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Background: Efforts to mitigate unwarranted variation in the quality of care require insight into the 'level' (eg, patient, physician, ward, hospital) at which observed variation exists. This systematic literature review aims to synthesise the results of studies that quantify the extent to which hospitals contribute to variation in quality indicator scores., Methods: Embase, Medline, Web of Science, Cochrane and Google Scholar were systematically searched from 2010 to November 2023. We included studies that reported a measure of between-hospital variation in quality indicator scores relative to total variation, typically expressed as a variance partition coefficient (VPC). The results were analysed by disease category and quality indicator type., Results: In total, 8373 studies were reviewed, of which 44 met the inclusion criteria. Casemix adjusted variation was studied for multiple disease categories using 144 indicators, divided over 5 types: intermediate clinical outcomes (n=81), final clinical outcomes (n=35), processes (n=10), patient-reported experiences (n=15) and patient-reported outcomes (n=3). In addition to an analysis of between-hospital variation, eight studies also reported physician-level variation (n=54 estimates). In general, variation that could be attributed to hospitals was limited (median VPC=3%, IQR=1%-9%). Between-hospital variation was highest for process indicators (17.4%, 10.8%-33.5%) and lowest for final clinical outcomes (1.4%, 0.6%-4.2%) and patient-reported outcomes (1.0%, 0.9%-1.5%). No clear pattern could be identified in the degree of between-hospital variation by disease category. Furthermore, the studies exhibited limited attention to the reliability of observed differences in indicator scores., Conclusion: Hospital-level variation in quality indicator scores is generally small relative to residual variation. However, meaningful variation between hospitals does exist for multiple indicators, especially for care processes which can be directly influenced by hospital policy. Quality improvement strategies are likely to generate more impact if preceded by level-specific and indicator-specific analyses of variation, and when absolute variation is also considered., Prospero Registration Number: CRD42022315850., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Data on variation in outcomes and costs of the treatment of inflammatory bowel disease (IBD) can be used to identify areas for cost and quality improvement. It can also help healthcare providers learn from each other and strive for equity in care. We aimed to assess the variation in outcomes and costs of IBD care between hospitals., Methods: We conducted a 12-month cohort study in 8 hospitals in the Netherlands. Patients with IBD who were treated with biologics and new small molecules were included. The percentage of variation in outcomes (following the International Consortium for Health Outcomes Measurement standard set) and costs attributable to the treating hospital were analyzed with intraclass correlation coefficients (ICCs) from case mix-adjusted (generalized) linear mixed models., Results: We included 1010 patients (median age 45 years, 55% female). Clinicians reported high remission rates (83%), while patient-reported rates were lower (40%). During the 12-month follow-up, 5.2% of patients used prednisolone for more than 3 months. Hospital costs (outpatient, inpatient, and medication costs) were substantial (median: €8323 per 6 months), mainly attributed to advanced therapies (€6611). Most of the variation in outcomes and costs among patients could not be attributed to the treating hospitals, with ICCs typically between 0% and 2%. Instead, patient-level characteristics, often with ICCs above 50%, accounted for these variations., Conclusions: Variation in outcomes and costs cannot be used to differentiate between hospitals for quality of care. Future quality improvement initiatives should look at differences in structure and process measures of care and implement patient-level interventions to improve quality of IBD care., Trial Registration Number: NL8276., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: Patients with head and neck squamous cell carcinoma (HNSCC) enter the palliative phase when cure is no longer possible or when they refuse curative treatment. The mean survival is five months, with a range of days until years. Realistic prognostic counseling enables patients to make well-considered end-of-life choices. However, physicians tend to overestimate survival. The aim of this study was to develop a prognostic model that calculates the overall survival (OS) probability of palliative HNSCC patients., Methods: Patients diagnosed with incurable HNSCC or patients who refused curative treatment for HNSCC between January 1st 2006 and June 3rd 2019 were included (n = 659). Three patients were lost to follow-up. Patients were considered to have incurable HNSCC due to tumor factors (e.g. inoperability with no other curative treatment options, distant metastasis) or patient factors (e.g. the presence of severe comorbidity and/or poor performance status).Tumor and patients factors accounted for 574 patients. An additional 82 patients refused curative treatment and were also considered palliative. The effect of 17 candidate predictors was estimated in the univariable cox proportional hazard regression model. Using backwards selection with a cut-off P-value < 0.10 resulted in a final multivariable prediction model. The C-statistic was calculated to determine the discriminative performance of the model. The final model was internally validated using bootstrapping techniques., Results: A total of 647 patients (98.6%) died during follow-up. Median OS time was 15.0 weeks (95% CI: 13.5;16.6). Of the 17 candidate predictors, seven were included in the final model: the reason for entering the palliative phase, the number of previous HNSCC, cT, cN, cM, weight loss in the 6 months before diagnosis, and the WHO performance status. The internally validated C-statistic was 0.66 indicating moderate discriminative ability. The model showed some optimism, with a shrinkage factor of 0.89., Conclusion: This study enabled the development and internal validation of a prognostic model that predicts the OS probability in HNSCC patients in the palliative phase. This model facilitates personalized prognostic counseling in the palliative phase. External validation and qualitative research are necessary before widespread use in patient counseling and end-of-life care., (© 2024. The Author(s).)

