synthesis of literature search

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How to Write a Literature Review

• 6. Synthesize
• Literature Reviews: A Recap
• Reading Journal Articles
• Does it Describe a Literature Review?
• 1. Identify the Question
• 2. Review Discipline Styles
• Searching Article Databases
• Finding Full-Text of an Article
• Citation Chaining
• When to Stop Searching
• 4. Manage Your References
• 5. Critically Analyze and Evaluate

Synthesis Visualization

Synthesis matrix example.

• 7. Write a Literature Review

• Synthesis Worksheet

About Synthesis

Approaches to synthesis.

You can sort the literature in various ways, for example:

How to Begin?

Read your sources carefully and find the main idea(s) of each source

Look for similarities in your sources – which sources are talking about the same main ideas? (for example, sources that discuss the historical background on your topic)

Use the worksheet (above) or synthesis matrix (below) to get organized

This work can be messy. Don't worry if you have to go through a few iterations of the worksheet or matrix as you work on your lit review!

Four Examples of Student Writing

In the four examples below, only ONE shows a good example of synthesis: the fourth column, or  Student D . For a web accessible version, click the link below the image.

Long description of "Four Examples of Student Writing" for web accessibility

• Download a copy of the "Four Examples of Student Writing" chart

Click on the example to view the pdf.

From Jennifer Lim

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• Next: 7. Write a Literature Review >>
• Last Updated: May 3, 2024 5:17 PM
• URL: https://researchguides.uoregon.edu/litreview

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Literature Syntheis 101

How To Synthesise The Existing Research (With Examples)

By: Derek Jansen (MBA) | Expert Reviewer: Eunice Rautenbach (DTech) | August 2023

One of the most common mistakes that students make when writing a literature review is that they err on the side of describing the existing literature rather than providing a critical synthesis of it. In this post, we’ll unpack what exactly synthesis means and show you how to craft a strong literature synthesis using practical examples.

This post is based on our popular online course, Literature Review Bootcamp . In the course, we walk you through the full process of developing a literature review, step by step. If it’s your first time writing a literature review, you definitely want to use this link to get 50% off the course (limited-time offer).

Overview: Literature Synthesis

• What exactly does “synthesis” mean?
• Aspect 1: Agreement
• Aspect 2: Disagreement
• Aspect 3: Key theories
• Aspect 4: Contexts
• Aspect 5: Methodologies
• Bringing it all together

What does “synthesis” actually mean?

As a starting point, let’s quickly define what exactly we mean when we use the term “synthesis” within the context of a literature review.

Simply put, literature synthesis means going beyond just describing what everyone has said and found. Instead, synthesis is about bringing together all the information from various sources to present a cohesive assessment of the current state of knowledge in relation to your study’s research aims and questions .

Put another way, a good synthesis tells the reader exactly where the current research is “at” in terms of the topic you’re interested in – specifically, what’s known , what’s not , and where there’s a need for more research .

So, how do you go about doing this?

Well, there’s no “one right way” when it comes to literature synthesis, but we’ve found that it’s particularly useful to ask yourself five key questions when you’re working on your literature review. Having done so,  you can then address them more articulately within your actual write up. So, let’s take a look at each of these questions.

1. Points Of Agreement

The first question that you need to ask yourself is: “Overall, what things seem to be agreed upon by the vast majority of the literature?”

For example, if your research aim is to identify which factors contribute toward job satisfaction, you’ll need to identify which factors are broadly agreed upon and “settled” within the literature. Naturally, there may at times be some lone contrarian that has a radical viewpoint , but, provided that the vast majority of researchers are in agreement, you can put these random outliers to the side. That is, of course, unless your research aims to explore a contrarian viewpoint and there’s a clear justification for doing so. 

Identifying what’s broadly agreed upon is an essential starting point for synthesising the literature, because you generally don’t want (or need) to reinvent the wheel or run down a road investigating something that is already well established . So, addressing this question first lays a foundation of “settled” knowledge.

Need a helping hand?

2. Points Of Disagreement

Related to the previous point, but on the other end of the spectrum, is the equally important question: “Where do the disagreements lie?” .

In other words, which things are not well agreed upon by current researchers? It’s important to clarify here that by disagreement, we don’t mean that researchers are (necessarily) fighting over it – just that there are relatively mixed findings within the empirical research , with no firm consensus amongst researchers.

This is a really important question to address as these “disagreements” will often set the stage for the research gap(s). In other words, they provide clues regarding potential opportunities for further research, which your study can then (hopefully) contribute toward filling. If you’re not familiar with the concept of a research gap, be sure to check out our explainer video covering exactly that .

3. Key Theories

The next question you need to ask yourself is: “Which key theories seem to be coming up repeatedly?” .

Within most research spaces, you’ll find that you keep running into a handful of key theories that are referred to over and over again. Apart from identifying these theories, you’ll also need to think about how they’re connected to each other. Specifically, you need to ask yourself:

• Are they all covering the same ground or do they have different focal points  or underlying assumptions ?
• Do some of them feed into each other and if so, is there an opportunity to integrate them into a more cohesive theory?
• Do some of them pull in different directions ? If so, why might this be?
• Do all of the theories define the key concepts and variables in the same way, or is there some disconnect? If so, what’s the impact of this ?

Simply put, you’ll need to pay careful attention to the key theories in your research area, as they will need to feature within your theoretical framework , which will form a critical component within your final literature review. This will set the foundation for your entire study, so it’s essential that you be critical in this area of your literature synthesis.

If this sounds a bit fluffy, don’t worry. We deep dive into the theoretical framework (as well as the conceptual framework) and look at practical examples in Literature Review Bootcamp . If you’d like to learn more, take advantage of our limited-time offer to get 60% off the standard price.

4. Contexts

The next question that you need to address in your literature synthesis is an important one, and that is: “Which contexts have (and have not) been covered by the existing research?” .

For example, sticking with our earlier hypothetical topic (factors that impact job satisfaction), you may find that most of the research has focused on white-collar , management-level staff within a primarily Western context, but little has been done on blue-collar workers in an Eastern context. Given the significant socio-cultural differences between these two groups, this is an important observation, as it could present a contextual research gap .

In practical terms, this means that you’ll need to carefully assess the context of each piece of literature that you’re engaging with, especially the empirical research (i.e., studies that have collected and analysed real-world data). Ideally, you should keep notes regarding the context of each study in some sort of catalogue or sheet, so that you can easily make sense of this before you start the writing phase. If you’d like, our free literature catalogue worksheet is a great tool for this task.

5. Methodological Approaches

Last but certainly not least, you need to ask yourself the question: “What types of research methodologies have (and haven’t) been used?”

For example, you might find that most studies have approached the topic using qualitative methods such as interviews and thematic analysis. Alternatively, you might find that most studies have used quantitative methods such as online surveys and statistical analysis.

But why does this matter?

Well, it can run in one of two potential directions . If you find that the vast majority of studies use a specific methodological approach, this could provide you with a firm foundation on which to base your own study’s methodology . In other words, you can use the methodologies of similar studies to inform (and justify) your own study’s research design .

On the other hand, you might argue that the lack of diverse methodological approaches presents a research gap , and therefore your study could contribute toward filling that gap by taking a different approach. For example, taking a qualitative approach to a research area that is typically approached quantitatively. Of course, if you’re going to go against the methodological grain, you’ll need to provide a strong justification for why your proposed approach makes sense. Nevertheless, it is something worth at least considering.

Regardless of which route you opt for, you need to pay careful attention to the methodologies used in the relevant studies and provide at least some discussion about this in your write-up. Again, it’s useful to keep track of this on some sort of spreadsheet or catalogue as you digest each article, so consider grabbing a copy of our free literature catalogue if you don’t have anything in place.

Bringing It All Together

Alright, so we’ve looked at five important questions that you need to ask (and answer) to help you develop a strong synthesis within your literature review.  To recap, these are:

• Which things are broadly agreed upon within the current research?
• Which things are the subject of disagreement (or at least, present mixed findings)?
• Which theories seem to be central to your research topic and how do they relate or compare to each other?
• Which contexts have (and haven’t) been covered?
• Which methodological approaches are most common?

Importantly, you’re not just asking yourself these questions for the sake of asking them – they’re not just a reflection exercise. You need to weave your answers to them into your actual literature review when you write it up. How exactly you do this will vary from project to project depending on the structure you opt for, but you’ll still need to address them within your literature review, whichever route you go.

The best approach is to spend some time actually writing out your answers to these questions, as opposed to just thinking about them in your head. Putting your thoughts onto paper really helps you flesh out your thinking . As you do this, don’t just write down the answers – instead, think about what they mean in terms of the research gap you’ll present , as well as the methodological approach you’ll take . Your literature synthesis needs to lay the groundwork for these two things, so it’s essential that you link all of it together in your mind, and of course, on paper.

Psst… there’s more!

This post is an extract from our bestselling short course, Literature Review Bootcamp . If you want to work smart, you don't want to miss this .

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• Write a Literature Review
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Get Organized

• Lit Review Prep Use this template to help you evaluate your sources, create article summaries for an annotated bibliography, and a synthesis matrix for your lit review outline.

Synthesize your Information

Synthesize: combine separate elements to form a whole.

Synthesis Matrix

A synthesis matrix helps you record the main points of each source and document how sources relate to each other.

After summarizing and evaluating your sources, arrange them in a matrix or use a citation manager to help you see how they relate to each other and apply to each of your themes or variables.  

By arranging your sources by theme or variable, you can see how your sources relate to each other, and can start thinking about how you weave them together to create a narrative.

• Step-by-Step Approach
• Example Matrix from NSCU
• Matrix Template
• << Previous: Summarize
• Next: Integrate >>
• Last Updated: Sep 26, 2023 10:25 AM
• URL: https://guides.library.jhu.edu/lit-review

How to Synthesize Written Information from Multiple Sources

Shona McCombes

Content Manager

B.A., English Literature, University of Glasgow

Shona McCombes is the content manager at Scribbr, Netherlands.

Learn about our Editorial Process

Saul Mcleod, PhD

Editor-in-Chief for Simply Psychology

BSc (Hons) Psychology, MRes, PhD, University of Manchester

Saul Mcleod, PhD., is a qualified psychology teacher with over 18 years of experience in further and higher education. He has been published in peer-reviewed journals, including the Journal of Clinical Psychology.

On This Page:

When you write a literature review or essay, you have to go beyond just summarizing the articles you’ve read – you need to synthesize the literature to show how it all fits together (and how your own research fits in).

Synthesizing simply means combining. Instead of summarizing the main points of each source in turn, you put together the ideas and findings of multiple sources in order to make an overall point.

At the most basic level, this involves looking for similarities and differences between your sources. Your synthesis should show the reader where the sources overlap and where they diverge.

Unsynthesized Example

Franz (2008) studied undergraduate online students. He looked at 17 females and 18 males and found that none of them liked APA. According to Franz, the evidence suggested that all students are reluctant to learn citations style. Perez (2010) also studies undergraduate students. She looked at 42 females and 50 males and found that males were significantly more inclined to use citation software ( p < .05). Findings suggest that females might graduate sooner. Goldstein (2012) looked at British undergraduates. Among a sample of 50, all females, all confident in their abilities to cite and were eager to write their dissertations.

Synthesized Example

Studies of undergraduate students reveal conflicting conclusions regarding relationships between advanced scholarly study and citation efficacy. Although Franz (2008) found that no participants enjoyed learning citation style, Goldstein (2012) determined in a larger study that all participants watched felt comfortable citing sources, suggesting that variables among participant and control group populations must be examined more closely. Although Perez (2010) expanded on Franz’s original study with a larger, more diverse sample…

Step 1: Organize your sources

After collecting the relevant literature, you’ve got a lot of information to work through, and no clear idea of how it all fits together.

Before you can start writing, you need to organize your notes in a way that allows you to see the relationships between sources.

One way to begin synthesizing the literature is to put your notes into a table. Depending on your topic and the type of literature you’re dealing with, there are a couple of different ways you can organize this.

Summary table

A summary table collates the key points of each source under consistent headings. This is a good approach if your sources tend to have a similar structure – for instance, if they’re all empirical papers.

Each row in the table lists one source, and each column identifies a specific part of the source. You can decide which headings to include based on what’s most relevant to the literature you’re dealing with.

For example, you might include columns for things like aims, methods, variables, population, sample size, and conclusion.

For each study, you briefly summarize each of these aspects. You can also include columns for your own evaluation and analysis.

The summary table gives you a quick overview of the key points of each source. This allows you to group sources by relevant similarities, as well as noticing important differences or contradictions in their findings.

Synthesis matrix

A synthesis matrix is useful when your sources are more varied in their purpose and structure – for example, when you’re dealing with books and essays making various different arguments about a topic.

Each column in the table lists one source. Each row is labeled with a specific concept, topic or theme that recurs across all or most of the sources.

Then, for each source, you summarize the main points or arguments related to the theme.

The purposes of the table is to identify the common points that connect the sources, as well as identifying points where they diverge or disagree.

Step 2: Outline your structure

Now you should have a clear overview of the main connections and differences between the sources you’ve read. Next, you need to decide how you’ll group them together and the order in which you’ll discuss them.

For shorter papers, your outline can just identify the focus of each paragraph; for longer papers, you might want to divide it into sections with headings.

There are a few different approaches you can take to help you structure your synthesis.

If your sources cover a broad time period, and you found patterns in how researchers approached the topic over time, you can organize your discussion chronologically .

That doesn’t mean you just summarize each paper in chronological order; instead, you should group articles into time periods and identify what they have in common, as well as signalling important turning points or developments in the literature.

If the literature covers various different topics, you can organize it thematically .

That means that each paragraph or section focuses on a specific theme and explains how that theme is approached in the literature.

Source Used with Permission: The Chicago School

If you’re drawing on literature from various different fields or they use a wide variety of research methods, you can organize your sources methodologically .

That means grouping together studies based on the type of research they did and discussing the findings that emerged from each method.

If your topic involves a debate between different schools of thought, you can organize it theoretically .

That means comparing the different theories that have been developed and grouping together papers based on the position or perspective they take on the topic, as well as evaluating which arguments are most convincing.

Step 3: Write paragraphs with topic sentences

What sets a synthesis apart from a summary is that it combines various sources. The easiest way to think about this is that each paragraph should discuss a few different sources, and you should be able to condense the overall point of the paragraph into one sentence.

This is called a topic sentence , and it usually appears at the start of the paragraph. The topic sentence signals what the whole paragraph is about; every sentence in the paragraph should be clearly related to it.

A topic sentence can be a simple summary of the paragraph’s content:

“Early research on [x] focused heavily on [y].”

For an effective synthesis, you can use topic sentences to link back to the previous paragraph, highlighting a point of debate or critique:

“Several scholars have pointed out the flaws in this approach.” “While recent research has attempted to address the problem, many of these studies have methodological flaws that limit their validity.”

By using topic sentences, you can ensure that your paragraphs are coherent and clearly show the connections between the articles you are discussing.

As you write your paragraphs, avoid quoting directly from sources: use your own words to explain the commonalities and differences that you found in the literature.

Don’t try to cover every single point from every single source – the key to synthesizing is to extract the most important and relevant information and combine it to give your reader an overall picture of the state of knowledge on your topic.

Step 4: Revise, edit and proofread

Like any other piece of academic writing, synthesizing literature doesn’t happen all in one go – it involves redrafting, revising, editing and proofreading your work.

Checklist for Synthesis

•   Do I introduce the paragraph with a clear, focused topic sentence?
•   Do I discuss more than one source in the paragraph?
•   Do I mention only the most relevant findings, rather than describing every part of the studies?
•   Do I discuss the similarities or differences between the sources, rather than summarizing each source in turn?
•   Do I put the findings or arguments of the sources in my own words?
•   Is the paragraph organized around a single idea?
•   Is the paragraph directly relevant to my research question or topic?
•   Is there a logical transition from this paragraph to the next one?

Further Information

How to Synthesise: a Step-by-Step Approach

Help…I”ve Been Asked to Synthesize!

Learn how to Synthesise (combine information from sources)

How to write a Psychology Essay

Literature Review Basics

• What is a Literature Review?
• Synthesizing Research
• Using Research & Synthesis Tables
• Additional Resources

Synthesis: What is it?

First, let's be perfectly clear about what synthesizing your research isn't :

• - It isn't  just summarizing the material you read
• - It isn't  generating a collection of annotations or comments (like an annotated bibliography)
• - It isn't  compiling a report on every single thing ever written in relation to your topic

When you  synthesize  your research, your job is to help your reader understand the current state of the conversation on your topic, relative to your research question.  That may include doing the following:

• - Selecting and using representative work on the topic
• - Identifying and discussing trends in published data or results
• - Identifying and explaining the impact of common features (study populations, interventions, etc.) that appear frequently in the literature
• - Explaining controversies, disputes, or central issues in the literature that are relevant to your research question
• - Identifying gaps in the literature, where more research is needed
• - Establishing the discussion to which your own research contributes and demonstrating the value of your contribution

Essentially, you're telling your reader where they are (and where you are) in the scholarly conversation about your project.

