26. Limitations

What to write

Study limitations, including sources of potential bias, statistical uncertainty and generalisability.

Explanation

Like other clinical trials and studies, diagnostic accuracy studies are at risk of bias; they can generate estimates of the test's accuracy that do not reflect the true performance of the test, due to flaws or deficiencies in study design and analysis.1,2 In addition, imprecise accuracy estimates, with wide CIs, should be interpreted with caution. Because of differences in design, participants and procedures, the findings generated by one particular diagnostic accuracy study may not be obtained in other conditions; their generalisability may be limited.3

In the Discussion section, authors should critically reflect on the validity of their findings, address potential limitations and elaborate on why study findings may or may not be generalisable. As bias can come down to overestimation or underestimation of the accuracy of the index test under investigation, authors should discuss the direction of potential bias, along with its likely magnitude. Readers are then informed of the likelihood that the limitations jeopardise the study's results and conclusions (see also Item 27).4

Some journals explicitly encourage authors to report on study limitations, but many are not specific about which elements should be addressed.5 For diagnostic accuracy studies, we highly recommend that at least potential sources of bias are discussed, as well as imprecision, and concerns related to the selection of patients and the setting in which the study was performed.

In the example, the authors identified two potential sources of bias that are common in diagnostic accuracy studies: not all test results were verified by the reference standard, and there was a time interval between index test and reference standard, allowing the target condition to change. They also discussed the magnitude of this potential bias, and the direction: whether this may have led to overestimations or underestimations of test accuracy.

Example

‘This study had limitations. First, not all patients who underwent CT colonography (CTC) were assessed by the reference standard methods. […] However, considering that the 41 patients who were eligible but did not undergo the reference standard procedures had negative or only mildly positive CTC findings, excluding them from the analysis of CTC diagnostic performance may have slightly overestimated the sensitivity of CTC (ie, partial verification bias). Second, there was a long time interval between CTC and the reference methods in some patients, predominately those with negative CTC findings. […] If anything, the prolonged interval would presumably slightly underestimate the sensitivity and NPV of CTC for non-cancerous lesions, since some “missed” lesions could have conceivably developed or increased in size since the time of CTC’.6

Training

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References

1.
Whiting P, Rutjes AWS, Reitsma JB, Glas AS, Bossuyt PMM, Kleijnen J. Sources of variation and bias in studies of diagnostic accuracy: A systematic review. Annals of Internal Medicine. 2004;140(3):189-202. doi:10.7326/0003-4819-140-3-200402030-00010
2.
Whiting PF, Rutjes AWS, Westwood ME, Mallett S. A systematic review classifies sources of bias and variation in diagnostic test accuracy studies. Journal of Clinical Epidemiology. 2013;66(10):1093-1104. doi:10.1016/j.jclinepi.2013.05.014
3.
Irwig LM , bossuyt PM , glasziou PP , et al . Designing studies to ensure that estimates of test accuracy will travel. In: Knottnerus JA, ed . The evidence base of clinical diagnosis. London: BMJ publishing group, 2002:95–116.
4.
Riet G ter, Chesley P, Gross AG, et al. All that glitters isn’t gold: A survey on acknowledgment of limitations in biomedical studies. Ouzounis CA, ed. PLoS ONE. 2013;8(11):e73623. doi:10.1371/journal.pone.0073623
5.
Ioannidis JPA. Limitations are not properly acknowledged in the scientific literature. Journal of Clinical Epidemiology. 2007;60(4):324-329. doi:10.1016/j.jclinepi.2006.09.011
6.
Park SH, Lee JH, Lee SS, et al. CT colonography for detection and characterisation of synchronous proximal colonic lesions in patients with stenosing colorectal cancer. Gut. 2011;61(12):1716-1722. doi:10.1136/gutjnl-2011-301135

Citation

For attribution, please cite this work as:
Bossuyt PM, Reitsma JB, Bruns DE, et al. The STARD reporting guideline for writing diagnostic accuracy study articles. The EQUATOR Network guideline dissemination platform. doi:10.1234/equator/1010101

Reporting Guidelines are recommendations to help describe your work clearly

Your research will be used by people from different disciplines and backgrounds for decades to come. Reporting guidelines list the information you should describe so that everyone can understand, replicate, and synthesise your work.