Background: Healthcare services worldwide are transforming themselves into value-based organizations. Integrated care is an important aspect of value-based healthcare (VBHC), but practical evidence-based recommendations for the successful implementation of integrated care within a VBHC context are lacking. This systematic review aims to identify how value-based integrated care (VBIC) is defined in literature, and to summarize the literature regarding the effects of VBIC, and the facilitators and barriers for its implementation., Methods: Embase, Medline ALL, Web of Science Core Collection, and Cochrane Central Register of Controlled Trails databases were searched from inception until January 2022. Empirical studies that implemented and evaluated an integrated care intervention within a VBHC context were included. Non-empirical studies were included if they described either a definition of VBIC or facilitators and barriers for its implementation. Theoretical articles and articles without an available full text were excluded. All included articles were analysed qualitatively. The Rainbow Model of Integrated Care (RMIC) was used to analyse the VBIC interventions. The quality of the articles was assessed using the Mixed Methods Appraisal Tool (MMAT)., Results: After screening 1328 titles/abstract and 485 full-text articles, 24 articles were included. No articles were excluded based on quality. One article provided a definition of VBIC. Eleven studies reported-mostly positive- effects of VBIC, on clinical outcomes, patient-reported outcomes, and healthcare utilization. Nineteen studies reported facilitators and barriers for the implementation of VBIC; factors related to reimbursement and information technology (IT) infrastructure were reported most frequently., Conclusion: The concept of VBIC is not well defined. The effect of VBIC seems promising, but the exact interpretation of effect evaluations is challenged by the precedence of multicomponent interventions, multiple testing and generalizability issues. For successful implementation of VBIC, it is imperative that healthcare organizations consider investing in adequate IT infrastructure and new reimbursement models. Systematic Review Registration: PROSPERO (CRD42021259025)., (© 2024 The Author(s); Published by Kerman University of Medical Sciences This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Missing data are frequently encountered in registries that are used to compare performance across hospitals. The most appropriate method for handling missing data when analysing differences in outcomes between hospitals with a generalised linear mixed model is unclear. We aimed to compare methods for handling missing data when comparing hospitals on ordinal and dichotomous outcomes. We performed a simulation study using data from the Multicentre Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR CLEAN) Registry, a prospective cohort study in 17 hospitals performing endovascular therapy for ischaemic stroke in the Netherlands. The investigated methods for handling missing data, both case-mix adjustment variables and outcomes, were complete case analysis, single imputation, multiple imputation, single imputation with deletion of imputed outcomes and multiple imputation with deletion of imputed outcomes. Data were generated as missing completely at random (MCAR), missing at random and missing not at random (MNAR) in three scenarios: (1) 10% missing data in case-mix and outcome; (2) 40% missing data in case-mix and outcome; and (3) 40% missing data in case-mix and outcome with varying degree of missing data among hospitals. Bias and reliability of the methods were compared on the mean squared error (MSE, a summary measure combining bias and reliability) relative to the hospital effect estimates from the complete reference data set. For both the ordinal outcome (ie, the modified Rankin Scale) and a common dichotomised version thereof, all methods of handling missing data were biased, likely due to shrinkage of the random effects. The MSE of all methods was on average lowest under MCAR and with fewer missing data, and highest with more missing data and under MNAR. The 'multiple imputation, then deletion' method had the lowest MSE for both outcomes under all simulated patterns of missing data. Thus, when estimating hospital effects on ordinal and dichotomous outcomes in the presence of missing data, the least biased and most reliable method to handle these missing data is 'multiple imputation, then deletion'., Competing Interests: Competing interests: WvZ has received consulting fees from Codman and Stryker. DD has received research grants from Stryker and Bracco Imaging., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The International Consortium for Health Outcomes Measurement has selected the self-administered comorbidity questionnaire (SCQ) to adjust case-mix when comparing outcomes of inflammatory bowel disease (IBD) treatment between healthcare providers. However, the SCQ has not been validated for use in IBD patients., Objectives: We assessed the validity of the SCQ for measuring comorbidities in IBD patients., Design: Cohort study., Methods: We assessed the criterion validity of the SCQ for IBD patients by comparing patient-reported and clinician-reported comorbidities (as noted in the electronic health record) of the 13 diseases of the SCQ using Cohen's kappa. Construct validity was assessed using the Spearman correlation coefficient between the SCQ and the Charlson Comorbidity Index (CCI), clinician-reported SCQ, quality of life, IBD-related healthcare and productivity costs, prevalence of disability, and IBD disease activity. We assessed responsiveness by correlating changes in the SCQ with changes in healthcare costs, productivity costs, quality of life, and disease activity after 15 months., Results: We included 613 patients. At least fair agreement (κ > 0.20) was found for most comorbidities, but the agreement was slight (κ < 0.20) for stomach disease [κ = 0.19, 95% CI (-0.03; 0.41)], blood disease [κ = 0.02, 95% CI (-0.06; 0.11)], and back pain [κ = 0.18, 95% CI (0.11; 0.25)]. Correlations were found between the SCQ and the clinician-reported SCQ [ρ = 0.60, 95% CI (0.55; 0.66)], CCI [ρ = 0.39, 95% CI (0.31; 0.45)], the prevalence of disability [ρ = 0.23, 95% CI (0.15; 0.32)], and quality of life [ρ = -0.30, 95% CI (-0.37; -0.22)], but not between the SCQ and healthcare or productivity costs or disease activity (|ρ| ⩽ 0.2). A change in the SCQ after 15 months was not correlated with a change in any of the outcomes., Conclusion: The SCQ is a valid tool for measuring comorbidity in IBD patients, but face and content validity should be improved before being used to correct case-mix differences., Competing Interests: RCAvL has nothing to disclose. ASH has nothing to disclose. NvL has nothing to disclose. JAH has nothing to disclose. CJvdW has received research grants from ZonMW, Falk, and Pfizer; has received consulting fees from Janssen, Galapagos, and Pfizer; and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ferring and AbbVie, all outside the submitted work. RLW reports personal fees from Ferring, Pfizer, Galapagos, AbbVie, and Janssen outside the submitted work. DvN reports personal fees from Janssen, Takeda, AbbVie, and Galapagos outside the submitted work., (© The Author(s), 2023.)

Traumatic brain injury (TBI) is a global public health problem and a leading cause of mortality, morbidity, and disability. The increasing incidence combined with the heterogeneity and complexity of TBI will inevitably place a substantial burden on health systems. These findings emphasize the importance of obtaining accurate and timely insights into healthcare consumption and costs on a multi-national scale. This study aimed to describe intramural healthcare consumption and costs across the full spectrum of TBI in Europe. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study is a prospective observational study conducted in 18 countries across Europe and in Israel. The baseline Glasgow Coma Scale (GCS) was used to differentiate patients by brain injury severity in mild (GCS 13-15), moderate (GCS 9-12), or severe (GCS ≤8) TBI. We analyzed seven main cost categories: pre-hospital care, hospital admission, surgical interventions, imaging, laboratory, blood products, and rehabilitation. Costs were estimated based on Dutch reference prices and converted to country-specific unit prices using gross domestic product (GDP)-purchasing power parity (PPP) adjustment. Mixed linear regression was used to identify between-country differences in length of stay (LOS), as a parameter of healthcare consumption. Mixed generalized linear models with gamma distribution and log link function quantified associations of patient characteristics with higher total costs. We included 4349 patients, of whom 2854 (66%) had mild, 371 (9%) had moderate, and 962 (22%) had severe TBI. Hospitalization accounted for the largest part of the intramural consumption and costs (60%). In the total study population, the mean LOS was 5.1 days at the intensive care unit (ICU) and 6.3 days at the ward. For mild, moderate, and severe TBI, mean LOS was, respectively, 1.8, 8.9, and 13.5 days at the ICU and 4.5, 10.1, and 10.3 days at the ward. Other large contributors to the total costs were rehabilitation (19%) and intracranial surgeries (8%). Total costs increased with higher age and greater trauma severity (mild; €3,800 [IQR €1,400-14,000], moderate; €37,800 [IQR €14,900-€74,200], severe; €60,400 [IQR €24,400-€112,700]). The adjusted analysis showed that female patients had lower costs than male patients (odds ratio (OR) 0.80 [CI 0.75-1.85]). Increasing TBI severity was associated with higher costs, OR 1.46 (confidence interval [CI] 1.31-1.63) and OR 1.67 [CI 1.52-1.84] for moderate and severe patients, respectively. A worse pre-morbid overall health state, increasing age and more severe systemic trauma, expressed in the Injury Severity Score (ISS), were also significantly associated with higher costs. Intramural costs of TBI are significant and are profoundly driven by hospitalization. Costs increased with trauma severity and age, and male patients incurred higher costs. Reducing LOS could be targeted with advanced care planning, in order to provide cost-effective care.

