5.3% of younger adults, 2.8% of older adults and 1.3% of elderly adults. For both of the above, the prevalence was significantly higher in younger adults compared with elderly adults (p<0.017 for both comparisons). However, no significant differences across age groups were reported for P. aeruginosa , Moraxella catarrhalis or Staphylococcus ( Sta .) aureus chronic infection.

P. aeruginosa infection was significantly associated with reduced FEV 1 [ 73 ], more severe disease [ 74 ], more frequent exacerbations [ 35 , 49 , 75 , 76 ], increased hospital admissions, reduced quality of life based on St. George's Respiratory Questionnaire (SGRQ) and increased and 4-year mortality [ 49 , 76 ]. Additionally, in a study reporting healthcare use and costs in the US between 2007–2013, healthcare costs and hospitalisation costs were found to be increased in patients infected with P. aeruginosa ($56 499 and $41 972 more than patients not infected with P. aeruginosa , respectively) [ 77 ]. In the same study, HCRU was also higher in patients infected with P. aeruginosa (fivefold increase in the number of hospitalisations and 84% more emergency department (ED) visits compared with patients not infected with P. aeruginosa ) [ 77 ].

Comorbidities

The most frequently reported comorbidities included cardiovascular (including heart failure, cerebrovascular disease and hypertension), respiratory (including asthma, COPD and sinusitis), metabolic (including diabetes and dyslipidaemia), malignancy (including haematological and solid malignancies), bone and joint-related (including osteoporosis and rheumatological disease), neurological (including anxiety and depression), renal, hepatic, and gastrointestinal comorbidities ( supplementary table S5 ). No data relating to comorbidities were reported for CFBE specifically. For further details and additional comorbidities, please see the supplemental Excel file .

In a study comparing bronchiectasis (people with CFBE excluded) in different age groups (younger adults: 18–65 years; older adults: 66–75 years; elderly adults: ≥76 years), younger adults had a significantly lower prevalence of diabetes compared with older adults, a significantly lower prevalence of stroke compared with elderly adults and a significantly lower prevalence of heart failure, solid tumours and renal failure compared with both older and elderly adults (p<0.0017 for all comparisons). Additionally, the prevalence of COPD was significantly lower in both younger and older adults compared with elderly adults (p<0.017) [ 63 ]. In studies reporting in children with bronchiectasis, the prevalence of comorbid asthma ranged from 22.2 to 25.8% [ 65 , 78 ] and the prevalence of sinusitis was reported to be 12.7% in a single study [ 79 ].

Charlson comorbidity index (CCI)

CCI scores can range from 0 to 37, with higher scores indicating a decreased estimate of 10-year survival. In this review, CCI scores ranged from 0.7 to 6.6 in studies reporting means (number of studies: 7). In one study, adults with bronchiectasis (people with CFBE excluded) who experienced ≥2 exacerbations per year were found to have significantly higher CCI scores (3.3) compared with patients who experienced less than two exacerbations per year (2.2) (p=0.001) [ 35 ]. In another study in adults with bronchiectasis (people with CFBE excluded), CCI scores increased significantly with increasing disease severity, with patients with mild (FACED score of 0–2), moderate (FACED score of 3–4) and severe (FACED score of 5–7) bronchiectasis reporting mean CCI scores of 3.9, 5.7 and 6.3, respectively [ 80 ]. No CCI scores were reported for CFBE specifically.

Prevalence of comorbidities in patients with bronchiectasis compared with control individuals

Several studies reported a higher prevalence of cardiovascular comorbidities. such as heart failure [ 81 ], stroke [ 82 , 83 ] and hypertension [ 82 – 84 ] in patients with bronchiectasis compared with a matched general population or healthy controls. Conversely, several additional studies reported no significant differences [ 81 , 85 , 86 ]. Two large studies reported an increased prevalence of diabetes in patients with bronchiectasis compared with nonbronchiectasis control groups [ 83 , 84 ]; however, three additional smaller studies reported no significant differences [ 81 , 82 , 86 ]. The prevalence of gastro–oesophageal reflux disease was found to be significantly higher in patients with bronchiectasis compared with matched nonbronchiectasis controls in one study [ 87 ], but no significant difference was reported in a second study [ 85 ]. Both anxiety and depression were found to be significantly more prevalent in patients with bronchiectasis compared with matched healthy controls in one study [ 55 ]. Lastly, two large studies reported an increased prevalence of asthma [ 84 , 87 ] and five studies reported a significantly higher prevalence of COPD [ 81 , 82 , 84 , 85 , 87 ] in patients with bronchiectasis compared with matched nonbronchiectasis controls or the general population. A smaller study reported conflicting evidence whereby no significant difference in the prevalence of asthma in patients with bronchiectasis compared with matched controls was reported [ 85 ].

Socioeconomic burden

Patient-reported outcomes.

Health-related quality of life (HRQoL), fatigue, anxiety and depression were reported across several PRO measures and domains. The most frequently reported PROs are discussed in further detail in the sections below ( table 2 ). Further details and additional PROs can be seen in the supplemental Excel file .

In a study comparing bronchiectasis (people with CFBE excluded) in different age groups (younger adults: 18–65 years; older adults: 66–75 years; elderly adults: ≥76 years), the median SGRQ total score was significantly higher in elderly adults (50.8) compared with younger adults (36.1), indicating a higher degree of limitation (p=0.017) [ 63 ].

In a study that reported Leicester Cough Questionnaire (LCQ) scores in men and women with bronchiectasis (people with CFBE excluded) separately, women had significantly lower LCQ total scores (14.9) when compared with men (17.5) (p=0.006), indicating worse quality of life [ 88 ]. Additionally, women had significantly lower scores across all three LCQ domains (p=0.014, p=0.005 and p=0.011 for physical, psychological and social domains, respectively) [ 88 ].

Exercise capacity

Exercise capacity in patients with bronchiectasis was reported using walking tests namely the 6-minute walk test (6MWT) and the incremental shuttle walk test (ISWT) ( supplementary table S6 ). The 6MWT data from patients with bronchiectasis generally fell within the normal range for healthy people; however, the ISWT data was below the normal range for healthy people ( supplementary table S6 ). Studies also reported on daily physical activity, daily sedentary time and number of steps per day in patients with bronchiectasis, and in children specifically ( supplementary table S6 ). No data relating to disease severity were reported for CFBE specifically. Further details can be seen in the supplemental Excel file .

Exercise capacity in patients with bronchiectasis compared with control individuals

In one study, the ISWT distance was reported to be significantly lower in patients with NCFBE compared with healthy controls (592.6 m versus 882.9 m; difference of ∼290 m; p<0.001) [ 89 ]. Additionally, patients with bronchiectasis spent significantly less time on activities of moderate and vigorous intensity compared with healthy controls (p=0.030 and 0.044, respectively) [ 89 ]. Lastly, a study reported that patients with NCFBE had a significantly lower step count per day compared with healthy controls (p<0.001) [ 89 ].

Mortality rate during study period

Mortality ranged from 0.24 to 67.6%; however, it should be noted that the study duration differed across studies. When limited to larger or multicentre studies, the mortality rate ranged from 0.24 to 28.1%. One study reported more deaths in patients with NCFBE (9.1%; 5.9-year mean follow-up period) compared with patients without bronchiectasis (0.8%; 5.4-year mean follow-up period) [ 84 ]. In one study, significantly more patients with COPD-related bronchiectasis died (37.5%) compared with other aetiologies (19.0%) (3.4-year mean follow-up period; p<0.001). After adjusting for several factors, multivariate analysis showed that the diagnosis of COPD as the primary cause of bronchiectasis increased the risk of death by 1.77 compared with the patients with other aetiologies [ 41 ]. Similarly, in another study, COPD-associated bronchiectasis was associated with higher mortality (55%) in multivariate analysis as compared with other aetiologies (rheumatic disease: 20%; post-infectious: 16%; idiopathic: 14%; ABPA: 13%; immunodeficiency: 11%) (hazard ratio 2.12, 95% CI 1.04–4.30; p=0.038; 5.2-year median follow-up period) [ 90 ].

Mortality rates by year

The 1-, 2-, 3-, 4- and 5-year mortality rates in patients with bronchiectasis (people with CFBE excluded, unless unspecified) ranged from 0.0 to 12.3%, 0.0 to 13.0%, 0.0 to 21.0%, 5.5 to 39.1% and 12.4 to 53.0%, respectively (number of studies: 9, 4, 7, 1 and 4, respectively). When limited to larger or multicentre studies, the 1-, 2-, 3- and 5-year mortality rates ranges were 0.4–7.9%, 3.9–13.0%, 3.7–21.0% and 12.4–53.0% (no 4-year mortality data from larger or multicentre studies). No data relating to mortality rates were reported for CFBE specifically.

Two studies reported mortality rate by bronchiectasis aetiology (people with CFBE excluded). In the first study, no significant difference in the 4-year mortality rate was reported across aetiologies (p=0.7; inflammatory bowel disease: 14.3%; post-TB: 13.4%; rheumatoid arthritis: 11.4%; idiopathic or post-infectious: 10.1%; ABPA: 6.1%; other aetiologies: 6.1%) [ 49 ]. In the second study, patients with post-TB bronchiectasis had a significantly higher 5-year mortality rate (30.0%) compared with patients with idiopathic bronchiectasis (18.0%) and other aetiologies (10.0%) (p<0.05 for both comparisons) [ 32 ].

In-hospital and intensive care unit mortality

In-hospital mortality ranged from 2.9 to 59.3% in patients with bronchiectasis (people with CFBE excluded, unless unspecified) hospitalised for an exacerbation or for other reasons (number of studies: 7). When limited to larger or multicentre studies, in-hospital mortality rate was reported in only one study (33.0%). One study reported mortality in bronchiectasis patients admitted to a tertiary care centre according to aetiology; in-hospital mortality was highest in patients with post-pneumonia bronchiectasis (15.8%), followed by patients with idiopathic (7.1%) and post-TB (2.6%) bronchiectasis. No deaths were reported in patients with COPD, ABPA or PCD aetiologies [ 42 ]. Intensive care unit mortality was reported in two studies and ranged from 24.6 to 36.1% [ 62 , 91 ]. No data relating to mortality rates were reported for CFBE specifically.

Impact on family and caregivers

Only two studies discussed the impact that having a child with bronchiectasis has on parents/caregivers. In the first study, parents of children with bronchiectasis (not specified whether children with CFBE were excluded) were more anxious and more depressed according to both the Hospital Anxiety and Depression Scale (HADS) and the Centre of Epidemiological Studies depression scale, compared with parents of children without any respiratory conditions (both p<0.001; sample size of 29 participants) [ 53 ]. In the second study, parents or carers of children with bronchiectasis (multicentre study with a sample size of 141 participants; children with CFBE excluded) were asked to vote for their top five greatest concerns or worries; the most common worries or concerns that were voted for by over 15% of parents were “impact on his/her adult life in the future, long-term effects, normal life” (29.8%), “ongoing declining health” (25.5%), “the cough” (24.8%), “impact on his/her life now as a child (play, development)” (24.1%), “lack of sleep/being tired” (24.1%), “concerns over aspects of antibiotic use” (22.7%), “missing school or daycare” (17.7%) and “breathing difficulties/shortness of breath” (16.3%) [ 92 ].

HCRU in terms of hospitalisations, ED visits, outpatient visits and length of stay overall and by bronchiectasis aetiology are reported in table 3 . No data relating to HCRU were reported for CFBE specifically.

In a study in children with bronchiectasis (children with CFBE excluded), 30.0% of children were hospitalised at least once in the previous year [ 65 ]. The median number of hospitalisations per year was 0 (interquartile range: 0–1) [ 65 ]. In another study, the mean length of hospital stay for children with bronchiectasis was 6.7 days (standard deviation: 4.8 days) [ 93 ]. In a study comparing bronchiectasis (people with CFBE excluded) in different age groups, significantly more elderly adults (≥76 years; 26.0%) were hospitalised at least once during the first year of follow-up compared with younger adults (18–65 years; 17.0%) and older adults (66–75 years; 17.0%) (p<0.017 for both comparisons) [ 63 ]. Additionally, length of stay was found to be significantly longer in male patients (mean: 17.6 days) compared with female patients (mean: 12.5 days) (p=0.03) [ 94 ].

HCRU in patients with bronchiectasis compared with control individuals

Length of stay was found to be 38% higher in patients with bronchiectasis (mean: 15.4 days; people with CFBE excluded) compared with patients with any other respiratory illness (mean: 9.6 days) (p<0.001) [ 94 ]. In a study reporting on HCRU in patients with bronchiectasis (people with CFBE excluded) over a 3-year period (Germany; 2012–2015) [ 85 ], a mean of 24.7 outpatient appointments per patient were reported; there was no significant difference in the number of outpatient appointments between patients with bronchiectasis and matched controls (patients without bronchiectasis matched by age, sex and distribution, and level of comorbidities) (mean: 23.4) (p=0.12). When assessing specific outpatient appointments over the 3-year period, patients with bronchiectasis attended a mean of 9.2 general practitioner appointments, 2.9 radiology appointments, 2.5 chest physician appointments and 0.8 cardiologist appointments. Patients with bronchiectasis had significantly fewer general practitioner appointments compared with matched controls (mean: 9.8) (p=0.002); however, they had significantly more radiology appointments (mean for matched controls: 2.3) and chest physician appointments (mean for matched controls: 1.4) compared with matched controls (p<0.001 for both comparisons).

Hospital admission rates

In England, Wales and Northern Ireland, the crude hospital admission rate in 2013 was 88.4 (95% CI 74.0–105.6) per 100 000 person-years [ 91 ]. In New Zealand (2008–2013), the crude and adjusted hospital admission rates were 25.7 and 20.4 per 100 000 population, respectively [ 95 ]. Lastly, in Australia and New Zealand (2004–2008) the hospital admission rate ranged from 0.7 to 2.9 per person-year [ 96 ]. In all of the abovementioned studies, people with CFBE were excluded.

Treatment burden

In two studies, the percentage of patients with bronchiectasis receiving any respiratory medication at baseline ranged from 60.8 to 85.7% [ 97 , 98 ]. Additionally, in a study comparing healthcare costs in patients with bronchiectasis before and after confirmation of P. aeruginosa infection, mean pharmacy visits in the year preceding diagnosis were reported to be 23.2; this increased significantly by 56.5% to 36.2 in the year post-diagnosis (p<0.0001) [ 99 ]. In another study, patients with bronchiectasis were prescribed a mean of 12 medications for bronchiectasis and other comorbidities [ 100 ]. In all of the abovementioned studies, people with CFBE were excluded. The most frequently reported respiratory treatments can be seen in supplementary table S7 . These included antibiotics (including macrolides), corticosteroids, bronchodilators, mucolytics and oxygen. No treatment data were reported for CFBE specifically. Other respiratory treatments included saline, anticholinergics and leukotriene receptor antagonists ( supplemental Excel file ).

In studies reporting in children with bronchiectasis, 23.9% of children were receiving any bronchodilator at baseline [ 101 ], 9.0–21.7% of children were receiving inhaled corticosteroids (ICS) at baseline [ 101 , 102 ], 4.3% of children were receiving oral corticosteroids at baseline [ 101 ] and 12.1% of children were receiving long-term oxygen therapy [ 103 ].

Medical and nonmedical indirect impacts and costs

Medical costs for bronchiectasis included overall costs, hospitalisation costs, ED visits and outpatient visit costs and costs of treatment; indirect impacts and costs included sick leave and sick pay, missed work and income loss for caregivers, and missed school or childcare for children ( table 4 and the supplemental Excel file ). People with CFBE were excluded from all of the studies in table 4 below. In studies reporting in currencies other than the €, costs were converted to € based on the average exchange rate for the year in which the study was conducted.

Bronchiectasis-related medical costs and indirect impacts and costs (individual studies)

No review to date has systematically evaluated the overall disease burden of bronchiectasis. Here, we present the first systematic literature review that comprehensively describes the clinical and socioeconomic burden of bronchiectasis overall and across individual aetiologies and associated diseases. A total of 338 publications were included in the final analysis. Together, the results indicate that the burden of clinically significant bronchiectasis on patients and their families, as well as on healthcare systems, is substantial, highlighting the urgent need for new disease-modifying therapies for bronchiectasis.

Bronchiectasis is associated with genetic, autoimmune, airway and infectious disorders. However, in many patients with bronchiectasis, an underlying aetiology cannot be identified (idiopathic bronchiectasis) [ 1 , 3 , 4 ]. This is supported by the results of this systematic literature review, in which up to 80.7% of patients were reported to have idiopathic bronchiectasis. The results are in line with those reported in a systematic literature review of bronchiectasis aetiology conducted by G ao et al. [ 13 ] (studies from Asia, Europe, North and South America, Africa and Oceania included) in which an idiopathic aetiology was reported in approximately 45% of patients with bronchiectasis, with a range of 5–82%. The maximum of 80.7% of patients with idiopathic bronchiectasis identified by this systematic literature review is much higher than in the recent report on the disease characteristics of the EMBARC where idiopathic bronchiectasis was the most common aetiology and reported in only ∼38% of patients with bronchiectasis [ 17 ]. This highlights the importance of sample size and geographic variation (80.7% reported from a single-country study with a small sample size versus ∼38% reported from a continent-wide study with a large sample size). Nevertheless, identifying the underlying aetiology is a recommendation of bronchiectasis guidelines as this can considerably alter the clinical management and prognosis [ 23 , 110 ]. Specific therapeutic interventions may be required for specific aetiologies, such as ICS for people with asthma-related bronchiectasis, antifungal treatment for those with ABPA-associated bronchiectasis and immunoglobulin replacement therapy for those with common variable immunodeficiency-related bronchiectasis [ 23 , 111 ]. Indeed, an observational study has shown that identification of the underlying aetiology affected management in 37% of people with bronchiectasis [ 112 ]. Future studies to determine the impact of identifying the underlying aetiology on management and prognosis are needed to fully understand its importance.