Synthesis: How do I do it?

Synthesis, step by step.

This is what you need to do  before  you write your review.

• Identify and clearly describe your research question (you may find the Formulating PICOT Questions table at  the Additional Resources tab helpful).
• Collect sources relevant to your research question.
• Organize and describe the sources you've found -- your job is to identify what  types  of sources you've collected (reviews, clinical trials, etc.), identify their  purpose  (what are they measuring, testing, or trying to discover?), determine the  level of evidence  they represent (see the Levels of Evidence table at the Additional Resources tab ), and briefly explain their  major findings . Use a Research Table to document this step.
• Study the information you've put in your Research Table and examine your collected sources, looking for  similarities  and  differences . Pay particular attention to  populations ,   methods  (especially relative to levels of evidence), and  findings .
• Analyze what you learn in (4) using a tool like a Synthesis Table. Your goal is to identify relevant themes, trends, gaps, and issues in the research.  Your literature review will collect the results of this analysis and explain them in relation to your research question.

Analysis tips

• - Sometimes, what you  don't  find in the literature is as important as what you do find -- look for questions that the existing research hasn't answered yet.
• - If any of the sources you've collected refer to or respond to each other, keep an eye on how they're related -- it may provide a clue as to whether or not study results have been successfully replicated.
• - Sorting your collected sources by level of evidence can provide valuable insight into how a particular topic has been covered, and it may help you to identify gaps worth addressing in your own work.
• << Previous: What is a Literature Review?
• Next: Using Research & Synthesis Tables >>
• Last Updated: Sep 26, 2023 12:06 PM
• URL: https://usi.libguides.com/literature-review-basics

Literature Review How To

• Things To Consider
• Synthesizing Sources
• Video Tutorials
• Books On Literature Reviews

What is Synthesis

What is Synthesis? Synthesis writing is a form of analysis related to comparison and contrast, classification and division. On a basic level, synthesis requires the writer to pull together two or more summaries, looking for themes in each text. In synthesis, you search for the links between various materials in order to make your point. Most advanced academic writing, including literature reviews, relies heavily on synthesis. (Temple University Writing Center)  

How To Synthesize Sources in a Literature Review

Literature reviews synthesize large amounts of information and present it in a coherent, organized fashion. In a literature review you will be combining material from several texts to create a new text – your literature review.

You will use common points among the sources you have gathered to help you synthesize the material. This will help ensure that your literature review is organized by subtopic, not by source. This means various authors' names can appear and reappear throughout the literature review, and each paragraph will mention several different authors. 

When you shift from writing summaries of the content of a source to synthesizing content from sources, there is a number things you must keep in mind: 

• Look for specific connections and or links between your sources and how those relate to your thesis or question.
• When writing and organizing your literature review be aware that your readers need to understand how and why the information from the different sources overlap.
• Organize your literature review by the themes you find within your sources or themes you have identified. 
• << Previous: Things To Consider
• Next: Video Tutorials >>
• Last Updated: Nov 30, 2018 4:51 PM
• URL: https://libguides.csun.edu/literature-review

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How to undertake a literature search: a step-by-step guide

Affiliation.

• 1 Literature Search Specialist, Library and Archive Service, Royal College of Nursing, London.
• PMID: 32279549
• DOI: 10.12968/bjon.2020.29.7.431

Undertaking a literature search can be a daunting prospect. Breaking the exercise down into smaller steps will make the process more manageable. This article suggests 10 steps that will help readers complete this task, from identifying key concepts to choosing databases for the search and saving the results and search strategy. It discusses each of the steps in a little more detail, with examples and suggestions on where to get help. This structured approach will help readers obtain a more focused set of results and, ultimately, save time and effort.

Keywords: Databases; Literature review; Literature search; Reference management software; Research questions; Search strategy.

• Databases, Bibliographic*
• Information Storage and Retrieval / methods*
• Nursing Research
• Review Literature as Topic*

Literature Searching

In this guide.

• Introduction
• Steps for searching the literature in PubMed
• Step 1 - Formulate a search question
• Step 2- Identify primary concepts and gather synonyms
• Step 3 - Locate subject headings (MeSH)
• Step 4 - Combine concepts using Boolean operators
• Step 5 - Refine search terms and search in PubMed
• Step 6 - Apply limits

Steps for Searching the Literature

Searching is an iterative process and often requires re-evaluation and testing by adding or changing keywords and the ways they relate to each other. To guide your search development, you can follow the search steps below. For more information on each step, navigate to its matching tab on the right menu. 

1. Formulate a clear, well-defined, answerable search question

Generally, the basic literature search process begins with formulating a clear, well-defined research question. Asking the right research question is essential to creating an effective search. Your research question(s) must be well-defined and answerable. If the question is too broad, your search will yield more information than you can possibly look through.

2. Identify primary concepts and gather synonyms

Your research question will also help identify the primary search concepts. This will allow you to think about how you want the concepts to relate to each other. Since different authors use different terminology to refer to the same concept, you will need to gather synonyms and all the ways authors might express them. However, it is important to balance the terms so that the synonyms do not go beyond the scope of how you've defined them.

3. Locate subject headings (MeSH)

Subject databases like PubMed use 'controlled vocabularies' made up of subject headings that are preassigned to indexed articles that share a similar topic. These subject headings are organized hierarchically within a family tree of broader and narrower concepts. In PubMed and MEDLINE, the subject headings are called Medical Subject Headings (MeSH). By including MeSH terms in your search, you will not have to think about word variations, word endings, plural or singular forms, or synonyms. Some topics or concepts may even have more than one appropriate MeSH term. There are also times when a topic or concept may not have a MeSH term. 

4. Combine concepts using Boolean operators AND/OR

Once you have identified your search concepts, synonyms, and MeSH terms, you'll need to put them together using nesting and Boolean operators (e.g. AND, OR, NOT). Nesting uses parentheses to put search terms into groups. Boolean operators are used to combine similar and different concepts into one query. 

5. Refine search terms and search in PubMed

There are various database search tactics you can use, such as field tags to limit the search to certain fields, quotation marks for phrase searching, and proximity operators to search a number of spaces between terms to refine your search terms. The constructed search string is ready to be pasted into PubMed. 

6. Apply limits (optional)

If you're getting too many results, you can further refine your search results by using limits on the left box of the results page. Limits allow you to narrow your search by a number of facets such as year, journal name, article type, language, age, etc. 

Depending on the nature of the literature review, the complexity and comprehensiveness of the search strategies and the choice of databases can be different. Please contact the Lane Librarians if you have any questions. 

The type of information you gather is influenced by the type of information source or database you select to search. Bibliographic databases contain references to published literature, such as journal articles, conference abstracts, books, reports, government and legal publications, and patents. Literature reviews typically synthesis indexed, peer-reviewed articles (i.e. works that generally represent the latest original research and have undergone rigorous expert screening before publication), and gray literature (i.e. materials not formally published by commercial publishers or peer-reviewed journals). PubMed offers a breadth of health sciences literature and is a good starting point to locate journal articles.

What is PubMed?

PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. Available to the public online since 1996, PubMed was developed and is maintained by the  National Center for Biotechnology Information (NCBI) , at the  U.S. National Library of Medicine (NLM) , located at the  National Institutes of Health (NIH) .

MEDLINE is the National Library of Medicine’s (NLM) premier bibliographic database that contains more than 27 million references to journal articles from more than 5,200 worldwide journals in life sciences with a concentration on biomedicine. The Literature Selection Technica Review Committee (LSTRC) reviews and selects journals for MEDLINE based on the research quality and impact of the journals. A distinctive feature of MEDLINE is that the records are indexed with NLM  Medical Subject Headings  (MeSH).

PubMed also contains citations for  PubMed Central (PMC)  articles. PMC is a full-text archive that includes articles from journals reviewed and selected by NLM for archiving (current and historical), as well as individual articles collected for archiving in compliance with funder policies.  PubMed allows users to search keywords in the bibliographic data, but not the full text of the PMC articles.

How to Access PubMed?

To access PubMed, go to the Lane Library homepage and click PubMed in "Top Resources" on the left. This PubMed link is coded with Find Fulltext @ Lane Library Stanford that links you to Lane's full-text articles online. 

• << Previous: Introduction
• Next: Step 1 - Formulate a search question >>
• Last Updated: Jan 9, 2024 10:30 AM
• URL: https://laneguides.stanford.edu/LitSearch

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Shimberg Health Sciences Library Florida Blue Health Knowledge Exchange

Shimberg health sciences library & florida blue health knowledge exchange, usf health libraries hours of operation, evidence synthesis / systematic reviews.

• So you want to do a systematic review
• What Review is Right for You?
• Other Review Types
• Manuals and Standards

SR Search Tools

• Cochrane Handbook Chapter 4: Searching for and selecting studies
• Developing a Search Strategy webinar (Covidence)
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• Prisma 2020 Checklist
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• USF Health Libraries Guide: How to Improve your searches
• Word Frequency Analyser from SR-Accelerator
• Yale MeSH Analyzer

Disclaimer:  While we are happy to advise on developing systematic review searches, we may not have the capacity to create or perform the search for you.

Identify databases and search terms

• Identify databases to conduct your search

You should plan to search at least 3 databases. Most reviewers expect to see Medline (either via PubMed or Ovid) as one of the databases for health topics. Additional databases should be included based on your subject area. For a list of all available databases, consult the USF Health Libraries A to Z database list. 

• Identify search terms to conduct your search

Searches for a systematic review need to be both comprehensive (prioritizing sensitivity over specificity) and reproducible . To make your search comprehensive, identify both key words and controlled vocabulary to describe the main concepts of your question.

• Develop search strategies for each database

Combine terms using appropriate Boolean operators and subject headings (if applicable) for every database. Searches should be as similar as possible between the database.

Consider meeting with a librarian

No matter how experienced you are in searching PubMed and the medical literature, you will likely need help creating a search strategy that meets the guidelines for evidence synthesis in the health sciences. In fact, both the Cochrane Handbook and the Institute of Medicine recommend including a librarian trained in systematic review searching on your team.  

While this may not be possible, you may wish to consult with a librarian early in the process to ensure that you do not miss critical terms and databases in your search. Once you have developed your search strategy, you may also wish to request that a librarian conduct a peer review of your strategy. This will ensure that your review is in compliance with Peer Review of Electronic Search Strategies (PRESS) guidelines for systematic reviews.

• Make a Systematic Review Consult appointment with a librarian Set up an appointment to meet with a health librarian. Select Systematic Review Consult and upload your protocol. This will ensure that your appointment time is most effective. Please note that a systematic review consult does not mean that the librarian is automatically a part of your systematic review team.
• PRESS Peer Review of Electronic Search Strategies: 2015 Guideline Statement McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 Guideline Statement. J Clin Epidemiol. 2016;75:40-46. doi:10.1016/j.jclinepi.2016.01.021

Conduct searches

• Run each search in the databases you selected, documenting your search strategy for each one. You should include these in your manuscript, typically as an appendix.
• clinical trial registries
• conference proceedings and reports
• white papers
• theses and dissertations
• For more information on grey literature, see the USF Health Libraries "Grey Literature" guide.

Record numbers in a PRISMA flowchart

The PRISMA diagram shows the flow of records through the phases of a systematic review. It maps the number of records identified, included and excluded, record sources, and the reasons for exclusions. Different templates are available depending on the type of review (new or updated) and sources used in the review.

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• Open access
• Published: 14 August 2018

Defining the process to literature searching in systematic reviews: a literature review of guidance and supporting studies

• Chris Cooper   ORCID: orcid.org/0000-0003-0864-5607 1 ,
• Andrew Booth 2 ,
• Jo Varley-Campbell 1 ,
• Nicky Britten 3 &
• Ruth Garside 4  

BMC Medical Research Methodology volume  18 , Article number:  85 ( 2018 ) Cite this article

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Systematic literature searching is recognised as a critical component of the systematic review process. It involves a systematic search for studies and aims for a transparent report of study identification, leaving readers clear about what was done to identify studies, and how the findings of the review are situated in the relevant evidence.

Information specialists and review teams appear to work from a shared and tacit model of the literature search process. How this tacit model has developed and evolved is unclear, and it has not been explicitly examined before.

The purpose of this review is to determine if a shared model of the literature searching process can be detected across systematic review guidance documents and, if so, how this process is reported in the guidance and supported by published studies.

A literature review.

Two types of literature were reviewed: guidance and published studies. Nine guidance documents were identified, including: The Cochrane and Campbell Handbooks. Published studies were identified through ‘pearl growing’, citation chasing, a search of PubMed using the systematic review methods filter, and the authors’ topic knowledge.

The relevant sections within each guidance document were then read and re-read, with the aim of determining key methodological stages. Methodological stages were identified and defined. This data was reviewed to identify agreements and areas of unique guidance between guidance documents. Consensus across multiple guidance documents was used to inform selection of ‘key stages’ in the process of literature searching.

Eight key stages were determined relating specifically to literature searching in systematic reviews. They were: who should literature search, aims and purpose of literature searching, preparation, the search strategy, searching databases, supplementary searching, managing references and reporting the search process.

Conclusions

Eight key stages to the process of literature searching in systematic reviews were identified. These key stages are consistently reported in the nine guidance documents, suggesting consensus on the key stages of literature searching, and therefore the process of literature searching as a whole, in systematic reviews. Further research to determine the suitability of using the same process of literature searching for all types of systematic review is indicated.

Peer Review reports

Systematic literature searching is recognised as a critical component of the systematic review process. It involves a systematic search for studies and aims for a transparent report of study identification, leaving review stakeholders clear about what was done to identify studies, and how the findings of the review are situated in the relevant evidence.

Information specialists and review teams appear to work from a shared and tacit model of the literature search process. How this tacit model has developed and evolved is unclear, and it has not been explicitly examined before. This is in contrast to the information science literature, which has developed information processing models as an explicit basis for dialogue and empirical testing. Without an explicit model, research in the process of systematic literature searching will remain immature and potentially uneven, and the development of shared information models will be assumed but never articulated.

One way of developing such a conceptual model is by formally examining the implicit “programme theory” as embodied in key methodological texts. The aim of this review is therefore to determine if a shared model of the literature searching process in systematic reviews can be detected across guidance documents and, if so, how this process is reported and supported.

Identifying guidance

Key texts (henceforth referred to as “guidance”) were identified based upon their accessibility to, and prominence within, United Kingdom systematic reviewing practice. The United Kingdom occupies a prominent position in the science of health information retrieval, as quantified by such objective measures as the authorship of papers, the number of Cochrane groups based in the UK, membership and leadership of groups such as the Cochrane Information Retrieval Methods Group, the HTA-I Information Specialists’ Group and historic association with such centres as the UK Cochrane Centre, the NHS Centre for Reviews and Dissemination, the Centre for Evidence Based Medicine and the National Institute for Clinical Excellence (NICE). Coupled with the linguistic dominance of English within medical and health science and the science of systematic reviews more generally, this offers a justification for a purposive sample that favours UK, European and Australian guidance documents.

Nine guidance documents were identified. These documents provide guidance for different types of reviews, namely: reviews of interventions, reviews of health technologies, reviews of qualitative research studies, reviews of social science topics, and reviews to inform guidance.

Whilst these guidance documents occasionally offer additional guidance on other types of systematic reviews, we have focused on the core and stated aims of these documents as they relate to literature searching. Table  1 sets out: the guidance document, the version audited, their core stated focus, and a bibliographical pointer to the main guidance relating to literature searching.

Once a list of key guidance documents was determined, it was checked by six senior information professionals based in the UK for relevance to current literature searching in systematic reviews.

Identifying supporting studies

In addition to identifying guidance, the authors sought to populate an evidence base of supporting studies (henceforth referred to as “studies”) that contribute to existing search practice. Studies were first identified by the authors from their knowledge on this topic area and, subsequently, through systematic citation chasing key studies (‘pearls’ [ 1 ]) located within each key stage of the search process. These studies are identified in Additional file  1 : Appendix Table 1. Citation chasing was conducted by analysing the bibliography of references for each study (backwards citation chasing) and through Google Scholar (forward citation chasing). A search of PubMed using the systematic review methods filter was undertaken in August 2017 (see Additional file 1 ). The search terms used were: (literature search*[Title/Abstract]) AND sysrev_methods[sb] and 586 results were returned. These results were sifted for relevance to the key stages in Fig.  1 by CC.

