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• Systematic reviews and meta-analyses
• Writing and publishing or archiving a research protocol
• Defining the research question
• Searching for literature and applying the chosen inclusion and exclusion criteria
• Assessing the methodological quality
• Extracting the data and converting the outcome parameters
• Presenting and interpreting results
• Reporting results
• References
• Information on other websites

A systematic review is a summary of the literature on a specific topic in which data are collected and described in a transparent and structured manner in order to prevent bias. A systematic review can describe qualitative and/or quantitative studies.

There are several phases involved in conducting a systematic review:

1. defining the research question
2. systematically searching electronic literature databases and applying the chosen inclusion and exclusion criteria to select the required literature
3. assessing the methodological quality of the publications,
4. extracting the required data from the selected articles,
5. systematically summarizing the outcomes of the studies, and
6. reporting the results of the systematic review.

For a systematic review of prognostic studies, a different structuring of these phases may be useful [1]. In some systematic reviews, a meta-analysis is also carried out to statistically combine the results from different but methodologically comparable studies [2].

Cochrane is an international organization that helps healthcare providers, policymakers, and patients make decisions about healthcare. This organization does this by presenting information on the effectiveness of healthcare in the form of systematic reviews. Cochrane Reviews and their protocols are published in The Cochrane Library.

Before researchers conduct a systematic review, it is advisable to draw up a research protocol. In this way, researchers clearly establish the research objectives, question, and methods before carrying out the study. When drawing up the research protocol, it is best to use the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist to verify that all required information is included in the document [3]. It is advisable to already contact a specialized methodologist, clinical information specialist, and/or statistician while writing the protocol. At this stage, it is also advisable to make agreements about who will be the authors and in what order they will appear on the eventual publication. Once the protocol has been drawn up, it is advisable to publish it or archive it publicly. Researchers can register a protocol with PROSPERO (International prospective register of systematic reviews) to archive it publicly. By publishing or publicly archiving the protocol, one demonstrates at a later stage to journal peer reviewers that the chosen research methods were established before the review was carried out, and that there was no “fishing” for an attractive result with a nice p-value. This also shows other researchers what one is currently working on, which reduces the chance of highly similar systematic reviews appearing.

In a systematic review, it is important to formulate the research question unambiguously. This can be done by defining the question based on PICOS (Population, Interventions, Comparators, Outcomes, Study designs). Some methodologists recommend also including a 'Timeframe' component. This component indicates the time period within which the treatment, exposure, or outcome took place. It is important to be sufficiently specific for each component of PICOS(T). A detailed elaboration of the research question based on PICOS(T) gives concrete direction to the conduct of the systematic review, such as the search strategy, inclusion and exclusion criteria, and data extraction.

Once a researcher has formulated a research question, it is advisable to check the literature to see whether a similar systematic review has already been published, or a similar protocol has already been archived in PROPERSO. If a similar systematic review exists or is in preparation, the researcher must critically consider whether their planned systematic review provides a meaningful addition to the scientific literature.

After defining the research question, inclusion and exclusion criteria are formulated. These criteria are used to set up the search and to select the studies that answer the research question. Based on the inclusion and exclusion criteria, a structured and sensitive literature search is conducted. Commonly used bibliographic databases of scientific publications are PubMed and Embase. The use of multiple databases and sources, of both published studies and grey literature, is recommended to prevent the risk of bias in the dataset. However, this often results in a large number of studies.

The studies found through the search are checked against the inclusion and exclusion criteria in order to select the studies that answer the review question. It is advisable to have this selection process carried out independently by at least two members of the research group.

A clinical information specialist, often affiliated with the medical library, can provide support in correctly translating the research question into a search query [4]. They can also advise on how to correctly and efficiently translate the inclusion and exclusion of studies into a search strategy.

Once the researcher has selected the studies to include in the review, a suitable checklist is used to assess their methodological quality. The right choice of checklist depends on the study design of the included studies. For example, checklists have been designed for randomized and non-randomized intervention studies [5], diagnostic studies [6], case studies [7], and checklists for answering etiological and prognostic research questions and prediction models. A specialized methodologist can advise on choosing the right checklist.

In this phase, the reported research data from the included studies are extracted and stored in a database. At Amsterdam UMC, this can be done, for example, in Castor. It is not recommended to store, edit, or analyze the data in Excel, because it is not possible to work with syntax in this package, which is a statistical requirement for good research practice. It is advisable for two researchers to extract the data from the studies independently of each other (double data entry). The two resulting data files are then compared with each other. If there are differences, the data are compared again with the source documents and the errors are corrected.

During the extraction process, it will sometimes also be necessary to decide exactly which numbers should be taken from an article. For instance, a number in a table may differ from the number given in the text. It is advisable to consult with the co-authors on this kind of decision and to note why a particular value was chosen. It is possible that, when extracting the research data, not all desired parameters are found in the articles. Sometimes it is possible to calculate these parameters based on other information in the article. An example of this is when the 'standard error' is reported, but the researcher needs the standard deviation. Depending on the information available, a statistician can help with the conversion. But sometimes there simply is not enough information available. In that case, one can consider emailing the corresponding author to ask whether the missing information can be found elsewhere, or to request that they send that information.

