a review or meta analysis synthesis existing knowledge

• Study protocol
• Open access
• Published: 03 August 2012

What is the most appropriate knowledge synthesis method to conduct a review? Protocol for a scoping review

• Monika Kastner 1 ,
• Andrea C Tricco 1 ,
• Charlene Soobiah 1 ,
• Erin Lillie 1 ,
• Laure Perrier 1 , 2 ,
• Tanya Horsley 3 ,
• Vivian Welch 4 ,
• Elise Cogo 1 ,
• Jesmin Antony 1 &
• Sharon E Straus 1 , 5  

BMC Medical Research Methodology volume  12 , Article number:  114 ( 2012 ) Cite this article

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A knowledge synthesis attempts to summarize all pertinent studies on a specific question, can improve the understanding of inconsistencies in diverse evidence, and can identify gaps in research evidence to define future research agendas. Knowledge synthesis activities in healthcare have largely focused on systematic reviews of interventions. However, a wider range of synthesis methods has emerged in the last decade addressing different types of questions (e.g., realist synthesis to explore mediating mechanisms and moderators of interventions). Many different knowledge synthesis methods exist in the literature across multiple disciplines, but locating these, particularly for qualitative research, present challenges. There is a need for a comprehensive manual for synthesis methods (quantitative/qualitative or mixed), outlining how these methods are related, and how to match the most appropriate knowledge synthesis method to answer a research question. The objectives of this scoping review are to: 1) conduct a systematic search of the literature for knowledge synthesis methods across multi-disciplinary fields; 2) compare and contrast the different knowledge synthesis methods; and, 3) map out the specific steps to conducting the knowledge syntheses to inform the development of a knowledge synthesis methods manual/tool.

We will search relevant electronic databases (e.g., MEDLINE, CINAHL), grey literature, and discipline-based listservs. The scoping review will consider all study designs including qualitative and quantitative methodologies (excluding economic analysis or clinical practice guideline development), and identify knowledge synthesis methods across the disciplines of health, education, sociology, and philosophy. Two reviewers will pilot-test the screening criteria and data abstraction forms, and will independently screen the literature and abstract the data. A three-step synthesis process will be used to map the literature to our objectives.

This project represents the first attempt to broadly and systematically identify, define and classify knowledge synthesis methods (i.e., less traditional knowledge synthesis methods). We anticipate that our results will lead to an accepted taxonomy for less traditional knowledge synthesis methods, and to the development and implementation of a methods manual for these reviews which will be relevant to a wide range of knowledge users, including researchers, funders, and journal editors.

Knowledge synthesis has the potential to inform the management of health problems [ 1 ] and is integral to the health of the Canadian population [ 2 ]. A knowledge synthesis summarizes all pertinent studies on a specific question, can improve the understanding of inconsistencies in diverse evidence, and can define future research agendas [ 1 , 3 ]. Knowledge synthesis is also an important part of the knowledge translation (KT) process (and ideally should form the ‘base unit’ of KT strategies for providers and policy makers), and be used to provide the evidence base for KT products including clinical practice guidelines, policy briefs and decision aids [ 4 ]. As such, knowledge synthesis can be used to interpret results of individual studies within the context of the totality of evidence. This is an important consideration, given that basing practice and policy decisions on a single study or expert opinion can be misleading [ 5 ].

Knowledge synthesis activities in healthcare have often focused on the methodologically rigorous Cochrane reviews, most commonly of interventions. The definition of a systematic review according to the Cochrane Collaboration is “A review of clearly formulated questions that uses systematic and explicit methods to identify, select, and critically appraise relevant research, and to collect and analyse data from the studies that are included in the review. Statistical methods (meta-analysis) may or may not be used to analyse and summarise the results of the included studies” [ 6 ]. However, Cochrane-like review methods may not always be applicable for answering all knowledge synthesis questions, particularly those investigating complex and multidisciplinary topics [ 7 , 8 ]. For example, members of our team recently attempted to conduct a systematic review to better understand the relationship between the perceived characteristics of clinical practice guidelines and their uptake by clinicians, and found that a flexible approach that borrowed relevant components of less traditional knowledge synthesis methods (i.e., including realist reviews and meta-ethnography) was more relevant to determine the mechanisms and circumstances underpinning guideline implementation [ 9 ]. This example highlights the need for less traditional methods for completing a review. By matching the appropriate design to fit the question, synthesis outputs are more likely to be relevant and be useful for end users.

Furthermore, a traditional review such as a Cochrane review cannot always explain why particular interventions work in some settings but not in others [ 10 ]. For example, a Cochrane review found that school feeding programs significantly improved the growth and cognitive performance of disadvantaged children [ 11 ], but failed to provide direction for policy-makers to decide which intervention should be implemented and under what circumstances. By conducting a realist review alongside the Cochrane review (which can be used to understand ‘what works for whom and under what circumstances’ [ 10 ]), the authors were able to provide concrete recommendations that could be implemented in practice and policy making [ 7 ]. To address these types of questions and adequately incorporate the needs, preferences and experiences of patients into healthcare delivery, there is an increasing need to consider less traditional review methods of complex evidence (i.e., heterogeneous, methodologically diverse, difficult to classify, and contradictory) [ 12 , 13 ]. Another approach is to consider conducting a systematic review as a “first step” to better understand complex evidence (or to conduct them in parallel with novel reviews), particularly for evidence generated from philosophy and the social sciences. The increasing number of synthesis methods that have recently emerged within the healthcare literature supports this need [ 14 – 17 ].

Table 1 summarizes a selection of knowledge synthesis methods that currently exist in the literature across multiple disciplines (identified through consultation with knowledge synthesis experts and qualitative researchers). Although many of these approaches can be applied to healthcare situations, the methods for conducting them have not been as clearly operationalized as traditional reviews of interventions. Consultation with researchers and end users of reviews that we conducted in preparation for this research indicate a lack of clarity around how to match the appropriate review method to the research question, the methods used to conduct these reviews, and how to analyze and present the results from the review to inform decision making. These issues are challenging for researchers interested in tackling reviews of complex questions and for decision makers trying to interpret and apply this evidence. Other identified challenges involve locating the numerous synthesis methods (particularly those for synthesizing qualitative research), which can be problematic and resource-intensive since they are scattered widely within the literature and across many different disciplines and databases. The terms used to describe the different synthesis methods are often similar (e.g., ‘meta-synthesis’, ‘meta-ethnography’, ‘meta-narrative’, ‘meta-study’, ‘meta-interpretation’) and their definitions can overlap [ 12 ]. This area of research is further complicated because some of these methods are referred to as a ‘complete’ synthesis method (i.e., providing guidance on the search strategy, study selection, appraisal, and analysis), while others provide guidance only on specific parts of the process, such as data analysis [ 12 ].

Some researchers have attempted to outline methods for the synthesis of qualitative [ 47 ] and mixed-methods research [ 36 , 45 ] and to build a typology of such reviews [ 41 ], while others have highlighted methods for knowledge synthesis reviews to inform specific end-user targets such as for management and policy-making in the health field [ 45 ]. A recent overview by Gough and colleagues attempted to outline the differences between review designs and methods by describing the important conceptual and practical differences amongst them [ 8 ]. However, a comprehensive manual for all of the different synthesis methods (quantitative/qualitative or mixed), outlining how they are related and how to decide which methodology is the most appropriate for a particular research question does not currently exist. To our knowledge, the current study will be the first to describe an overall taxonomy of all existing types of knowledge synthesis methods, to characterise the differences between them, and to develop a strategy for knowledge users to be able to select the most appropriate method to answer their research questions.

The specific objectives of the current study are to: (1) to conduct a systematic search for knowledge synthesis methods across multi-disciplinary fields, such as health and philosophy; (2) compare and contrast the different knowledge synthesis methods; and, (3) map out the specific steps to conducting the knowledge synthesis methods, which will be used to inform the development of a knowledge synthesis methods manual/tool.

Methods/Design

Search strategy.

We will use the methodologically rigorous scoping review approach proposed by Arksey and O’Malley [ 48 ] to conduct a systematic search across the disciplines of health and philosophy. We will search the following electronic databases from inception onwards: MEDLINE, CINAHL, EMBASE, PsycInfo, the Cochrane Methodology Register, Cochrane Database of Systematic Reviews, Social Sciences Abstracts, LISA, Philosopher’s Index, and ERIC. We will also perform targeted searches for grey literature (i.e., difficult to locate or unpublished material) by searching 1) Google, 2) relevant discipline-based listservs (e.g., CANMEDLIB, MEDLIB), and 3) the websites of agencies that fund or conduct knowledge synthesis (e.g., CIHR, Canadian Agency for Drugs and Technologies in Health, Agency for Healthcare Research and Quality, Cochrane and Campbell Collaborations, Joanna Briggs Institute, Centre for Reviews and Dissemination).

The draft literature search for MEDLINE can be found in Additional file 1 , which uses a combination of medical sub-headings (MeSH) and free text terms. It will be modified as necessary for the other databases. The search strategy will not be limited by study design, year or language of dissemination and will be peer reviewed by another information specialist using the Peer Review of Electronic Search Strategies (PRESS) checklist [ 49 ]. The literature search will be supplemented by scanning the reference lists of included studies, searching authors’ personal files, and contacting methodological experts in each field.

Study selection: inclusion criteria

Study design : All study designs will be considered including qualitative and quantitative methods such as methodology reports; knowledge syntheses (including a description of the synthesis method); short reports describing the development, use, or comparison of methods for knowledge synthesis. Type of knowledge synthesis : We will focus on synthesis methods above and beyond traditional systematic reviews and exclude methods on economic analysis or clinical practice guidelines. Disciplines : Health: “ A state of complete physical, mental and social well-being and not merely the absence of disease or infirmity ” [ 50 ] (and thus includes the disciplines of psychology, education and sociology) and philosophy. These were selected because many of the knowledge synthesis methods originated from these disciplines (e.g., systematic review methods rooted in education and psychology; realist reviews based on philosophy).

Study selection: screening

Prior to commencing the screening process, a calibration exercise will be conducted to ensure reliability in correctly selecting articles for inclusion. It will entail independently screening a random sample of 5% of the included citations by two reviewers. Eligibility criteria will be modified if low agreement is observed between the reviewers (e.g., a kappa statistic less than 50%). The reviewers will then independently screen the remainder of the search results using a pre-defined relevance criteria form for all levels of screening (e.g., title and abstract, full-text review). Discrepancies will be resolved by discussion with a third reviewer.

Data abstraction

A data abstraction form will be tested independently by two reviewers on a random sample of 10 articles and revised iteratively, as needed. It is anticipated that the data items will include study characteristics (e.g., first author, year of publication) and characteristics related to the method (e.g., general description of the review method, discipline) (Additional file 1 ). Two investigators will independently read each article and extract the relevant data. Differences in abstraction will be resolved by discussion or the involvement of a third reviewer. We will not formally appraise methodological quality because the aim of a scoping review is to identify gaps in the evidence base and to target topic areas for future reviews.

Data analysis

We will analyze the data according to a three-stage process aimed at addressing the three research objectives: to characterize the synthesis methodologies (Synthesis objective 1); to identify the similarities and differences amongst these methods (Synthesis objective 2); and to map out a process for conducting different synthesis methods and to provide an approach for matching the research question to the appropriate methods (Synthesis objective 3). Table 2 shows the analysis plan and anticipated outputs for each of these objectives. Data analysis will involve quantitative (e.g., frequency analysis) and qualitative (e.g., thematic analysis) methods. We anticipate that this multi-layer synthesis process will also identify existing gaps in the literature, and reveal potential topics for conducting other systematic or novel reviews in the future.

Engagement of knowledge users and KT plan

We have adopted an integrated KT approach to this project through the inclusion of knowledge users (i.e., systematic review methodologists, journal editors, review funders, policy makers, students and educators who teach knowledge synthesis methodology), who have been and will continue to be involved in every step of the process through to the reporting format and the methods for disseminating and implementing findings, drawing on Graham’s Knowledge-to-Action (KTA) framework [ 51 ]. We plan to develop an active KT plan by: 1) identifying the key messages arising from this research project; 2) determining the principal target audiences for each of these messages; 3) seeking out the most credible messenger for these messages and engaging their interest in becoming involved in the communication of these messages; and 4) launching a KT strategy grounded in the best available research evidence. We will use a diverse range of approaches to disseminate the results of this review to the different stakeholder groups (including an interactive workshop that will bring together the key target audiences for our research). These strategies will ensure that the research continues to reflect the relevant needs of the end users of this information, and to facilitate appropriate dissemination of outputs.

Anticipated challenges

We foresee some potential challenges related to this scoping review. First, the yield of the literature search might be more extensive than anticipated—the team will work closely with the information specialist to ensure that the scope is manageable. Second, it might be challenging to categorize the knowledge synthesis methods accurately (e.g., distinguishing between quantitative/qualitative or mixed / hybrid approaches or those not formally categorized) and to appropriately match a research question with a synthesis method. However, we have a strong team with diverse experience in different research methods, and are planning to hold stakeholder meetings to iteratively receive in-depth feedback from our end users.

The proposed scoping review has the potential to impact practice and policy and will make several contributions to the KT and health services research literature. First, the work will advance the science of knowledge synthesis by providing a systematic process for key knowledge users to make informed decisions about which synthesis method is the most appropriate to answer their research questions. This may also augment the quality of the research evidence produced. In particular, the work will highlight the potential for novel knowledge synthesis methods to clarify complex, multi-component, and multi-disciplinary healthcare interventions [ 13 ], and to contribute to the advancement of evidence-based practice and evidence-based decision-making. Second, there is currently no comprehensive manual for all available synthesis methods (quantitative/qualitative or mixed). To develop this manual, a taxonomy and comparison of all available synthesis methods are needed. Our work aims to develop the taxonomy of synthesis methods across multiple disciplines such as health and philosophy. Third, the scoping review will help map the literature, identify gaps where primary methods evidence is lacking and needed, and where systematic reviews are required; we anticipate that this work will lead to multiple subsequent systematic reviews. For example, one future systematic review may focus on knowledge synthesis methods for health services research and another may focus on knowledge synthesis of qualitative data. Fourth, the work has the potential to directly influence knowledge synthesis funders such as the Canadian Institutes of Health Research (CIHR) in developing resources (e.g., modules) that can be used to increase awareness of novel synthesis methods and their relevance for addressing complex evidence. This information is especially imperative for those conducting peer review of knowledge synthesis grants. Fifth, the scoping review can be used by publishers and editors to assist with the peer review of manuscripts describing these types of knowledge syntheses. Sixth, our findings have the potential to influence health research methods curricula within clinical epidemiology programs, by expanding the current understanding of synthesis methods. The development and evaluation of complex interventions has emerged as an important component of KT, so expertise in conducting non-traditional review methods will become increasingly important for researchers, teachers, and students. Lastly, the work will be targeted across a broad scope of health disciplines, which will provide the opportunity to elicit more generalizable findings that can directly inform practice and policy decisions within these disciplines. Results from this work will be the starting point of a comprehensive manual and decision algorithm on how to conduct the different synthesis methods and the proposed KT strategy will serve to engage the relevant stakeholders in clarifying and fulfilling the research agenda proposed in the scoping review (Table 3 summarizes the anticipated products that will be generated).

Conducting a scoping review of available knowledge synthesis methods across multi-disciplinary fields will help funders, publishers, policy-makers, researchers, teachers, and students make informed decisions about the most appropriate synthesis method to answer research questions about complex evidence, and provide the opportunity to elicit findings directly informing practice and policy decisions.

The study was funded by a Canadian Institutes of Health Research (CIHR) Knowledge Synthesis grant. MK holds a CIHR Banting Postdoctoral Fellowship, ACT a CIHR/DSEN new investigator award, and SES a Tier 1 Canada Research Chair in Knowledge Translation.

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Acknowledgements

We thank Drs. Jeremy Grimshaw, David Moher, and Peter Tugwell, who provided their support and expertise in knowledge synthesis methods and knowledge translation on this protocol.

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Kastner, M., Tricco, A.C., Soobiah, C. et al. What is the most appropriate knowledge synthesis method to conduct a review? Protocol for a scoping review. BMC Med Res Methodol 12 , 114 (2012). https://doi.org/10.1186/1471-2288-12-114

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Meta-analysis and the science of research synthesis

• Jessica Gurevitch 1 ,
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Meta-analysis is the quantitative, scientific synthesis of research results. Since the term and modern approaches to research synthesis were first introduced in the 1970s, meta-analysis has had a revolutionary effect in many scientific fields, helping to establish evidence-based practice and to resolve seemingly contradictory research outcomes. At the same time, its implementation has engendered criticism and controversy, in some cases general and others specific to particular disciplines. Here we take the opportunity provided by the recent fortieth anniversary of meta-analysis to reflect on the accomplishments, limitations, recent advances and directions for future developments in the field of research synthesis.

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Acknowledgements

We dedicate this Review to the memory of Ingram Olkin and William Shadish, founding members of the Society for Research Synthesis Methodology who made tremendous contributions to the development of meta-analysis and research synthesis and to the supervision of generations of students. We thank L. Lagisz for help in preparing the figures. We are grateful to the Center for Open Science and the Laura and John Arnold Foundation for hosting and funding a workshop, which was the origination of this article. S.N. is supported by Australian Research Council Future Fellowship (FT130100268). J.G. acknowledges funding from the US National Science Foundation (ABI 1262402).

