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.

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.

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.

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.

Serum HE4 and diagnosis of ovarian cancer in postmenopausal women with adnexal masses.

BACKGROUND: Transvaginal ultrasound and serum CA125 are routinely used for differential diagnosis of pelvic adnexal mass. Use of human epididymis 4 was approved in the United States in 2011. However, there is scarcity of studies evaluating the additional value of human epididymis 4. OBJECTIVE: The objective of the study was to evaluate the performance characteristics of transvaginal ultrasound, CA125, and human epididymis 4 for differential diagnosis of ovarian cancer in postmenopausal women with adnexal masses. STUDY DESIGN: This was a cohort study nested within the screen arms of the multicenter randomized controlled trial, United Kingdom Collaborative Trial of Ovarian Cancer Screening, based in England, Wales, and Northern Ireland. In United Kingdom Collaborative Trial of Ovarian Cancer Screening, 48,230 women randomized to transvaginal ultrasound screening and 50,078 to multimodal screening (serum CA125 interpreted by Risk of Ovarian Cancer Algorithm with second line transvaginal ultrasound) underwent the first (prevalence) screen. Women with adnexal lesions and/or persistently elevated risk were clinically assessed and underwent surgery or follow-up for a median of 10.9 years. Banked samples taken within 6 months of transvaginal ultrasound from all clinically assessed women were assayed for human epididymis 4 and CA125. Area under the curve and sensitivity for diagnosing ovarian cancer of multiple penalized logistic regression models incorporating logCA125, log human epididymis 4, age, and simple ultrasound features of the adnexal mass were compared. RESULTS: Of 1590 (158 multimodal, 1432 ultrasound) women with adnexal masses, 78 were diagnosed with ovarian cancer (48 invasive epithelial ovarian, 14 type I, 34 type II; 24 borderline epithelial; 6 nonepithelial) within 1 year of scan. The area under the curve (0.893 vs 0.896; P = .453) and sensitivity (74.4% vs 75.6% ;P = .564) at fixed specificity of 90% of the model incorporating age, ultrasound, and CA125 were similar to that also including human epididymis 4. Both models had high sensitivity for invasive epithelial ovarian (89.6%) and type II (>91%) cancers. CONCLUSION: Our population cohort study suggests that human epididymis 4 adds little value to concurrent use of CA125 and transvaginal ultrasound in the differential diagnosis of adnexal masses in postmenopausal women.

Adaptive trial designs in diagnostic accuracy research.

The aim of diagnostic accuracy studies is to evaluate how accurately a diagnostic test can distinguish diseased from nondiseased individuals. Depending on the research question, different study designs and accuracy measures are appropriate. As the prior knowledge in the planning phase is often very limited, modifications of design aspects such as the sample size during the ongoing trial could increase the efficiency of diagnostic trials. In intervention studies, group sequential and adaptive designs are well established. Such designs are characterized by preplanned interim analyses, giving the opportunity to stop early for efficacy or futility or to modify elements of the study design. In contrast, in diagnostic accuracy studies, such flexible designs are less common, even if they are as important as for intervention studies. However, diagnostic accuracy studies have specific features, which may require adaptations of the statistical methods or may lead to specific advantages or limitations of sequential and adaptive designs. In this article, we summarize the current status of methodological research and applications of flexible designs in diagnostic accuracy research. Furthermore, we indicate and advocate future development of adaptive design methodology and their use in diagnostic accuracy trials from an interdisciplinary viewpoint. The term "interdisciplinary viewpoint" describes the collaboration of experts of the academic and nonacademic research.

Biological variation of measured and estimated glomerular filtration rate in patients with chronic kidney disease.