Reporting guidelines do not prescribe how research should be designed or conducted. Rather, they help authors transparently describe what they did, why they did it, and what they found.

Reporting guidelines make writing research easier, and transparent research leads to better patient outcomes.

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Who reads research?

You work will be read by different people, for different reasons, around the world, and for decades to come. Reporting guidelines help you consider all of your potential audiences. For example, your research may be read by researchers from different fields, by clinicians, patients, evidence synthesisers, peer reviewers, or editors. Your readers will need information to understand, to replicate, apply, appraise, synthesise, and use your work.

Cohort studies

A cohort study is an observational study in which a group of people with a particular exposure (e.g. a putative risk factor or protective factor) and a group of people without this exposure are followed over time. The outcomes of the people in the exposed group are compared to the outcomes of the people in the unexposed group to see if the exposure is associated with particular outcomes (e.g. getting cancer or length of life).

Source.

Case-control studies

A case-control study is a research method used in healthcare to investigate potential risk factors for a specific disease. It involves comparing individuals who have been diagnosed with the disease (cases) to those who have not (controls). By analysing the differences between the two groups, researchers can identify factors that may contribute to the development of the disease.

An example would be when researchers conducted a case-control study examining whether exposure to diesel exhaust particles increases the risk of respiratory disease in underground miners. Cases included miners diagnosed with respiratory disease, while controls were miners without respiratory disease. Participants' past occupational exposures to diesel exhaust particles were evaluated to compare exposure rates between cases and controls.

Source.

Cross-sectional studies

A cross-sectional study (also sometimes called a "cross-sectional survey") serves as an observational tool, where researchers capture data from a cohort of participants at a singular point. This approach provides a 'snapshot'— a brief glimpse into the characteristics or outcomes prevalent within a designated population at that precise point in time. The primary aim here is not to track changes or developments over an extended period but to assess and quantify the current situation regarding specific variables or conditions. Such a methodology is instrumental in identifying patterns or correlations among various factors within the population, providing a basis for further, more detailed investigation.

Source

Systematic reviews

A systematic review is a comprehensive approach designed to identify, evaluate, and synthesise all available evidence relevant to a specific research question. In essence, it collects all possible studies related to a given topic and design, and reviews and analyses their results.

The process involves a highly sensitive search strategy to ensure that as much pertinent information as possible is gathered. Once collected, this evidence is often critically appraised to assess its quality and relevance, ensuring that conclusions drawn are based on robust data. Systematic reviews often involve defining inclusion and exclusion criteria, which help to focus the analysis on the most relevant studies, ultimately synthesising the findings into a coherent narrative or statistical synthesis. Some systematic reviews will include a meta-analysis.

Source

Systematic review protocols

TODO

Meta analyses of Observational Studies

TODO

Randomised Trials

A randomised controlled trial (RCT) is a trial in which participants are randomly assigned to one of two or more groups: the experimental group or groups receive the intervention or interventions being tested; the comparison group (control group) receive usual care or no treatment or a placebo. The groups are then followed up to see if there are any differences between the results. This helps in assessing the effectiveness of the intervention.

Source

Randomised Trial Protocols

TODO

Qualitative research

Research that aims to gather and analyse non-numerical (descriptive) data in order to gain an understanding of individuals' social reality, including understanding their attitudes, beliefs, and motivation. This type of research typically involves in-depth interviews, focus groups, or field observations in order to collect data that is rich in detail and context. Qualitative research is often used to explore complex phenomena or to gain insight into people's experiences and perspectives on a particular topic. It is particularly useful when researchers want to understand the meaning that people attach to their experiences or when they want to uncover the underlying reasons for people's behavior. Qualitative methods include ethnography, grounded theory, discourse analysis, and interpretative phenomenological analysis.

Source

Case Reports

TODO

Diagnostic Test Accuracy Studies

Diagnostic accuracy studies focus on estimating the ability of the test(s) to correctly identify subjects with a predefined target condition, or the condition of interest (sensitivity) as well as to clearly identify those without the condition (specificity).

