Systematic reviews aim to provide a comprehensive and rigorous synthesis of the best available evidence to inform health policy and practice.1-4 Although case series are not traditionally included in systematic reviews assessing the effectiveness of an intervention or therapy, they have contributed greatly to the medical literature and can offer valuable information relating to the benefits and harms of certain treatments.5,6 As such, case series can be considered for inclusion in systematic reviews of effectiveness, particularly in the absence of experimental designs such as randomized controlled trials and observational analytical studies.
There is an element of confusion regarding both the nomenclature and characteristics of a case series, with the definition varying across the medical literature, resulting in the inconsistent use of the term.7-9 The gamut of case series is wide, with some studies claiming to be a case series that are realistically a collection of case reports, while others are more akin to cohort studies or even quasi-experimental, before and after studies. This has created difficulty in assigning case series a position in the hierarchy of evidence and identifying an appropriate critical appraisal tool.7-9 This is not only a challenge with case series studies but also within the broader epidemiological literature, resulting in efforts to classify and group various features of different types of research studies through the use of algorithms or flowcharts.10-13 In these guidance documents, case series are described as an observational and non-comparative study design.
According to one dictionary of epidemiology, case series are “a collection of subjects (usually, patients) with common characteristics used to describe some clinical, pathophysiological, or operational aspect of a disease, treatment, exposure, or diagnostic procedure.”14(p.33) It is noted that a case series “does not include a comparison group and is often based on prevalent cases and on a sample of convenience.”14(p.33) In the authors’ view, case series are best described as observational (that is, not experimental and not randomized), descriptive studies, without a control (or comparator group). Dekkers et al.8 define a case series as a study in which “only patients with the outcome are sampled (either those who have an exposure or those who are selected without regard to exposure), which does not permit calculation of an absolute risk.”(p.39) The outcome could be a disease or disease-related. This is in contrast to cohort studies, where sampling is based on exposure (or characteristic), and case-control studies, where there is a comparison group without the disease.
All systematic reviews incorporate a process of critiquing and appraising the research evidence. The purpose of this appraisal is to assess the methodological quality of a study and to determine the extent to which a study has addressed the possibility of bias in its design, conduct, and analysis.15 All studies selected for inclusion in a systematic review (that is, those that fulfill the a priori eligibility criteria described in the protocol) need to be subjected to rigorous assessment of their quality of conduct by two independent critical appraisers. The results of this appraisal can then be used to inform synthesis and interpretation of the results of the systematic review.15
Systematic reviews often use critical appraisal tools that are study-design specific. There may be separate tools used to appraise randomized controlled trials, cohort studies, cross-sectional studies, and so on.4 Because case series are an uncontrolled (and non-experimental) study design, they are associated with an increased risk of bias5 and must be appraised with the same scrutiny expected of study designs associated with higher levels of evidence.16 For example, the completeness of a case series contributes to its reliability,8 with studies that indicate a consecutive and complete inclusion considered more reliable than those that do not.
The JBI approach to systematic reviews is one of pragmatism, where the aim is to include a summary of the best available evidence and not only randomized controlled trials.17-19 As such, there was a need for a standardized tool that would allow for transparent and repeatable appraisals of case series included in systematic reviews of effectiveness. This paper documents the process of the creation and application of such a tool.
In 2014, a working group of researchers and methodologists was formed within JBI to investigate the use of case series studies in systematic reviews and the development of a critical appraisal tool for these designs. It was clear from the beginning that the group needed to ensure a clear understanding and definition for case series among all members. The group agreed with the principles outlined by Dekkers et al.8 and defined case series as studies where only patients with a certain disease or disease-related outcome are sampled. Before proceeding to develop a new tool, the group conducted a search and review of existing methodological, epidemiological, and health research literature on case series as well as previously published appraisal tools for case series. Although few guides and tools were identified,20-22 the group felt that this guidance inadequately covered all important methodological areas specific to case series designs. Over a period of one year with many methodological discussions, the group developed a tool, which was then piloted internally by the authors. Items covered in the tools were selected based on the authors’ review of the methodological literature and relevant items from other JBI tools. Based on the results of this pilot, the final tool was then drafted and sent to the JBI international Scientific Committee for further review and feedback. Following minor modifications, the tool was approved by the Scientific Committee and made available to JBI reviewers (Table 1).23 It was also embedded in the JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; Adelaide, Australia, JBI).24
Within the tool, some of the items relate to risk of bias, whereas others relate to ensuring adequate reporting and statistical analysis. A response of “no” to any of the following questions negatively impacts the overall quality of a case series.