Background: Standardized Mortality Ratios (SMRs) are case-mix adjusted mortality rates per hospital and are used to evaluate quality of care. However, acute care is increasingly organized on a regional level, with more severe patients admitted to specialized hospitals. We hypothesize that the current case-mix adjustment insufficiently captures differences in case-mix between non-specialized and specialized hospitals. We aim to improve the SMR by adding proxies of disease severity to the model and by calculating a regional SMR (RSMR) for acute cerebrovascular disease (CVD) and myocardial infarction (MI)., Methods: We used data from the Dutch National Basic Registration of Hospital Care. We selected all admissions from 2016 to 2018. SMRs and RSMRs were calculated by dividing the observed in-hospital mortality by the expected in-hospital mortality. The expected in-hospital mortality was calculated using logistic regression with adjustment for age, sex, socioeconomic status, severity of main diagnosis, urgency of admission, Charlson comorbidity index, place of residence before admission, month/year of admission, and in-hospital mortality as outcome., Results: The IQR of hospital SMRs of CVD was 0.85-1.10, median 0.94, with higher SMRs for specialized hospitals (median 1.12, IQR 1.00-1.28, 71%-SMR > 1) than for non-specialized hospitals (median 0.92, IQR 0.82-1.07, 32%-SMR > 1). The IQR of RSMRs was 0.92-1.09, median 1.00. The IQR of hospital SMRs of MI was 0.76-1.14, median 0.98, with higher SMRs for specialized hospitals (median 1.00, IQR 0.89-1.25, 50%-SMR > 1 versus median 0.94, IQR 0.74-1.11, 44%-SMR > 1). The IQR of RSMRs was 0.90-1.08, median 1.00. Adjustment for proxies of disease severity mostly led to lower SMRs of specialized hospitals., Conclusion: SMRs of acute regionally organized diseases do not only measure differences in quality of care between hospitals, but merely measure differences in case-mix between hospitals. Although the addition of proxies of disease severity improves the model to calculate SMRs, real disease severity scores would be preferred. However, such scores are not available in administrative data. As a consequence, the usefulness of the current SMR as quality indicator is very limited. RSMRs are potentially more useful, since they fit regional organization and might be a more valid representation of quality of care., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background Insight into outcome variation between hospitals could help to improve quality of care. We aimed to assess the validity of early outcomes as quality indicators for acute ischemic stroke care for patients treated with endovascular therapy (EVT). Methods and Results We used data from the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, a large multicenter prospective cohort study including 3279 patients with acute ischemic stroke undergoing EVT. Random effect linear and proportional odds regression were used to analyze the effect of case mix on between-hospital differences in 2 early outcomes: the National Institutes of Health Stroke Scale (NIHSS) score at 24 to 48 hours and the expanded thrombolysis in cerebral infarction score. Between-hospital variation in outcomes was assessed using the variance of random hospital effects (tau 2 ). In addition, we estimated the correlation between hospitals' EVT-patient volume and (case-mix-adjusted) outcomes. Both early outcomes and case-mix characteristics varied significantly across hospitals. Between-hospital variation in the expanded thrombolysis in cerebral infarction score was not influenced by case-mix adjustment (tau 2 =0.17 in both models). In contrast, for the NIHSS score at 24 to 48 hours, case-mix adjustment led to a decrease in variation between hospitals (tau 2 decreases from 0.19 to 0.17). Hospitals' EVT-patient volume was strongly correlated with higher expanded thrombolysis in cerebral infarction scores ( r =0.48) and weakly with lower NIHSS score at 24 to 48 hours ( r =0.15). Conclusions Between-hospital variation in NIHSS score at 24 to 48 hours is significantly influenced by case-mix but not by patient volume. In contrast, between-hospital variation in expanded thrombolysis in cerebral infarction score is strongly influenced by EVT-patient volume but not by case-mix. Both outcomes may be suitable for comparing hospitals on quality of care, provided that adequate adjustment for case-mix is applied for NIHSS score.

Background and Objectives: The EuroQol Group 5-Dimension Self-Reported Questionnaire (EQ-5D) is a well-established instrument to assess quality of life and generates generic utility values for health states reported by patients, derived from assessments by the general public. We hypothesized that language problems and other nonmotor deficits are not captured as well as motor deficits by this system. We aimed to quantify the association between disabling neurologic deficits and the EQ-5D dimension scores and the utility score in patients with ischemic stroke., Methods: We used data of the Interventional Management of Stroke III trial. Missing data were imputed by multiple imputation. The association between neurologic deficits (individual NIH Stroke Scale [NIHSS] item scores) and the EQ-5D-3L (5 three-level dimension scores and utility score) at 90 days was assessed with ordinal logistic regression and Tobit regression, respectively. The explained variance of each model was estimated with Nagelkerke pseudo-R 2 or R 2 ., Results: In total, 525 surviving patients were included. Complete data on both the NIHSS and EQ-5D were available for 481/525 (91.6%) patients. At 90 days, 161/491 (32.8%) patients had aphasia and 226/491 (46.0%) patients had paresis of at least 1 limb. Limb paresis, facial palsy, sensory loss, and dysarthria explained most of the variance in all EQ-5D dimension scores and the utility score. In the utility score, 8.9% of the variance was explained by neglect, 10.0% by aphasia, 10.8% by hemianopia, and 17.5%-24.1% by limb paresis., Discussion: The impact of neurologic deficits on the EQ-5D in patients with ischemic stroke is mostly due to limb paresis, while the EQ-5D is less sensitive to other nonmotor deficits such as hemianopia, aphasia, and neglect. This may lead to overestimation of quality of life and, consequently, underestimation of the (cost-)effectiveness of treatments and interventions., Trial Registration Information: ClinicalTrials.gov. Unique identifier: NCT00359424., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: To ensure the feasibility of implementing PROMs in clinical practice, they must be continually appraised for undue burden placed on patients and clinicians and their usefulness for decision-making. This study assesses correlations between the CLEFT-Q psychosocial scales in the International Consortium for Health Outcomes Measurement Standard Set for cleft and explores their associations with patient characteristics and psychosocial care referral., Methods: Spearman correlation coefficients were calculated for CLEFT-Q psychological function, social function, school function, face, speech function, and speech-related distress scales. Logistic regressions were used to assess the association of cleft phenotype, syndrome, sex, and adoption status on scale scores and clinical referral to psychosocial care for further evaluation and management., Results: Data were obtained from 3067 patients with cleft lip and/or palate at three centers. Strong correlations were observed between social function and psychological function (r > 0.69) and school function (r > 0.78) scales. Correlation between school function and psychological function scales was lower (r = 0.59 to 0.68). Genetic syndrome (OR, 2.37; 95% CI, 1.04 to 5.41), psychological function (OR, 0.92; 95% CI, 0.88 to 0.97), school function (OR, 0.94; 95% CI, 0.90 to 0.98), and face (OR, 0.96; 95% CI, 0.94 to 0.98) were significant predictors for referral to psychosocial care., Conclusions: Because social function as measured by the CLEFT-Q showed strong correlations with both school and psychological function, its additional value for measuring psychosocial function within the Standard Set is limited, and it is reasonable to consider removing this scale from the International Consortium for Health Outcomes Measurement Standard Set for cleft., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.)

Background: In traumatic brain injury (TBI), large between-center differences in treatment and outcome for patients managed in the intensive care unit (ICU) have been shown. The aim of this study is to explore if European neurotrauma centers can be clustered, based on their treatment preference in different domains of TBI care in the ICU., Methods: Provider profiles of centers participating in the Collaborative European Neurotrauma Effectiveness Research in TBI study were used to assess correlations within and between the predefined domains: intracranial pressure monitoring, coagulation and transfusion, surgery, prophylactic antibiotics, and more general ICU treatment policies. Hierarchical clustering using Ward's minimum variance method was applied to group data with the highest similarity. Heat maps were used to visualize whether hospitals could be grouped to uncover types of hospitals adhering to certain treatment strategies., Results: Provider profiles were available from 66 centers in 20 different countries in Europe and Israel. Correlations within most of the predefined domains varied from low to high correlations (mean correlation coefficients 0.2-0.7). Correlations between domains were lower, with mean correlation coefficients of 0.2. Cluster analysis showed that policies could be grouped, but hospitals could not be grouped based on their preference., Conclusions: Although correlations between treatment policies within domains were found, the failure to cluster hospitals indicates that a specific treatment choice within a domain is not a proxy for other treatment choices within or outside the domain. These results imply that studying the effects of specific TBI interventions on outcome can be based on between-center variation without being substantially confounded by other treatments., Trial Registration: We do not report the results of a health care intervention., (© 2021. The Author(s).)