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Jessica Gurevitch

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Julia Koricheva

Evolution and Ecology Research Centre and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, 2052, New South Wales, Australia

Shinichi Nakagawa

Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, 2010, New South Wales, Australia

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Gavin Stewart

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Gurevitch, J., Koricheva, J., Nakagawa, S. et al. Meta-analysis and the science of research synthesis. Nature 555 , 175–182 (2018). https://doi.org/10.1038/nature25753

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Knowledge syntheses: systematic & scoping reviews, and other review types.

• Before you start
• Getting Started
• Different Types of Knowledge Syntheses
• Assemble a Team
• Develop your Protocol
• Eligibility Criteria
• Screening for articles
• Data Extraction
• Critical appraisal
• What are Systematic Reviews?

When is conducting a meta-analysis appropriate?

Elements of a meta-analysis, methods and guidance.

• What are Scoping Reviews?
• What are Rapid Reviews?
• What are Realist Reviews?
• What are Mapping Reviews?
• What are Integrative Reviews?
• What are Umbrella Reviews?
• Standards and Guidelines
• Supplementary Resources for All Review Types
• Resources for Qualitative Synthesis
• Resources for Quantitative Synthesis
• Resources for Mixed Methods Synthesis
• Bibliography
• More Questions?
• Common Mistakes in Systematic Reviews, scoping reviews, and other review types

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

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

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

Conducting meta-analyses can have the following benefits, according to Deeks et al. (2019, section 10.2) :

To improve precision. Many studies are too small to provide convincing evidence about intervention effects in isolation. Estimation is usually improved when it is based on more information.

To answer questions not posed by the individual studies. Primary studies often involve a specific type of participant and explicitly defined interventions. A selection of studies in which these characteristics differ can allow investigation of the consistency of effect across a wider range of populations and interventions. It may also, if relevant, allow reasons for differences in effect estimates to be investigated.

To settle controversies arising from apparently conflicting studies or to generate new hypotheses. Statistical synthesis of findings allows the degree of conflict to be formally assessed, and reasons for different results to be explored and quantified.

The following characteristics, strengths, and challenges of conducting meta-analyses in systematic reviews are derived from Grant & Booth (2009) , Haidlich (2010) and  Deeks et al. (2019) .

Characteristics:

A meta-analysis can only be conducted after the completion of a systematic review, as the meta-analysis statistically summarizes the findings from the studies synthesized in a particular systematic review. A meta-analysis cannot exist without a pre-existing systematic review. Grant & Booth (2009) state that "although many systematic reviews present their results without statistically combining data [in a meta-analysis], a good systematic review is essential to a meta-analysis of the literature" (p. 98).

Conducting a meta-analysis requires all studies that will be statistically summarized to be similar - i.e. the population, intervention, and comparison. Grant & Booth (2009) state that "most importantly, it requires that the same measure or outcome be measured in the same way at the same time intervals" (p. 98).

The end product is a quantitative review that is often complex in nature

Consolidates individual studies that on their own do not have much practical impact, having a solid package of evidence benefits decision-makers who often can't afford to read many individual studies.

Challenges:

It can be challenging to ensure that studies used in a meta-analysis are similar enough, which is a crucial component

Meta-analyses can perhaps be misleading due to biases such as those concerning specific study designs, reporting, and biases within studies

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

METHODS & GUIDANCE

• Cochrane Training: Chapter 10: Analysing data and undertaking meta-analyses

Provides a comprehensive overview on meta-analyses.

REPORTING GUIDELINE

• PRISMA 2020 Checklist

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

SUPPLEMENTARY RESOURCES

Check out the  supplementary resources page  for additional information on meta-analyses.

• << Previous: What are Systematic Reviews?
• Next: What are Scoping Reviews? >>
• Last Updated: Jul 30, 2024 11:11 AM
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Systematic Review and Evidence Synthesis

Acknowledgements.

This guide is directly informed by and selectively reuses, with permission, content from: 

• Systematic Reviews, Scoping Reviews, and other Knowledge Syntheses by Genevieve Gore and Jill Boruff, McGill University (CC-BY-NC-SA)
• A Guide to Evidence Synthesis , Cornell University Library Evidence Synthesis Service

Primary University of Minnesota Libraries authors are: Meghan Lafferty, Scott Marsalis, & Erin Reardon

Last updated: September 2022

Guidance by Methodology

• PRISMA reporting guidelines
• Systematic review guidance
• Meta-analysis guidance
• Scoping review guidance
• Evidence and gap map guidance
• Rapid review guidance
• Qualitative meta-synthesis guidance
• Umbrella review guidance

PRISMA Statement introduction

Prisma statement introduction.

The PRISMA statement is the main reporting standard for evidence synthesis. The acronym refers to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. In addition to the main PRISMA statement there are many extensions for other methodologies; these are notated by a suffix. Please refer to  www.prisma-statement.org  for the most recent information and updates and a complete list of extensions. We list only the most frequently used on this page.

When using PRISMA or its extensions it is important to carefully read the key documents. Typically there will be a paper introducing the standard and its development,  an "E&E" or "Explanation & Elaboration" paper which explains the components of the statement and gives examples, and a checklist, which helps the authors make sure they fully comply in reporting their study.

One of the most familiar aspects of PRISMA is the flow diagram which summarized the flow of information through the process, from record identification through screening and synthesis. Only including the flow diagram is not enough to comply with PRISMA or its extensions.

PRISMA Key Documents

• PRISMA 2020 Checklist
• PRISMA 2020 flow diagram
• PRISMA 2020 Statement  
• PRISMA 2020 Explanation and Elaboration

PRISMA Extensions

• PRISMA for Abstracts
• PRISMA for Acupuncture
• PRISMA for Diagnostic Test Accuracy
• PRISMA for EcoEvo
• PRISMA Equity
• PRISMA Harms (for reviews including Harm outcomes)
• PRISMA Individual Patient Data
• PRISMA for Network Meta-Analyses
• PRISMA for Protocols
• PRISMA for Scoping Reviews
• PRISMA for Searching
• Extensions in development

Systematic Review Guidance

Cochrane Handbook for Systematic Reviews of Interventions

Finding What Works in Health Care: Standards for Systematic Reviews

An Introduction to Systematic Reviews

JBI Manual for Evidence Synthesis

Meta-Analysis Guidance

Research synthesis and meta-analysis : a step-by-step approach (Fifth edition.) Cooper. (2017). Research synthesis and meta-analysis : a step-by-step approach (Fifth edition.). SAGE Publications, Inc.

Scoping Review Guidance

• JBI Manual for Evidence Synthesis - Chapter 10: Scoping Reviews
• Tricco, A., Lillie, E., Zarin, W., O'Brien, K., Colquhoun, H., Levac, D., . . . Straus, S. (2018). PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation. Annals of Internal Medicine, 169(7), 467-473. https://doi.org/10.7326/M18-0850.  
• Arksey, H. & O'Malley, L. (2005) Scoping studies: towards a methodological framework. International Journal of Social Research Methodology, 8:1, 19-32, DOI: 10.1080/1364557032000119616
• Peters, M.D., Marnie, C., Tricco, A.C., Pollock, D., Munn, Z., Alexander, L., McInerney, P., Godfrey, C.M. and Khalil, H., (2020). Updated methodological guidance for the conduct of scoping reviews. JBI Evidence Synthesis, 18(10), pp.2119-2126.
• Munn Z, Peters MDJ, Stern C, Tufanaru C, McArthur A, Aromataris E. Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. BMC Med Res Methodol. 2018;18(1):143. doi: 10.1186/s12874-018-0611-x (Open access)

Evidence & Gap Map Guidance

• White, H., Albers, B., Gaarder, M., Kornør, H., Little, J., Marshall, Z., Mathew, C., Pigott, T., Snilsveit, B., Waddington, H., & Welch, V. (2020). Guidance for producing a Campbell evidence and gap map. Campbell Systematic Review, 16(4).
• Ashrita Saran. (2020). Evidence and gap maps. Campbell Systematic Review, 16(1).
• Ashrita Saran, & Howard White. (2018). Evidence and gap maps: A comparison of different approaches. Campbell Systematic Review, 14(1), 1-38.

Rapid Review Guidance

• Tricco, A., Antony, J., Zarin, W., Strifler, L., Ghassemi, M., Ivory, J., Perrier, L., Hutton, B., Moher, D., & Straus, S. (2015). A scoping review of rapid review methods . BMC Medicine, 13(1), 224.

Qualitative Meta-Synthesis Guidance

• Aguirre, R. T., & Bolton, K. W. (2014). Qualitative interpretive meta-synthesis in social work research: Uncharted territory. Journal of Social Work, 14(3), 279-294. https://doi.org/10.1177/1468017313476797
• Hannes, K., & Lockwood, C. (2012). Synthesizing Qualitative Research: Choosing the Right Approach. John Wiley & Sons. 
• Sandelowski, M., & Barroso, J. (2002). Reading Qualitative Studies. International Journal of Qualitative Methods, 1(1), 74-108.

Umbrella Review Guidance

• JBI Manual for Evidence Synthesis - Chapter 10: Umbrella Reviews
• Aromataris, E., Fernandez, R.S., Godfrey, C., Holly, C., Khalil, H., & Tungpunkom, P. (2014). Methodology for JBI umbrella reviews.
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• Next: Existing Reviews: Finding, Evaluating, Updating >>

Introduction to Systematic Reviews

In this guide.

• Introduction
• Types of Reviews
• Systematic Review Process
• Protocols & Guidelines
• Data Extraction and Screening
• Resources & Tools

Before You Start Checklist

Are you ready to carry out a knowledge synthesis project such as a systematic review, meta-analysis, or scoping review? Remember that systematic reviews require:

• a team to carry out screening, extraction, and critical appraisal methods
• a significant amount of time to complete
• enough high quality studies to make a systematic review feasible
• a rigorous protocol (that should be registered)
• adherence to transparent and rigorous methods
• a strong project management component with defined goals, responsibilities, deliverables, and timelines 
• financial resources to complete the project 

What Review Is Right For You?

If you're unsure what type of knowledge synthesis best suits your research purposes, follow along this flowchart or complete this short quiz to find your personalized review methodologies: https://whatreviewisrightforyou.knowledgetranslation.net/

Reproduced from  "What type of review could you write?" Yale Medical Library. 

Types of Knowledge Syntheses

Conducting effective reviews is essential to advance the knowledge and understand the breadth of research on a topic; synthesize existing evidence; develop theories or provide a conceptual background for subsequent research; and identify research gaps. However, there are over 100 different kinds of reviews to choose from. The following provides a comparison of common review types.

Reproduced from Grant, M. J., & Booth, A. (2009). A typology of reviews: an analysis of 14 review types and associated methodologies. Health Information & Libraries Journal, 26 (2), 91-108. DOI: 10.1111/J.1471-1842.2009.00848.X

Fifty Shades of Review - Dr Andrew Booth from ScHARR Library on Youtube .

Books on Knowledge Synthesis

• Finding What Works in Health Care by Jill Eden (Editor); Laura Levit (Editor); Alfred Berg (Editor); Sally Morton (Editor); Committee on Standards for Systematic Reviews of Comparative Effectiveness Research; Institute of Medicine; Board on Health Care Services Staff ISBN: 0309164257 Publication Date: 2011

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• URL: https://laneguides.stanford.edu/systematicreviews

• Mayo Clinic Libraries
• Evidence Synthesis Guide
• Synthesis & Meta-Analysis

Evidence Synthesis Guide : Synthesis & Meta-Analysis

• Review Types & Decision Tree
• Standards & Reporting Results
• Materials in the Mayo Clinic Libraries
• Training Resources
• Review Teams
• Develop & Refine Your Research Question
• Develop a Timeline
• Project Management
• Communication
• PRISMA-P Checklist
• Eligibility Criteria
• Register your Protocol
• Other Resources
• Other Screening Tools
• Grey Literature Searching
• Citation Searching
• Data Extraction Tools
• Minimize Bias
• Risk of Bias by Study Design
• GRADE & GRADE-CERQual
• Publishing your Review

Bringing It All Together

Synthesis involves pooling the extracted data from the included studies and summarizing the findings based on the overall strength of the evidence and consistency of observed effects. All reviews should include a qualitative synthesis and may also include a quantitative synthesis (i.e. meta-analysis). Data from sufficiently comparable and reliable studies are weighted and evaluated to determine the cumulative outcome in a meta-analysis.  Tabulation and graphical display  of the results (e.g. forest plot showing the mean, range and variance from each study visually aligned) are typically included for most forms of synthesis. Generally, conclusions are drawn about the usefulness of an intervention or  the relevant body of literature with suggestions for future research directions.

An AHRQ guide  and c hapters  9 ,  10 ,  11 , and  12 of the Cochrane Handbook  and further address meta-analyses and other synthesis methods.

Consult Cochrane Interactive Learning Module 6: Analyzing the Data and Module 7. Interpreting the Findings for further information.  *Please note you will need to register for a Cochrane account while initially on the Mayo network. You'll receive an email message containing a link to create a password and activate your account.*

References & Recommended Reading

• Morton SC, Murad MH, O’Connor E, Lee CS, Booth M, Vandermeer BW, Snowden JM, D’Anci KE, Fu R, Gartlehner G, Wang Z, Steele DW. Quantitative Synthesis—An Update . 2018 Feb 23. In: Methods Guide for Effectiveness and Comparative Effectiveness Reviews [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US).
• McKenzie, JE, et al. Chapter 9: Summarizing study characteristics and preparing for synthesis. In: Higgins JPT, et al. (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2. Cochrane, 2021. Available from  www.training.cochrane.org/handbook See - Section 9 
• Deeks, JJ, et al. Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JPT, et al. (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2. Cochrane, 2021. Available from  www.training.cochrane.org/handbook See - Section 10 
• Chaimani, A, et al. Chapter 11: Undertaking network meta-analyses. In: Higgins JPT, et al. (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2. Cochrane, 2021. Available from  www.training.cochrane.org/handbook See - Section 11 
• McKenzie, JE, Brennan SE. Chapter 12: Synthesizing and presenting findings using other methods. In: Higgins JPT, et al. (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2. Cochrane, 2021. Available from  www.training.cochrane.org/handbook See - Section 12  
• Campbell M, McKenzie JE, Sowden A, et al.  Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline.  BMJ (Clinical research ed). 2020;368:l6890.
• Alavi M, Hunt GE, Visentin DC, Watson R, Thapa DK, Cleary M.  Seeing the forest for the trees: How to interpret a meta-analysis forest plot.  Journal of advanced nursing. 2021;77(3):1097-1101. doi:https://dx.doi.org/10.1111/jan.14721
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Knowledge Synthesis: Systematic & Scoping Reviews

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Is a Systematic/Scoping Review Right for You?

Systematic Reviews and Scoping Reviews are types of literature reviews that use systematic methods to collect studies and each have their own complex steps.  ‘New’ researchers will experience a steep learning curve and should be prepared to be trained in the art of searching before the review is conducted. 

To help you understand the difference between a systematic or scoping review as well as provide you with a high-level overview of the work involved, please review the side-by-side comparison chart below.

If performing a systematic review, we highly recommend that you complete all of the Cochrane Interactive Learning Modules before you begin. 

Should you require support anytime throughout your research process and would like to book a research consult, please contact a member of the Western Libraries Systematic and Scoping Review Team .

If you determine a systematic or scoping review is NOT  currently the right path for you and you need research support, please fill out this  research consultation form .

Timeline of your project is key. One common mistake of researchers undergoing a Systematic or Scoping Review is an unrealistic project timeline. Please see Cochrane timeline below

Box 2.3.b: Timeline for a Cochrane review

Average Systematic / Scoping Review Timeline

The information below has been adapted from:  Cochrane’s Handbook for Systematic Reviews of Interventions  &  McGill Library’s Systematic Reviews, Scoping Reviews, and other Knowledge Syntheses  Guide &  UofT Libraries’  Knowledge syntheses: Systematic & Scoping Reviews, and other review types  Guide 

Formulate Research Question

Formulating a well-constructed research question is essential for a successful review. You should have a draft research question before you choose the type of review that you will conduct to ensure a systematic or scoping review is the appropriate choice.  

A clearly defined question will allow you to focus your search so that it is more efficient and effective, make it easier to find and combine appropriate terms, and help identify relevant results.  

To define and focus your question you can utilize a concept mapping method. Please see our How to Develop a Research Question video as an introductory resource on developing research questions.

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Investigate for Previous SRs

Once you have a clearly defined research question, it is important to make sure your question has not already been recently and successfully undertaken. This means it is important to find out if there are other reviews that have been published or that are in the process of being published on your topic. 

Even if you do find another review or synthesis on your topic, it may be sufficiently out of date or you may find other defendable reasons to perform it again. In addition, looking at other reviews published around your topic may also help you refocus your question or redirect your research toward other gaps in the literature. 

To find published reviews or protocols on your topic, you can check resources such as: 

PROSPERO - to find protocols 

Cochrane Library – to find systematic reviews 

Other databases or journals that index systematic/scoping reviews or protocols 

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Devise Search Strategy

When devising a search strategy, remember it is supposed to be thorough, objective and reproducible. It involves searching more than one database and using a combination of keywords as well as subject headings.   

It is recommended to consult a librarian at this stage of your review. 

For more information on devising a comprehensive search strategy visit our  Searching Techniques Page  which can be found within our Systematic and Scoping Review Guide. 

Write/Register Protocol

What is a protocol? 

A protocol is a document that serves as a work plan for your review that describes the rationale, hypothesis, and planned methods of the review.  Your protocol should be prepared before you start your review, even if things change along the way.  Following a protocol allows for transparency, reproducibility, and minimizes biases. 

For systematic reviews, the PRISMA website provides several sources of guidance on  writing a protocol . 