Patients with bronchiectasis experienced a significant symptom burden, with dyspnoea, cough, wheezing, sputum production and haemoptysis reported most commonly. These symptoms were also reported in children with bronchiectasis at slightly lower frequencies. Dealing with bronchiectasis symptoms are some of the greatest concerns from a patient's perspective. In a study assessing the aspects of bronchiectasis that patients found most difficult to deal with, sputum, dyspnoea and cough were the first, fifth and sixth most common answers, respectively [ 113 ]. Some aetiologies were reported to have a higher prevalence of certain symptoms. For example, in single studies, patients with PCD-related bronchiectasis were found to have a significantly higher prevalence of cough and wheezing [ 39 ], patients with COPD-related bronchiectasis were found to have a significantly higher prevalence of sputum production [ 41 ], and patients with post-TB bronchiectasis were found to have a higher prevalence of haemoptysis [ 30 ] compared with other aetiologies. Together, these results highlight the need for novel treatments that reduce the symptom burden of bronchiectasis. They also highlight the importance of teaching patients to perform and adhere to regular nonpharmacological interventions, such as airway clearance using physiotherapy techniques, which have been shown to improve cough-related health status and chronic sputum production [ 110 ]. Future studies assessing when airway clearance techniques should be started, and which ones are the most effective, are a research priority [ 113 ].

The burden of exacerbations in patients with bronchiectasis was high, with patients experiencing three or more exacerbations in the previous year (up to 73.6%), per year (up to 55.6%) or in the first year of follow-up (up to 32.4%). Few studies reported significant differences between aetiologies. Importantly, exacerbations are the second-most concerning aspect of bronchiectasis from the patient's perspective [ 113 ]. Patients with frequent exacerbations have more frequent hospitalisations and increased 5-year mortality [ 114 ] and exacerbations are also associated with poorer quality of life [ 114 , 115 ]. Therefore, prevention of exacerbations is of great importance in the management of bronchiectasis [ 116 ]. The exact cause of exacerbations in bronchiectasis (believed to be multifactorial) is not fully understood due a lack of mechanistic studies [ 116 ]. Future studies into the causes and risk factors for exacerbations [ 113 ] may lead to improvements in their prevention.

Many patients with bronchiectasis, including children, experienced chronic infections with bacterial pathogens such as P. aeruginosa , H. influenzae , Sta. aureus and Str. pneumoniae as well as non-tuberculous mycobacteria. Importantly, P. aeruginosa infection was significantly associated with more severe disease, reduced lung function and quality of life, and increased exacerbations, hospital admission, morality, HCRU and healthcare costs. Due to the clear and consistent association between P. aeruginosa and poor outcomes, patients with chronic P. aeruginosa colonisation should be considered to be at a higher risk of bronchiectasis-related complications [ 110 ]. Additionally, regular sputum microbiology screening should be performed in people with clinically significant bronchiectasis to detect new isolation of P. aeruginosa [ 110 ]; in which case, patients should be offered eradication antibiotic treatment [ 23 ]. Eradication of P. aeruginosa is not only of clinical importance, but also of economic importance due to the associated HCRU and healthcare costs. As such, a better understanding of the key factors leading to P. aeruginosa infection is a priority for future research [ 113 ].

Bronchiectasis markedly impacted HRQoL across several PROs including the SGRQ, Quality of Life–Bronchiectasis score, LCQ, COPD Assessment Test and Bronchiectasis Health Questionnaire. In children with bronchiectasis, significantly lower quality of life (according to the Paediatric Quality of Life Inventory score) compared with age-matched controls was reported [ 53 ]. The majority of studies reporting HRQoL in individual aetiologies and associated diseases either reported in a single aetiology, did not perform any statistical analyses to compare aetiologies, or reported no significant differences across aetiologies. Patients also experienced mild-to-moderate anxiety and depression according to the HADS-Anxiety, HADS-Depression and 9-question Patient Health Questionnaire scores, with very limited data reported in individual aetiologies. When compared with healthy controls, anxiety and depression were found to be significantly more prevalent in patients with bronchiectasis [ 55 ]. Additionally, exercise capacity was reduced, with patients with bronchiectasis reported to spend significantly less time on activities of moderate and vigorous intensity and have a significantly lower step count per day compared with healthy controls [ 89 ]. Improvements in anxiety, depression and exercise capacity are important priorities for people with bronchiectasis; in a study assessing the aspects of bronchiectasis that patients found most difficult to manage, “not feeling fit for daily activities”, anxiety and depression were the fourth, eighth and ninth most common answers, respectively [ 113 ].

The studies relating to HCRU and costs in this review were heterogeneous in terms of methodology, time period, country and currency, making them challenging to compare. Nevertheless, this study found that HCRU was substantial, with patients reporting a maximum of 1.3 hospitalisation, 1.3 ED and 21.0 outpatient visits per year. Length of stay was found to be significantly longer in patients with bronchiectasis compared with patients with any other respiratory illness in one study [ 91 ]. In another study, patients with bronchiectasis reported significantly more specialist appointments (radiologist appointments and chest physician appointments) compared with matched controls [ 85 ]. Patients with bronchiectasis also experienced a significant treatment burden, with up to 36.4, 58.0 and 83.0% of patients receiving long-term inhaled antibiotics, oral antibiotics and macrolides, respectively, up to 80.4% receiving long-term ICS and up to 61.7% and 81.4% receiving long-term long-acting muscarinic antagonists and long-acting beta agonists, respectively. Wide ranges of treatment use were reported in this study, which may reflect geographic variation in treatment patterns. Heterogeneous treatment patterns across Europe were observed in the EMBARC registry data with generally higher medication use in the UK and Northern/Western Europe and lower medication use in Eastern Europe (inhaled antibiotics: 1.8–8.9%; macrolides: 0.9–24.4%; ICS: 37.2–58.5%; long-acting beta agonists: 42.7–52.8%; long-acting muscarinic antagonists: 26.5–29.8%) [ 17 ]. Similarly, data from the Indian bronchiectasis registry indicate that the treatment of bronchiectasis in India is also diverse [ 19 ]. Furthermore, in a comparison of the European and Indian registry data, both long-term oral and inhaled antibiotics were more commonly used in Europe compared with India [ 19 ].

Cost varied widely across studies. However, patients, payers and healthcare systems generally accrued substantial medical costs due to hospitalisations, ED visits, outpatient visits, hospital-in-the-home and treatment-related costs. Other medical costs incurred included physiotherapy and outpatient remedies (including breathing or drainage techniques), outpatient medical aids (including nebulisers and respiration therapy equipment) and the cost of attending convalescence centres. Only one study compared the medical costs in patients with bronchiectasis and matched controls (age, sex and comorbidities) and found that patients with bronchiectasis had significantly higher total direct medical expenditure, hospitalisation costs, treatment costs for certain medications and costs associated with outpatient remedies and medical aids [ 85 ]. Bronchiectasis was also associated with indirect impacts and costs, including sick leave, sick pay and income lost due to absenteeism and missed work, and lost wages for caregivers of patients with bronchiectasis. Children with bronchiectasis also reported absenteeism from school or childcare.

Our findings regarding HRCU and costs in bronchiectasis are mirrored by a recent systematic literature review by R oberts et al . [ 117 ] estimating the annual economic burden of bronchiectasis in adults and children over the 2001–2022 time period. R oberts et al . [ 117 ] found that annual total healthcare costs per adult patient ranged from €3027 to €69 817 (costs were converted from USD to € based on the average exchange rate in 2021), predominantly driven by hospitalisation costs. Likewise, we report annual costs per patient ranging from €218 to €51 033, with annual hospital costs ranging from €1215 to €27 612 (adults and children included) ( table 4 ). Further, R oberts et al . [ 117 ] reports a mean annual hospitalisation rate ranging from 0.11 to 2.9, which is similar to our finding of 0.03–1.3 hospitalisations per year ( table 3 ). With regard to outpatient visits, R oberts et al . [ 117 ] reports a mean annual outpatient respiratory physician attendance ranging from 0.83 to 6.8 visits, whereas we report a maximum of 21 visits per year ( table 3 ). It should be noted, however, that our value is not restricted to visits to a respiratory physician. With regard to indirect annual costs per adult patient, R oberts et al . [ 117 ] reports a loss of income because of illness of €1109–€2451 (costs were converted from USD to € based on the average exchange rate in 2021), whereas we report a figure of ∼€1410 ( table 4 ). Finally, burden on children is similarly reported by us and R oberts et al . [ 117 ], with children missing 12 days of school per year per child ( table 4 ).

Limitations of this review and the existing literature

Due to the nature of this systematic literature review, no formal statistical analyses or formal risk of bias assessments were performed.

Several limitations within the existing literature were identified. Firstly, the vast majority of studies reported patients with NCFBE overall, with limited availability of literature reporting on individual aetiologies and associated disease. Furthermore, where this literature was available, it was limited to a handful of individual aetiologies and associated diseases, and in many of these studies, no statistical analyses to compare different aetiologies and associated disease were performed. Additionally, the methods used to determine aetiologies within individual studies may have differed. Literature on NCFBE and CFBE has traditionally been very distinct; as such, most of the studies included in this review have excluded people with CF. As the general term “CF lung disease” was not included in our search string in order to limit the number of hits, limited data on CFBE are included in this review. Bronchiectasis remains largely under-recognised and underdiagnosed, thus limiting the availability of literature. There is a particular knowledge gap with respect to paediatric NCFBE; however, initiatives such as the Children's Bronchiectasis Education Advocacy and Research Network (Child-BEAR-Net) ( www.improvebe.org ) are aiming to create multinational registries for paediatric bronchiectasis.

There were variations in the amount of literature available for the individual burdens. While there was more literature available on the clinical burden of bronchiectasis, economic data (related to both medical costs and indirect costs) and data on the impact of bronchiectasis on families and caregivers, were limited. Additionally, cost comparisons across studies and populations were difficult due to differences in cost definitions, currencies and healthcare systems.

Sample sizes of the studies included in this systematic literature review varied greatly, with the majority of studies reporting on a small number of participants. Furthermore, many of the studies were single-centre studies, thus limiting the ability to make generalisations about the larger bronchiectasis population, and cross-sectional, thus limiting the ability to assess the clinical and socioeconomic burden of bronchiectasis over a patient's lifetime. Furthermore, there may be potential sex/gender bias in reporting that has not been considered in this systematic literature review.

Finally, for many of the reported outcomes, data varied greatly across studies, with wide estimates for the frequency of different aetiologies and comorbidities as well as disease characteristics such as exacerbations and healthcare costs noted. This reflects the heterogeneity of both the study designs (including sample size and inclusion and exclusion criteria) and the study populations themselves. Additionally, the use of non-standardised terms across articles posed a limitation for data synthesis. Systematic collection of standardised data across multiple centres, with standardised inclusion and exclusion criteria such as that being applied in international registries, is likely to provide more accurate estimates than those derived from small single-centre studies.

Conclusions

Collectively, the evidence identified and presented in this systematic literature review show that bronchiectasis imposes a significant clinical and socioeconomic burden on patients and their families and employers, as well as on healthcare systems. Disease-modifying therapies that reduce symptoms, improve quality of life, and reduce both HCRU and overall costs are urgently needed. Further systematic analyses of the disease burden of specific bronchiectasis aetiologies and associated disease (particularly PCD-, COPD- and post-TB-associated bronchiectasis, which appear to impose a greater burden in some aspects) and paediatric bronchiectasis (the majority of data included in this study were obtained from adults) may provide more insight into the unmet therapeutic needs for these specific patient populations.

Questions for future research

Further research into the clinical and socioeconomic burden of bronchiectasis for individual aetiologies and associated diseases is required.

Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary figures and tables ERR-0049-2024.SUPPLEMENT

Supplementary Excel file ERR-0049-2024.SUPPLEMENT

Acknowledgements

Laura Cottino, PhD, of Nucleus Global, provided writing, editorial support, and formatting assistance, which was contracted and funded by Boehringer Ingelheim.

Provenance: Submitted article, peer reviewed.

Conflict of interest: The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell, and received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon. M.A. Mall reports research grants paid to their institution from the German Research Foundation (DFG), German Ministry for Education and Research (BMBF), German Innovation Fund, Vertex Pharmaceuticals and Boehringer Ingelheim; consultancy fees from AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense and Vertex Pharmaceuticals; speaker fees from Vertex Pharmaceuticals; and travel support from Boehringer Ingelheim and Vertex Pharmaceuticals. M.A. Mall also reports advisory board participation for AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari and Vertex Pharmaceuticals and is a fellow of ERS (unpaid). P.J. McShane is an advisory board member for Boehringer Ingelheim's Airleaf trial and Insmed's Aspen trial. P.J. McShane is also a principal investigator for clinical trials with the following pharmaceutical companies: Insmed: Aspen, 416; Boehringer Ingelheim: Airleaf; Paratek: oral omadacycline; AN2 Therapeutics: epetraborole; Renovian: ARINA-1; Redhill; Spero; and Armata. K.G. Nielsen reports advisory board membership for Boehringer Ingelheim. M. Shteinberg reports having received research grants from Novartis, Trudell Pharma and GlaxoSmithKline; travel grants from Novartis, Actelion, Boehringer Ingelheim, GlaxoSmithKline and Rafa; speaker fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Insmed, Teva, Novartis, Kamada and Sanofi; and advisory fees (including steering committee membership) from GlaxoSmithKline, Boehringer Ingelheim, Kamada, Syncrony Medical, Zambon and Vertex Pharmaceuticals. M. Shteinberg also reports data and safety monitoring board participation for Bonus Therapeutics, Israel and is an ERS Task Force member on bronchiectasis guideline development. S.D. Sullivan has participated in advisory boards for Boehringer Ingelheim and has research grants from Pfizer, Bayer and GlaxoSmithKline. S.H. Chotirmall is on advisory boards for CSL Behring, Boehringer Ingelheim and Pneumagen Ltd, served on a data and safety monitoring board for Inovio Pharmaceuticals Inc., and has received personal fees from AstraZeneca and Chiesi Farmaceutici.

Support statement: This systematic literature review was funded by Boehringer Ingelheim International GmbH. The authors did not receive payment related to the development of the manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Funding information for this article has been deposited with the Crossref Funder Registry .

Received March 8, 2024.
Accepted June 4, 2024.
Copyright ©The authors 2024

This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.

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Urinary CXCL-10, a prognostic biomarker for kidney graft injuries: a systematic review and meta-analysis

Sahar Janfeshan 1 ,
Afsoon Afshari 1 ,
Ramin Yaghobi 2 &
Jamshid Roozbeh 1

BMC Nephrology volume 25 , Article number: 292 ( 2024 ) Cite this article

Metrics details

The challenges of long-term graft survival and the side effects of current immunosuppressive therapies in kidney transplantation highlight the need for improved drugs with fewer adverse effects. Biomarkers play a crucial role in quickly detecting post-transplant complications, with new biomarkers showing promise for ongoing monitoring of disease and potentially reducing the need for unnecessary invasive biopsies. The chemokines such as C-X-C motif chemokine ligand 10 (CXCL10), are particularly promising protein biomarkers for acute renal rejection, with urine samples being a desirable source for biomarkers. The aim of this review is to analyze the literature on the potential role of urinary CXCL10 protein in predicting kidney graft injuries. The results of this study demonstrate that evaluating urinary CXCL10 levels is more successful in identifying post-transplant injuries compared to assessing the CXCL10/Cr ratio.

Peer Review reports

Introduction

Kidney allograft transplantation is the best treatment for end-stage renal disease (ESRD), but long-term graft survival and adverse effects of current immunosuppressive regimens remain significant challenges [ 1 , 2 ]. Laboratory tests, including serum urea, creatinine, and proteinuria, play a crucial role in monitoring kidney transplants. While histopathological analysis of graft biopsies remains the gold standard for diagnosing post-transplant injuries, it has limitations due to its invasive nature, potential sampling errors, and high costs. Consequently, this method is impractical for continuous graft monitoring over time [ 3 , 4 ]. Therefore, exploring novel biomarkers for early detection of post-transplant injuries holds promise for reducing unnecessary biopsies [ 4 , 5 ]. Considering these facts, urine samples, which directly reflect allograft function and are minimally affected by systemic inflammation, represent an optimal source for biomarkers in this context [ 5 ].