Survival rates of adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are inferior to those of pediatric ALL patients. In part, this may be caused by differences in treatment setting. Generally, children are treated in specialized pediatric hemato-oncology settings, whereas AYAs are treated in adult hemato-oncology settings. Since 2005, adult treatment protocols have included pediatric-inspired chemotherapy, which has been the standard of care for AYAs from 2008 onwards. This study aims to assess whether, despite protocols in both settings having become more similar, there remains an effect of treatment in specialized pediatric hemato-oncology settings on 5-year survival for ALL patients in the Netherlands. We used nationwide registry data (2004-2013) on 472 ALL patients aged between 10 and 30 years old. A fuzzy regression discontinuity design was applied to estimate the treatment effect using two-stage least squares regression with the treatment threshold at 17 years and 7 months of age, adjusting for sex, age at diagnosis, and immunophenotype. We found a risk difference of 0.419 ( p = 0.092; 95% CI = -0.0686; 0.907), meaning a 41.9 percentage point greater probability of surviving five years after diagnosis for ALL patients treated in specialized pediatric hemato-oncology settings. Our results suggest that ALL patients around the threshold could benefit from increased collaboration between pediatric and adult hemato-oncology in terms of survival.

Introduction: Various statistical approaches can be used to deal with unmeasured confounding when estimating treatment effects in observational studies, each with its own pros and cons. This study aimed to compare treatment effects as estimated by different statistical approaches for two interventions in observational stroke care data., Patients and Methods: We used prospectively collected data from the MR CLEAN registry including all patients (n = 3279) with ischemic stroke who underwent endovascular treatment (EVT) from 2014 to 2017 in 17 Dutch hospitals. Treatment effects of two interventions - i.e., receiving an intravenous thrombolytic (IVT) and undergoing general anesthesia (GA) before EVT - on good functional outcome (modified Rankin Scale ≤2) were estimated. We used three statistical regression-based approaches that vary in assumptions regarding the source of unmeasured confounding: individual-level (two subtypes), ecological, and instrumental variable analyses. In the latter, the preference for using the interventions in each hospital was used as an instrument., Results: Use of IVT (range 66-87%) and GA (range 0-93%) varied substantially between hospitals. For IVT, the individual-level (OR ~ 1.33) resulted in significant positive effect estimates whereas in instrumental variable analysis no significant treatment effect was found (OR 1.11; 95% CI 0.58-1.56). The ecological analysis indicated no statistically significant different likelihood (β = - 0.002%; P = 0.99) of good functional outcome at hospitals using IVT 1% more frequently. For GA, we found non-significant opposite directions of points estimates the treatment effect in the individual-level (ORs ~ 0.60) versus the instrumental variable approach (OR = 1.04). The ecological analysis also resulted in a non-significant negative association (0.03% lower probability)., Discussion and Conclusion: Both magnitude and direction of the estimated treatment effects for both interventions depend strongly on the statistical approach and thus on the source of (unmeasured) confounding. These issues should be understood concerning the specific characteristics of data, before applying an approach and interpreting the results. Instrumental variable analysis might be considered when unobserved confounding and practice variation is expected in observational multicenter studies., (© 2022. The Author(s).)

Background: Identifying branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) at lowest risk of progression may allow for a reduced intensity of surveillance., Objective: We aimed to externally validate the previously developed Dutch-American Risk stratification Tool (DART-1; https://rtools.mayo.edu/DART/), which identifies cysts at low risk of developing worrisome features (WFs) or high-risk stigmata (HRS)., Methods: Three prospective cohorts of individuals under surveillance for BD-IPMNs were combined, independent from the original development cohort. We assessed the performance (discrimination and calibration) of DART-1, a multivariable Cox-proportional logistic regression model with five predictors for the development of WFs or HRS., Results: Of 832 individuals (mean age 77 years, SD 11.5) under surveillance for a median of 40 months (IQR 44), 163 (20%) developed WFs or HRS. DART-1's discriminative ability (C-statistic 0.68) was similar to that in the development cohort (0.64-0.72) and showed moderate calibration. DART-1 adequately estimated the risk for patients in the middle risk quintile, and slightly underestimated it in the lowest quintiles. Their range of predicted versus observed 3-year risk was 0%-0% versus 0%-3.7% for Q1; 0.3%-0.4% versus 3%-11% for Q2; and 2.6%-3% versus 2.4%-9.8% for Q3. The development of WFs or HRS was associated with pancreatic cancer (p < 0.001). Vice versa, in absence of WFs or HRS, the risk of malignancy was low (0.3%)., Conclusions: The performance of DART-1 to predict the development of WFs or HRS in BD-IPMN was validated in an external international cohort, with a discriminative ability equal as in the development cohort. Risk estimations were most accurate for patients with BD-IPMNs in the middle risk quintile and slightly underestimated in the lowest quintiles., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Importance: Prognostication is an important aspect of clinical decision-making, but it is often challenging. Previous studies show that both patients and physicians tend to overestimate survival chances. Prediction models may assist in estimating and quantifying prognosis. However, insufficient understanding of the development, possibilities, and limitations of such models can lead to misinterpretations. Although many excellent books and comprehensive methodological articles on prognostic model research are published, they may not be accessible enough for the clinical audience. Our aim is to provide an overview on the main issues regarding prediction research for health care professionals to achieve better interpretation and increase the use of prognostic models in daily clinical practice., Observations: The first steps of model development include coding of predictors, model specification, and estimation. Next, we discuss the assessment of the performance of a prediction model, including discrimination and calibration aspects, followed by approaches to internal and external validation and updating. Finally, model reporting, presentation, and steps toward clinical implementation are presented., Conclusions and Relevance: After thorough consideration of the research question, data inspection, and coding of predictors, one can start with the specification of a prediction model. The number of candidate predictors should be kept limited, in view of the number of events in the data, to prevent overfitting. Calibration and discrimination are 2 aspects of model performance that complement each other and should be assessed preferably at external validation. Model development should be accompanied by qualitative research among patients and physicians to facilitate the development of a valuable tool and maximize possibilities for successful implementation. After model presentation is optimized, impact studies are required to assess the clinical value of a prediction model.