For scoping reviews, the Joanna Briggs Institute provides guidance for writing a protocol in section 11.2 of their chapter on scoping reviews. Resources for scoping reviews can be found through the  JBI Scoping Review Network .

In general, your protocol should have the following elements: 

• Background literature review 
• Review question 
• Criteria for inclusion/exclusion of studies 
• Types of studies, populations, interventions/exposures, outcome measures 
• Search strategy for identification of studies 
• Study selection methods 
• Assessment of methodological quality (if applicable) 
• Data extraction and synthesis 
• Timeframe for conducting the review 

(Adapted from: Booth, A., Sutton, A. and Papaioannou, D. (2016). Defining the scope.  Systematic Approaches to a Successful Literature Review , 2nd edition.) 

Registering or Publishing A Completed Protocol

Once you have written your protocol, consider registering it with an organization or publishing it in a journal.  Listed below are a few example resources: 

PROSPERO  - Initiated in early 2011, this international database allows free registration of systematic reviews of interventions and strategies to prevent, diagnose, treat, and monitor health conditions in humans, for which there is a health-related outcome. At the present time, PROSPERO does not accept scoping review protocols. 

More information and guidance on registering in PROSPERO can be found on their  website . 

• OSF Registries  - Use the OSF (Open Science Framework) platform to preregister the protocol for your knowledge synthesis. This is a useful option if you are not publishing a systematic review or a review of interventions with health-related outcomes. 
• BioMed Central Protocols  - BioMed Central will consider protocols of any type of research for publication, following the standard peer review. 
• BMJ Open  - BMJ Open "will consider publishing without peer review protocols that have formal ethical approval and funding from a recognized, open access advocating research-funding body". Otherwise, protocols are peer reviewed. 
• Systematic Reviews, a BioMed Central journal  - This open access title publishes protocols of systematic reviews broadly related to health sciences. 

Primary Search

Now it’s time to execute your search strategy in each of the databases that you have identified.  We recommend developing the search strategy in one database before translating the search strategy to the other selected databases. It is also recommended that you create an account with each database in order to save and rerun your searches. 

This will make it easier to keep track of things. If you subsequently find terms in the other selected databases, you can then go back and add them to the searches that you have already developed. 

Grey Literature Search

Finding studies relevant to your question should not depend solely on database searching: Supplementary search methods, such as grey literature searching, are recommended in order to avoid different forms of bias in what studies are ultimately included in the review. 

Grey literature is usually understood to be literature not formally published in books or journals. This can include theses or dissertations, conference proceedings, clinical trials registries, white papers, government reports, and more. 

Some grey literature will be retrievable through database searching, but it depends on the databases.  Grey literature is also available on websites. One suggestion is to identify associations, organizations, institutions, etc. that are likely to make documents or reports relevant to your question, and then selectively search or browse those sites. 

For more information on where to find Grey Literature refer to the  Sources Page  which can be found within our Systematic and Scoping Review Guide. 

De-Duplicate

To remove duplicate citations there are a few options available. Citation managers, such as Mendeley, Zotero, and EndNote, allow you to remove duplicate citations and assist with citing sources. Also available is systematic review software that will remove duplicates and help with the screening process. Western Libraries subscribes to  Covidence  and is available to students, faculty, and staff.  

Title and Abstract Screening

In the initial stage of screening, at least two reviewers from the review team will independently scan titles and abstracts of articles that were retrieved from a comprehensive (i.e. multiple source) search, and make decisions whether to include or exclude articles. To do this in a streamlined, unbiased, and method-driven way, reviewers should adhere to the pre-defined eligibility criteria, or guidance form. 

Obtain Full Text

Full-Text articles are available within the database and library catalogue. If you cannot find the full-text article you can request a copy through Interlibrary Loans .

Full Text Screening

The second level of screening is a more rigourous, in-depth process in which the articles that were included in the initial stage of screening are read in full-text. Similar to the initial screening, this is done independently by at least two reviewers from the review team, and the eligibility criteria that was used as a guideline for the initial screening is largely the same. 

However, the full-text screening differs in these important ways: 

The reason(s) for exclusion must be recorded and reported 

You can now screen for outcome(s). Ask yourself: does the study report on the outcome(s) you're interested in? 

Although the eligibility criteria is the same, it will require additional detail (clarifying questions may arise during the first stage of screening) 

Supplemental Search

After selecting the full-text articles you can use citation tracking/chaining to ensure that you did not miss any relevant citations in your primary search.  

Data Extraction

Using the full-text of each article identified for inclusion in the review, extract the pertinent data using a standardized data extraction/coding form. The data extraction form should be as long or as short as necessary and can be coded for computer analysis if desired. 

Data Synthesis

Data synthesis is a process of bringing together data from a set of included studies with the aim of drawing conclusions about a body of evidence. This will include synthesis of study characteristics and, potentially, statistical synthesis of study findings. 

For more information on the data synthesis process please refer to  Chapter 9 of the Cochrane Handbook . 

Data Analysis

It can be tempting to jump prematurely into a statistical analysis when undertaking a systematic review. Results of meta-analyses can be very misleading if suitable attention has not been given to formulating the review question; specifying eligibility criteria; identifying and selecting studies; collecting appropriate data; considering risk of bias; planning intervention comparisons; and deciding what data would be meaningful to analyze. Review authors should consult the chapters that precede this one before a meta-analysis is undertaken. 

For more information on the data analysis process please refer to  Chapter 10 of the Cochrane Handbook .   

Re-Run Primary Search

Conducting a systematic review is a lengthy process and most likely a considerable amount of time has passed since running your primary search. It is recommended that you re-run your primary search in order to ensure that you aren’t missing any articles published since that time.  If you have identified new articles make sure you go back to the Title and Abstract Screening stage and go through each step with this updated set of citations.  

Write-Up Review

Congratulations, you are almost done!   

There are different guidelines depending on the review you are undertaking, your review topic, and where you are intending to publish.  Be sure to check with the journal’s guidelines, as well as  PRISMA’s Guideline Checklist , to make sure you are including all the necessary elements in your manuscript. 

Writing up your review should be an ongoing process throughout the different stages of the systematic review. 

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Systematic reviews & evidence synthesis methods.

• Schedule a Consultation / Meet our Team
• What is Evidence Synthesis?
• Types of Evidence Synthesis
• Evidence Synthesis Across Disciplines
• Finding and Appraising Existing Systematic Reviews
• 0. Preliminary Searching
• 1. Develop a Protocol
• 2. Draft your Research Question
• 3. Select Databases
• 4. Select Grey Literature Sources
• 5. Write a Search Strategy
• 6. Register a Protocol
• 7. Translate Search Strategies
• 8. Citation Management
• 9. Article Screening
• 10. Risk of Bias Assessment
• 11. Data Extraction
• 12. Synthesize, Map, or Describe the Results
• Evidence Synthesis Resources & Tools

What are evidence syntheses?

According to the Royal Society, 'evidence synthesis' refers to the process of bringing together information from a range of sources and disciplines to inform debates and decisions on specific issues. They generally include a methodical and comprehensive literature synthesis focused on a well-formulated research question. Their aim is to identify and synthesize all of the scholarly research on a particular topic, including both published and unpublished studies. Evidence syntheses are conducted in an unbiased, reproducible way to provide evidence for practice and policy-making, as well as to identify gaps in the research. Evidence syntheses may also include a meta-analysis, a more quantitative process of synthesizing and visualizing data retrieved from various studies.

Evidence syntheses are much more time-intensive than traditional literature reviews and require a multi-person research team. See this PredicTER tool to get a sense of a systematic review timeline (one type of evidence synthesis). Before embarking on an evidence synthesis, it's important to clearly identify your reasons for conducting one. For a list of types of evidence synthesis projects, see the Types of Evidence Synthesis tab.

How does a traditional literature review differ from evidence synthesis?

One commonly used form of evidence synthesis is a systematic review. This table compares a traditional literature review with a systematic review.

Video: Reproducibility and transparent methods (Video 3:25)

Reporting standards

There are some reporting standards for evidence syntheses. These can serve as guidelines for protocol and manuscript preparation and journals may require that these standards are followed for the review type that is being employed (e.g. systematic review, scoping review, etc).​

• PRISMA checklist Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) is an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses.
• PRISMA-P Standards An updated version of the original PRISMA standards for protocol development.
• PRISMA - ScR Reporting guidelines for scoping reviews and evidence maps
• PRISMA-IPD Standards Extension of the original PRISMA standards for systematic reviews and meta-analyses of individual participant data.
• EQUATOR Network The EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network is an international initiative that seeks to improve the reliability and value of published health research literature by promoting transparent and accurate reporting and wider use of robust reporting guidelines. They provide a list of various standards for reporting in systematic reviews.

Video: Guidelines and reporting standards

PRISMA flow diagram

The PRISMA flow diagram depicts the flow of information through the different phases of an evidence synthesis. It maps the search (number of records identified), screening (number of records included and excluded), and selection (reasons for exclusion). Many evidence syntheses include a PRISMA flow diagram in the published manuscript.

See below for resources to help you generate your own PRISMA flow diagram.

• PRISMA Flow Diagram Tool
• PRISMA Flow Diagram Word Template
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Knowledge synthesis: Literature reviews

Introduction

CJNR welcomes a variety of review types (integrative reviews, systematic reviews, meta-analyses, qualitative reviews, and scoping reviews of relevance to nursing and related clinical sciences). The goal of these scientific reviews is to develop a set of defensible recommendations or a theoretical formation in the area under review. The review must provide a clear understanding of the quality of the studies, the state of the art in the field of interest, and empirically justified recommendations for clinical practice, health policy, or theory development.

CJNR does not publish narrative reviews (where the questions guiding the review are not clearly specified, the search and selection strategy for relevant documents is not laid out, and analysis of extracted data is not conducted). We caution authors that literature reviews prepared for other purposes (for instance, grant or dissertation proposals), even when trimmed or extended to article length, are unlikely to meet our basic criteria.

Some suggested standard guidelines for reporting knowledge syntheses of different methodologies may be found among the References listed below.

Where relevant, refer to the following:

• PRISMA guidelines and checklist in the preparation of systematic reviews and meta-analyses of RCTs
• RAMESES publication standards for preparing systematic qualitative reviews ( http://onlinelibrary.wiley.com/doi/10.1111/jan.12095/full or ( http://onlinelibrary.wiley.com/doi/10.1111/jan.12092/full ).
• ENTREQ standards for reporting a synthesis of qualitative research
• MOOSE publication standards for reporting meta-analyses of observational studies

Your paper should be a maximum of 20 double-spaced pages, including references and (if necessary) one table or figure. Headings and subheadings should be used throughout. An organizational guideline is provided merely as a suggestion. The style reference to be followed is the Publication Manual of the American Psychological Association, 6th Edition.

ORGANIZATIONAL STRUCTURE AND COMPONENTS

The Background section comprises the following elements:

• a clearly stated, empirically justified problem
• the theoretical, methodological, and/or clinical context
• the use of primary sources, often within the delineated context of the stated framework

State the review objective and questions to be addressed.

For systematic reviews and meta-analyses, state the questions in relation to PICOS (see the PRISMA 2002 checklist).

All integrative reviews, systematic reviews, meta-analyses, and qualitative reviews require a highly focused research question.

Methodology

State and justify the methodology/theoretical framework used to guide the review, such as integrative review, meta-analysis, grounded theory synthesis, or thematic synthesis.

State whether the type/scope of search is comprehensive or iterative and justify your inclusion/exclusion criteria.

Search Methods

Identify your sampling strategy, such as purposive sampling, and justify your decision. More than one strategy should be used to enhance a comprehensive sampling frame.

Identify the electronic search strategies and databases for the review.

Provide a list of search terms relevant to your topic.

Identify other search sources, such as journal references or research registries, to ensure that you have accessed the full range of studies available with respect to your topic.

Provide an explicit account of the steps that were followed according to the guideline or framework used, with justification, reporting the outcomes at each phase.

Highlight any deviations from your planned approach.

Data Evaluation

Provide the rationale and approach used to evaluate the studies from your search.

Describe the strategy for selecting the primary sources, the inclusion/exclusion criteria, and how data were coded.

Data Extraction

This section should consist of the following:

• approach to selecting the primary sources, inclusion/exclusion criteria, and the methods used for identifying, extracting/abstracting, and organizing the data
• concepts or sections of the articles that were extracted
• the means by which the quality of the primary sources was evaluated
• the coding process of primary sources and the rating score

In a meta-analysis, the summary measures used, such as risk ratio, mean difference, and measures of consistency, should be stated (see PRISMA guideline checklist).

Provide the number and types of studies constituting the final sample, which may include both empirical and theoretical papers — for example, case studies or cross-sectional, intervention, grounded theory, or instrument-development designs (Whittemore & Knafl, 2005).

Identify the data associated with the criteria used to extract relevant primary sources, and justify your observations with references.

Illustrate the findings with a flow sheet showing the results obtained at each phase of the literature search.

Link the extracted information, variables, and concepts to underlying theoretical contexts.

Present the results of your coding scale according to the criteria you used to evaluate each study.

Identify any findings of bias in the final data set.

Methods of Analysis

Describe the method used to guide your data analysis.

Describe how the data were analyzed, the categories, and, where relevant, how different data sets from different methodologies were combined.

Identify the criteria used to assess the data, the coding procedure (rating scheme, if relevant), and how data were categorized and synthesized across primary sources resulting in an integrated evaluation of the topic of interest, and from that a set of derived, evidenced-based recommendations.

Present the synthesis in the form of a model, theory, or defensible recommendations.

Discuss the findings in terms of other evidence.

Discuss the applicability of the findings to theory, practice, or stakeholders.

Discuss the findings in the context of perceived limitations of the review.

Summarize the relevance of recommendations in terms of limitations and generalizability. Describe the extent to which the recommendations contribute to research, clinical practice, or policy-making.

http://www.prisma-statement.org/

Armstrong, R., Hall, B. J., Doyle, J., & Waters, E. (2011). Cochrane update: Scoping the scope of a Cochrane review. Journal of Public Health, 33 (1), 147–150.

Broome, M.E. (2000). Integrative literature reviews for the development of concepts. In B. Rodgers & K. Knafl (Eds.), Concept 0development in nursing (2nd ed.) (pp. 231–250). Philadelphia: Saunders.

Grimshaw, J. (n.d.). A knowledge synthesis chapter . Ottawa: Canadian Institutes of Health Research.

Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P. A., . . . Moher, D. (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. Annals of Internal Medicine, 151 (4), W65–W94.

Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & the PRISMA Group. (2009). Preferred reporting items for systematic reviews and meta analyses: The PRISMA statement. Annals of Internal Medicine, 151 (4), 264–269

O’Brien, B. C., Harris, I. B., Beckman, T. J., Reed, D. A., & Cook, D. A. (2014). Standards for reporting qualitative research: A synthesis of recommendations. Academic Medicine, 89 (9), 1245­–1251.

Pai, M., McCulloch, M., Gorman, J. D., Pai, N., Enanoria, W., Kennedy, G., . . . Colford, J. M. Jr. (2004). Systematic reviews and meta-analyses: An illustrated, step-by-step guide . National Medical Journal of India, 17 (2), 86–95.

Riley, R. D., Lambert, P. C., & bo-Zaid, G. (2010). Meta analysis of individual participant data: Rationale, conduct and reporting. British Medical Journal, 340, c221. PMID 20139215.

Stroup, D. F., Berlin, J. A., Morton, S. C., Olkin, I., Williamson, G. D., Rennie, D., . . . Thacker, S. B. (2000). Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. Journal of the American Medical Association, 283 (15), 2008–2012.

Tong, A., Flemming, K., McInnes, E., Oliver, S., & Craig, J. (2012). Enhancing transparency in reporting the synthesis of qualitative research: ENTREQ. BMC Medical Research Methodology, 12 (1), 181.

Whittemore, R., & Knafl, K. (2005). The integrated review: Updated methodology. Journal of Advanced Nursing, 52 (5), 546–553.

Wong, G., Greenhalgh, T., Westhorp, G., Buckingham, J., & Pawson, R. (2013). RAMESES publication standards: Meta-narrative reviews. BMC Medicine, 11, 20. PMID 23360661.

Wong, G., Greenhalgh, T., Westhorp, G., Buckingham, J., & Pawson, R. (2013). RAMESES publication standards: Realist syntheses. BMC Medicine, 11, 21. PMID: 23360677.

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• Conducting a Literature Review by Ann Dyer Last Updated Aug 13, 2024 1985 views this year

Doing Diligence

The first step in any systematic review or other type of evidence synthesis project is to search the existing literature to identify what research, both primary and secondary, has already been conducted. As with any publication, your review will likely need to be original/novel in order to be of interest to editors and publications. In addition, duplicating a previously done study may not add new understandings to the body of evidence. Here are some questions for consideration:

• Has your research question already been answered?
• How recently has the existing secondary research been conducted/published?
• Does the existing secondary research need to be updated due to new original research that has been conducted after its publication?
• Is there existing secondary research that answers a different research question than the one you want to answer?
• How does your question, methodology, or timing differ from existing research?

All of these questions will help you identify  why  you would conduct this new study. It is disheartening (at best) to learn part way through an evidence synthesis project that the research has already been conducted.

Search Published Literature

Search for published studies that address your research question. This should be done in several different databases to ensure you have a solid sense of what has already been accomplished. It will also inform the way that you create your search strategy for this study, as you'll learn the types of words that are used to describe this research question, publications that have published these types of studies, and how the articles have been indexed within the databases. Below are a few databases that you might consider searching for health sciences publications.