The key stages of literature search guidance as identified from nine key texts

Extracting the data

To reveal the implicit process of literature searching within each guidance document, the relevant sections (chapters) on literature searching were read and re-read, with the aim of determining key methodological stages. We defined a key methodological stage as a distinct step in the overall process for which specific guidance is reported, and action is taken, that collectively would result in a completed literature search.

The chapter or section sub-heading for each methodological stage was extracted into a table using the exact language as reported in each guidance document. The lead author (CC) then read and re-read these data, and the paragraphs of the document to which the headings referred, summarising section details. This table was then reviewed, using comparison and contrast to identify agreements and areas of unique guidance. Consensus across multiple guidelines was used to inform selection of ‘key stages’ in the process of literature searching.

Having determined the key stages to literature searching, we then read and re-read the sections relating to literature searching again, extracting specific detail relating to the methodological process of literature searching within each key stage. Again, the guidance was then read and re-read, first on a document-by-document-basis and, secondly, across all the documents above, to identify both commonalities and areas of unique guidance.

Results and discussion

Our findings.

We were able to identify consensus across the guidance on literature searching for systematic reviews suggesting a shared implicit model within the information retrieval community. Whilst the structure of the guidance varies between documents, the same key stages are reported, even where the core focus of each document is different. We were able to identify specific areas of unique guidance, where a document reported guidance not summarised in other documents, together with areas of consensus across guidance.

Unique guidance

Only one document provided guidance on the topic of when to stop searching [ 2 ]. This guidance from 2005 anticipates a topic of increasing importance with the current interest in time-limited (i.e. “rapid”) reviews. Quality assurance (or peer review) of literature searches was only covered in two guidance documents [ 3 , 4 ]. This topic has emerged as increasingly important as indicated by the development of the PRESS instrument [ 5 ]. Text mining was discussed in four guidance documents [ 4 , 6 , 7 , 8 ] where the automation of some manual review work may offer efficiencies in literature searching [ 8 ].

Agreement between guidance: Defining the key stages of literature searching

Where there was agreement on the process, we determined that this constituted a key stage in the process of literature searching to inform systematic reviews.

From the guidance, we determined eight key stages that relate specifically to literature searching in systematic reviews. These are summarised at Fig. 1 . The data extraction table to inform Fig. 1 is reported in Table  2 . Table 2 reports the areas of common agreement and it demonstrates that the language used to describe key stages and processes varies significantly between guidance documents.

For each key stage, we set out the specific guidance, followed by discussion on how this guidance is situated within the wider literature.

Key stage one: Deciding who should undertake the literature search

The guidance.

Eight documents provided guidance on who should undertake literature searching in systematic reviews [ 2 , 4 , 6 , 7 , 8 , 9 , 10 , 11 ]. The guidance affirms that people with relevant expertise of literature searching should ‘ideally’ be included within the review team [ 6 ]. Information specialists (or information scientists), librarians or trial search co-ordinators (TSCs) are indicated as appropriate researchers in six guidance documents [ 2 , 7 , 8 , 9 , 10 , 11 ].

How the guidance corresponds to the published studies

The guidance is consistent with studies that call for the involvement of information specialists and librarians in systematic reviews [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ] and which demonstrate how their training as ‘expert searchers’ and ‘analysers and organisers of data’ can be put to good use [ 13 ] in a variety of roles [ 12 , 16 , 20 , 21 , 24 , 25 , 26 ]. These arguments make sense in the context of the aims and purposes of literature searching in systematic reviews, explored below. The need for ‘thorough’ and ‘replicable’ literature searches was fundamental to the guidance and recurs in key stage two. Studies have found poor reporting, and a lack of replicable literature searches, to be a weakness in systematic reviews [ 17 , 18 , 27 , 28 ] and they argue that involvement of information specialists/ librarians would be associated with better reporting and better quality literature searching. Indeed, Meert et al. [ 29 ] demonstrated that involving a librarian as a co-author to a systematic review correlated with a higher score in the literature searching component of a systematic review [ 29 ]. As ‘new styles’ of rapid and scoping reviews emerge, where decisions on how to search are more iterative and creative, a clear role is made here too [ 30 ].

Knowing where to search for studies was noted as important in the guidance, with no agreement as to the appropriate number of databases to be searched [ 2 , 6 ]. Database (and resource selection more broadly) is acknowledged as a relevant key skill of information specialists and librarians [ 12 , 15 , 16 , 31 ].

Whilst arguments for including information specialists and librarians in the process of systematic review might be considered self-evident, Koffel and Rethlefsen [ 31 ] have questioned if the necessary involvement is actually happening [ 31 ].

Key stage two: Determining the aim and purpose of a literature search

The aim: Five of the nine guidance documents use adjectives such as ‘thorough’, ‘comprehensive’, ‘transparent’ and ‘reproducible’ to define the aim of literature searching [ 6 , 7 , 8 , 9 , 10 ]. Analogous phrases were present in a further three guidance documents, namely: ‘to identify the best available evidence’ [ 4 ] or ‘the aim of the literature search is not to retrieve everything. It is to retrieve everything of relevance’ [ 2 ] or ‘A systematic literature search aims to identify all publications relevant to the particular research question’ [ 3 ]. The Joanna Briggs Institute reviewers’ manual was the only guidance document where a clear statement on the aim of literature searching could not be identified. The purpose of literature searching was defined in three guidance documents, namely to minimise bias in the resultant review [ 6 , 8 , 10 ]. Accordingly, eight of nine documents clearly asserted that thorough and comprehensive literature searches are required as a potential mechanism for minimising bias.

The need for thorough and comprehensive literature searches appears as uniform within the eight guidance documents that describe approaches to literature searching in systematic reviews of effectiveness. Reviews of effectiveness (of intervention or cost), accuracy and prognosis, require thorough and comprehensive literature searches to transparently produce a reliable estimate of intervention effect. The belief that all relevant studies have been ‘comprehensively’ identified, and that this process has been ‘transparently’ reported, increases confidence in the estimate of effect and the conclusions that can be drawn [ 32 ]. The supporting literature exploring the need for comprehensive literature searches focuses almost exclusively on reviews of intervention effectiveness and meta-analysis. Different ‘styles’ of review may have different standards however; the alternative, offered by purposive sampling, has been suggested in the specific context of qualitative evidence syntheses [ 33 ].

What is a comprehensive literature search?

Whilst the guidance calls for thorough and comprehensive literature searches, it lacks clarity on what constitutes a thorough and comprehensive literature search, beyond the implication that all of the literature search methods in Table 2 should be used to identify studies. Egger et al. [ 34 ], in an empirical study evaluating the importance of comprehensive literature searches for trials in systematic reviews, defined a comprehensive search for trials as:

a search not restricted to English language;

where Cochrane CENTRAL or at least two other electronic databases had been searched (such as MEDLINE or EMBASE); and

at least one of the following search methods has been used to identify unpublished trials: searches for (I) conference abstracts, (ii) theses, (iii) trials registers; and (iv) contacts with experts in the field [ 34 ].

Tricco et al. (2008) used a similar threshold of bibliographic database searching AND a supplementary search method in a review when examining the risk of bias in systematic reviews. Their criteria were: one database (limited using the Cochrane Highly Sensitive Search Strategy (HSSS)) and handsearching [ 35 ].

Together with the guidance, this would suggest that comprehensive literature searching requires the use of BOTH bibliographic database searching AND supplementary search methods.

Comprehensiveness in literature searching, in the sense of how much searching should be undertaken, remains unclear. Egger et al. recommend that ‘investigators should consider the type of literature search and degree of comprehension that is appropriate for the review in question, taking into account budget and time constraints’ [ 34 ]. This view tallies with the Cochrane Handbook, which stipulates clearly, that study identification should be undertaken ‘within resource limits’ [ 9 ]. This would suggest that the limitations to comprehension are recognised but it raises questions on how this is decided and reported [ 36 ].

What is the point of comprehensive literature searching?

The purpose of thorough and comprehensive literature searches is to avoid missing key studies and to minimize bias [ 6 , 8 , 10 , 34 , 37 , 38 , 39 ] since a systematic review based only on published (or easily accessible) studies may have an exaggerated effect size [ 35 ]. Felson (1992) sets out potential biases that could affect the estimate of effect in a meta-analysis [ 40 ] and Tricco et al. summarize the evidence concerning bias and confounding in systematic reviews [ 35 ]. Egger et al. point to non-publication of studies, publication bias, language bias and MEDLINE bias, as key biases [ 34 , 35 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Comprehensive searches are not the sole factor to mitigate these biases but their contribution is thought to be significant [ 2 , 32 , 34 ]. Fehrmann (2011) suggests that ‘the search process being described in detail’ and that, where standard comprehensive search techniques have been applied, increases confidence in the search results [ 32 ].

Does comprehensive literature searching work?

Egger et al., and other study authors, have demonstrated a change in the estimate of intervention effectiveness where relevant studies were excluded from meta-analysis [ 34 , 47 ]. This would suggest that missing studies in literature searching alters the reliability of effectiveness estimates. This is an argument for comprehensive literature searching. Conversely, Egger et al. found that ‘comprehensive’ searches still missed studies and that comprehensive searches could, in fact, introduce bias into a review rather than preventing it, through the identification of low quality studies then being included in the meta-analysis [ 34 ]. Studies query if identifying and including low quality or grey literature studies changes the estimate of effect [ 43 , 48 ] and question if time is better invested updating systematic reviews rather than searching for unpublished studies [ 49 ], or mapping studies for review as opposed to aiming for high sensitivity in literature searching [ 50 ].

Aim and purpose beyond reviews of effectiveness

The need for comprehensive literature searches is less certain in reviews of qualitative studies, and for reviews where a comprehensive identification of studies is difficult to achieve (for example, in Public health) [ 33 , 51 , 52 , 53 , 54 , 55 ]. Literature searching for qualitative studies, and in public health topics, typically generates a greater number of studies to sift than in reviews of effectiveness [ 39 ] and demonstrating the ‘value’ of studies identified or missed is harder [ 56 ], since the study data do not typically support meta-analysis. Nussbaumer-Streit et al. (2016) have registered a review protocol to assess whether abbreviated literature searches (as opposed to comprehensive literature searches) has an impact on conclusions across multiple bodies of evidence, not only on effect estimates [ 57 ] which may develop this understanding. It may be that decision makers and users of systematic reviews are willing to trade the certainty from a comprehensive literature search and systematic review in exchange for different approaches to evidence synthesis [ 58 ], and that comprehensive literature searches are not necessarily a marker of literature search quality, as previously thought [ 36 ]. Different approaches to literature searching [ 37 , 38 , 59 , 60 , 61 , 62 ] and developing the concept of when to stop searching are important areas for further study [ 36 , 59 ].

The study by Nussbaumer-Streit et al. has been published since the submission of this literature review [ 63 ]. Nussbaumer-Streit et al. (2018) conclude that abbreviated literature searches are viable options for rapid evidence syntheses, if decision-makers are willing to trade the certainty from a comprehensive literature search and systematic review, but that decision-making which demands detailed scrutiny should still be based on comprehensive literature searches [ 63 ].

Key stage three: Preparing for the literature search

Six documents provided guidance on preparing for a literature search [ 2 , 3 , 6 , 7 , 9 , 10 ]. The Cochrane Handbook clearly stated that Cochrane authors (i.e. researchers) should seek advice from a trial search co-ordinator (i.e. a person with specific skills in literature searching) ‘before’ starting a literature search [ 9 ].

Two key tasks were perceptible in preparing for a literature searching [ 2 , 6 , 7 , 10 , 11 ]. First, to determine if there are any existing or on-going reviews, or if a new review is justified [ 6 , 11 ]; and, secondly, to develop an initial literature search strategy to estimate the volume of relevant literature (and quality of a small sample of relevant studies [ 10 ]) and indicate the resources required for literature searching and the review of the studies that follows [ 7 , 10 ].

Three documents summarised guidance on where to search to determine if a new review was justified [ 2 , 6 , 11 ]. These focused on searching databases of systematic reviews (The Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE)), institutional registries (including PROSPERO), and MEDLINE [ 6 , 11 ]. It is worth noting, however, that as of 2015, DARE (and NHS EEDs) are no longer being updated and so the relevance of this (these) resource(s) will diminish over-time [ 64 ]. One guidance document, ‘Systematic reviews in the Social Sciences’, noted, however, that databases are not the only source of information and unpublished reports, conference proceeding and grey literature may also be required, depending on the nature of the review question [ 2 ].

Two documents reported clearly that this preparation (or ‘scoping’) exercise should be undertaken before the actual search strategy is developed [ 7 , 10 ]).

The guidance offers the best available source on preparing the literature search with the published studies not typically reporting how their scoping informed the development of their search strategies nor how their search approaches were developed. Text mining has been proposed as a technique to develop search strategies in the scoping stages of a review although this work is still exploratory [ 65 ]. ‘Clustering documents’ and word frequency analysis have also been tested to identify search terms and studies for review [ 66 , 67 ]. Preparing for literature searches and scoping constitutes an area for future research.

Key stage four: Designing the search strategy

The Population, Intervention, Comparator, Outcome (PICO) structure was the commonly reported structure promoted to design a literature search strategy. Five documents suggested that the eligibility criteria or review question will determine which concepts of PICO will be populated to develop the search strategy [ 1 , 4 , 7 , 8 , 9 ]. The NICE handbook promoted multiple structures, namely PICO, SPICE (Setting, Perspective, Intervention, Comparison, Evaluation) and multi-stranded approaches [ 4 ].

With the exclusion of The Joanna Briggs Institute reviewers’ manual, the guidance offered detail on selecting key search terms, synonyms, Boolean language, selecting database indexing terms and combining search terms. The CEE handbook suggested that ‘search terms may be compiled with the help of the commissioning organisation and stakeholders’ [ 10 ].

The use of limits, such as language or date limits, were discussed in all documents [ 2 , 3 , 4 , 6 , 7 , 8 , 9 , 10 , 11 ].

Search strategy structure

The guidance typically relates to reviews of intervention effectiveness so PICO – with its focus on intervention and comparator - is the dominant model used to structure literature search strategies [ 68 ]. PICOs – where the S denotes study design - is also commonly used in effectiveness reviews [ 6 , 68 ]. As the NICE handbook notes, alternative models to structure literature search strategies have been developed and tested. Booth provides an overview on formulating questions for evidence based practice [ 69 ] and has developed a number of alternatives to the PICO structure, namely: BeHEMoTh (Behaviour of interest; Health context; Exclusions; Models or Theories) for use when systematically identifying theory [ 55 ]; SPICE (Setting, Perspective, Intervention, Comparison, Evaluation) for identification of social science and evaluation studies [ 69 ] and, working with Cooke and colleagues, SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) [ 70 ]. SPIDER has been compared to PICO and PICOs in a study by Methley et al. [ 68 ].

The NICE handbook also suggests the use of multi-stranded approaches to developing literature search strategies [ 4 ]. Glanville developed this idea in a study by Whitting et al. [ 71 ] and a worked example of this approach is included in the development of a search filter by Cooper et al. [ 72 ].

Writing search strategies: Conceptual and objective approaches

Hausner et al. [ 73 ] provide guidance on writing literature search strategies, delineating between conceptually and objectively derived approaches. The conceptual approach, advocated by and explained in the guidance documents, relies on the expertise of the literature searcher to identify key search terms and then develop key terms to include synonyms and controlled syntax. Hausner and colleagues set out the objective approach [ 73 ] and describe what may be done to validate it [ 74 ].

The use of limits

The guidance documents offer direction on the use of limits within a literature search. Limits can be used to focus literature searching to specific study designs or by other markers (such as by date) which limits the number of studies returned by a literature search. The use of limits should be described and the implications explored [ 34 ] since limiting literature searching can introduce bias (explored above). Craven et al. have suggested the use of a supporting narrative to explain decisions made in the process of developing literature searches and this advice would usefully capture decisions on the use of search limits [ 75 ].

Key stage five: Determining the process of literature searching and deciding where to search (bibliographic database searching)

Table 2 summarises the process of literature searching as reported in each guidance document. Searching bibliographic databases was consistently reported as the ‘first step’ to literature searching in all nine guidance documents.

Three documents reported specific guidance on where to search, in each case specific to the type of review their guidance informed, and as a minimum requirement [ 4 , 9 , 11 ]. Seven of the key guidance documents suggest that the selection of bibliographic databases depends on the topic of review [ 2 , 3 , 4 , 6 , 7 , 8 , 10 ], with two documents noting the absence of an agreed standard on what constitutes an acceptable number of databases searched [ 2 , 6 ].