Introduction: Biologics are effective for the treatment of inflammatory bowel disease (IBD). However, unwarranted variation in processes and outcomes has been reported in the treatment of IBD. A care pathway for the treatment of IBD has the potential to reduce practice variation and improve outcomes. This study aims to compare the effect of a uniform care pathway for the treatment of patients with IBD with biologics to the current situation., Methods and Analysis: IBD Value is a longitudinal multicentre non-randomised parallel cluster trial with a baseline period. The study takes place in eight centres in the Netherlands. The baseline period will run for 12 months, after which the care pathway will be implemented in 6 of the 8 participating hospitals during the implementation phase of 3 months. Hereafter, the effect of the care pathway will be assessed for 12 months. Total study period is 27 months. The primary outcome is the effect of the care pathway on disease control (IBD-Control questionnaire). Secondary outcomes are the effect of the care pathway on the other outcomes of the International Consortium of Health Outcomes Measurement IBD standard set, health-related generic quality of life, patient experiences and degree of variation; cost effectiveness of the care pathway; and the variation between hospitals in the aforementioned outcomes in the baseline period. Outcomes will be measured every 6 months. The study started on 1 December 2020 and a minimum of 200 patients will be included., Ethics and Dissemination: The study was deemed not to be subject to Dutch law (WMO; Medical Research Involving Human Subjects Act) by the Medical Ethics Committee of the Erasmus MC, the Netherlands (registration number: MEC-2020-075) and a waiver was provided. Results will be disseminated through peer-reviewed journals and presented at (inter)national conferences., Trial Registration Number: NL8276., Competing Interests: Competing interests: RCAvL, NvL, DN, EB, MS, VdJ, KEV and JAH has nothing to disclose. CJvdW reports grants from Pfizer and Janssen and personal fees from AbbVie and Celltrion outside the submitted work. DvN reports personal fees from Janssen and Takeda outside the submitted work. RLW reports personal fees from AbbVie, Janssen and Pfizer outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although the provision of performance feedback to healthcare professionals based on data from quality registries is common practice in many fields of medicine, observational studies of its effect on the quality of care have shown mixed results. The objective of this study is to evaluate the effect of performance feedback on the quality of care for acute ischemic stroke., Methods: PERFEQTOS is a stepped wedge cluster randomized trial in 13 hospitals in the Netherlands providing endovascular thrombectomy for ischemic stroke. The primary outcome is the hospital's door-to-groin time. The study starts with a 6-month period in which none of the hospitals receives the performance feedback intervention. Subsequently, every 6 months, three or four hospitals are randomized to cross over from the control to the intervention conditions, until all hospitals receive the feedback intervention. The feedback intervention consists of a dashboard with quarterly reports on patient characteristics, structure, process, and outcome indicators related to patients with ischemic stroke treated with endovascular thrombectomy. Hospitals can compare their present performance with their own performance in the past and with other hospitals. The performance feedback is provided to local quality improvement teams in each hospital, who define their own targets on specific indicators and develop performance improvement plans. The impact of the performance feedback and improvement plans will be evaluated by comparing the primary outcome before and after the intervention., Discussion: This study will provide evidence on the effectiveness of performance feedback to healthcare providers. The results will be actively disseminated through peer-reviewed journals, conference presentations, and various stakeholder engagement activities., Trial Registration: Netherlands Trial Register NL9090 . Registered on December 3, 2020., (© 2021. The Author(s).)

Background: To evaluate the cost-effectiveness of prophylactic hysterectomy (PH) in women with Lynch syndrome (LS)., Methods: We developed a microsimulation model incorporating the natural history for the development of hyperplasia with and without atypia into endometrial cancer (EC) based on the MISCAN-framework. We simulated women identified as first-degree relatives (FDR) with LS of colorectal cancer patients after universal testing for LS. We estimated costs and benefits of offering this cohort PH, accounting for reduced quality of life after PH and for having EC. Three minimum ages (30/35/40) and three maximum ages (70/75/80) were compared to no PH., Results: In the absence of PH, the estimated number of EC cases was 300 per 1,000 women with LS. Total associated costs for treatment of EC were $5.9 million. Offering PH to FDRs aged 40-80 years was considered optimal. This strategy reduced the number of endometrial cancer cases to 5.4 (-98%), resulting in 516 quality-adjusted life years (QALY) gained and increasing the costs (treatment of endometrial cancer and PH) to $15.0 million (+154%) per 1,000 women. PH from earlier ages was more costly and resulted in fewer QALYs, although this finding was sensitive to disutility for PH., Conclusions: Offering PH to 40- to 80-year-old women with LS is expected to add 0.5 QALY per person at acceptable costs. Women may decide to have PH at a younger age, depending on their individual disutility for PH and premature menopause., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives The aim of this study was to explore the perspectives of healthcare providers and researchers in a large academic hospital on facilitators and barriers for implementing patient-reported outcome measures (PROMs) in clinical care. Methods A customized web-based questionnaire was developed and disseminated to healthcare providers and researchers across multiple medical departments involved in a value-based health care initiative in the hospital. Questionnaire statements were rated using a 5-point Likert scale ranging from "strongly agree" to "strongly disagree". In addition, 8 open-ended questions were included allowing respondents to mention additional facilitators and barriers for implementing PROMs. Descriptive statistics were used to summarize the results. Results In total, 61 participants from both surgical and non-surgical departments completed the survey. Most respondents (51%) were medical specialists and the median employment duration was 14 years. Frequently reported facilitators were the presence of a PROM coordinator in the (outpatient) clinic (85%), the integration of PROMs in the electronic health record (81%), and the intrinsic motivation of members involved in the implementation (N=9 open responses). Commonly reported barriers were language barriers (76%), IT issues (N=17 open responses), and time constraints (N=14 open responses). Conclusions For the successful implementation of PROMs in clinical practice, it is imperative that healthcare organizations consider supporting motivated healthcare professionals, involving PROMs coordinators, and investing in an adequate IT infrastructure, and removal of language barriers., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Disclosing prognostic information is necessary to enable patients to make well-informed treatment decisions. OncologIQ is a prognostic model that predicts the overall survival (OS) probability in patients with head and neck squamous cell carcinoma (HNSCC). We aimed to externally validate and update the model with new prognostic factors and translate it to a clinically useful tool., Methods: A consecutive retrospective sample of 2189 patients eligible for curative treatment of a primary HNSCC were selected. Discriminative performance was determined using the C-statistic., Results: External validation showed systematic underestimation of OS in the new population, and reasonable discrimination (C-statistic 0.67). Adding smoking, pack years, BMI, weight loss, WHO performance, socioeconomic status, and p16 positivity to the recalibrated multivariable model, improved the internally validated C-statistic to 0.71. The model showed minor optimism and was translated in an online tool (www.oncologiq.nl)., Conclusions: The updated model enables personalized patient counseling during treatment decision consultations., (© 2021 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Introduction: Given clinicians' frequent concerns about unfavourable outcomes, Intensive Care Unit (ICU) triage decisions in acutely ill cancer patients can be difficult, as clinicians may have doubts about the appropriateness of an ICU admission. To aid to this decision making, we studied the survival and performance status of cancer patients 2 years following an unplanned ICU admission., Materials and Methods: This was a retrospective cohort study in a large tertiary referral university hospital in the Netherlands. We categorized all adult patients with an unplanned ICU admission in 2017 into two groups: patients with or without an active malignancy. Descriptive statistics, Pearson's Chi-square tests and the Mann-Whitney U tests were used to evaluate the primary objective 2-year mortality and performance status. A good performance status was defined as ECOG performance status 0 (fully active) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out light work). A multivariable binary logistic regression analysis was used to identify factors associated with 2-year mortality within cancer patients., Results: Of the 1046 unplanned ICU admissions, 125 (12%) patients had cancer. The 2-year mortality in patients with cancer was significantly higher than in patients without cancer (72% and 42.5%, P <0.001). The median performance status at 2 years in cancer patients was 1 (IQR 0-2). Only an ECOG performance status of 2 (OR 8.94; 95% CI 1.21-65.89) was independently associated with 2-year mortality., Conclusions: In our study, the majority of the survivors have a good performance status 2 years after ICU admission. However, at that point, three-quarter of these cancer patients had died, and mortality in cancer patients was significantly higher than in patients without cancer. ICU admission decisions in acutely ill cancer patients should be based on performance status, severity of illness and long-term prognosis, and this should be communicated in the shared decision making. An ICU admission decision should not solely be based on the presence of a malignancy., Competing Interests: The authors have declared that no competing interests exist.