Based on the search results provided, the primary new biomarkers being studied for the detection of kidney transplant complications are urinary C-X-C motif chemokine ligand 9 (CXCL9) and 10 (CXCL10) [ 6 ]. Additionally, the analysis of urinary mRNA transcripts such as CD3 + , perforin, granzyme B, CD103, and CXCR3, has been conducted [ 6 , 7 ]. Urinary perforin and granzyme B and CD103, can serve as screening tools for acute rejection. Moreover, elevated levels of donor-derived cell-free DNA (dd-cf DNA) in the blood or urine may indicate acute rejection, while declining levels could signal recovery from rejection [ 6 , 7 , 8 , 9 , 10 ]. In conclusion, urinary and blood transcriptomics are emerging as promising biomarkers in the field of kidney transplantation, offering valuable insights into the status of kidney allografts. The identification of specific mRNAs and microRNAs associated with rejection episodes has proven beneficial in detecting T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), thereby enhancing our understanding of the immunological processes involved in kidney transplant rejection [ 11 ]. Some of mentioned biomarkers such as the CXCL9 and CXCL10, seems to be more promising for kidney graft problems early detection and ongoing disease monitoring. These chemokines recruit T cells to inflammatory sites and have shown potential as biomarkers for diagnosing rejection [ 6 ]. A multicenter prospective study found that urinary CXCL9 and CXCL10 protein levels were significantly higher in patients with acute rejection compared to stable graft conditions, and low urinary CXCL9 protein levels could be used to rule out acute rejection with a high negative predictive value (NPV). Furthermore, CXCL10 levels have been shown to increase up to 30 days before the biopsy, which can help identify patients at risk for acute rejection [ 6 ]. CXCL9 is also a promising biomarker, but CXCL10 has a more robust and consistent association with graft complications, making it a more reliable indicator [ 12 ]. CXCL10 is a member of the CXC chemokine family also known as IFNγ-induced protein 10 (IP-10). It is an 8.7 kDa protein encoded by the CXCL10 gene located on human chromosome 4q21. The CXCL10 gene consists of 4 exons and 3 introns and elicits its effects by binding to the cell surface chemokine receptor CXCR3. This chemokine secreted by monocytes, endothelial cells and fibroblasts in response to IFNγ and recruit immune cells to sites of inflammation. It also plays roles in anti-tumor activity, adhesion of T cells, and inhibition of angiogenesis and bone marrow colony formation [ 13 , 14 ]. Studies have demonstrated that CXCL10 is directly involved in the development of kidney conditions through its chemoattractant properties and effects on cell proliferation [ 14 ]. CXCL10 or its ratio to creatinine has been more extensively studied and validated as a biomarker for kidney allograft rejection and can predict early rejection risk and longer-term graft survival [ 5 , 6 , 15 , 16 , 17 , 18 , 19 , 20 ]. This chemokine, is detected as a urinary biomarker for both TCMR and ABMR. Low levels of CXCL10 are associated with immunological quietness, making it ideal for ruling out rejection and identifying transplant recipients at low immunological risk [ 21 ].

Integrating the urinary CXCL10 biomarker with clinical indicators such as serum urea, creatinine, and proteinuria holds promise for reducing unnecessary invasive biopsies and improving patient outcomes [ 22 ].

Aim of this review

The aim of this systematic review and meta-analysis is to examine the existing literature to determine the potential role of urinary CXCL10 protein in predicting kidney graft injuries.

Materials and methods

Literature search.

This review is conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 23 ]. The objectives of the study, the search strategy, inclusion and exclusion criteria, and study evaluation method were carefully designed, refined, and unanimously approved by all contributing authors well in advance. Pubmed, Scopus, Web of Sciences, EMBASE electric databases were searched from 6 March 2022 to 2 October 2023. The medical subject headings (MeSH) and their entry terms used in the literature search included: ((“Renal Transplantation*”) or (“Kidney Transplantation*”) or (“Kidney Graft*”) or (“Renal Graft*”)) and ((“Chemokine CXCL10”) or (“Interferon-Inducible Protein 10”) or (“Small Inducible Cytokine B10”) or (“IFN-gamma-Inducible Protein, 10 kDa”)). We applied no restrictions regarding the language or the publication date of the sources. Furthermore, a manual search of references in review articles was conducted to uncover additional relevant studies.

Selection process and data extraction

In the preliminary phase of the eligibility assessment, the screening of titles and abstracts was conducted independently by two investigators (A.A., S.J.). This initial review aimed to identify original research articles that investigated the utility of urinary CXCL10, either singularly or in combination with creatinine, in the prediction of kidney injuries post-transplantation.

In the course of our study, we excluded abstracts, reviews, and research focusing on CXCL10 derived from sources other than urine, such as blood samples or histological stains. Studies that primarily evaluated different outcomes, including infections or allograft survival, were also excluded. Subsequently, in the inclusion phase, the selected articles underwent an independent full-text review by two researchers (A.A., S.J.), ensuring a comprehensive and rigorous evaluation of the relevant literature. Discrepancies in the assessments made by the two investigators were deliberated upon and resolved through consultative discussions involving the entire authorial team. Data extraction from the included studies was carried out using a pre-defined spreadsheet and an extraction table, collaboratively developed and refined by all authors. The extracted data encompassed a range of variables, including, authors, years of enrollment, exposure, protein cut-off, outcome, sensitivity, specificity, and measures of diagnostic accuracy such as True Positive (TP), False Negative (FN), False Positive (FP), True Negative (TN), and the Area Under the Receiver Operating Characteristic Curve (AUC) for protein. These variables were systematically tabulated for descriptive analysis. Two independent investigators conducted a thorough review of eligible publications, meticulously extracting relevant data into a standardized format. This rigorous selection process involved an initial review of titles and abstracts, followed by a detailed examination of the full texts. Any discrepancies encountered during this process were effectively resolved through consultation with a third reviewer.

Quality assessment

In the present meta-analysis, the integrity and robustness of the included studies were rigorously assessed using the Newcastle Ottawa Scale (NOS), a bespoke tool for the evaluation of nonrandomized studies. The NOS framework awards up to nine points, distributed across three critical dimensions: the selection process of study participants (maximum of 4 points), the comparability of the study groups (maximum of 2 points), and the accuracy and reliability of outcome assessment (maximum of 3 points). Studies achieving a score of 7 to 9 are classified as high quality, indicating lower risk of bias. Those garnering 4 to 6 points are categorized as having a high risk of bias, while a score of 0 to 3 suggests a very high risk of bias, potentially impacting the reliability of their findings.

Statistical analysis

In the initial phase of our analysis, we computed the natural logarithms (Ln) of the Relative Risks (RRs) along with their 95% Confidence Intervals (CIs) to derive the summary Effect Size (ES). To assess the comparative impact of the highest versus lowest categories, we implemented a random-effects model, specifically chosen to adequately account for the variability among studies (between-study heterogeneity). Furthermore, this model was instrumental in calculating I² values, which serve as quantitative measures of heterogeneity. We considered I² values exceeding 50% as a threshold for significant between-study heterogeneity. Upon encountering substantial heterogeneity, our analytical strategy included conducting subgroup analyses, with a particular focus on differing outcomes, to elucidate potential sources of variability among the included studies.

Summary of searches and study selection process

Upon conducting a comprehensive search of the relevant database, a total of 878 articles were initially retrieved. Rigorous deduplication procedures resulted in removing 224 articles. A cursory examination of titles and abstracts facilitated the exclusion of 587 articles, which primarily consisted of review articles, conference proceedings, and additional publications by the same author. A more in-depth evaluation led to the further exclusion of 23, 31 and 4 articles in three steps due to reasons including the assay techniques, the use of non-urinary sample types, and the inability to extract complete data sets. Consequently, a final selection of 9 articles [ 18 , 20 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], representing 10 studies (with one article encompassing two studies), was made [ 27 ] (Fig. 1 ).

Flow diagram for screening related articles; a total of 878 articles were initially retrieved and finally after removing deduplication (224), incompatibility of titles and abstracts )587(, further exclusion of 23, 31 and 4 articles due to the assay techniques, use of non-urinary sample types, and the inability of extracting data, resulted in 9 articles

The basic characteristics of literatures

The fundamental characteristics of the selected publications are systematically cataloged in Table-S1. From each study, we meticulously extracted key data components, encompassing the first author’s name, country of research, publication date, exposure details, protein cut-off values, and the primary diagnostic metrics, including the number of true positives, false positives, false negatives, and true negatives.

Quality evaluation results

The result of quality assessment using NOS is shown in Fig. 2 . The quality assessment of the 9 selected articles was performed using Stata14 (metareg), as illustrated in Fig. 3 . Overall, the quality of the included literature was deemed satisfactory. Each study adopted a case-control design, with the unanimous gold standard for diagnosis across all experiments being the pathological results post-transplantation. An analysis of quality scores in relation to sensitivity revealed that the study quality did not significantly influence the sensitivity outcomes. The pertinent data and findings from this analysis are detailed in Table 1 .

The quality assessment of included studies using the Newcastle-Ottawa Scale (NOS); The NOS evaluates studies on their selection of groups, comparability of groups, and ascertainment of exposure or outcomes, represented in the star ratings displayed in X-axis

The metareg plot evaluating the quality of included studies in the meta-analysis; This plot visually displays the relationship between the study quality scores based on sensitivity

Statistical analysis results

In this meta-analysis, Stata 14 was utilized as the primary statistical software. Due to significant heterogeneity observed in the initial results, indicated by an I2 value exceeding 50%, comprehensive subgroup analyses and meta-regression were undertaken to delve deeper into the data. The subgroup analysis was specifically tailored based on the study outcomes, with a particular focus on the methodologies used for CXCL10 quantification (isolated CXCL10 measurement versus the CXCL10/Creatinine ratio). The heterogeneity analysis revealed that the I 2 values for sensitivity and specificity, when utilizing the CXCL10 only measurement approach, were 63.4% ( p = 0.027) and 80.4% ( p = 0.000) respectively, as illustrated in Fig. 4 . In contrast, the I 2 values for sensitivity and specificity with the CXCL10/Creatinine ratio method were 0% ( p = 0.454) and 97.6% ( p = 0.000) respectively, detailed in Fig. 5 .

Forest plots; show the 5 included studies heterogeneity and estimated exposures, sensitivity (left) and specificity (right), with urinary CXCL10 as outcome

Forest plots; show the 5 included studies heterogeneity and estimated exposures, sensitivity (left) and specificity (right), with urinary CXCL10/Cr as outcome

Publication bias test

Funnel plots are commonly used in meta-analysis to assess publication bias and small-study effects. Asymmetric funnel plots can indicate the presence of such biases, but they can also be caused by other factors such as the choice of the plotted effect size, the presence of a moderator correlated with the study effect and size, or chance. These plots add contours of statistical significance to the funnel plot to aid interpretation. Stata 14 was used to draw funnel plot. As displayed in Fig. 6 , it had a moderate asymmetry.

The funnel plot; used to assess the potential for publication bias among the included studies for sensitivity as the exposure

Previous research underscores the significance of CXCL10 as a biomarker in the prognosis of kidney graft injuries (acute rejection (AR), TCMR, ABMR), examining its presence in both serum and urinary assays. Investigations have not only focused on CXCL10 as an isolated marker but have also encompassed its correlative studies with serum creatinine levels.

These studies propose that CXCL10 may serve as an integral biomarker, offering predictive insights into the functional status of renal transplants [ 5 , 6 , 15 , 16 , 17 , 20 ]. Rabant et al. suggested that low levels of urinary CXCL10 could predict immunological quiescence, or a low risk of acute rejection, as early as one month into stable graft conditions [ 31 ]. The study by Mühlbacher J et al. highlighted that the association of urinary CXCL10/Cr ratio with donor-specific antibodies (DSA) significantly improved the identification of ABMR and the prediction of graft loss. Their finding emphasizes the potential of CXCL10 as a biomarker in transplant medicine [ 19 ]. Earlier research, demonstrated that measuring the serum level of CXCL10 before kidney transplantation could be a predictor of acute rejection which suggest that CXCL10 levels could serve as an important indicator for preemptive measures in transplant recipients [ 32 ]. Finally, Jackson et al. concluded that CXCL10 levels don’t seem to distinguish between AR and BK virus infection. They both show elevated levels of this chemokine, although diagnostic certainty is still possible when combined with other tests like a creatinine assay [ 33 ].This study presents a comprehensive systematic review and meta-analysis that focuses on the clinical validation and comparison of CXCL10 and CXCL10/Cr urinary levels in the detection of post-kidney transplantation injuries. The analysis encompasses data from 10 studies (9 articles) involving a total of 3035 kidney transplant recipients. The findings indicate that CXCL10 protein level demonstrated a sensitivity of 0.78 (0.69–0.89) and a specificity of 0.82 (0.72–0.94), while CXCL10/Cr level exhibited a sensitivity of 0.77 (0.72–0.81) and a specificity of 0.73 (0.60–0.90). These results indicate that assessing the sensitivity and specificity of CXCL10, as opposed to CXCL10/Cr, may offer greater efficacy in predicting injuries in kidney transplant recipients. It may be related to notable variations in urinary creatinine excretion rates (uCER) among kidney transplant recipients. For instance, those with delayed graft function may have values below 300 mg/day, while patients showing prompt graft function can exceed 2,100 mg/day [ 34 ]. These differences can be influenced by several factors, including age, sex, race [ 35 ], daily changes in creatinine production, levels of physical activity, dietary habits, emotional stress, muscle mass, and overall health condition [ 36 ]. Research indicates that urinary creatinine can fluctuate significantly even within an individual, with intraindividual coefficients of variation (CVs) reported to be between 10.5% and 14.4%. Additionally, creatinine excretion may vary throughout the day and across different days [ 37 ]. Some studies have found that normalizing urinary biomarker values to creatinine, such as in the case of neutrophil gelatinase-associated lipocalin (NGAL), can help lower these intraindividual CVs [ 38 , 39 ]. Waikar et al. noted that kidney injury molecule-1(KIM-1) excretion and uCER have different responses during acute disease states [ 34 ], suggesting that normalizing to creatinine is not always appropriate. Therefore, the appropriateness of normalizing urinary creatinine depends significantly on the specific research objectives, the biomarker involved, and the clinical context of the patients being studied [ 40 ].

This review encompassed nine articles [ 18 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ], five of which examined urinary CXCL10 protein levels, [ 25 , 26 , 27 , 29 , 30 ] while one included two groups [ 27 ]. The first group exclusively evaluated urinary CXCL10 protein levels, while the second group measured urinary CXCL10 to serum Cr ratio. The other four articles in the review explored urinary CXCL10 to urinary Cr ratio as a biomarker under study [ 18 , 24 , 28 , 31 ].

Moreover, Matz et al. conducted a study involving two groups, acute cellular rejection and borderline rejection (BR), which were assessed at three different time points (2/3, 4/5, and 6/7 days) prior to rejection. The study reported varying sensitivities of 0.47, 0.62, and 0.71, with a consistent specificity of 0.95 for all time points, focusing on early post-transplant urinary CXCL10 protein levels after kidney transplantation. These data were subsequently aggregated for inclusion in the final evaluation, yielding a combined sensitivity and specificity of 0.63 and 0.95, respectively [ 29 ].

The other study that was pooled is Rabant et al. that examined urinary samples collected at three time points post-kidney transplantation 10 days, 1 month, and 3 months. The study focused on measuring the CXCL10/Cr ratio in recipients with ABMR, TCMR, and mixed rejection. The reported sensitivities for these time points were 0.57, 0.83, and 0.53, with specificities of 0.52, 0.51, and 0.76, respectively. Upon combining the data from these time points, the resulting sensitivity and specificity were 0.74 and 0.66, respectively [ 31 ].

The last study that was pooled for including in meta-analysis is Van loon et al. [ 24 ] who assessed the CXCL10/Cr protein level through an automated immunoassay method at three distinct thresholds (5%, 16%, and 25%) derived from a 5-parametere model for the non-invasive detection of acute rejection. The sensitivities reported at theses thresholds were 0.882, 0.392, and 0.248, with corresponding specificities of 0.314, 0.9, and 0.96. When the data of these threshold were combined the resulting sensitivity and specificity were 0.8 and 0.93, respectively.

The detection methods used for urinary CXCL10 in the included studies were based on assessing protein expression levels. All studies detected this urinary protein using ELISA, except for Hu [ 30 ] and Van loon [ 24 ] who used luminex assay and automated immunoassay, respectively. Across all included studies, an increased level of urinary CXCL10 was associated with a type of kidney graft injury. All urinary samples were collected post-transplantation and almost always before biopsy procedures (Table S1 ). Finally, it is worth noting that measuring urinary protein levels based on antibody-using tests such as ELISA is currently one of the most reliable and accurate existing methods.

The injuries related to the included studies in this review encompassed 14 different types of dysfunctions of kidney grafts. These included AR, TCMR, ABMR, mixed rejection (MR), BR, subclinical rejection (SR), clinical rejection (CLR), acute vascular rejection (AVR), BK virus nephropathy (BKVN), acute tubular necrosis (ATN), chronic rejection (CHR), late clinical rejection, graft functional decline, and graft loss. This review discusses the potential role of urinary CXCL10 assessment before performing an invasive biopsy procedure in identifying high-risk kidney transplant recipients who were developing at least one of the 14 different types of dysfunctions. Therefore, serial urinary CXCL10 monitoring in the weeks and months following transplantation may help accelerate clinical diagnosis of recipients at risk for rejection or graft loss which might help in reducing the number of biopsies. Accordingly, CXCL10 shows promise as a marker for identifying post-kidney transplant injuries, particularly rejection, further comprehensive studies are essential. These studies should focus on standardizing factors such as study design, sample type, evaluation methods, types of post-transplant injuries, and patient monitoring for a minimum of 6 months before and after transplantation. Moreover, combining the clinical data of CXCL10 with indicators like serum urea, creatinine, and proteinuria could lead to more precise models for predicting various potential injuries following kidney transplantation.

This manuscript is subject to several limitations. Firstly, numerous articles were excluded from the analysis due to insufficient information for calculating effect size. Additionally, a standardized method for grouping patients was not available, resulting in the comparison of studies with vastly different study groups, making it impossible to merge their results. Moreover, the articles employed two distinct approaches - studying CXCL10 levels and CXCL10/Cr ratios - which are not compatible for combination. These factors led to a significant decrease in the number of studies included in the meta-analysis.

