Influence of diffusion weighted imaging and contrast enhanced T1 sequences on the diagnostic accuracy of magnetic resonance enterography for Crohn's disease.

OBJECTIVES: To evaluate the additional diagnostic benefit of diffusion weighted imaging (DWI) and contrast enhanced (CE) images during MR enterography (MRE) of Crohn's disease. METHODS: Datasets from 73 patients (mean age 32; 40 male) (28 new-diagnosis, 45 relapsed) were read independently by two radiologists selected from a pool of 13. Radiologists interpreted datasets using three sequential sequence blocks: (1) T2 weighted and steady state free precession gradient echo (SSFP) images alone (T2^); (2) T2 weighted and SSFP images with DWI (T2 + DWI^) and; (3) T2 weighted images, SSFP, DWI and post-contrast enhanced (CE) T1 images (T2 + DWI + CE^), documenting presence, location, and activity of small bowel disease. For each sequence block, sensitivity and specificity (readers combined) was calculated against an outcome-based construct reference standard. RESULTS: 59/73 patients had small bowel disease. Per-patient sensitivity for disease detection was essentially identical (80 % [95 % CI 72, 86], 81 % [73,87], and 79 % [71,86] for T2^, T2 + DWI^and T2 + DWI + CE^respectively). Specificity was identical (82 % [64 to 92]). Per patient sensitivity for disease extent was 56 % (47,65), 56 % (47,65) and 52 % (43 to 61) respectively, and specificity was 82 % (64 to 92) for all blocks. Sensitivity for active disease was 97 % (90,99), 97 % (90,99) and 98 % (92,99), and specificity was also comparable between all sequence combination reads. Results were consistent across segments and newly diagnosed/relapse patients. CONCLUSION: There is no additional diagnostic benefit of adding either DWI or CE to T2 FSE and SSFP sequences for evaluating small bowel Crohn's disease, suggesting MRE protocols can be simplified safely.

Investigating harms of testing for ovarian cancer - psychological outcomes and cancer conversion rates in women with symptoms of ovarian cancer: A cohort study embedded in the multicentre ROCkeTS prospective diagnostic study.

OBJECTIVE: To investigate psychological correlates in women referred with suspected ovarian cancer via the fast-track pathway, explore how anxiety and distress levels change at 12 months post-testing, and report cancer conversion rates by age and referral pathway. DESIGN: Single-arm prospective cohort study. SETTING: Multicentre. Secondary care including outpatient clinics and emergency admissions. POPULATION: A cohort of 2596 newly presenting symptomatic women with a raised CA125 level, abnormal imaging or both. METHODS: Women completed anxiety and distress questionnaires at recruitment and at 12 months for those who had not undergone surgery or a biopsy within 3 months of recruitment. MAIN OUTCOME MEASURES: Anxiety and distress levels measured using a six-item short form of the State-Trait Anxiety Inventory (STAI-6) and the Impact of Event Scale - Revised (IES-r) questionnaire. Ovarian cancer (OC) conversion rates by age, menopausal status and referral pathway. RESULTS: Overall, 1355/2596 (52.1%) and 1781/2596 (68.6%) experienced moderate-to-severe distress and anxiety, respectively, at recruitment. Younger age and emergency presentations had higher distress levels. The clinical category for anxiety and distress remained unchanged/worsened in 76% of respondents at 12 months, despite a non-cancer diagnosis. The OC rates by age were 1.6% (95% CI 0.5%-5.9%) for age <40 years and 10.9% (95% CI 8.7%-13.6%) for age ≥40 years. In women referred through fast-track pathways, 3.3% (95% CI 1.9%-5.7%) of pre- and 18.5% (95% CI 16.1%-21.0%) of postmenopausal women were diagnosed with OC. CONCLUSIONS: Women undergoing diagnostic testing display severe anxiety and distress. Younger women are especially vulnerable and should be targeted for support. Women under the age of 40 years have low conversion rates and we advocate reducing testing in this group to reduce the harms of testing.

A simple, clinically usable whole-body MRI system of joint assessment in adolescents and young people with juvenile idiopathic arthritis.

OBJECTIVES: To introduce and evaluate a simple method for assessing joint inflammation and structural damage on whole-body MRI (WBMRI) in juvenile idiopathic arthritis (JIA), which is usable in clinical practice. METHODS: The proposed system utilises post-contrast Dixon WBMRI scans. Joints are assessed for synovitis (grade 0-2) and structural damage (present/absent) at 81 sites. The synovitis grading is based on features including above-normal intensity synovial enhancement, synovial hypertrophy, joint effusion, subarticular bone marrow oedema and peri-articular soft tissue oedema.This system was evaluated in a prospective study of 60 young people (47 patients with JIA and 13 controls with non-inflammatory musculoskeletal pain) who underwent a WBMRI. Three readers (blinded to diagnosis) independently reviewed all images and re-reviewed 20 individual scans. The intra- and inter-reader overall agreement (OA) and the intra- and inter-reader Gwet's agreement coefficients 2 (GAC2) were measured for the detection of a) participants with ≥1 joint with inflammation or structural damage and b) joint inflammation or structural damage for each joint. RESULTS: The inter-reader OA for detecting patients with ≥1 joint with inflammation, defined as grade 2 synovitis (G2), and ≥1 joint with structural damage were 80% and 73%, respectively. The intra-reader OA for readers 1-3 were 80-90% and 75-90% respectively. The inter-reader OA and GAC2 for joint inflammation (G2) at each joint were both ≥85% for all joints but were lower if grade 1 synovitis was included as positive. CONCLUSION: The intra- and inter-reader agreements of this WBMRI assessment system are adequate for assessing objective joint inflammation and damage in JIA.