The results of the systematic review are presented in the form of tables and figures, such as a PRISMA flowchart to show the results of the search strategy. A 'Summary of Findings' table gives a concise overview of the amount of 'evidence', the quality of that evidence, and the size of the effects. GRADE is the designated method for assessing the strength of evidence.

A meta-analysis is a statistical technique in which the results of different studies are combined into an 'overall' result [2]. An important condition for performing a meta-analysis is that the studies are sufficiently similar to one another. In general, it is not recommended to perform a meta-analysis on results from a combination of randomized trials, observational cohorts, and case series. It is also not recommended to include very small studies or studies of "poor" methodological quality. Furthermore, it is advisable to check whether it is plausible that each individual is included only once in the meta-analysis. This is especially important when there are multiple articles describing a single randomized trial, cohort, or registry.

When reporting or publishing the systematic review, it is important to include all the necessary information. The PRISMA guidelines provide good guidance here [8]. Sometimes it is sufficient to use only the PRISMA guidelines. But extensions of these have also been published. These extensions of the PRISMA guidelines give specific instructions on what information should be included in certain types of systematic reviews. For example, there are guidelines for reviews of diagnostic studies [9], adverse effects [10], and reviews that use a network meta-analysis [11] or individual patient-level data [12]. For reviews of quantitative studies, the ENTREQ guideline has been established [13].

Finally, it is important to clearly state in the report or publication, with the relevant reference, that a protocol was written before the systematic review was conducted.

1. Riley RD, Moons KGM, Snell KIE, Ensor J, Hooft L, Altman DG, Hayden J, Collins GS, Debray TPA. A guide to systematic review and meta-analysis of prognostic factor studies. BMJ. 2019 Jan 30;364:k4597. DOI 10.1136/bmj.k4597
2. Field AP, Gillett R. How to do a meta-analysis. Br J Math Stat Psychol. 2010 Nov;63(Pt 3):665-94. DOI 10.1348/000711010X502733
3. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA; PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015 Jan 1;4:1. DOI 10.1186/2046-4053-4-1.
4. 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 Jul;75:40-6.DOI 10.1016/j.jclinepi.2016.01.021.
5. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011 Oct 18;343:d5928. DOI 10.1136/bmj.d5928.
6. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MM, Sterne JA, Bossuyt PM; QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011 Oct 18;155(8):529-36. DOI 10.7326/0003-4819-155-8-201110180-00009.
7. Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med. 2018 Apr;23(2):60-63. DOI 10.1136/bmjebm-2017-110853.
8. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009 Oct;62(10):1006-12. DOI 10.1016/j.jclinepi.2009.06.005.
9. McInnes MDF, Moher D, Thombs BD, McGrath TA, Bossuyt PM; the PRISMA-DTA Group, Clifford T, Cohen JF, Deeks JJ, Gatsonis C, Hooft L, Hunt HA, Hyde CJ, Korevaar DA, Leeflang MMG, Macaskill P, Reitsma JB, Rodin R, Rutjes AWS, Salameh JP, Stevens A, Takwoingi Y, Tonelli M, Weeks L, Whiting P, Willis BH. Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement. JAMA. 2018 Jan 23;319(4):388-396. DOI 10.1001/jama.2017.19163.
10. Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, Moher D, Vohra S; PRISMAHarms Group. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ. 2016 Feb 1;352:i157. DOI 10.1136/bmj.i157.
11. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, Mulrow C, Catalá-López F, Gøtzsche PC, Dickersin K, Boutron I, Altman DG, Moher D. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015 Jun 2;162(11):777-84. DOI 10.7326/M14-2385.
12. Stewart LA, Clarke M, Rovers M, Riley RD, Simmonds M, Stewart G, Tierney JF; PRISMA-IPD Development Group. Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA. 2015 Apr 28;313(16):1657-65. DOI 10.1001/jama.2015.3656.
13. Tong A, Flemming K, McInnes E, Oliver S, Craig J. Enhancing transparency in reporting the synthesis of qualitative research: ENTREQ. BMC Med Res Methodol. 2012 Nov 27;12:181. DOI 10.1186/1471-2288-12-181.

• Cochrane Netherlands is one of the centers worldwide that represents the work of Cochrane.
• The Cochrane Handbook for Systematic Reviews.
• Cochrane Reviews and their protocols are published in The Cochrane Library.
• Researchers can register a protocol with PROSPERO, the international prospective register of systematic reviews, in order to archive it publicly.
• The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
• Cochrane Methods Prognosis Review Group Tools.
• Cochrane Qualitative and Implementation Methods Group
• The Equator Network has a library of guidelines about what information should be included in a scientific article.
• The GRADE working group.

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