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Objectives: To evaluate whether (1) first‐trimester prognostic models for gestational diabetes mellitus (GDM) outperform the currently used single risk factor approach, and (2) a first‐trimester random venous glucose measurement improves model performance. Design: Prospective population‐based multicentre cohort. Setting: Thirty‐one independent midwifery practices and six hospitals in the Netherlands. Population: Women recruited before 14 weeks of gestation without pre‐existing diabetes. Methods: The single risk factor approach (presence of at least one risk factor: BMI ≥30 kg/m2, previous macrosomia, history of GDM, positive first‐degree family history of diabetes, non‐western ethnicity) was compared with the four best performing models in our previously published external validation study (Gabbay‐Benziv 2014, Nanda 2011, Teede 2011, van Leeuwen 2010) with and without the addition of glucose. Main outcome measures: Discrimination was assessed by c‐statistics, calibration by calibration plots, added value of glucose by the likelihood ratio chi‐square test, net benefit by decision curve analysis and reclassification by reclassification plots. Results: Of the 3723 women included, a total of 181 (4.9%) developed GDM. The c‐statistics of the prognostic models were higher, ranging from 0.74 to 0.78 without glucose and from 0.78 to 0.80 with glucose, compared with the single risk factor approach (0.72). Models showed adequate calibration, and yielded a higher net benefit than the single risk factor approach for most threshold probabilities. Teede 2011 performed best in the reclassification analysis. Conclusions: First‐trimester prognostic models seem to outperform the currently used single risk factor approach in screening for GDM, particularly when glucose was added as a predictor. Prognostic models seem to outperform the currently used single risk factor approach in screening for gestational diabetes. Prognostic models seem to outperform the currently used single risk factor approach in screening for gestational diabetes. [ABSTRACT FROM AUTHOR]

Objective: Early-onset fetal growth restriction affects about 0.3% of pregnancies, posing high perinatal risks due to placental insufficiency. Early-onset fetal growth restriction often coincides with early-onset pre-eclampsia, associated with significant mortality and morbidity. Clinical management varies among clinicians, with emphasis on intensive monitoring and timely delivery. Our objective was to improve clinical prediction of perinatal mortality in early-onset fetal growth restriction for parental counseling., Study Design: This was a secondary analysis of prospective cohort data from the Dutch STRIDER trial. The study included 215 pregnant women diagnosed with severe early-onset fetal growth restriction between 20 + 0 and 29 + 6 weeks of gestation, from tertiary and secondary antenatal care centers in The Netherlands. Maternal and fetal characteristics were collected at inclusion, including sonographic and laboratory measurements. Analysis was performed using univariable and multivariable binary logistic regression to create a prediction model for perinatal mortality. The main outcome measures were fetal demise and neonatal mortality up to discharge., Results: 215 Participants were included for this analysis. Perinatal mortality occurred in 84 (39 %) cases; 51 (24 %) were fetal and 33 (15 %) neonatal. Fetal abdominal circumference, gestational age at diagnosis, estimated fetal weight Multiple of Median, absent or reversed end-diastolic flow of the umbilical artery, umbilical artery pulsatility index Multiple of Median, non-Caucasian ethnicity, male sex, placental growth factor level and uterine artery pulsatility index were independent predictors of perinatal mortality. Randomization allocation (sildenafil or placebo) had no predictive value for mortality. The prediction model including gestational age at diagnosis, estimated fetal weight Multiple of Median and umbilical artery pulsatility index Multiple of Median showed an area under the receiver operating characteristic curve of 0.840 (P < 0.01). Placental growth factor was measured in a subset of patients and was an independent prognostic factor and performed significantly better within the predictive model, however it did not improve the predictive value of the model., Conclusions: Prediction of perinatal mortality in early-onset fetal growth restriction is feasible with commonly available tests and measurements and could support decision making in management of pregnancy. However, implementation in practice requires further studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Low-value care is healthcare leading to no or little clinical benefit for the patient. The best (combinations of) interventions to reduce low-value care are unclear., Purpose: To provide an overview of randomized controlled trials (RCTs) evaluating deimplementation strategies, to quantify the effectiveness and describe different combinations of strategies., Methods: Analysis of 121 RCTs (1990-2019) evaluating a strategy to reduce low-value care, identified by a systematic review. Deimplementation strategies were described and associations between strategy characteristics and effectiveness explored., Results: Of 109 trials comparing deimplementation to usual care, 75 (69%) reported a significant reduction of low-value healthcare practices. Seventy-three trials included in a quantitative analysis showed a median relative reduction of 17% (IQR 7%-42%). The effectiveness of deimplementation strategies was not associated with the number and types of interventions applied., Conclusions and Implications: Most deimplementation strategies achieved a considerable reduction of low-value care. We found no signs that a particular type or number of interventions works best for deimplementation. Future deimplementation studies should map relevant contextual factors, such as the workplace culture or economic factors. Interventions should be tailored to these factors and provide details regarding sustainability of the effect., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the National Association for Healthcare Quality.)

Background: In several settings, a shorter time to diagnosis has been shown to lead to improved clinical outcomes. The implementation of a rapid laboratory testing allows for a pre-visit testing in the outpatient clinic, meaning that test results are available during the first outpatient visit., Objective: To determine whether the pre-visit laboratory testing leads to a shorter time to diagnosis in the general internal medicine outpatient clinic., Design: An "on-off" trial, allocating subjects to one of two treatment arms in consecutive alternating blocks., Participants: All new referrals to the internal medicine outpatient clinic of a university hospital were included, excluding second opinions. A total of 595 patients were eligible; one person declined to participate, leaving data from 594 patients for analysis., Intervention: In the intervention group, patients had a standardized pre-visit laboratory testing before the first visit., Main Measures: The primary outcome was the time to diagnosis. Secondary outcomes were the correctness of the preliminary diagnosis on the first day, health care utilization, and patient and physician satisfaction., Key Results: There was no difference in time to diagnosis between the two groups (median 35 days vs 35 days; hazard ratio 1.03 [0.87-1.22]; p = .71). The pre-visit testing group had higher proportions of both correct preliminary diagnoses on day 1 (24% vs 14%; p = .003) and diagnostic workups being completed on day 1 (10% vs 3%; p < .001). The intervention group had more laboratory tests done (50.0 [interquartile range (IQR) 39.0-69.0] vs 43.0 [IQR 31.0-68.5]; p < .001). Otherwise, there were no differences between the groups., Conclusions: Pre-visit testing did not lead to a shorter overall time to diagnosis. However, a greater proportion of patients had a correct diagnosis on the first day. Further studies should focus on customizing pre-visit laboratory panels, to improve their efficacy., Trial Registration: NL5009., (© 2021. The Author(s).)

