Benefit-Harm Analysis for Informed Decision Making on Participating in Colorectal Cancer Screening: A Modeling Study.

OBJECTIVES: To facilitate informed decision making on participating in colorectal cancer (CRC) screening, we assessed the benefit-harm balance of CRC screening for a wide range of subgroups over different time horizons. METHODS: The study combined incidence proportions of benefits and harms of (not) participating in CRC screening estimated by the Adenoma and Serrated pathway to CAncer microsimulation model, a preference eliciting survey, and benefit-harm balance modeling combining all outcomes to determine the net health benefit of CRC screening over 10, 20, and 30 years. Probability of net health benefit was estimated for 210 different subgroups based on age, sex, previous participation in CRC screening, and lifestyle. RESULTS: CRC screening was net beneficial in 183 of 210 subgroups over 30 years (median probability [MP] of 0.79, interquartile range [IQR] of 0.69-0.85) across subgroups. Net health benefit was greater for men (MP 0.82; IQR 0.69-0.89) than women (MP 0.76; IQR 0.67-0.83) and for those without history of participation in previous screenings (MP 0.84; IQR 0.80-0.89) compared with those with (MP 0.69; IQR 0.59-0.75). Net health benefit decreased with increasing age, from MP of 0.84 (IQR 0.80-0.86) at age 55 to 0.61 (IQR 0.56-0.71) at age 75. Shorter time horizons led to lower benefit, with MP of 0.70 (IQR 0.62-0.80) over 20 years and 0.54 (IQR 0.48-0.67) over 10 years. CONCLUSIONS: Our benefit-harm analysis provides information about net health benefit of screening participation, based on important characteristics and preferences of individuals, which could assist screening invitees in making informed decisions on screening participation.

Perceived Importance of the Benefits and Harms of Colorectal Cancer Screening: A Best-Worst Scaling Study.

OBJECTIVES: To elicit the relative importance of the benefits and harms of colorectal cancer (CRC) screening among potential screening participants in the Dutch population. METHODS: In a consensus meeting with 11 experts, risk reduction of CRC and CRC deaths (benefits) and complications from colonoscopy, stress of receiving positive fecal immunological test (FIT) results, as well as false-positive and false-negative FIT results (harms) were selected as determinant end points to consider during decision making. We conducted an online best-worst scaling survey among adults aged 55 to 75 years from the Dutch Health Care Consumer Panel of The Netherlands Institute for Health Services Research to elicit preference values for these outcomes. The preference values were estimated using conditional logit regression. RESULTS: Of 265 participants, 234 (89%) had ever participated in CRC screening. Compared with the stress of receiving a positive FIT result, the outcome perceived most important was the risk of CRC death (odds ratio [OR] 4.5; 95% confidence interval [CI] 3.9-5.1), followed by risk of CRC (OR 4.1; 95% CI 3.6-4.7), a false-negative FIT result (OR 3.1; 95% CI 2.7-3.5), colonoscopy complications (OR 1.6; 95% CI 1.4-1.8), and a false-positive FIT result (OR 1.4; 95% CI 1.3-1.6). The magnitude of these differences in perceived importance varied according to age, educational level, ethnic background, and whether the individual had previously participated in CRC screening. CONCLUSION: Dutch men and women eligible for FIT-based CRC screening perceive the benefits of screening to be more important than the harms.

Cross-Sectional Evaluation of Open Science Practices at Imaging Journals: A Meta-Research Study.

Objective: To evaluate open science policies of imaging journals, and compliance to these policies in published articles. Methods: From imaging journals listed we extracted open science policy details: protocol registration, reporting guidelines, funding, ethics and conflicts of interest (COI), data sharing, and open access publishing. The 10 most recently published studies from each journal were assessed to determine adherence to these policies. We calculated the proportion of open science policies into an Open Science Score (OSS) for all journals and articles. We evaluated relationships between OSS and journal/article level variables. Results: 82 journals/820 articles were included. The OSS of journals and articles was 58.3% and 31.8%, respectively. Of the journals, 65.9% had registration and 78.1% had reporting guideline policies. 79.3% of journals were members of COPE, 81.7% had plagiarism policies, 100% required disclosure of funding, and 97.6% required disclosure of COI and ethics approval. 81.7% had data sharing policies and 15.9% were fully open access. 7.8% of articles had a registered protocol, 8.4% followed a reporting guideline, 77.4% disclosed funding, 88.7% disclosed COI, and 85.6% reported ethics approval. 12.3% of articles shared their data. 51% of articles were available through open access or as a preprint. OSS was higher for journal with DOAJ membership (80% vs 54.2%; P < .0001). Impact factor was not correlated with journal OSS. Knowledge synthesis articles has a higher OSS scores (44.5%) than prospective/retrospective studies (32.6%, 30.0%, P < .0001). Conclusion: Imaging journals endorsed just over half of open science practices considered; however, the application of these practices at the article level was lower.

