Jacqueline Dinnes

MANAGEMENT OF ENDOCRINE DISEASE: Imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis.

Objective Adrenal masses are incidentally discovered in 5% of CT scans. In 2013/2014, 81 million CT examinations were undertaken in the USA and 5 million in the UK. However, uncertainty remains around the optimal imaging approach for diagnosing malignancy. We aimed to review the evidence on the accuracy of imaging tests for differentiating malignant from benign adrenal masses. Design A systematic review and meta-analysis was conducted. Methods We searched MEDLINE, EMBASE, Cochrane CENTRAL Register of Controlled Trials, Science Citation Index, Conference Proceedings Citation Index, and ZETOC (January 1990 to August 2015). We included studies evaluating the accuracy of CT, MRI, or 18F-fluoro-deoxyglucose (FDG)-PET compared with an adequate histological or imaging-based follow-up reference standard. Results We identified 37 studies suitable for inclusion, after screening 5469 references and 525 full-text articles. Studies evaluated the accuracy of CT (n=16), MRI (n=15), and FDG-PET (n=9) and were generally small and at high or unclear risk of bias. Only 19 studies were eligible for meta-analysis. Limited data suggest that CT density >10HU has high sensitivity for detection of adrenal malignancy in participants with no prior indication for adrenal imaging, that is, masses with ≤10HU are unlikely to be malignant. All other estimates of test performance are based on too small numbers. Conclusions Despite their widespread use in routine assessment, there is insufficient evidence for the diagnostic value of individual imaging tests in distinguishing benign from malignant adrenal masses. Future research is urgently needed and should include prospective test validation studies for imaging and novel diagnostic approaches alongside detailed health economics analysis.

The basis for monitoring strategies in clinical guidelines: a case study of prostate-specific antigen for monitoring in prostate cancer

Background: The volume of published literature on the evaluation and use of tests for monitoring purposes is sparse. Our aim was to determine the extent to which recommendations for monitoring prostate-specific antigen to detect recurrent prostate cancer consider key factors that should inform rule-based strategies for monitoring. Methods: We reviewed the recommendations made in clinical guidelines for the repeated measurement of prostate-specific antigen in men who have received primary treatment for localized prostate cancer. We assessed the guidelines using the Appraisal of Guidelines for Research and Evaluation Framework. Results: We identified guidelines and statements of best practice from nine organizations. We saw considerable inconsistency in recommendations for testing for prostate-specific antigen as a form of monitoring. Recommendations on when to test appeared to be almost exclusively determined using standard follow-up schedules rather than any scientific basis. Recommendations on when to take action were primarily based on consensus statements or retrospective case series. Eight of the nine guidelines acknowledged the potential presence of measurement variability, but they did not attempt to account for the effect of such variability on the interpretation of the results of tests for prostate-specific antigen. Many recommendations were made with few or no supporting references; however, a variety of papers were cited across guidelines. Of 48 papers cited, 29.1% (14/48) were reviews; the remaining 70.8% (34/48) of papers cited were primary studies. Interpretation: A systematic approach to the development of monitoring schedules using prostate-specific antigen in guidelines for prostate cancer is lacking, due to inadequacies in the available evidence and its use.

Tests to assist in the staging of cutaneous squamous cell carcinoma: a generic protocol

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To determine the diagnostic accuracy of sentinel lymph node biopsy (SLNB) for the detection of nodal metastases (in the investigated nodal basin) for the staging of cutaneous squamous cell cancer (cSCC). To determine the diagnostic accuracy of imaging tests, including ultrasound, computed tomography, magnetic resonance imaging and positron emission tomography, alone or in combination, for the detection of any metastasis for the staging of cutaneous squamous cell cancer. To determine the diagnostic accuracy of imaging tests for the detection of nodal metastases in the staging of cutaneous squamous cell cancer. To determine the diagnostic accuracy of imaging tests for the detection of distant metastases in the staging of cutaneous squamous cell cancer. We will estimate these separately for those undergoing primary staging and those who have experienced a disease recurrence. Sources of heterogeneity We will consider a range of potential sources of heterogeneity for investigation in each individual test review. These may vary between reviews but may include the following. i. Population characteristics • Primary tumour site (head and neck, trunk, limb, and other) • Primary staging versus mixed or unclear populations (i.e. including staging of recurrent disease) 1 Tests to assist in the staging of cutaneous squamous cell carcinoma: a generic protocol (Protocol) Copyright

The Moses-Littenberg meta-analytical method generates systematic differences in test accuracy compared to hierarchical meta-analytical models.