The guidance documents summarise ‘how to’ search bibliographic databases in detail and this guidance is further contextualised above in terms of developing the search strategy. The documents provide guidance of selecting bibliographic databases, in some cases stating acceptable minima (i.e. The Cochrane Handbook states Cochrane CENTRAL, MEDLINE and EMBASE), and in other cases simply listing bibliographic database available to search. Studies have explored the value in searching specific bibliographic databases, with Wright et al. (2015) noting the contribution of CINAHL in identifying qualitative studies [ 76 ], Beckles et al. (2013) questioning the contribution of CINAHL to identifying clinical studies for guideline development [ 77 ], and Cooper et al. (2015) exploring the role of UK-focused bibliographic databases to identify UK-relevant studies [ 78 ]. The host of the database (e.g. OVID or ProQuest) has been shown to alter the search returns offered. Younger and Boddy [ 79 ] report differing search returns from the same database (AMED) but where the ‘host’ was different [ 79 ].

The average number of bibliographic database searched in systematic reviews has risen in the period 1994–2014 (from 1 to 4) [ 80 ] but there remains (as attested to by the guidance) no consensus on what constitutes an acceptable number of databases searched [ 48 ]. This is perhaps because thinking about the number of databases searched is the wrong question, researchers should be focused on which databases were searched and why, and which databases were not searched and why. The discussion should re-orientate to the differential value of sources but researchers need to think about how to report this in studies to allow findings to be generalised. Bethel (2017) has proposed ‘search summaries’, completed by the literature searcher, to record where included studies were identified, whether from database (and which databases specifically) or supplementary search methods [ 81 ]. Search summaries document both yield and accuracy of searches, which could prospectively inform resource use and decisions to search or not to search specific databases in topic areas. The prospective use of such data presupposes, however, that past searches are a potential predictor of future search performance (i.e. that each topic is to be considered representative and not unique). In offering a body of practice, this data would be of greater practicable use than current studies which are considered as little more than individual case studies [ 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ].

When to database search is another question posed in the literature. Beyer et al. [ 91 ] report that databases can be prioritised for literature searching which, whilst not addressing the question of which databases to search, may at least bring clarity as to which databases to search first [ 91 ]. Paradoxically, this links to studies that suggest PubMed should be searched in addition to MEDLINE (OVID interface) since this improves the currency of systematic reviews [ 92 , 93 ]. Cooper et al. (2017) have tested the idea of database searching not as a primary search method (as suggested in the guidance) but as a supplementary search method in order to manage the volume of studies identified for an environmental effectiveness systematic review. Their case study compared the effectiveness of database searching versus a protocol using supplementary search methods and found that the latter identified more relevant studies for review than searching bibliographic databases [ 94 ].

Key stage six: Determining the process of literature searching and deciding where to search (supplementary search methods)

Table 2 also summaries the process of literature searching which follows bibliographic database searching. As Table 2 sets out, guidance that supplementary literature search methods should be used in systematic reviews recurs across documents, but the order in which these methods are used, and the extent to which they are used, varies. We noted inconsistency in the labelling of supplementary search methods between guidance documents.

Rather than focus on the guidance on how to use the methods (which has been summarised in a recent review [ 95 ]), we focus on the aim or purpose of supplementary search methods.

The Cochrane Handbook reported that ‘efforts’ to identify unpublished studies should be made [ 9 ]. Four guidance documents [ 2 , 3 , 6 , 9 ] acknowledged that searching beyond bibliographic databases was necessary since ‘databases are not the only source of literature’ [ 2 ]. Only one document reported any guidance on determining when to use supplementary methods. The IQWiG handbook reported that the use of handsearching (in their example) could be determined on a ‘case-by-case basis’ which implies that the use of these methods is optional rather than mandatory. This is in contrast to the guidance (above) on bibliographic database searching.

The issue for supplementary search methods is similar in many ways to the issue of searching bibliographic databases: demonstrating value. The purpose and contribution of supplementary search methods in systematic reviews is increasingly acknowledged [ 37 , 61 , 62 , 96 , 97 , 98 , 99 , 100 , 101 ] but understanding the value of the search methods to identify studies and data is unclear. In a recently published review, Cooper et al. (2017) reviewed the literature on supplementary search methods looking to determine the advantages, disadvantages and resource implications of using supplementary search methods [ 95 ]. This review also summarises the key guidance and empirical studies and seeks to address the question on when to use these search methods and when not to [ 95 ]. The guidance is limited in this regard and, as Table 2 demonstrates, offers conflicting advice on the order of searching, and the extent to which these search methods should be used in systematic reviews.

Key stage seven: Managing the references

Five of the documents provided guidance on managing references, for example downloading, de-duplicating and managing the output of literature searches [ 2 , 4 , 6 , 8 , 10 ]. This guidance typically itemised available bibliographic management tools rather than offering guidance on how to use them specifically [ 2 , 4 , 6 , 8 ]. The CEE handbook provided guidance on importing data where no direct export option is available (e.g. web-searching) [ 10 ].

The literature on using bibliographic management tools is not large relative to the number of ‘how to’ videos on platforms such as YouTube (see for example [ 102 ]). These YouTube videos confirm the overall lack of ‘how to’ guidance identified in this study and offer useful instruction on managing references. Bramer et al. set out methods for de-duplicating data and reviewing references in Endnote [ 103 , 104 ] and Gall tests the direct search function within Endnote to access databases such as PubMed, finding a number of limitations [ 105 ]. Coar et al. and Ahmed et al. consider the role of the free-source tool, Zotero [ 106 , 107 ]. Managing references is a key administrative function in the process of review particularly for documenting searches in PRISMA guidance.

Key stage eight: Documenting the search

The Cochrane Handbook was the only guidance document to recommend a specific reporting guideline: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [ 9 ]. Six documents provided guidance on reporting the process of literature searching with specific criteria to report [ 3 , 4 , 6 , 8 , 9 , 10 ]. There was consensus on reporting: the databases searched (and the host searched by), the search strategies used, and any use of limits (e.g. date, language, search filters (The CRD handbook called for these limits to be justified [ 6 ])). Three guidance documents reported that the number of studies identified should be recorded [ 3 , 6 , 10 ]. The number of duplicates identified [ 10 ], the screening decisions [ 3 ], a comprehensive list of grey literature sources searched (and full detail for other supplementary search methods) [ 8 ], and an annotation of search terms tested but not used [ 4 ] were identified as unique items in four documents.

The Cochrane Handbook was the only guidance document to note that the full search strategies for each database should be included in the Additional file 1 of the review [ 9 ].

All guidance documents should ultimately deliver completed systematic reviews that fulfil the requirements of the PRISMA reporting guidelines [ 108 ]. The guidance broadly requires the reporting of data that corresponds with the requirements of the PRISMA statement although documents typically ask for diverse and additional items [ 108 ]. In 2008, Sampson et al. observed a lack of consensus on reporting search methods in systematic reviews [ 109 ] and this remains the case as of 2017, as evidenced in the guidance documents, and in spite of the publication of the PRISMA guidelines in 2009 [ 110 ]. It is unclear why the collective guidance does not more explicitly endorse adherence to the PRISMA guidance.

Reporting of literature searching is a key area in systematic reviews since it sets out clearly what was done and how the conclusions of the review can be believed [ 52 , 109 ]. Despite strong endorsement in the guidance documents, specifically supported in PRISMA guidance, and other related reporting standards too (such as ENTREQ for qualitative evidence synthesis, STROBE for reviews of observational studies), authors still highlight the prevalence of poor standards of literature search reporting [ 31 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 ]. To explore issues experienced by authors in reporting literature searches, and look at uptake of PRISMA, Radar et al. [ 120 ] surveyed over 260 review authors to determine common problems and their work summaries the practical aspects of reporting literature searching [ 120 ]. Atkinson et al. [ 121 ] have also analysed reporting standards for literature searching, summarising recommendations and gaps for reporting search strategies [ 121 ].

One area that is less well covered by the guidance, but nevertheless appears in this literature, is the quality appraisal or peer review of literature search strategies. The PRESS checklist is the most prominent and it aims to develop evidence-based guidelines to peer review of electronic search strategies [ 5 , 122 , 123 ]. A corresponding guideline for documentation of supplementary search methods does not yet exist although this idea is currently being explored.

How the reporting of the literature searching process corresponds to critical appraisal tools is an area for further research. In the survey undertaken by Radar et al. (2014), 86% of survey respondents (153/178) identified a need for further guidance on what aspects of the literature search process to report [ 120 ]. The PRISMA statement offers a brief summary of what to report but little practical guidance on how to report it [ 108 ]. Critical appraisal tools for systematic reviews, such as AMSTAR 2 (Shea et al. [ 124 ]) and ROBIS (Whiting et al. [ 125 ]), can usefully be read alongside PRISMA guidance, since they offer greater detail on how the reporting of the literature search will be appraised and, therefore, they offer a proxy on what to report [ 124 , 125 ]. Further research in the form of a study which undertakes a comparison between PRISMA and quality appraisal checklists for systematic reviews would seem to begin addressing the call, identified by Radar et al., for further guidance on what to report [ 120 ].

Limitations

Other handbooks exist.

A potential limitation of this literature review is the focus on guidance produced in Europe (the UK specifically) and Australia. We justify the decision for our selection of the nine guidance documents reviewed in this literature review in section “ Identifying guidance ”. In brief, these nine guidance documents were selected as the most relevant health care guidance that inform UK systematic reviewing practice, given that the UK occupies a prominent position in the science of health information retrieval. We acknowledge the existence of other guidance documents, such as those from North America (e.g. the Agency for Healthcare Research and Quality (AHRQ) [ 126 ], The Institute of Medicine [ 127 ] and the guidance and resources produced by the Canadian Agency for Drugs and Technologies in Health (CADTH) [ 128 ]). We comment further on this directly below.

The handbooks are potentially linked to one another

What is not clear is the extent to which the guidance documents inter-relate or provide guidance uniquely. The Cochrane Handbook, first published in 1994, is notably a key source of reference in guidance and systematic reviews beyond Cochrane reviews. It is not clear to what extent broadening the sample of guidance handbooks to include North American handbooks, and guidance handbooks from other relevant countries too, would alter the findings of this literature review or develop further support for the process model. Since we cannot be clear, we raise this as a potential limitation of this literature review. On our initial review of a sample of North American, and other, guidance documents (before selecting the guidance documents considered in this review), however, we do not consider that the inclusion of these further handbooks would alter significantly the findings of this literature review.

This is a literature review

A further limitation of this review was that the review of published studies is not a systematic review of the evidence for each key stage. It is possible that other relevant studies could help contribute to the exploration and development of the key stages identified in this review.

This literature review would appear to demonstrate the existence of a shared model of the literature searching process in systematic reviews. We call this model ‘the conventional approach’, since it appears to be common convention in nine different guidance documents.

The findings reported above reveal eight key stages in the process of literature searching for systematic reviews. These key stages are consistently reported in the nine guidance documents which suggests consensus on the key stages of literature searching, and therefore the process of literature searching as a whole, in systematic reviews.

In Table 2 , we demonstrate consensus regarding the application of literature search methods. All guidance documents distinguish between primary and supplementary search methods. Bibliographic database searching is consistently the first method of literature searching referenced in each guidance document. Whilst the guidance uniformly supports the use of supplementary search methods, there is little evidence for a consistent process with diverse guidance across documents. This may reflect differences in the core focus across each document, linked to differences in identifying effectiveness studies or qualitative studies, for instance.

Eight of the nine guidance documents reported on the aims of literature searching. The shared understanding was that literature searching should be thorough and comprehensive in its aim and that this process should be reported transparently so that that it could be reproduced. Whilst only three documents explicitly link this understanding to minimising bias, it is clear that comprehensive literature searching is implicitly linked to ‘not missing relevant studies’ which is approximately the same point.

Defining the key stages in this review helps categorise the scholarship available, and it prioritises areas for development or further study. The supporting studies on preparing for literature searching (key stage three, ‘preparation’) were, for example, comparatively few, and yet this key stage represents a decisive moment in literature searching for systematic reviews. It is where search strategy structure is determined, search terms are chosen or discarded, and the resources to be searched are selected. Information specialists, librarians and researchers, are well placed to develop these and other areas within the key stages we identify.

This review calls for further research to determine the suitability of using the conventional approach. The publication dates of the guidance documents which underpin the conventional approach may raise questions as to whether the process which they each report remains valid for current systematic literature searching. In addition, it may be useful to test whether it is desirable to use the same process model of literature searching for qualitative evidence synthesis as that for reviews of intervention effectiveness, which this literature review demonstrates is presently recommended best practice.

Abbreviations

Behaviour of interest; Health context; Exclusions; Models or Theories

Cochrane Database of Systematic Reviews

The Cochrane Central Register of Controlled Trials

Database of Abstracts of Reviews of Effects

Enhancing transparency in reporting the synthesis of qualitative research

Institute for Quality and Efficiency in Healthcare

National Institute for Clinical Excellence

Population, Intervention, Comparator, Outcome

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Setting, Perspective, Intervention, Comparison, Evaluation

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

STrengthening the Reporting of OBservational studies in Epidemiology

Trial Search Co-ordinators

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Acknowledgements

CC acknowledges the supervision offered by Professor Chris Hyde.

This publication forms a part of CC’s PhD. CC’s PhD was funded through the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme (Project Number 16/54/11). The open access fee for this publication was paid for by Exeter Medical School.

RG and NB were partially supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula.

The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

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CC conceived the idea for this study and wrote the first draft of the manuscript. CC discussed this publication in PhD supervision with AB and separately with JVC. CC revised the publication with input and comments from AB, JVC, RG and NB. All authors revised the manuscript prior to submission. All authors read and approved the final manuscript.

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Additional file 1:.

Appendix tables and PubMed search strategy. Key studies used for pearl growing per key stage, working data extraction tables and the PubMed search strategy. (DOCX 30 kb)

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Cooper, C., Booth, A., Varley-Campbell, J. et al. Defining the process to literature searching in systematic reviews: a literature review of guidance and supporting studies. BMC Med Res Methodol 18 , 85 (2018). https://doi.org/10.1186/s12874-018-0545-3

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Synthesizing Sources

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When you look for areas where your sources agree or disagree and try to draw broader conclusions about your topic based on what your sources say, you are engaging in synthesis. Writing a research paper usually requires synthesizing the available sources in order to provide new insight or a different perspective into your particular topic (as opposed to simply restating what each individual source says about your research topic).

Note that synthesizing is not the same as summarizing.  

• A summary restates the information in one or more sources without providing new insight or reaching new conclusions.
• A synthesis draws on multiple sources to reach a broader conclusion.

There are two types of syntheses: explanatory syntheses and argumentative syntheses . Explanatory syntheses seek to bring sources together to explain a perspective and the reasoning behind it. Argumentative syntheses seek to bring sources together to make an argument. Both types of synthesis involve looking for relationships between sources and drawing conclusions.

In order to successfully synthesize your sources, you might begin by grouping your sources by topic and looking for connections. For example, if you were researching the pros and cons of encouraging healthy eating in children, you would want to separate your sources to find which ones agree with each other and which ones disagree.

After you have a good idea of what your sources are saying, you want to construct your body paragraphs in a way that acknowledges different sources and highlights where you can draw new conclusions.

As you continue synthesizing, here are a few points to remember:

• Don’t force a relationship between sources if there isn’t one. Not all of your sources have to complement one another.
• Do your best to highlight the relationships between sources in very clear ways.
• Don’t ignore any outliers in your research. It’s important to take note of every perspective (even those that disagree with your broader conclusions).

Example Syntheses

Below are two examples of synthesis: one where synthesis is NOT utilized well, and one where it is.

Parents are always trying to find ways to encourage healthy eating in their children. Elena Pearl Ben-Joseph, a doctor and writer for KidsHealth , encourages parents to be role models for their children by not dieting or vocalizing concerns about their body image. The first popular diet began in 1863. William Banting named it the “Banting” diet after himself, and it consisted of eating fruits, vegetables, meat, and dry wine. Despite the fact that dieting has been around for over a hundred and fifty years, parents should not diet because it hinders children’s understanding of healthy eating.

In this sample paragraph, the paragraph begins with one idea then drastically shifts to another. Rather than comparing the sources, the author simply describes their content. This leads the paragraph to veer in an different direction at the end, and it prevents the paragraph from expressing any strong arguments or conclusions.

An example of a stronger synthesis can be found below.