Background: Implementation of new diagnostic criteria for gestational diabetes mellitus (GDM) are still a subject of debate, mostly due to concerns regarding the effects on the number of women diagnosed with GDM and the risk profile of the women newly diagnosed., Aim: To estimate the impact of the World Health Organization (WHO) 2013 criteria compared with the WHO 1999 criteria on the incidence of gestational diabetes mellitus as well as to determine the diagnostic accuracy for detecting adverse pregnancy outcomes., Methods: We retrospectively analyzed a single center Dutch cohort of 3338 women undergoing a 75 g oral glucose tolerance test where the WHO 1999 criteria to diagnose GDM were clinically applied. Women were categorized into four groups: non-GDM by both criteria, GDM by WHO 1999 only (excluded from GDM), GDM by WHO 2013 only (newly diagnosed) and GDM by both criteria. We compared maternal characteristics, pregnancy outcomes and likelihood ratios for adverse pregnancy outcomes., Results: Retrospectively applying the WHO 2013 criteria increased the cohort incidence by 13.1%, from 19.3% to 32.4%. Discordant diagnoses occurred in 21.3%; 4.1% would no longer be labelled as GDM, and 17.2% were newly diagnosed. Compared to the non-GDM group, women newly diagnosed were older, had higher rates of obesity, higher diastolic blood pressure and higher rates of caesarean deliveries. Their infants were more often delivered preterm, large-for-gestational-age and were at higher risk of a 5 min Apgar score < 7. Women excluded from GDM were older and had similar pregnancy outcomes compared to the non-GDM group, except for higher rates of shoulder dystocia (4.3% vs 1.3%, P = 0.015). Positive likelihood ratios for adverse outcomes in all groups were generally low, ranging from 0.54 to 2.95., Conclusion: Applying the WHO 2013 criteria would result in a substantial increase in GDM diagnoses. Newly diagnosed women are at increased risk for pregnancy adverse outcomes. This risk, however, seems to be lower than those identified by the WHO 1999 criteria. This could potentially influence the treatment effect that can be achieved in this group. Evidence on treatment effects in newly diagnosed women is urgently needed., Competing Interests: Conflict-of-interest statement: The authors declare that there is no duality of interest associated with this manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: It is recognised that medical tests are overused in primary care; however, it is unclear how best to reduce their use., Aim: To identify which strategies are effective in reducing the use of low-value medical tests in primary care settings., Design and Setting: Systematic review., Method: The databases MEDLINE, EMBASE, and Rx for Change were searched (January 1990 to November 2019) for randomised controlled trials (RCTs) that evaluated strategies to reduce the use of low-value medical tests in primary care settings. Two reviewers selected eligible RCTs, extracted data, and assessed their risk of bias., Results: Of the 16 RCTs included in the review, 11 reported a statistically significant reduction in the use of low-value medical tests. The median of the differences between the relative reductions in the intervention and control arms was 17% (interquartile range 12% to 24%). Strategies using reminders or audit/feedback showed larger reduction than those without these components (22% versus 14%, and 22% versus 13%, respectively) and patient-targeted strategies showed larger reductions than those not targeted at patients (51% versus 17%). Very few studies investigated the sustainability of the effect, adverse events, cost-effectiveness, or patient-reported outcomes related to reducing the use of low-value tests., Conclusion: This review indicates that it is possible to reduce the use of low-value medical tests in primary care, especially by using multiple components including reminders, audit/feedback, and patient-targeted interventions. To implement these strategies widely in primary care settings, more research is needed not only to investigate their effectiveness, but also to examine adverse events, cost-effectiveness, and patient-reported outcomes., (© British Journal of General Practice 2020.)

Objective: To assess the association between ketonuria and hyperemesis gravidarum (HG) disease severity., Study Design: We included pregnant women hospitalised for HG who participated in the Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER) trial and women who were eligible, chose not to be randomised and agreed to participate in the observational cohort. Between October 2013 and March 2016, in 19 hospitals in the Netherlands, women hospitalised for HG were approached for study participation. The presence of ketonuria was not required for study entry. Ketonuria was measured at hospital admission with a dipstick, which distinguishes 5 categories: negative and 1+ through 4 + . The outcome measures were multiple measures of HG disease severity at different time points: 1) At hospital admission (study entry): severity of nausea and vomiting, quality of life and weight change compared to pre-pregnancy weight, 2) One week after hospital admission: severity of nausea and vomiting, quality of life and weight change compared to admission, 3) Duration of index hospital admission and readmission for HG at any time point RESULTS: 215 women where included. Ketonuria was not associated with severity of nausea and vomiting, quality of life or weight loss at hospital admission, nor was the degree of ketonuria at admission associated with any of the outcomes 1 week after hospital admission. The degree of ketonuria was also not associated with the number of readmissions. However, women with a higher degree of ketonuria had a statistically significant longer duration of hospital stay (per 1+ ketonuria, difference: 0.27 days, 95 % CI: 0.05 to 0.48)., Conclusions: There was no association between the degree of ketonuria at admission and severity of symptoms, quality of life, maternal weight loss, or number of readmissions, suggesting that ketonuria provides no information about disease severity or disease course. Despite this, women with a higher degree of ketonuria at admission were hospitalised for longer. This could suggest that health care professionals base length of hospital stay on the degree of ketonuria. Based on the lack of association between ketonuria and disease severity, we suggest it has no additional value in the clinical management of HG., Competing Interests: Declaration of Competing Interest None declared. Completed disclosure of interests form available to view online as supporting information., (Copyright © 2020. Published by Elsevier B.V.)