Detection of inflammation by whole-body MRI in young people with juvenile idiopathic arthritis.

OBJECTIVES: To assess the frequency of joint inflammation detected by whole-body MRI (WBMRI) in young people (YP) with JIA and controls, and to determine the relationship between WBMRI-detected inflammation and clinical findings. METHODS: YP aged 14-24 years, with JIA (patients) or arthralgia without JIA (controls), recruited from one centre, underwent a WBMRI scan after formal clinical assessment. Consensus between at least two of the three independent radiologists was required to define inflammation and damage on WBMRI, according to predefined criteria. YP with JIA were deemed clinically active as per accepted definitions. The proportions of YP with positive WBMRI scans for joint inflammation (≥1 inflamed joint) as well as serum biomarkers were compared between active vs inactive JIA patients and controls. RESULTS: Forty-seven YP with JIA (25 active and 22 inactive patients) and 13 controls were included. WBMRI detected joint inflammation in 60% (28/47) patients with JIA vs 15% (2/13) controls (difference: 44%, 95% CI 20%, 68%). More active than inactive JIA patients had WBMRI-detected inflammation [76% (19/25) vs 41% (9/22), difference: 35% (95% CI 9%, 62%)], and this was associated with a specific biomarker signature. WBMRI identified inflammation in ≥ 1 clinically inactive joint in 23/47 (49%) patients (14/25 active vs 9/22 inactive JIA patients). CONCLUSIONS: WBMRI's validity in joint assessment was demonstrated by the higher frequency of inflammation in JIA patients vs controls, and in active vs inactive JIA patients. WBMRI found unsuspected joint inflammation in 49% YP with JIA, which needs further investigation of potential clinical implications.

Diagnostic performance of sonographic activity scores for adult terminal ileal Crohn's disease compared to magnetic resonance and histological reference standards: experience from the METRIC trial.

OBJECTIVES: The simple ultrasound activity score for Crohn's disease (SUS-CD) and bowel ultrasound score (BUSS) are promising intestinal ultrasound (IUS) indices of CD, but studied mainly in small settings with few sonographers. We compared SUS-CD and BUSS against histological and magnetic resonance enterography (MRE) reference standards in a post hoc analysis of a prospective multicentre, multireader trial. METHODS: Participants recruited to the METRIC trial (ISRCTN03982913) were studied, including those with available terminal ileal (TI) biopsies. Sensitivity and specificity of SUS-CD and BUSS for TI CD activity were calculated with 95% confidence intervals (CI), from the prospective observations of the original METRIC trial sonographers against the histological activity index (HAI) and the simplified magnetic resonance index of activity (sMARIA). RESULTS: We included 284 patients (median 31.5 years, IQR 23-46) from 8 centres, who underwent IUS and MRE. Of these, 111 patients had available terminal ileal biopsies with HAI scoring. Against histology, sensitivity and specificity for active disease were 79% (95% CI 69-86%) and 50% (31-69%) for SUS-CD, and 66% (56-75%) and 68% (47-84%) for BUSS, respectively. Compared to sMARIA, the sensitivity and specificity for active CD were 81% (74-86%) and 75% (66-83%) for SUS-CD, and 68% (61-74%) and 85% (76-91%) for BUSS, respectively. The sensitivity of SUS-CD was significantly greater than that of BUSS against HAI and sMARIA (p < 0.001), but its specificity was significantly lower than of BUSS against the MRE reference standard (p = 0.003). CONCLUSIONS: Particularly when compared to MRE activity scoring, SUS-CD and BUSS are promising tools in a real-world clinical setting. CLINICAL RELEVANCE STATEMENT: When tested using data from a multicentre, multireader diagnostic accuracy trial, the simple ultrasound activity score for Crohn's disease (SUS-CD) and bowel ultrasound score (BUSS) were clinically viable intestinal ultrasound indices that were reasonably sensitive and specific for terminal ileal Crohn's disease, especially when compared to a magnetic resonance reference standard. KEY POINTS: The simple ultrasound activity score for Crohn's disease and bowel ultrasound score are promising intestinal ultrasound indices of Crohn's disease but to date studied mainly in small settings with few sonographers. Compared to histology and the magnetic resonance reference standard in a multicentre, multireader setting, the sensitivity of simple ultrasound activity score for Crohn's disease is significantly greater than that of bowel ultrasound score. The specificity of simple ultrasound activity score for Crohn's disease was significantly lower than that of bowel ultrasound score compared to the magnetic resonance enterography reference standard. The specificity of both indices was numerically higher when the magnetic resonance enterography reference standard was adopted.

Identifying the Optimum Strategy for Identifying Adults and Children With Celiac Disease: A Cost-Effectiveness and Value of Information Analysis.