Evaluating the Impact of Peer Review on the Completeness of Reporting in Imaging Diagnostic Test Accuracy Research.

BACKGROUND: Despite the nearly ubiquitous reported use of peer review among reputable medical journals, there is limited evidence to support the use of peer review to improve the quality of biomedical research and in particular, imaging diagnostic test accuracy (DTA) research. PURPOSE: To evaluate whether peer review of DTA studies published by imaging journals is associated with changes in completeness of reporting, transparency for risk of bias assessment, and spin. STUDY TYPE: Retrospective cross-sectional study. STUDY SAMPLE: Cross-sectional study of articles published in Journal of Magnetic Resonance Imaging (JMRI), Canadian Association of Radiologists Journal (CARJ), and European Radiology (EuRad) before March 31, 2020. ASSESSMENT: Initial submitted and final versions of manuscripts were evaluated for completeness of reporting using the Standards for Reporting Diagnostic Accuracy Studies (STARD) 2015 and STARD for Abstracts guidelines, transparency of reporting for risk of bias assessment based on Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), and actual and potential spin using modified published criteria. STATISTICAL TESTS: Two-tailed paired t-tests and paired Wilcoxon signed-rank tests were used for comparisons. A P value <0.05 was considered to be statistically significant. RESULTS: We included 84 diagnostic accuracy studies accepted by three journals between 2014 and 2020 (JMRI = 30, CARJ = 23, and EuRad = 31) of the 692 which were screened. Completeness of reporting according to STARD 2015 increased significantly between initial submissions and final accepted versions (average reported items: 16.67 vs. 17.47, change of 0.80 [95% confidence interval 0.25-1.17]). No significant difference was found for the reporting of STARD for Abstracts (5.28 vs. 5.25, change of -0.03 [-0.15 to 0.11], P = 0.74), QUADAS-2 (6.08 vs. 6.11, change of 0.03 [-1.00 to 0.50], P = 0.92), actual "spin" (2.36 vs. 2.40, change of 0.04 [0.00 to 1.00], P = 0.39) or potential "spin" (2.93 vs. 2.81, change of -0.12 [-1.00 to 0.00], P = 0.23) practices. CONCLUSION: Peer review is associated with a marginal improvement in completeness of reporting in published imaging DTA studies, but not with improvement in transparency for risk of bias assessment or reduction in spin. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 1.

Association of Accuracy, Conclusions, and Reporting Completeness With Acceptance by Radiology Conferences and Journals.

BACKGROUND: Preferential publication of studies with positive findings can lead to overestimation of diagnostic test accuracy (i.e. publication bias). Understanding the contribution of the editorial process to publication bias could inform interventions to optimize the evidence guiding clinical decisions. PURPOSE/HYPOTHESIS: To evaluate whether accuracy estimates, abstract conclusion positivity, and completeness of abstract reporting are associated with acceptance to radiology conferences and journals. STUDY TYPE: Meta-research. POPULATION: Abstracts submitted to radiology conferences (European Society of Gastrointestinal and Abdominal Radiology (ESGAR) and International Society for Magnetic Resonance in Medicine (ISMRM)) from 2008 to 2018 and manuscripts submitted to radiology journals (Radiology, Journal of Magnetic Resonance Imaging [JMRI]) from 2017 to 2018. Primary clinical studies evaluating sensitivity and specificity of a diagnostic imaging test in humans with available editorial decisions were included. ASSESSMENT: Primary variables (Youden's index [YI > 0.8 vs. <0.8], abstract conclusion positivity [positive vs. neutral/negative], number of reported items on the Standards for Reporting of Diagnostic Accuracy Studies [STARD] for Abstract guideline) and confounding variables (prospective vs. retrospective/unreported, sample size, study duration, interobserver agreement assessment, subspecialty, modality) were extracted. STATISTICAL TESTS: Multivariable logistic regression to obtain adjusted odds ratio (OR) as a measure of the association between the primary variables and acceptance by radiology conferences and journals; 95% confidence intervals (CIs) and P-values were obtained; the threshold for statistical significance was P < 0.05. RESULTS: A total of 1000 conference abstracts (500 ESGAR and 500 ISMRM) and 1000 journal manuscripts (505 Radiology and 495 JMRI) were included. Conference abstract acceptance was not significantly associated with YI (adjusted OR = 0.97 for YI > 0.8; CI = 0.70-1.35), conclusion positivity (OR = 1.21 for positive conclusions; CI = 0.75-1.90) or STARD for Abstracts adherence (OR = 0.96 per unit increase in reported items; CI = 0.82-1.18). Manuscripts with positive abstract conclusions were less likely to be accepted by radiology journals (OR = 0.45; CI = 0.24-0.86), while YI (OR = 0.85; CI = 0.56-1.29) and STARD for Abstracts adherence (OR = 1.06; CI = 0.87-1.30) showed no significant association. Positive conclusions were present in 86.7% of submitted conference abstracts and 90.2% of journal manuscripts. DATA CONCLUSION: Diagnostic test accuracy studies with positive findings were not preferentially accepted by the evaluated radiology conferences or journals. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