Background: Because diagnosing asthma in school-aged children is challenging, a variety of proxies for asthma are used in clinical practice and research settings as indicators of this disease. We aimed to provide insight into the agreement between various asthma indicators based on parental report, medical diagnosis and spirometry., Methods: Children from the WHISTLER birth cohort performed spirometry and were followed up with parental ISAAC (International Study of Asthma and Allergies in Childhood) questionnaires about asthma at 5 and 8 years of age. Medical data were extracted from primary care records. We compared 15 asthma indicators based on parental report, medical diagnosis and spirometry using positive agreement, κ statistics and latent class cluster analysis., Results: At 5 years of age, 1007 children completed a study visit, while 803 children visited at 8 years of age. Depending on the indicator, the responder and child's age, the asthma prevalence ranged from 0.2% to 26.6%. Cluster analysis revealed classes related to the presence of recent symptoms and a decreased lung function. Agreement between parents and doctors was generally low with κ coefficients ranging from 0.07 (recent wheeze) to 0.52 (recent asthma medication). Additionally, parental report showed to be sensitive to recall bias over time., Conclusions: Dependent on the asthma indicator, the responder and the age of the child, substantial differences in agreement were observed between commonly used indicators associated with asthmatic disease in school-aged children. Most agreement between parents and doctors was seen for objective and recent indicators such as the recent use of asthma medication. We advocate caution when literature with different asthma indicators is compared., Competing Interests: Conflict of interest: K. Korsten has nothing to disclose. Conflict of interest: C.A. Naaktgeboren has nothing to disclose. Conflict of interest: L.J. Bont is the founding chairman of the ReSViNET Foundation. L.J. Bont has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. UMCU has received major funding (greater than €100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, Janssen, the Bill and Melinda Gates Foundation, Nutricia (Danone) and MeMed Diagnostics. UMCU has received major cash or in-kind funding as part of the public–private partnership IMI-funded RESCEU project from GSK, Novavax, Janssen, AstraZeneca, Pfizer and Sanofi. UMCU has received major funding by Julius Clinical for participating in the INFORM study sponsored by MedImmune. UMCU has received minor funding for participation in trials by Regeneron and Janssen from 2015–2017 (total annual estimate less than €20 000). UMCU received minor funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, Novavax, Pfizer, Janssen (total annual estimate less than €20 000). Conflict of interest: C.K. van der Ent reports grants from GSK, Nutricia, TEVA, Gilead, Vertex, ProQR, Proteostasis and Galapagos NV, outside the submitted work. Conflict of interest: M.L.A. de Hoog has nothing to disclose., (Copyright ©ERS 2020.)

Background: To reduce overutilization of laboratory testing many interventions have been tried, but selecting the most effective intervention for a given setting is challenging. To be sustainable, interventions need to align with healthcare providers' needs and daily practices. This study aimed to assess the extent of overutilization and the perspectives of healthcare providers, which may be used to guide the choice of intervention., Methods: The extent of inappropriate laboratory testing in internal medicine inpatients was evaluated using a database. Surveys and focus groups were used to investigate healthcare providers' perceptions on its causes and solutions., Results: On average, patients had 5.7 laboratory orders done during the first week of admission, whereas guidelines advise performing laboratory testing no more than twice per week. Repeat testing of normal test results occurred in up to 85% of patients. The frequency of laboratory testing was underestimated by survey responders, even though the majority of responders (78%) thought that laboratory tests are ordered too frequently. Residents were considered to be most responsible for laboratory test ordering.The primary causes of overutilization discussed were personal factors, such as a lack of awareness and knowledge, as well as feelings of insecurity. Regarding possible solutions, residents generally recommended educational interventions, whereas specialists tended to favour technical solutions such as lockouts., Conclusion: Inappropriate laboratory testing is common in internal medicine. The most important causes are a lack of awareness and knowledge, especially in residents. The intervention most favoured by residents is education, suggesting educational interventions may be most applicable., Competing Interests: None of the authors have any actual or potential conflict of interest to disclose pertaining to this study., (© 2020 The Authors.)

Respiratory syncytial virus (RSV) causes significant mortality in hospitalized adults. Prediction of poor outcomes improves targeted management and clinical outcomes. We externally validated and updated existing models to predict poor outcome in hospitalized RSV-infected adults. In this single center, retrospective, observational cohort study, we included hospitalized adults with respiratory tract infections (RTIs) and a positive polymerase chain reaction for RSV (A/B) on respiratory tract samples (2005-2018). We validated existing prediction models and updated the best discriminating model by revision, recalibration, and incremental value testing. We included 192 RSV-infected patients (median age 60.7 years, 57% male, 65% immunocompromised, and 43% with lower RTI). Sixteen patients (8%) died within 30 days. During hospitalization, 16 (8%) died, 30 (16%) were admitted to intensive care unit, 21 (11%) needed invasive mechanical ventilation, and 5 (3%) noninvasive positive pressure ventilation. Existing models performed moderately at external validation, with C-statistics 0.6 to 0.7 and moderate calibration. Updating to a model including lower RTI, chronic pulmonary disease, temperature, confusion and urea, increased the C-statistic to 0.76 (95% confidence interval, 0.61-0.91) to predict in-hospital mortality. In conclusion, existing models to predict poor prognosis among hospitalized RSV-infected adults perform moderately at external validation. A prognostic model may help to identify and treat RSV-infected adults at high-risk of death., (© 2019 The Authors. Journal of Medical Virology published by Wiley Periodicals, Inc.)