Prediction Models

Prediction model research is used to test the accurarcy of a model or test in estimating an outcome value or risk. Most models estimate the probability of the presence of a particular health condition (diagnostic) or whether a particular outcome will occur in the future (prognostic). Prediction models are used to support clinical decision making, such as whether to refer patients for further testing, monitor disease deterioration or treatment effects, or initiate treatment or lifestyle changes. Examples of well known prediction models include EuroSCORE II for cardiac surgery, the Gail model for breast cancer, the Framingham risk score for cardiovascular disease, IMPACT for traumatic brain injury, and FRAX for osteoporotic and hip fractures.

Source

Animal Research

TODO

Quality Improvement in Healthcare

Quality improvement research is about finding out how to improve and make changes in the most effective way. It is about systematically and rigourously exploring "what works" to improve quality in healthcare and the best ways to measure and disseminate this to ensure positive change. Most quality improvement effectiveness research is conducted in hospital settings, is focused on multiple quality improvement interventions, and uses process measures as outcomes. There is a great deal of variation in the research designs used to examine quality improvement effectiveness.

Source

Economic Evaluations in Healthcare

TODO

Meta Analyses

A meta-analysis is a statistical technique that amalgamates data from multiple studies to yield a single estimate of the effect size. This approach enhances precision and offers a more comprehensive understanding by integrating quantitative findings. Central to a meta-analysis is the evaluation of heterogeneity, which examines variations in study outcomes to ensure that differences in populations, interventions, or methodologies do not skew results. Techniques such as meta-regression or subgroup analysis are frequently employed to explore how various factors might influence the outcomes. This method is particularly effective when aiming to quantify the effect size, odds ratio, or risk ratio, providing a clearer numerical estimate that can significantly inform clinical or policy decisions.

How Meta-analyses and Systematic Reviews Work Together

Systematic reviews and meta-analyses function together, each complementing the other to provide a more robust understanding of research evidence. A systematic review meticulously gathers and evaluates all pertinent studies, establishing a solid foundation of qualitative and quantitative data. Within this framework, if the collected data exhibit sufficient homogeneity, a meta-analysis can be performed. This statistical synthesis allows for the integration of quantitative results from individual studies, producing a unified estimate of effect size. Techniques such as meta-regression or subgroup analysis may further refine these findings, elucidating how different variables impact the overall outcome. By combining these methodologies, researchers can achieve both a comprehensive narrative synthesis and a precise quantitative measure, enhancing the reliability and applicability of their conclusions. This integrated approach ensures that the findings are not only well-rounded but also statistically robust, providing greater confidence in the evidence base.

Why Don't All Systematic Reviews Use a Meta-Analysis?

Systematic reviews do not always have meta-analyses, due to variations in the data. For a meta-analysis to be viable, the data from different studies must be sufficiently similar, or homogeneous, in terms of design, population, and interventions. When the data shows significant heterogeneity, meaning there are considerable differences among the studies, combining them could lead to skewed or misleading conclusions. Furthermore, the quality of the included studies is critical; if the studies are of low methodological quality, merging their results could obscure true effects rather than explain them.

Protocol

A plan or set of steps that defines how something will be done. Before carrying out a research study, for example, the research protocol sets out what question is to be answered and how information will be collected and analysed.

Source

Medical test

Any method for collecting additional information about the current or future health status of a patient.

Index test

The test under evaluation.

Target condition

The disease or condition that the index test is expected to detect.

Clinical reference standard

The best available method for establishing the presence or absence of the target condition; a gold standard would be an error-free reference standard.

Sensitivity

Proportion of those with the target condition who test positive with the index test.

Specificity

Proportion of those without the target condition who test negative with the index test.

Intended use of the test

Whether the index test is used for diagnosis, screening, staging, monitoring, surveillance, prediction, prognosis, or other reasons.

Role of the test

The position of the index test relative to other tests for the same condition (for example, triage, replacement, add-on, new test).

Indeterminate results

Results that are neither positive or negative.