Background: The aim of this study was to identify risk factors for the development of second primary tumors (SPTs) in the head and neck region, lungs, and esophagus in patients with head and neck cancer., Methods: We collected data from 1581 patients. A cause-specific Cox model for the development of an SPT was fitted, accounting for the competing risks residual/recurrent tumor and mortality., Results: Of all patients, 246 (15.6%) developed SPTs. Analysis showed that tobacco and alcohol use, comorbidity, and the oral cavity subsite were risk factors for SPTs. The C-index, the discriminative accuracy, of the model for SPT was 0.65 (95% confidence interval, 0.61-0.68)., Conclusions: Our results show that there is potential to identify patients who have an increased risk to develop an SPT. This might increase their survival chances and quality of life. More research is needed to provide head and neck clinicians with definitive recommendations., (© 2021 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background: Previous studies describe a large variation in the proportion of patients undergoing treatment with curative intent for esophageal (EC) and gastric cancer (GC). Since centralization of surgical care was initiated and more awareness regarding hospital practice variation was potentially present, we hypothesized that hospital practice variation for potentially curable EC and GC patients changed over time., Methods: Patients with potentially curable EC (n = 10,115) or GC (n = 3988) diagnosed between 2012-2017 were selected from the Netherlands Cancer Registry. Multilevel multivariable logistic regression was used to analyze the differences in the probability of treatment with curative intent between hospitals of diagnosis over time, comparing 2012-2014 with 2015-2017. Relative survival (RS) between hospitals with different probabilities of treatment with curative intent were compared., Results: The range of proportions of patients undergoing treatment with curative intent per hospital of diagnosis for EC was 45-95 % in 2012-2014 and 54-89 % in 2015-2017, and for GC 52-100 % and 45-100 %. The adjusted variation declined for EC with Odds Ratios ranging from 0.50 to 1.72 between centers in the first period to 0.70-1.44 in the second period (p < 0.001) and did not change for GC (Odds Ratios ranging from 0.78 to 1.23 to 0.82-1.23, (p = 1.00)). A higher probability of treatment with curative intent was associated with a better survival for both malignancies., Conclusion: Although substantial variation between hospitals of diagnosis in the probability in receiving treatment with curative intent still exists for both malignancies, it has decreased for EC. A low probability of receiving curative treatment remained associated with worse survival., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: The aim of this study was to evaluate the psychometric performance of the patient- and parent-reported measures in the International Consortium for Health Outcomes Measurement (ICHOM) Standard Set for Cleft Care, and to identify ways of improving concept coverage., Methods: Data from 714 patients with cleft lip and/or palate, aged 8 to 9, 10 to 12.5, and 22 years were collected between November 2015 and April 2019 at Erasmus University Medical Center, Boston Children's Hospital, Duke Children's Hospital, and from participating sites in the CLEFT-Q Phase 3 study. The Standard Set includes 9 CLEFT-Q scales, the Nasal Obstruction Symptom Evaluation (NOSE) questionnaire, the Child Oral Health Impact Profile-Oral Symptoms Scale (COHIP-OSS), and the Intelligibility in Context Scale (ICS). Targeting, item-fit statistics, thresholds for item responses, and measurement precision (PSI) were analyzed using Rasch measurement theory., Results: The proportion of the sample to score within each instruments range of measurement varied from 69% (ICS) to 92% (CLEFT-Q teeth and COHIP-OSS). Specific problems with individual items within the NOSE and COHIP-OSS questionnaires were noted, such as poor item fit to the Rasch model and disordered thresholds (6 of 10). Reliability measured with PSI was above 0.82 for the ICS and all but one CLEFT-Q scale (speech distress). PSIs were lowest for the COHIP-OSS (0.43) and NOSE questionnaire (0.35)., Conclusion: The patient- and parent-reported components within the facial appearance, psychosocial function, and speech domains are valid measures; however, the facial function and oral health domains are not sufficiently covered by the CLEFT-Q eating and drinking, NOSE, and COHIP-OSS, and these questionnaires may not be accurate enough to stratify cleft-related outcomes., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: Between-center variation in outcome may offer opportunities to identify variation in quality of care. By intervening on these quality differences, patient outcomes may be improved. However, whether observed differences in outcome reflect the true quality improvement potential is not known for many diseases. Therefore, we aimed to analyze the effect of differences in performance on structure and processes of care, and case-mix on between-center differences in outcome after endovascular treatment (EVT) for ischemic stroke., Methods: In this observational cohort study, ischemic stroke patients who received EVT between 2014 and 2017 in all 17 Dutch EVT-centers were included. Primary outcome was the modified Rankin Scale, ranging from 0 (no symptoms) to 6 (death), at 90 days. We used random effect proportional odds regression modelling, to analyze the effect of differences in structure indicators (center volume and year of admission), process indicators (time to treatment and use of general anesthesia) and case-mix, by tracking changes in tau 2 , which represents the amount of between-center variation in outcome., Results: Three thousand two hundred seventy-nine patients were included. Performance on structure and process indicators varied significantly between EVT-centers (P < 0.001). Predicted probability of good functional outcome (modified Rankin Scale 0-2 at 90 days), which can be interpreted as an overall measure of a center's case-mix, varied significantly between 17 and 50% across centers. The amount of between-center variation (tau 2 ) was estimated at 0.040 in a model only accounting for random variation. This estimate more than doubled after adding case-mix variables (tau 2 : 0.086) to the model, while a small amount of between-center variation was explained by variation in performance on structure and process indicators (tau 2 : 0.081 and 0.089, respectively). This indicates that variation in case-mix affects the differences in outcome to a much larger extent., Conclusions: Between-center variation in outcome of ischemic stroke patients mostly reflects differences in case-mix, rather than differences in structure or process of care. Since the latter two capture the real quality improvement potential, these should be used as indicators for comparing center performance. Especially when a strong association exists between those indicators and outcome, as is the case for time to treatment in ischemic stroke.

Background: Patient-Reported Outcome Measures (PROMs) have been proposed for benchmarking health care quality across hospitals, which requires extensive case-mix adjustment. The current study's aim was to develop and compare case-mix models for mortality, a functional outcome, and a patient-reported outcome measure (PROM) in ischemic stroke care., Methods: Data from ischemic stroke patients, admitted to four stroke centers in the Netherlands between 2014 and 2016 with available outcome information (N = 1022), was analyzed. Case-mix adjustment models were developed for mortality, modified Rankin Scale (mRS) scores and EQ-5D index scores with respectively binary logistic, proportional odds and linear regression models with stepwise backward selection. Predictive ability of these models was determined with R-squared (R 2 ) and area-under-the-receiver-operating-characteristic-curve (AUC) statistics., Results: Age, NIHSS score on admission, and heart failure were the only common predictors across all three case-mix adjustment models. Specific predictors for the EQ-5D index score were sex (β = 0.041), socio-economic status (β = - 0.019) and nationality (β = - 0.074). R 2 -values for the regression models for mortality (5 predictors), mRS score (9 predictors) and EQ-5D utility score (12 predictors), were respectively R 2  = 0.44, R 2  = 0.42 and R 2  = 0.37., Conclusions: The set of case-mix adjustment variables for the EQ-5D at three months differed considerably from the set for clinical outcomes in stroke care. The case-mix adjustment variables that were specific to this PROM were sex, socio-economic status and nationality. These variables should be considered in future attempts to risk-adjust for PROMs during benchmarking of hospitals.