When assessing changes in glomerular filtration rate (GFR) it is important to differentiate pathological change from intrinsic biological and analytical variation. GFR is measured using complex reference methods (e.g., iohexol clearance). In clinical practice measurement of creatinine and cystatin C are used in the Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equations to provide estimated GFR. Here we studied the biological variability of measured and estimated GFR in twenty nephrology outpatients (10 male, 10 female; median age 71, range 50-80 years) with moderate CKD (GFR 30-59 ml/min per 1.73 m2). Patients underwent weekly GFR measurement by iohexol clearance over four consecutive weeks. Simultaneously, GFR was estimated using the MDRD, CKD-EPIcreatinine, CKD-EPIcystatinC and CKD-EPIcreatinine+cystatinC equations. Within-subject biological variation expressed as a percentage [95% confidence interval] for the MDRD (5.0% [4.3-6.1]), CKD-EPIcreatinine (5.3% [4.5-6.4]), CKD-EPIcystatinC (5.3% [4.5-6.5]), and CKD-EPIcreatinine+cystatinC (5.0% [4.3-6.2]) equations were broadly equivalent. The within-subject biological variation for MDRD and CKD- EPIcreatinine+cystatinC estimated GFR were each significantly lower than that of the measured GFR (6.7% [5.6-8.2]). Reference change values, the point at which a true change in a biomarker in an individual can be inferred to have occurred with 95% probability were calculated. By the MDRD equation, positive and negative reference change values were 15.1% and 13.1% respectively. If an individual's baseline MDRD estimated GFR (ml/min per 1.73 m2) was 59, significant increases or decreases would be to values over 68 or under 51 respectively. Within-subject variability of estimated GFR was lower than measured GFR. Reference change values can be used to understand GFR changes in clinical practice. Thus, estimates of GFR are at least as reliable as measured GFR for monitoring patients over time.

Improving the design of studies evaluating the impact of diagnostic tests for tuberculosis on health outcomes: a qualitative study of perspectives of diverse stakeholders.

Background: Studies evaluating the impact of Xpert MTB/RIF testing for tuberculosis (TB) have demonstrated varied effects on health outcomes with many studies showing inconclusive results. We explored perceptions among diverse stakeholders about studies evaluating the impact of TB diagnostic tests, and identified suggestions for improving these studies. Methods: We used purposive sampling with consideration for differing expertise and geographical balance and conducted in depth semi-structured interviews. We interviewed English-speaking participants, including TB patients, and others involved in research, care or decision-making about TB diagnostics. We used the thematic approach to code and analyse the interview transcripts. Results: We interviewed 31 participants. Our study showed that stakeholders had different expectations with regard to test impact and how it is measured. TB test impact studies were perceived to be important for supporting implementation of tests but there were concerns about the unrealistic expectations placed on tests to improve outcomes in health systems with many influencing factors. To improve TB test impact studies, respondents suggested conducting health system assessments prior to the study; developing clear guidance on the study methodology and interpretation; improving study design by describing questions and interventions that consider the influences of the health-care ecosystem on the diagnostic test; selecting the target population at the health-care level most likely to benefit from the test; setting realistic targets for effect sizes in the sample size calculations; and interpreting study results carefully and avoiding categorisation and interpretation of results based on statistical significance alone. Researchers should involve multiple stakeholders in the design of studies. Advocating for more funding to support robust studies is essential. Conclusion: TB test impact studies were perceived to be important to support implementation of tests but there were concerns about their complexity. Process evaluations of their health system context and guidance for their design and interpretation are recommended.

Variation in the observed effect of Xpert MTB/RIF testing for tuberculosis on mortality: A systematic review and analysis of trial design considerations.

Background: Most studies evaluating the effect of Xpert MTB/RIF testing for tuberculosis (TB) concluded that it did not reduce overall mortality compared to usual care. We conducted a systematic review to assess whether key study design and execution features contributed to earlier identification of patients with TB and decreased pre-treatment loss to follow-up, thereby reducing the potential impact of Xpert MTB/RIF testing. Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Scopus for literature published from 1 st January 2009 to February 2019. We included all primary intervention studies that had evaluated the effect of Xpert MTB/RIF on mortality compared to usual care in participants with presumptive pulmonary TB. We critically reviewed features of included studies across: Study setting and context, Study population, Participant recruitment and enrolment, Study procedures, and Study follow-up. Results: We included seven randomised and one non-randomised study.  All included studies demonstrated relative reductions in overall mortality in the Xpert MTB/RIF arm ranging from 6% to 40%. However, mortality reduction was reported to be statistically significant in two studies. Study features that could explain the lack of observed effect on mortality included: the higher quality of care at study sites; inclusion of patients with a higher pre-test probability of TB leading to higher than expected empirical rates; performance of additional diagnostic testing not done in usual care leading to increased TB diagnosis or empiric treatment initiation; the recruitment of participants likely to return for follow-up; and involvement of study staff in ensuring adherence with care and follow-up. Conclusion: Most studies of Xpert MTB/RIF were designed and conducted in a manner that resulted in more patients being diagnosed and treated for TB, minimising the potential difference in mortality Xpert MTB/RIF testing could have achieved compared to usual care.