The identification of specific and sensitive biomarkers could potentially reduce unnecessary biopsies, leading to more individualized treatment plans and improved health outcomes. While urinary CXCL10 levels have been studied as an important inflammatory chemokine in kidney post-transplant outcomes, relying solely on CXCL10 is insufficient for determining graft complications. Therefore, considering other critical clinical parameters alongside CXCL10 may facilitate early detection and intervention in graft-related complications. Notably, urinary CXCL10 assessment appears more effective in detecting post-transplant injuries than measuring the CXCL10/Cr ratio.

Data availability

“All data generated or analyzed during this study are included in this published article and its supplementary information file.”

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Acknowledgements

The authors wish to thank Shiraz University of Medical Sciences for their corporation in data gathering.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Sahar Janfeshan, Afsoon Afshari & Jamshid Roozbeh

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Janfeshan, S., Afshari, A., Yaghobi, R. et al. Urinary CXCL-10, a prognostic biomarker for kidney graft injuries: a systematic review and meta-analysis. BMC Nephrol 25 , 292 (2024). https://doi.org/10.1186/s12882-024-03728-2

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An overview of methodological approaches in systematic reviews

Prabhakar veginadu.

1 Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, Bendigo Victoria, Australia

Hanny Calache

2 Lincoln International Institute for Rural Health, University of Lincoln, Brayford Pool, Lincoln UK

Akshaya Pandian

3 Department of Orthodontics, Saveetha Dental College, Chennai Tamil Nadu, India

Mohd Masood

Associated data.

APPENDIX B: List of excluded studies with detailed reasons for exclusion

APPENDIX C: Quality assessment of included reviews using AMSTAR 2

The aim of this overview is to identify and collate evidence from existing published systematic review (SR) articles evaluating various methodological approaches used at each stage of an SR.

The search was conducted in five electronic databases from inception to November 2020 and updated in February 2022: MEDLINE, Embase, Web of Science Core Collection, Cochrane Database of Systematic Reviews, and APA PsycINFO. Title and abstract screening were performed in two stages by one reviewer, supported by a second reviewer. Full‐text screening, data extraction, and quality appraisal were performed by two reviewers independently. The quality of the included SRs was assessed using the AMSTAR 2 checklist.

The search retrieved 41,556 unique citations, of which 9 SRs were deemed eligible for inclusion in final synthesis. Included SRs evaluated 24 unique methodological approaches used for defining the review scope and eligibility, literature search, screening, data extraction, and quality appraisal in the SR process. Limited evidence supports the following (a) searching multiple resources (electronic databases, handsearching, and reference lists) to identify relevant literature; (b) excluding non‐English, gray, and unpublished literature, and (c) use of text‐mining approaches during title and abstract screening.

The overview identified limited SR‐level evidence on various methodological approaches currently employed during five of the seven fundamental steps in the SR process, as well as some methodological modifications currently used in expedited SRs. Overall, findings of this overview highlight the dearth of published SRs focused on SR methodologies and this warrants future work in this area.

1. INTRODUCTION

Evidence synthesis is a prerequisite for knowledge translation. 1 A well conducted systematic review (SR), often in conjunction with meta‐analyses (MA) when appropriate, is considered the “gold standard” of methods for synthesizing evidence related to a topic of interest. 2 The central strength of an SR is the transparency of the methods used to systematically search, appraise, and synthesize the available evidence. 3 Several guidelines, developed by various organizations, are available for the conduct of an SR; 4 , 5 , 6 , 7 among these, Cochrane is considered a pioneer in developing rigorous and highly structured methodology for the conduct of SRs. 8 The guidelines developed by these organizations outline seven fundamental steps required in SR process: defining the scope of the review and eligibility criteria, literature searching and retrieval, selecting eligible studies, extracting relevant data, assessing risk of bias (RoB) in included studies, synthesizing results, and assessing certainty of evidence (CoE) and presenting findings. 4 , 5 , 6 , 7

The methodological rigor involved in an SR can require a significant amount of time and resource, which may not always be available. 9 As a result, there has been a proliferation of modifications made to the traditional SR process, such as refining, shortening, bypassing, or omitting one or more steps, 10 , 11 for example, limits on the number and type of databases searched, limits on publication date, language, and types of studies included, and limiting to one reviewer for screening and selection of studies, as opposed to two or more reviewers. 10 , 11 These methodological modifications are made to accommodate the needs of and resource constraints of the reviewers and stakeholders (e.g., organizations, policymakers, health care professionals, and other knowledge users). While such modifications are considered time and resource efficient, they may introduce bias in the review process reducing their usefulness. 5

Substantial research has been conducted examining various approaches used in the standardized SR methodology and their impact on the validity of SR results. There are a number of published reviews examining the approaches or modifications corresponding to single 12 , 13 or multiple steps 14 involved in an SR. However, there is yet to be a comprehensive summary of the SR‐level evidence for all the seven fundamental steps in an SR. Such a holistic evidence synthesis will provide an empirical basis to confirm the validity of current accepted practices in the conduct of SRs. Furthermore, sometimes there is a balance that needs to be achieved between the resource availability and the need to synthesize the evidence in the best way possible, given the constraints. This evidence base will also inform the choice of modifications to be made to the SR methods, as well as the potential impact of these modifications on the SR results. An overview is considered the choice of approach for summarizing existing evidence on a broad topic, directing the reader to evidence, or highlighting the gaps in evidence, where the evidence is derived exclusively from SRs. 15 Therefore, for this review, an overview approach was used to (a) identify and collate evidence from existing published SR articles evaluating various methodological approaches employed in each of the seven fundamental steps of an SR and (b) highlight both the gaps in the current research and the potential areas for future research on the methods employed in SRs.

An a priori protocol was developed for this overview but was not registered with the International Prospective Register of Systematic Reviews (PROSPERO), as the review was primarily methodological in nature and did not meet PROSPERO eligibility criteria for registration. The protocol is available from the corresponding author upon reasonable request. This overview was conducted based on the guidelines for the conduct of overviews as outlined in The Cochrane Handbook. 15 Reporting followed the Preferred Reporting Items for Systematic reviews and Meta‐analyses (PRISMA) statement. 3

2.1. Eligibility criteria

Only published SRs, with or without associated MA, were included in this overview. We adopted the defining characteristics of SRs from The Cochrane Handbook. 5 According to The Cochrane Handbook, a review was considered systematic if it satisfied the following criteria: (a) clearly states the objectives and eligibility criteria for study inclusion; (b) provides reproducible methodology; (c) includes a systematic search to identify all eligible studies; (d) reports assessment of validity of findings of included studies (e.g., RoB assessment of the included studies); (e) systematically presents all the characteristics or findings of the included studies. 5 Reviews that did not meet all of the above criteria were not considered a SR for this study and were excluded. MA‐only articles were included if it was mentioned that the MA was based on an SR.

SRs and/or MA of primary studies evaluating methodological approaches used in defining review scope and study eligibility, literature search, study selection, data extraction, RoB assessment, data synthesis, and CoE assessment and reporting were included. The methodological approaches examined in these SRs and/or MA can also be related to the substeps or elements of these steps; for example, applying limits on date or type of publication are the elements of literature search. Included SRs examined or compared various aspects of a method or methods, and the associated factors, including but not limited to: precision or effectiveness; accuracy or reliability; impact on the SR and/or MA results; reproducibility of an SR steps or bias occurred; time and/or resource efficiency. SRs assessing the methodological quality of SRs (e.g., adherence to reporting guidelines), evaluating techniques for building search strategies or the use of specific database filters (e.g., use of Boolean operators or search filters for randomized controlled trials), examining various tools used for RoB or CoE assessment (e.g., ROBINS vs. Cochrane RoB tool), or evaluating statistical techniques used in meta‐analyses were excluded. 14

2.2. Search

The search for published SRs was performed on the following scientific databases initially from inception to third week of November 2020 and updated in the last week of February 2022: MEDLINE (via Ovid), Embase (via Ovid), Web of Science Core Collection, Cochrane Database of Systematic Reviews, and American Psychological Association (APA) PsycINFO. Search was restricted to English language publications. Following the objectives of this study, study design filters within databases were used to restrict the search to SRs and MA, where available. The reference lists of included SRs were also searched for potentially relevant publications.

The search terms included keywords, truncations, and subject headings for the key concepts in the review question: SRs and/or MA, methods, and evaluation. Some of the terms were adopted from the search strategy used in a previous review by Robson et al., which reviewed primary studies on methodological approaches used in study selection, data extraction, and quality appraisal steps of SR process. 14 Individual search strategies were developed for respective databases by combining the search terms using appropriate proximity and Boolean operators, along with the related subject headings in order to identify SRs and/or MA. 16 , 17 A senior librarian was consulted in the design of the search terms and strategy. Appendix A presents the detailed search strategies for all five databases.

2.3. Study selection and data extraction

Title and abstract screening of references were performed in three steps. First, one reviewer (PV) screened all the titles and excluded obviously irrelevant citations, for example, articles on topics not related to SRs, non‐SR publications (such as randomized controlled trials, observational studies, scoping reviews, etc.). Next, from the remaining citations, a random sample of 200 titles and abstracts were screened against the predefined eligibility criteria by two reviewers (PV and MM), independently, in duplicate. Discrepancies were discussed and resolved by consensus. This step ensured that the responses of the two reviewers were calibrated for consistency in the application of the eligibility criteria in the screening process. Finally, all the remaining titles and abstracts were reviewed by a single “calibrated” reviewer (PV) to identify potential full‐text records. Full‐text screening was performed by at least two authors independently (PV screened all the records, and duplicate assessment was conducted by MM, HC, or MG), with discrepancies resolved via discussions or by consulting a third reviewer.

Data related to review characteristics, results, key findings, and conclusions were extracted by at least two reviewers independently (PV performed data extraction for all the reviews and duplicate extraction was performed by AP, HC, or MG).

2.4. Quality assessment of included reviews

The quality assessment of the included SRs was performed using the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews). The tool consists of a 16‐item checklist addressing critical and noncritical domains. 18 For the purpose of this study, the domain related to MA was reclassified from critical to noncritical, as SRs with and without MA were included. The other six critical domains were used according to the tool guidelines. 18 Two reviewers (PV and AP) independently responded to each of the 16 items in the checklist with either “yes,” “partial yes,” or “no.” Based on the interpretations of the critical and noncritical domains, the overall quality of the review was rated as high, moderate, low, or critically low. 18 Disagreements were resolved through discussion or by consulting a third reviewer.

2.5. Data synthesis

To provide an understandable summary of existing evidence syntheses, characteristics of the methods evaluated in the included SRs were examined and key findings were categorized and presented based on the corresponding step in the SR process. The categories of key elements within each step were discussed and agreed by the authors. Results of the included reviews were tabulated and summarized descriptively, along with a discussion on any overlap in the primary studies. 15 No quantitative analyses of the data were performed.

From 41,556 unique citations identified through literature search, 50 full‐text records were reviewed, and nine systematic reviews 14 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 were deemed eligible for inclusion. The flow of studies through the screening process is presented in Figure 1 . A list of excluded studies with reasons can be found in Appendix B .

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Study selection flowchart

3.1. Characteristics of included reviews

Table 1 summarizes the characteristics of included SRs. The majority of the included reviews (six of nine) were published after 2010. 14 , 22 , 23 , 24 , 25 , 26 Four of the nine included SRs were Cochrane reviews. 20 , 21 , 22 , 23 The number of databases searched in the reviews ranged from 2 to 14, 2 reviews searched gray literature sources, 24 , 25 and 7 reviews included a supplementary search strategy to identify relevant literature. 14 , 19 , 20 , 21 , 22 , 23 , 26 Three of the included SRs (all Cochrane reviews) included an integrated MA. 20 , 21 , 23

Characteristics of included studies

Author, year	Search strategy (year last searched; no. databases; supplementary searches)	SR design (type of review; no. of studies included)	Topic; subject area	SR objectives	SR authors’ comments on study quality
Crumley, 2005	2004; Seven databases; four journals handsearched, reference lists and contacting authors	SR; = 64	RCTs and CCTs; not specified	To identify and quantitatively review studies comparing two or more different resources (e.g., databases, Internet, handsearching) used to identify RCTs and CCTs for systematic reviews.	Most of the studies adequately described reproducible search methods, expected search yield. Poor quality in studies was mainly due to lack of rigor in reporting selection methodology. Majority of the studies did not indicate the number of people involved in independently screening the searches or applying eligibility criteria to identify potentially relevant studies.
Hopewell, 2007	2002; eight databases; selected journals and published abstracts handsearched, and contacting authors	SR and MA; = 34 (34 in quantitative analysis)	RCTs; health care	To review systematically empirical studies, which have compared the results of handsearching with the results of searching one or more electronic databases to identify reports of randomized trials.	The electronic search was designed and carried out appropriately in majority of the studies, while the appropriateness of handsearching was unclear in half the studies because of limited information. The screening studies methods used in both groups were comparable in most of the studies.
Hopewell, 2007	2005; two databases; selected journals and published abstracts handsearched, reference lists, citations and contacting authors	SR and MA; = 5 (5 in quantitative analysis)	RCTs; health care	To review systematically research studies, which have investigated the impact of gray literature in meta‐analyses of randomized trials of health care interventions.	In majority of the studies, electronic searches were designed and conducted appropriately, and the selection of studies for eligibility was similar for handsearching and database searching. Insufficient data for most studies to assess the appropriateness of handsearching and investigator agreeability on the eligibility of the trial reports.
Horsley, 2011	2008; three databases; reference lists, citations and contacting authors	SR; = 12	Any topic or study area	To investigate the effectiveness of checking reference lists for the identification of additional, relevant studies for systematic reviews. Effectiveness is defined as the proportion of relevant studies identified by review authors solely by checking reference lists.	Interpretability and generalizability of included studies was difficult. Extensive heterogeneity among the studies in the number and type of databases used. Lack of control in majority of the studies related to the quality and comprehensiveness of searching.
Morrison, 2012	2011; six databases and gray literature	SR; = 5	RCTs; conventional medicine	To examine the impact of English language restriction on systematic review‐based meta‐analyses	The included studies were assessed to have good reporting quality and validity of results. Methodological issues were mainly noted in the areas of sample power calculation and distribution of confounders.
Robson, 2019	2016; three databases; reference lists and contacting authors	SR; = 37	N/R	To identify and summarize studies assessing methodologies for study selection, data abstraction, or quality appraisal in systematic reviews.	The quality of the included studies was generally low. Only one study was assessed as having low RoB across all four domains. Majority of the studies were assessed to having unclear RoB across one or more domains.
Schmucker, 2017	2016; four databases; reference lists	SR; = 10	Study data; medicine	To assess whether the inclusion of data that were not published at all and/or published only in the gray literature influences pooled effect estimates in meta‐analyses and leads to different interpretation.	Majority of the included studies could not be judged on the adequacy of matching or adjusting for confounders of the gray/unpublished data in comparison to published data.
					Also, generalizability of results was low or unclear in four research projects
Morissette, 2011	2009; five databases; reference lists and contacting authors	SR and MA; = 6 (5 included in quantitative analysis)	N/R	To determine whether blinded versus unblinded assessments of risk of bias result in similar or systematically different assessments in studies included in a systematic review.	Four studies had unclear risk of bias, while two studies had high risk of bias.
O'Mara‐Eves, 2015	2013; 14 databases and gray literature	SR; = 44	N/R	To gather and present the available research evidence on existing methods for text mining related to the title and abstract screening stage in a systematic review, including the performance metrics used to evaluate these technologies.	Quality appraised based on two criteria‐sampling of test cases and adequacy of methods description for replication. No study was excluded based on the quality (author contact).

SR = systematic review; MA = meta‐analysis; RCT = randomized controlled trial; CCT = controlled clinical trial; N/R = not reported.

The included SRs evaluated 24 unique methodological approaches (26 in total) used across five steps in the SR process; 8 SRs evaluated 6 approaches, 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 while 1 review evaluated 18 approaches. 14 Exclusion of gray or unpublished literature 21 , 26 and blinding of reviewers for RoB assessment 14 , 23 were evaluated in two reviews each. Included SRs evaluated methods used in five different steps in the SR process, including methods used in defining the scope of review ( n = 3), literature search ( n = 3), study selection ( n = 2), data extraction ( n = 1), and RoB assessment ( n = 2) (Table 2 ).

