Over-accrual in Bayesian adaptive trials with continuous futility stopping.

BACKGROUND: We explore frequentist operating characteristics of a Bayesian adaptive design that allows continuous early stopping for futility. In particular, we focus on the power versus sample size relationship when more patients are accrued than originally planned. METHODS: We consider the case of a phase II single-arm study and a Bayesian phase II outcome-adaptive randomization design. For the former, analytical calculations are possible; for the latter, simulations are conducted. RESULTS: Results for both cases show a decrease in power with an increasing sample size. It appears that this effect is due to the increasing cumulative probability of incorrectly stopping for futility. CONCLUSION: The increase in cumulative probability of incorrectly stopping for futility is related to the continuous nature of the early stopping, which increases the number of interim analyses with accrual. The issue can be addressed by, for instance, delaying the start of testing for futility, reducing the number of futility tests to be performed or by setting stricter criteria for concluding futility.

Correcting for the Absence of a Gold Standard Improves Diagnostic Accuracy of Biomarkers in Alzheimer's Disease.

BACKGROUND: Studies investigating the diagnostic accuracy of biomarkers for Alzheimer's disease (AD) are typically performed using the clinical diagnosis or amyloid-ß positron emission tomography as the reference test. However, neither can be considered a gold standard or a perfect reference test for AD. Not accounting for errors in the reference test is known to cause bias in the diagnostic accuracy of biomarkers. OBJECTIVE: To determine the diagnostic accuracy of AD biomarkers while taking the imperfectness of the reference test into account. METHODS: To determine the diagnostic accuracy of AD biomarkers and taking the imperfectness of the reference test into account, we have developed a Bayesian method. This method establishes the biomarkers' true value in predicting the AD-pathology status by combining the reference test and the biomarker data with available information on the reliability of the reference test. The new methodology was applied to two clinical datasets to establish the joint accuracy of three cerebrospinal fluid biomarkers (amyloid-ß 1 - 42, Total tau, and P-tau181p) by including the clinical diagnosis as imperfect reference test into the analysis. RESULTS: The area under the receiver-operating-characteristics curve to discriminate between AD and controls, increases from 0.949 (with 95% credible interval [0.935,0.960]) to 0.990 ([0.985,0.995]) and from 0.870 ([0.817,0.912]) to 0.975 ([0.943,0.990]) for the cohorts, respectively. CONCLUSIONS: Use of the Bayesian methodology enables an improved estimate of the exact diagnostic value of AD biomarkers and overcomes the lack of a gold standard for AD. Using the new method will increase the diagnostic confidence for early stages of AD.

Variability of patient safety culture in Belgian acute hospitals.

OBJECTIVES: The aim of this study was to measure differences in safety culture perceptions within Belgian acute hospitals and to examine variability based on language, work area, staff position, and work experience. METHODS: The Hospital Survey on Patient Safety Culture was distributed to hospitals participating in the national quality and safety program (2007-2009). Hospitals were invited to participate in a comparative study. Data of 47,136 respondents from 89 acute hospitals were used for quantitative analysis. Percentages of positive response were calculated on 12 dimensions. Generalized estimating equations models were fitted to explore differences in safety culture. RESULTS: Handoffs and transitions, staffing, and management support for patient safety were considered as major problem areas. Dutch-speaking hospitals had higher odds of positive perceptions for most dimensions in comparison with French-speaking hospitals. Safety culture scores were more positive for respondents working in pediatrics, psychiatry, and rehabilitation compared with the emergency department, operating theater, and multiple hospital units. We found an important gap in safety culture perceptions between leaders and assistants within disciplines. Administration and middle management had lower perceptions toward patient safety. Respondents working less than 1 year in the current hospital had more positive safety culture perceptions in comparison with all other respondents. CONCLUSIONS: Large comparative databases provide the opportunity to identify distinct high and low scoring groups. In our study, language, work area, and profession were identified as important safety culture predictors. Years of experience in the hospital had only a small effect on safety culture perceptions.