Eustachian tube dysfunction: A diagnostic accuracy study and proposed diagnostic pathway.

BACKGROUND AND AIMS: Eustachian tube dysfunction (ETD) is a commonly diagnosed disorder of Eustachian tube opening and closure, which may be associated with severe symptoms and middle ear disease. Currently the diagnosis of obstructive and patulous forms of ETD is primarily based on non-specific symptoms or examination findings, rather than measurement of the underlying function of the Eustachian tube. This has proved problematic when selecting patients for treatment, and when designing trial inclusion criteria and outcomes. This study aims to determine the correlation and diagnostic value of various tests of ET opening and patient reported outcome measures (PROMs), in order to generate a recommended diagnostic pathway for ETD. METHODS: Index tests included two PROMs and 14 tests of ET opening (nine for obstructive, five for patulous ETD). In the absence of an accepted reference standard two methods were adopted to establish index test accuracy: expert panel diagnosis and latent class analysis. Index test results were assessed with Pearson correlation and principle component analysis, and test accuracy was determined. Logistic regression models assessed the predictive value of grouped test results. RESULTS: The expert panel diagnosis and PROMs results correlated with each other, but not with ET function measured by tests of ET opening. All index tests were found to be feasible in clinic, and acceptable to patients. PROMs had very poor specificity, and no diagnostic value. Combining the results of tests of ET function appeared beneficial. The latent class model suggested tympanometry, sonotubometry and tubomanometry have the best diagnostic performance for obstructive ETD, and these are included in a proposed diagnostic pathway. CONCLUSIONS: ETD should be diagnosed on the basis of clinical assessment and tests of ET opening, as PROMs have no diagnostic value. Currently diagnostic uncertainty exists for some patients who appear to have intermittent ETD clinically, but have negative index test results.

PET-PANC: multicentre prospective diagnostic accuracy and health economic analysis study of the impact of combined modality 18fluorine-2-fluoro-2-deoxy-d-glucose positron emission tomography with computed tomography scanning in the diagnosis and management of pancreatic cancer.