• PubMed This link to PubMed is for those affiliated with WSU. PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
• EMBASE Embase is an abstract and Indexing (A & I) database covering over 8,500 journal titles, 30 million articles back to 1974, all disciplines of medicine and biomedical science, and includes substantial coverage of Allied Health subjects.
• CINAHL Complete (EBSCOHost) CINAHL Complete is the world's most comprehensive source of full-text for nursing & allied health journals, providing full text for more than 1,300 journals indexed in CINAHL.
• APA PsycInfo (ProQuest) This link opens in a new window An index with summaries of citations to articles in over 1,300 psychology research journals. Articles date from 1806 - present. Note: There are less than 146 records with publication dates prior to 1890. Updated weekly.

Search for Preregistrations

In addition to finding articles that have already been published, you will need to search registries to see if others are currently in the process of researching this topic/question, just as you would for clinical research. Here are a few repositories for you to search:

• Open Science Framework (OSF) Registries
• Cochrane Preregistrations
• Campbell Preregistrations

Identification of Review Type

While considering conducting a literature review, you should compare your draft research question to the different review types that can be used to explore the existing research. Some types, such as narrative reviews, do not consider the literature search as a formal methodology, while others such as Systematic Reviews view the literature search as a reproducible research methodology.

As a first step, search the literature for other published articles and studies that address the same or similar research question. The quantity, quality, and depth of existing research will be an important component in deciding on a review type.

Selection of the review type includes not only aspirations for what the review could accomplish, but also pragmatic limitations based on how much time the team has to devote to the project, how many team members are participating in the review, and deadlines for the review completion (such as the date of an upcoming conference). In addition, the breadth of the research question may result in a large number of search results; this should be considered in terms of the number of team members involved in the screening and abstraction of the included studies, as well as whether the research question should be narrowed or include more limitations/exclusion criteria in order to satisfy the practical limitations of the team.

Use the decision tree below from Cornell University to determine what type of review best suits your question/topic and available resources. The PDF is linked for you to view/download along with descriptions of the review types, with an image of the decision tree displayed on this page. To learn more about the different types, purposes, and methods of reviews, click the "Types of Reviews" link below the decision tree. 

Types of Reviews

• What Type of Review is Right For You? | Decision Tree

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

Develop a Searchable Question

When developing a searchable question, it helps to identify the key concepts of your research proposal. A clear and precise search question can be used to develop search terms during the literature searching process.

There are a number of frameworks available to use to help you break your question into its key concepts. Take a look at the frameworks below. 

• Evidence-Based Practice
• General Health
• Health Management

From BMJ Best Practice :

The PICO (Population, Intervention, Comparator and Outcomes) model captures the key elements and is a good strategy to provide answerable questions.

Population : who are the relevant patients or the target audience for the problem being addressed?      Example: In women with non-tubal infertility

Intervention : what intervention is being considered?     Example: …would intrauterine insemination…

Comparator : what is the main comparator to the intervention that you want to assess?      Example: …when compared with fallopian tube sperm perfusion…

Outcomes : what are the consequences of the interventions for the patient? Or what are the main outcomes of interest to the patient or decision maker?      Example: …lead to higher live birth rates with no increase in multiple pregnancy, miscarriage or ectopic pregnancy rates?

How to clarify a clinical question. (n.d.). BMJ Best Practice . Retrieved October 26, 2022, from https://bestpractice.bmj.com/info/us/toolkit/learn-ebm/how-to-clarify-a-clinical-question/

From "Formulating the Evidence Based Practice Question":

Setting : What is the context for the question? The research evidence should reflect the context or the research findings may not be transferable.

Perspective : Who are the users, potential users, or stakeholders of the service?

Intervention : What is being done for the users, potential users, or stakeholders?

Comparison : What are the alternatives? An alternative might maintain the status quo and change nothing.

Evaluation : What measurement will determine the intervention’s success? In other words, what is the result?

Davies, K. S. (2011). Formulating the Evidence Based Practice Question: A Review of the Frameworks. Evidence Based Library and Information Practice , 6 (2), Article 2. https://doi.org/10.18438/B8WS5N

From "How CLIP became ECLIPSE":

Expectation —what does the search requester want the information for (the original ‘I’s)? Client Group Location Impact:  what is the change in the service, if any, which is being looked for? What would constitute success? How is this being measured? Professionals Service:  for which service are you looking for information? For example, outpatient services, nurse-led clinics, intermediate care

Wildridge, V., & Bell, L. (2002). How CLIP became ECLIPSE: A mnemonic to assist in searching for health policy/management information. Health Information & Libraries Journal , 19 (2), 113–115. https://doi.org/10.1046/j.1471-1842.2002.00378.x

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• Last Updated: Aug 14, 2024 1:22 PM
• URL: https://libguides.libraries.wsu.edu/evidencesynthesis

• Research article
• Open access
• Published: 15 August 2024

The impact of adverse childhood experiences on multimorbidity: a systematic review and meta-analysis

• Dhaneesha N. S. Senaratne 1 ,
• Bhushan Thakkar 1 ,
• Blair H. Smith 1 ,
• Tim G. Hales 2 ,
• Louise Marryat 3 &
• Lesley A. Colvin 1  

BMC Medicine volume  22 , Article number:  315 ( 2024 ) Cite this article

505 Accesses

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Metrics details

Adverse childhood experiences (ACEs) have been implicated in the aetiology of a range of health outcomes, including multimorbidity. In this systematic review and meta-analysis, we aimed to identify, synthesise, and quantify the current evidence linking ACEs and multimorbidity.

We searched seven databases from inception to 20 July 2023: APA PsycNET, CINAHL Plus, Cochrane CENTRAL, Embase, MEDLINE, Scopus, and Web of Science. We selected studies investigating adverse events occurring during childhood (< 18 years) and an assessment of multimorbidity in adulthood (≥ 18 years). Studies that only assessed adverse events in adulthood or health outcomes in children were excluded. Risk of bias was assessed using the ROBINS-E tool. Meta-analysis of prevalence and dose–response meta-analysis methods were used for quantitative data synthesis. This review was pre-registered with PROSPERO (CRD42023389528).

From 15,586 records, 25 studies were eligible for inclusion (total participants = 372,162). The prevalence of exposure to ≥ 1 ACEs was 48.1% (95% CI 33.4 to 63.1%). The prevalence of multimorbidity was 34.5% (95% CI 23.4 to 47.5%). Eight studies provided sufficient data for dose–response meta-analysis (total participants = 197,981). There was a significant dose-dependent relationship between ACE exposure and multimorbidity ( p  < 0.001), with every additional ACE exposure contributing to a 12.9% (95% CI 7.9 to 17.9%) increase in the odds for multimorbidity. However, there was heterogeneity among the included studies ( I 2  = 76.9%, Cochran Q  = 102, p  < 0.001).

Conclusions

This is the first systematic review and meta-analysis to synthesise the literature on ACEs and multimorbidity, showing a dose-dependent relationship across a large number of participants. It consolidates and enhances an extensive body of literature that shows an association between ACEs and individual long-term health conditions, risky health behaviours, and other poor health outcomes.

Peer Review reports

In recent years, adverse childhood experiences (ACEs) have been identified as factors of interest in the aetiology of many conditions [ 1 ]. ACEs are potentially stressful events or environments that occur before the age of 18. They have typically been considered in terms of abuse (e.g. physical, emotional, sexual), neglect (e.g. physical, emotional), and household dysfunction (e.g. parental separation, household member incarceration, household member mental illness) but could also include other forms of stress, such as bullying, famine, and war. ACEs are common: estimates suggest that 47% of the UK population have experienced at least one form, with 12% experiencing four or more [ 2 ]. ACEs are associated with poor outcomes in a range of physical health, mental health, and social parameters in adulthood, with greater ACE burden being associated with worse outcomes [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ].

Over a similar timescale, multimorbidity has emerged as a significant heath challenge. It is commonly defined as the co-occurrence of two or more long-term conditions (LTCs), with a long-term condition defined as any physical or mental health condition lasting, or expected to last, longer than 1 year [ 9 ]. Multimorbidity is both common and age-dependent, with a global adult prevalence of 37% that rises to 51% in adults over 60 [ 10 , 11 ]. Individuals living with multimorbidity face additional challenges in managing their health, such as multiple appointments, polypharmacy, and the lack of continuity of care [ 12 , 13 , 14 ]. Meanwhile, many healthcare systems struggle to manage the additional cost and complexity of people with multimorbidity as they have often evolved to address the single disease model [ 15 , 16 ]. As global populations continue to age, with an estimated 2.1 billion adults over 60 by 2050, the pressures facing already strained healthcare systems will continue to grow [ 17 ]. Identifying factors early in the aetiology of multimorbidity may help to mitigate the consequences of this developing healthcare crisis.

Many mechanisms have been suggested for how ACEs might influence later life health outcomes, including the risk of developing individual LTCs. Collectively, they contribute to the idea of ‘toxic stress’; cumulative stress during key developmental phases may affect development [ 18 ]. ACEs are associated with measures of accelerated cellular ageing, including changes in DNA methylation and telomere length [ 19 , 20 ]. ACEs may lead to alterations in stress-signalling pathways, including changes to the immune, endocrine, and cardiovascular systems [ 21 , 22 , 23 ]. ACEs are also associated with both structural and functional differences in the brain [ 24 , 25 , 26 , 27 ]. These diverse biological changes underpin psychological and behavioural changes, predisposing individuals to poorer self-esteem and risky health behaviours, which may in turn lead to increased risk of developing individual LTCs [ 1 , 2 , 28 , 29 , 30 , 31 , 32 ]. A growing body of evidence has therefore led to an increased focus on developing trauma-informed models of healthcare, in which the impact of negative life experiences is incorporated into the assessment and management of LTCs [ 33 ].

Given the contributory role of ACEs in the aetiology of individual LTCs, it is reasonable to suspect that ACEs may also be an important factor in the development of multimorbidity. Several studies have implicated ACEs in the aetiology of multimorbidity, across different cohorts and populations, but to date no meta-analyses have been performed to aggregate this evidence. In this review, we aim to summarise the state of the evidence linking ACEs and multimorbidity, to quantify the strength of any associations through meta-analysis, and to highlight the challenges of research in this area.

Search strategy and selection criteria

We conducted a systematic review and meta-analysis that was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) on 25 January 2023 (ID: CRD42023389528) and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

We developed a search strategy based on previously published literature reviews and refined it following input from subject experts, an academic librarian, and patient and public partners (Additional File 1: Table S1). We searched the following seven databases from inception to 20 July 2023: APA PsycNET, CINAHL Plus, Cochrane CENTRAL, Embase, MEDLINE, Scopus, and Web of Science. The search results were imported into Covidence (Veritas Health Innovation, Melbourne, Australia), which automatically identified and removed duplicate entries. Two reviewers (DS and BT) independently performed title and abstract screening and full text review. Discrepancies were resolved by a third reviewer (LC).

Reports were eligible for review if they included adults (≥ 18 years), adverse events occurring during childhood (< 18 years), and an assessment of multimorbidity or health status based on LTCs. Reports that only assessed adverse events in adulthood or health outcomes in children were excluded.

The following study designs were eligible for review: randomised controlled trials, cohort studies, case–control studies, cross-sectional studies, and review articles with meta-analysis. Editorials, case reports, and conference abstracts were excluded. Systematic reviews without a meta-analysis and narrative synthesis review articles were also excluded; however, their reference lists were screened for relevant citations.

Data analysis

Two reviewers (DS and BT) independently performed data extraction into Microsoft Excel (Microsoft Corporation, Redmond, USA) using a pre-agreed template. Discrepancies were resolved by consensus discussion with a third reviewer (LC). Data extracted from each report included study details (author, year, study design, sample cohort, sample size, sample country of origin), patient characteristics (age, sex), ACE information (definition, childhood cut-off age, ACE assessment tool, number of ACEs, list of ACEs, prevalence), multimorbidity information (definition, multimorbidity assessment tool, number of LTCs, list of LTCs, prevalence), and analysis parameters (effect size, model adjustments). For meta-analysis, we extracted ACE groups, number of ACE cases, number of multimorbidity cases, number of participants, odds ratios or regression beta coefficients, and 95% confidence intervals (95% CI). Where data were partially reported or missing, we contacted the study authors directly for further information.

Two reviewers (DS and BT) independently performed risk of bias assessments of each included study using the Risk Of Bias In Non-randomized Studies of Exposures (ROBINS-E) tool [ 34 ]. The ROBINS-E tool assesses the risk of bias for the study outcome relevant to the systematic review question, which may not be the primary study outcome. It assesses risk of bias across seven domains; confounding, measurement of the exposure, participant selection, post-exposure interventions, missing data, measurement of the outcome, and selection of the reported result. The overall risk of bias for each study was determined using the ROBINS-E algorithm. Discrepancies were resolved by consensus discussion.

All statistical analyses were performed in R version 4.2.2 using the RStudio integrated development environment (RStudio Team, Boston, USA). To avoid repetition of participant data, where multiple studies analysed the same patient cohort, we selected the study with the best reporting of raw data for meta-analysis and the largest sample size. Meta-analysis of prevalence was performed with the meta package [ 35 ], using logit transformations within a generalised linear mixed model, and reporting the random-effects model [ 36 ]. Inter-study heterogeneity was assessed and reported using the I 2 statistic, Cochran Q statistic, and Cochran Q p -value. Dose–response meta-analysis was performed using the dosresmeta package [ 37 ] following the method outlined by Greenland and Longnecker (1992) [ 38 , 39 ]. Log-linear and non-linear (restricted cubic spline, with knots at 5%, 35%, 65%, and 95%) random effects models were generated, and goodness of fit was evaluated using a Wald-type test (denoted by X 2 ) and the Akaike information criterion (AIC) [ 39 ].

Patient and public involvement

The Consortium Against Pain Inequality (CAPE) Chronic Pain Advisory Group (CPAG) consists of individuals with lived experiences of ACEs, chronic pain, and multimorbidity. CPAG was involved in developing the research question. The group has experience in systematic review co-production (in progress).

The search identified 15,586 records, of which 25 met inclusion criteria for the systematic review (Fig.  1 ) [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ]. The summary characteristics can be found in Additional File 1: Table S2. Most studies examined European ( n  = 11) or North American ( n  = 9) populations, with a few looking at Asian ( n  = 3) or South American ( n  = 1) populations and one study examining a mixed cohort (European and North American populations). The total participant count (excluding studies performed on the same cohort) was 372,162. Most studies had a female predominance (median 53.8%, interquartile range (IQR) 50.9 to 57.4%).

Flow chart of selection of studies into the systematic review and meta-analysis. Flow chart of selection of studies into the systematic review and meta-analysis. ACE, adverse childhood experience; MM, multimorbidity; DRMA, dose–response meta-analysis

All studies were observational in design, and so risk of bias assessments were performed using the ROBINS-E tool (Additional File 1: Table S3) [ 34 ]. There were some consistent risks observed across the studies, especially in domain 1 (risk of bias due to confounding) and domain 3 (risk of bias due to participant selection). In domain 1, most studies were ‘high risk’ ( n  = 24) as they controlled for variables that could have been affected by ACE exposure (e.g. smoking status) [ 40 , 41 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ]. In domain 3, some studies were ‘high risk’ ( n  = 7) as participant selection was based on participant characteristics that could have been influenced by ACE exposure (e.g. through recruitment at an outpatient clinic) [ 45 , 48 , 49 , 51 , 53 , 54 , 58 ]. The remaining studies were deemed as having ‘some concerns’ ( n  = 18) as participant selection occurred at a time after ACE exposure, introducing a risk of survivorship bias [ 40 , 41 , 42 , 43 , 44 , 46 , 47 , 50 , 52 , 55 , 56 , 57 , 59 , 60 , 61 , 62 , 63 , 64 ].

Key differences in risk of bias were seen in domain 2 (risk of bias due to exposure measurement) and domain 5 (risk of bias due to missing data). In domain 2, some studies were ‘high risk’ as they used a narrow or atypical measure of ACEs ( n  = 8) [ 40 , 42 , 44 , 46 , 55 , 56 , 60 , 64 ]; others were graded as having ‘some concerns’ as they used a broader but still incomplete measure of ACEs ( n  = 8) [ 43 , 45 , 48 , 49 , 50 , 52 , 54 , 62 ]; the remainder were ‘low risk’ as they used an established or comprehensive list of ACE questions [ 41 , 47 , 51 , 53 , 57 , 58 , 59 , 61 , 63 ]. In domain 5, some studies were ‘high risk’ as they failed to acknowledge or appropriately address missing data ( n  = 7) [ 40 , 42 , 43 , 45 , 51 , 53 , 60 ]; others were graded as having ‘some concerns’ as they had a significant amount of missing data (> 10% for exposure, outcome, or confounders) but mitigated for this with appropriate strategies ( n  = 6) [ 41 , 50 , 56 , 57 , 62 , 64 ]; the remainder were ‘low risk’ as they reported low levels of missing data ( n  = 12) [ 44 , 46 , 47 , 48 , 49 , 52 , 54 , 55 , 58 , 59 , 61 , 63 ].