Parents are always trying to find ways to encourage healthy eating in their children. Different scientists and educators have different strategies for promoting a well-rounded diet while still encouraging body positivity in children. David R. Just and Joseph Price suggest in their article “Using Incentives to Encourage Healthy Eating in Children” that children are more likely to eat fruits and vegetables if they are given a reward (855-856). Similarly, Elena Pearl Ben-Joseph, a doctor and writer for Kids Health , encourages parents to be role models for their children. She states that “parents who are always dieting or complaining about their bodies may foster these same negative feelings in their kids. Try to keep a positive approach about food” (Ben-Joseph). Martha J. Nepper and Weiwen Chai support Ben-Joseph’s suggestions in their article “Parents’ Barriers and Strategies to Promote Healthy Eating among School-age Children.” Nepper and Chai note, “Parents felt that patience, consistency, educating themselves on proper nutrition, and having more healthy foods available in the home were important strategies when developing healthy eating habits for their children.” By following some of these ideas, parents can help their children develop healthy eating habits while still maintaining body positivity.

In this example, the author puts different sources in conversation with one another. Rather than simply describing the content of the sources in order, the author uses transitions (like "similarly") and makes the relationship between the sources evident.

A Guide to Evidence Synthesis: 4. Write a Search Strategy

• Meet Our Team
• Our Published Reviews and Protocols
• What is Evidence Synthesis?
• Types of Evidence Synthesis
• Evidence Synthesis Across Disciplines
• Finding and Appraising Existing Systematic Reviews
• 0. Develop a Protocol
• 1. Draft your Research Question
• 2. Select Databases
• 3. Select Grey Literature Sources
• 4. Write a Search Strategy
• 5. Register a Protocol
• 6. Translate Search Strategies
• 7. Citation Management
• 8. Article Screening
• 9. Risk of Bias Assessment
• 10. Data Extraction
• 11. Synthesize, Map, or Describe the Results
• Evidence Synthesis Institute for Librarians
• Open Access Evidence Synthesis Resources

Video: Databases and search strategies (3:40 minutes)

Writing a Search Strategy

It is recommended that you work with a librarian to help you design comprehensive search strategies across a variety of databases. Writing a successful search strategy takes an intimate knowledge of bibliographic databases.  

Using Boolean logic is an important component of writing a search strategy: 

• "AND" narrows the search, e.g.  children AND exercise
• "OR" broadens the search, e.g.  (children OR adolescents) AND (exercise OR diet) 
• "NOT" excludes terms, e.g.  exercise NOT diet 
• "*" at the root of a word finds all forms of that word, e.g.  (child* OR adolescen*) AND (exercise* OR diet*)
• parentheses ensure all terms will be searched together as a set 
• quotations around a phrase searches that exact phrase, e.g.  (child* OR adolescen* OR "young adult*") 

Evidence Synthesis Search Strategy Examples

Agriculture example: .

• Research question:  What are the strategies that farmer organizations use, and what impacts do those strategies have on small-scale producers in Sub Saharan Africa and India? 
• Key concepts from the question combined with AND:  (farmer organizations) AND (Sub-Saharan Africa OR India) 
• Protocol and search strategies for this question in CAB Abstracts, Scopus, EconLit, and grey literature
• Published scoping review for this question

Nutrition Example: 

• Research question:  What are the health benefits and safety of folic acid fortification of wheat and maize flour (i.e. alone or in combination with other micronutrients) on folate status and health outcomes in the overall population, compared to wheat or maize flour without folic acid (or no intervention)? 
• Key concepts from the question combined with AND:  (folic acid) AND (fortification) 
• Protocol on PROSPERO
• Published systematic review for this question with search strategies used in 14 databases

Search Strategy Template and Filters

• Human Studies Filter
• Randomized Controlled Trial Filters
• Other Methodology Search Filters

If you want to exclude animal studies from your search results, you may add a "human studies filter" to the end of your search strategy. This approach works best with databases that use Medical Subject Headings (MeSH) or other controlled vocabulary. You can see an example of how this was used in the MEDLINE(Ovid) search strategy of this published review (lines 13-14).

A simplified explanation of this filter can be seen below:

Add the following lines to the end of your search strategy to filter for randomized controlled trials. These are "validated search filters" meaning they have been tested for sensitivity and specificity, and the results of those tests have been published as a scientific article. The ISSG Search Filters Resource provides validated search filters for many other study design types. 

Highly Sensitive MEDLINE (via PubMed) Filter from Cochrane  

(randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab])

Highly Sensitive MEDLINE (OVID) Filter from Cochrane 

((randomized controlled trial.pt. or controlled clinical trial.pt. or randomized.ab. or placebo.ab. or drug therapy.fs. or randomly.ab. or trial.ab. or groups.ab.) not (exp animals/ not humans.sh.)) ​

CINAHL Filter from Cochrane 

TX allocat* random* OR (MH "Quantitative Studies") OR (MH "Placebos") OR TX placebo* OR TX random* allocat* OR (MH "Random Assignment") OR TX randomi* control* trial* OR TX ( (singl* n1 blind*) OR (singl* n1 mask*) ) OR TX ( (doubl* n1 blind*) OR (doubl* n1 mask*) ) OR TX ( (tripl* n1 blind*) OR (tripl* n1 mask*) ) OR TX ( (trebl* n1 blind*) OR (trebl* n1 mask*) ) OR TX clinic* n1 trial* OR PT Clinical trial OR (MH "Clinical Trials+")

PsycINFO Filter from ProQuest:

SU.EXACT("Treatment Effectiveness Evaluation") OR SU.EXACT.EXPLODE("Treatment Outcomes") OR SU.EXACT("Placebo") OR SU.EXACT("Followup Studies") OR placebo* OR random* OR "comparative stud*" OR  clinical NEAR/3 trial* OR research NEAR/3 design OR evaluat* NEAR/3 stud* OR prospectiv* NEAR/3 stud* OR (singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*)

Web Of Science (WoS) Filter from University of Alberta - Not Validated

TS= clinical trial* OR TS=research design OR TS=comparative stud* OR TS=evaluation stud* OR TS=controlled trial* OR TS=follow-up stud* OR TS=prospective stud* OR TS=random* OR TS=placebo* OR TS=(single blind*) OR TS=(double blind*)

Scopus Filter from Children's Mercy Kansas City

TITLE-ABS-KEY((clinic* w/1 trial*) OR (randomi* w/1 control*) OR (randomi* w/2 trial*) OR (random* w/1 assign*) OR (random* w/1 allocat*) OR (control* w/1 clinic*) OR (control* w/1 trial) OR placebo* OR (Quantitat* w/1 Stud*) OR (control* w/1 stud*) OR (randomi* w/1 stud*) OR (singl* w/1 blind*) or (singl* w/1 mask*) OR (doubl* w/1 blind*) OR (doubl* w/1 mask*) OR (tripl* w/1 blind*) OR (tripl* w/1 mask*) OR (trebl* w/1 blind*) OR (trebl* w/1 mask*)) AND NOT (SRCTYPE(b) OR SRCTYPE(k) OR SRCTYPE(p) OR SRCTYPE(r) OR SRCTYPE(d) OR DOCTYPE(ab) OR DOCTYPE(bk) OR DOCTYPE(ch) OR DOCTYPE(bz) OR DOCTYPE(cr) OR DOCTYPE(ed) OR DOCTYPE(er) OR DOCTYPE(le) OR DOCTYPE(no) OR DOCTYPE(pr) OR DOCTYPE(rp) OR DOCTYPE(re) OR DOCTYPE(sh))

Sources and more information:

• Cochrane Handbook for Systematic Reviews of Interventions
• Cochrane RCT Filters for Different Databases
• American University of Beirut University Libraries Search Filters / Hedges
• Methodology Search Filters by Study Design - Countway Library of Medicine, Harvard University Filters for RCTs, CCTs, Non-randomized/observational designs, and tests of diagnostic accuracy.
• Search Filters - American University of Beirut University Libraries Filters for RCTs, GUIDELINEs, systematic reviews, qualitative studies, etc.

Pre-generated queries in Scopus for the UN Sustainable Development Goals

Pre-written SDG search strategies available in Scopus 

Scopus, a multidisciplinary research database, provides pre-written search strategies to capture articles on topics about each of the 17 United Nations Sustainable Development Goals  (SDGs). These search strategies were updated in 2023 and are no longer available directly on "Advanced Document Search". To use these SDG search strategies:

• Go to the Elsevier 2023 Sustainable Development Goals (SDGs) Mapping page.
• Under Files , click on the SDG 2023 Queries folder.
• Download the .txt file for each pre-written search strategy you are interested in. You will need to know the number of the SDG of interest (e.g., SDG01.txt is for SDG 1: No Poverty). This .txt file will contain the entire search string for the SDG, already written in Scopus syntax .
• In Scopus , click on "Advanced Document Search".
• Copy and paste the pre-written SDG search strategy into the search field.

More about the Sustainable Development Goals: 

" The 2030 Agenda for Sustainable Development,  adopted by all United Nations Member States in 2015, provides a shared blueprint for peace and prosperity for people and the planet, now and into the future. At its heart are the 17 Sustainable Development Goals (SDGs), which are an urgent call for action by all countries - developed and developing - in a global partnership. They recognize that ending poverty and other deprivations must go hand-in-hand with strategies that improve health and education, reduce inequality, and spur economic growth – all while tackling climate change and working to preserve our oceans and forests."

Source:  https://sdgs.un.org/goals 

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Subject Guides

Literature Review and Evidence Synthesis

• Reviews as Assignments
• Annotated Bibliography
• Narrative Literature Review
• Integrative Review
• Scoping Review This link opens in a new window
• Systematic Review This link opens in a new window
• Other Review Types
• Subject Librarian Assistance with Reviews
• Grey Literature This link opens in a new window

Citation Managers

Review tools.

Citation managers are tools that can help you stay organized during the searching stage of a systematic review. 

• Keep track of  search results
• De-deduplicate your search results
• Allow for group projects
• Provide notification of retracted articles
• Cite and Write capabilities
• Bibliographic formatting

Citation Management Subject Guide : a library guide which provides details regarding the various types of citation managers and other resources. 

Covidence:  

• Covidence is a web-based screening and data extraction tool
• Covidence Knowledge Base tutorials
• Covidence Academy
• Introductory demonstration video

Rayyan:  

• An AI powered tool for systematic reviews

Citation Chaser

Citation Chaser can be used to easily identify articles that are citing or are being cited by specific articles you have identified as being relevant to your research topic.

PubMed PubReMiner

The PubMed PubReMiner can be used to identify the most used subject headings for your exemplar articles, to help you identify relevant MeSH terms for your search strategy.

Yale MeSH Analyzer

A MeSH analysis grid can help identify the problems in your search strategy by presenting the ways articles are indexed in the MEDLINE database in an easy-to-scan tabular format. Librarians can then easily scan the grid and identify appropriate MesH terms, term variants, indexing consistency, and the reasons why some articles are retrieved and others are not. This inevitably leads to fresh iterations of the search strategy to include missing important terms.

MeSH On Demand

This simple tool from the NLM will automatically identify potential MeSH terms for a given text, such as a title, abstract, or research question.

Medsyntax  

Medsyntax is  a free, open-source tool for visualizing and editing literature searches. It transforms search terms into HTML elements to visualize the search strategy effectively, provides an inline scope-driven editor and offers real-time error detection. 

Polyglot Search

Polyglot is a tool that will automatically translate your search from PubMed to other major databases such as Scopus and CINAHL. Note that Polyglot can only translate search syntax, so you will still need to manually translate your controlled vocabulary terms.

Systematic Review Accelator

The Systematic Review Accelerator is a collection of tools to help automate and streamline the SR process.

The Systematic Review Toolbox

The Systematic Review Toolbox is an online catalogue of tools that support various tasks within the systematic review and wider evidence synthesis process. You can use the toolbox to search for help with a specific task, or browse tools by what stage of the systematic review you are working on.

• << Previous: Grey Literature
• Last Updated: May 7, 2024 3:25 PM
• URL: https://libraryguides.binghamton.edu/literaturereview
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• Volume 10, Issue 1
• Incidence and prevalence of interstitial lung diseases worldwide: a systematic literature review
• Article Text
• Article info
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• Rapid Responses
• Article metrics

• http://orcid.org/0000-0001-9784-416X Rikisha Shah Gupta 1 , 2 ,
• Ardita Koteci 3 , 4 ,
• Ann Morgan 3 , 4 ,
• Peter M George 5 and
• Jennifer K Quint 1 , 3
• 1 National Heart and Lung Institute , Imperial College London , London , UK
• 2 Real-World Evidence , Gilead Sciences , Foster City , CA , USA
• 3 Imperial College London , London , UK
• 4 NIHR Imperial Biomedical Research Centre , London , UK
• 5 Royal Brompton and Harefield NHS Foundation Trust , London , UK
• Correspondence to Rikisha Shah Gupta; r.shah20{at}imperial.ac.uk

Interstitial lung disease (ILD) is a collective term representing a diverse group of pulmonary fibrotic and inflammatory conditions. Due to the diversity of ILD conditions, paucity of guidance and updates to diagnostic criteria over time, it has been challenging to precisely determine ILD incidence and prevalence. This systematic review provides a synthesis of published data at a global level and highlights gaps in the current knowledge base. Medline and Embase databases were searched systematically for studies reporting incidence and prevalence of various ILDs. Randomised controlled trials, case reports and conference abstracts were excluded. 80 studies were included, the most described subgroup was autoimmune-related ILD, and the most studied conditions were rheumatoid arthritis (RA)-associated ILD, systemic sclerosis associated (SSc) ILD and idiopathic pulmonary fibrosis (IPF). The prevalence of IPF was mostly established using healthcare datasets, whereas the prevalence of autoimmune ILD tended to be reported in smaller autoimmune cohorts. The prevalence of IPF ranged from 7 to 1650 per 100 000 persons. Prevalence of SSc ILD and RA ILD ranged from 26.1% to 88.1% and 0.6% to 63.7%, respectively. Significant heterogeneity was observed in the reported incidence of various ILD subtypes. This review demonstrates the challenges in establishing trends over time across regions and highlights a need to standardise ILD diagnostic criteria.PROSPERO registration number: CRD42020203035.

• Asbestos Induced Lung Disease
• Clinical Epidemiology
• Interstitial Fibrosis
• Systemic disease and lungs

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjresp-2022-001291

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Introduction

Interstitial lung disease (ILD) is a collective term representing a diverse group of lung conditions characterised by the presence of non-infective infiltrates, most commonly in the pulmonary interstitium and alveoli, which in certain cases manifest as architectural distortion and irreversible fibrosis. These conditions vary in their aetiology, clinical pathways, severity and prognosis. 1 Some conditions resolve completely without pharmacological intervention, whereas others, such as idiopathic pulmonary fibrosis (IPF) and non-IPF progressive fibrosing (PF) ILDs, inexorably progress to respiratory failure and premature mortality despite treatment.

Given its universally progressive nature and poor prognosis, IPF has attracted the most research attention and the current literature suggests a wide variation in disease distribution across Europe and USA. IPF prevalence varies between 0.63 and 7.6 per 100 000 persons in the USA and Europe 2 3 with a sharp increase with age.

More recently, there have been several studies investigating the incidence and prevalence of non-IPF ILDs, mainly autoimmune ILDs. Most of these reviews included studies drawn from single centres. Epidemiological data for non-IPF ILDs is inconsistent which makes it challenging to fully appreciate the ILD landscape. A recent review reported the prevalence of ILD in myositis conditions ranged from 23% in America to 50% in Asia. 4 Sambataro et al 5 reported about 20% of primary Sjogren’s syndrome patients were diagnosed with ILD. Additionally, there have been a few studies evaluating the incidence of drug induced ILD (DILD). 6–8 Guo et al 9 reported ILD incidence ranged from 4.6 to 31.5 per 100 000 persons in Europe and North America. A recent study using Global Burden of Disease data indicated the global ILD incidence in the past 10 years has risen by 51% (313.2 cases in 1990 to 207.2 per 1 00 000 cases in 2019). 10 These published estimates highlight a discernible variation in the ILD epidemiology across countries. It is unclear whether this is an ‘actual’ difference in the numbers across regions or whether the heterogeneity is driven by lack of guidelines and inconsistencies in ILD diagnostic pathways and standards of care. Likewise, while evidence suggests that the incidence of ILD has been rising over time, 9 whether this increase reflects a true increase in the disease burden, possibly related to an ageing population or whether this is due to improvements in detection, increased availability of cross-sectional imaging or coding practices over time is unknown.

This systematic review appraises the published literature on the incidence and prevalence of various ILDs over the last 6 years. We aimed to provide a comprehensive understanding of global incidence and prevalence. Specifically, we sought to identify areas where data are robust, to better appreciate the burden of ILD conditions and to comprehend the implications on healthcare utilisation and resources. We also set out to highlight areas where there remains a need for further study.

Study registration

This protocol has been drafted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines 11 and registered with the International Prospective Register of Systematic Reviews, PROSPERO ( CRD42020203035 ). Please refer to the online supplemental material for the full study protocol.