BACKGROUND: Pancreatic cancer diagnosis and staging can be difficult in 10-20% of patients. Positron emission tomography (PET)/computed tomography (CT) adds precise anatomical localisation to functional data. The use of PET/CT may add further value to the diagnosis and staging of pancreatic cancer. OBJECTIVE: To determine the incremental diagnostic accuracy and impact of PET/CT in addition to standard diagnostic work-up in patients with suspected pancreatic cancer. DESIGN: A multicentre prospective diagnostic accuracy and clinical value study of PET/CT in suspected pancreatic malignancy. PARTICIPANTS: Patients with suspected pancreatic malignancy. INTERVENTIONS: All patients to undergo PET/CT following standard diagnostic work-up. MAIN OUTCOME MEASURES: The primary outcome was the incremental diagnostic value of PET/CT in addition to standard diagnostic work-up with multidetector computed tomography (MDCT). Secondary outcomes were (1) changes in patients' diagnosis, staging and management as a result of PET/CT; (2) changes in the costs and effectiveness of patient management as a result of PET/CT; (3) the incremental diagnostic value of PET/CT in chronic pancreatitis; (4) the identification of groups of patients who would benefit most from PET/CT; and (5) the incremental diagnostic value of PET/CT in other pancreatic tumours. RESULTS: Between 2011 and 2013, 589 patients with suspected pancreatic cancer underwent MDCT and PET/CT, with 550 patients having complete data and in-range PET/CT. Sensitivity and specificity for the diagnosis of pancreatic cancer were 88.5% and 70.6%, respectively, for MDCT and 92.7% and 75.8%, respectively, for PET/CT. The maximum standardised uptake value (SUVmax.) for a pancreatic cancer diagnosis was 7.5. PET/CT demonstrated a significant improvement in relative sensitivity (p = 0.01) and specificity (p = 0.023) compared with MDCT. Incremental likelihood ratios demonstrated that PET/CT significantly improved diagnostic accuracy in all scenarios (p < 0.0002). PET/CT correctly changed the staging of pancreatic cancer in 56 patients (p = 0.001). PET/CT influenced management in 250 (45%) patients. PET/CT stopped resection in 58 (20%) patients who were due to have surgery. The benefit of PET/CT was limited in patients with chronic pancreatitis or other pancreatic tumours. PET/CT was associated with a gain in quality-adjusted life-years of 0.0157 (95% confidence interval -0.0101 to 0.0430). In the base-case model PET/CT was seen to dominate MDCT alone and is thus highly likely to be cost-effective for the UK NHS. PET/CT was seen to be most cost-effective for the subgroup of patients with suspected pancreatic cancer who were thought to be resectable. CONCLUSION: PET/CT provided a significant incremental diagnostic benefit in the diagnosis of pancreatic cancer and significantly influenced the staging and management of patients. PET/CT had limited utility in chronic pancreatitis and other pancreatic tumours. PET/CT is likely to be cost-effective at current reimbursement rates for PET/CT to the UK NHS. This was not a randomised controlled trial and therefore we do not have any information from patients who would have undergone MDCT only for comparison. In addition, there were issues in estimating costs for PET/CT. Future work should evaluate the role of PET/CT in intraductal papillary mucinous neoplasm and prognosis and response to therapy in patients with pancreatic cancer. STUDY REGISTRATION: Current Controlled Trials ISRCTN73852054 and UKCRN 8166. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

MICE or NICE? An economic evaluation of clinical decision rules in the diagnosis of heart failure in primary care.

BACKGROUND: Detection and treatment of heart failure (HF) can improve quality of life and reduce premature mortality. However, symptoms such as breathlessness are common in primary care, have a variety of causes and not all patients require cardiac imaging. In systems where healthcare resources are limited, ensuring those patients who are likely to have HF undergo appropriate and timely investigation is vital. DESIGN: A decision tree was developed to assess the cost-effectiveness of using the MICE (Male, Infarction, Crepitations, Edema) decision rule compared to other diagnostic strategies to identify HF patients presenting to primary care. METHODS: Data from REFER (REFer for EchocaRdiogram), a HF diagnostic accuracy study, was used to determine which patients received the correct diagnosis decision. The model adopted a UK National Health Service (NHS) perspective. RESULTS: The current recommended National Institute for Health and Care Excellence (NICE) guidelines for identifying patients with HF was the most cost-effective option with a cost of £4400 per quality adjusted life year (QALY) gained compared to a "do nothing" strategy. That is, patients presenting with symptoms suggestive of HF should be referred straight for echocardiography if they had a history of myocardial infarction or if their NT-proBNP level was ≥400pg/ml. The MICE rule was more expensive and less effective than the other comparators. Base-case results were robust to sensitivity analyses. CONCLUSIONS: This represents the first cost-utility analysis comparing HF diagnostic strategies for symptomatic patients. Current guidelines in England were the most cost-effective option for identifying patients for confirmatory HF diagnosis. The low number of HF with Reduced Ejection Fraction patients (12%) in the REFER patient population limited the benefits of early detection.

Development and validation of Prediction models for Risks of complications in Early-onset Pre-eclampsia (PREP): a prospective cohort study.