Most studies assessed an exposure that was ‘adverse childhood experiences’ ( n  = 10) [ 41 , 42 , 50 , 51 , 53 , 57 , 58 , 61 , 63 , 64 ], ‘childhood maltreatment’ ( n  = 6) [ 44 , 45 , 46 , 48 , 49 , 59 ], or ‘childhood adversity’ ( n  = 3) [ 47 , 54 , 62 ]. The other exposures studied were ‘birth phase relative to World War Two’ [ 40 ], ‘childhood abuse’ [ 43 ], ‘childhood disadvantage’ [ 56 ], ‘childhood racial discrimination’ [ 55 ], ‘childhood trauma’ [ 52 ], and ‘quality of childhood’ (all n  = 1) [ 60 ]. More than half of studies ( n  = 13) did not provide a formal definition of their exposure of choice [ 42 , 43 , 44 , 45 , 49 , 52 , 53 , 54 , 57 , 58 , 60 , 61 , 64 ]. The upper age limit for childhood ranged from < 15 to < 18 years with the most common cut-off being < 18 years ( n  = 9). The median number of ACEs measured in each study was 7 (IQR 4–10). In total, 58 different ACEs were reported; 17 ACEs were reported by at least three studies, whilst 33 ACEs were reported by only one study. The most frequently reported ACEs were physical abuse ( n  = 19) and sexual abuse ( n  = 16) (Table  1 ). The exposure details for each study can be found in Additional File 1: Table S4.

Thirteen studies provided sufficient data to allow for a meta-analysis of the prevalence of exposure to ≥ 1 ACE; the pooled prevalence was 48.1% (95% CI 33.4 to 63.1%, I 2  = 99.9%, Cochran Q  = 18,092, p  < 0.001) (Fig.  2 ) [ 41 , 43 , 44 , 46 , 47 , 49 , 50 , 52 , 53 , 57 , 59 , 61 , 63 ]. Six studies provided sufficient data to allow for a meta-analysis of the prevalence of exposure to ≥ 4 ACEs; the pooled prevalence was 12.3% (95% CI 3.5 to 35.4%, I 2  = 99.9%, Cochran Q  = 9071, p  < 0.001) (Additional File 1: Fig. S1) [ 46 , 50 , 51 , 53 , 59 , 63 ].

Meta-analysis of prevalence of exposure to ≥ 1 adverse childhood experiences. Meta-analysis of prevalence of exposure to ≥ 1 adverse childhood experience. ACE, adverse childhood experience; CI, confidence interval

Thirteen studies explicitly assessed multimorbidity as an outcome, and all of these defined the threshold for multimorbidity as the presence of two or more LTCs [ 40 , 41 , 42 , 44 , 46 , 47 , 50 , 55 , 57 , 60 , 61 , 62 , 64 ]. The remaining studies assessed comorbidities, morbidity, or disease counts [ 43 , 45 , 48 , 49 , 51 , 52 , 53 , 54 , 56 , 58 , 59 , 63 ]. The median number of LTCs measured in each study was 14 (IQR 12–21). In total, 115 different LTCs were reported; 36 LTCs were reported by at least three studies, whilst 63 LTCs were reported by only one study. Two studies did not report the specific LTCs that they measured [ 51 , 53 ]. The most frequently reported LTCs were hypertension ( n  = 22) and diabetes ( n  = 19) (Table  2 ). Fourteen studies included at least one mental health LTC. The outcome details for each study can be found in Additional File 1: Table S5.

Fifteen studies provided sufficient data to allow for a meta-analysis of the prevalence of multimorbidity; the pooled prevalence was 34.5% (95% CI 23.4 to 47.5%, I 2  = 99.9%, Cochran Q  = 24,072, p  < 0.001) (Fig.  3 ) [ 40 , 41 , 44 , 46 , 47 , 49 , 50 , 51 , 52 , 55 , 57 , 58 , 59 , 60 , 63 ].

Meta-analysis of prevalence of multimorbidity. Meta-analysis of prevalence of multimorbidity. CI, confidence interval; LTC, long-term condition; MM, multimorbidity

All studies reported significant positive associations between measures of ACE and multimorbidity, though they varied in their means of analysis and reporting of the relationship. Nine studies reported an association between the number of ACEs (variably considered as a continuous or categorical parameter) and multimorbidity [ 41 , 43 , 46 , 47 , 50 , 56 , 57 , 61 , 64 ]. Eight studies reported an association between the number of ACEs and comorbidity counts in specific patient populations [ 45 , 48 , 49 , 51 , 53 , 58 , 59 , 63 ]. Six studies reported an association between individual ACEs or ACE subgroups and multimorbidity [ 42 , 43 , 44 , 47 , 55 , 62 ]. Two studies incorporated a measure of frequency within their ACE measurement tool and reported an association between this ACE score and multimorbidity [ 52 , 54 ]. Two studies reported an association between proxy measures for ACEs and multimorbidity; one reported ‘birth phase relative to World War Two’, and the other reported a self-report on the overall quality of childhood [ 40 , 60 ].

Eight studies, involving a total of 197,981 participants, provided sufficient data (either in the primary text, or following author correspondence) for quantitative synthesis [ 41 , 46 , 47 , 49 , 50 , 51 , 57 , 58 ]. Log-linear (Fig.  4 ) and non-linear (Additional File 1: Fig. S2) random effects models were compared for goodness of fit: the Wald-type test for linearity was non-significant ( χ 2  = 3.7, p  = 0.16) and the AIC was lower for the linear model (− 7.82 vs 15.86) indicating that the log-linear assumption was valid. There was a significant dose-dependent relationship between ACE exposure and multimorbidity ( p  < 0.001), with every additional ACE exposure contributing to a 12.9% (95% CI 7.9 to 17.9%) increase in the odds for multimorbidity ( I 2  = 76.9%, Cochran Q  = 102, p  < 0.001).

Dose–response meta-analysis of the relationship between adverse childhood experiences and multimorbidity. Dose–response meta-analysis of the relationship between adverse childhood experiences and multimorbidity. Solid black line represents the estimated relationship; dotted black lines represent the 95% confidence intervals for this estimate. ACE, adverse childhood experience

This systematic review and meta-analysis synthesised the literature on ACEs and multimorbidity and showed a dose-dependent relationship across a large number of participants. Each additional ACE exposure contributed to a 12.9% (95% CI 7.9 to 17.9%) increase in the odds for multimorbidity. This adds to previous meta-analyses that have shown an association between ACEs and individual LTCs, health behaviours, and other health outcomes [ 1 , 28 , 31 , 65 , 66 ]. However, we also identified substantial inter-study heterogeneity that is likely to have arisen due to variation in the definitions, methodology, and analysis of the included studies, and so our results should be interpreted with these limitations in mind.

Although 25 years have passed since the landmark Adverse Childhood Experiences Study by Felitti et al. [ 3 ], there is still no consistent approach to determining what constitutes an ACE. This is reflected in this review, where fewer than half of the 58 different ACEs ( n  = 25, 43.1%) were reported by more than one study and no study reported more than 15 ACEs. Even ACE types that are commonly included are not always assessed in the same way [ 67 ], and furthermore, the same question can be interpreted differently in different contexts (e.g. physical punishment for bad behaviour was socially acceptable 50 years ago but is now considered physical abuse in the UK). Although a few validated questionnaires exist, they often focus on a narrow range of ACEs; for example, the childhood trauma questionnaire demonstrates good reliability and validity but focuses on interpersonal ACEs, missing out on household factors (e.g. parental separation), and community factors (e.g. bullying) [ 68 ]. Many studies were performed on pre-existing research cohorts or historic healthcare data, where the study authors had limited or no influence on the data collected. As a result, very few individual studies reported on the full breadth of potential ACEs.

ACE research is often based on ACE counts, where the types of ACEs experienced are summed into a single score that is taken as a proxy measure of the burden of childhood stress. The original Adverse Childhood Experiences Study by Felitti et al. took this approach [ 3 ], as did 17 of the studies included in this review and our own quantitative synthesis. At the population level, there are benefits to this: ACE counts provide quantifiable and comparable metrics, they are easy to collect and analyse, and in many datasets, they are the only means by which an assessment of childhood stress can be derived. However, there are clear limitations to this method when considering experiences at the individual level, not least the inherent assumptions that different ACEs in the same person are of equal weight or that the same ACE in different people carries the same burden of childhood stress. This limitation was strongly reinforced by our patient and public involvement group (CPAG). Two studies in this review incorporated frequency within their ACE scoring system [ 52 , 54 ], which adds another dimension to the assessment, but this is insufficient to understand and quantify the ‘impact’ of an ACE within an epidemiological framework.

The definitions of multimorbidity were consistent across the relevant studies but the contributory long-term conditions varied. Fewer than half of the 115 different LTCs ( n  = 52, 45.2%) were reported by more than one study. Part of the challenge is the classification of healthcare conditions. For example, myocardial infarction is commonly caused by coronary heart disease, and both are a form of heart disease. All three were reported as LTCs in the included studies, but which level of pathology should be reported? Mental health LTCs were under-represented within the condition list, with just over half of the included studies assessing at least one ( n  = 14, 56.0%). Given the strong links between ACEs and mental health, and the impact of mental health on quality of life, this is an area for improvement in future research [ 31 , 32 ]. A recent Delphi consensus study by Ho et al. may help to address these issues: following input from professionals and members of the public they identified 24 LTCs to ‘always include’ and 35 LTCs to ‘usually include’ in multimorbidity research, including nine mental health conditions [ 9 ].

As outlined in the introduction, there is a strong evidence base supporting the link between ACEs and long-term health outcomes, including specific LTCs. It is not unreasonable to extrapolate this association to ACEs and multimorbidity, though to our knowledge, the pathophysiological processes that link the two have not been precisely identified. However, similar lines of research are being independently followed in both fields and these areas of overlap may suggest possible mechanisms for a relationship. For example, both ACEs and multimorbidity have been associated with markers of accelerated epigenetic ageing [ 69 , 70 ], mitochondrial dysfunction [ 71 , 72 ], and inflammation [ 22 , 73 ]. More work is required to better understand how these concepts might be linked.

This review used data from a large participant base, with information from 372,162 people contributing to the systematic review and information from 197,981 people contributing to the dose–response meta-analysis. Data from the included studies originated from a range of sources, including healthcare settings and dedicated research cohorts. We believe this is of a sufficient scale and variety to demonstrate the nature and magnitude of the association between ACEs and multimorbidity in these populations.

However, there are some limitations. Firstly, although data came from 11 different countries, only two of those were from outside Europe and North America, and all were from either high- or middle-income countries. Data on ACEs from low-income countries have indicated a higher prevalence of any ACE exposure (consistently > 70%) [ 74 , 75 ], though how well this predicts health outcomes in these populations is unknown.

Secondly, studies in this review utilised retrospective participant-reported ACE data and so are at risk of recall and reporting bias. Studies utilising prospective assessments are rare and much of the wider ACE literature is open to a similar risk of bias. To date, two studies have compared prospective and retrospective ACE measurements, demonstrating inconsistent results [ 76 , 77 ]. However, these studies were performed in New Zealand and South Africa, two countries not represented by studies in our review, and had relatively small sample sizes (1037 and 1595 respectively). It is unclear whether these are generalisable to other population groups.

Thirdly, previous research has indicated a close relationship between ACEs and childhood socio-economic status (SES) [ 78 ] and between SES and multimorbidity [ 10 , 79 ]. However, the limitations of the included studies meant we were unable to separate the effect of ACEs from the effect of childhood SES on multimorbidity in this review. Whilst two studies included childhood SES as covariates in their models, others used measures from adulthood (such as adulthood SES, income level, and education level) that are potentially influenced by ACEs and therefore increase the risk of bias due to confounding (Additional File 1: Table S3). Furthermore, as for ACEs and multimorbidity, there is no consistently applied definition of SES and different measures of SES may produce different apparent effects [ 80 ]. The complex relationships between ACEs, childhood SES, and multimorbidity remain a challenge for research in this field.

Fourthly, there was a high degree of heterogeneity within included studies, especially relating to the definition and measurement of ACEs and multimorbidity. Whilst this suggests that our results should be interpreted with caution, it is reassuring to see that our meta-analysis of prevalence estimates for exposure to any ACE (48.1%) and multimorbidity (34.5%) are in line with previous estimates in similar populations [ 2 , 11 ]. Furthermore, we believe that the quantitative synthesis of these relatively heterogenous studies provides important benefit by demonstrating a strong dose–response relationship across a range of contexts.

Our results strengthen the evidence supporting the lasting influence of childhood conditions on adult health and wellbeing. How this understanding is best incorporated into routine practice is still not clear. Currently, the lack of consistency in assessing ACEs limits our ability to understand their impact at both the individual and population level and poses challenges for those looking to incorporate a formalised assessment. Whilst most risk factors for disease (e.g. blood pressure) are usually only relevant within healthcare settings, ACEs are relevant to many other sectors (e.g. social care, education, policing) [ 81 , 82 , 83 , 84 ], and so consistency of assessment across society is both more important and more challenging to achieve.

Some have suggested that the evidence for the impact of ACEs is strong enough to warrant screening, which would allow early identification of potential harms to children and interventions to prevent them. This approach has been implemented in California, USA [ 85 , 86 , 87 ]. However, this is controversial, and others argue that screening is premature with the current evidence base [ 88 , 89 , 90 ]. Firstly, not everyone who is exposed to ACEs develops poor health outcomes, and it is not clear how to identify those who are at highest risk. Many people appear to be vulnerable, with more adverse health outcomes following ACE exposure than those who are not exposed, whilst others appear to be more resilient, with good health in later life despite multiple ACE exposures [ 91 ] It may be that supportive environments can mitigate the long-term effects of ACE exposure and promote resilience [ 92 , 93 ]. Secondly, there are no accepted interventions for managing the impact of an identified ACE. As identified above, different ACEs may require input from different sectors (e.g. healthcare, social care, education, police), and so collating this evidence may be challenging. At present, ACEs screening does not meet the Wilson-Jungner criteria for a screening programme [ 94 ].

Existing healthcare systems are poorly designed to deal with the complexities of addressing ACEs and multimorbidity. Possibly, ways to improve this might be allocating more time per patient, prioritising continuity of care to foster long-term relationships, and greater integration between different healthcare providers (most notably primary vs secondary care teams, or physical vs mental health teams). However, such changes often demand additional resources (e.g. staff, infrastructure, processes), which are challenging to source when existing healthcare systems are already stretched [ 95 , 96 ]. Nevertheless, increasing the spotlight on ACEs and multimorbidity may help to focus attention and ultimately bring improvements to patient care and experience.

ACEs are associated with a range of poor long-term health outcomes, including harmful health behaviours and individual long-term conditions. Multimorbidity is becoming more common as global populations age, and it increases the complexity and cost of healthcare provision. This is the first systematic review and meta-analysis to synthesise the literature on ACEs and multimorbidity, showing a statistically significant dose-dependent relationship across a large number of participants, albeit with a high degree of inter-study heterogeneity. This consolidates and enhances an increasing body of data supporting the role of ACEs in determining long-term health outcomes. Whilst these observational studies do not confirm causality, the weight and consistency of evidence is such that we can be confident in the link. The challenge for healthcare practitioners, managers, policymakers, and governments is incorporating this body of evidence into routine practice to improve the health and wellbeing of our societies.

Availability of data and materials

No additional data was generated for this review. The data used were found in the referenced papers or provided through correspondence with the study authors.

Abbreviations

Adverse childhood experience

Akaike information criterion

CONSORTIUM Against pain inequality

Confidence interval

Chronic pain advisory group

Interquartile range

Long-term condition

International prospective register of systematic reviews

Preferred reporting items for systematic reviews and meta-analyses

Risk of bias in non-randomised studies of exposures

Socio-economic status

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Acknowledgements

The authors thank the members of the CAPE CPAG patient and public involvement group for providing insights gained from relevant lived experiences.

The authors are members of the Advanced Pain Discovery Platform (APDP) supported by UK Research & Innovation (UKRI), Versus Arthritis, and Eli Lilly. DS is a fellow on the Multimorbidity Doctoral Training Programme for Health Professionals, which is supported by the Wellcome Trust [223499/Z/21/Z]. BT, BS, and LC are supported by an APDP grant as part of the Partnership for Assessment and Investigation of Neuropathic Pain: Studies Tracking Outcomes, Risks and Mechanisms (PAINSTORM) consortium [MR/W002388/1]. TH and LC are supported by an APDP grant as part of the Consortium Against Pain Inequality [MR/W002566/1]. The funding bodies had no role in study design, data collection/analysis/interpretation, report writing, or the decision to submit the manuscript for publication.

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DS and LC contributed to review conception and design. DC, BT, BS, TH, LM, and LC contributed to search strategy design. DS and BT contributed to study selection and data extraction, with input from LC. DS and BT accessed and verified the underlying data. DS conducted the meta-analyses, with input from BT, BS, TH, LM, and LC. DS drafted the manuscript, with input from DC, BT, BS, TH, LM, and LC. DC, BT, BS, TH, LM, and LC read and approved the final manuscript.

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Additional File 1: Tables S1-S5 and Figures S1-S2. Table S1: Search strategy, Table S2: Characteristics of studies included in the systematic review, Table S3: Risk of bias assessment (ROBINS-E), Table S4: Exposure details (adverse childhood experiences), Table S5: Outcome details (multimorbidity), Figure S1: Meta-analysis of prevalence of exposure to ≥4 adverse childhood experiences, Figure S2: Dose-response meta-analysis of the relationship between adverse childhood experiences and multimorbidity (using a non-linear/restricted cubic spline model).