Introduction: Preterm birth complicates >15 million pregnancies annually worldwide. In many countries, women who present with signs of preterm labour are treated with tocolytics for 48 hours. Although this delays birth, it has never been shown to improve neonatal outcome. In 2015, the WHO stated that the use of tocolytics should be reconsidered and that large placebo-controlled studies to evaluate the effectiveness of tocolytics are urgently needed., Methods and Analysis: We designed an international, multicentre, randomised, double-blinded, placebo-controlled clinical trial. Women with threatened preterm birth (gestational age 30-34 weeks), defined as uterine contractions with (1) a cervical length of < 15 mm or (2) a cervical length of 15-30 mm and a positive fibronectin test or (3) in centres where cervical length measurement is not part of the local protocol: a positive fibronectin test or insulin-like growth factor binding protein-1 (Actim-Partus test) or (4) ruptured membranes, will be randomly allocated to treatment with atosiban or placebo for 48 hours. The primary outcome is a composite of perinatal mortality and severe neonatal morbidity. Analysis will be by intention to treat. A sample size of 1514 participants (757 per group) will detect a reduction in adverse neonatal outcome from 10% to 6% (alpha 0.05, beta 0.2). A cost-effectiveness analysis will be performed from a societal perspective., Ethics and Dissemination: This study has been approved by the Research Ethics Committee (REC) of the Amsterdam University Medical Centres, location AMC, as well as the REC's in Dublin and the UK. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results., Trial Registration Number: Nederlands Trial Register (Trial NL6469)., Competing Interests: Competing interests: JT received a number of lectures and medical advisory fees from Ferring pharmaceuticals between 2000 and 2016., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Objective: To demonstrate how decision analytic models (DAMs) can be used to quantify impact of using a (diagnostic or prognostic) prediction model in clinical practice and provide general guidance on how to perform such assessments., Study Design and Setting: A DAM was developed to assess the impact of using the HEART score for predicting major adverse cardiac events (MACE). Impact on patient health outcomes and health care costs was assessed in scenarios by varying compliance with and informed deviation (ID) (using additional clinical knowledge) from HEART score management recommendations. Probabilistic sensitivity analysis was used to assess estimated impact robustness., Results: Impact of using the HEART score on health outcomes and health care costs was influenced by an interplay of compliance with and ID from HEART score management recommendations. Compliance of 50% (with 0% ID) resulted in increased missed MACE and costs compared with usual care. Any compliance combined with at least 50% ID reduced both costs and missed MACE. Other scenarios yielded a reduction in missed MACE at higher costs., Conclusion: Decision analytic modeling is a useful approach to assess impact of using a prediction model in practice on health outcomes and health care costs. This approach is recommended before conducting an impact trial to improve its design and conduct., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM., Methods: The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle., Ethics and Dissemination: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NTR6134; Pre-results., Competing Interests: Competing interests: JHD sits on advisory boards for Novo Nordisk A/S. BWM is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). BWM reports consultancy for ObsEva, Merck KGaA and Guerbet., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: If a gold standard is lacking in a diagnostic test accuracy study, expert diagnosis is frequently used as reference standard. However, interobserver and intraobserver agreements are imperfect. The aim of this study was to quantify the reproducibility of a panel diagnosis for pediatric infectious diseases., Study Design and Setting: Pediatricians from six countries adjudicated a diagnosis (i.e., bacterial infection, viral infection, or indeterminate) for febrile children. Diagnosis was reached when the majority of panel members came to the same diagnosis, leaving others inconclusive. We evaluated intraobserver and intrapanel agreement with 6 weeks and 3 years' time intervals. We calculated the proportion of inconclusive diagnosis for a three-, five-, and seven-expert panel., Results: For both time intervals (i.e., 6 weeks and 3 years), intrapanel agreement was higher (kappa 0.88, 95%CI: 0.81-0.94 and 0.80, 95%CI: NA) compared to intraobserver agreement (kappa 0.77, 95%CI: 0.71-0.83 and 0.65, 95%CI: 0.52-0.78). After expanding the three-expert panel to five or seven experts, the proportion of inconclusive diagnoses (11%) remained the same., Conclusion: A panel consisting of three experts provides more reproducible diagnoses than an individual expert in children with lower respiratory tract infection or fever without source. Increasing the size of a panel beyond three experts has no major advantage for diagnosis reproducibility., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Inappropriate use of laboratory testing is a challenging problem. Estimated overuse rates of approximately 20% have been reported. Effective, sustainable solutions to stimulate optimal use are needed., Objective: To determine the association of a multifaceted intervention with laboratory test volume., Design, Setting, and Participants: A before-after quality improvement study was performed between August 1, 2016, and April 30, 2018, in the internal medicine departments of 4 teaching hospitals in the Netherlands. Data on laboratory order volumes from 19 comparable hospitals were used as controls. The participants were clinicians ordering laboratory tests., Interventions: The intervention included creating awareness through education and feedback, intensified supervision of residents, and changes in order entry systems. Interventions were performed by local project teams and guided by a central project team during a 6-month period. Sustainability was investigated during an 8-month follow-up period., Main Outcomes and Measures: The primary outcome was the change in slope for laboratory test volume. Secondary outcomes were change in slope for laboratory expenditure, order volumes and expenditure for other diagnostic procedures, and clinical outcomes. Data were collected on duration of hospital stay, rate of repeated outpatient visits, 30-day readmission rate, and rate of unexpected prolonged duration of hospital stay for patients admitted for pneumonia., Results: The numbers of internists and residents ordering tests in hospitals 1 to 4 were 16 and 30, 18 and 20, 13 and 17, and 21 and 60, respectively. Statistically significant changes in slope for laboratory test volume per patient contact were found at hospital 1 (change in slope, -1.55; 95% CI, -1.98 to -1.11; P < .001), hospital 3 (change in slope, -0.74; 95% CI, -1.42 to -0.07; P = .03), and hospital 4 (change in slope, -2.18; 95% CI, -3.27 to -1.08; P < .001). At hospital 2, the change in slope was not statistically significant (-0.34; 95% CI, -2.27 to 1.58; P = .73). Laboratory test volume per patient contact decreased by 11.4%, whereas the volume increased by 2.4% in 19 comparable hospitals. Statistically significant changes in slopes for laboratory costs and volumes and costs for other diagnostic procedures were also observed. Clinical outcomes were not associated with negative changes. Important facilitators were education, continuous attention for overuse, feedback, and residents' involvement. Important barriers were difficulties in data retrieval, difficulty in incorporation of principles in daily practice, and high resident turnover., Conclusions and Relevance: A set of interventions aimed at changing caregivers' mindset was associated with a reduction in the laboratory test volume in all departments, whereas the volume increased in comparable hospitals in the Netherlands. This study provides a framework for nationwide implementation of interventions to reduce unnecessary laboratory testing.

Objectives: The objective of this study was to study the impact of ignoring uncertainty by forcing dichotomous classification (presence or absence) of the target disease on estimates of diagnostic accuracy of an index test., Study Design and Setting: We evaluated the bias in estimated index test accuracy when forcing an expert panel to make a dichotomous target disease classification for each individual. Data for various scenarios with expert panels were simulated by varying the number and accuracy of "component reference tests" available to the expert panel, index test sensitivity and specificity, and target disease prevalence., Results: Index test accuracy estimates are likely to be biased when there is uncertainty surrounding the presence or absence of the target disease. Direction and amount of bias depend on the number and accuracy of component reference tests, target disease prevalence, and the true values of index test sensitivity and specificity., Conclusion: In this simulation, forcing expert panels to make a dichotomous decision on target disease classification in the presence of uncertainty leads to biased estimates of index test accuracy. Empirical studies are needed to demonstrate whether this bias can be reduced by assigning a probability of target disease presence for each individual, or using advanced statistical methods to account for uncertainty in target disease classification., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To perform an external validation of all published prognostic models for first-trimester prediction of the risk of developing preeclampsia (PE)., Methods: Women <14 weeks of pregnancy were recruited in the Netherlands. All systematically identified prognostic models for PE that contained predictors commonly available were eligible for external validation., Results: 3,736 women were included; 87 (2.3%) developed PE. Calibration was poor due to overestimation. Discrimination of 9 models for LO-PE ranged from 0.58 to 0.71 and of 9 models for all PE from 0.55 to 0.75., Conclusion: Only a few easily applicable prognostic models for all PE showed discrimination above 0.70, which is considered an acceptable performance.

