A comparison of methods for treatment selection in seamless phase II/III clinical trials incorporating information on short-term endpoints

In an adaptive seamless phase II/III clinical trial interim analysis data are used for treatment selection, enabling resources to be focussed on comparison of more effective treatment(s) with a control. In this paper we compare two methods recently proposed to enable use of short-term endpoint data for decision-making at the interim analysis. The comparison focusses on the power and the probability of correctly identifying the most promising treatment. We show that the choice of method depends on how well short-term data predict the best treatment, which may be measured by the correlation between treatment effects on short-term and long-term endpoints

A statistical evaluation of the effects of gender differences in assessment of acute inhalation toxicity

Acute inhalation toxicity of chemicals has conventionally been assessed by the median lethal concentration (LC50) test (organisation for economic co-operation and development (OECD) TG 403). Two new methods, the recently adopted acute toxic class method (ATC; OECD TG 436) and a proposed fixed concentration procedure (FCP), have recently been considered, but statistical evaluations of these methods did not investigate the influence of differential sensitivity between male and female rats on the outcomes. This paper presents an analysis of data from the assessment of acute inhalation toxicity for 56 substances. Statistically significant differences between the LC50 for males and females were found for 16 substances, with greater than 10-fold differences in the LC50 for two substances. The paper also reports a statistical evaluation of the three test methods in the presence of unanticipated gender differences. With TG 403, a gender difference leads to a slightly greater chance of under-classification. This is also the case for the ATC method, but more pronounced than for TG 403, with misclassification of nearly all substances from Globally Harmonised System (GHS) class 3 into class 4. As the FCP uses females only, if females are more sensitive, the classification is unchanged. If males are more sensitive, the procedure may lead to under-classification. Additional research on modification of the FCP is thus proposed

To add or not to add a new treatment arm to a multiarm study: A decision-theoretic framework.

Multiarm clinical trials, which compare several experimental treatments against control, are frequently recommended due to their efficiency gain. In practise, all potential treatments may not be ready to be tested in a phase II/III trial at the same time. It has become appealing to allow new treatment arms to be added into on-going clinical trials using a "platform" trial approach. To the best of our knowledge, many aspects of when to add arms to an existing trial have not been explored in the literature. Most works on adding arm(s) assume that a new arm is opened whenever a new treatment becomes available. This strategy may prolong the overall duration of a study or cause reduction in marginal power for each hypothesis if the adaptation is not well accommodated. Within a two-stage trial setting, we propose a decision-theoretic framework to investigate when to add or not to add a new treatment arm based on the observed stage one treatment responses. To account for different prospect of multiarm studies, we define utility in two different ways; one for a trial that aims to maximise the number of rejected hypotheses; the other for a trial that would declare a success when at least one hypothesis is rejected from the study. Our framework shows that it is not always optimal to add a new treatment arm to an existing trial. We illustrate a case study by considering a completed trial on knee osteoarthritis

Point and interval estimation in two-stage adaptive designs with time to event data and biomarker-driven subpopulation selection

In personalized medicine, it is often desired to determine if all patients or only a subset of them benefit from a treatment. We consider estimation in two‐stage adaptive designs that in stage 1 recruit patients from the full population. In stage 2, patient recruitment is restricted to the part of the population, which, based on stage 1 data, benefits from the experimental treatment. Existing estimators, which adjust for using stage 1 data for selecting the part of the population from which stage 2 patients are recruited, as well as for the confirmatory analysis after stage 2, do not consider time to event patient outcomes. In this work, for time to event data, we have derived a new asymptotically unbiased estimator for the log hazard ratio and a new interval estimator with good coverage probabilities and probabilities that the upper bounds are below the true values. The estimators are appropriate for several selection rules that are based on a single or multiple biomarkers, which can be categorical or continuous

Response of the Jovian thermosphere to a transient ‘pulse’ in solar wind pressure

The importance of the Jovian thermosphere with regard to magnetosphere-ionosphere coupling is often neglected in magnetospheric physics. We present the first study to investigate the response of the Jovian thermosphere to transient variations in solar wind dynamic pressure, using an azimuthally symmetric global circulation model coupled to a simple magnetosphere and fixed auroral conductivity model. In our simulations, the Jovian magnetosphere encounters a solar wind shock or rarefaction region and is subsequently compressed or expanded. We present the ensuing response of the coupling currents, thermospheric flows, heating and cooling terms, and the aurora to these transient events. Transient compressions cause the reversal, with respect to steady state, of magnetosphere-ionosphere coupling currents and momentum transfer between the thermosphere and magnetosphere. They also cause at least a factor of two increase in the Joule heating rate. Ion drag significantly changes the kinetic energy of the thermospheric neutrals depending on whether the magnetosphere is compressed or expanded. Local temperature variations appear between View the MathML source for the compression scenario and View the MathML source for the expansion case. Extended regions of equatorward flow develop in the wake of compression events - we discuss the implications of this behaviour for global energy transport. Both compressions and expansions lead to a View the MathML source increase in the total power dissipated or deposited in the thermosphere. In terms of auroral processes, transient compressions increase main oval UV emission by a factor of ∼4.5 whilst transient expansions increase this main emission by a more modest 37%. Both types of transient event cause shifts in the position of the main oval, of up to 1° latitude

Designing Digital Content to Support Science Journalism

Journalists need to become more effective at communicating science and countering post-truth activities that seek to undermine scientific processes and evidence. Digital support for journalists when investigating and writing about sciencerelated topics is one means of improving this science communication. However, little bespoke digital support is available. This paper reports the research and development of one new form of such digital support. During a participatory design process, experienced science journalists and other professionals were interviewed about their challenges experienced and understanding of good practices in science journalism. These challenges and good practices informed the development of a prototype of a new form of digital tool that was evaluated by journalists without specialist science training. A new version of the prototype, called INQUEST, was implemented to automate some parts of good practices in order to augment journalists’ capabilities. These practices included the retrieval of science information from diverse sources, targeting different science audiences, and providing different forms of guidance for explaining science to the target audience. This prototype is presented, and an early evaluation of it is reported