Supplemental material

Search strategy and selection criteria.

A systematic search of Medline and Embase was carried out in September 2021 to identify relevant studies investigating the incidence and prevalence of various ILDs. The search criteria were developed with support of librarian ( online supplemental figure E1 ). Due to the high volume of papers, we restricted this study period to papers published in the past 6 years. This search was limited to human studies written in English that were published between 2015 and 2021. The full search strategy and data sources included are described in online supplemental material .

Study population

Inclusion criteria included observational studies reporting the incidence and/or prevalence of individual ILDs, with study participants aged over 18 years old. Randomised controlled trials, case reports, reviews and conference abstracts were excluded. Studies which referred to DILD only were excluded because (1) there were many abstracts reporting on DILD, therefore this could be a standalone review and (2) epidemiology of DILD was a subject of a recent systematic review. 12 The first author (RG) screened all records by title and abstract; to begin with, the second reviewer (AK) independently screened 10% of all records. If there was a disagreement between RG and AK, an additional 15% were screened by AK. All studies identified as eligible for full text review were reviewed by RG, with AK reviewing 50% of eligible studies. Any disagreement was resolved through discussion with other authors, including an ILD expert. Reference of included studies were searched for additional literature.

Following full text review, RG carried out data extraction for eligible studies. AK independently extracted data for 25% of studies using the same template. RG assessed the quality for all included studies, reporting incidence and/or prevalence using a modified Newcastle Ottawa Scale (NOS). There were two NOS modified scales, one each for studies reporting prevalence and/incidence. AK independently assessed the quality of 25% of included studies. If there was a discrepancy between the data extraction and/or quality assessment conducted by RG and AK, then additional 15% were extracted and/or reviewed by AK.

It was noted that for IPF, many authors adopted what they termed ‘broad’ and ‘narrow’ case definitions. For example, Raghu et al 2 defined patients with International Classification of Disease, Ninth Revision (ICD-9) code 516.3 as a broadly defined case of IPF, and those who had this ICD-9 code alongside a claim for a surgical lung biopsy, transbronchial lung biopsy, or CT thorax as a narrowly defined case. We summarised the data using various reported case definitions. If multiple estimates were reported in a study, only the most recent estimate was included in this review.

There were two common themes around the reporting of prevalence. Studies drawn from the general population (reported prevalence per 100 000 persons) and studies drawn from multicentre or single centres (reported prevalence as the proportion of patients with ILD in the study cohort).

For this review, we have classified ILDs based on aetiology, grouped by conditions linked to environmental or occupational exposures, conditions typified by granulomatous inflammation, autoimmune ILDs and ILDs with no known cause ( online supplemental figure E2 ). 1

Evidence synthesis

The initial plan for this review was to conduct meta-analysis. However, due to high heterogeneity, we were unable to meta-analyse. Therefore, we have proceeded with data synthesis across the ILD subgroups.

Total number of included studies

The literature search yielded a total of 12 924 studies, of which 80 were included in this review. Online supplemental figure E3 demonstrates the selection process for all studies and highlights reasons for exclusion at each stage.

Although 80 unique publications were included, some papers explored the epidemiology of more than one ILD, the total count of reported estimates is 88. Half of the included publications explored autoimmune-related ILDs (n=44/88)( online supplemental figure E4 ).

Geographically, ILD publications represented all major world regions, but were predominantly from Asia (n=30, 34.1%) and Europe (n=23, 26.1%) ( figure 1 ).

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Geographical distribution of publications included.

Studies reporting prevalence

Eight studies reported the prevalence of IPF in general population. Prevalence of IPF was commonly reported applying ‘primary’, ‘broad’, ‘intermediate’ and/or ‘narrow’ case definitions. In the general population, the prevalence of IPF ranged from 7 to 1650 per 100 000 persons ( table 1 ). When explored within various case definitions, the prevalence for ‘broad’ cases ranged from 11 (USA, 2010) 2 to 1160 (USA, 2021) 16 ; for ‘narrow’ cases, this ranged from 7 (USA, 2010) 2 to 725 (USA, 2019). 16 There was only one study that reported IPF prevalence of 8.6% using a multicentre study setting. 19

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Studies reporting IPF prevalence per 100 000 persons by various case definitions

Twelve studies reported estimates for non-IPF ILDs in the general population ( online supplemental figure E5 ), with most of these conducted in the USA. The prevalence of systemic sclerosis (SSc) ILD in the general population ranged from 2.3 (Canada, 2018) 20 to 19 (USA, 2017) 21 per 100 000 persons. The highest SSc-ILD prevalence was reported in Medicare data which included patients aged 65 years and above. 21 22 For rheumatoid arthritis (RA) ILD, prevalence in an RA Medicare cohort was 2%. 23

Forty-six studies reported the prevalence of autoimmune-related ILD in cohorts of patients with an autoimmune condition or occupational ILD in workers with specific exposures. These studies primarily reported prevalence as a proportion, with the denominator representing patients with an autoimmune disorder or people working at a factory with exposure to certain agents, such as silica or asbestosis ( figure 2 ). Most of these estimates were drawn from cohorts at single or multiple tertiary centres, disease registries or a factory in the case of occupational ILD. Significant heterogeneity was noted in the reported prevalence of ILD associated with SSc, RA and Sjogren’s ( figure 2 ). The prevalence of ILD in SSc ranged from 26.1% (Australia, 2015) 36 to 88.1% (India, 2013). 44 Similarly, Sjogren’s ILD ranged from 1% (Sweden, 2011) 55 to 87.8% (Saudi Arabia, 2021). 56 In addition to dissimilarities in the prevalence across various regions, we also observed variation within region-specific estimates. For example, the 4 studies 47 50–52 which reported Sjogren’s ILD prevalence within China, estimated a 4-fold variation in magnitude (18.6% in 2011 47 to 78.6% in 2014). 52 Likewise, for RA ILD, there was substantial variation in the reported prevalence in Egypt (0.8% vs 63.7%). 31 32 Among the occupational-related ILDs ( figure 2 ), silicosis was the most explored condition (n=8)). Among these eight studies, there was a considerable variation in the reported prevalence of silicosis. Souza et al 61 reported an approximately 7-fold higher estimate of silicosis prevalence than that reported by Siribaddana et al (37% vs 5.6%, respectively). 65

Studies reporting non-IPF prevalence as percentage of study population. DM, dermatomyositis; HP, hypersensitivity pneumonitis; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease; LAM, lymphangioleiomyomatosis; MCTD, mixed connective tissue disorder; multiC, multicentre; PLCH, pulmonary langerhans cell histiocytosis; PM, polymyositis; RA, rheumatoid arthritis; reg, registry; single, single centre; SSc, systemic sclerosis. Details on the study population, sample size and ILD diagnosis methods are summarised in online supplemental tables E1–E31 .

Studies reporting incidence

Significant discrepancies were observed in reported ILD incidence across subgroups and individual conditions, mainly due to differences in the study setting. Depending on the study setting and type of data source used, some authors reported an incidence rate (per 100 000 person-years), while others reported incidence proportion. Table 2 lists IPF incidence by case classification and country, and figure 3 provides a list of studies reporting incidence of non-IPF ILDs.

Published estimates of IPF incidence, stratified by various case definitions

Studies reporting ILD incidence, grouped by ILD subgroups. ICD-9-CM, International Classification of Disease, Ninth Revision, Clinical Modification; ILD, interstitial lung disease; py, person-years; RA, rheumatoid arthritis; SSc, systemic sclerosis. Ɨ Narrow silicosis definition used: Medicare beneficiaries with any claim that included ICD-9-CM code 502, pneumoconiosis due to other silica or silicates, listed in any position during 1999–2014, with at least one inpatient, skilled nursing or home health agency claim, or at least two outpatient provider claims within 365 days of each other and cases with a chest X-ray or CT scan 30 days before or 30 days after a silicosis claim. Details on the study population, sample size and ILD diagnosis methods are summarised in online supplemental tables E1–E31 .

In this review, we synthesised the evidence for the incidence and prevalence of ILDs from studies published between 2015 and 2021. Considering the changing ILD nomenclature and the desire to reflect more current estimates, in this review, we decided to restrict the study period to past 6 years. We took this conscious effort with the aim to limit the heterogeneity across reported estimates. We evaluated 39 incidence and 78 prevalence estimates for individual ILD disorders that were distributed globally. We noted an increase in the number of studies investigating non-IPF ILDs and more specifically autoimmune ILDs in recent years. There was a 6-fold rise in the autoimmune ILDs studies, in 2021 when compared with 2015 (18 vs 3 studies, respectively). This increase in non-IPF ILD studies may be related to the emergence of antifibrotic therapies for non-IPF fibrosing lung diseases. 91–93 Interestingly, the publication trend for IPF has remained unchanged.

This review revealed considerable inconsistencies in the incidence and prevalence estimated of the main ILD subgroups. The reported prevalence of IPF ranged from 7 to 1650 per 100 000 persons, 2 16 an approximately 800-fold difference across case definitions, despite most studies reporting IPF prevalence in the general population. The incidence and prevalence estimates reported by Zhang et al 16 were a notable outlier; this study was based on the USA veterans’ healthcare database which included mostly White patients aged over 70 years—the demographic in which IPF is most common. Aside from this study, the majority of studies reported a prevalence of IPF ranging from 7 to 42 per 100 000 persons across different case definitions. 2 17

Unlike prevalence, we found considerable inconsistencies in how the incidence of IPF is reported. An important factor is the lack of uniformity in reporting units. Half of the studies reported incidence using person-years, whereas others reported per 100 000 person-years. We were, therefore, unable to compare incidence estimates in a similar fashion to prevalence. It is also important to note that changes in diagnostic guidelines for IPF over the years may have made it more challenging to accurately estimate its burden and temporal trends. 94–96

For non-IPF subgroups, such as autoimmune ILDs, there were wide variations in prevalence estimates between countries and within different healthcare settings in the same country. Overall, the variation in prevalence and incidence estimates was even greater for non-IPF ILDs than IPF. This can be attributed to several factors. First, in clinical practice, it is common for the clinical presentation and serological autoantibody profiles to result in overlap syndromes. Autoimmune conditions can coexist and patients with occupational ILDs may also have autoimmune conditions. Such fluidity of diagnoses at a clinical level reflects the challenges in estimating non-IPF ILDs. Second, the denominator more frequently differs for non-IPF ILDs, resulting in lack of standardised reporting. Unlike IPF, for which there are published validated algorithms to identify ‘true’ cases in the general population. 18 24 97 For non-IPF ILDs, studies relied on disease registries or were conducted at single/multispecialist clinics.

Majority of the autoimmune-related ILD estimates were in RA and SSc ILD. When assessing SSc ILD prevalence, we observed a wide range (26.1% to 88.1%) 37 44 in reported estimates, but when studies were dichotomised into single-centre studies and multicentre studies, it became clear that the highest variability was contributed by single centre studies (SSc prevalence, 31.2%–88.1%). 43–46 Owing to a smaller number of studies reporting incidence, we were unable to observe whether the same challenge existed.

The prevalence of silicosis ranged from 5.6% 65 to 37% 61 in workers exposed to silica. Occupational ILD studies were conducted at a factory, in a neighbourhood with proximity to industries, a registry or multicentre settings. Therefore, lack of generalisability and applicability of findings only to certain populations contributed largely to the wide variabilities of these reported estimates. The geographical distribution of occupational ILD papers alludes to dominance of exposure related ILDs in low-income and middle-income countries in Asia and South America (42.8% were in Asia).

While historical diagnostic classification has been founded on underlying aetiology or clinical pathways, there is now a growing emphasis on disease behaviour. 98 99 Attention has focused on a subgroup of ILD patients who go on to develop a PF phenotype. IPF is the archetypal PF ILD but other ILDs such as chronic hypersensitivity pneumonitis (HP), SSc ILD can exhibit ‘IPF-like’ behaviour, including rapid decline in lung function and early mortality. 100 The epidemiology of PF ILD is particularly challenging to examine as accepted guidelines on definition and diagnosis have yet to be published The reported prevalence of PF ILDs (per 100 000 persons) was 19.4 in France and 57.8 in the USA. 88 89 The future direction of research will likely focus on PF ILD as a phenotype which transcends previously adhered-to diagnostic labels and is associated with poorer outcomes and increased mortality. 100 101

Among the 39 studies reporting ILD incidence ( online supplemental figure E6 ), most studies were categorised as medium risk (n=25/39, 64.1%). Two studies were categorised as high-risk primarily because of lack of information on ILD diagnosis and poor quality of reporting estimates (ie, descriptive statistics were not reported, were incomplete or did not include proper measures of dispersion).

Similarly, there were 78 prevalence assessments ( online supplemental figure E7 ) of which approximately 18% (n=14/78) were categorised as high risk, 64.1% (n=50/78) as medium risk and 18% (n=14/76) as low risk. Most studies assessed as high risk were studies reporting autoimmune ILDs, mainly because of ILD diagnosis, single-centre studies or small sample size. Most of the studies reporting prevalence based on large healthcare datasets or disease registries were classified as low risk.

There are several strengths of this systematic review. We have provided an assessment of the incidence and prevalence of several ILD conditions globally and have grouped ILDs based on their aetiology to allow the appraisal of incidence and/prevalence at a disease level with as much granularity as possible. This review underlines the need for standardisation of diagnostic classifications for non-IPF ILDs—the narrower estimates for IPF provide the evidence that clear and consistent diagnostic guidelines are of great clinical utility. Guidelines have recently emerged for the diagnosis of HP 102 103 which we envisage will further improve the epidemiological reporting of this important condition, although incorporation of guidelines into routine clinical practice and then into epidemiological estimates takes time. Cross-specialty guideline groups will undoubtedly improve standardisation of reporting for autoimmune driven ILDs.

It is possible that genetic differences between individuals from different ethnic backgrounds may play a role in the global variability in incidence and prevalence. For example, the MUC5B promoter polymorphism (rs35705950) is the dominant risk factor for IPF 104 and is also a key risk factor for other ILDs such as RA. 105 This gain of function polymorphism is frequent in those of European decent but almost completely absent in those of African ancestry. 106 As more research is performed unravelling the complex interplay between genetics and environment in the development of ILD, it is likely that genetic variability will be found to play an important role in the global variability of ILD.

Despite the strengths, there are limitations to this systematic review. The certainty of the ILD case definition varied across studies. It was not always possible to be sure of how reliable the ascertainment method was. However, we attempted to reflect the differences in the ILD diagnostic methods in our risk of bias quality assessment. Along with the uncertainty in the diagnosis of ILD, there were different disease definitions used across studies. Therefore, in this review due to high heterogeneity, in how ILD was defined, we were unable to perform a meta-analysis. In this review, we have only included studies reporting ILD estimates in general populations, registries or populations with a specific disorder of interest. For single-centre studies reporting incidence and/or prevalence of autoimmune or exposure ILDs, the estimates were not generalisable and this has been reflected in the risk of bias quality assessment score. This review is limited to English publications only. However, due to high volume of papers found with the study period, we are confident it has a minimal effect on the overall conclusion. 107

This review highlights the lack of uniformity in the published estimates of incidence and prevalence of ILD conditions. In addition, there is a dissimilarity in disease definitions across the studies and geographical regions. Owing to these discrepancies, we were unable to derive estimates for the global incidence and prevalence of ILD and moreover unable to confirm whether there has been a ‘true’ increase in ILD incidence over time. Revisions to diagnostic criteria have augmented the challenges of estimating incidence and prevalence of individual ILD conditions and determining the drivers for temporal trends in incidence. Improving our estimates of the burden of fibrosing lung conditions is essential for future health service planning, a need that has been heightened by the development of new antifibrotic treatments. Guidelines have recently emerged for non-IPF ILDs, we envisage this may improve the epidemiological reporting for future research. There is a fundamental need to standardise ILD diagnosis, disease definitions and reporting in order to provide the data which will drive the provision of a consistently high level of care for these patients across the globe. 108

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• Data supplement 1

Twitter @DrPeter_George

Contributors RG, AM, PMG and JKQ developed the research question. RG, AM, PMG and JKQ developed the study protocol. RG developed the search strategy with input from AM and JKQ. RG screened the studies for inclusion, extracted the data from included studies and carried out quality assessment of the data. AK was the secondary reviewer for screening, data extraction and quality assessment. PMG supported with the understanding of various ILD diseases and their clinical pathways. All authors interpreted the review results. RG drafted the manuscript. All authors read, commented on and approved the manuscript.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

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Competing interests RG is a current employee of Gilead Sciences, outside the submitted work. JKQ has received grants from The Health Foundation, MRC, GSK, Bayer, BI, British Lung Foundation, IQVIA, Chiesi AZ, Insmed and Asthma UK. JKQ has received personal fees for advisory board participation or speaking fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Bayer and Insmed. PMG has received grants from the MRC, Boehringer Ingelheim and Roche Pharmaceuticals and personal fees from Boehringer Ingelheim, Roche Pharmaceuticals, Teva, Cippla, AZ and Brainomix. AK and AM have nothing to disclose.