Severe respiratory syncytial virus (RSV) infection during infancy is associated with ongoing respiratory morbidity. In a large birth cohort of 2210 healthy preterm infants born at 32-35 weeks of gestation, we aimed to determine the role of atopy in the link between RSV hospitalization and current wheeze at age 6. We defined current wheeze as parent-reported wheeze or the use of respiratory medication in the past 12 months. Based on a positive family history of atopic disease, we distinguished between children with and without atopic predisposition. Six-year follow-up data was obtained in 997/1559 (64%) children of which 102 (10.2%) children had been hospitalized with RSV during infancy. Current wheeze was present in 184/997 (18.6%) children. RSV hospitalization was an independent risk factor for current wheeze in children without atopic predisposition (aOR 4.05 [95% CI 1.22-12.52]) but not in children with this atopic background (aOR 1.50 [95% CI 0.81-2.71]).Conclusion: This is the largest published birth cohort demonstrating that in late preterm infants, atopic predisposition defines the relationship between RSV hospitalization and current wheeze. Future RSV prevention trials aiming to prevent ongoing respiratory symptoms should be analyzed separately for atopic status. What is Known: • RSV infection is responsible for a significant burden of disease in young children worldwide. • Severe RSV infection in early life is associated with asthmatic symptoms later in life. What is New: • This is the largest published birth cohort reporting about the role of atopic predisposition in the link between severe RSV infection and current wheeze at school age. • We show that RSV hospitalization in infancy is an independent risk factor for current wheeze in late preterm children without atopic predisposition at age 6. This was not seen in children with atopic predisposition.

Background: Studies addressing the appropriateness of laboratory testing have revealed approximately 20% overutilization. We conducted a narrative review to (1) describe current interventions aimed at reducing unnecessary laboratory testing, specifically in hospital settings, and (2) provide estimates of their efficacy in reducing test order volume and improving patient-related clinical outcomes., Methods: The PubMed, Embase, Scopus, Web of Science, and Canadian Agency for Drugs and Technologies in Health-Health Technology Assessment databases were searched for studies describing the effects of interventions aimed at reducing unnecessary laboratory tests. Data on test order volume and clinical outcomes were extracted by one reviewer, while uncertainties were discussed with two other reviewers. Because of the heterogeneity of interventions and outcomes, no meta-analysis was performed., Results: Eighty-four studies were included. Interventions were categorized into educational, (computerized) provider order entry [(C)POE], audit and feedback, or other interventions. Nearly all studies reported a reduction in test order volume. Only 15 assessed sustainability up to two years. Patient-related clinical outcomes were reported in 45 studies, two of which found negative effects., Conclusions: Interventions from all categories have the potential to reduce unnecessary laboratory testing, although long-term sustainability is questionable. Owing to the heterogeneity of the interventions studied, it is difficult to conclude which approach was most successful, and for which tests. Most studies had methodological limitations, such as the absence of a control arm. Therefore, well-designed, controlled trials using clearly described interventions and relevant clinical outcomes are needed., Competing Interests: No potential conflicts of interest relevant to this article were reported., (© The Korean Society for Laboratory Medicine.)

Aim: Diabetes is associated with a high risk of adverse pregnancy outcomes. Optimal glycaemic control is fundamental and is traditionally monitored with self-measured glucose profiles and periodic HbA1c measurements. We investigated the effectiveness of additional use of retrospective continuous glucose monitoring (CGM) in diabetic pregnancies., Material and Methods: We performed a nationwide multicentre, open label, randomized, controlled trial to study pregnant women with type 1 or type 2 diabetes who were undergoing insulin therapy at gestational age < 16 weeks, or women who were undergoing insulin treatment for gestational diabetes at gestational age < 30 weeks. Women were randomly allocated (1:1) to intermittent use of retrospective CGM or to standard treatment. Glycaemic control was assessed by CGM for 5-7 days every 6 weeks in the CGM group, while self-monitoring of blood glucose and HbA1c measurements were applied in both groups. Primary outcome was macrosomia, defined as birth weight above the 90th percentile. Secondary outcomes were glycaemic control and maternal and neonatal complications., Results: Between July 2011 and September 2015, we randomized 300 pregnant women with type 1 (n = 109), type 2 (n = 82) or with gestational (n = 109) diabetes to either CGM (n = 147) or standard treatment (n = 153). The incidence of macrosomia was 31.0% in the CGM group and 28.4% in the standard treatment group (relative risk [RR], 1.06; 95% CI, 0.83-1.37). HbA1c levels were similar between treatment groups., Conclusions: In diabetic pregnancy, use of intermittent retrospective CGM did not reduce the risk of macrosomia. CGM provides detailed information concerning glycaemic fluctuations but, as a treatment strategy, does not translate into improved pregnancy outcome., (© 2018 John Wiley & Sons Ltd.)