How to use this tool
- Were there clear criteria for inclusion in the case series?
- The authors should provide clear inclusion criteria (and exclusion criteria where appropriate) for the study participants. The inclusion/exclusion criteria should be specified (eg, risk, stage of disease progression) with sufficient detail and all the necessary information critical to the study.
- Was the condition measured in a standard, reliable way for all participants included in the case series?
- The study should clearly describe the method of measurement of the condition. This should be done in a standard (ie, same way for all patients) and reliable (ie, repeatable and reproducible results) way.
- Were valid methods used for identification of the condition for all participants included in the case series?
- Many health problems are not easily diagnosed or defined, and some measures may not be capable of including or excluding appropriate levels or stages of the health problem. If the outcomes were assessed based on existing definitions or diagnostic criteria, then the answer to this question is likely to be “yes.” If the outcomes were assessed using observer-reported or self-reported scales, the risk of over- or under-reporting is increased, and objectivity is compromised. Importantly, researchers need to determine if the measurement tools used were validated instruments, as this has a significant impact on outcome assessment validity.
- Did the case series have consecutive inclusion of participants?
- Studies that indicate a consecutive inclusion are more reliable than those that do not. For example, a case series that states, “We included all patients (24) with osteosarcoma who presented to our clinic between March 2005 and June 2006” is more reliable than a study that simply states, “We report a case series of 24 people with osteosarcoma.”
- Did the case series have complete inclusion of participants?
- The completeness of a case series contributes to its reliability.8 Studies that indicate a complete inclusion are more reliable than those that do not. As stated above, a case series that states, “We included all patients (24) with osteosarcoma who presented to our clinic between March 2005 and June 2006” is more reliable than a study that simply states, “We report a case series of 24 people with osteosarcoma.”
- Was there clear reporting of the demographics of the participants included in the study?
- The case series should clearly describe relevant participants’ demographics such as the following information where relevant: participant's age, sex, education, geographic region, ethnicity, and time period.
- Was there clear reporting of clinical information of the participants?
- There should be clear reporting of clinical information of the participants, such as the following information where relevant: disease status, comorbidities, stage of disease, previous interventions/treatment, results of diagnostic tests, etc.
- Were the outcomes or follow-up results of cases clearly reported?
- The results of any intervention or treatment should be clearly reported in the case series. A good case series should clearly describe the clinical condition post-intervention in terms of the presence or lack of symptoms. The outcomes of management/treatment when presented as images or figures can help in conveying the information to the reader/clinician. It is important that adverse events are clearly documented and described, particularly when a new or unique condition is being treated or when a new drug or treatment is used. In addition, unanticipated events, if any, that may yield new or useful information should be identified and clearly described.
- Was there clear reporting of the presenting sites’/clinics’ demographic information?
- Certain diseases or conditions vary in prevalence across different geographic regions and populations (eg, women men, sociodemographic variables between countries). The study sample should be described in sufficient detail so that other researchers can determine if it is comparable to the population of interest to them.
- Was statistical analysis appropriate?
- As with any consideration of statistical analysis, consideration should be given to whether there was a more appropriate alternate statistical method that could have been used. The methods section of studies should be detailed enough for reviewers to identify which analytical techniques were used and whether these were suitable.