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Classification of the Methods for the Synthesis of Polyhydroxylated Fullerenes. Part 2. One‑Step and Multi‑Step Procedures

• Published: 10 May 2024

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• V. V. Ignatev 1 ,
• R. Muller 1 ,
• S. G. Pasynkov 1 ,
• A. M. Petunin 1 &
• K. A. Bardina 2  

A complete analysis of the existing methods of synthesis of polyhydroxylated fullerenes using direct chemical interaction, as well as alternative methods of creation has been carried out in order to identify the optimal methods of obtaining, for their implementation in various technological and biomedical fields. The scientific literature on this field of research is summarized and classified, and a comparative assessment of the efficiency and feasibility of practical implementation of the developed synthesis methods is given on the basis of a comprehensive review of literature and patent documents.

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Ignatev, V.V., Muller, R., Pasynkov, S.G. et al. Classification of the Methods for the Synthesis of Polyhydroxylated Fullerenes. Part 2. One‑Step and Multi‑Step Procedures. Chem Technol Fuels Oils (2024). https://doi.org/10.1007/s10553-024-01679-w

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• Published: 10 May 2024

A rare case of TFEB /6p21/ VEGFA -amplified renal cell carcinoma diagnosed by whole-exome sequencing: clinicopathological and genetic feature report and literature review

• Ruiqi Zhang 1   na1 ,
• Meili Ding 2   na1 ,
• Xingyao Zhu 1 ,
• Xiang Li 3 ,
• Lin Tao 4 ,
• Wenhao Hu 4 &
• Hong Zou 1  

Diagnostic Pathology volume  19 , Article number:  66 ( 2024 ) Cite this article

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TFEB /6p21/ VEGFA -amplified renal cell carcinoma (RCC) is rare and difficult to diagnose, with diverse histological patterns and immunohistochemical and poorly defined molecular genetic characteristics.

Case presentation

We report a case of a 63-year-old male admitted in 2017 with complex histomorphology, three morphological features of clear cell, eosinophilic and papillary RCC and resembling areas of glomerular and tubular formation. The immunophenotype also showed a mixture of CD10 and P504s. RCC with a high suspicion of collision tumors was indicated according to the 2014 WHO classification system; no precise diagnosis was possible. The patient was diagnosed at a different hospital with poorly differentiated lung squamous cell carcinoma one year after RCC surgery. We exploited molecular technology advances to retrospectively investigate the patient’s molecular genetic alterations by whole-exome sequencing. The results revealed a 6p21 amplification in VEGFA and TFEB gene acquisition absent in other RCC subtypes. Clear cell, papillary, chromophobe, TFE3 -translocation, eosinophilic solid and cystic RCC were excluded. Strong TFEB and Melan-A protein positivity prompted rediagnosis as TFEB /6p21/ VEGFA -amplified RCC as per 2022 WHO classification. TMB-L (low tumor mutational load), CCND3 gene acquisition and MRE11A and ATM gene deletion mutations indicated sensitivity to PD-1/PD-L1 inhibitor combinations and the FDA-approved targeted agents Niraparib (Grade C), Olaparib (Grade C), Rucaparib (Grade C) and Talazoparib (Class C). GO (Gene Ontology) and KEGG enrichment analyses revealed major mutations and abnormal CNVs in genes involved in biological processes such as the TGF-β, Hippo, E-cadherin, lysosomal biogenesis and autophagy signaling pathways, biofilm synthesis cell adhesion substance metabolism regulation and others. We compared TFEB /6p21/ VEGFA -amplified with TFEB -translocated RCC; significant differences in disease onset age, histological patterns, pathological stages, clinical prognoses, and genetic characteristics were revealed.

We clarified the patient’s challenging diagnosis and discussed the clinicopathology, immunophenotype, differential diagnosis, and molecular genetic information regarding TFEB /6p21/ VEGFA -amplified RCC via exome analysis and a literature review.

1. For the first time, the molecular genetics of TFEB /6p21/ VEGFA -amplified renal cell carcinoma were completely and systematically characterized by exon sequencing.

2. The first case of TFEB /6p21/ VEGFA -amplified renal cell carcinoma with genomic instability was reported, presenting a new outlook on the treatment and prognosis of this tumor.

3. A systematic review and differentiation of TFEB /6p21/ VEGFA -amplified renal cell carcinoma and TFEB -translocated renal cell carcinoma in clinicopathological, histological, immunophenotypic, and molecular genetic features was performed.

TFEB /6p21/ VEGFA -amplified renal cell carcinoma is a rare subtype of renal cell carcinoma that was first proposed as a separate subtype by Argani et al. in 2016 (ref. [ 1 , 2 ]) and was not included in the WHO until 2022 due to its unique and rare nature. The interpretation of this tumor is imprecise; it is described as a relatively rare and highly aggressive tumor with a specific rate of recurrence and metastasis that tends to occur in middle-aged and older adults [ 3 , 4 ]. The tissue morphology of the tumor is diverse, mostly resembling papillary renal cell carcinoma (PRCC) with clear cell renal cell carcinoma (CCRCC)- or chromophobe renal cell carcinoma (CHRCC)-like morphology. These tumors demonstrate similar immunohistochemistry results to TFEB translocation renal cell carcinoma, commonly expressing pigment differentiation-related markers (Melan-A, HMB45, and cathepsin k). Molecular genetics suggests the presence of altered polyploid amplification in the region where the TFEB gene is located (6p21 region), including amplification of the critical genes VEGFA and CCND3 , suspected to be highly associated with the aggressive clinical course of this tumor in the absence of TFEB gene translocations [ 5 , 6 ].

The rare case we report with a mixture of clear cell carcinoma, eosinophilic carcinoma, and papillary renal carcinoma morphology phenotypes and characteristics was found in 2017 and initially diagnosed with renal cell carcinoma by regular morphology and immunohistochemistry analyses due to the limited molecular pathology available at the time [ 7 , 8 ]. Collision tumor was highly suspected in this patient; one year later, he developed poorly differentiated squamous cell carcinoma of the lung. As second-generation sequencing methods had matured, we continued evaluating this case by whole-exome sequencing and obtained hints of diagnostic value after obtaining in-depth mining sequencing results. Then, through immunohistochemical analysis and an extensive literature review, we differentiated the patient’s tumor from various types of renal cancer and diagnosed it as TFEB /6p21/ VEGFA -amplified renal cell carcinoma. The in-depth analysis of the molecular genetic changes in this case combined with a literature review to explore the relationships of these changes with diagnosis, prognosis, treatment and differential diagnosis with TFEB translocation renal cell carcinoma deepens our understanding of such tumors.

A 63-year-old male, was admitted to the hospital for right-sided low back pain in 2017. Fatty liver and a solid mass of the left kidney (internal partial liquefaction) were shown by abdominal ultrasonography, and a space-occupying lesion in the middle and lower part of the left kidney was observed by urinary CT, suggesting the possibility of renal carcinoma. A CT scan of the right kidney, bilateral ureters, and bladder showed no definite abnormal changes, though the rectal wall was slightly thickened. Lung CT showed no obvious abnormality. After admission, the patient underwent laparoscopic radical resection of left renal cancer under general anesthesia, and the operation went smoothly. The patient was diagnosed with poorly differentiated lung squamous cell carcinoma one year after RCC surgery, as shown in Fig.  1 h. After receiving two cycles of the "Docetaxel + Cis-platinum + Endo star" systemic intravenous chemotherapy regimen,the patient died. The postoperative survival time of patients with renal cancer was less than three years.

Gross images of the patient and HE staining of the tumor tissue. a The left kidney and surrounding fatty tissue were sent for examination, with a total size of 19 × 13 × 7 cm, and the size of the incised kidney was 13.5 × 8 × 6 cm. Most areas of the perirenal fat capsule were easy to peel off, and the focal renal epithelium was adherent to the adipose tissue, with a multicolored appearance and partial dark red necrosis. No lymph nodes were detected in the fatty tissue at the renal hilum. b The tumor tissue was biphasic, with areas of eosinophilic and clear cell coexistence. c Hemorrhagic and necrotic areas. d , e The tumor cells are arranged in a nested papillary pattern, and the papillae have a slender fibrovascular axis. f Tumor cells had abundant cytoplasm and clear cytoplasm. g The tumor cells were arranged in a striated papillary pattern. h Foam cell. i A fibrous pseudoenvelope is seen around the tumor. J , k Pseudo papillae and similar glomerular and tubular-like structures. l The tumor tissue was biphasic, with areas of eosinophilic and clear cell coexistence. m Tumor cells have abundant cytoplasm and eosinophilic cytoplasm. n Poorly differentiated squamous cell carcinoma of the lung

One left kidney with its surrounding adipose tissue was sent for examination, with a total size of 19 × 13 × 7 cm, and the kidney was dissected to a length of 13.5 × 8 × 6 cm. Most areas of the perirenal fat capsule were easy to peel off, and the focal renal epithelium adhered to the fatty tissue. A mass of 8.3 × 5.8 × 6 cm in size was seen in the middle and lower poles of the kidney, with a colorful external appearance, partly dark red necrosis, partially protruding into the renal pelvis, with a sebaceous thickness of 0.5 cm, and a medullary thickness of 2.8 cm. The ureter was 5 cm long and 0.4–0.5 cm in length. No lymph nodes were detected in the adipose tissue at the renal hilum (Fig.  1 a). Microscopically, a fibrous pseudocapsule was observed around the tumor (Fig.  1 i), and the tumor cells had a complex composition and diverse morphology (Fig.  1 b, l). Some cells were typical of clear cell carcinoma with nested and tubular distribution (Fig.  1 d), and some cells resembled eosinophilic papillary carcinoma with a fine fibrous vascular axis in the papilla (Fig.  1 e). Foam cells were observed in the focal interstitium (Fig.  1 h). In addition, pseudopapillaries and structures resembling glomeruli and renal tubules (Fig.  1 j, k) were observed, shift areas were observed in clear cells and the papillary regions, hemorrhage and necrosis were observed in some areas (Fig.  1 c), and focal interstitial edema was observed. There was no prominent cell atypia, and mitosis was rare. PAX-8 ( +) and AE1/3 (focal +) were positively expressed in the tumor cells overall, and CD10 ( +) (Fig.  2 d) and CA9 (focal + , cancer cells were positive in the clear differentiation area and negative in the tubular differentiation area) were positively expressed in the clear cell area (Fig.  2 g). CD31 staining showed strong positive epithelial AMACR (diffuse +) in the papillary carcinoma area except for in the clear cell area with more abundant interstitial vessels (Fig.  2 e). There was no loss of SDHB expression in the tumor cells (Fig.  2 i). The cells were all negative for CK20, TFE3 (Fig.  2 c), CD117 (Fig.  2 f), and CK7 (Fig.  2 h), and the tumor and had a low Ki-67 proliferation index of approximately 3–5% (Fig.  2 l). RCC with a high suspicion of collision tumors was indicated according to the 2014 WHO classification system; no precise diagnosis was possible.

Immunohistochemistry results. a Tumor cell nuclei were strongly positive for TFEB × 20 ( b ) Melan-A positive × 20 ( c ) TFE3 negative × 20 ( d ) CD10( +) positive in the clear cell area × 20 ( e ) AMACR diffuse positive in the papillary carcinoma area × 20 ( f ) CD117 negative × 20 ( g ) CA9 focally positive with cancer cells positive in clear differentiation areas and negative in tubular differentiation areas × 20 ( h ) CK7 negative × 20 ( i ) SDHB positive × 20 ( j ) MSH6 negative × 20 and ( k ) MSH2 positive × 20 ( l ) The proliferation index of Ki67 was less than 10% × 20

To determine the molecular genetic alterations in the tumor, we extracted DNA from the patient’s normal tissue and parafn-embedded tumor tissue, performed exon sequencing in 2020. The summary of global mutations in the molecular genetics of this patient was shown in Supplementary Table  1 . Given the mutational advantage of CNV in cancer species and overall characteristics, high-frequency CNV analysis was performed on samples to obtain diagnostic information, as shown in Fig.  3 . CNVs were concentrated on chromosomes 6, 18, 19, and 21, and the patient demonstrated six significant regions of acquisition, including 6p21.1, 6p12.3, 18q12.1-18q23, 19p13.2, 19q13.2, 19q13.31 and six critical areas of deletion, including 6p21.1–21.3, 6p22.1–22.3, 11q11-11q25, 11p11-11p13, 17q25.1–25.3, and 18q12.1-18q23. Amplification of TFEB , VEGFA , and CCND3 genes located on the chromosome 6p21.1 segment (amplification fold > 2) was present, and the E2F3 gene was lost on the chromosome 6p22.3 segment. The somatic copy number variation (SCNA) characteristics of this patient were further combined and compared with classical oncogenes to find significantly associated driver genes. The DCC tumor suppressor gene was absent at 45,100,000–50460000 on chromosome 18. Genetic abnormalities associated with prognosis and treatment shows that the patient had TMB-L (low tumor mutation burden). The amplification mutation of CCND3 in somatic mutations suggested that the patient would be relatively sensitive to abemaciclib (grade D), palbociclib (grade D), and ribociclib (grade D). The MRE11A deletion mutation suggested relative sensitivity to niraparib (grade C), olaparib (grade C), rucaparib (grade C), and talazoparib (grade C). The ATM deletion mutation indicated relative sensitivity to Niraparib (grade C), Olaparib (grade C), Rucaparib (grade C), and Talazoparib (grade C) (Table  1 ).

Distribution diagram of high-frequency CNV. The horizontal coordinates are chromosomes 1–22, and sex chromosomes were not considered in this analysis. The vertical coordinates indicate the scores of high-frequency CNV segments by GISTIC software, and higher scores indicate a higher frequency of CNV in this segment. Red indicates an increase in copy number, and blue indicates a decrease in copy number

To further understand the molecular genetic abnormalities of patients, germline mutations were screened by combining SNP comparisons with normal tissues to derive possible tumor susceptibility genes, as shown in Fig.  4 a ( MED23, PTPRB, ZFHX3, TSC1, AXIN2, CDK12, NFE2L2, AHNAK, ACNA1D, MN1, NRG1 BRCA2, IDH2, FGFR2, IRF2, DIS3, TP53, CEP290, RHBDF2 ). We identified 19 significant mutant genes for somatic variants in the exon coding region: MRE11A, ATM, NOTCH2, ATOH8, ASCC1, DOPEY2, HIST2H2AC, APC, ZCWPW1, POU2F3, CTC1, EXOC1, SLC5A12, MEN1, ATP12A, MNX1, SERPINB3, SERPINB4 , and BCL2 . On this basis, the somatic mutation of the patient was compared with the known driver genes in the database. The possible driver genes in the tumor sample were screened as ARID1B, MAX, NOTCH2 and APC (Fig.  4 b), in which a missense mutation of base C instead of base T occurred in the NOTCH2 gene located at position 120,471,691 on chromosome 1. Finally, 220 differential genes were screened among single nucleotide polymorphisms (SNPs) between tumor tissues and normal control tissues. These 220 genes were classified into 229 functional categories using the Gene Ontology (GO) database, as shown in Fig.  5 a, mainly involving biological processes such as biofilm synthesis, cell adhesion, regulation of substance metabolism, regulation of enzyme activity, rRNA processing, and biotransformation. Furthermore, 35 significant pathways related to this tumor were obtained by KEGG pathway enrichment analysis, as shown in Fig.  5 b, of which tumor-related routes accounted for 11.4% (4/35), metabolic pathways and other pathways accounted for 25.7% (9/35) and 62.9% (22/35), respectively. Inspired by the patient's lung cancer status during the last follow-up, investigated the microsatellite status. We identified a missense mutation in the exon region of the PMS2 gene located at 6,026,775 on chromosome 7, in which base C replaced base T.

a Landscape map of susceptibility genes. b Landscape of known driver genes

a Venn diagram of differentially expressed genes with missense mutations in SNPs of tumor samples versus normal samples. b Major pathways involved in SNPs differ between tumor tissue and control tissue in this patient

After exon sequencing, we used IHC technology to verify some genes that showed key changes in the sequencing results. Tumor cell nuclei were strongly positive for TFEB ( +) (Fig.  2 a), positive for Melan-A, MSH2 (present +) (Fig.  2 k), MLH1 (present +), and PMS2 (present + , focal -), and negative for MSH6 and HMB45.

