88 research outputs found

    Point estimation for adaptive trial designs II: Practical considerations and guidance

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    In adaptive clinical trials, the conventional end-of-trial point estimate of a treatment effect is prone to bias, that is, a systematic tendency to deviate from its true value. As stated in recent FDA guidance on adaptive designs, it is desirable to report estimates of treatment effects that reduce or remove this bias. However, it may be unclear which of the available estimators are preferable, and their use remains rare in practice. This article is the second in a two-part series that studies the issue of bias in point estimation for adaptive trials. Part I provided a methodological review of approaches to remove or reduce the potential bias in point estimation for adaptive designs. In part II, we discuss how bias can affect standard estimators and assess the negative impact this can have. We review current practice for reporting point estimates and illustrate the computation of different estimators using a real adaptive trial example (including code), which we use as a basis for a simulation study. We show that while on average the values of these estimators can be similar, for a particular trial realization they can give noticeably different values for the estimated treatment effect. Finally, we propose guidelines for researchers around the choice of estimators and the reporting of estimates following an adaptive design. The issue of bias should be considered throughout the whole lifecycle of an adaptive design, with the estimation strategy prespecified in the statistical analysis plan. When available, unbiased or bias-reduced estimates are to be preferred

    Laser-Induced Fluorometry for Capillary Electrophoresis

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    Laser-induced fluorometry (LIF) has achieved the detection of single molecules, which ranks it among the most sensitive of detection techniques, whereas capillary electrophoresis (CE) is known as a powerful separation method with resolution that is beyond the reach of many other types of chromatography. Therefore, a coupling of LIF with CE has established an unrivaled analytical technique in terms of sensitivity and resolution. CE-LIF has demonstrated excellent performance in bioanalytical chemistry for the high-resolution separation and highly sensitive detection of DNAs, proteins, and small bioactive molecules. This review describes the CE-LIF methods developed by the author's group that include indirect and direct detection using diode lasers, post-column derivatization, and Hadamard transformation, as well as applications to the binding assays of specific DNA immunoassays of proteins and to the determination of anticancer drugs

    Schreibersite: an effective catalyst in the formose reaction network

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    We report on the ability of the meteoritic material schreibersite to catalyze the generation of higher sugars from simple carbohydrates in the formose reaction network. Since the analysis of carbonaceous meteorites like the Murchison meteorite it has become generally accepted that a substantial amount of organic material has been delivered to the early earth and, therefore, ought to be considered in scenarios for the origin (s) of life. Also for the open question of accessible phosphorus sources, an extraterrestrial material called schreibersite has been identified that is capable of releasing soluble and reactive phosphorus oxyanions that would react with organics to form for instance nucleotides and membrane associated molecules. We have reinvestigated this material using capillary electrophoresis to monitor its corrosion process in water and probed its ability to phosphorylate a wide range of organics. Although showing a poor reactivity of schreibersite, we have found that the material catalyzes the aldol reaction of small carbohydrates forming larger sugar molecules. This reaction in the formose reaction network is a prebiotically likely route to biologically relevant sugars. The results of our study present one of the first instances of connecting extraterrestrial material to prebiotic chemistry on the early earth

    Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs.

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    Funder: Cancer Research UK; doi: http://dx.doi.org/10.13039/501100000289Adaptive designs for clinical trials permit alterations to a study in response to accumulating data in order to make trials more flexible, ethical, and efficient. These benefits are achieved while preserving the integrity and validity of the trial, through the pre-specification and proper adjustment for the possible alterations during the course of the trial. Despite much research in the statistical literature highlighting the potential advantages of adaptive designs over traditional fixed designs, the uptake of such methods in clinical research has been slow. One major reason for this is that different adaptations to trial designs, as well as their advantages and limitations, remain unfamiliar to large parts of the clinical community. The aim of this paper is to clarify where adaptive designs can be used to address specific questions of scientific interest; we introduce the main features of adaptive designs and commonly used terminology, highlighting their utility and pitfalls, and illustrate their use through case studies of adaptive trials ranging from early-phase dose escalation to confirmatory phase III studies

    Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs

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    Adaptive designs for clinical trials permit alterations to a study in response to accumulating data in order to make trials more ļ¬‚exible, ethical and eļ¬ƒcient. These beneļ¬ts are achieved while preserving the integrity and validity of the trial, through the pre-speciļ¬cation and proper adjustment for the possible alterations during the course of the trial. Despite much research in the statistical literature highlighting the potential advantages of adaptive designs over traditional ļ¬xed designs, the uptake of such methods in clinical research has been slow. One major reason for this is that diļ¬€erent adaptations to trial designs, as well as their advantages and limitations, remain unfamiliar to large parts of the clinical community. The aim of this paper is to clarify where adaptive designs can be used to address speciļ¬c questions of scientiļ¬c interest; we introduce the main features of adaptive designs and commonly used terminology, highlighting their utility and pitfalls, and illustrate their use through case studies of adaptive trials ranging from early-phase dose escalation to conļ¬rmatory Phase III studies