Background: Respiratory syncytial virus (RSV) infection is associated with subsequent wheeze and asthma. We previously reported on the causal relationship between prevention of RSV infection during infancy and reduced frequency of subsequent wheeze using a double-blind, randomised, placebo-controlled trial (MAKI). We continued follow-up and analysed the effect of RSV prevention during infancy on asthma and lung function at age 6 years., Methods: We studied 429 infants born at 32-35 weeks of gestation between 2008-10 who had randomly received either palivizumab for RSV immunoprophylaxis or placebo during the RSV season of their first year of life. After the first year of follow-up, single, assessor-blind follow-up of children continued until they were aged 6 years. Primary outcomes were parent-reported current asthma and forced expiratory volume in 0·5 s (FEV 0·5 ). The trial is registered in the ISRCTN registry, number ISRCTN73641710., Findings: 395 (92%) of 429 participants completed this 6-year follow-up study. Parent-reported current asthma was reported in 28 (14·1%) of 199 children in the RSV prevention group and 47 (24·0%) of 196 children in the placebo group (absolute risk reduction [ARR] 9·9%, 95% CI 2·2 to 17·6). The difference in current asthma, which was a composite endpoint, was due to a difference in infrequent wheeze (one to three episodes in the past year; 12 [6·0%] of 199 vs 26 [13·4%] of 194, ARR 7·4%, 95% CI 1·5 to 13·2). FEV 0·5 percentage predicted values were similar between the RSV prevention group (89·1% [SD 10·6]) and placebo group (90·1% [11·1]), with a mean difference of 1·0 (95% CI -1·3 to 3·3). The proportion of children with current physician-diagnosed asthma was similar between the RSV prevention group (19 [10·3%] of 185) and placebo group (18 [9·9%] of 182), with an ARR of -0·4 (95% CI -6·5 to 5·8)., Interpretation: In otherwise healthy preterm infants, this single-blind, randomised, placebo-controlled trial showed that RSV prevention did not have a major effect on current asthma or lung function at age 6 years. Future research will inform on the effect of RSV prevention on asthma at school age in the general population., Funding: AbbVie., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Of the warning scores in use for recognition of high-risk patients at the Emergency Department (ED), few incorporate laboratory results. Although hematological characteristics have shown prognostic value in small studies, large studies in elderly ED populations are lacking. We studied the association between blood cell and platelet counts and characteristics as well as C-reactive protein (CRP) at ED presentation with mortality in non-multitrauma patients ≥ 65 years. Comparison between survivors and non-survivors showed small, significant differences with AUROCs ranging between 56.6% and 65.2% for 30-day mortality. Combining parameters yielded an evident improvement (AUROC of 70.4%). Efforts should be pursued to study the added value of hematological parameters on top of clinical data when assessing patient risk.

Objective: To provide insight into how and in what clinical fields overdiagnosis is studied and give directions for further applied and methodological research., Design: Scoping review., Data Sources: Medline up to August 2017., Study Selection: All English studies on humans, in which overdiagnosis was discussed as a dominant theme., Data Extraction: Studies were assessed on clinical field, study aim (ie, methodological or non-methodological), article type (eg, primary study, review), the type and role of diagnostic test(s) studied and the context in which these studies discussed overdiagnosis., Results: From 4896 studies, 1851 were included for analysis. Half of all studies on overdiagnosis were performed in the field of oncology (50%). Other prevalent clinical fields included mental disorders, infectious diseases and cardiovascular diseases accounting for 9%, 8% and 6% of studies, respectively. Overdiagnosis was addressed from a methodological perspective in 20% of studies. Primary studies were the most common article type (58%). The type of diagnostic tests most commonly studied were imaging tests (32%), although these were predominantly seen in oncology and cardiovascular disease (84%). Diagnostic tests were studied in a screening setting in 43% of all studies, but as high as 75% of all oncological studies. The context in which studies addressed overdiagnosis related most frequently to its estimation, accounting for 53%. Methodology on overdiagnosis estimation and definition provided a source for extensive discussion. Other contexts of discussion included definition of disease, overdiagnosis communication, trends in increasing disease prevalence, drivers and consequences of overdiagnosis, incidental findings and genomics., Conclusions: Overdiagnosis is discussed across virtually all clinical fields and in different contexts. The variability in characteristics between studies and lack of consensus on overdiagnosis definition indicate the need for a uniform typology to improve coherence and comparability of studies on overdiagnosis., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Preterm birth is in quantity and in severity the most important topic in obstetric care in the developed world. Progestogens and cervical pessaries have been studied as potential preventive treatments with conflicting results. So far, no study has compared both treatments., Methods/design: The Quadruple P study aims to compare the efficacy of vaginal progesterone and cervical pessary in the prevention of adverse perinatal outcome associated with preterm birth in asymptomatic women with a short cervix, in singleton and multiple pregnancies separately. It is a nationwide open-label multicentre randomized clinical trial (RCT) with a superiority design and will be accompanied by an economic analysis. Pregnant women undergoing the routine anomaly scan will be offered cervical length measurement between 18 and 22 weeks in a singleton and at 16-22 weeks in a multiple pregnancy. Women with a short cervix, defined as less than, or equal to 35 mm in a singleton and less than 38 mm in a multiple pregnancy, will be invited to participate in the study. Eligible women will be randomly allocated to receive either progesterone or a cervical pessary. Following randomization, the silicone cervical pessary will be placed during vaginal examination or 200 mg progesterone capsules will be daily self-administered vaginally. Both interventions will be continued until 36 weeks gestation or until delivery, whichever comes first. Primary outcome will be composite adverse perinatal outcome of perinatal mortality and perinatal morbidity including bronchopulmonary dysplasia, intraventricular haemorrhage grade III and IV, periventricular leukomalacia higher than grade I, necrotizing enterocolitis higher than stage I, Retinopathy of prematurity (ROP) or culture proven sepsis. These outcomes will be measured up until 10 weeks after the expected due date. Secondary outcomes will be, among others, time to delivery, preterm birth rate before 28, 32, 34 and 37 weeks, admission to neonatal intensive care unit, maternal morbidity, maternal admission days for threatened preterm labour and costs., Discussion: This trial will provide evidence on whether vaginal progesterone or a cervical pessary is more effective in decreasing adverse perinatal outcome in both singletons and multiples., Trial Registration: Trial registration number: NTR 4414 . Date of registration January 29th 2014.

Objective: To evaluate the cost-effectiveness of a diagnostic laparoscopy prior to primary cytoreductive surgery to prevent futile primary cytoreductive surgery (i.e. leaving >1cm residual disease) in patients suspected of advanced stage ovarian cancer., Methods: An economic analysis was conducted alongside a randomized controlled trial in which patients suspected of advanced stage ovarian cancer who qualified for primary cytoreductive surgery were randomized to either laparoscopy or primary cytoreductive surgery. Direct medical costs from a health care perspective over a 6-month time horizon were analyzed. Health outcomes were expressed in quality-adjusted life-years (QALYs) and utility was based on patient's response to the EQ-5D questionnaires. We primarily focused on direct medical costs based on Dutch standard prices., Results: We studied 201 patients, of whom 102 were randomized to laparoscopy and 99 to primary cytoreductive surgery. No significant difference in QALYs (utility=0.01; 95% CI 0.006 to 0.02) was observed. Laparoscopy reduced the number of futile laparotomies from 39% to 10%, while its costs were € 1400 per intervention, making the overall costs of both strategies comparable (difference € -80 per patient (95% CI -470 to 300)). Findings were consistent across various sensitivity analyses., Conclusion: In patients with suspected advanced stage ovarian cancer, a diagnostic laparoscopy reduced the number of futile laparotomies, without increasing total direct medical health care costs, or adversely affecting complications or quality of life., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS.