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• Adverse childhood experiences
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Promoting patient-centered care in CAR-T therapy for hematologic malignancy: a qualitative meta-synthesis

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• Published: 16 August 2024
• Volume 32 , article number  591 , ( 2024 )

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• Caiqin Xie 1   na1 ,
• Haoran Duan 1   na1 ,
• Hui Liu 2 ,
• Yunhua Wang 1 ,
• Zhuanyi Sun 1 &
• Meijuan Lan 1  

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CAR-T therapy has emerged as a potentially effective treatment for individuals diagnosed with hematologic malignancies. Understanding patients’ unique experiences with this therapeutic approach is essential. This knowledge will enable the development of tailored nursing interventions that align with the increasing importance of patient-centered care.

To examine and synthesize qualitative data on patients and their family caregivers’ experiences during the treatment journey.

We conducted a systematic review and qualitative meta-synthesis. Eligible studies contained adult patient or family caregiver quotes about experiences of CAR-T therapy, published in English or Chinese in a peer-reviewed journal since 2015. Data sources included MEDLINE, CINAHL, Embase, PsycINFO, Web of Science, Scopus, Cochrane Library, CNKI, and WanFang.

Systematic search yielded 6373 identified articles. Of these, 12 reports were included in the analysis, which covered 11 separate studies. Two reviewers independently extracted data into NVIVO 12.0. Qualitative meta-synthesis was performed through line-by-line coding of full text, organization of codes into descriptive themes, and development themes.

The qualitative meta-synthesis yielded eight primary themes. Noteworthy revelations from patients and their family caregivers regarding the CAR-T therapy journey encompassed various aspects. Prior to CAR-T therapy, patients experienced a lack of actual choice, struggled with expectations for treatment outcomes, and encountered intricate emotional experiences. During or immediately after CAR-T therapy, patients reported both comfortable and uncomfortable experiences. Additionally, patients emphasized that concerns regarding treatment efficacy and adverse reactions intensified treatment-related distress. After CAR-T therapy, significant changes were observed, and the burden of home-based rehabilitation. Additionally, we found factors contributed to the high CAR-T therapy cost.

Conclusions

To ensure the safety and sustainability of CAR-T therapy, it is crucial to address the physical and psychological aspects of the patient's experience. Effective communication and comprehensive management are highly valued by patients and their caregivers. Further research should investigate ways to reduce burdens and develop self-management education programs for patients and their families.

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Introduction

Hematologic malignancies are dangerous myeloid and lymphatic tumors caused by disruption of normal hematopoietic function that are essential contributors to the global cancer burden [ 1 , 2 , 3 ]. Common types of hematologic malignancies include leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma [ 4 ]. Chimeric antigen receptor (CAR) T therapy, a breakthrough immunotherapy authorized by the Food and Drug Administration (FDA), has great potential as a treatment for hematologic malignancies including relapsed or refractory multiple myeloma, large B cell lymphoma, refractory or second and subsequent relapses of B cell precursor acute lymphoblastic leukemia, relapsed or refractory follicular lymphomas. It offers promising durable response rates and has been shown to improve patient survival [ 5 , 6 , 7 , 8 ]. As of April 15, 2022, the global immuno-oncology pipeline includes 2,756 actively developed cell therapies. CAR-T cell therapies dominate this category with 1,432 therapies, marking a 24% increase from the previous year, nearly 857 CAR-T cell therapies are in clinical trials, a 22% increase from last year [ 9 ]. Despite the growing understanding of their mechanism of action, infusion process, and therapeutic efficacy, CAR-T therapy present complex challenges. These include symptom management, rehabilitation, and psychological issues [ 10 ]. Furthermore, the costs of these treatments and the uncertainty of their clinical applications are rapidly changing the care landscape for patients with hematologic malignant neoplasms [ 11 ]. Hence, providing patient-centered care is crucial to ensure they can access demanded healthcare services and improve the quality of care [ 12 , 13 , 14 ].

However, patients receiving CAR-T therapy experience distinct challenges and encounters in contrast to conventional radiation and chemotherapy treatments [ 15 ]. These include the complexity of the treatment process, specific adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [ 16 ], and the emotional impact of undergoing a potentially life-saving but uncertain therapy [ 10 ]. Therefore, the CAR-T therapy process and related adverse effects on the physical and psychological well-being of patients are of utmost importance. Although previous research has primarily assessed treatment efficacy and adverse effects through patient self-reporting [ 17 , 18 ], it has not thoroughly investigated the specific experiences of CAR-T therapy to identify critical care concerns [ 19 ]. This has led to a limited understanding of patients’ self-reported experiences before, during, and after treatment, thereby impeding the implementation of personalized care [ 20 , 21 ]. Therefore, the study aims to review and synthesize existing relevant studies to reveal new insights and explore the comprehensive experiences of individuals with hematological malignancies undergoing CAR-T therapy, including patients’ and family caregivers’ perspectives regarding the treatment procedure, adverse effects, and the emotional and psychological aspects of their journey.

These findings will enhance healthcare practitioners' comprehension of the effects of CAR-T therapy on patients and offer more targeted recommendations for clinical practice. Furthermore, the results of this study will offer valuable direction for developing clinical care programs benefiting patients and their families. Ultimately, we hope this study will improve CAR-T therapy outcomes and enhance patients' overall well-being.

Study design

We performed a comprehensive analysis and qualitative meta-synthesis (PROSPERO CRD42024497174), adhering to the Enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) declaration [ 22 ]. We chose this study methodology because of its ability to synthesize data from multiple qualitative studies conducted in different contexts, helping us generate new theoretical or conceptual models and provide evidence for developing, implementing, and evaluating health interventions [ 22 ]. This study utilized the JBI methodology (PICOT framework) to guide the literature search and selection process [ 23 ].

Search strategy

A university librarian, a qualitative research specialist, and our research team developed predetermined search terms for a study on CAR-T therapy from the perspectives of adult patients and family caregivers. To identify search terms related to the type of study, we refer to the definition of qualitative research: those using methodologies such as contentment analysis, focus group, grounded theory, hermeneutics, phenomenology, iterative process, narrative or thematic analysis, and/or primarily analyzing textual to development concepts which help us to understand the meanings, experiences, and views of all the participants [ 24 , 25 ]. We searched the following electronic databases for eligible studies: MEDLINE, CINAHL, Embase, PsycINFO, Web of Science, Scopus, Cochrane Library, CNKI, and WanFang using Boolean logic, adapted to syntax and subject headings of each database. In addition to the electronic searches, we searched reference lists of included studies. The search was limited to articles published in English and Chinese from January 2015 (The starting point of the time window was selected considering that the first CAR-T therapy was only approved by the US FDA in 2017) to October 2023, updated to include articles up to January 18, 2024. This decision was made to avoid the significant time and financial resources required to translate qualitative works into English for inclusion in this synthesis. Taking the Medline and CINAHL databases as an example, the comprehensive search strategy for the database may be found in the Supplementary File Appendix A .

Eligible studies are those published in peer-reviewed journals that feature qualitative research, mixed-methods research, or qualitative components of observational or interventional studies. These studies should involve adult patients diagnosed with hematologic malignancies who have undergone CAR-T therapy, or their family caregivers. However, we included a comprehensive list of hematologic diseases in Appendix A to provide context and support the focused analysis on hematologic malignancies, facilitating transparency and comprehensiveness to avoid any potential confusion about the scope of our data collection and analysis. Studies with multi-stakeholders were also included, but only findings perspectives for those patients and family members. Articles that merely reported clinicians’ thoughts and experiences with CAR-T therapy were excluded.

Study selection and data extraction

The search results were imported into EndnoteX9, then duplicates were removed. Two independent review authors assessed the titles and abstracts of the identified records to determine their eligibility. The full text of all potentially relevant papers was obtained, as identified by one or both review authors. These papers were then independently evaluated by the two review authors. Any disagreements between the authors were resolved through discussion or, if necessary, by seeking the opinion of a third review author. When needed, we reached out to the study authors for additional information. Eligible data was extracted into the software NVivo 12, which includes: i) general study and sample characteristics; ii) methods; iii) participants’ quotes; iv) themes and conclusion; v) discussion, vi) Infographics or logic models.

Appraisal of methodological quality

The Critical Appraisal Skills Programme (CASP) guided the evaluation of the quality of these included articles [ 26 ]. The CASP tool was selected due to its widespread usage as a quality evaluation tool in the integration of health-related qualitative evidence. It is endorsed by the Cochrane Qualitative and Implementation Methods Group. Two researchers independently evaluated each article. Disagreements were also resolved by discussion and additional evaluation. It has been shown that studies of lower quality have a lesser contribution to the synthesis [ 27 ]. Consequently, the synthesis is biased toward the results of the higher-quality investigations. Studies in which the first three items were judged to be "NO" were excluded.

Data synthesis

For meta-synthesis, qualitative findings from each study were also extracted, and the correctness of extracted data was reviewed by other authors. We analyzed and synthesized qualitative evidence using Thomas and Hardens’ three-stage thematic synthesis approach: i) the coding of relevant text “line-by-line”; ii) the development of “descriptive themes”; and iii) the generation of “analytical themes” [ 28 ]. We chose this thematic integration method because it is the most accessible form of integration. It has a transparent methodology that allows for “thin” data to generate descriptive themes and “thick” data to be analyzed to develop from descriptive to more in-depth analytical themes. Coding was inductive, as was the development of descriptive and analytical themes. NVivo 12 was used to organize data during analysis.

In our analysis, we chose to categorize the treatment journey into different stages to tailor nursing care to the varying needs of patients at each stage. This approach enables nurses to provide more focused and effective patient-centered care. It aligns with studies showing that stage-specific care significantly enhances patient outcomes and satisfaction [ 29 ]. For data analysis, the three authors (DHR, XCQ, LH) read and reread the studies collected according to context and coded separately. The project leader (LMJ) merged the three authors’ sub-projects back into the main project and exported it to Microsoft Word, where data was accessible at any time, and opinions and comments could be freely exchanged among the three authors to increase communication and the reliability of inter-coders. We reported the proportion of words associated with each theme identified in NVivo 12 to provide a quantitative measure of the themes’ relative importance and prevalence within the data. This approach helps to illustrate the depth of the analysis and substantiate our thematic findings, making it easier to understand which aspects were most significant in the discussions or narratives analyzed.

Rigor, trustworthiness, and reflexivity

We prioritized the analysis of participant quotations to thoroughly examine the viewpoints and experiences of patients and family caregivers rather than the author’s themes or interpretations. The multidisciplinary team comprised academic nurses, research assistants, and a physician, who have specialized knowledge in research, critical care, palliative care, and hematologic malignancy. The academic nurses and research assistants were all trained in qualitative methods and conducted study selection (DHR, WYH, SZY), extraction (DHR, XCQ), appraisal (DHR, LH, XCQ), and synthesis (DHR, XCQ, LMJ). After the study selection, team members communicated regularly face-to-face in the demonstration room to perform the meta-synthesis and interpret the findings. A physician provided us with training and guidance on expertise related to CAR-T therapy and was involved in interpreting the findings. When necessary, disagreements were resolved through discussion, and assessment by a third review.

Description of studies

Our systematic search of the published qualitative literature yielded 6373 identified articles, of which 12 articles reported 11 studies were included, Shah et al. studied the patient experiences of relapsed and refractory multiple myeloma (RRMM) patients participating in the KarMMa trial during treatment and 2 years after the end of treatment, respectively [ 19 , 30 ] (Fig.  1 ; Supplementary File, Appendix C ). The studies (2015–2024) were conducted in Europe ( n  = 3) [ 19 , 30 , 31 ], North America ( n  = 8) [ 12 , 13 , 21 , 29 , 32 , 33 , 34 , 35 ], and Asia ( n  = 1) [ 15 ]. Various qualitative analysis methods were used, most commonly thematic analysis ( n  = 4) and content analysis ( n  = 6). In terms of qualitative methodology, the most common approach was generic qualitative research ( n  = 8), which did not clearly adhere to any specific traditional qualitative design. The quality assessment revealed that most studies met the Critical Appraisal Skills Programme guidance (Supplementary File, Appendix B ). One study used a theoretical framework [ 31 ]. Disease types include refractory or relapsed multiple myeloma ( n  = 4), B cell lymphoma ( n  = 4), and all types of hematological malignancies ( n  = 4). There were 244 participants (224 patients, 20 family caregivers). When reported, most patients were male (57%). The average age of the patient was 58.8 years.

The PRISMA flow diagram [ 36 ] of initial searches and inclusion (2015–January 2024)

Qualitative meta-synthesis

The process of data extraction resulted in the identification of 288 quotes provided by patients and their families, which were utilized for the qualitative meta-synthesis. Upon initial categorization, it was observed that the majority of the data about patients’ treatment journeys were specific to different stages, thus highlighting the necessity to conduct separate analyses for each treatment stage. Meta-synthesis ultimately results in eight major themes. Themes with many exemplary quotations are presented below and in supplementary material (Fig.  2 ; Supplementary File, Appendix D ).

The nature of the CAR-T therapy experience (175/238, 74%)

Themes and subthemes of treatment experienced by patients with Hematologic malignancies during CAR-T therapy journey

Before CAR-T therapy

Theme 1: patients lacked a sense of actual choice (15/238,6%).

The CAR-T therapy is commonly contemplated as a recourse when alternative therapies prove ineffective or unsuitable, and it is perceived by patients and their family caregivers as an unavoidable option for receiving life-saving measures. Consequently, decisions made in the context of a matter of life or death diminish the patient’s perception of having genuine agency. The potential risks associated with the therapy and even lower rates of success do not exert a substantial influence on the decision to pursue this treatment:

I don’t think I had a choice really. . .it was that or you won’t be here much longer. [ 32 ] (Patient) If she didn’t have it, she was going to die anyway so our view is even with the smallest percentage it was worth the risk to take. [ 32 ] (Caregiver)

Theme 2: Struggled with expectations for treatment outcomes (24/238,10%)

Patients undergoing CAR-T therapy have varying expectations and goals based on their circumstances, understanding of the treatment, and condition. Some patients hope for groundbreaking, effective, and life-saving results, aiming for complete remission and a cancer-free life:

CAR-T was overwhelmingly discussed as a ‘cure’ with words such as revolutionary treatment’ and a way to be ‘cancer-free’ [ 34 ]. (Patient) I’m looking forward to having a pause in treatment and some quality of life come back to me [ 13 ] (Patient) Several patients hoped that cilta-cel would be a cure and would be the last treatment they would undergo [ 29 ] (Patient)

Patients and caregivers said that the illness and ongoing care had disrupted their lives, aspirations, social roles, and relationships, leaving them with a diminished sense of control. They called this state a “bubble” representing life's vulnerability, which they attributed to failed treatments and their understanding of cancer as “relentless” and treatment as “cyclical.” This patient group views CAR-T therapy as just another treatment option, aiming for only a small increase in survival. They consider the possibility of treatment not working and plan for alternative treatments if needed:

If it comes back in four/five years’ time there will be another trial, then I’ll take that trial, get back in remission for two years, but it’s a vicious circle. But I do believe that once you’ve got cancer, you’ll never get rid of it, it will always come back in your lifetime and bite you in the backside [ 32 ] (Patient) It’s a bit of a bubble isn’t it when you have a chronic illness, and it’s a revolving circle of going from one treatment to the next and [she] is in that bubble and I feel like I’m – I’m not on the outside – but you know, you feel sometimes out of control [ 32 ] (caregiver)

Patients desire doctors to provide statistical data such as remission and survival rates, along with treatment side effects. This information helps patients and their families establish realistic treatment goals and prevent the emotional strain caused by unrealistic expectations:

Expectations of treatment toxicity were focussed on neurotoxicity and intensive care admission [ 32 ] (Patient) When [the doctor] gave me the figure of 35-40% that made me think, well we have to be realistic here, because otherwise I’m feeling more for my carer at least now [she] is in a mindset that it could go wrong [ 13 ] (Patient)

Theme 3: Intricate emotional experiences (37/238, 16%)

Theme 3 believed that patients’ emotions were more complex before treatment compared to during and after treatment. This intricate emotional condition arises from the CAR-T therapy and the present symptoms experience. Patients reported struggling with their emotional well-being before CAR-T therapy.

Patients described anticipating treatment outcomes as making them “excited,” “anxious,” and “nervous” about their upcoming CAR-T therapy: excitement related to their hope for the effectiveness of CAR-T therapy, anxiousness and nervousness related to uncertainty about what might happen, which includes “potential need for another treatment after treatment failure,” “uncertainty of the long-term effects,” “uncertainty of any treatment response,” “uncertainty of the duration of treatment response,” “unknown future side effects”:

I don’t know what’s going to happen, so… there’s a lot of anxiety. So, I would say the anxiety is the biggest problem. [ 29 ] (Patient) 1 was concerned about possible strong side effects after treatment. [ 29 ] (Patient) I need to know more about CAR T-cell therapy, such as the response rate of CAR T-cell therapy, whether there is a possibility of relapse after treatment, any serious adverse effects, and other more effective treatments. The more I know, the more I feel at ease. [ 15 ] (Patient)

Patients also described a lack of understanding and loneliness.

They’re not going to understand. I mean, they can sympathize, but they can’t empathize with what I am going through. [ 29 ] (Patient) There were others obviously world-wide, but I was the only in the UK. So, I felt a bit lonely, being the only one… [ 31 ] (Patient) [I felt] fear and isolated because I didn’t know anyone else who was going through it. [ 21 ] (Patient)

In addition to emotional stress related to CAR-T therapy, patients may also encounter irritation, despair, disillusionment, and solitude due to cancer and reduced family or social capabilities:

Well, I haven’t gone on vacation, and my mom likes to travel, and my friends like to travel, and I do as well. It’s very disappointing… And I’m all sad because I feel like I can’t go, especially on a cruise because I can’t catch like a virus, you know? [ 29 ] (Patient)It’s easy to make you irritable, or depressed when you have to deal with the pain every day. [ 29 ] (Patient)

During or immediately after CAR-T therapy

Theme 1: patients expressed both comfortable and uncomfortable experiences. (40/238, 17%).