Summary of findings from review evaluating systematic review methods

Key elements	Author, year	Method assessed	Evaluations/outcomes (P—primary; S—secondary)	Summary of SR authors’ conclusions	Quality of review

Excluding study data based on publication status	Hopewell, 2007	Gray vs. published literature	Pooled effect estimate	Published trials are usually larger and show an overall greater treatment effect than gray trials. Excluding trials reported in gray literature from SRs and MAs may exaggerate the results.	Moderate
	Schmucker, 2017	Gray and/or unpublished vs. published literature	P: Pooled effect estimate	Excluding unpublished trials had no or only a small effect on the pooled estimates of treatment effects. Insufficient evidence to conclude the impact of including unpublished or gray study data on MA conclusions.	Moderate
			S: Impact on interpretation of MA
Excluding study data based on language of publication	Morrison, 2012	English language vs. non‐English language publications	P: Bias in summary treatment effects	No evidence of a systematic bias from the use of English language restrictions in systematic review‐based meta‐analyses in conventional medicine. Conflicting results on the methodological and reporting quality of English and non‐English language RCTs. Further research required.	Low
			S: number of included studies and patients, methodological quality and statistical heterogeneity

Resources searching	Crumley, 2005	Two or more resources searching vs. resource‐specific searching	Recall and precision	Multiple‐source comprehensive searches are necessary to identify all RCTs for a systematic review. For electronic databases, using the Cochrane HSS or complex search strategy in consultation with a librarian is recommended.	Critically low
Supplementary searching	Hopewell, 2007	Handsearching only vs. one or more electronic database(s) searching	Number of identified randomized trials	Handsearching is important for identifying trial reports for inclusion in systematic reviews of health care interventions published in nonindexed journals. Where time and resources are limited, majority of the full English‐language trial reports can be identified using a complex search or the Cochrane HSS.	Moderate
	Horsley, 2011	Checking reference list (no comparison)	P: additional yield of checking reference lists	There is some evidence to support the use of checking reference lists to complement literature search in systematic reviews.	Low
			S: additional yield by publication type, study design or both and data pertaining to costs

Reviewer characteristics	Robson, 2019	Single vs. double reviewer screening	P: Accuracy, reliability, or efficiency of a method	Using two reviewers for screening is recommended. If resources are limited, one reviewer can screen, and other reviewer can verify the list of excluded studies.	Low
			S: factors affecting accuracy or reliability of a method
		Experienced vs. inexperienced reviewers for screening		Screening must be performed by experienced reviewers
		Screening by blinded vs. unblinded reviewers		Authors do not recommend blinding of reviewers during screening as the blinding process was time‐consuming and had little impact on the results of MA
Use of technology for study selection	Robson, 2019	Use of dual computer monitors vs. nonuse of dual monitors for screening	P: Accuracy, reliability, or efficiency of a method	There are no significant differences in the time spent on abstract or full‐text screening with the use and nonuse of dual monitors	Low
			S: factors affecting accuracy or reliability of a method
		Use of Google translate to translate non‐English citations to facilitate screening		Use of Google translate to screen German language citations
	O'Mara‐Eves, 2015	Use of text mining for title and abstract screening	Any evaluation concerning workload reduction	Text mining approaches can be used to reduce the number of studies to be screened, increase the rate of screening, improve the workflow with screening prioritization, and replace the second reviewer. The evaluated approaches reported saving a workload of between 30% and 70%	Critically low
Order of screening	Robson, 2019	Title‐first screening vs. title‐and‐abstract simultaneous screening	P: Accuracy, reliability, or efficiency of a method	Title‐first screening showed no substantial gain in time when compared to simultaneous title and abstract screening.	Low
			S: factors affecting accuracy or reliability of a method

Reviewer characteristics	Robson, 2019	Single vs. double reviewer data extraction	P: Accuracy, reliability, or efficiency of a method	Use two reviewers for data extraction. Single reviewer data extraction followed by the verification of outcome data by a second reviewer (where statistical analysis is planned), if resources preclude	Low
			S: factors affecting accuracy or reliability of a method
		Experienced vs. inexperienced reviewers for data extraction		Experienced reviewers must be used for extracting continuous outcomes data
		Data extraction by blinded vs. unblinded reviewers		Authors do not recommend blinding of reviewers during data extraction as it had no impact on the results of MA
Use of technology for data extraction		Use of dual computer monitors vs. nonuse of dual monitors for data extraction		Using two computer monitors may improve the efficiency of data extraction
		Data extraction by two English reviewers using Google translate vs. data extraction by two reviewers fluent in respective languages		Google translate provides limited accuracy for data extraction
		Computer‐assisted vs. double reviewer extraction of graphical data		Use of computer‐assisted programs to extract graphical data
Obtaining additional data		Contacting study authors for additional data		Recommend contacting authors for obtaining additional relevant data

Reviewer characteristics	Robson, 2019	Quality appraisal by blinded vs. unblinded reviewers	P: Accuracy, reliability, or efficiency of a method	Inconsistent results on RoB assessments performed by blinded and unblinded reviewers. Blinding reviewers for quality appraisal not recommended	Low
			S: factors affecting accuracy or reliability of a method
	Morissette, 2011	Risk of bias (RoB) assessment by blinded vs. unblinded reviewers	P: Mean difference and 95% confidence interval between RoB assessment scores	Findings related to the difference between blinded and unblinded RoB assessments are inconsistent from the studies. Pooled effects show no differences in RoB assessments for assessments completed in a blinded or unblinded manner.	Moderate
			S: qualitative level of agreement, mean RoB scores and measures of variance for the results of the RoB assessments, and inter‐rater reliability between blinded and unblinded reviewers
	Robson, 2019	Experienced vs. inexperienced reviewers for quality appraisal	P: Accuracy, reliability, or efficiency of a method	Reviewers performing quality appraisal must be trained. Quality assessment tool must be pilot tested.	Low
			S: factors affecting accuracy or reliability of a method
		Use of additional guidance vs. nonuse of additional guidance for quality appraisal		Providing guidance and decision rules for quality appraisal improved the inter‐rater reliability in RoB assessments.
Obtaining additional data		Contacting study authors for obtaining additional information/use of supplementary information available in the published trials vs. no additional information for quality appraisal		Additional data related to study quality obtained by contacting study authors improved the quality assessment.
RoB assessment of qualitative studies		Structured vs. unstructured appraisal of qualitative research studies		Use of structured tool if qualitative and quantitative studies designs are included in the review. For qualitative reviews, either structured or unstructured quality appraisal tool can be used.

There was some overlap in the primary studies evaluated in the included SRs on the same topics: Schmucker et al. 26 and Hopewell et al. 21 ( n = 4), Hopewell et al. 20 and Crumley et al. 19 ( n = 30), and Robson et al. 14 and Morissette et al. 23 ( n = 4). There were no conflicting results between any of the identified SRs on the same topic.

3.2. Methodological quality of included reviews

Overall, the quality of the included reviews was assessed as moderate at best (Table 2 ). The most common critical weakness in the reviews was failure to provide justification for excluding individual studies (four reviews). Detailed quality assessment is provided in Appendix C .

3.3. Evidence on systematic review methods

3.3.1. methods for defining review scope and eligibility.

Two SRs investigated the effect of excluding data obtained from gray or unpublished sources on the pooled effect estimates of MA. 21 , 26 Hopewell et al. 21 reviewed five studies that compared the impact of gray literature on the results of a cohort of MA of RCTs in health care interventions. Gray literature was defined as information published in “print or electronic sources not controlled by commercial or academic publishers.” Findings showed an overall greater treatment effect for published trials than trials reported in gray literature. In a more recent review, Schmucker et al. 26 addressed similar objectives, by investigating gray and unpublished data in medicine. In addition to gray literature, defined similar to the previous review by Hopewell et al., the authors also evaluated unpublished data—defined as “supplemental unpublished data related to published trials, data obtained from the Food and Drug Administration or other regulatory websites or postmarketing analyses hidden from the public.” The review found that in majority of the MA, excluding gray literature had little or no effect on the pooled effect estimates. The evidence was limited to conclude if the data from gray and unpublished literature had an impact on the conclusions of MA. 26

Morrison et al. 24 examined five studies measuring the effect of excluding non‐English language RCTs on the summary treatment effects of SR‐based MA in various fields of conventional medicine. Although none of the included studies reported major difference in the treatment effect estimates between English only and non‐English inclusive MA, the review found inconsistent evidence regarding the methodological and reporting quality of English and non‐English trials. 24 As such, there might be a risk of introducing “language bias” when excluding non‐English language RCTs. The authors also noted that the numbers of non‐English trials vary across medical specialties, as does the impact of these trials on MA results. Based on these findings, Morrison et al. 24 conclude that literature searches must include non‐English studies when resources and time are available to minimize the risk of introducing “language bias.”

3.3.2. Methods for searching studies

Crumley et al. 19 analyzed recall (also referred to as “sensitivity” by some researchers; defined as “percentage of relevant studies identified by the search”) and precision (defined as “percentage of studies identified by the search that were relevant”) when searching a single resource to identify randomized controlled trials and controlled clinical trials, as opposed to searching multiple resources. The studies included in their review frequently compared a MEDLINE only search with the search involving a combination of other resources. The review found low median recall estimates (median values between 24% and 92%) and very low median precisions (median values between 0% and 49%) for most of the electronic databases when searched singularly. 19 A between‐database comparison, based on the type of search strategy used, showed better recall and precision for complex and Cochrane Highly Sensitive search strategies (CHSSS). In conclusion, the authors emphasize that literature searches for trials in SRs must include multiple sources. 19

In an SR comparing handsearching and electronic database searching, Hopewell et al. 20 found that handsearching retrieved more relevant RCTs (retrieval rate of 92%−100%) than searching in a single electronic database (retrieval rates of 67% for PsycINFO/PsycLIT, 55% for MEDLINE, and 49% for Embase). The retrieval rates varied depending on the quality of handsearching, type of electronic search strategy used (e.g., simple, complex or CHSSS), and type of trial reports searched (e.g., full reports, conference abstracts, etc.). The authors concluded that handsearching was particularly important in identifying full trials published in nonindexed journals and in languages other than English, as well as those published as abstracts and letters. 20

The effectiveness of checking reference lists to retrieve additional relevant studies for an SR was investigated by Horsley et al. 22 The review reported that checking reference lists yielded 2.5%–40% more studies depending on the quality and comprehensiveness of the electronic search used. The authors conclude that there is some evidence, although from poor quality studies, to support use of checking reference lists to supplement database searching. 22

3.3.3. Methods for selecting studies

Three approaches relevant to reviewer characteristics, including number, experience, and blinding of reviewers involved in the screening process were highlighted in an SR by Robson et al. 14 Based on the retrieved evidence, the authors recommended that two independent, experienced, and unblinded reviewers be involved in study selection. 14 A modified approach has also been suggested by the review authors, where one reviewer screens and the other reviewer verifies the list of excluded studies, when the resources are limited. It should be noted however this suggestion is likely based on the authors’ opinion, as there was no evidence related to this from the studies included in the review.

Robson et al. 14 also reported two methods describing the use of technology for screening studies: use of Google Translate for translating languages (for example, German language articles to English) to facilitate screening was considered a viable method, while using two computer monitors for screening did not increase the screening efficiency in SR. Title‐first screening was found to be more efficient than simultaneous screening of titles and abstracts, although the gain in time with the former method was lesser than the latter. Therefore, considering that the search results are routinely exported as titles and abstracts, Robson et al. 14 recommend screening titles and abstracts simultaneously. However, the authors note that these conclusions were based on very limited number (in most instances one study per method) of low‐quality studies. 14

3.3.4. Methods for data extraction

Robson et al. 14 examined three approaches for data extraction relevant to reviewer characteristics, including number, experience, and blinding of reviewers (similar to the study selection step). Although based on limited evidence from a small number of studies, the authors recommended use of two experienced and unblinded reviewers for data extraction. The experience of the reviewers was suggested to be especially important when extracting continuous outcomes (or quantitative) data. However, when the resources are limited, data extraction by one reviewer and a verification of the outcomes data by a second reviewer was recommended.

As for the methods involving use of technology, Robson et al. 14 identified limited evidence on the use of two monitors to improve the data extraction efficiency and computer‐assisted programs for graphical data extraction. However, use of Google Translate for data extraction in non‐English articles was not considered to be viable. 14 In the same review, Robson et al. 14 identified evidence supporting contacting authors for obtaining additional relevant data.

3.3.5. Methods for RoB assessment

Two SRs examined the impact of blinding of reviewers for RoB assessments. 14 , 23 Morissette et al. 23 investigated the mean differences between the blinded and unblinded RoB assessment scores and found inconsistent differences among the included studies providing no definitive conclusions. Similar conclusions were drawn in a more recent review by Robson et al., 14 which included four studies on reviewer blinding for RoB assessment that completely overlapped with Morissette et al. 23

Use of experienced reviewers and provision of additional guidance for RoB assessment were examined by Robson et al. 14 The review concluded that providing intensive training and guidance on assessing studies reporting insufficient data to the reviewers improves RoB assessments. 14 Obtaining additional data related to quality assessment by contacting study authors was also found to help the RoB assessments, although based on limited evidence. When assessing the qualitative or mixed method reviews, Robson et al. 14 recommends the use of a structured RoB tool as opposed to an unstructured tool. No SRs were identified on data synthesis and CoE assessment and reporting steps.

4. DISCUSSION

4.1. summary of findings.

Nine SRs examining 24 unique methods used across five steps in the SR process were identified in this overview. The collective evidence supports some current traditional and modified SR practices, while challenging other approaches. However, the quality of the included reviews was assessed to be moderate at best and in the majority of the included SRs, evidence related to the evaluated methods was obtained from very limited numbers of primary studies. As such, the interpretations from these SRs should be made cautiously.

The evidence gathered from the included SRs corroborate a few current SR approaches. 5 For example, it is important to search multiple resources for identifying relevant trials (RCTs and/or CCTs). The resources must include a combination of electronic database searching, handsearching, and reference lists of retrieved articles. 5 However, no SRs have been identified that evaluated the impact of the number of electronic databases searched. A recent study by Halladay et al. 27 found that articles on therapeutic intervention, retrieved by searching databases other than PubMed (including Embase), contributed only a small amount of information to the MA and also had a minimal impact on the MA results. The authors concluded that when the resources are limited and when large number of studies are expected to be retrieved for the SR or MA, PubMed‐only search can yield reliable results. 27

Findings from the included SRs also reiterate some methodological modifications currently employed to “expedite” the SR process. 10 , 11 For example, excluding non‐English language trials and gray/unpublished trials from MA have been shown to have minimal or no impact on the results of MA. 24 , 26 However, the efficiency of these SR methods, in terms of time and the resources used, have not been evaluated in the included SRs. 24 , 26 Of the SRs included, only two have focused on the aspect of efficiency 14 , 25 ; O'Mara‐Eves et al. 25 report some evidence to support the use of text‐mining approaches for title and abstract screening in order to increase the rate of screening. Moreover, only one included SR 14 considered primary studies that evaluated reliability (inter‐ or intra‐reviewer consistency) and accuracy (validity when compared against a “gold standard” method) of the SR methods. This can be attributed to the limited number of primary studies that evaluated these outcomes when evaluating the SR methods. 14 Lack of outcome measures related to reliability, accuracy, and efficiency precludes making definitive recommendations on the use of these methods/modifications. Future research studies must focus on these outcomes.

Some evaluated methods may be relevant to multiple steps; for example, exclusions based on publication status (gray/unpublished literature) and language of publication (non‐English language studies) can be outlined in the a priori eligibility criteria or can be incorporated as search limits in the search strategy. SRs included in this overview focused on the effect of study exclusions on pooled treatment effect estimates or MA conclusions. Excluding studies from the search results, after conducting a comprehensive search, based on different eligibility criteria may yield different results when compared to the results obtained when limiting the search itself. 28 Further studies are required to examine this aspect.

Although we acknowledge the lack of standardized quality assessment tools for methodological study designs, we adhered to the Cochrane criteria for identifying SRs in this overview. This was done to ensure consistency in the quality of the included evidence. As a result, we excluded three reviews that did not provide any form of discussion on the quality of the included studies. The methods investigated in these reviews concern supplementary search, 29 data extraction, 12 and screening. 13 However, methods reported in two of these three reviews, by Mathes et al. 12 and Waffenschmidt et al., 13 have also been examined in the SR by Robson et al., 14 which was included in this overview; in most instances (with the exception of one study included in Mathes et al. 12 and Waffenschmidt et al. 13 each), the studies examined in these excluded reviews overlapped with those in the SR by Robson et al. 14

One of the key gaps in the knowledge observed in this overview was the dearth of SRs on the methods used in the data synthesis component of SR. Narrative and quantitative syntheses are the two most commonly used approaches for synthesizing data in evidence synthesis. 5 There are some published studies on the proposed indications and implications of these two approaches. 30 , 31 These studies found that both data synthesis methods produced comparable results and have their own advantages, suggesting that the choice of the method must be based on the purpose of the review. 31 With increasing number of “expedited” SR approaches (so called “rapid reviews”) avoiding MA, 10 , 11 further research studies are warranted in this area to determine the impact of the type of data synthesis on the results of the SR.

4.2. Implications for future research

The findings of this overview highlight several areas of paucity in primary research and evidence synthesis on SR methods. First, no SRs were identified on methods used in two important components of the SR process, including data synthesis and CoE and reporting. As for the included SRs, a limited number of evaluation studies have been identified for several methods. This indicates that further research is required to corroborate many of the methods recommended in current SR guidelines. 4 , 5 , 6 , 7 Second, some SRs evaluated the impact of methods on the results of quantitative synthesis and MA conclusions. Future research studies must also focus on the interpretations of SR results. 28 , 32 Finally, most of the included SRs were conducted on specific topics related to the field of health care, limiting the generalizability of the findings to other areas. It is important that future research studies evaluating evidence syntheses broaden the objectives and include studies on different topics within the field of health care.

4.3. Strengths and limitations

To our knowledge, this is the first overview summarizing current evidence from SRs and MA on different methodological approaches used in several fundamental steps in SR conduct. The overview methodology followed well established guidelines and strict criteria defined for the inclusion of SRs.