Background: Randomized controlled trials (RCTs) pose specific challenges in rare and heterogeneous neurological diseases due to the small numbers of patients and heterogeneity in disease course. Two analytical approaches have been proposed to optimally handle these issues in RCTs: covariate adjustment and ordinal analysis. We investigated the potential gain in efficiency of these approaches in rare and heterogeneous neurological diseases, using Guillain-Barré syndrome (GBS) as an example., Methods: We analyzed two published GBS trials with primary outcome 'at least one grade improvement' on the GBS disability scale. We estimated the treatment effect using logistic regression models with and without adjustment for prognostic factors. The difference between the unadjusted and adjusted estimates was disentangled in imbalance (random differences in baseline covariates between treatment arms) and stratification (change of the estimate due to covariate adjustment). Second, we applied proportional odds regression, which exploits the ordinal nature of the GBS disability score. The standard error of the estimated treatment effect indicated the statistical efficiency., Results: Both trials were slightly imbalanced with respect to baseline characteristics, which was corrected in the adjusted analysis. Covariate adjustment increased the estimated treatment effect in the two trials by 8% and 18% respectively. Proportional odds analysis resulted in lower standard errors indicating more statistical power., Conclusion: Covariate adjustment and proportional odds analysis most efficiently use the available data and ensure balance between the treatment arms to obtain reliable and valid treatment effect estimates. These approaches merit application in future trials in rare and heterogeneous neurological diseases like GBS., Competing Interests: BJ received unrestricted research support from the Netherlands Organization for Health Research and Development, Erasmus MC, Prinses Beatrix Spierfonds, GBS-CIDP Foundation International, Baxalta, CSLBehring, Grifols, and Annexon. PvD received unrestricted research support from the Prinses Beatrix Spierfonds, Janivo Stichting, Baxalta, Grifols, and Sanquin Plasma Pharmaceuticals. No other disclosures were reported. The commercial funder does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: Regression discontinuity (RD) is a quasi-experimental design that may provide valid estimates of treatment effects in case of continuous outcomes. We aimed to evaluate validity and precision in the RD design for dichotomous outcomes., Study Design and Setting: We performed validation studies in three large randomized controlled trials (RCTs) (Corticosteroid Randomization After Significant Head injury [CRASH], the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO], and PROspective Study of Pravastatin in elderly individuals at risk of vascular disease [PROSPER]). To mimic the RD design, we selected patients above and below a cutoff (e.g., age 75 years) randomized to treatment and control, respectively. Adjusted logistic regression models using restricted cubic splines (RCS) and polynomials and local logistic regression models estimated the odds ratio (OR) for treatment, with 95% confidence intervals (CIs) to indicate precision., Results: In CRASH, treatment increased mortality with OR 1.22 [95% CI 1.06-1.40] in the RCT. The RD estimates were 1.42 (0.94-2.16) and 1.13 (0.90-1.40) with RCS adjustment and local regression, respectively. In GUSTO, treatment reduced mortality (OR 0.83 [0.72-0.95]), with more extreme estimates in the RD analysis (OR 0.57 [0.35; 0.92] and 0.67 [0.51; 0.86]). In PROSPER, similar RCT and RD estimates were found, again with less precision in RD designs., Conclusion: We conclude that the RD design provides similar but substantially less precise treatment effect estimates compared with an RCT, with local regression being the preferred method of analysis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In epidemiology, the regression discontinuity design has received increasing attention recently and might be an alternative to randomized controlled trials (RCTs) to evaluate treatment effects. In regression discontinuity, treatment is assigned above a certain threshold of an assignment variable for which the treatment effect is adjusted in the analysis. We performed simulations and a validation study in which we used treatment effect estimates from an RCT as the reference for a prospectively performed regression discontinuity study. We estimated the treatment effect using linear regression adjusting for the assignment variable both as linear terms and restricted cubic spline and using local linear regression models. In the first validation study, the estimated treatment effect from a cardiovascular RCT was -4.0 mmHg blood pressure (95% confidence interval: -5.4, -2.6) at 2 years after inclusion. The estimated effect in regression discontinuity was -5.9 mmHg (95% confidence interval: -10.8, -1.0) with restricted cubic spline adjustment. Regression discontinuity showed different, local effects when analyzed with local linear regression. In the second RCT, regression discontinuity treatment effect estimates on total cholesterol level at 3 months after inclusion were similar to RCT estimates, but at least six times less precise. In conclusion, regression discontinuity may provide similar estimates of treatment effects to RCT estimates, but requires the assumption of a global treatment effect over the range of the assignment variable. In addition to a risk of bias due to wrong assumptions, researchers need to weigh better recruitment against the substantial loss in precision when considering a study with regression discontinuity versus RCT design.

Background: Guillain-Barré syndrome (GBS) has a highly variable clinical course, leading to frequent transfers within and between hospitals and high associated costs. We defined the current admissions, transfers and costs in relation to disease severity of GBS., Methods: Dutch neurologists were requested to report patients diagnosed with GBS between November 2009 and November 2010. Information regarding clinical course and transfers was obtained via neurologists and general practitioners., Results: 87 GBS patients were included with maximal GBS disability score of 1 or 2 (28%), 3 or 4 (53%), 5 (18%) and 6 (1%). Four mildly affected GBS patients were not hospital admitted. Of the 83 hospitalized patients 68 (82%) were initially admitted at a neurology department, 4 (5%) at an ICU, 4 (5%) at pediatrics, 4 (5%) at pediatrics neurology and 3 (4%) at internal medicine. Median hospital stay was 17 days (IQR 11-26 days, absolute range 1-133 days). Transfers between departments or hospitals occurred in 33 (40%) patients and 25 (30%) were transferred 2 times or more. From a cost-effectiveness perspective 21 (25%) of the admissions was suboptimal. Median costs for hospital admission of GBS patients were 15,060 Euro (IQR 11,226-23,683). Maximal GBS disability score was significantly correlated with total length of stay, number of transfers, ICU admission and costs., Conclusions: Hospital admissions for GBS patients are highly heterogeneous, with frequent transfers and higher costs for those with more severe disease. Future research should aim to develop prediction models to early identify the most cost-effective allocation in individual patients.

The objective of this study was to cross-sectionally explore the mediating role of self-serving cognitions in the relationship between antisocial behavior and psychopathic traits. A sample of 970 high school students completed self-report questionnaires assessing antisocial behavior, cognitive distortions, and psychopathic traits. Cognitive distortions partially mediated (and gender moderated) the relationship between antisocial behavior and psychopathic traits. Gender was found to moderate this relationship. Longitudinal studies would permit a fuller understanding of how these relationships interrelate-an understanding that may have important implications for clinical intervention.

Guillain-Barré syndrome (GBS) encompasses a broad spectrum of health-related quality of life (HRQL) determinants, including mobility, fatigue, pain, and depression. We systematically reviewed the literature on functional outcome domains in which GBS patients experience limitations in the short and long terms and evaluated determinants of HRQL in GBS patients. MEDLINE and EMBASE were systematically searched by two independent reviewers for articles covering HRQL data of GBS patients. Of 730 abstracts screened, 17 articles covering data of 14 studies matched the selection criteria. The included articles showed that many GBS patients experienced physical limitations, even years after the acute phase of the disease, while results were inconsistent for perceived levels of pain, fatigue, and general mental well-being. Only three papers covered HRQL assessments at more than one time point, generally showing large improvements in HRQL in the first year after GBS onset, but not thereafter. We appraised the methodological quality of included studies using a 13-item checklist; none of the articles fulfilled all items and only seven articles presented data on correlations between HRQL and determinants. In conclusion, the majority of studies on HRQL in GBS patients are cross-sectional and of low methodological quality. This paper provides guidance for much needed high-quality studies on patterns of patient-perceived recovery after GBS onset., (© 2014 Peripheral Nerve Society.)