OBJECTIVES: Celiac disease (CD) is thought to affect around 1% of people in the United Kingdom, but only approximately 30% are diagnosed. The aim of this work was to assess the cost-effectiveness of strategies for identifying adults and children with CD in terms of who to test and which tests to use. METHODS: A decision tree and Markov model were used to describe testing strategies and model long-term consequences of CD. The analysis compared a selection of pre-test probabilities of CD above which patients should be screened, as well as the use of different serological tests, with or without genetic testing. Value of information analysis was used to prioritize parameters for future research. RESULTS: Using serological testing alone in adults, immunoglobulin A (IgA) tissue transglutaminase (tTG) at a 1% pre-test probability (equivalent to population screening) was most cost-effective. If combining serological testing with genetic testing, human leukocyte antigen combined with IgA tTG at a 5% pre-test probability was most cost-effective. In children, the most cost-effective strategy was a 10% pre-test probability with human leukocyte antigen plus IgA tTG. Value of information analysis highlighted the probability of late diagnosis of CD and the accuracy of serological tests as important parameters. The analysis also suggested prioritizing research in adult women over adult men or children. CONCLUSIONS: For adults, these cost-effectiveness results suggest UK National Screening Committee Criteria for population-based screening for CD should be explored. Substantial uncertainty in the results indicate a high value in conducting further research.

Prognostic factors to identify resolution of small bowel obstruction without need for operative management: systematic review.

OBJECTIVES: To identify imaging, clinical, and laboratory variables potentially prognostic for surgical management of small bowel obstruction. METHODS: Two researchers systematically reviewed indexed literature 2001-2021 inclusive for imaging, clinical, and laboratory variables potentially predictive of surgical management of small bowl obstruction and/or ischaemia at surgery, where performed. Risk of bias was assessed. Contingency tables for variables reported in at least 5 studies were extracted and meta-analysed to identify strong evidence of association with clinical outcomes, across studies. RESULTS: Thirty-one studies were ultimately included, reporting 4638 patients (44 to 313 per study). 11 (35%) studies raised no risk of bias concerns. CT was the modality reported most (29 studies, 94%). Meta-analysis of 21 predictors identified 5 strongly associated with surgical intervention, 3 derived from CT (peritoneal free fluid, odds ratio [OR] 3.24, 95%CI 2.45 to 4.29; high grade obstruction, OR 3.58, 95%CI 2.46 to 5.20; mesenteric inflammation, OR 2.61, 95%CI 1.94 to 3.50; abdominal distension, OR 2.43, 95%CI 1.34 to 4.42; peritonism, OR 3.97, 95%CI 2.67 to 5.90) and one with conservative management (previous abdominopelvic surgery, OR 0.58, 95%CI 0.40 to 0.85). Meta-analysis of 10 predictors identified 3 strongly associated with ischaemia at surgery, 2 derived from CT (peritoneal free fluid, OR 3.49, 95%CI 2.28 to 5.35; bowel thickening, OR 3.26 95%CI 1.91 to 5.55; white cell count, OR 4.76, 95%CI 2.71 to 8.36). CONCLUSIONS: Systematic review of patients with small bowel obstruction identified four imaging, three clinical, and one laboratory predictors associated strongly with surgical intervention and/or ischaemia at surgery. CLINICAL RELEVANCE STATEMENT: Via systematic review and meta-analysis, we identified imaging, clinical, and laboratory predictors strongly associated with surgical management of small bowel obstruction and/or ischaemia. Multivariable model development to guide management should incorporate these since they display strong evidence of potential utility. KEY POINTS: • While multivariable models incorporating clinical, laboratory, and imaging factors could predict surgical management of small bowel obstruction, none are used widely. • Via systematic review and meta-analysis we identified imaging, clinical, and laboratory variables strongly associated with surgical management and/or ischaemia at surgery. • Development of multivariable models to guide management should incorporate these predictors, notably CT scanning, since they display strong evidence of potential utility.

Meta-research: How many diagnostic or prognostic models published in radiological journals are evaluated externally?

OBJECTIVES: Prognostic and diagnostic models must work in their intended clinical setting, proven via "external evaluation", preferably by authors uninvolved with model development. By systematic review, we determined the proportion of models published in high-impact radiological journals that are evaluated subsequently. METHODS: We hand-searched three radiological journals for multivariable diagnostic/prognostic models 2013-2015 inclusive, developed using regression. We assessed completeness of data presentation to allow subsequent external evaluation. We then searched literature to August 2022 to identify external evaluations of these index models. RESULTS: We identified 98 index studies (73 prognostic; 25 diagnostic) describing 145 models. Only 15 (15%) index studies presented an evaluation (two external). No model was updated. Only 20 (20%) studies presented a model equation. Just 7 (15%) studies developing Cox models presented a risk table, and just 4 (9%) presented the baseline hazard. Two (4%) studies developing non-Cox models presented the intercept. Just 20 (20%) articles presented a Kaplan-Meier curve of the final model. The 98 index studies attracted 4224 citations (including 559 self-citations), median 28 per study. We identified just six (6%) subsequent external evaluations of an index model, five of which were external evaluations by researchers uninvolved with model development, and from a different institution. CONCLUSIONS: Very few prognostic or diagnostic models published in radiological literature are evaluated externally, suggesting wasted research effort and resources. Authors' published models should present data sufficient to allow external evaluation by others. To achieve clinical utility, researchers should concentrate on model evaluation and updating rather than continual redevelopment. CLINICAL RELEVANCE STATEMENT: The large majority of prognostic and diagnostic models published in high-impact radiological journals are never evaluated. It would be more efficient for researchers to evaluate existing models rather than practice continual redevelopment. KEY POINTS: • Systematic review of highly cited radiological literature identified few diagnostic or prognostic models that were evaluated subsequently by researchers uninvolved with the original model. • Published radiological models frequently omit important information necessary for others to perform an external evaluation: Only 20% of studies presented a model equation or nomogram. • A large proportion of research citing published models focuses on redevelopment and ignores evaluation and updating, which would be a more efficient use of research resources.

Interobserver variability studies in diagnostic imaging: a methodological systematic review.