BACKGROUND: The prognosis of early-onset pre-eclampsia (before 34 weeks' gestation) is variable. Accurate prediction of complications is required to plan appropriate management in high-risk women. OBJECTIVE: To develop and validate prediction models for outcomes in early-onset pre-eclampsia. DESIGN: Prospective cohort for model development, with validation in two external data sets. SETTING: Model development: 53 obstetric units in the UK. Model transportability: PIERS (Pre-eclampsia Integrated Estimate of RiSk for mothers) and PETRA (Pre-Eclampsia TRial Amsterdam) studies. PARTICIPANTS: Pregnant women with early-onset pre-eclampsia. SAMPLE SIZE: Nine hundred and forty-six women in the model development data set and 850 women (634 in PIERS, 216 in PETRA) in the transportability (external validation) data sets. PREDICTORS: The predictors were identified from systematic reviews of tests to predict complications in pre-eclampsia and were prioritised by Delphi survey. MAIN OUTCOME MEASURES: The primary outcome was the composite of adverse maternal outcomes established using Delphi surveys. The secondary outcome was the composite of fetal and neonatal complications. ANALYSIS: We developed two prediction models: a logistic regression model (PREP-L) to assess the overall risk of any maternal outcome until postnatal discharge and a survival analysis model (PREP-S) to obtain individual risk estimates at daily intervals from diagnosis until 34 weeks. Shrinkage was used to adjust for overoptimism of predictor effects. For internal validation (of the full models in the development data) and external validation (of the reduced models in the transportability data), we computed the ability of the models to discriminate between those with and without poor outcomes (c-statistic), and the agreement between predicted and observed risk (calibration slope). RESULTS: The PREP-L model included maternal age, gestational age at diagnosis, medical history, systolic blood pressure, urine protein-to-creatinine ratio, platelet count, serum urea concentration, oxygen saturation, baseline treatment with antihypertensive drugs and administration of magnesium sulphate. The PREP-S model additionally included exaggerated tendon reflexes and serum alanine aminotransaminase and creatinine concentration. Both models showed good discrimination for maternal complications, with anoptimism-adjusted c-statistic of 0.82 [95% confidence interval (CI) 0.80 to 0.84] for PREP-L and 0.75 (95% CI 0.73 to 0.78) for the PREP-S model in the internal validation. External validation of the reduced PREP-L model showed good performance with a c-statistic of 0.81 (95% CI 0.77 to 0.85) in PIERS and 0.75 (95% CI 0.64 to 0.86) in PETRA cohorts for maternal complications, and calibrated well with slopes of 0.93 (95% CI 0.72 to 1.10) and 0.90 (95% CI 0.48 to 1.32), respectively. In the PIERS data set, the reduced PREP-S model had a c-statistic of 0.71 (95% CI 0.67 to 0.75) and a calibration slope of 0.67 (95% CI 0.56 to 0.79). Low gestational age at diagnosis, high urine protein-to-creatinine ratio, increased serum urea concentration, treatment with antihypertensive drugs, magnesium sulphate, abnormal uterine artery Doppler scan findings and estimated fetal weight below the 10th centile were associated with fetal complications. CONCLUSIONS: The PREP-L model provided individualised risk estimates in early-onset pre-eclampsia to plan management of high- or low-risk individuals. The PREP-S model has the potential to be used as a triage tool for risk assessment. The impacts of the model use on outcomes need further evaluation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN40384046. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Development and validation of prediction models for risk of adverse outcomes in women with early-onset pre-eclampsia: protocol of the prospective cohort PREP study.

BACKGROUND: Early-onset pre-eclampsia with raised blood pressure and protein in the urine before 34 weeks' gestation is one of the leading causes of maternal deaths in the UK. The benefits to the child from prolonging the pregnancy need to be balanced against the risk of maternal deterioration. Accurate prediction models of risks are needed to plan management. METHODS: We aim to undertake a multicentre prospective cohort study (Prediction of Risks in Early onset Pre-eclampsia (PREP)) to develop clinical prediction models in women with early-onset pre-eclampsia, for risk of adverse maternal outcomes by 48 h and by discharge. We will externally validate the models in two independent cohorts with 634 and 216 women. In the secondary analyses, we will assess risk of adverse fetal and neonatal outcomes at birth and by discharge. DISCUSSION: The PREP study will quantify the risk of maternal complications at various time points and provide individualised estimates of overall risk in women with early-onset pre-eclampsia to plan the management. TRIAL REGISTRATION: ISRCTN registry, ISRCTN40384046.