This critical appraisal tool for case series studies has been publicly available on the JBI website since December, 2017. Since then, it has been used in systematic reviews25-27 and cited in systematic review protocols.28-30 As evidenced from these reviews and protocols, the inclusion of a case series is typically most beneficial in reviews of effectiveness, prevalence and/or incidence, and etiology and/or risk, particularly when there are no other studies to consider.31
Recently, multiple new case series tools have been published in the literature.5,22 Both Murad et al.5 and Guo et al.22 have documented the creation and provision of similar tools to evaluate the methodological quality of a case series. The majority of the questions included in both of these tools address similar issues to those presented in the JBI tool, with minor variations in wording that could have ramifications for how appraisers interpret the results after using each tool. While there are advantages and disadvantages associated with each tool, the assessment of risk of bias, particularly when assessing observational studies, may be too complex a task for any single tool.32 Assessment of risk of bias can be further hampered by a lack of compatibility between the chosen tool and the review team, with some teams feeling more comfortable or familiar with one tool over another. This highlights the importance of piloting the tool during the critical appraisal process. Some questions may need to be tailored to suit the research focus, while a scoring framework of “yes,” “no,” or “not applicable (N/A)” may not be suitable for each question relevant to the study design or the research parameters. It is the authors’ opinion that all three tools provide a clear and logical format for the appraisal of case series. The advantage of the Guo et al.22 and JBI tools is that they are designed specifically for case series (as opposed to a joint tool for case series and case reports), which allows them to have additional questions and be more specific to case series designs.32
In addition to these tools, there is a tool that has been developed to assess the risk of bias when conducting an effectiveness review and when including non-randomized studies: the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I).33 This is a domain-based tool, and although it is designed for non-randomized studies, it is particularly designed for studies with “cohort-like” designs or designs with a control group. As case series studies do not have a control group, this tool may not be ideal for these study designs, nor would the Newcastle-Ottawa scale.34 In a review of tools for critically appraising non-randomized studies, Quigley et al.35 recommend that because there is no current consensus on which tool to use, systematic reviewers should select an appropriate tool based on the study design of selected papers for inclusion in their review.
Many researchers prefer using a domain-based approach in the critical appraisal of primary literature.36,37 The main domains of bias assessed in observational studies include confounding bias, selection bias and information bias (including measurement, detection, classification, analysis, and reporting bias), and these biases can be assessed through the use of signaling questions.37 Although the tool presented in this paper has not been designed based on the domain approach, the questions can be seen as signaling questions for particular domains of bias. For example, questions 1, 4, and 5 can be considered signaling questions for the domain “bias in selection of participants into the study”; questions 2 and 3 for the domain “bias in measurement of outcomes”; questions 6 and 7 for the domain “bias in selection of the reported results”; and question 8 for the domain “bias due to missing data.”
The authors often receive queries from reviewers wishing to use the tool to provide advice on how much weight to assign each question, and what the cut-off score should be for inclusion in a systematic review. These questions presuppose that the purpose of appraisal in systematic reviews is to include only those studies that are of high quality and to exclude those of poor quality. While this is one way to use the results of critical appraisal in reviews, it is not the only approach, and it may not be appropriate in many situations. The guidance to authors wishing to use this tool in terms of cut-off values/scores and determining whether a study is low, moderate or high quality, is that these thresholds are best decided by the systematic reviewers themselves. Generally, cut-off scores are advised against, because the critical appraisal questions are not all “equal.” As such, simply tallying the “yes” responses does not truly give an accurate indication of the specific problems of a study. The authors suggest presenting the results of critical appraisal for all questions via a table rather than summarizing with a score. Ideally, two reviewers will be involved in the critical appraisal for the review.
This tool is now in active use by the JBI Collaboration and other systematic reviewers who are including case series designs in their reviews. This tool was developed based on methodological and epidemiological principles and has been reviewed internally by the author group in addition to the JBI Scientific Committee. It has been deemed as acceptable and appropriate by these groups and as such has demonstrated face validity. Further validation efforts are now required to establish the psychometric properties of the tool in addition to other issues, such as its acceptability, timeliness, and ease of use. As previously described, another program of work relates to transferring this tool into a domain-based approach. However, given the lack of any current validated tool for critiquing case series studies, it was the view of the group that this tool be made widely available to assist systematic reviewers with the conduct of their reviews.
When there is limited availability of high-quality experimental studies (such as randomized controlled trials) on the effectiveness or harms of an intervention, case series may represent the best available evidence to inform clinical practice. As such, a critical appraisal tool is required. The JBI critical appraisal tool for case series offers systematic reviewers an approved method to assess the methodological quality of these studies.
Dr. Kylie Porritt for her contribution during the drafting of this paper.
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