A few patients reported the infusion as an “anticlimax” or a “nonevent”. The procedure was easy to undergo and caused them to feel comfortable:

It’s a lot easier and I feel better. And I would take this any day over, like getting the chemo and all that stuff. Yes. I would definitely do this again [ 29 ] (Patient)

Many patients praised the nurses' attentive care, thorough assessments, and compassionate interventions, which made them feel safe and well-cared for during their stay:

They’re trained to recognize the issues that come out of CAR-T, and if they detect something, (a) they recognize it, and (b) they can handle it right away. [ 13 ] (Patient) Topnotch. I have a really good care team…, monitoring me, checking up on me,’’ and ‘‘When I was in the hospital, it was pretty much anything I needed. I mean, if you’re hungry, thirsty, hot, cold—whatever you need, they take care of it. [ 13 ] (Patient)

Frequent medical and nursing procedures, the emergence of symptoms associated with therapy that impact the patient's level of comfort, as one patient described, “follow-up monitoring was a ‘nuisance’, the 24-h urine collection was a ‘minor annoyance’, and that she had significant anxiety about her most recent bone marrow biopsy.” Significantly, patients expressed experiencing worse sleep quality, intense sensations of constraint, and strong dislike:

I got real tired of staying in the hospital for 10 days, especially after my fever broke…. when I was running the fever… I guess I was happy to be there, but after the fever broke…I had nothing to do, and I wasn’t really happy about being there for 10 days. [ 29 ] (Patient) The prolonged hospital admission and intensive monitoring were associated with a feeling of confinement…I felt like a caged animal. [ 13 ] (Patient) their most consistent complaint related to sleep, as frequent monitoring interrupted their rest. [ 32 ] (Patient)

Patients interviewed felt lonely because they were away from their families.

…. feeling isolated or confined and being away from family [ 19 ] (Patient) Not being present with loved ones (especially children or pets) [ 13 ] (Patient)

Theme 2 Patients emphasized that concerns regarding treatment efficacy and adverse reactions intensified treatment-related distress. (20/238, 20%)

Patients experienced distress during or immediately after CAR-T therapy in all aspects of their being, encompassing cognitive, physical, and uncertainty. Patients felt frightened, angry, depressed, misunderstood, frustrated, and overwhelmed. As one sufferer recounted, “I wasn’t fearful that I couldn’t make it through it, but it’s more the unknown of some of these side effects seem pretty wicked”. In addition, patients are concerned that the exhaustion caused by treatment would hinder their ability to resume their daily activities :

The changes mean a lot because living in pain and being tired, or just being careful, walking gingerly, that stuff was like a new normal and it bothered me because I know within myself I wasn’t like that. [ 29 ] (Patient) It’s just the thought that if I get [into remission] will it be long lasting, will I have to go down another route and can I emotionally cope with that anymore? [ 32 ] (Patient)

The presence of cognitive impairment instills fear and may even induce feelings of depression in individuals.

He kind of didn’t have any interest in interacting with anyone else. I think that he kind of got into a…I guess, depression. He was frustrated with himself all the time because he couldn’t remember anything. [ 33 ] (caregiver)

After CAR-T therapy

Theme 1: meaningful changes (18/238, 8%).

Patients consider meaningful change as symptom improvement and return to normalcy. The evaluation of CAR-T therapy's efficacy varies among patients based on their understanding of the disease. Those in remission prioritize treatment side effects, recovery, and symptom improvement. They considered experiencing “fewer, manageable or no side effects,” “successful and easy or difficult recovery,” “no need for maintenance therapy,” “improvement in symptoms compared to pre-treatment,” “increased activities of daily living,” and “return to a normal life” as meaningful changes:

…changes in symptoms and HRQoL that occurred after treatment as extremely meaningful. [ 13 ] (Patient) I’ve been in remission for, what, a year and a half. Well I feel very lucky and fortunate. [ 30 ] (Patient) feeling more optimistic about the future, and that they were able to make life plans and live life like a ‘normal’ person [ 29 ] (Patient)

Patients with no or slight treatment remission or relapse, which may be accompanied by worsened health and well-being and treatment-related severe side effects, “lifestyle changes due to immunodeficiency” express low treatment satisfaction and perceive the treatment as causing negative changes in themselves:

Relationships and social functioning had less marked improvement [ 29 ] (Patient) The only bad parts of it were the risk associated with the actual infusion, I think it’s called … Cytokine release syndrome. The risk of that [ 30 ] (Patient) It would be very difficult to have to go through it again. [ 34 ] (Patient)

Theme 2: Burden of home-based rehabilitation (21/238, 9%)

During out-of-hospital rehabilitation, patients and families want to stay in touch with medical staff. Getting counseling from professionals helps reduce the psychological burden. Patients were unsure about the details and results of each follow-up appointment, and the frequent visits disrupted their daily routines, causing travel stress and psychological strain.

….I had an hour and a half travelling time to get there, and then an hour and a half traveling time to get back, so that was a much more substantial time cost. [ 31 ] (Patient) This led to me frustrated that I did not know precisely what the endpoint of the therapy might look like and as a result how long the follow-up might continue for. [ 35 ] (Patient) This burden of travel is known to aggravate anxiety and depression… [ 12 ] (Patient)

The patient also worried about the carer’s inability to recognize and manage somatic symptoms promptly.

Inability to access care immediately when needed (e.g., MRI, blood work) [ 13 ] (Patient) Safety concerns if caregivers do not recognize side effects that need to be addressed. [ 13 ] (Patient)

Patients voiced apprehension regarding potential, unpredictable occurrences and the incapacity to resume their daily routines.

felt anxious and stressed due to uncertainty surrounding treatment effectiveness and logistics [ 29 ] (Patient) I feel that I am a burden to my family because of my illness. I used to take care of my parents, but now they have to take care of me. Moreover, I have no energy to take care of my children. [ 15 ] (Patient)

The family caregiver’s strain is compounded by onerous healthcare responsibilities and a lack of caregiving expertise.

I was quite worried, being in the hotel with him, knowing things that could have happened. [ 32 ] (Patient) Travel time to hospital and concern about delays in admission for care. [ 13 ] (Patient)

Factors contributing to the high CAR-T therapy cost (63/238 quotes, 26%)

Patients reported experiencing a treatment cost burden before, during, and after treatment in all aspects of their being, encompassing the costs directly related to clinical care (e.g.,: costs of drugs for side effects, effect and duration of treatments, limited access to clinical trials/new therapies with multiple treatment lines), the indirect treatment costs (e.g.,: cost of time off/reduced productivity at work/changing careers, the cost of transport, accommodation, and food), the emotional toll of treatment (eg: psychological effects of uncertainty, emotional toll of running out of treatment options), the physical toll of treatment (e.g.,: Loss of physical ability). This topic provides insight into the factors leading to high costs from the patient’s perspective and helps patients and caregivers understand the value of health outcomes [ 35 ].

The cost of CAR T-cell therapy is too high for the average family to afford. Because I am sick and can't go to work, my quality of life has declined significantly. I hope the government can give me some subsidies or cover part of the cost of CAR T-cell therapy as medical insurance [ 15 ] (Patient) I have been ill for more than two years. I have spent much money, and I do not know how much money I will spend in the future. I have added much financial burden to my family [ 15 ] (Patient) you need to have somewhere to stay. I had to continue to pay for car insurance, pay for my vehicle, pay for activities that my child has. So, it was very difficult [ 33 ] (Patient)

This study analyzed 12 qualitative studies to examine the experiences and nursing concerns of patients with hematological malignancies undergoing CAR-T therapy at different stages. Key patient- and family-centered insights include: Distinct emotions and treatment expectations experienced prior to treatment; different comfort experiences and fewer medical explanations during or immediately after treatment; patients and families value out-of-hospital rehabilitation, communication, and connectedness with healthcare experts after treatment.

After analyzing the treatment expectations and experiences of individuals, we found a strong connection between them. If there is a mismatch between expectations and experiences, it can affect patients’ satisfaction with therapy, which is consistent with recent research [ 37 , 38 ]. In the context of CAR-T therapy, factors such as patient experience, understanding of the disease, attitude towards treatment, and current situation influence treatment expectations. Meaningful changes for patients include clinical efficacy, physical symptoms, and returning to normal life. However, we did not find a direct correlation between treatment expectations and these changes. Cockle et al. believed that patients’ treatment expectations will change according to the treatment process and results [ 37 ]. Therefore, this correlation is complex and requires more in-depth original research.

Before receiving CAR-T therapy, patients experienced a range of emotions and distress, including excitement, nervousness, anxiety, and emotional, physical, relational, and spiritual distress. This strong emotional reaction is often due to the perception of CAR-T therapy as a final option for patients hoping for a cure or remission. While high-dose chemotherapy and radiotherapy also present considerable emotional and physical challenges, CAR-T therapy is associated with its unique complications, such as cytokine release syndrome. This condition can be quite severe and demands rigorous management. Additionally, the newness and uncertain results of CAR-T therapy can further heighten anxiety among patients. As a result, pre-treatment patients lack support from peers, feel uncertain about treatment, and have concerns about the treatment selection process that their family and healthcare team may not understand. These factors, along with physical pain and a desire for normalcy, make it difficult for pre-treatment patients to maintain a stable emotional state when faced with complex emotional situations. Our research aligns with previous studies on this matter [ 31 ]. Patients’ experiences in treatment programs are complex as they have multiple roles and obligations [ 39 , 40 ]. It is crucial to address their maladaptive emotions and psychological barriers before treatment and provide peer support.

This study shows that patients in hospital rehabilitation need comfort care and clear explanations of side effects. Palliative care may be necessary for patients with ineffective treatment. Patients will receive intensive care from post-infusion of the CAR-T cell. However, frequent ward rounds, medical procedures (e.g., blood draws), and adverse reactions (e.g., fever, cognitive problems, and pain) significantly affect the quality of patients’ sleep and cause fear, anxiety, and other negative feelings, resulting in physical and mental discomfort. Patients recognize that physical and mental well-being are closely connected in therapeutic settings [ 41 ], and receiving palliative care, promoting comfort is an essential part of nursing intervention [ 42 ], Therefore, we propose the need for the application of Kolcaba’s comfort theory at this stage of the process [ 43 ]. Subjective toxicity refers to the individual’s own experience of subjective adverse reactions or side effects while receiving medication treatment, particularly for cancer [ 44 ], subjective toxicity in the context of CAR-T therapy includes, but is not limited to, nausea, loss of appetite, and headaches. Unlike traditional cancer therapies, the subjective toxicities reported by patients undergoing CAR-T therapy can be linked to severe side effects such as cytokine release syndrome (CRS) and neurotoxicity. These symptoms may be experienced concurrently and synergistically, significantly increasing the overall impact on the patient’s symptom burden, quality of life, and psychological stress [ 45 , 46 ]. In the future, we will thoroughly study the advantages of a patient education program for those with hematological malignancies receiving CAR-T therapy. This program aims to improve their ability to independently handle subjective toxicity symptoms.

Patients and caregivers recovering at home prioritize feeling safe. They express concerns about their lack of experience in rehabilitation and care, uncertainty about potential risks, confusion about follow-up appointments, worries about accidents during transportation, and a desire for effective communication with healthcare professionals. Caregivers of patients play a critical role during treatment, often experiencing psychological stress and misinterpretation of symptoms [ 47 ]. However, there is limited research on rehabilitation for patients receiving CAR-T therapy. Extensive research, including numerous systematic reviews and meta-analyses, has consistently demonstrated that physical activity significantly alleviates fatigue across various patient populations [ 48 , 49 , 50 ]. These studies highlight the efficacy of exercise interventions in not only reducing fatigue but also enhancing psychological well-being and quality of life. A recent study also suggests that rehabilitation practices can be inferred from the limited functional information available on patients who completed treatment [ 51 ]. Our suggestion is to use the Chronic Disease Self-Management Model [ 52 ] to develop targeted interventions and establish effective communication channels to guide patients and carers in learning and applying self-management skills to reduce anxiety.

The perception of CAR-T therapy as a last-resort treatment significantly influences patient and family decision-making. Often considered only after exhausting conventional options, CAR-T therapy is not only a potentially life-saving intervention but also an inevitable choice, limiting patients' sense of autonomy. This sentiment aligns with studies on decision-making in severe chronic illnesses, where urgency can overshadow the patient’s desire for control [ 53 ]. Faced with life-threatening conditions, patients may prioritize immediate survival over potential risk. This complex dynamic underscores the necessity for robust patient support and counseling to help navigate these tough decisions. Enhancing communication between healthcare providers and patients, discussing realistic outcomes, and clarifying available choices can mitigate feelings of coercion and support a more informed decision-making process.

Implications for nursing practice

Our findings emphasize the need for a comfortable environment, procedures, and communication as the primary means to give patients targeted nursing at different stages. Nurses need to be aware of the patient’s specific care needs throughout treatment to create a personalized care plan that prioritizes safety, effectiveness, and patient comfort. We propose a sequential care approach: Before treatment, communicate positively with the patient, identify their negative emotions, assess treatment expectations, address unrealistic expectations, and establish a positive mindset for treatment. During or after treatment, provide comfort care and share medical knowledge to enhance the patient’s ability to manage subjective toxicity and improve their overall well-being. For some patients for whom treatment is unsuccessful, palliative care may be considered during this period. To improve patients’ quality of life after leaving the hospital, we will create a program and communication system for their rehabilitation.

Strengths and limitations

Strengths of this study include: the systematic approach to study retrieval and data synthesis; international representation of included studies; the acquisition, inclusion, and analysis of the full range of content obtained in the original studies; and the prioritization of patients and families’ voices, including understanding the patient’s experience from quotes from family members. Limitations include that the included studies were conducted mainly in developed countries because CAR-T therapy is less available in developing countries due to medical conditions. This limitation may have led to cultural bias. However, this bias has been mitigated by the cultural and disciplinary diversity of the research teams.

This study discovered that patients face similar physical, psychological, and social challenges during CAR-T treatment. However, these challenges are unique due to the complex nature of the treatment and its stronger side effects. Researchers have not yet focused on the factors that help patients and their families cope with these challenges, which will be explored in future studies. Promoting the safety and sustainability of CAR-T therapy requires prioritizing teaching programs that help patients enhance their self-management skills. These references will serve as valuable resources for guiding patients during their treatment.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

The authors would like to thank Professor Ying from the School of Nursing, Zhejiang University, for her suggestions and revisions.

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Caiqin Xie and Haoran Duan are considered joint first authors of this paper.

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Nursing Department, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Shangcheng District, Hangzhou, 310009, China

Caiqin Xie, Haoran Duan, Yunhua Wang, Zhuanyi Sun & Meijuan Lan

Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China

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XCQ and DHR wrote the main manuscript text. The academic nurses and research assistants conducted study selection (DHR, WYH, SZY), extraction (DHR, XCQ), appraisal (DHR, HL, XCQ), and synthesis (DHR, XCQ, LMJ). All authors reviewed the manuscript.

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Contribution of the paper

What is already known about the topic?

Chimeric antigen receptor (CAR) T therapy is a novel approach that has the potential to improve the clinical outcomes of many patients with hematological malignancies.

Nurses play an important role throughout the CAR-T therapy procedure. Nurses’ professional competence and comprehensive care are critical to the effectiveness of CAR-T therapy, patient safety, and out-of-hospital rehabilitation.

Due to limited knowledge about patients' care needs at different treatment stages, dedicated palliative and supportive care services may not be taken into account.

What this paper adds?

Discussing potential factors contributing to the high cost of CAR-T therapy with patients and their families before treatment can help them make decisions and reduce extra expenses during the treatment journey.

Effective communication is vital throughout CAR-T therapy, including understanding patients' expectations, educating them about symptoms, defining treatment value, and addressing psychological needs.

We suggest prioritizing patient comfort during CAR-T therapy hospitalization and implementing an off-site rehabilitation coaching program to enhance physical recovery and ensure patient safety.

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Xie, C., Duan, H., Liu, H. et al. Promoting patient-centered care in CAR-T therapy for hematologic malignancy: a qualitative meta-synthesis. Support Care Cancer 32 , 591 (2024). https://doi.org/10.1007/s00520-024-08799-3

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What is the most appropriate knowledge synthesis method to conduct a review? Protocol for a scoping review

Monika kastner.

1 Li Ka Shing Knowledge Institute of St. Michael’s hospital, 209 Victoria Street, Toronto, ON, M5B 1W8, Canada

Andrea C Tricco

Charlene soobiah, erin lillie, laure perrier.

2 Continuing Education and Professional Development, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

Tanya Horsley

3 Royal College of Physicians and Surgeons of Canada, Ottawa, ON, Canada

Vivian Welch

4 Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, ON, Canada

Jesmin Antony

Sharon e straus.

5 Department of Medicine, Faculty of medicine, University of Toronto, Toronto, ON, Canada

Associated Data

A knowledge synthesis attempts to summarize all pertinent studies on a specific question, can improve the understanding of inconsistencies in diverse evidence, and can identify gaps in research evidence to define future research agendas. Knowledge synthesis activities in healthcare have largely focused on systematic reviews of interventions. However, a wider range of synthesis methods has emerged in the last decade addressing different types of questions (e.g., realist synthesis to explore mediating mechanisms and moderators of interventions). Many different knowledge synthesis methods exist in the literature across multiple disciplines, but locating these, particularly for qualitative research, present challenges. There is a need for a comprehensive manual for synthesis methods (quantitative/qualitative or mixed), outlining how these methods are related, and how to match the most appropriate knowledge synthesis method to answer a research question. The objectives of this scoping review are to: 1) conduct a systematic search of the literature for knowledge synthesis methods across multi-disciplinary fields; 2) compare and contrast the different knowledge synthesis methods; and, 3) map out the specific steps to conducting the knowledge syntheses to inform the development of a knowledge synthesis methods manual/tool.