QUADAS-C: A Tool for Assessing Risk of Bias in Comparative Diagnostic Accuracy Studies.

Comparative diagnostic test accuracy studies assess and compare the accuracy of 2 or more tests in the same study. Although these studies have the potential to yield reliable evidence regarding comparative accuracy, shortcomings in the design, conduct, and analysis may bias their results. The currently recommended quality assessment tool for diagnostic test accuracy studies, QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2), is not designed for the assessment of test comparisons. The QUADAS-C (Quality Assessment of Diagnostic Accuracy Studies-Comparative) tool was developed as an extension of QUADAS-2 to assess the risk of bias in comparative diagnostic test accuracy studies. Through a 4-round Delphi study involving 24 international experts in test evaluation and a face-to-face consensus meeting, an initial version of the tool was developed that was revised and finalized following a pilot study among potential users. The QUADAS-C tool retains the same 4-domain structure of QUADAS-2 (Patient Selection, Index Test, Reference Standard, and Flow and Timing) and comprises additional questions to each QUADAS-2 domain. A risk-of-bias judgment for comparative accuracy requires a risk-of-bias judgment for the accuracy of each test (resulting from QUADAS-2) and additional criteria specific to test comparisons. Examples of such additional criteria include whether participants either received all index tests or were randomly assigned to index tests, and whether index tests were interpreted with blinding to the results of other index tests. The QUADAS-C tool will be useful for systematic reviews of diagnostic test accuracy addressing comparative questions. Furthermore, researchers may use this tool to identify and avoid risk of bias when designing a comparative diagnostic test accuracy study.

A novel prognostic model for transplant-free survival in primary sclerosing cholangitis.

OBJECTIVE: Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. The aim of this study was to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables. DESIGN: The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected. We derived the prognostic index from a multivariable Cox regression model in which predictors were selected and parameters were estimated using the least absolute shrinkage and selection operator. The composite end point of PSC-related death and liver transplantation was used. To quantify the models' predictive value, we calculated the C-statistic as discrimination index and established its calibration accuracy by comparing predicted curves with Kaplan-Meier estimates. RESULTS: The final model included the variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up. CONCLUSION: The Amsterdam-Oxford model for PSC showed adequate performance in estimating PSC-related death and/or liver transplant in a predominantly population-based setting. The transplant-free survival probability can be recalculated when updated biochemical values are available.

Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement.