Objective To compare meta-analyses of diagnostic test accuracy using the Moses–Littenberg summary receiver operating characteristic (SROC) approach with those of the hierarchical SROC (HSROC) model. Study Design and Setting Twenty-six data sets from existing test accuracy systematic reviews were reanalyzed with the Moses–Littenberg model, using equal weighting (“E-ML”) and weighting by the inverse variance of the log DOR (“W-ML”), and with the HSROC model. The diagnostic odds ratios (DORs) were estimated and covariates added to both models to estimate relative DORs (RDORs) between subgroups. Models were compared by calculating the ratio of DORs, the ratio of RDORs, and P-values for detecting asymmetry and effects of covariates on DOR. Results Compared to the HSROC model, the Moses–Littenberg model DOR estimates were a median of 22% (“E-ML”) and 47% (“W-ML”) lower at Q*, and 7% and 42% lower at the central point in the data. Instances of the ML models giving estimates higher than the HSROC model also occurred. Investigations of heterogeneity also differed; the Moses–Littenberg models on average estimating smaller differences in RDOR. Conclusions Moses–Littenberg meta-analyses can generate lower estimates of test accuracy, and smaller differences in accuracy, compared to mathematically superior hierarchical models. This has implications for the usefulness of meta-analyses using this approach. We recommend meta-analysis of diagnostic test accuracy studies to be conducted using available hierarchical model–based approaches.

Tests to assist in the staging of cutaneous melanoma: A generic protocol

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To determine the diagnostic accuracy of SLNB for the detection of nodal metastases (in the investigated nodal basin) for the staging of cutaneous invasive melanoma. To determine the diagnostic accuracy of imaging tests for the detection of any metastasis in the primary staging of cutaneous invasive melanoma (i.e. staging at presentation). To determine the diagnostic accuracy of imaging tests for the detection of any metastasis in the staging of recurrence in cutaneous invasive melanoma (i.e. re-staging prompted by findings on routine follow-up). To determine the diagnostic accuracy of imaging tests for the detection of nodal metastases in the staging of cutaneous invasive melanoma. To determine the diagnostic accuracy of imaging tests for the detection of distant metastases in the staging of cutaneous invasive melanoma. These will be estimated separately for those undergoing primary staging and those who have experienced a disease recurrence. Investigation of sources of heterogeneity We will consider a range of potential sources of heterogeneity for investigation in each individual test review. These may vary between reviews but may include the following. 1 Tests to assist in the staging of cutaneous melanoma: a generic protocol (Protocol) Copyright

Test-treatment RCTs are susceptible to bias: a review of the methodological quality of randomized trials that evaluate diagnostic tests

BackgroundThere is a growing recognition for the need to expand our evidence base for the clinical effectiveness of diagnostic tests. Many international bodies are calling for diagnostic randomized controlled trials to provide the most rigorous evidence of impact to patient health. Although these so-called test-treatment RCTs are very challenging to undertake due to their methodological complexity, they have not been subjected to a systematic appraisal of their methodological quality. The extent to which these trials may be producing biased results therefore remains unknown. We set out to address this issue by conducting a methodological review of published test-treatment trials to determine how often they implement adequate methods to limit bias and safeguard the validity of results.MethodsWe ascertained all test-treatment RCTs published 2004–2007, indexed in CENTRAL, including RCTs which randomized patients to diagnostic tests and measured patient outcomes after treatment. Tests used for screening, monitoring or prognosis were excluded. We assessed adequacy of sequence generation, allocation concealment and intention-to-treat, appropriateness of primary analyses, blinding and reporting of power calculations, and extracted study characteristics including the primary outcome.ResultsOne hundred three trials compared 105 control with 119 experimental interventions, and reported 150 primary outcomes. Randomization and allocation concealment were adequate in 57 and 37% of trials. Blinding was uncommon (patients 5%, clinicians 4%, outcome assessors 21%), as was an adequate intention-to-treat analysis (29%). Overall 101 of 103 trials (98%) were at risk of bias, as judged using standard Cochrane criteria.ConclusionTest-treatment trials are particularly susceptible to attrition and inadequate primary analyses, lack of blinding and under-powering. These weaknesses pose much greater methodological and practical challenges to conducting reliable RCT evaluations of test-treatment strategies than standard treatment interventions. We suggest a cautious approach that first examines whether a test-treatment intervention can accommodate the methodological safeguards necessary to minimize bias, and highlight that test-treatment RCTs require different methods to ensure reliability than standard treatment trials.Please see the companion paper to this article: http://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-016-0286-0.

What can available randomised controlled trials evaluating monitoring strategies tell us about the design and analysis of future trials

Background Randomised controlled trials (RCTs) of monitoring regimes present unique challenges. Trials of monitoring evaluate a strategy, “a planned and organised system of repeated assessments and subsequent decisions about additional interventions, such as starting, stopping or modifying treatment” [1] all of which should be specified in advance, and ideally supported by previous research. The complexity of the intervention and consequent potential for “interactions between tests, repeated tests, test results and the decisions based on these results” [1] also necessitates large sample sizes in order to detect an effect on important patient outcomes.