OBJECTIVES: To review the methodology of interobserver variability studies; including current practice and quality of conducting and reporting studies. METHODS: Interobserver variability studies between January 2019 and January 2020 were included; extracted data comprised of study characteristics, populations, variability measures, key results, and conclusions. Risk of bias was assessed using the COSMIN tool for assessing reliability and measurement error. RESULTS: Seventy-nine full-text studies were included covering various imaging tests and clinical areas. The median number of patients was 47 (IQR:23-88), and observers were 4 (IQR:2-7), with sample size justified in 12 (15%) studies. Most studies used static images (n = 75, 95%), where all observers interpreted images for all patients (n = 67, 85%). Intraclass correlation coefficients (ICC) (n = 41, 52%), Kappa (κ) statistics (n = 31, 39%) and percentage agreement (n = 15, 19%) were most commonly used. Interpretation of variability estimates often did not correspond with study conclusions. The COSMIN risk of bias tool gave a very good/adequate rating for 52 studies (66%) including any studies that used variability measures listed in the tool. For studies using static images, some study design standards were not applicable and did not contribute to the overall rating. CONCLUSIONS: Interobserver variability studies have diverse study designs and methods, the impact of which requires further evaluation. Sample size for patients and observers was often small without justification. Most studies report ICC and κ values, which did not always coincide with the study conclusion. High ratings were assigned to many studies using the COSMIN risk of bias tool, with certain standards scored 'not applicable' when static images were used. ADVANCES IN KNOWLEDGE: The sample size for both patients and observers was often small without justification. For most studies, observers interpreted static images and did not evaluate the process of acquiring the imaging test, meaning it was not possible to assess many COSMIN risk of bias standards for studies with this design. Most studies reported intraclass correlation coefficient and κ statistics; study conclusions often did not correspond with results.

Assessing violence risk in first-episode psychosis: external validation, updating and net benefit of a prediction tool (OxMIV).

BACKGROUND: Violence perpetration is a key outcome to prevent for an important subgroup of individuals presenting to mental health services, including early intervention in psychosis (EIP) services. Needs and risks are typically assessed without structured methods, which could facilitate consistency and accuracy. Prediction tools, such as OxMIV (Oxford Mental Illness and Violence tool), could provide a structured risk stratification approach, but require external validation in clinical settings. OBJECTIVES: We aimed to validate and update OxMIV in first-episode psychosis and consider its benefit as a complement to clinical assessment. METHODS: A retrospective cohort of individuals assessed in two UK EIP services was included. Electronic health records were used to extract predictors and risk judgements made by assessing clinicians. Outcome data involved police and healthcare records for violence perpetration in the 12 months post-assessment. FINDINGS: Of 1145 individuals presenting to EIP services, 131 (11%) perpetrated violence during the 12 month follow-up. OxMIV showed good discrimination (area under the curve 0.75, 95% CI 0.71 to 0.80). Calibration-in-the-large was also good after updating the model constant. Using a 10% cut-off, sensitivity was 71% (95% CI 63% to 80%), specificity 66% (63% to 69%), positive predictive value 22% (19% to 24%) and negative predictive value 95% (93% to 96%). In contrast, clinical judgement sensitivity was 40% and specificity 89%. Decision curve analysis showed net benefit of OxMIV over comparison approaches. CONCLUSIONS: OxMIV performed well in this real-world validation, with improved sensitivity compared with unstructured assessments. CLINICAL IMPLICATIONS: Structured tools to assess violence risk, such as OxMIV, have potential in first-episode psychosis to support a stratified approach to allocating non-harmful interventions to individuals who may benefit from the largest absolute risk reduction.

Health technology assessment of diagnostic tests: a state of the art review of methods guidance from international organizations.

OBJECTIVES: To identify which international health technology assessment (HTA) agencies are undertaking evaluations of medical tests, summarize commonalities and differences in methodological approach, and highlight examples of good practice. METHODS: A methodological review incorporating: systematic identification of HTA guidance documents mentioning evaluation of tests; identification of key contributing organizations and abstraction of approaches to all essential HTA steps; summary of similarities and differences between organizations; and identification of important emergent themes which define the current state of the art and frontiers where further development is needed. RESULTS: Seven key organizations were identified from 216 screened. The main themes were: elucidation of claims of test benefits; attitude to direct and indirect evidence of clinical effectiveness (including evidence linkage); searching; quality assessment; and health economic evaluation. With the exception of dealing with test accuracy data, approaches were largely based on general approaches to HTA with few test-specific modifications. Elucidation of test claims and attitude to direct and indirect evidence are where we identified the biggest dissimilarities in approach. CONCLUSIONS: There is consensus on some aspects of HTA of tests, such as dealing with test accuracy, and examples of good practice which HTA organizations new to test evaluation can emulate. The focus on test accuracy contrasts with universal acknowledgment that it is not a sufficient evidence base for test evaluation. There are frontiers where methodological development is urgently required, notably integrating direct and indirect evidence and standardizing approaches to evidence linkage.

Defining the optimum strategy for identifying adults and children with coeliac disease: systematic review and economic modelling.