    Point estimation for adaptive trial designs

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    Recent FDA guidance on adaptive clinical trial designs defines bias as "a systematic tendency for the estimate of treatment effect to deviate from its true value", and states that it is desirable to obtain and report estimates of treatment effects that reduce or remove this bias. In many adaptive designs, the conventional end-of-trial point estimates of the treatment effects are prone to bias, because they do not take into account the potential and realised trial adaptations. While much of the methodological developments on adaptive designs have tended to focus on control of type I error rates and power considerations, in contrast the question of biased estimation has received less attention. This article addresses this issue by providing a comprehensive overview of proposed approaches to remove or reduce the potential bias in point estimation of treatment effects in an adaptive design, as well as illustrating how to implement them. We first discuss how bias can affect standard estimators and critically assess the negative impact this can have. We then describe and compare proposed unbiased and bias-adjusted estimators of treatment effects for different types of adaptive designs. Furthermore, we illustrate the computation of different estimators in practice using a real trial example. Finally, we propose a set of guidelines for researchers around the choice of estimators and the reporting of estimates following an adaptive design

    Medicines and Healthcare products Regulatory Agencyā€™s ā€œConsultation on proposals for legislative changes for clinical trialsā€: a response from the Trials Methodology Research Partnership Adaptive Designs Working Group, with a focus on data sharing

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    In the UK, the Medicines and Healthcare products Regulatory Agency consulted on proposals ā€œto improve and strengthen the UK clinical trials legislation to help us make the UK the best place to research and develop safe and innovative medicinesā€. The purpose of the consultation was to help finalise the proposals and contribute to the drafting of secondary legislation. We discussed these proposals as members of the Trials Methodology Research Partnership Adaptive Designs Working Group, which is jointly funded by the Medical Research Council and the National Institute for Health and Care Research. Two topics arose frequently in the discussion: the emphasis on legislation, and the absence of questions on data sharing. It is our opinion that the proposals rely heavily on legislation to change practice. However, clinical trials are heterogeneous, and as a result some trials will struggle to comply with all of the proposed legislation. Furthermore, adaptive design clinical trials are even more heterogeneous than their non-adaptive counterparts, and face more challenges. Consequently, it is possible that increased legislation could have a greater negative impact on adaptive designs than non-adaptive designs. Overall, we are sceptical that the introduction of legislation will achieve the desired outcomes, with some exceptions. Meanwhile the topic of data sharing ā€” making anonymised individual-level clinical trial data available to other investigators for further use ā€” is entirely absent from the proposals and the consultation in general. However, as an aspect of the wider concept of open science and reproducible research, data sharing is an increasingly important aspect of clinical trials. The benefits of data sharing include faster innovation, improved surveillance of drug safety and effectiveness and decreasing participant exposure to unnecessary risk. There are already a number of UK-focused documents that discuss and encourage data sharing, for example, the Concordat on Open Research Data and the Medical Research Councilā€™s Data Sharing Policy. We strongly suggest that data sharing should be the norm rather than the exception, and hope that the forthcoming proposals on clinical trials invite discussion on this important topic

    Performance of seven different paediatric early warning scores to predict critical care admission in febrile children presenting to the emergency department: a retrospective cohort study

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    Objective Paediatric Early Warning Scores (PEWS) are widely used in the UK, but the heterogeneity across tools and the limited data on their predictive performance represent obstacles to improving best practice. The standardisation of practice through the proposed National PEWS will rely on robust validation. Therefore, we compared the performance of the National PEWS with six other PEWS currently used in NHS hospitals, for their ability to predict critical care (CC) admission in febrile children attending the emergency department (ED). Design Retrospective single-centre cohort study. Setting Tertiary hospital paediatric ED. Participants A total of 11 449 eligible febrile ED attendances were identified from the electronic patient record over a 2-year period. Seven PEWS scores were calculated (Alder Hey, Bedside, Bristol, National, Newcastle and Scotland PEWS, and the Paediatric Observation Priority Score, using the worst observations recorded during their ED stay. Outcomes The primary outcome was CC admission within 48 hours, the secondary outcomes were hospital length of stay (LOS) >48 hours and sepsis-related mortality. Results Of 11 449 febrile children, 134 (1.2%) were admitted to CC within 48 hours of ED presentation, 606 (5.3%) had a hospital LOS >48 hours. 10 (0.09%) children died, 5 (0.04%) were sepsis-related. All seven PEWS demonstrated excellent discrimination for CC admission (range area under the receiver operating characteristic curves (AUC) 0.91ā€“0.95) and sepsis-related mortality (range AUC 0.95ā€“0.99), most demonstrated moderate discrimination for hospital LOS (range AUC 0.69ā€“0.75). In CC admission threshold analyses, bedside PEWS (AUC 0.90; 95% CI 0.86 to 0.93) and National PEWS (AUC 0.90; 0.87ā€“0.93) were the most discriminative, both at a threshold of ā‰„6. Conclusions Our results support the use of the proposed National PEWS in the paediatric ED for the recognition of suspected sepsis to improve outcomes, but further validation is required in other settings and presentations
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