Importance: Systematic reviews of diagnostic test accuracy synthesize data from primary diagnostic studies that have evaluated the accuracy of 1 or more index tests against a reference standard, provide estimates of test performance, allow comparisons of the accuracy of different tests, and facilitate the identification of sources of variability in test accuracy. Objective: To develop the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagnostic test accuracy guideline as a stand-alone extension of the PRISMA statement. Modifications to the PRISMA statement reflect the specific requirements for reporting of systematic reviews and meta-analyses of diagnostic test accuracy studies and the abstracts for these reviews. Design: Established standards from the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network were followed for the development of the guideline. The original PRISMA statement was used as a framework on which to modify and add items. A group of 24 multidisciplinary experts used a systematic review of articles on existing reporting guidelines and methods, a 3-round Delphi process, a consensus meeting, pilot testing, and iterative refinement to develop the PRISMA diagnostic test accuracy guideline. The final version of the PRISMA diagnostic test accuracy guideline checklist was approved by the group. Findings: The systematic review (produced 64 items) and the Delphi process (provided feedback on 7 proposed items; 1 item was later split into 2 items) identified 71 potentially relevant items for consideration. The Delphi process reduced these to 60 items that were discussed at the consensus meeting. Following the meeting, pilot testing and iterative feedback were used to generate the 27-item PRISMA diagnostic test accuracy checklist. To reflect specific or optimal contemporary systematic review methods for diagnostic test accuracy, 8 of the 27 original PRISMA items were left unchanged, 17 were modified, 2 were added, and 2 were omitted. Conclusions and Relevance: The 27-item PRISMA diagnostic test accuracy checklist provides specific guidance for reporting of systematic reviews. The PRISMA diagnostic test accuracy guideline can facilitate the transparent reporting of reviews, and may assist in the evaluation of validity and applicability, enhance replicability of reviews, and make the results from systematic reviews of diagnostic test accuracy studies more useful.

Rapid Tests for Influenza, Respiratory Syncytial Virus, and Other Respiratory Viruses: A Systematic Review and Meta-analysis.

Rapid diagnosis of respiratory virus infections contributes to patient care. This systematic review evaluates the diagnostic accuracy of rapid tests for the detection of respiratory viruses. We searched Medline and EMBASE for studies evaluating these tests against polymerase chain reaction as the reference standard. Of 179 studies included, 134 evaluated rapid tests for influenza viruses, 32 for respiratory syncytial virus (RSV), and 13 for other respiratory viruses. We used the bivariate random effects model for quantitative meta-analysis of the results. Most tests detected only influenza viruses or RSV. Summary sensitivity and specificity estimates of tests for influenza were 61.1% and 98.9%. For RSV, summary sensitivity was 75.3%, and specificity, 98.7%. We assessed the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist. Because of incomplete reporting, the risk of bias was often unclear. Despite their intended use at the point of care, 26.3% of tests were evaluated in a laboratory setting. Although newly developed tests seem more sensitive, high-quality evaluations of these tests are lacking.

Overinterpretation of Research Findings: Evidence of "Spin" in Systematic Reviews of Diagnostic Accuracy Studies.

BACKGROUND: We wished to assess the frequency of overinterpretation in systematic reviews of diagnostic accuracy studies. METHODS: MEDLINE was searched through PubMed from December 2015 to January 2016. Systematic reviews of diagnostic accuracy studies in English were included if they reported one or more metaanalyses of accuracy estimates. We built and piloted a list of 10 items that represent actual overinterpretation in the abstract and/or full-text conclusion, and a list of 9 items that represent potential overinterpretation. Two investigators independently used the items to score each included systematic review, with disagreements resolved by consensus. RESULTS: We included 112 systematic reviews. The majority had a positive conclusion regarding the accuracy or clinical usefulness of the investigated test in the abstract (n = 83; 74%) and full-text (n = 83; 74%). Of the 112 reviews, 81 (72%) contained at least 1 actual form of overinterpretation in the abstract, and 77 (69%) in the full-text. This was most often a "positive conclusion, not reflecting the reported summary accuracy estimates," in 55 (49%) abstracts and 56 (50%) full-texts and a "positive conclusion, not taking high risk of bias and/or applicability concerns into account," in 47 abstracts (42%) and 26 full-texts (23%). Of these 112 reviews, 107 (96%) contained a form of potential overinterpretation, most frequently "nonrecommended statistical methods for metaanalysis performed" (n = 57; 51%). CONCLUSIONS: Most recent systematic reviews of diagnostic accuracy studies present positive conclusions and a majority contain a form of overinterpretation. This may lead to unjustified optimism about test performance and erroneous clinical decisions and recommendations.

Molecular malaria diagnostics: A systematic review and meta-analysis.