BACKGROUND: Coeliac disease is an autoimmune disorder triggered by ingesting gluten. It affects approximately 1% of the UK population, but only one in three people is thought to have a diagnosis. Untreated coeliac disease may lead to malnutrition, anaemia, osteoporosis and lymphoma. OBJECTIVES: The objectives were to define at-risk groups and determine the cost-effectiveness of active case-finding strategies in primary care. DESIGN: (1) Systematic review of the accuracy of potential diagnostic indicators for coeliac disease. (2) Routine data analysis to develop prediction models for identification of people who may benefit from testing for coeliac disease. (3) Systematic review of the accuracy of diagnostic tests for coeliac disease. (4) Systematic review of the accuracy of genetic tests for coeliac disease (literature search conducted in April 2021). (5) Online survey to identify diagnostic thresholds for testing, starting treatment and referral for biopsy. (6) Economic modelling to identify the cost-effectiveness of different active case-finding strategies, informed by the findings from previous objectives. DATA SOURCES: For the first systematic review, the following databases were searched from 1997 to April 2021: MEDLINE® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), Cochrane Library, Web of Science™ (Clarivate™, Philadelphia, PA, USA), the World Health Organization International Clinical Trials Registry Platform ( WHO ICTRP ) and the National Institutes of Health Clinical Trials database. For the second systematic review, the following databases were searched from January 1990 to August 2020: MEDLINE, Embase, Cochrane Library, Web of Science, Kleijnen Systematic Reviews ( KSR ) Evidence, WHO ICTRP and the National Institutes of Health Clinical Trials database. For prediction model development, Clinical Practice Research Datalink GOLD, Clinical Practice Research Datalink Aurum and a subcohort of the Avon Longitudinal Study of Parents and Children were used; for estimates for the economic models, Clinical Practice Research Datalink Aurum was used. REVIEW METHODS: For review 1, cohort and case-control studies reporting on a diagnostic indicator in a population with and a population without coeliac disease were eligible. For review 2, diagnostic cohort studies including patients presenting with coeliac disease symptoms who were tested with serological tests for coeliac disease and underwent a duodenal biopsy as reference standard were eligible. In both reviews, risk of bias was assessed using the quality assessment of diagnostic accuracy studies 2 tool. Bivariate random-effects meta-analyses were fitted, in which binomial likelihoods for the numbers of true positives and true negatives were assumed. RESULTS: People with dermatitis herpetiformis, a family history of coeliac disease, migraine, anaemia, type 1 diabetes, osteoporosis or chronic liver disease are 1.5-2 times more likely than the general population to have coeliac disease; individual gastrointestinal symptoms were not useful for identifying coeliac disease. For children, women and men, prediction models included 24, 24 and 21 indicators of coeliac disease, respectively. The models showed good discrimination between patients with and patients without coeliac disease, but performed less well when externally validated. Serological tests were found to have good diagnostic accuracy for coeliac disease. Immunoglobulin A tissue transglutaminase had the highest sensitivity and endomysial antibody the highest specificity. There was little improvement when tests were used in combination. Survey respondents (n = 472) wanted to be 66% certain of the diagnosis from a blood test before starting a gluten-free diet if symptomatic, and 90% certain if asymptomatic. Cost-effectiveness analyses found that, among adults, and using serological testing alone, immunoglobulin A tissue transglutaminase was most cost-effective at a 1% pre-test probability (equivalent to population screening). Strategies using immunoglobulin A endomysial antibody plus human leucocyte antigen or human leucocyte antigen plus immunoglobulin A tissue transglutaminase with any pre-test probability had similar cost-effectiveness results, which were also similar to the cost-effectiveness results of immunoglobulin A tissue transglutaminase at a 1% pre-test probability. The most practical alternative for implementation within the NHS is likely to be a combination of human leucocyte antigen and immunoglobulin A tissue transglutaminase testing among those with a pre-test probability above 1.5%. Among children, the most cost-effective strategy was a 10% pre-test probability with human leucocyte antigen plus immunoglobulin A tissue transglutaminase, but there was uncertainty around the most cost-effective pre-test probability. There was substantial uncertainty in economic model results, which means that there would be great value in conducting further research. LIMITATIONS: The interpretation of meta-analyses was limited by the substantial heterogeneity between the included studies, and most included studies were judged to be at high risk of bias. The main limitations of the prediction models were that we were restricted to diagnostic indicators that were recorded by general practitioners and that, because coeliac disease is underdiagnosed, it is also under-reported in health-care data. The cost-effectiveness model is a simplification of coeliac disease and modelled an average cohort rather than individuals. Evidence was weak on the probability of routine coeliac disease diagnosis, the accuracy of serological and genetic tests and the utility of a gluten-free diet. CONCLUSIONS: Population screening with immunoglobulin A tissue transglutaminase (1% pre-test probability) and of immunoglobulin A endomysial antibody followed by human leucocyte antigen testing or human leucocyte antigen testing followed by immunoglobulin A tissue transglutaminase with any pre-test probability appear to have similar cost-effectiveness results. As decisions to implement population screening cannot be made based on our economic analysis alone, and given the practical challenges of identifying patients with higher pre-test probabilities, we recommend that human leucocyte antigen combined with immunoglobulin A tissue transglutaminase testing should be considered for adults with at least a 1.5% pre-test probability of coeliac disease, equivalent to having at least one predictor. A more targeted strategy of 10% pre-test probability is recommended for children (e.g. children with anaemia). FUTURE WORK: Future work should consider whether or not population-based screening for coeliac disease could meet the UK National Screening Committee criteria and whether or not it necessitates a long-term randomised controlled trial of screening strategies. Large prospective cohort studies in which all participants receive accurate tests for coeliac disease are needed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019115506 and CRD42020170766. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 44. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Around 1 in 100 people in the UK has coeliac disease. It develops when the immune system attacks the lining of the gut after eating gluten. It is thought that only one in three people with coeliac disease is currently diagnosed. Without treatment, people with coeliac disease are at an increased risk of anaemia, osteoporosis and cancer. Treatment is a lifelong gluten-free diet. Diagnosing coeliac disease is difficult. Some people have minimal or non-specific symptoms, such as pain, indigestion or bloating, so knowing who to test is tricky. WHAT DID WE DO?: We wanted to establish who should be tested for coeliac disease, what tests should be used and whether or not invasive testing (a gut biopsy) is necessary for everyone. We looked at existing studies and data from general practices, and conducted an online survey, and brought everything together in an economic (cost) analysis. WHAT DID WE FIND?: Using individual symptoms is not helpful to identify people who may have coeliac disease. People with coeliac disease are more likely to have a combination of symptoms. People with anaemia, type 1 diabetes, osteoporosis, thyroid disorders, immunoglobulin A deficiency, Down syndrome, Turner syndrome or a family history of coeliac disease are more likely to have coeliac disease and should be offered tests. Common blood tests for coeliac disease are very accurate, particularly when used in combination with genetic testing. Blood tests alone can be used for diagnosis for some people. Others will need a biopsy to confirm the diagnosis. Whether or not this is needed depends on their risk of coeliac disease: whether or not they have symptoms and whether or not they have a condition that puts them at higher risk. Shared decision-making is important for individuals considering an invasive test, depending on how certain they want to be about their diagnosis before starting a gluten-free diet.