Erratum to: Methods for evaluating medical tests and biomarkers.

[This corrects the article DOI: 10.1186/s41512-016-0001-y.].

Refining Ovarian Cancer Test accuracy Scores (ROCkeTS): protocol for a prospective longitudinal test accuracy study to validate new risk scores in women with symptoms of suspected ovarian cancer.

INTRODUCTION: Ovarian cancer (OC) is associated with non-specific symptoms such as bloating, making accurate diagnosis challenging: only 1 in 3 women with OC presents through primary care referral. National Institute for Health and Care Excellence guidelines recommends sequential testing with CA125 and routine ultrasound in primary care. However, these diagnostic tests have limited sensitivity or specificity. Improving accurate triage in women with vague symptoms is likely to improve mortality by streamlining referral and care pathways. The Refining Ovarian Cancer Test Accuracy Scores (ROCkeTS; HTA 13/13/01) project will derive and validate new tests/risk prediction models that estimate the probability of having OC in women with symptoms. This protocol refers to the prospective study only (phase III). METHODS AND ANALYSIS: ROCkeTS comprises four parallel phases. The full ROCkeTS protocol can be found at http://www.birmingham.ac.uk/ROCKETS. Phase III is a prospective test accuracy study. The study will recruit 2450 patients from 15 UK sites. Recruited patients complete symptom and anxiety questionnaires, donate a serum sample and undergo ultrasound scored as per International Ovarian Tumour Analysis (IOTA) criteria. Recruitment is at rapid access clinics, emergency departments and elective clinics. Models to be evaluated include those based on ultrasound derived by the IOTA group and novel models derived from analysis of existing data sets. Estimates of sensitivity, specificity, c-statistic (area under receiver operating curve), positive predictive value and negative predictive value of diagnostic tests are evaluated and a calibration plot for models will be presented. ROCkeTS has received ethical approval from the NHS West Midlands REC (14/WM/1241) and is registered on the controlled trials website (ISRCTN17160843) and the National Institute of Health Research Cancer and Reproductive Health portfolios.

A scoping review of competencies for scientific editors of biomedical journals.

BACKGROUND: Biomedical journals are the main route for disseminating the results of health-related research. Despite this, their editors operate largely without formal training or certification. To our knowledge, no body of literature systematically identifying core competencies for scientific editors of biomedical journals exists. Therefore, we aimed to conduct a scoping review to determine what is known on the competency requirements for scientific editors of biomedical journals. METHODS: We searched the MEDLINE®, Cochrane Library, Embase®, CINAHL, PsycINFO, and ERIC databases (from inception to November 2014) and conducted a grey literature search for research and non-research articles with competency-related statements (i.e. competencies, knowledge, skills, behaviors, and tasks) pertaining to the role of scientific editors of peer-reviewed health-related journals. We also conducted an environmental scan, searched the results of a previous environmental scan, and searched the websites of existing networks, major biomedical journal publishers, and organizations that offer resources for editors. RESULTS: A total of 225 full-text publications were included, 25 of which were research articles. We extracted a total of 1,566 statements possibly related to core competencies for scientific editors of biomedical journals from these publications. We then collated overlapping or duplicate statements which produced a list of 203 unique statements. Finally, we grouped these statements into seven emergent themes: (1) dealing with authors, (2) dealing with peer reviewers, (3) journal publishing, (4) journal promotion, (5) editing, (6) ethics and integrity, and (7) qualities and characteristics of editors. DISCUSSION: To our knowledge, this scoping review is the first attempt to systematically identify possible competencies of editors. Limitations are that (1) we may not have captured all aspects of a biomedical editor's work in our searches, (2) removing redundant and overlapping items may have led to the elimination of some nuances between items, (3) restricting to certain databases, and only French and English publications, may have excluded relevant publications, and (4) some statements may not necessarily be competencies. CONCLUSION: This scoping review is the first step of a program to develop a minimum set of core competencies for scientific editors of biomedical journals which will be followed by a training needs assessment, a Delphi exercise, and a consensus meeting.