Self-serving cognitions and callous-unemotional traits play important roles in adolescent antisocial behavior. The objective of this study was to cross-sectionally explore the mediating role of self-serving cognitions in the relationship between callous-unemotional traits and antisocial behavior. A sample of 972 high-school students completed self-report questionnaires assessing callous-unemotional traits, self-serving cognitive distortions and antisocial behavior. Two competing models exploring indirect effects accounting for the relationships between self-serving cognitive distortions, callous-unemotional traits and antisocial behaviors were tested. Both models revealed significant indirect effects, suggesting both pathways are possible. Gender was found to moderate these models. These findings suggest the importance of targeting self-serving cognitions in therapeutic interventions and increase our understanding of the role of self-serving cognitions in antisocial behavior.

Purpose: DNA methylation is associated with bladder cancer and these modifications could serve as useful biomarkers. FGFR3 mutations are present in 60% to 70% of non-muscle invasive bladder cancer (NMIBC). Low-grade bladder cancer recurs in more than 50% of patients. The aim of this study is to determine the sensitivity and specificity of a urine assay for the diagnosis of recurrences in patients with a previous primary NMIBC G1/G2 by using cystoscopy as the reference standard., Experimental Design: We selected eight CpG islands (CGI) methylated in bladder cancer from our earlier genome-wide study. Sensitivity of the CGIs for recurrences detection was investigated on a test set of 101 preTUR urines. Specificity was determined on 70 urines from healthy males aged more than 50 years. A 3-plex assay for the best combination was developed and validated on an independent set of 95 preTUR, recurrence free, and nonmalignant urines (n=130)., Results: The 3-plex assay identified recurrent bladder cancer in voided urine with a sensitivity of 74% in the validation set. In combination with the FGFR3 mutation assay, a sensitivity of 79% was reached (specificity of 77%). Sensitivity of FGFR3 and cytology was 52% and 57%, respectively., Conclusion: The combination of methylation and FGFR3 assays efficiently detects recurrent bladder cancer without the need for stratification of patients regarding methylation/mutation status of the primary tumor. We conclude that the sensitivity of this combination is in the same range as cystoscopy and paves the way for a subsequent study that investigates a modified surveillance protocol consisting of the urine test followed by cystoscopy only when the urine test is positive., (©2013 AACR.)

Although adolescent cannabis users have been reported not to be a homogeneous group, they are few typological studies and only one based on psychopathological variables. A better knowledge of the typology of cannabis users might contribute to the identification of specific needs concerning prevention or treatment. Among 199 adolescents using cannabis at least monthly during the last six month, cluster analysis yielded three clusters based on depressive symptoms, social anxiety, borderline personality traits, and psychopathic traits (impulsivity and callous-unemotional traits). The largest cluster, called 'ordinary' was well below the mean on all measures. Another cluster, labeled 'borderline' was distinguished by high levels of borderline traits, depressed mood, and social anxiety. The smallest cluster, called 'impulsive' was well above the mean in impulsivity and callous traits but low on all other measures. Frequency of cannabis use was higher in the borderline and impulsive clusters than in the ordinary cluster. Multiple regression analyses suggested that the contributions of psychopathological variables to cannabis use varied across clusters., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Major extracranial injury (MEI) is common in traumatic brain injury (TBI) patients, but the effect on outcome is controversial., Objective: To assess the prognostic value of MEI on mortality after TBI in an individual patient data meta-analysis of 3 observational TBI studies (International Mission on Prognosis and Clinical Trial Design in TBI [IMPACT]), a randomized controlled trial (Corticosteroid Randomization After Significant Head Injury [CRASH]), and a trauma registry (Trauma Audit and Research Network [TARN])., Methods: MEI (extracranial injury with an Abbreviated Injury Scale ≥ 3 or requiring hospital admission) was related to mortality with logistic regression analysis, adjusted for age, Glasgow Coma Scale motor score, and pupil reactivity and stratified by TBI severity. We pooled odds ratios (ORs) with random-effects meta-analysis., Results: We included 39,274 patients. Mortality was 25%, and 32% had MEI. MEI was a strong predictor for mortality in TARN, with adjusted odds ratios of 2.81 (95% confidence interval [CI], 2.44-3.23) in mild, 2.18 (95% CI, 1.80-2.65) in moderate, and 2.14 (95% CI, 1.95-2.35) in severe TBI patients. The prognostic effect was smaller in IMPACT and CRASH, with pooled adjusted odds ratios of 2.14 (95% CI, 0.93-4.91) in mild, 1.46 (95% CI, 1.14-1.85) in moderate, and 1.18 (95% CI, 1.03-1.55) in severe TBI. When patients who died within 6 hours after injury were excluded from TARN, the effect of MEI was comparable with IMPACT and CRASH., Conclusion: MEI is an important prognostic factor for mortality in TBI patients. However, the effect varies by population, which explains the controversy in the literature. The strength of the effect is smaller in patients with more severe brain injury and depends on time of inclusion in a study.

The present study explored the relations between sadistic traits and suicidality in nonclinical adolescents. Participants were 615 high-school students who completed self-report questionnaires. Hierarchical multiple regression analyses showed that self-reported sadistic traits explained unique variance in self-reported suicidality among both genders. This result is confronted with the psychodynamic hypothesis linking sadism turned inward and suicidality.

The aim of the authors' study was to explore a model of suicidal ideation among adolescents in which environmental risk factors were mediated by both depression and defensive psychopathology. Suicidal ideation, depression, defensive psychopathology (substance use, borderline traits or symptoms, dissociative symptoms), parental attachment, and stressful life events were assessed among 615 adolescents (62% male). Despite gender differences, the proposed model received support. Findings suggest a psychodynamic relationship linking suicidal ideation to defensive mechanisms, aiming to alleviate depressive affects.

This study explored the contributions of sociocultural and psychopathological factors to suicidal ideation among adolescents. A sample of 292 French high school students with an immigrant background completed a questionnaire assessing suicidal ideation, borderline personality traits, depressive symptoms, parental attachment, life events, acculturation orientations, ethnic identity, cannabis and alcohol consumption, socioeconomic status and academic failure. Although stressful life events, depressive symptoms, and individualism were risk factors, and attachment to parents a protective factor for both boys and girls, some gender differences emerged. Borderline traits (risk factor), assimilation and marginalization (both protective factors) were significant predictors only among girls.

The aim of the study was to evaluate the contribution of cannabis to the prediction of delinquent behaviors. Participants were 615 high-school students who completed self-report questionnaires. Hierarchical multiple regression analyses showed that cannabis use was a significant independent predictor of delinquent behaviors after adjustment for alcohol use, psychopathological and socio-familial variables. Cannabis use was associated with greater numbers of delinquent behaviors among adolescents with higher scores on psychopathic traits or depressive symptoms., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Immigrant adolescents and adolescents born of immigrant parents are at increased risk of substance use which has been linked to difficulties in acculturation processes. However very few studies have examined the role of the different acculturation strategies and none of them have controlled for relevant psychopathological and socio-familial factors. The aim of this study was to investigate the role of acculturation in cannabis use in a sample of adolescents born of immigrant parents taking into account potential confounding variables. A sample of 292 high school students born in France from at least one foreign parent completed a questionnaire assessing cannabis use, acculturation orientations, ethnic identity and the most relevant potential confounders (depressive symptoms, sensation seeking, borderline and psychopathic traits, alcohol and tobacco use, parental attachment, life events, socioeconomic status and academic achievement). A regression analysis showed that acculturation orientations and ethnic identity explained a significant part of the variance in the frequency of cannabis use. Individualism, integration and assimilation were negatively associated with the frequency of cannabis use suggesting they might serve as protective factors.