METRIC-EF: magnetic resonance enterography to predict disabling disease in newly diagnosed Crohn's disease-protocol for a multicentre, non-randomised, single-arm, prospective study.

INTRODUCTION: Crohn's disease (CD) is characterised by discontinuous, relapsing enteric inflammation. Instituting advanced therapies at an early stage to suppress inflammation aims to prevent future complications such as stricturing or penetrating disease, and subsequent surgical resection. Therapeutics are effective but associated with certain side-effects and relatively expensive. There is therefore an urgent need for robust methods to predict which newly diagnosed patients will develop disabling disease, to identify patients who are most likely to benefit from early, advanced therapies. We aim to determine if magnetic resonance enterography (MRE) features at diagnosis improve prediction of disabling CD within 5 years of diagnosis. METHODS AND ANALYSIS: We describe the protocol for a multicentre, non-randomised, single-arm, prospective study of adult patients with newly diagnosed CD. We will use patients already recruited to the METRIC study and extend their clinical follow-up, as well as a separate group of newly diagnosed patients who were not part of the METRIC trial (MRE within 3 months of diagnosis), to ensure an adequate sample size. Follow-up will extend for at least 4 years. The primary outcome is to evaluate the comparative predictive ability of prognostic models incorporating MRE severity scores (Magnetic resonance Enterography Global Score (MEGS), simplified MAgnetic Resonance Index of Activity (sMaRIA) and Lémann Index) versus models using standard characteristics alone to predict disabling CD (modified Beaugerie definition) within 5 years of new diagnosis. ETHICS AND DISSEMINATION: This study protocol achieved National Health Service Research Ethics Committee (NHS REC), London-Hampstead Research Ethics Committee approval (IRAS 217422). Our findings will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN76899103.

TOMAS-R: A template to identify and plan analysis for clinically important variation and multiplicity in diagnostic test accuracy systematic reviews.

The Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (DTA) provides guidance on important aspects of conducting a test accuracy systematic review. In this paper we present TOMAS-R (Template of Multiplicity and Analysis in Systematic Reviews), a structured template to use in conjunction with current Cochrane DTA guidance, to help identify complexities in the review question and to assist planning of data extraction and analysis when clinically important variation and multiplicity is present. Examples of clinically important variation and multiplicity could include differences in participants, index tests and test methods, target conditions and reference standards used to define them, study design and methodological quality. Our TOMAS-R template goes beyond the broad topic headings in current guidance that are sources of potential variation and multiplicity, by providing prompts for common sources of heterogeneity encountered from our experience of authoring over 100 reviews. We provide examples from two reviews to assist users. The TOMAS-R template adds value by supplementing available guidance for DTA reviews by providing a tool to facilitate discussions between methodologists, clinicians, statisticians and patient/public team members to identify the full breadth of review question complexities early in the process. The use of a structured set of prompting questions at the important stage of writing the protocol ensures clinical relevance as a main focus of the review, while allowing identification of key clinical components for data extraction and later analysis thereby facilitating a more efficient review process.

Menopausal status, ultrasound and biomarker tests in combination for the diagnosis of ovarian cancer in symptomatic women.