Accurate diagnosis of malaria is essential for identification and subsequent treatment of the disease. Currently, microscopy and rapid diagnostic tests are the most commonly used diagnostics, next to treatment based on clinical signs only. These tests are easy to deploy, but have a relatively high detection limit. With declining prevalence in many areas, there is an increasing need for more sensitive diagnostics. Molecular tools may be a suitable alternative, although costs and technical requirements currently hamper their implementation in resource limited settings. A range of (near) point-of-care diagnostics is therefore under development, including simplifications in sample preparation, amplification and/or read-out of the test. Accuracy data, in combination with technical characteristics, are essential in determining which molecular test, if any, would be the most promising to be deployed. This review presents a comprehensive overview of the currently available molecular malaria diagnostics, ranging from well-known tests to platforms in early stages of evaluation, and systematically evaluates their published accuracy. No important difference in accuracy was found between the most commonly used PCR-based assays (conventional, nested and real-time PCR), with most of them having high sensitivity and specificity, implying that there are no reasons other than practical ones to choose one technique over the other. Loop-mediated isothermal amplification and other (novel) diagnostics appear to be highly accurate as well, with some offering potential to be used in resource-limited settings.

Predicting Fluid Responsiveness by Passive Leg Raising: A Systematic Review and Meta-Analysis of 23 Clinical Trials.

OBJECTIVE: Passive leg raising creates a reversible increase in venous return allowing for the prediction of fluid responsiveness. However, the amount of venous return may vary in various clinical settings potentially affecting the diagnostic performance of passive leg raising. Therefore we performed a systematic meta-analysis determining the diagnostic performance of passive leg raising in different clinical settings with exploration of patient characteristics, measurement techniques, and outcome variables. DATA SOURCES: PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and citation tracking of relevant articles. STUDY SELECTION: Clinical trials were selected when passive leg raising was performed in combination with a fluid challenge as gold standard to define fluid responders and non-responders. DATA EXTRACTION: Trials were included if data were reported allowing the extraction of sensitivity, specificity, and area under the receiver operating characteristic curve. DATA SYNTHESIS: Twenty-three studies with a total of 1,013 patients and 1,034 fluid challenges were included. The analysis demonstrated a pooled sensitivity of 86% (95% CI, 79-92), pooled specificity of 92% (95% CI, 88-96), and a summary area under the receiver operating characteristic curve of 0.95 (95% CI, 0.92-0.98). Mode of ventilation, type of fluid used, passive leg raising starting position, and measurement technique did not affect the diagnostic performance of passive leg raising. The use of changes in pulse pressure on passive leg raising showed a lower diagnostic performance when compared with passive leg raising-induced changes in flow variables, such as cardiac output or its direct derivatives (sensitivity of 58% [95% CI, 44-70] and specificity of 83% [95% CI, 68-92] vs sensitivity of 85% [95% CI, 78-90] and specificity of 92% [95% CI, 87-94], respectively; p < 0.001). CONCLUSIONS: Passive leg raising retains a high diagnostic performance in various clinical settings and patient groups. The predictive value of a change in pulse pressure on passive leg raising is inferior to a passive leg raising-induced change in a flow variable.

Alkaline phosphatase at diagnosis of primary sclerosing cholangitis and 1 year later: evaluation of prognostic value.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a slowly progressive liver disease. Reliable biomarkers to predict outcome are urgently needed to serve as surrogate endpoints and/or stratifiers in clinical trials. Reduction in serum alkaline phosphatase (ALP) has been proposed as prognostic surrogate marker in PSC. The aim of this study was to asses if ALP at diagnosis (T0), 1 year later (T1), and percentage change between both time points hold prognostic value, and to determine the optimal threshold. METHODS: We retrospectively collected ALP levels at T0 and T1 for patients included in a large PSC cohort. The association of ALP at T0, T1, and percentage change with the combined endpoint (PSC-related death, liver transplantation) was analysed. Predictive value was determined using C-statistics. RESULTS: A total of 366 patients were included, of whom 66 (18%) reached an endpoint: 26 (7%) PSC-related death, 40 (11%) liver transplantation. At T0 and T1, 84% used ursodeoxycholic acid. A positive association was observed between level of ALP at T0 and T1 and the hazard of reaching an endpoint, up to values around 2.5 times upper limit of normal (xULN). A larger decrease in ALP between T0 and T1 decreased the event rate. A range of thresholds (0.5-3×ULN) with about similar C-statistics was found. In this cohort, the optimal threshold was 1.3×ULN at T1. CONCLUSION: ALP can be used to discriminate between PSC patients with a good and a poor prognosis. These findings indicate that ALP can serve as stratifier, and potentially as surrogate endpoint for clinical trials in PSC.

Defining the clinical pathway in cochrane diagnostic test accuracy reviews.