There are several limitations related to the nature of the included reviews. Evidence for most of the methods investigated in the included reviews was derived from a limited number of primary studies. Also, the majority of the included SRs may be considered outdated as they were published (or last updated) more than 5 years ago 33 ; only three of the nine SRs have been published in the last 5 years. 14 , 25 , 26 Therefore, important and recent evidence related to these topics may not have been included. Substantial numbers of included SRs were conducted in the field of health, which may limit the generalizability of the findings. Some method evaluations in the included SRs focused on quantitative analyses components and MA conclusions only. As such, the applicability of these findings to SR more broadly is still unclear. 28 Considering the methodological nature of our overview, limiting the inclusion of SRs according to the Cochrane criteria might have resulted in missing some relevant evidence from those reviews without a quality assessment component. 12 , 13 , 29 Although the included SRs performed some form of quality appraisal of the included studies, most of them did not use a standardized RoB tool, which may impact the confidence in their conclusions. Due to the type of outcome measures used for the method evaluations in the primary studies and the included SRs, some of the identified methods have not been validated against a reference standard.

Some limitations in the overview process must be noted. While our literature search was exhaustive covering five bibliographic databases and supplementary search of reference lists, no gray sources or other evidence resources were searched. Also, the search was primarily conducted in health databases, which might have resulted in missing SRs published in other fields. Moreover, only English language SRs were included for feasibility. As the literature search retrieved large number of citations (i.e., 41,556), the title and abstract screening was performed by a single reviewer, calibrated for consistency in the screening process by another reviewer, owing to time and resource limitations. These might have potentially resulted in some errors when retrieving and selecting relevant SRs. The SR methods were grouped based on key elements of each recommended SR step, as agreed by the authors. This categorization pertains to the identified set of methods and should be considered subjective.

5. CONCLUSIONS

This overview identified limited SR‐level evidence on various methodological approaches currently employed during five of the seven fundamental steps in the SR process. Limited evidence was also identified on some methodological modifications currently used to expedite the SR process. Overall, findings highlight the dearth of SRs on SR methodologies, warranting further work to confirm several current recommendations on conventional and expedited SR processes.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

Supporting information

APPENDIX A: Detailed search strategies

ACKNOWLEDGMENTS

The first author is supported by a La Trobe University Full Fee Research Scholarship and a Graduate Research Scholarship.

Open Access Funding provided by La Trobe University.

Veginadu P, Calache H, Gussy M, Pandian A, Masood M. An overview of methodological approaches in systematic reviews . J Evid Based Med . 2022; 15 :39–54. 10.1111/jebm.12468 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

Risk and Influencing Factors for School Absenteeism among Students on the Autism Spectrum—A Systematic Review

Review Paper
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Published: 05 September 2024

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Isabella Sasso ORCID: orcid.org/0009-0007-0726-0939 1 &
Teresa Sansour 1

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School plays an important role in the development of a child. The impact of school absenteeism extends beyond academic achievement, affecting one's ability to participate in life successfully. In particular, children with difficulties in communication and interaction are at risk of developing school absences. This systematic review therefore focused on school absenteeism among children on the autism spectrum and examined the risk and influencing factors contributing to school absences. Eighteen studies were included, thirteen of which used a quantitative design, two of which were mixed-method studies, and three of which had a qualitative design. Different studies had varying definitions of school absenteeism and employed diverse study designs, prompting the need for a narrative synthesis. We evaluated the data regarding the factors of individual, parental, and school based on the KiTes bioecological systems framework for school attendance and absence by Melvin et al. (2019). We identified the majority of risks and influences in relation to the school factor and identified interacting factors contributing to school absenteeism in all factors. We recognised research gaps and provided guidance for further research.

School Attendance Problems Among Children with Neurodevelopmental Conditions One year Following the Start of the COVID-19 Pandemic

Risk Factors for School Absenteeism and Dropout: A Meta-Analytic Review

Child and parental mental health as correlates of school non-attendance and school refusal in children on the autism spectrum.

Avoid common mistakes on your manuscript.

Introduction

When children and youth attend school, they have access to education, a right proclaimed in Article 28 of the United Nations Convention on the Rights of the Child (The United Nations, 1989 ). School education fundamentally contributes to the cognitive, social, and emotional development of children and young people while simultaneously fulfilling essential social tasks (Pellegrini, 2007 ). Accordingly, absences from school have enormous consequences not only for educational success but also for emotional and social development and successful participation in life. School absenteeism increases the risk of all forms of mental illness (Lenzen et al., 2013 ; Melvin et al., 2019 ). Absences can cause distress in families (Gallé-Tessonneau & Heyne, 2020 ) and challenge professionals and resources (Wilson et al., 2008 ; Finning et al., 2019 ).

Defining School Absenteeism

In international research, scholars utilise a range of terms and criteria to assess school absenteeism. Consequently, it's imperative to interpret and compare research findings within this context. For the scope of this review, we employ the term 'school absenteeism' as an overarching concept. Absenteeism, broadly defined, refers to a student's absence from school for any reason, encompassing various forms of non-attendance (Kearney, 2016 ).

A distinction exists between problematic and non-problematic absences. Non-problematic absences may result from factors such as illness, bereavement, or other causes. However, even initially non-problematic or technically excused absences can transition into problematic ones if more than 10% of lessons are missed (Heyne et al., 2019 ; Lenzen et al., 2013 ), or if the child's development is compromised by the absence, leading to decreased grades or challenges in reintegrating into the academic environment (Kearney, 2016 ). Hence, Kearney ( 2003 ) defines non-problematic absenteeism as short- or long-term absences mutually agreed upon by parents and the school, with the possibility of compensatory measures. Additional terms for distinguishing between problematic and non-problematic absences include unexcused/excused, unauthorised/authorised (Gentle-Genitty et al., 2015 ), and illegitimate/legitimate (Kearney, 2003 ).

Heyne et al. ( 2019 ) differentiates four types of problematic absenteeism:

School refusal is defined as non-attendance at school due to emotional stress related to school attendance, where the parents are informed of absences and make reasonable efforts to ensure the child's attendance at school.

School withdrawal is defined as non-attendance with the knowledge of the parents or withholding by the parents.

Truancy includes absence without permission from the school and the parents. In addition, there are efforts to hide truancy from parents.

In the case of school exclusion , the school initiates the absence, for example, as a disciplinary action.

Kearney et al. ( 2019 ) intend to categorise heterogeneous concepts and provide general descriptions of common terms. School refusal must be distinguished from school refusal behaviour . While school refusal involves absence from school, school refusal behaviour is a broader term for various behaviour patterns based on the goal of avoiding school, whether anxiety-related or not (Kearney, 2016 ). School avoidance refers to an absence based on anxiety related to school. Most of these terms refer to an absence initiated by the individual, while school exclusion is initiated by the school, and school withdrawal is parent-initiated (Kearney et al., 2019 ).

Risk and Influencing Factors for School Absenteeism

To identify factors increasing the likelihood of experiencing school absenteeism, various system levels must be considered (Kearney, 2008 ). Melvin et al. ( 2019 ) propose a multilevel approach that applies Bronfenbrenner’s bio-ecological model to the factors associated with school absenteeism.

At the micro- and meso-system levels, factors such as the individual, parental/family, and school levels have been demonstrated to be associated with school attendance. Knowledge of these factors and their interactions can contribute to an understanding of school absenteeism (Melvin et al., 2019 ) (Fig. 1 ).

The KiTeS bioecological systems framework for school attendance and absence (Melvin et al., 2019 )

To categorise different types of absenteeism according to their initiation and relationship to the individual, the school, and the parental level, we constructed Fig. 2 . The categorisation is based on comprehensive research regarding different types of school absenteeism and their relation (Heyne et al., 2019 ; Kearney, 2008 ; Reissner et al., 2019 ; Tonge & Silverman, 2019 ).

Categorisation of absenteeism types based on individual, school, and parental levels

Defining Autism

The World Health Organisation (WHO, 2023 ) categorises “Autism Spectrum Disorder” (ASD) as a neurodevelopmental disorder characterised by “persistent deficits in the ability to initiate and to sustain reciprocal social interaction and social communication”. Another criterion implies “a range of restricted, repetitive, and inflexible patterns of behaviour, interests or activities that are clearly atypical or excessive for the individual’s age and sociocultural context”. The onset is typically in early childhood, but symptoms may manifest when social demands increase. Since there is a surge in social demands at school age, coping with developmental tasks becomes even more difficult, and special support is often needed (Kamp-Becker & Bölte, 2021 ). Overall, transitions from different developmental and life phases are important, as these are associated with a rise in vulnerability. As the term ‘spectrum’ suggests, symptoms and therefore needs for support vary among autistic individuals (Kamp-Becker & Bölte, 2021 ). Since autism is a lifelong condition, most individuals need support and services throughout their lifetime. Most services (such as therapy and social skills training) are used in early and middle childhood (Song et al., 2022 ). The US Center for Disease Control and Prevention (CDC, 2023 ) estimated that one in 36 children is diagnosed with ASD. ASD was 3,8 times more prevalent among boys than among girls (approximately 4% of boys and 1% of girls). In total, 37.9% of the autistic individuals had an intellectual disability (IQ < 70), 23.5% had an IQ between 71 and 85, and 38.6% had an IQ > 85. However, it should be noted that the prevalence varies between countries and studies. Autism is also often associated with psychiatric conditions. It is estimated that 70–72% of autistic youth have at least one psychiatric condition. Some of the most common disorders are anxiety, depression and attention deficit hyperactivity disorder (ADHD; Rosen et al., 2018 ).

School Absenteeism among Autistic Individuals

According to the Department for Education ( 2019 ) autistic students in England explore higher rates of school absences than non-autistic students with or without special educational needs. When educational needs align with challenges in social skills and communication, absenteeism rates tend to increase. On the other hand, schools comprise a variety of communication and interaction situations (Ashburner et al., 2010 ). Autistic students often find social interactions stressful, thereby facing an increased risk of limited participation and social exclusion (Roberts & Simpson, 2016 ). These circumstances elevate the risk of psychiatric conditions (Hebron & Humphrey, 2014 ). These co-occurring psychiatric conditions heighten the risk of school absenteeism (Finning et al., 2019 ).

To date no systematic review has investigated the risk factors of school absenteeism among autistic students. The aim of this study is to systematically review studies regarding the risk and influence factors for school absenteeism in autistic students. In particular, individual, educational, and parental factors of the micro- and mesosystems are considered. Another aim is to identify research gaps for further investigations.

The primary research questions for this systematic review include:

What types of school absenteeism have been identified in prior studies for autistic students?

What individual, school, and parental factors contribute to school absenteeism among autistic students?

Review Methods

The protocol for this systematic review has been registered online at PROSPERO, an international register for systematic reviews (Registration number: CRD42022343467). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) standards has been followed for all stages of this systematic review (Page et al., 2021 ). The following electronic databases covering all relevant disciplines have been searched for journal articles: ERIC (Ped), Web of Science and Scopus (Psych), and PubMed (Med) on 26th June 2022. Prior to this search, a preliminary search was performed and an updated search was carried out on 30th November 2023. The Cochrane and PROSPERO databases have been searched to confirm that there was no other existing or registered systematic review about the current topic. The search strategy included terms regarding autism and school absenteeism (see Table 1 ).

Inclusion Criteria

The studies included in this review have been selected based on the following predetermined inclusion criteria: (a) they focused on school-aged individuals with a formal diagnosis of autism; (b) they focused on individual, family or school factors having an influence on any form of school absenteeism; and (c) they were published in German or English. No restrictions were applied regarding the publication period of the included articles.

Exclusion Criteria

Studies were excluded from the review based on one or more of the following criteria: (a) they were published in languages other than English or German; (b) they were not empirical studies; (c) they focused on non-autism samples or mixed etiology groups and the data for autistic individuals were not reported separately; and (d) they did not scrutinise school absenteeism and influencing factors. This review did not include grey literature, but the search was not restricted to peer-reviewed articles.

Study Selection

Electronic searches identified 322 records. Following the removal of duplicates, each reviewer independently assessed 148 articles based on the title and abstract; each reviewer was blinded to the other’s ratings. Disagreements were solved by discussion.

After screening the full texts, 18 studies that met the inclusion criteria were identified and included in the current review.

Quality Assessment

The quality of each included study was assessed by both reviewers independently by using the Mixed Method Appraisal Tool (MMAT) described by Hong et al. ( 2018 ). Disagreements were resolved by both authors discussing the information presented. The MMAT is an appraisal tool for systematic reviews that include quantitative, qualitative and mixed methods studies. Hong et al. ( 2018 ) developed the tool based on a literature review of critical appraisal tools. By using this tool, the study quality was categorised as good, moderate or low. Sixteen studies were rated as ‘good’, and two studies were rated as ‘moderate’. One of these studies has limitations in its quality since the actual research question was not answered (Ochi et al., 2020 ). However, the authors identified these limitations. The other study did not formulate any explicit research questions (Kurita, 1991 ). No studies were excluded due to low quality.

Data Extraction

The first author (I.S.) extracted the data according to predefined criteria. The second author (T.S.) controlled the integrity and verified the accuracy of all the extracted data.

Data were extracted and coded for each study that met the inclusion criteria. The following descriptive data were extracted: study details, information about the sample, the definition of school absenteeism, the criteria for school absenteeism (e.g., 10% absence of school days), the data collection tool for school absenteeism, the risk and influencing factors, the absence rate, the intervention, and the effect of the intervention.

A narrative synthesis was provided due to the heterogeneity of the studies, especially regarding the terminology and measurement of school absenteeism as well as the criteria of different forms of school absenteeism.

Figure 3 shows the evaluation and screening process used to select the 18 studies included in this systematic review. Table 1 provides the details for each included study.

PRISMA 2020 flow diagram

Three studies were from the same research group (Bitsika et al., 2020 , 2021 , 2022 ). All three address the topic of bullying. Bitsika et al. ( 2022 ) studied a subsample of a larger cohort from Bitsika and Sharpley ( 2016 ). Bitsika et al. ( 2021 ) used a sample from Bitsika et al. ( 2020 ). Each article has a different research question.

Munkhaugen et al. ( 2019 ) based their research on a subsample from the first study (Munkhaugen et al., 2017 ).

Study Characteristics

All studies except Kurita ( 1991 ) are very recent (2017–2023). These studies were conducted in Australia (Adams, 2021 ; Bitsika et al., 2020 , 2021 , 2022 ), the United Kingdom (Gray et al., 2023 ; Martin-Denham, 2022 ; O’Hagan et al., 2022 ; Preece & Howley, 2018 ; Totsika et al., 2020 ; Truman et al., 2021 ), Sweden (Anderson, 2020 ), Japan (Kurita, 1991 ; Ochi et al., 2020 ), Norway (Munkhaugen et al., 2017 , 2019 ), the United States (Mattson et al., 2022 ; McClemont et al., 2021 ) and Denmark (Lassen et al., 2022 ).

Three of the 18 studies used qualitative designs, two used mixed method designs, and 13 used quantitative designs. Eleven studies employed cross-sectional designs, while there was also an evaluative case study that aimed to identify the impact of an intervention, a retrospective chart review study, a longitudinal study based on retrospective school datasets, a brief report of an observational study, a qualitative study with a multi-informant approach, a qualitative study that is based on case reports and a qualitative study consisting of an interpretative phenomenological approach.

The sample size ranged from N = 1799 in a quantitative cross-sectional study to N = 3 in qualitative case reports. The total sample included 3304 autistic students. The ages ranged between 3 and 21 years. Two studies examined absenteeism in preschoolers with autism. The sample was predominantly male except for the only qualitative study that explicitly focused on girls with autism (O’Hagan et al., 2022 ). Fourteen studies based their results on parental reports, and four studies considered additional school staff or other professionals involved. One qualitative study collected data by interviewing the autistic young people and one used a multi-informant approach by interviewing parents, professionals and school staff. Two studies focused on data bases: one used clinical data (Ochi et al., 2020 ) and the other used school datasets (Mattson et al., 2022 ). All studies collected data regarding mainstream schools. Six studies also collected data in a special school setting. The detailed information for each included study is summarised in Table 1 .

Types of School Absenteeism

In the included studies, school refusal was the most commonly used term for absenteeism. In total, 11 studies referred to this term (Adams, 2021 ; Bitsika et al., 2020 , 2021 , 2022 ; Kurita, 1991 ; McClemont et al., 2021 ; Munkhaugen et al., 2017 , 2019 ; Ochi et al., 2020 ; Preece & Howley, 2018 ; Totsika et al., 2020 ). The studies are based on the definition in which school refusal occurs due to emotional distress with knowledge of the parents (Heyne et al., 2019 ; Kearney, 2008 ). Totsika et al. ( 2020 ) referred to school withdrawal, truancy, school exclusion, and nonproblematic absence, as these are all categories included in the data collection tool they used (the School Non-Attendance Checklist [SNACK] by Heyne et al., 2019 ). Adams ( 2021 ) also used the SNACK and referred to the types defined by Heyne et al. ( 2019 ) but also described the difference between emerging and established school refusal . Furthermore, the author investigated full- and half-day absences. Bitsika et al., ( 2020 , 2021 , 2022 ) also followed the definition of school refusal established by Heyne et al. ( 2019 ). They argued that school refusal is often associated with absence from school, but it is not necessarily defined by absence; therefore, they used the term emerging school refusal (Bitsika et al., 2020 ).

Munkhaugen et al., ( 2017 , 2019 ) chose school refusal behaviour as the object of research. They referred to Kearney ( 2008 ) who defined school refusal behaviour as ‘child-motivated refusal to attend school and/or difficulties remaining in class’ (Munkhaugen et al., 2017 ).

Kurita ( 1991 ) operationalised school refusal according to Berg et al.’s ( 1969 ) definition as absence from school due to reluctance to attend with the knowledge of the parents, while no antisocial disorders occur with this absence.