Background: Numerous prediction models for gestational diabetes mellitus (GDM) have been developed, but their methodological quality is unknown. The objective is to systematically review all studies describing first-trimester prediction models for GDM and to assess their methodological quality., Methods: MEDLINE and EMBASE were searched until December 2014. Key words for GDM, first trimester of pregnancy, and prediction modeling studies were combined. Prediction models for GDM performed up to 14 weeks of gestation that only include routinely measured predictors were eligible.Data was extracted by the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS). Data on risk predictors and performance measures were also extracted. Each study was scored for risk of bias., Results: Our search yielded 7761 articles, of which 17 were eligible for review (14 development studies and 3 external validation studies). The definition and prevalence of GDM varied widely across studies. Maternal age and body mass index were the most common predictors. Discrimination was acceptable for all studies. Calibration was reported for four studies. Risk of bias for participant selection, predictor assessment, and outcome assessment was low in general. Moderate to high risk of bias was seen for the number of events, attrition, and analysis., Conclusions: Most studies showed moderate to low methodological quality, and few prediction models for GDM have been externally validated. External validation is recommended to enhance generalizability and assess their true value in clinical practice., Competing Interests: The authors declare that they have no competing interests.

Competing Interests: Competing interests: None declared.

Objective: Preterm birth is the most common cause of neonatal morbidity and mortality. Around one third of preterm deliveries starts with preterm prelabor rupture of membranes (PPROM). The aim of this trial was to study the effect of prolonged tocolysis with nifedipine versus placebo in women with PPROM on perinatal outcome and prolongation of pregnancy., Study Design: The Apostel IV was a nationwide multicenter randomized placebo controlled trial. We included women with PPROM without contractions between 24(+0) and 33(+6) weeks of gestation. Participants were randomly allocated to daily 80mg nifedipine or placebo, until the start of labor, with a maximum of 18 days. The primary outcome measure was a composite of poor neonatal outcome, including perinatal death, bronchopulmonary dysplasia, periventricular leukomalacia>grade 1, intraventricular hemorrhage>grade 2, necrotizing enterocolitis>stage 1 and culture proven sepsis. Secondary outcomes were gestational age at delivery and prolongation of pregnancy. Analysis was by intention to treat. To detect a reduction of poor neonatal outcome from 30% to 10%, 120 women needed to be randomized., Trial Registry: NTR 3363., Results: Between October 2012 and December 2014 we randomized 25 women to nifedipine and 25 women to placebo. Due to slow recruitment the study was stopped prematurely. The median gestational age at randomization was 29.9 weeks (IQR 27.7-31.3) in the nifedipine group and 27.0 weeks (IQR 24.7-29.9) in the placebo group. Other baseline characteristics were comparable. The adverse perinatal outcome occurred in 9 neonates (33.3%) in the nifedipine group and 9 neonates (32.1%) in the placebo group (RR 1.04, 95% CI 0.49-2.2). Two perinatal deaths occurred, both in the nifedipine group. Bronchopulmonary dysplasia was seen less frequently in the nifedipine group (0% versus 17.9%; p=0.03). Prolongation of pregnancy did not differ between the nifedipine and placebo group (median 11 versus 8 days, HR 1.02; 95% CI 0.58-1.79)., Conclusion: This randomized trial did not show a beneficial effect of prolonged tocolysis on neonatal outcomes or prolongation of pregnancy in women with PPROM without contractions. However, since results are based on a small sample size, a difference in effectiveness cannot be excluded., (Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective:  To perform an external validation and direct comparison of published prognostic models for early prediction of the risk of gestational diabetes mellitus, including predictors applicable in the first trimester of pregnancy., Design:  External validation of all published prognostic models in large scale, prospective, multicentre cohort study., Setting:  31 independent midwifery practices and six hospitals in the Netherlands., Participants:  Women recruited in their first trimester (<14 weeks) of pregnancy between December 2012 and January 2014, at their initial prenatal visit. Women with pre-existing diabetes mellitus of any type were excluded., Main Outcome Measures:  Discrimination of the prognostic models was assessed by the C statistic, and calibration assessed by calibration plots., Results:  3723 women were included for analysis, of whom 181 (4.9%) developed gestational diabetes mellitus in pregnancy. 12 prognostic models for the disorder could be validated in the cohort. C statistics ranged from 0.67 to 0.78. Calibration plots showed that eight of the 12 models were well calibrated. The four models with the highest C statistics included almost all of the following predictors: maternal age, maternal body mass index, history of gestational diabetes mellitus, ethnicity, and family history of diabetes. Prognostic models had a similar performance in a subgroup of nulliparous women only. Decision curve analysis showed that the use of these four models always had a positive net benefit., Conclusions:  In this external validation study, most of the published prognostic models for gestational diabetes mellitus show acceptable discrimination and calibration. The four models with the highest discriminative abilities in this study cohort, which also perform well in a subgroup of nulliparous women, are easy models to apply in clinical practice and therefore deserve further evaluation regarding their clinical impact., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

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.

Background: Small-study effects and time trends have been identified in meta-analyses of randomized trials. We evaluated whether these effects are also present in meta-analyses of diagnostic test accuracy studies., Methods: A systematic search identified test accuracy meta-analyses published between May and September 2012. In each meta-analysis, the strength of the associations between estimated accuracy of the test (diagnostic odds ratio (DOR), sensitivity, and specificity) and sample size and between accuracy estimates and time since first publication were evaluated using meta-regression models. The regression coefficients over all meta-analyses were summarized using random effects meta-analysis., Results: Forty-six meta-analyses and their corresponding primary studies (N = 859) were included. There was a non-significant relative change in the DOR of 1.01 per 100 additional participants (95% CI 1.00 to 1.03; P = 0.07). In the subgroup of imaging studies, there was a relative increase in sensitivity of 1.13 per 100 additional diseased subjects (95% CI 1.05 to 1.22; P = 0.002). The relative change in DOR with time since first publication was 0.94 per 5 years (95% CI 0.80 to 1.10; P = 0.42). Sensitivity was lower in studies published later (relative change 0.89, 95% CI 0.80 to 0.99; P = 0.04)., Conclusions: Small-study effects and time trends do not seem to be as pronounced in meta-analyses of test accuracy studies as they are in meta-analyses of randomized trials. Small-study effects seem to be reversed in imaging, where larger studies tend to report higher sensitivity.