BACKGROUND: The value of a medical test depends on the context in which it might be used. Ideally, questions, results and conclusions of a diagnostic test accuracy (DTA) systematic review should be presented in light of this context. There is increasing acceptance of the value for knowing the impact a test can have on downstream consequences such as costs, implications for further testing and treatment options however there is currently no explicit guidance on how to address this. Authors of a Cochrane diagnostic review have recently been asked to include the clinical pathway in which a test maybe used. We aimed to evaluate how authors were developing their clinical pathways in the light of this. METHODS: We searched the Cochrane Database of Systematic Reviews for all published DTA reviews. We included only those reviews that included a clinical pathway. We developed a checklist, based on the guidance in the Cochrane Handbook for DTA review authors. To this, we added a number of additional descriptors. We checked if the included pathways fulfilled these descriptors as defined by our checklist. RESULTS: We found 47 reviews, of which 33 (73 %) contained aspects pertaining to a clinical pathway. The 33 reviews addressed the clinical pathway differently, both in content and format. Of these, 21 provided a textual description and 12 include visual and textual descriptions. There was considerable variation in how comprehensively review authors adhered to our checklist. Eighteen reviews (51 %) linked the index test results to downstream clinical management actions and patient consequences, but only eight went on to differentially report on the consequences for false negative results and nine on the consequences for false positive results. CONCLUSION: There is substantial variation in the clinical pathway descriptions in Cochrane systematic reviews of test accuracy. Most reviews do not link misclassifications (i.e. false negatives and false positive) to downstream patient consequences. Review authors could benefit from more explicit guidance on how to create such pathways, which in turn can help guide them in their evidence selection and appraisal of the evidence in the context of downstream consequences of testing.

Assessing variability in results in systematic reviews of diagnostic studies.

BACKGROUND: To describe approaches used in systematic reviews of diagnostic test accuracy studies for assessing variability in estimates of accuracy between studies and to provide guidance in this area. METHODS: Meta-analyses of diagnostic test accuracy studies published between May and September 2012 were systematically identified. Information on how the variability in results was investigated was extracted. RESULTS: Of the 53 meta-analyses included in the review, most (n=48; 91%) presented variability in diagnostic accuracy estimates visually either through forest plots or ROC plots and the majority (n=40; 75%) presented a test or statistical measure for the variability. Twenty-eight reviews (53%) tested for variability beyond chance using Cochran's Q test and 31 (58%) reviews quantified it with I(2). 7 reviews (13%) presented between-study variance estimates (τ(2)) from random effects models and 3 of these presented a prediction interval or ellipse to facilitate interpretation. Half of all the meta-analyses specified what was considered a significant amount of variability (n=24; 49%). CONCLUSIONS: Approaches to assessing variability in estimates of accuracy varied widely between diagnostic test accuracy reviews and there is room for improvement. We provide initial guidance, complemented by an overview of the currently available approaches.

Applicability and prognostic value of histologic scoring systems in primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. At present, there is no appropriate histologic scoring system available for PSC, evaluating both degree of necroinflammatory activity (grade) and fibrosis (stage). The aim of this study was to assess if three scoring systems, commonly used in different liver diseases could be applied for grading and/or staging of PSC. METHODS: Sixty-four PSC patients from a Dutch cohort, who underwent diagnostic liver biopsy, were included. Staging was scored using Ishak, Nakanuma, and Ludwig systems. Grading was scored using Ishak and Nakanuma systems. Three measures of outcome were defined; transplant-free survival, time to liver transplantation (LTx) and occurrence of cirrhosis related symptoms (CRS). Association of grade and stage with outcome was estimated using Kaplan-Meier log-rank test, and Cox regression analysis. Correlation with biochemistry was assessed by Spearman's rank test. RESULTS: There were strong associations between disease stage measured by Ishak, Nakanuma, and Ludwig staging systems with both outcome measuring transplant-free survival (Hazard ratio (HR) 2.56; 95% CI 1.11-5.89, HR 6.53; 95% CI 2.01-21.22, HR 1.94; 95% CI 1.00-3.79, respectively), and time to LTx (HR 4.18; 95%CI 1.51-11.56, HR 7.05; 95% CI 1.77-28.11, HR 3.13; 95%CI 1.42-6.87, respectively). Ishak and Nakanuma grading systems were not associated with CRS. Weak correlations between histopathology and liver biochemistry were shown. CONCLUSION: Applying the Nakanuma, Ishak, and Ludwig histopathological staging systems is feasible and clinically relevant given their association with transplant-free survival and time to LTx. This suggests that these staging systems could be likely candidates for surrogate endpoints and stratification purposes in clinical trials in PSC.