O’Hagan et al. ( 2022 ) used the phrase ‘emotionally based’ school avoidance and referred to Munkhaugen et al. ( 2017 ). Hence, it can be assumed that O’Hagan et al. ( 2022 ) used school avoidance as a synonym for school refusal behaviour . Gray et al. ( 2023 ) also used the term school avoidance as a synonym for school refusal .

Truman et al. ( 2021 ) did not directly focus on school absenteeism. They evaluate school experiences in the context of extreme demand avoidance behaviour. One aspect relating to this group of autistic children is school exclusion due to challenging behaviour. They included both formal and informal exclusions. In contrast, Gray et al. ( 2023 ) and Martin-Denham ( 2022 ) had an explicit focus on school exclusion. Martin-Denham ( 2022 ) referred to the Education Act and the European Court, which stated that a decision to exclude has to be lawful, rational, proportionate and fair. A differentiation was made between a fixed period exclusion, where a student was excluded from school for a set period, and a permanent exclusion, when a student did not return to school. Gray et al. ( 2023 ) also referred to this differentiation between fixed-term and permanent exclusion.

Two other included studies addressed the differentiation between unexcused and excused absences (Mattson et al., 2022 ), school absences and nonproblematic absences, respectively (Anderson, 2020 ) (Table 2 ).

Criteria and Frequency of School Absenteeism

Criteria for school absenteeism.

The included studies used different criteria to operationalise absenteeism. Two studies used the criterion of 10% absence from school days (O’Hagan et al., 2022 ; Totsika et al., 2020 ). Adams ( 2021 ) also used this criterion but to discuss ‘persistent’ absence. Munkhaugen et al., ( 2017 , 2019 ) relied on the criteria described by Kearney and Silverman ( 1996 ), who differentiated between ‘self-corrective’ for < 2 weeks, ‘acute’ absence for 2–52 weeks, and ‘chronic’ absence for > 53 weeks. However, they did not provide information about how often the behaviour occurred during the period. Ochi et al. ( 2020 ) used more than 30 days per year as a criterion. Gray et al. ( 2023 ) utilised a broad definition of school exclusion “to ensure it captured the full range of experiences of autistic pupils who had persistent, problematic attendance and experience of leaving a mainstream setting due to unmet needs”. Martin-Denham ( 2022 ) refers to school exclusion as a legal term. Five studies did not explicitly determine a criterion for absence in terms of a number. Rather, they explained it with descriptions such as ‘prolonged’ (Preece & Howley, 2018 ). For the remaining five studies, it was not necessary to determine the criterion thematically or because of the study design.

Frequency of Absences

Despite the different study designs and terms, the results regarding the frequencies of absences are considered in the following.

Adams ( 2021 ) reported the highest rate of absenteeism: 72.6% of autistic children had shown ‘persistent absence’, defined as a 10% absence within the 20-day survey period. The average absenteeism rate in the study was 6.3 full days and 3.8 half days. In addition, 5.7% of the autistic students were absent for 4 weeks; all of them (partly among other reasons) did so due to school refusal.

Totsika et al. ( 2020 ) reported that 43% of autistic children showed persistent absence during a 23-day period. The average absence rate was 5 days. The median number of days missed was 2. Moreover, 64% of the autistic children missed at least 1 day, and 7% did not attend school on any of the 23 days. Similarly, Munkhaugen et al. ( 2017 ) reported that 42.6% of autistic students exhibited school refusal behaviour. Bitsika et al. ( 2020 ) reported that 56.1% of autistic boys who reported being bullied experienced emerging school refusal, but as seen in the definition stated above, this is not a clear indication of actual absence from school.

Kurita ( 1991 ) reported the lowest frequencies: 23.7% of autistic students experienced school refusal (as defined above). In addition, 28.1% were reported to have shown an unwillingness to go to school that did not result in absenteeism. According to the data provided by parents of autistic children, 35% indicated that their child had already refused to go to school (McClemont et al., 2021 ). Regarding school exclusion, Truman et al. ( 2021 ) reported that 50% of autistic children were informally excluded from school.

Anderson ( 2020 ) reported the frequency of absences between different school types. The rates of absences for reasons other than illness (unexcused absence) did not significantly differ between primary (51.3%) and secondary (57.6%) schools. In primary schools for students with learning disabilities absences due to illness (excused absences) were the main cause (83.8%) among autistic students. The rate of absenteeism for reasons other than illness (unexcused absence) increased in secondary schools for students with learning disabilities (36.3%). In elementary schools, the median percentage of school day absences was 9.1% in the study by Mattson et al. ( 2022 ). On 39.1% of all missed school days analysed, students had excused absences, while 60.9% of absences were unexcused. Lassen et al. ( 2022 ) reported more absences among autistic children than among the control group.

Data Collection Tool for School Absenteeism

As stated above, two studies used the SNACK conducted by Heyne et al. ( 2019 ). Adams ( 2021 ) modified the SNACK by also asking about half-day absences.

The majority of studies used nonvalidated scales. Six studies used self-constructed questionnaires (Anderson, 2020 ; Bitsika et al., 2020 , 2021 , 2022 ; Kurita, 1991 ; McClemont et al., 2021 ; Munkhaugen et al., 2017 , 2019 ; Truman et al., 2021 ). Lassen et al. ( 2022 ) asked about frequency via a 5-point Likert scale with descriptive ratings (never, rarely, sometimes, often, very often).

Qualitative studies (Gray et al., 2023 ; Martin-Denham, 2022 ; O’Hagan et al., 2022 ) as well as a mixed-method study (Preece & Howley, 2018 ) have used interviews for data collection.

Two studies used existing datasets. One of them used clinical data (Ochi et al., 2020 ), whereas the other used school datasets (Mattson et al., 2022 ).

Risk and Influencing Factors

According to the Kids and Teens at School Framework (KiTeS) by Melvin et al. ( 2019 ), the extracted risk and influencing factors for school absenteeism among autistic students were divided into individual, school and parental factors.

Individual Factors

Age, gender, diagnosis, intellectual level and psychiatric conditions were identified as factors at the individual level.

Mattson et al. ( 2022 ) reported that age was weakly and negatively correlated with the median percentage of days absent. They demonstrated that younger participants exhibited more frequent absences on average than older students. Another study reported that the mean age at the onset of school refusal was 12.6 ± 2.2 years in autistic students, which was significantly younger than in those without autism (13.8 ± 2.1 years; Ochi et al., 2020 ). In contrast, Totsika et al. ( 2020 ) reported slightly increased rates of not attending school with increasing age. Among children who missed any school days, refusal was more likely among older children.

Anderson ( 2020 ) revealed a gender difference in the disadvantage of girls on the autism spectrum. They exhibited higher rates of absence (54.6%) for reasons other than illness than autistic boys (43.9%). Compared with boys, girls exhibited significantly more short absences for reasons other than illness. For continuous periods of absence longer than four weeks, there was no significant difference between boys and girls.

In the study of O’Hagan et al. ( 2022 ), two mothers of autistic children with school avoidance indicated that feeling different from others without an explanation of a diagnosis led to low confidence and self-esteem. Families and professionals, in the study of Preece and Howley ( 2018 ), identified a late diagnosis as contributing to non-attendance since the special needs of autistic students were therefore not recognised and addressed. The findings of Martin-Denham ( 2022 ) indicate “barriers to gaining prompt assessment and identification of special educational needs and disability (SEND)”. However, students who already have a diagnosis may struggle with feeling different (Martin-Denham, 2022 ) and having a “desire to fit in” (Gray et al., 2023 ).

Intellectual Level

While most of the related studies have focused on autistic students without intellectual disabilities, Kurita ( 1991 ) found that autistic students who experienced school refusal tended to be more intelligent than those who did not. The intellectual level was significantly greater for autistic children who refused school than for those who did not.

Psychiatric Conditions

Truman et al. ( 2021 ) focused on a group of autistic children with extreme demand avoidance behaviour. These children showed more specific behavioural difficulties. They were able to mask their difficulties at school and then experienced a meltdown after. Fifty percent of parents informally excluded their children from school so that they could be home-educated, reducing their anxiety and stress.

On the other hand, the parents in the study of Gray et al. ( 2023 ) reported that they did not notice the anxiety of their children because they could not communicate their feelings. Anxiety was also demonstrated by aggression, which in turn led to school exclusions and, in some cases, led to symptoms of depression, including self-harm and suicide attempts.

Adams ( 2021 ) reported a 3% increased risk for half-day absences when the child experienced anxiety.

Munkhaugen et al. ( 2019 ) showed that autistic students with school refusal behaviour were more socially impaired than those without such behaviour. Nonetheless, low social motivation had the strongest association with school refusal behaviour. Parents commented that negative thoughts about relationships with peers and teachers, as well as about school subjects, were frequent reasons for their children’s school refusal behaviour. Lassen et al. ( 2022 ) reported that school absence is accompanied by internalising symptoms such as anxiety. This association was even stronger than that with autistic or externalising symptoms and was not unique to the autism group.

School Factors

School factors had the greatest influence on school absenteeism. Five studies focused their research on bullying. Other factors related to the school setting are the school type, the school environment and negative experiences.

The significance of school factors can even be seen in the oldest study. Two-thirds of parents of autistic children who refused school indicated that school refusal behaviour was a precipitating factor. The majority were school-related, with “teasing by schoolmates” being the most common factor (Kurita, 1991 ).

McClemont et al. ( 2021 ) reported that autistic children with ADHD were more likely to refuse school due to bullying (68%) than autistic children without ADHD (28%) or no diagnosis (18%). In this study, an autism diagnosis or another diagnosis did not impact the frequency of school refusal due to bullying compared to children with no diagnosis. In contrast, Ochi et al. ( 2020 ) reported that bullying was significantly associated with school refusal in autistic boys and girls. In the sample of Bitsika et al. ( 2020 ), which consisted only of autistic boys, “being bullied explained more of the variance in emerging school refusal than did age, ASD-related difficulties (judged by their mothers), and self-reported anxiety and depression”. Eighty-five percent of the surveyed boys reported that they had been bullied at school, and 56% of them asked their parents if they could stay at home as a result of the bullying. Bitsika et al. ( 2021 ) identified in another sample from a previous study (Bitsika & Sharpley, 2016 ) the most common bullying experiences: being called mean names or being sworn at (experienced by 75.9% of the sample); being joked about or laughed at (67.2%); being hit, pushed, or kicked (63.8%); having had something taken from them (55.1%); being “ganged up on” (56.9%); and having been reported to teachers when they had not done things that were reportable (51.3%). A participant of Gray et al. ( 2023 ) talked about being bullied because he “didn’t know what they were going on about”.

McClemont et al. ( 2021 ) described another aspect of bullying: autistic youth with a behaviour support plan (BSP) were more likely to refuse school due to bullying than were those without. Anderson ( 2020 ) cited bullying as a factor that had a limited influence. The remaining factors outlined below exerted a more pronounced influence on absences.

School Type

Totsika et al. ( 2020 ) highlighted the significance of school type. The risk for persistent non-attendance increased by 104% when the autistic child attended a mainstream school, by 100% for total days absent, and by 79% for total number of days missed. Additionally, school exclusions were slightly more frequent in mainstream schools. Anderson ( 2020 ) also revealed a significant difference between school type and absence from school. School absence due to illness was the main cause of absence in primary schools for students with learning disabilities (83.8%), but the rate of absenteeism for reasons other than illness increased when students attended secondary schools for students with learning disabilities (36.3%). The results indicate that the rate of school absenteeism among autistic students in primary school is relatively high and increases when pupils start secondary school. Gray et al. ( 2023 ) revealed that the amount of support in schools varied “depending on knowledge, willingness to accommodate needs and carrying out advice and implementing statutory guidelines”.

In a study by Martin-Denham ( 2022 ), caregivers noted a lack of knowledge, skills, understanding, and funding in mainstream secondary schools. All participants noted that barriers to mainstream education occurred because the school staff was not adequately trained in supporting children with SEND. Similar factors regarding the school staff were mentioned by participants in the study by Gray et al. ( 2023 ): lack of understanding of autism, negative attitudes and problematic responses and interactions. Additional factors included a lack of flexibility regarding rules and homework on the one hand and unstructured times on the other hand. Not knowing the needs and not understanding the reactions of the autistic children led to school exclusions or exclusions from school events.

Anderson ( 2020 ) asserted that a lack of autism competence among school staff was the most common reason for children’s school absence.

School Environment

The second most common reason in the study by Anderson ( 2020 ) was the lack of adaptation of the school environment (24.3%), followed by a lack of support in learning (23.5%) and social situations (23.8%). Factors identified by Preece and Howley ( 2018 ) regarding the school environment include a lack of understanding and appropriate support, the size of the school, and the number of students because of sensory issues such as noise. Gray et al. ( 2023 ) also listed the sensory issues of participants. The number of people, large classrooms with bright light and unstructured times led to feelings of overwhelm or sensory overload. Contrary to reports recommending the use of safe spaces to support emotional regulation, Martin-Denham ( 2022 ) noted that schools were unable to implement them due to a lack of space. A different perspective regarding the learning environment was found in the study by Gray et al. ( 2023 ). Many young people described meltdowns when doing homework because of their need for “straight separation between school and home”.

Negative Experiences

The factors described above led in the study by Gray et al. ( 2023 ) to a feeling of being treated unfairly, “which made me just feel stressed and I just refused to engage [in school]”. The results of a parent and teacher questionnaire survey of autistic students by Munkhaugen et al. ( 2017 ) suggested avoiding specific subjects, conflicts with peers or teachers, and insufficient information concerning the subjects or activities in school as possible reasons for school refusal behaviour. In the study of Truman et al. ( 2021 ), parents described negative school experiences to be at least partly caused by a lack of understanding of autism. Some of these parents considered the reason for the misunderstanding in their child’s ability to mask their difficulties. The parents also indicated that ‘masking’ may be the reason why their children’s special needs were not adequately addressed. Others reported that home-education can reduce the anxiety of their autistic children: “All the stress of having to deal with the situations gone. Can now concentrate on learning and living” (Truman et al., 2021 ). A mother in the study by Martin-Denham ( 2022 ) described that anxiety due to a focus on negative aspects in school led to a desire to die: “You can see the anxiety, and when your son says he wants to die that is hard to listen to. So, every day he would come home with this planner and […] there would be no positives, […]. So, he felt down all the time”.

Parental Factors

Parental factors that exert an influence are parental unemployment and illness. In addition, demographic characteristics are closely linked to parental factors, such as living in a two-parent household or having educational qualifications. In most studies, demographic characteristics had no influence on school absenteeism (Kurita, 1991 ; McClemont et al., 2021 ; Munkhaugen et al., 2017 , 2019 ). However, Totsika et al. ( 2020 ) reported an association between school exclusions and not living in a two-parent household: the risk increased by 37% to 75%.

Parental Unemployment

The risk of non-attendance increased by 52% to 78% if parents were unemployed. Fifty-two percent had persistent absence, 57% had total days missed, and 78% had days absent (Totsika et al., 2020 ). Adams ( 2021 ) even reported an increase of 85% when parents reported not having paid employment. On the other hand, parents in two studies (Gray et al., 2023 ; Martin-Denham, 2022 ) reported “having to give up” their jobs as a result of school absenteeism.

Illness of family members

In the study by Munkhaugen et al. ( 2017 ), illness of other family members was the only sociodemographic factor that showed a significant association with school refusal behaviour in autistic students. Similarly, Adams ( 2021 ) reported that the risk of school refusal increased by 20% as parental depression scores increased.

Supporting Factors

Mainly, four included studies (Gray et al., 2023 ; Martin-Denham, 2022 ; O’Hagan et al., 2022 ; Preece & Howley, 2018 ) identified several aspects to support re-engagement. The most mentioned aspects were the quality of interactions between teachers and autistic students, as well as between parents and teachers. The development of a flexible learning approach was identified as supporting, as well as incorporating the voice of the young person into their support plan and the opportunity to ask questions (Martin-Denham, 2022 ; O’Hagan et al., 2022 ). Autistic students valued a flexible and structured approach in support, as well as the opportunity to control their own learning and feel respected and listened to (Gray et al., 2023 ). Additionally, regarding the overall school environment, smaller group sizes and structures in the classroom and learning were mentioned, as well as being part of the school community and relationships with peers (Gray et al., 2023 ; O’Hagan et al., 2022 ; Preece & Howley, 2018 ). The consistent and effective collaboration and communication between parents and teachers were affirmed by both parents and teachers (Gray et al., 2023 ; Martin-Denham, 2022 ). Parents also claim that an earlier diagnosis contributes to school engagement (Martin-Denham, 2022 ; O’Hagan et al., 2022 ).

The risk and influencing factors of school absenteeism among students on the autism spectrum were systematically reviewed across 18 studies. Nine studies solely included parents as participants, one study additionally included teachers, and one other study additionally included autistic children. Three studies based their data on the children, parents and professional staff. Two studies used existing records.

The most common term for school absenteeism was school refusal, while studies have used different criteria for determining absences. Based on the frequencies of school absenteeism shown among different study designs, it is clear that this is a serious phenomenon that occurs among autistic students internationally. Several identified factors also showed similarities and complementarities within the included studies.

The school level predominantly exhibited the most significant factors influencing absenteeism. Bullying was the most frequently studied influence and the factor with the greatest impact.