BACKGROUND: Ovarian cancer (OC) has the highest case fatality rate of all gynaecological cancers. Diagnostic delays are caused by non-specific symptoms. Existing systematic reviews have not comprehensively covered tests in current practice, not estimated accuracy separately in pre- and postmenopausal women, or used inappropriate meta-analytic methods. OBJECTIVES: To establish the accuracy of combinations of menopausal status, ultrasound scan (USS) and biomarkers for the diagnosis of ovarian cancer in pre- and postmenopausal women and compare the accuracy of different test combinations. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), five other databases and three trial registries from 1991 to 2015 and MEDLINE (Ovid) and Embase (Ovid) form June 2015 to June 2019. We also searched conference proceedings from the European Society of Gynaecological Oncology, International Gynecologic Cancer Society, American Society of Clinical Oncology and Society of Gynecologic Oncology, ZETOC and Conference Proceedings Citation Index (Web of Knowledge). We searched reference lists of included studies and published systematic reviews. SELECTION CRITERIA: We included cross-sectional diagnostic test accuracy studies evaluating single tests or comparing two or more tests, randomised trials comparing two or more tests, and studies validating multivariable models for the diagnosis of OC investigating test combinations, compared with a reference standard of histological confirmation or clinical follow-up in women with a pelvic mass (detected clinically or through USS) suspicious for OC. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed quality using QUADAS-2. We used the bivariate hierarchical model to indirectly compare tests at commonly reported thresholds in pre- and postmenopausal women separately. We indirectly compared tests across all thresholds and estimated sensitivity at fixed specificities of 80% and 90% by fitting hierarchical summary receiver operating characteristic (HSROC) models in pre- and postmenopausal women separately. MAIN RESULTS: We included 59 studies (32,059 women, 9545 cases of OC). Two tests evaluated the accuracy of a combination of menopausal status and USS findings (IOTA Logistic Regression Model 2 (LR2) and the Assessment of Different NEoplasias in the adneXa model (ADNEX)); one test evaluated the accuracy of a combination of menopausal status, USS findings and serum biomarker CA125 (Risk of Malignancy Index (RMI)); and one test evaluated the accuracy of a combination of menopausal status and two serum biomarkers (CA125 and HE4) (Risk of Ovarian Malignancy Algorithm (ROMA)). Most studies were at high or unclear risk of bias in participant, reference standard, and flow and timing domains. All studies were in hospital settings. Prevalence was 16% (RMI, ROMA), 22% (LR2) and 27% (ADNEX) in premenopausal women and 38% (RMI), 45% (ROMA), 52% (LR2) and 55% (ADNEX) in postmenopausal women. The prevalence of OC in the studies was considerably higher than would be expected in symptomatic women presenting in community-based settings, or in women referred from the community to hospital with a suspicion of OC. Studies were at high or unclear applicability because presenting features were not reported, or USS was performed by experienced ultrasonographers for RMI, LR2 and ADNEX. The higher sensitivity and lower specificity observed in postmenopausal compared to premenopausal women across all index tests and at all thresholds may reflect highly selected patient cohorts in the included studies. In premenopausal women, ROMA at a threshold of 13.1 (± 2), LR2 at a threshold to achieve a post-test probability of OC of 10% and ADNEX (post-test probability 10%) demonstrated a higher sensitivity (ROMA: 77.4%, 95% CI 72.7% to 81.5%; LR2: 83.3%, 95% CI 74.7% to 89.5%; ADNEX: 95.5%, 95% CI 91.0% to 97.8%) compared to RMI (57.2%, 95% CI 50.3% to 63.8%). The specificity of ROMA and ADNEX were lower in premenopausal women (ROMA: 84.3%, 95% CI 81.2% to 87.0%; ADNEX: 77.8%, 95% CI 67.4% to 85.5%) compared to RMI 92.5% (95% CI 90.3% to 94.2%). The specificity of LR2 was comparable to RMI (90.4%, 95% CI 84.6% to 94.1%). In postmenopausal women, ROMA at a threshold of 27.7 (± 2), LR2 (post-test probability 10%) and ADNEX (post-test probability 10%) demonstrated a higher sensitivity (ROMA: 90.3%, 95% CI 87.5% to 92.6%; LR2: 94.8%, 95% CI 92.3% to 96.6%; ADNEX: 97.6%, 95% CI 95.6% to 98.7%) compared to RMI (78.4%, 95% CI 74.6% to 81.7%). Specificity of ROMA at a threshold of 27.7 (± 2) (81.5, 95% CI 76.5% to 85.5%) was comparable to RMI (85.4%, 95% CI 82.0% to 88.2%), whereas for LR2 (post-test probability 10%) and ADNEX (post-test probability 10%) specificity was lower (LR2: 60.6%, 95% CI 50.5% to 69.9%; ADNEX: 55.0%, 95% CI 42.8% to 66.6%). AUTHORS' CONCLUSIONS: In specialist healthcare settings in both premenopausal and postmenopausal women, RMI has poor sensitivity. In premenopausal women, ROMA, LR2 and ADNEX offer better sensitivity (fewer missed cancers), but for ROMA and ADNEX this is off-set by a decrease in specificity and increase in false positives. In postmenopausal women, ROMA demonstrates a higher sensitivity and comparable specificity to RMI. ADNEX has the highest sensitivity in postmenopausal women, but reduced specificity. The prevalence of OC in included studies is representative of a highly selected referred population, rather than a population in whom referral is being considered. The comparative accuracy of tests observed here may not be transferable to non-specialist settings. Ultimately health systems need to balance accuracy and resource implications to identify the most suitable test.

Vitiligo International Task force for an Agreed List of core data (VITAL): study protocol of a vitiligo core outcome set (COS) and contextual factors for clinical trials, registries, and clinical practice.