Objectives: To examine how authors explore and report on sources of heterogeneity in systematic reviews of diagnostic accuracy studies., Study Design and Setting: A cohort of systematic reviews of diagnostic tests was systematically identified. Data were extracted on whether an exploration of the sources of heterogeneity was undertaken, how this was done, the number and type of potential sources explored, and how results and conclusions were reported., Results: Of the 65 systematic reviews, 12 did not perform a meta-analysis and eight of these gave heterogeneity between studies as a reason. Of the 53 reviews containing a meta-analysis, 40 explored potential sources of heterogeneity in a formal manner and 27 identified at least one source of heterogeneity. The reviews not investigating heterogeneity were smaller than those that did (median [interquartile range {IQR}], 8 [5-15] vs. 14 [11-19] primary studies). Twelve reviews performed a sensitivity analysis, 25 stratified analyses, and 19 metaregression. Many sources of heterogeneity were explored compared with the number of primary studies in a meta-analysis (median ratio, 1:5). Review authors placed importance on the exploration of sources of heterogeneity; 37 mentioned the exploration or the findings thereof in the abstract or conclusion of the main text.results, Conclusion: Methods for investigating sources of heterogeneity varied widely between reviews. Based on our findings of the review, we made suggestions on what to consider and report on when exploring sources of heterogeneity in systematic reviews of diagnostic studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Drawing conclusions from systematic reviews of test accuracy studies without considering the methodological quality (risk of bias) of included studies may lead to unwarranted optimism about the value of the test(s) under study. We sought to identify to what extent the results of quality assessment of included studies are incorporated in the conclusions of diagnostic accuracy reviews., Methods: We searched MEDLINE and EMBASE for test accuracy reviews published between May and September 2012. We examined the abstracts and main texts of these reviews to see whether and how the results of quality assessment were linked to the accuracy estimates when drawing conclusions., Results: We included 65 reviews of which 53 contained a meta-analysis. Sixty articles (92%) had formally assessed the methodological quality of included studies, most often using the original QUADAS tool (n = 44, 68%). Quality assessment was mentioned in 28 abstracts (43%); with a majority (n = 21) mentioning it in the methods section. In only 5 abstracts (8%) were results of quality assessment incorporated in the conclusions. Thirteen reviews (20%) presented results of quality assessment in the main text only, without further discussion. Forty-seven reviews (72%) discussed results of quality assessment; the most frequent form was as limitations in assessing quality (n = 28). Only 6 reviews (9%) further linked the results of quality assessment to their conclusions, 3 of which did not conduct a meta-analysis due to limitations in the quality of included studies. In the reviews with a meta-analysis, 19 (36%) incorporated quality in the analysis. Eight reported significant effects of quality on the pooled estimates; in none of them these effects were factored in the conclusions., Conclusion: While almost all recent diagnostic accuracy reviews evaluate the quality of included studies, very few consider results of quality assessment when drawing conclusions. The practice of reporting systematic reviews of test accuracy should improve if readers not only want to be informed about the limitations in the available evidence, but also on the associated implications for the performance of the evaluated tests.

Latent class models (LCMs) combine the results of multiple diagnostic tests through a statistical model to obtain estimates of disease prevalence and diagnostic test accuracy in situations where there is no single, accurate reference standard. We performed a systematic review of the methodology and reporting of LCMs in diagnostic accuracy studies. This review shows that the use of LCMs in such studies increased sharply in the past decade, notably in the domain of infectious diseases (overall contribution: 59%). The 64 reviewed studies used a range of differently specified parametric latent variable models, applying Bayesian and frequentist methods. The critical assumption underlying the majority of LCM applications (61%) is that the test observations must be independent within 2 classes. Because violations of this assumption can lead to biased estimates of accuracy and prevalence, performing and reporting checks of whether assumptions are met is essential. Unfortunately, our review shows that 28% of the included studies failed to report any information that enables verification of model assumptions or performance. Because of the lack of information on model fit and adequate evidence "external" to the LCMs, it is often difficult for readers to judge the validity of LCM-based inferences and conclusions reached.

Background: In diagnostic studies, a single and error-free test that can be used as the reference (gold) standard often does not exist. One solution is the use of panel diagnosis, i.e., a group of experts who assess the results from multiple tests to reach a final diagnosis in each patient. Although panel diagnosis, also known as consensus or expert diagnosis, is frequently used as the reference standard, guidance on preferred methodology is lacking. The aim of this study is to provide an overview of methods used in panel diagnoses and to provide initial guidance on the use and reporting of panel diagnosis as reference standard., Methods and Findings: PubMed was systematically searched for diagnostic studies applying a panel diagnosis as reference standard published up to May 31, 2012. We included diagnostic studies in which the final diagnosis was made by two or more persons based on results from multiple tests. General study characteristics and details of panel methodology were extracted. Eighty-one studies were included, of which most reported on psychiatry (37%) and cardiovascular (21%) diseases. Data extraction was hampered by incomplete reporting; one or more pieces of critical information about panel reference standard methodology was missing in 83% of studies. In most studies (75%), the panel consisted of three or fewer members. Panel members were blinded to the results of the index test results in 31% of studies. Reproducibility of the decision process was assessed in 17 (21%) studies. Reported details on panel constitution, information for diagnosis and methods of decision making varied considerably between studies., Conclusions: Methods of panel diagnosis varied substantially across studies and many aspects of the procedure were either unclear or not reported. On the basis of our review, we identified areas for improvement and developed a checklist and flow chart for initial guidance for researchers conducting and reporting of studies involving panel diagnosis. Please see later in the article for the Editors' Summary.

A universal challenge in studies that quantify the accuracy of diagnostic tests is establishing whether each participant has the disease of interest. Ideally, the same preferred reference standard would be used for all participants; however, for practical or ethical reasons, alternative reference standards that are often less accurate are frequently used instead. The use of different reference standards across participants in a single study is known as differential verification.Differential verification can cause severely biased accuracy estimates of the test or model being studied. Many variations of differential verification exist, but not all introduce the same risk of bias. A risk-of-bias assessment requires detailed information about which participants receive which reference standards and an estimate of the accuracy of the alternative reference standard. This article classifies types of differential verification and explores how they can lead to bias. It also provides guidance on how to report results and assess the risk of bias when differential verification occurs and highlights potential ways to correct for the bias.