Other factors at the school level that significantly influenced absenteeism included school type, school environment, and negative experiences. In five studies, bullying was found to be a risk factor for school absenteeism (McClemont et al., 2021 ; Ochi et al., 2020 ; Bitsika et al., 2020 , 2021 , 2022 ). All studies revealed significant associations between bullying and absenteeism. Being bullied can also lead to anxiety and depression up to suicidal attempts or ideation (Martin-Denham, 2022 ). Autistic students with school refusal had higher scores for major depression, general anxiety, and separation anxiety, as well as significantly greater levels of somatic symptoms and sleeping difficulties (Bitsika et al., 2022 ). Conversely, individual factors, including externalizing symptoms and reduced social motivation, also increase the risk for bullying (Karande, 2018 ). However, other studies that examined bullying, among other factors, found that these factors had greater influences on absences (Anderson, 2020 ; Gray et al., 2023 ). The influence of school type was mostly related to a lack of knowledge of school staff in mainstream schools (Anderson, 2020 ; Gray et al., 2023 ; Martin-Denham, 2022 ). This factor was accompanied by a lack of adapting to the school environment due to a lack of resources or support (Anderson, 2020 ; Gray et al., 2023 ; Martin-Denham, 2022 ; Preece & Howley, 2018 ). A lack of support and understanding in schools increases the risk of anxiety and depression (Martin-Denham, 2022 ). The results may suggest that these conditions are contributing factors because individual needs are not addressed. Therefore, it is necessary to explore in more detail what leads to bullying and which interactional processes take place. Similarly, more research focusing on interactive processes in schools is needed.

At the individual level, age, gender, diagnosis, intellectual level and psychiatric conditions were identified. Three studies reported on the influence of age (Mattson et al., 2022 ; Ochi et al., 2020 ; Totsika et al., 2020 ). Autistic students were younger at the onset of school absences, and the frequency of absences increased with age. These results are consistent with the increasing social demands at school age (Kamp-Becker & Bölte, 2021 ). However, there is a need for further investigation of the influence of age. Mediating variables associated with age must also be considered. Anderson ( 2020 ) showed that girls had greater rates of short absences than boys. There was no other statement regarding gender since most participants were boys. Recent surveys continue to show that autism is four times more prevalent in boys than in girls (CDC, 2020 ). Nevertheless, there is clearly a lack of research regarding autism in female students. Three studies showed that feeling different from others contributed to school absences (Gray et al., 2023 ; Martin-Denham, 2022 ; O’Hagan et al., 2022 ). This shows the need for education on neurodiversity in schools (Honeybourne, 2018 ). Since Kurita ( 1991 ) reported that autistic students who experienced school refusal tended to be more intelligent, studies have focused on autistic students without intellectual disability. Nevertheless, more current research on the school attendance of autistic children with intellectual disabilities would be desirable. Five studies acknowledged the contribution of psychiatric conditions to school absences (Adams, 2021 ; Gray et al., 2023 ; Lassen et al., 2022 ; Munkhaugen et al., 2019 ; Truman et al., 2021 ). All five studies found anxiety to be a contributing factor. Lassen et al. ( 2022 ) even found a stronger association with internalising symptoms such as anxiety than with externalising or autistic symptoms. As anxiety is one of the most common psychiatric conditions in autistic individuals, it can influence school outcomes (for more information, see the review of Adams et al., 2019 ). The influence of other psychiatric disorders should be investigated in more detail in further research.

The parental factors that influence school absenteeism are parental unemployment and illness.

Two studies (Adams, 2021 ; Totsika et al., 2020 ) revealed an increased risk when parents were unemployed.

On the other hand, parents reported having to quit their jobs due to the school absenteeism of their children (Gray et al., 2023 ; Martin-Denham, 2022 ). Due to the effects on the socioeconomic status of a family, a further link between these two aspects should be explored in further research.

The effect of the illness of a family member was also reported by two studies. Munkhaugen et al. ( 2017 ) found this to be the only sociodemographic factor with a significant association. However, Adams ( 2021 ) reported an increased risk when parents had high depression scores. Mental health issues in parents due to stress and guilt were also shown to result from school absenteeism in two studies (Gray et al., 2023 ; Martin-Denham, 2022 ). Parents mentioned that they also need support in regard to school absenteeism in their autistic children (Martin-Denham, 2022 ). Families benefit from organisations that support the family as well as the school (Martin-Denham, 2022 ). In particular, children with special needs are dependent on the support of their parents or other caregivers (Romero & Lee, 2007 ), emphasising the need to support them in dealing with their children and school. Research that involves further system levels is needed. Support for parents can also be provided through interaction between parents and schools. Successful collaboration between parents and schools has a positive impact on the school experience of autistic students (Lilley, 2019 ) (Fig. 4 ).

Interactions between factors

Missing school is claimed to be going hand in hand with missing important developmental steps for life in society (Pellegrini, 2007 ). However, as seen in the results, for children on the autism spectrum, there are also risks for development and mental health in schools, which need to be fixed to enable the development of autistic children in schools. Parents affirmed home-education as a possibility for their autistic children to “concentrate on learning and living” (Truman et al., 2021 ). The advantages and disadvantages of home-education could be further investigated, as school is an important area in the lives of children and adolescents. The results show that the interaction between parental and individual factors is necessary but has not been adequately investigated. None of the included studies investigated parental withholding. Nevertheless, this sensitive and complex phenomenon should be examined in future research.

The results show that the school situation of autistic children should be investigated further. There is a lack of longitudinal studies regarding the education and school situation of autistic students, as well as a lack of validated scales for data collection. Nevertheless, the actuality of the included studies indicates that there is a growing research base on this topic.

Limitations

The results of this systematic review must be classified within its limitations. Given the overall scarcity of research in this area, a research question was developed that yielded the broadest possible results while allowing us to draw consistent conclusions. Therefore, studies with different terms of school absenteeism and different study designs were included. In addition, school absenteeism must be viewed in the context of school and health care systems in each country. This diversity makes comparability difficult and was carried out by the researchers on the basis of a narrative synthesis. The synthesis might reflect the researcher’s interpretation of the data. Given the heterogeneity, it is possible that other studies included risk and influencing factors that were not identified. The specific influences of the COVID-19 pandemic were not considered. Due to limited resources, this review was conducted by only two researchers, which may have introduced limitations in the search strategy. Finally, only studies published in English or German were considered.

This systematic review provides a comprehensive summary of mainly recently published studies on the factors influencing school absenteeism among autistic students. Eighteen studies were included, each with a different research focus and study design. Taken together, the results provide a picture of the different influences at the individual, school and parental levels. Future research should incorporate other system levels as well as self-reports of autistic students and validated scales to draw conclusions for the inclusion of neurodivergent students.

Studies included in the review:

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McClemont, A. J., Morton, H. E., Gillis, J. M., & Romanczyk, R. G. (2021). Brief report: Predictors of school refusal due to bullying in children with autism spectrum disorder and attention-deficit/hyperactivity disorder. Journal of Autism and Developmental Disorders, 51 (5), 1781–1788. https://doi.org/10.1007/s10803-020-04640-y

Munkhaugen, E. K., Gjevik, E., Pripp, A. H., Sponheim, E., & Diseth, T. H. (2017). School refusal behaviour: Are children and adolescents with autism spectrum disorder at a higher risk? Research in Autism Spectrum Disorders, 41–42 , 31–38. https://doi.org/10.1016/j.rasd.2017.07.001

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Ochi, M., Kawabe, K., Ochi, S., Miyama, T., Horiuchi, F., & Ueno, S. (2020). School refusal and bullying in children with autism spectrum disorder. Child and Adolescent Psychiatry and Mental Health, 14 (1), 17. https://doi.org/10.1186/s13034-020-00325-7

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Preece, D., & Howley, M. (2018). An approach to supporting young people with autism spectrum disorder and high anxiety to re-engage with formal education – the impact on young people and their families. International Journal of Adolescence and Youth , 1–14. https://doi.org/10.1080/02673843.2018.1433695

Totsika, V., Hastings, R. P., Dutton, Y., Worsley, A., Melvin, G., Gray, K., Tonge, B., & Heyne, D. (2020). Types and correlates of school non-attendance in students with autism spectrum disorders. Autism, 24 (7), 1639–1649. https://doi.org/10.1177/1362361320916967

Truman, C., Crane, L., Howlin, P., & Pellicano, E. (2021). The educational experiences of autistic children with and without extreme demand avoidance behaviours. International Journal of Inclusive Education , 1–21. https://doi.org/10.1080/13603116.2021.1916108

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Sasso, I., Sansour, T. Risk and Influencing Factors for School Absenteeism among Students on the Autism Spectrum—A Systematic Review. Rev J Autism Dev Disord (2024). https://doi.org/10.1007/s40489-024-00474-x

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Systematic literature review X narrative review
Systematic literature review X narrative review. June 2007. Acta Paulista de Enfermagem 20 (2):v-vi. DOI: 10.1590/S0103-21002007000200001. License. CC BY-NC 4.0. Authors: Edna Rother. Hospital ...
The Difference Between Narrative Review and Systematic Review
The Difference Between Narrative Review and Systematic ...
How to Write a Systematic Review: A Narrative Review
Background. A systematic review, as its name suggests, is a systematic way of collecting, evaluating, integrating, and presenting findings from several studies on a specific question or topic.[] A systematic review is a research that, by identifying and combining evidence, is tailored to and answers the research question, based on an assessment of all relevant studies.[2,3] To identify assess ...
An Introduction to Writing Narrative and Systematic Reviews
There are two standard types of reviews: narrative reviews, also known as traditional or non-systematic reviews; and, systematic reviews, which may or may not be followed by a meta-analysis. A narrative review is the "older" format of the two, presenting a (non-systematic) summation and analysis of available literature on a specific topic ...
Narrative Reviews: Flexible, Rigorous, and Practical
Narrative Reviews: Flexible, Rigorous, and Practical - PMC
How to Conduct a Systematic Review: A Narrative Literature Review
How to Conduct a Systematic Review: A Narrative ...
How to Do a Systematic Review: A Best Practice Guide for Conducting and
The best reviews synthesize studies to draw broad theoretical conclusions about what a literature means, linking theory to evidence and evidence to theory. This guide describes how to plan, conduct, organize, and present a systematic review of quantitative (meta-analysis) or qualitative (narrative review, meta-synthesis) information.
How to Do a Systematic Review: A Best Practice Guide ...
The best reviews synthesize studies to draw broad theoretical conclusions about what a literature means, linking theory to evidence and evidence to theory. This guide describes how to plan, conduct, organize, and present a systematic review of quantitative (meta-analysis) or qualitative (narrative review, meta-synthesis) information.
How to Conduct a Systematic Review: A Narrative Literature Review
Our goal with this paper is to conduct a narrative review of the literature about systematic reviews and outline the essential elements of a systematic review along with the limitations of such a review. Keywords: meta-analysis; narrative literature review; prisma checklist; systematic reviews.
Guidance on Conducting a Systematic Literature Review
Guidance on Conducting a Systematic Literature Review
Systematic literature review X narrative review
Systematic literature review X narrative review. Acta Paulista de Enfermagem. ISSN 1982-0194. EN; PT; ES; Home; About . About Acta Editorial Policy Editorial Board Editorial Responsibilities. ... Systematic literature review X narrative review. Acta Paul Enferm. [online]. 2007, vol. 20, n. 2, [cited 2024-09-03], pp.v-vi. Available from: <https ...
Systematic literature review X narrative review
2024. TLDR. Through a systematic literature review, which visualization tools best promote Machine Learning in K-12 schools are determined and all teachers should be sensitized to adopt participatory learning pedagogy to enhance the effective use of machine learning in K-12 schools. Expand. 1 Excerpt.
Narrative reanalysis: A methodological framework for a new brand of reviews
Narrative reviews offer a synthesis of existing literature to describe the current state-of-the-art on a topic, typically without stringent methodological restrictions, which helps to expand the understanding of the topic. 8, 9 They allow for a broader and more abstract set of questions and are particularly useful when empirical data is scarce ...
Systematic-narrative hybrid literature review: A strategy for
The proposed style draws on characteristics of both the narrative and systematic review traditions. Therefore, we label this style 'Systematic-narrative hybrid literature review'. The similarities and differences between our proposed method compared to the narrative and systematic approaches are outlined in Table 1.
SANRA—a scale for the quality assessment of narrative review articles
Background Narrative reviews are the commonest type of articles in the medical literature. However, unlike systematic reviews and randomized controlled trials (RCT) articles, for which formal instruments exist to evaluate quality, there is currently no instrument available to assess the quality of narrative reviews. In response to this gap, we developed SANRA, the Scale for the Assessment of ...
RAMESES publication standards: meta-narrative reviews
Background Meta-narrative review is one of an emerging menu of new approaches to qualitative and mixed-method systematic review. A meta-narrative review seeks to illuminate a heterogeneous topic area by highlighting the contrasting and complementary ways in which researchers have studied the same or a similar topic. No previous publication standards exist for the reporting of meta-narrative ...
Systematic and other reviews: criteria and complexities
A systematic review follows explicit methodology to answer a well-defined research question by searching the literature comprehensively, evaluating the quantity and quality of research evidence rigorously, and analyzing the evidence to synthesize an answer to the research question. The evidence gathered in systematic reviews can be qualitative ...
Narrative Reviews
According to The SAGE Encyclopedia of Communication Research Methods, "A literature review is a thorough and critical evaluation of previous research on a topic of interest to the author.The review summarizes a particular area of research that helps to explain why an author is interested in a particular topic. A literature review is primarily associated with formal academic writing, such as a ...
How to Conduct a Systematic Review: A Narrative Literature Review
Systematic reviews are ranked very high in research and are considered the most valid form of medical evidence. They provide a complete summary of the current literature relevant to a research question and can be of immense use to medical professionals. Our goal with this paper is to conduct a narrative review of the literature about systematic reviews and outline the essential elements of a ...
Reviews: From Systematic to Narrative: Review By Type
Mixed Studies Review or Mixed Methods Review. Overview. Qualitative Systematic Review or Qualitative Evidence Synthesis. Rapid Review. Scoping review. Systematic Search and Reviews. Systematized Review. Umbrella Review . Source: Grant, MJ, Booth, A. A typology of reviews: an analysis of 14 review types and associated methodologies. Health Info ...
Reviews: From Systematic to Narrative: Narrative Review
The labels Narrative Review and Literature Review are often describing the same type of review. For scientific purposes, the term Literature Review is the one used most often. ... The difference between a Systematic Review and a Narrative Review can be summarized as follows: Good Quality Systematic Reviews: Traditional Narrative Reviews:
A systematic literature review of the clinical and socioeconomic burden
Editorials, narrative reviews and systematic literature reviews were included to identify primary studies. PRISMA guidelines were followed. Results 1585 unique publications were identified, of which 587 full texts were screened and 149 were included. A further 189 citations were included from reference lists of editorials and reviews, resulting ...
Exploring organizational career growth: a systematic literature review
Based on a systematic literature review (SLR) methodology that complies with PRISMA guidelines, this study synthesised 40 empirical articles on OCG published between 2013 and 2024. First, it summarised the characteristics of the articles on OCG research and addressed that the themes concerning OCG are concentrated in personal traits and work ...
Why Systematic Review rather than Narrative Review?
Why Systematic Review rather than Narrative Review? - PMC
Skills for the twin transition in manufacturing: a Systematic
A Systematic Literature Review (SLR) was performed to explore and understand which skills are essential for a CE in the manufacturing sector, including those needed to leverage digital technologies for a circular approach. Drawing from the existing body of literature, this method is particularly relevant as it synthesizes the skills that ...
Hearing preservation and quality of life in small to medium sized
A systematic review of the available literature was conducted using PubMed/MEDLINE, Embase, and Cochrane up December 08, 2023. Meta-analysis was performed using a random-effect model to calculate mean difference (MD) and relative risk (RR). A leave-one-out analysis was conducted. The risk of bias was assessed via the Risk of Bias in Non ...
Urinary CXCL-10, a prognostic biomarker for kidney graft injuries: a
Literature search. This review is conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [].The objectives of the study, the search strategy, inclusion and exclusion criteria, and study evaluation method were carefully designed, refined, and unanimously approved by all contributing authors well in advance.
An overview of methodological approaches in systematic reviews
1. INTRODUCTION. Evidence synthesis is a prerequisite for knowledge translation. 1 A well conducted systematic review (SR), often in conjunction with meta‐analyses (MA) when appropriate, is considered the "gold standard" of methods for synthesizing evidence related to a topic of interest. 2 The central strength of an SR is the transparency of the methods used to systematically search ...
Risk and Influencing Factors for School Absenteeism among ...
School plays an important role in the development of a child. The impact of school absenteeism extends beyond academic achievement, affecting one's ability to participate in life successfully. In particular, children with difficulties in communication and interaction are at risk of developing school absences. This systematic review therefore focused on school absenteeism among children on the ...

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RAMESES publication standards: meta-narrative reviews

What is a meta-narrative review?

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The RAMESES publication standards for meta-narrative reviews

Explanation

Item 2: Abstract

Introduction section

Item 3: Rationale for review

Item 4: Objectives and focus of review

Methods section

Item 5: Changes in the review process

Item 6: Rationale for using the meta-narrative approach

Item 7: Evidence of adherence to guiding principles of meta-narrative review

Item 8: Scoping the literature

Item 9: Searching process

Item 10: Selection and appraisal of documents

Item 11: Data extraction

Item 12: Analysis and synthesis processes

Results section

Item 13: Document flow diagram

Item 14: Document characteristics

Item 15: Main findings

Discussion section

Item 16: Summary of findings

Item 17: Strengths, limitations and future research directions

Item 18: Comparison with existing literature

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Item 20: Funding

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