BACKGROUND: There is a lack of consensus related to the collection of standardized data for individuals with vitiligo enrolled in clinical trials and registries as well as those seen in clinical practice which causes difficulty in accurately interpreting, comparing, and pooling of data. Several years ago, efforts to initiate work on developing core outcome sets were performed and a consensus was reached in 2015 on the first core domain set for vitiligo clinical trials. METHODS/DESIGN: This project aims to further develop a core outcome set for vitiligo clinical trials as well as create internationally agreed-upon core outcome sets for registries and clinical practice. These core outcome sets will include a core domain set and a core measurement instruments set and will be supplemented by contextual factors, including baseline and treatment-related characteristics. In a preparatory exercise, the 2015 core domain set will be re-evaluated and will serve as the basis for the list of outcome domains used to initiate the consensus process. This project will consist of two parts. Part 1 will focus on the selection of a core domain set, or "what to measure" and contextual factors, for each setting based on electronic surveys (e-Delphi technique) and a conclusive consensus meeting by a large group of international stakeholders. Part 2 will include selection of core measurement instruments, or "how to measure," and measurement details (e.g., scale and timing) for the core domain sets and contextual factors agreed upon in part 1. Part 2 will be based on consensus meetings with stakeholders involved in part 1 and will be guided by C3 (CHORD-COUSIN Collaboration), Harmonising Outcome Measures for Eczema (HOME), COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN), and Outcome Measures in Rheumatology (OMERACT) recommendations including information on measurement properties of available instruments (systematic review and expert/patient opinion). At the end of part 2, all stakeholders involved will be invited to participate in a final meeting in which the ultimate core data sets (core outcome sets and contextual factors) will be presented and the dissemination plan and implementation goals will be defined. DISCUSSION: This project will harmonize data collection between clinical trials, registries, and clinical practices, facilitating new insights in vitiligo. TRIAL REGISTRATION: This study is registered in the Core Outcome Measures for Effectiveness Trials (COMET) database and on the C3 (CHORD-COUSIN Collaboration) website.

Diagnostic Models Combining Clinical Information, Ultrasound and Biochemical Markers for Ovarian Cancer: Cochrane Systematic Review and Meta-Analysis.

Background: Ovarian cancer (OC) is a diagnostic challenge, with the majority diagnosed at late stages. Existing systematic reviews of diagnostic models either use inappropriate meta-analytic methods or do not conduct statistical comparisons of models or stratify test performance by menopausal status. Methods: We searched CENTRAL, MEDLINE, EMBASE, CINAHL, CDSR, DARE, Health Technology Assessment Database and SCI Science Citation Index, trials registers, conference proceedings from 1991 to June 2019. Cochrane collaboration review methods included QUADAS-2 quality assessment and meta-analysis using hierarchical modelling. RMI, ROMA or ADNEX at any test positivity threshold were investigated. Histology or clinical follow-up was the reference standard. We excluded screening studies, studies restricted to pregnancy, recurrent or metastatic OC. 2 × 2 diagnostic tables were extracted separately for pre- and post-menopausal women. Results: We included 58 studies (30,121 patients, 9061 cases of ovarian cancer). Prevalence of OC ranged from 16 to 55% in studies. For premenopausal women, ROMA at a threshold of 13.1 (+/−2) and ADNEX at a threshold of 10% demonstrated significantly higher sensitivity compared to RMI I at 200 (p < 0.0001) 77.8 (72.5, 82.4), 94.9 (92.5, 96.6), and 57.1% (50.6 to 63.4) but lower specificity (p < 0.002), 92.5 (90.0, 94.4), 84.3 (81.3, 86.8), and 78.2 (75.8, 80.4). For postmenopausal women, ROMA at a threshold of 27.7 (+/−2) and AdNEX at a threshold of 10% demonstrated significantly higher sensitivity compared to RMI I at a threshold of 200 (p < 0.001) 90.4 (87.4, 92.7), 97.6 (96.2, 98.5), and 78.7 (74.3, 82.5), specificity of ROMA was comparable, whilst ADneX was lower, 85.5 (81.3, 88.9), 81.3 (76.9, 85.0) (p = 0.155), compared to RMI 55.2 (51.2, 59.1) (p < 0.001). Conclusions: In pre-menopausal women, ROMA and ADNEX offer significantly higher sensitivity but significantly decreased specificity. In post-menopausal women, ROMA demonstrates significantly higher sensitivity and comparable specificity to RMI I, ADNEX has the highest sensitivity of all models, but with significantly reduced specificity. RMI I has poor sensitivity compared to ROMA or ADNEX. Choice between ROMA and ADNEX as a replacement test will depend on cost effectiveness and resource implications.

Imaging features for the prediction of clinical endpoints in chronic liver disease: a scoping review protocol.

INTRODUCTION: Chronic liver disease is a growing cause of morbidity and mortality in the UK. Acute presentation with advanced disease is common and prioritisation of resources to those at highest risk at earlier disease stages is essential to improving patient outcomes. Existing prognostic tools are of limited accuracy and to date no imaging-based tools are used in clinical practice, despite multiple anatomical imaging features that worsen with disease severity.In this paper, we outline our scoping review protocol that aims to provide an overview of existing prognostic factors and models that link anatomical imaging features with clinical endpoints in chronic liver disease. This will provide a summary of the number, type and methods used by existing imaging feature-based prognostic studies and indicate if there are sufficient studies to justify future systematic reviews. METHODS AND ANALYSIS: The protocol was developed in accordance with existing scoping review guidelines. Searches of MEDLINE and Embase will be conducted using titles, abstracts and Medical Subject Headings restricted to publications after 1980 to ensure imaging method relevance on OvidSP. Initial screening will be undertaken by two independent reviewers. Full-text data extraction will be undertaken by three pretrained reviewers who have participated in a group data extraction session to ensure reviewer consensus and reduce inter-rater variability. Where needed, data extraction queries will be resolved by reviewer team discussion. Reporting of results will be based on grouping of related factors and their cumulative frequencies. Prognostic anatomical imaging features and clinical endpoints will be reported using descriptive statistics to summarise the number of studies, study characteristics and the statistical methods used. ETHICS AND DISSEMINATION: Ethical approval is not required as this study is based on previously published work. Findings will be disseminated by peer-reviewed publication and/or conference presentations.