We will search relevant electronic databases (e.g., MEDLINE, CINAHL), grey literature, and discipline-based listservs. The scoping review will consider all study designs including qualitative and quantitative methodologies (excluding economic analysis or clinical practice guideline development), and identify knowledge synthesis methods across the disciplines of health, education, sociology, and philosophy. Two reviewers will pilot-test the screening criteria and data abstraction forms, and will independently screen the literature and abstract the data. A three-step synthesis process will be used to map the literature to our objectives.

This project represents the first attempt to broadly and systematically identify, define and classify knowledge synthesis methods (i.e., less traditional knowledge synthesis methods). We anticipate that our results will lead to an accepted taxonomy for less traditional knowledge synthesis methods, and to the development and implementation of a methods manual for these reviews which will be relevant to a wide range of knowledge users, including researchers, funders, and journal editors.

Knowledge synthesis has the potential to inform the management of health problems [ 1 ] and is integral to the health of the Canadian population [ 2 ]. A knowledge synthesis summarizes all pertinent studies on a specific question, can improve the understanding of inconsistencies in diverse evidence, and can define future research agendas [ 1 , 3 ]. Knowledge synthesis is also an important part of the knowledge translation (KT) process (and ideally should form the ‘base unit’ of KT strategies for providers and policy makers), and be used to provide the evidence base for KT products including clinical practice guidelines, policy briefs and decision aids [ 4 ]. As such, knowledge synthesis can be used to interpret results of individual studies within the context of the totality of evidence. This is an important consideration, given that basing practice and policy decisions on a single study or expert opinion can be misleading [ 5 ].

Knowledge synthesis activities in healthcare have often focused on the methodologically rigorous Cochrane reviews, most commonly of interventions. The definition of a systematic review according to the Cochrane Collaboration is “A review of clearly formulated questions that uses systematic and explicit methods to identify, select, and critically appraise relevant research, and to collect and analyse data from the studies that are included in the review. Statistical methods (meta-analysis) may or may not be used to analyse and summarise the results of the included studies” [ 6 ]. However, Cochrane-like review methods may not always be applicable for answering all knowledge synthesis questions, particularly those investigating complex and multidisciplinary topics [ 7 , 8 ]. For example, members of our team recently attempted to conduct a systematic review to better understand the relationship between the perceived characteristics of clinical practice guidelines and their uptake by clinicians, and found that a flexible approach that borrowed relevant components of less traditional knowledge synthesis methods (i.e., including realist reviews and meta-ethnography) was more relevant to determine the mechanisms and circumstances underpinning guideline implementation [ 9 ]. This example highlights the need for less traditional methods for completing a review. By matching the appropriate design to fit the question, synthesis outputs are more likely to be relevant and be useful for end users.

Furthermore, a traditional review such as a Cochrane review cannot always explain why particular interventions work in some settings but not in others [ 10 ]. For example, a Cochrane review found that school feeding programs significantly improved the growth and cognitive performance of disadvantaged children [ 11 ], but failed to provide direction for policy-makers to decide which intervention should be implemented and under what circumstances. By conducting a realist review alongside the Cochrane review (which can be used to understand ‘what works for whom and under what circumstances’ [ 10 ]), the authors were able to provide concrete recommendations that could be implemented in practice and policy making [ 7 ]. To address these types of questions and adequately incorporate the needs, preferences and experiences of patients into healthcare delivery, there is an increasing need to consider less traditional review methods of complex evidence (i.e., heterogeneous, methodologically diverse, difficult to classify, and contradictory) [ 12 , 13 ]. Another approach is to consider conducting a systematic review as a “first step” to better understand complex evidence (or to conduct them in parallel with novel reviews), particularly for evidence generated from philosophy and the social sciences. The increasing number of synthesis methods that have recently emerged within the healthcare literature supports this need [ 14 - 17 ].

Table ​ Table1 1 summarizes a selection of knowledge synthesis methods that currently exist in the literature across multiple disciplines (identified through consultation with knowledge synthesis experts and qualitative researchers). Although many of these approaches can be applied to healthcare situations, the methods for conducting them have not been as clearly operationalized as traditional reviews of interventions. Consultation with researchers and end users of reviews that we conducted in preparation for this research indicate a lack of clarity around how to match the appropriate review method to the research question, the methods used to conduct these reviews, and how to analyze and present the results from the review to inform decision making. These issues are challenging for researchers interested in tackling reviews of complex questions and for decision makers trying to interpret and apply this evidence. Other identified challenges involve locating the numerous synthesis methods (particularly those for synthesizing qualitative research), which can be problematic and resource-intensive since they are scattered widely within the literature and across many different disciplines and databases. The terms used to describe the different synthesis methods are often similar (e.g., ‘meta-synthesis’, ‘meta-ethnography’, ‘meta-narrative’, ‘meta-study’, ‘meta-interpretation’) and their definitions can overlap [ 12 ]. This area of research is further complicated because some of these methods are referred to as a ‘complete’ synthesis method (i.e., providing guidance on the search strategy, study selection, appraisal, and analysis), while others provide guidance only on specific parts of the process, such as data analysis [ 12 ].

Characteristics of a preliminary list of existing knowledge synthesis methods

Some researchers have attempted to outline methods for the synthesis of qualitative [ 47 ] and mixed-methods research [ 36 , 45 ] and to build a typology of such reviews [ 41 ], while others have highlighted methods for knowledge synthesis reviews to inform specific end-user targets such as for management and policy-making in the health field [ 45 ]. A recent overview by Gough and colleagues attempted to outline the differences between review designs and methods by describing the important conceptual and practical differences amongst them [ 8 ]. However, a comprehensive manual for all of the different synthesis methods (quantitative/qualitative or mixed), outlining how they are related and how to decide which methodology is the most appropriate for a particular research question does not currently exist. To our knowledge, the current study will be the first to describe an overall taxonomy of all existing types of knowledge synthesis methods, to characterise the differences between them, and to develop a strategy for knowledge users to be able to select the most appropriate method to answer their research questions.

The specific objectives of the current study are to: (1) to conduct a systematic search for knowledge synthesis methods across multi-disciplinary fields, such as health and philosophy; (2) compare and contrast the different knowledge synthesis methods; and, (3) map out the specific steps to conducting the knowledge synthesis methods, which will be used to inform the development of a knowledge synthesis methods manual/tool.

Methods/Design

Search strategy.

We will use the methodologically rigorous scoping review approach proposed by Arksey and O’Malley [ 48 ] to conduct a systematic search across the disciplines of health and philosophy. We will search the following electronic databases from inception onwards: MEDLINE, CINAHL, EMBASE, PsycInfo, the Cochrane Methodology Register, Cochrane Database of Systematic Reviews, Social Sciences Abstracts, LISA, Philosopher’s Index, and ERIC. We will also perform targeted searches for grey literature (i.e., difficult to locate or unpublished material) by searching 1) Google, 2) relevant discipline-based listservs (e.g., CANMEDLIB, MEDLIB), and 3) the websites of agencies that fund or conduct knowledge synthesis (e.g., CIHR, Canadian Agency for Drugs and Technologies in Health, Agency for Healthcare Research and Quality, Cochrane and Campbell Collaborations, Joanna Briggs Institute, Centre for Reviews and Dissemination).

The draft literature search for MEDLINE can be found in Additional file 1 , which uses a combination of medical sub-headings (MeSH) and free text terms. It will be modified as necessary for the other databases. The search strategy will not be limited by study design, year or language of dissemination and will be peer reviewed by another information specialist using the Peer Review of Electronic Search Strategies (PRESS) checklist [ 49 ]. The literature search will be supplemented by scanning the reference lists of included studies, searching authors’ personal files, and contacting methodological experts in each field.

Study selection: inclusion criteria

Study design : All study designs will be considered including qualitative and quantitative methods such as methodology reports; knowledge syntheses (including a description of the synthesis method); short reports describing the development, use, or comparison of methods for knowledge synthesis. Type of knowledge synthesis : We will focus on synthesis methods above and beyond traditional systematic reviews and exclude methods on economic analysis or clinical practice guidelines. Disciplines : Health: “ A state of complete physical, mental and social well-being and not merely the absence of disease or infirmity ” [ 50 ] (and thus includes the disciplines of psychology, education and sociology) and philosophy. These were selected because many of the knowledge synthesis methods originated from these disciplines (e.g., systematic review methods rooted in education and psychology; realist reviews based on philosophy).

Study selection: screening

Prior to commencing the screening process, a calibration exercise will be conducted to ensure reliability in correctly selecting articles for inclusion. It will entail independently screening a random sample of 5% of the included citations by two reviewers. Eligibility criteria will be modified if low agreement is observed between the reviewers (e.g., a kappa statistic less than 50%). The reviewers will then independently screen the remainder of the search results using a pre-defined relevance criteria form for all levels of screening (e.g., title and abstract, full-text review). Discrepancies will be resolved by discussion with a third reviewer.

Data abstraction

A data abstraction form will be tested independently by two reviewers on a random sample of 10 articles and revised iteratively, as needed. It is anticipated that the data items will include study characteristics (e.g., first author, year of publication) and characteristics related to the method (e.g., general description of the review method, discipline) (Additional file 1 ). Two investigators will independently read each article and extract the relevant data. Differences in abstraction will be resolved by discussion or the involvement of a third reviewer. We will not formally appraise methodological quality because the aim of a scoping review is to identify gaps in the evidence base and to target topic areas for future reviews.

Data analysis

We will analyze the data according to a three-stage process aimed at addressing the three research objectives: to characterize the synthesis methodologies (Synthesis objective 1); to identify the similarities and differences amongst these methods (Synthesis objective 2); and to map out a process for conducting different synthesis methods and to provide an approach for matching the research question to the appropriate methods (Synthesis objective 3). Table ​ Table2 2 shows the analysis plan and anticipated outputs for each of these objectives. Data analysis will involve quantitative (e.g., frequency analysis) and qualitative (e.g., thematic analysis) methods. We anticipate that this multi-layer synthesis process will also identify existing gaps in the literature, and reveal potential topics for conducting other systematic or novel reviews in the future.

Analysis plan and anticipated outputs for each of the 3 synthesis objectives

Engagement of knowledge users and KT plan

We have adopted an integrated KT approach to this project through the inclusion of knowledge users (i.e., systematic review methodologists, journal editors, review funders, policy makers, students and educators who teach knowledge synthesis methodology), who have been and will continue to be involved in every step of the process through to the reporting format and the methods for disseminating and implementing findings, drawing on Graham’s Knowledge-to-Action (KTA) framework [ 51 ]. We plan to develop an active KT plan by: 1) identifying the key messages arising from this research project; 2) determining the principal target audiences for each of these messages; 3) seeking out the most credible messenger for these messages and engaging their interest in becoming involved in the communication of these messages; and 4) launching a KT strategy grounded in the best available research evidence. We will use a diverse range of approaches to disseminate the results of this review to the different stakeholder groups (including an interactive workshop that will bring together the key target audiences for our research). These strategies will ensure that the research continues to reflect the relevant needs of the end users of this information, and to facilitate appropriate dissemination of outputs.

Anticipated challenges

We foresee some potential challenges related to this scoping review. First, the yield of the literature search might be more extensive than anticipated—the team will work closely with the information specialist to ensure that the scope is manageable. Second, it might be challenging to categorize the knowledge synthesis methods accurately (e.g., distinguishing between quantitative/qualitative or mixed / hybrid approaches or those not formally categorized) and to appropriately match a research question with a synthesis method. However, we have a strong team with diverse experience in different research methods, and are planning to hold stakeholder meetings to iteratively receive in-depth feedback from our end users.

The proposed scoping review has the potential to impact practice and policy and will make several contributions to the KT and health services research literature. First, the work will advance the science of knowledge synthesis by providing a systematic process for key knowledge users to make informed decisions about which synthesis method is the most appropriate to answer their research questions. This may also augment the quality of the research evidence produced. In particular, the work will highlight the potential for novel knowledge synthesis methods to clarify complex, multi-component, and multi-disciplinary healthcare interventions [ 13 ], and to contribute to the advancement of evidence-based practice and evidence-based decision-making. Second, there is currently no comprehensive manual for all available synthesis methods (quantitative/qualitative or mixed). To develop this manual, a taxonomy and comparison of all available synthesis methods are needed. Our work aims to develop the taxonomy of synthesis methods across multiple disciplines such as health and philosophy. Third, the scoping review will help map the literature, identify gaps where primary methods evidence is lacking and needed, and where systematic reviews are required; we anticipate that this work will lead to multiple subsequent systematic reviews. For example, one future systematic review may focus on knowledge synthesis methods for health services research and another may focus on knowledge synthesis of qualitative data. Fourth, the work has the potential to directly influence knowledge synthesis funders such as the Canadian Institutes of Health Research (CIHR) in developing resources (e.g., modules) that can be used to increase awareness of novel synthesis methods and their relevance for addressing complex evidence. This information is especially imperative for those conducting peer review of knowledge synthesis grants. Fifth, the scoping review can be used by publishers and editors to assist with the peer review of manuscripts describing these types of knowledge syntheses. Sixth, our findings have the potential to influence health research methods curricula within clinical epidemiology programs, by expanding the current understanding of synthesis methods. The development and evaluation of complex interventions has emerged as an important component of KT, so expertise in conducting non-traditional review methods will become increasingly important for researchers, teachers, and students. Lastly, the work will be targeted across a broad scope of health disciplines, which will provide the opportunity to elicit more generalizable findings that can directly inform practice and policy decisions within these disciplines. Results from this work will be the starting point of a comprehensive manual and decision algorithm on how to conduct the different synthesis methods and the proposed KT strategy will serve to engage the relevant stakeholders in clarifying and fulfilling the research agenda proposed in the scoping review (Table ​ (Table3 3 summarizes the anticipated products that will be generated).

Anticipated products generated by the scoping review

Abbreviations: KT knowledge translation; CIHR Canadian Institutes of Health Research.

Conducting a scoping review of available knowledge synthesis methods across multi-disciplinary fields will help funders, publishers, policy-makers, researchers, teachers, and students make informed decisions about the most appropriate synthesis method to answer research questions about complex evidence, and provide the opportunity to elicit findings directly informing practice and policy decisions.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

All authors participated in the design and development of the protocol. MK, ACT, and SES drafted the manuscript, and all authors read and approved the final manuscript.

The study was funded by a Canadian Institutes of Health Research (CIHR) Knowledge Synthesis grant. MK holds a CIHR Banting Postdoctoral Fellowship, ACT a CIHR/DSEN new investigator award, and SES a Tier 1 Canada Research Chair in Knowledge Translation.

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2288/12/114/prepub

Supplementary Material

Appendices.

Acknowledgements

We thank Drs. Jeremy Grimshaw, David Moher, and Peter Tugwell, who provided their support and expertise in knowledge synthesis methods and knowledge translation on this protocol.

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The effect of plant-based protein ingestion on athletic ability in healthy people—a bayesian meta-analysis with systematic review of randomized controlled trials.

Graphical Abstract

1. Key Points

2. background, 3.1. search strategy, 3.2. inclusion and exclusion criteria, 3.3. selection process, 3.4. risk of bias assessment, 3.5. certainty in evidence, 3.6. data extraction, 3.7. summary measures and synthesis, 3.8. subgroup analysis, 4.1. study characteristics, 4.2. risk of bias of included studies, 4.3. quality grade in each outcome, 4.4. convergence of the markov chain, 4.5. meta-analysis, 4.5.1. results of plant-based protein vs. no protein, 4.5.2. results of plant-based protein vs. other types of protein, 4.5.3. subgroup analysis, 4.5.4. subgroup analysis based on types of athletic performance, 4.5.5. subgroup analysis based on age, 4.6. risk of bias (funnel plots), 4.6.1. results of plant-based protein vs. no protein, 4.6.2. results of plant-based protein vs. other types of protein, 5. discussion, 5.1. plant-based protein vs. no protein, 5.2. plant-based protein vs. other types of protein, 6. strengths and limitations, 7. conclusions, supplementary materials, author contributions, data availability statement, conflicts of interest, abbreviations.

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Zhao, S.; Xu, Y.; Li, J.; Ning, Z. The Effect of Plant-Based Protein Ingestion on Athletic Ability in Healthy People—A Bayesian Meta-Analysis with Systematic Review of Randomized Controlled Trials. Nutrients 2024 , 16 , 2748. https://doi.org/10.3390/nu16162748

Zhao S, Xu Y, Li J, Ning Z. The Effect of Plant-Based Protein Ingestion on Athletic Ability in Healthy People—A Bayesian Meta-Analysis with Systematic Review of Randomized Controlled Trials. Nutrients . 2024; 16(16):2748. https://doi.org/10.3390/nu16162748

Zhao, Shiao, Yipin Xu, Jiarui Li, and Ziheng Ning. 2024. "The Effect of Plant-Based Protein Ingestion on Athletic Ability in Healthy People—A Bayesian Meta-Analysis with Systematic Review of Randomized Controlled Trials" Nutrients 16, no. 16: 2748. https://doi.org/10.3390/nu16162748

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