TFEB /6p21/ VEGFA -amplified RCC defined by the 6p21.1 chromosomal region is a rare and gradually recognized RCC subtype that exists independently of TFEB -translocated RCC and has been included in the molecularly defined renal cancer subtypes by the World Health Organization in 2022 [ 9 ]. Our knowledge of this tumor is mainly derived from the preliminary studies of Gupta et al. [ 2 , 3 , 4 , 5 , 6 ], and the overall understanding of its biology is minimal. The lack of diagnosis and treatment guidelines makes this tumor challenging to treat, and 40% of cases experience aggressive metastasis or death.

We retrieved 8 papers with complete information about 50 cases of TFEB -amplified renal cell carcinoma (Supplementary Table  2 ) patients whose main characteristics were as follows: (1) Sex: there were 30 cases in males and 20 cases in females, with a male to female ratio of 3:2. (2) Age: the patients’ age ranged from 23 to 80 years, with a mean age of 63.46 and a median age of 65.00. (3) Tumor size: the average tumor size was 8.73 cm. (4) TNM stage: The percentage of TNM stage ≥ pT3 was 30/50. (5) ISUP grading: there was 1 case with a low grade, accounting for 1/40; 3 cases with grade 2, accounting for 3/40; 24 cases with grade 3, accounting for 24/40; 12 cases with grade 4, accounting for 12/40. (6) The presence of distant or regional metastases was confirmed at diagnosis or follow-up: there were 20 cases with complete follow-up information, of which 15 had metastases, representing a metastasis rate of 15/20. (7) Morphological features: microscopically, the tumor cells were morphologically diverse, with cells in nested (12/45), papillary (14/45), pseudopapillary (6/45), tubular papillary (18/45), and clear cell areas (20/45), and such tumors had an overall increase in cytoplasmic eosinophils, accounting for 27/45, some with cell necrosis (7/45). (8) Immunohistochemistry: the analyses revealed positivity for TFEB (+ , 5/7), cathepsin k(+ , 16/27), Melan-A (+ , 28/36) and HMB45 (+ , 6/30) (9) FISH: TFEB FISH revealed breaks & GT (10 signals, 32/33); VEGFA FISH revealed breaks & GT (10 signals; 14/14). (10) The other molecular genetic features observed were loss of chromosome 3p (6/12), loss of chromosome 7 (2/9), loss of chromosome 17 (4/9), occasional missense mutations in the SMARCB1 gene, and nonsense mutations in the FH gene.

In the 2022 WHO classification of renal cancer, in addition to TFEB amplifying renal cancer, TFEB -translocated renal cell carcinoma is included, which is a relatively rare subtype of kidney cancer typified by a translocation between the TFEB gene on chromosome 6 and the MALAT1/Alpha gene on chromosome 11 [ 10 ]. In a review of 40 cases of TFEB translocated renal cell carcinoma reported in the literature [ 3 , 6 , 11 , 12 ] (Supplementary Table  3 ), combined with the studies of Gupta and Qiuyang Lu et al. [ 3 , 6 , 10 , 13 ], we found significant differences between TFEB translocation and TFEB -amplified tumors in terms of age of disease onset, histological morphology, melanocyte markers, expression of cathepsin k, VEGFA/CCND3 gene expression, and aggressive behavior. The above differences contribute to the differential diagnosis of the two, as described in detail below (Table  2 ): 1. Clinicopathological features: there was no noticeable sex difference between the two groups. The former tumor occurred in adults and was small; the latter tumor developed at an older age and occurred in older patients, and the tumor volume was more prominent. 2. Histologic features: both tumors are primarily nonspecific, generally well-defined, and reddish-brown on the cut surface. The typical biphasic histopathological features of "large epithelioid cells and small cells clustered around clear basement membrane-like tissue" are more common in translocated RCC. More extensive morphological features, such as sclerosis and ossification, are occasionally seen in TFEB -translocated RCC. Amplified tumors were morphologically diverse, with cytoplasmic eosinophilia ( p  = 0.013) and pseudopapillary, necrotic and true papilla, the characteristics of the amplified tumor. RCC with aberrant TFEB expression was a highly graded RCC, and TFEB -amplified renal cell carcinoma had a higher proportion of ≥ pT3 in TNM staging ( p  = 0.047). 3. Immunophenotypic features: overexpression of TFEB genes frequently drives abnormal expression of melanocyte-associated antigens (HMB45, Melan-A) and osteoblast histone k (cathepsin k); overexpression of cathepsin k ( p  < 0.000), HMB45 ( p  < 0.000), and Melan-A ( p  = 0.028) is more commonly found in TFEB -translocated renal cell carcinoma. 4. TFEB expression assay: the results of the TFEB gene expression assay are correlated with the immunohistochemistry results [ 2 , 3 , 6 , 14 ], but at the genetic level, amplified renal tumors have a low tendency to express TFEB , which is often accompanied by VEGFA gene amplification. Several studies suggest that the low expression of TFEB in amplified renal tumors may be attributed to their lack of typical biphasic morphology. 5. Prognosis: translocated RCC had an excellent clinical prognosis with a low recurrence and distant metastasis rate (1/8). Renal tumors with amplifications had a more aggressive clinical course, a higher recurrence and distant metastasis rate (15/20, p  = 0.004), and a poorer clinical prognosis.

In sequencing, the CNV mutation in this case was consistent with the already reported by our team [ 15 ]. High-frequency CNV analysis yielded diagnostically significant alterations on chromosome 6. The CNV results further suggested that the gain in chromosomes 1q, 2p, 4q, 6p, 16p, 17q, 18q, 19q, 22q and loss in chromosome 18q were consistent with previous findings in TFEB -amplified renal cell carcinoma [ 3 , 4 , 16 ]. Nevertheless, the amplification of chromosomes 1p, 4p, 10q, 18q, 19p, and 21p and the loss of chromosome 17q in the present case has not been previously reported.

Subsequently, the germline mutations in this case were analyzed. The susceptibility of TP53 to mutation in normal tissues adjacent to cancer revealed the instability of the patient's tumor. Single nucleotide polymorphisms (SNPs) between tumor tissues and normal control tissues were analyzed, and the obtained differentially expressed genes were mapped to the KEGG and GO databases. The results are shown in Fig. 5 . The results can be interpreted from three levels. First, classical pathways associated with cancer, such as the TGF-β signaling pathway [ 17 , 18 ] and Hippo signaling pathway [ 19 ], were involved. Metabolism-related courses accounted for 25.7%, which was in line with results from previous studies that showed that kidney cancer is a metabolism-driven disease [ 20 ]. After enrichment, some pathways were associated with biological dysfunction and abnormal behavior caused by aberrant overexpression of TFEB genes, such as E-cadherin, an essential regulator of tumor cell-to-cell interactions, lysosomal biogenesis [ 21 ], and autophagy of tumor cells [ 22 , 23 ]. Given the close correlation between the above partial enrichment pathway and amplified mutations of the TFEB gene, which was consistent with our previous CNV results suggesting the presence of TFEB amplification, the rationale supporting the diagnosis of TFEB -amplified renal cell carcinoma was more robust. Among the genes with somatic missense mutations, NOTCH2 , NR3C1 , NT5E , PLAGL1 , and ACAT2 correlate with the occurrence and development of renal tumors. Among them, the NOTCH2 gene was related to cell stemness [ 24 ], which could induce and regulate the occurrence and apoptosis of tumor cells; NT5E could inhibit the growth, EMT process, and AKT/GSK-3β signaling pathway of sunitinib-resistant cells in renal cell carcinoma [ 25 ]. It has also been proposed that PLAGL1 protein levels in CCRCC tissues are positively correlated with distant metastasis and worse patient prognosis [ 26 , 27 ]; the ACAT2 gene was related to lipid metabolism [ 28 ], and its downregulation could lead to a poor tumor-specific survival prognosis. The remaining genes with missense mutations suggest changes associated with cell proliferation and differentiation, amino acid metabolism, nucleotide metabolism, and signal transduction pathways. In this case, a frameshift deletion occurred in the APC gene on chromosome 5, which encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway and is also involved in other processes, including cell migration and adhesion. Transcriptional activation and apoptosis have also been reported in CHRCC metastatic chromophobe renal cell carcinoma with APC mutation [ 26 ].

During interpreting data, we obtained the diagnosis of TFEB -amplified RCC after summarizing the molecular genetic alterations of common and rare subtypes of kidney cancer by the latest guidelines and literature [ 8 , 29 ]. The development of molecular pathology has constantly advanced our understanding of kidney cancer, and some tumor subtypes based on specific molecular alterations, such as "translocation-associated renal cell carcinoma," were first introduced in the WHO classification in 2004 [ 7 ]. However, these molecularly defined tumors have shown a broad morphological spectrum in some recent studies, and whether there is a clear correlation between genotype and phenotype is worth discussing; thus, it is crucial to broaden the idea of differential diagnosis of tumors with the help of molecular tests such as second-generation sequencing [ 7 , 8 , 9 ].

During the follow-up, the patient developed poorly differentiated squamous cell carcinoma in the lung one year after kidney cancer surgery; the secondary lung malignancy led us to speculate whether there were some specific alterations at the genetic level in the patient. We first examined tumor mutation burden (TMB) and microsatellite instability (MSI), which are predictors of the efficacy of immune checkpoint inhibitor therapy. The results showed that the TMB was low. Regarding MSI, we first noticed the expression of MMR mismatch repair (MMR) protein and obtained the impact of low expression of MSH6 protein. Meanwhile, seven common loci in MSI were detected by next-generation sequencing technology, and the results suggested that they were microsatellite stable (MMS). However, we found in the exon sequencing results that there was a missense mutation in the exon region of the PMS2 gene on chromosome [ 7 ], in which base C replaced base T. Could the above situation suggest microsatellite instability in this patient? Considering the heterogeneity of the tumor during the assay and the methodology of the assay, the results of this patient's MSI status need to be further discussed and analyzed in the context of the literature.

This patient has multiple tumor characteristics, which was another interesting aspect of this case. Analyzing the expression of genes associated with homologous recombination repair could be beneficial in guiding the patient's clinical treatment. The sequencing results suggested that this patient had a homologous recombination-deficient (HRD) tumor, with the loss of ATM and MRE11A , which are key genes involved in the process of homologous recombination (HR) repair, suggesting that we could try targeted therapy with poly ADP ribose polymerase (PARP) inhibitors: this patient was relatively sensitive to niraparib (class C), olaparib (class C), rucaparib (class C), and talazoparib (class C). Olaparib, an inhibitor of oral poly ADP-ribose polymerase (PARP), is increasingly being demonstrated in clinical studies to be effective in HRD gene-deficient cell lines, such as those lacking ATM , in addition to providing sensitization in combination with chemotherapeutic agents and killing BRCA1 or BRCA2 gene-mutated tumor cells. Clinical trials are underway in patients with renal clear cell carcinoma, urothelial carcinoma, and prostate cancer. Talazoparib is a next-generation PARP inhibitor with a dual mechanism of action that stimulates tumor cell death by blocking PARP enzyme activity and binding PARP enzyme to DNA damage sites, and clinical trials of its use in patients with renal clear cell carcinoma are ongoing. The targeting effects of these drugs still need to be explored in depth. Sequencing results can guide targeted dosing, and the loss of these 2 genes may improve the benefit rate of PD-1/PD-L1 inhibitors; thus, this patient may benefit from immunotherapy.

The above findings help explain the complex pathogenesis of lung cancer secondary to kidney cancer two years after the initial patient diagnosis and provide some guidance for the clinical treatment of this disease; unfortunately, the patient developed the disease early and did not have a chance to receive the treatment with relevant drugs. By describing this case, we hope that more patients with a similar disease will have the option to try HRD-related targeted therapy and immunotherapy.

Kidney cancer is a complex disease with unpredictable clinical progression due to typical intertumor and intratumor heterogeneity and high genomic variability [ 30 , 31 ], which makes it difficult for traditional radiotherapy, chemotherapy, and targeted therapy to overcome the tumor. With the advent of the immune checkpoint inhibitor (ICI) era, a new generation of comprehensive treatment for kidney cancer has emerged [ 32 , 33 ]. In pre-kidney cancer studies, the mTOR inhibitors everolimus and tesilimus have been approved by the FDA for treating advanced metastatic renal cell carcinoma. These drugs are effective for metastatic TFEB-translocated renal cell carcinoma [ 34 ]. Pembrolizumab (Keytruda or pembrolizumab), approved by the US Food and Drug Administration (FDA), is a PD-L1 inhibitor for the treatment of patients with solid tumors, which has brought some clinical benefits to some patients [ 35 , 36 , 37 ]. Studies have further shown that TFEB affects the biological progression of renal cancer by acting on the mTOR pathway and positively correlates with the expression of PD-L1. In this case, the amplification of TFEB and the evaluation of genomic stability provide new opportunities for the combination of targeted therapy and immunotherapy for this type of cancer. Could MSI be a relevant immunotherapeutic marker for kidney cancer treatment? Can mTOR/PARP inhibitors be combined with PD-L1 inhibitors such as pembrolizumab in TFEB /6p21/ VEGFA -amplified RCC? Given the rarity of TFEB /6p21/ VEGFA -amplified renal cell carcinoma, pathologists and clinicians have not reported it domestically or internationally, and the above ideas need to be validated.

Whole-exome molecular genetic analysis of TFEB /6p21/ VEGFA -amplified renal cell carcinoma has enhanced our understanding of this type of tumor. For the first time, we reported possible tumor-related driver genes, alterations in specific chromosomal regions of CNV, and critical genes associated with targeted therapy in TFEB /6p21/ VEGFA -amplified renal cell carcinoma (Table  1 ), which deepened our understanding of the diagnosis and molecular genetic alterations of TFEB /6p21/ VEGFA -amplified renal cell carcinoma and provided new information for their prognosis and treatment.

Availability of data and materials

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

Abbreviations

Gene ontology

Kyoto Encyclopedia of Genes and Genomes

Biological Process

Cellular Component

Molecular Function

Somatic copy number variation

Papillary renal cell carcinoma

Clear cell renal cell carcinoma

Chromophobe renal cell carcinoma

Acquired cystic kidney disease-associated renal cell carcinoma

Tubulocystic renal cell carcinoma

Hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma

Immunohistochemistry

Transcription Factor EB

Paired box protein 8

A-methylacyl-CoA racemase

Cytokeratin protein 7

Cluster of differentiation 10

Cluster of differentiation 117

Cluster of differentiation 31

Melanoma antigen recognized by T cell-1

Melanoma-related marker

Cytokeratin 20

Carbonic anhydrase IX

Succinate dehydrogenase B

MutL homolog 1

MutS homolog 2

MutS homolog 6

PMS1 homolog 2

Single nucleotide polymorphism

Insertion and deletion

Copy number variation

Single nucleotide variant

Microsatellite instability

Microsatellite instability-high

Mismatch repair

Deficient mismatch repair

Homologous Recombination Deficiency

Poly ADP ribose polymerase

Immune checkpoint inhibitor

Tumor mutation burden

Human leukocyte antigen class 1

Fluorescence in situ hybridization

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Acknowledgements

Not applicable.

This research was funded by the National Natural Science Foundation of China (grant numbers 81660411, 81460383) and the International Cooperation Project of Xinjiang Production and Construction Corps of China (grant number 2019BC001). The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Ruiqi Zhang and Meili Ding are co-first authors and contributed equally to this work.

Authors and Affiliations

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

Ruiqi Zhang, Xingyao Zhu & Hong Zou

Department of Pathology, The Yangxin County People’s Hospital, Binzhou, 251800, China

Department of Pathology, People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, 830001, China

Department of Pathology, The First Affiliated Hospital, Shihezi University School of Medicine, Xinjiang, 832002, China

Qi Hu, Lin Tao & Wenhao Hu

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All authors conceived this research. RZ and MD collected and analyzed clinical samples and data. XZ and MD completed the construction of the tissue microarray and the production of HE slices. HZ designed and supervised the entire project scientifically. RZ and HZ are major contributors in writing the manuscript, QH participated in the manuscript writing and submission, HW and LT reviewed and edited the paper. HZ had final responsibility for the decision to submit for publication. All authors have read and approved the final manuscript.

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Correspondence to Hong Zou .

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Zhang, R., Ding, M., Zhu, X. et al. A rare case of TFEB /6p21/ VEGFA -amplified renal cell carcinoma diagnosed by whole-exome sequencing: clinicopathological and genetic feature report and literature review. Diagn Pathol 19 , 66 (2024). https://doi.org/10.1186/s13000-024-01476-3

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Received : 29 March 2023

Accepted : 02 March 2024

Published : 10 May 2024

DOI : https://doi.org/10.1186/s13000-024-01476-3

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