Statistical testing strategies for assessing treatment efficacy and marker accuracy in phase III trials

When a candidate predictive marker is available, but evidence on its predictive ability is not sufficiently reliable, all‐comers trials with marker stratification are frequently conducted. We propose a framework for planning and evaluating prospective testing strategies in confirmatory, phase III marker‐stratified clinical trials based on a natural assumption on heterogeneity of treatment effects across marker‐defined subpopulations, where weak rather than strong control is permitted for multiple population tests. For phase III marker‐stratified trials, it is expected that treatment efficacy is established in a particular patient population, possibly in a marker‐defined subpopulation, and that the marker accuracy is assessed when the marker is used to restrict the indication or labelling of the treatment to a marker‐based subpopulation, ie, assessment of the clinical validity of the marker. In this paper, we develop statistical testing strategies based on criteria that are explicitly designated to the marker assessment, including those examining treatment effects in marker‐negative patients. As existing and developed statistical testing strategies can assert treatment efficacy for either the overall patient population or the marker‐positive subpopulation, we also develop criteria for evaluating the operating characteristics of the statistical testing strategies based on the probabilities of asserting treatment efficacy across marker subpopulations. Numerical evaluations to compare the statistical testing strategies based on the developed criteria are provided.     

Administration of daily 5 mg tadalafil improves endothelial function in patients with benign prostatic hyperplasia

Introduction: Tadalafil is a promising phosphodiesterase (PDE) 5 inhibitor prescribed for erectile dysfunction (ED). Daily low dose (5?mg) of tadalafil has also been used for the treatment of male lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH). PDE5 inhibitors induce relaxation of smooth muscle cells in the urethra, prostate, bladder neck, and blood vessels. The aim of this study was to investigate the efficacy of tadalafil on vessels endothelial function, in patients with male LUTS symptoms associated with BPH.

Methods: The Institutional Review Board (IRB) approved this clinical study and informed consents had been obtained from 81 BPH patients.

The following male LUTS parameters: international prostate symptom score (IPSS), overactive bladder symptom score (OABSS), voiding volume, max and mean voiding flow on voiding flowmetry examination and post-voiding residual urine (RU) were compared at 0, 1, 3, 6, and 12 months after a daily dose of 5?mg tadalafil.

In addition, erectile function was evaluated by the sexual health inventory for men (SHIM) score and vessels endothelial function and peripheral neuropathy were assessed by the brachial-ankle pulse wave velocity (baPWV), ankle brachial index (ABI), and vibration perception threshold (VPT) at 0, 3, 6, and 12 months after treatment.

Results: The mean age of 81 patients was 66.4?±?11.4 years old. Their prostate size was 30.2?±?22.1?ml.

Male LUTS parameters including IPSS, OABSS, and RU showed significant improvement from 1 to 12 months after tadalafil administration. Max and mean voiding flow was significantly increased at 6 months after tadalafil treatment.

The SHIM score showed significant improvement after 3 months. Whilst, the results of baPWV also showed significant improvement from 3 to 12 months. ABI was also significantly improved at 6 months. However, there was no change in the VPT at any time point.

Conclusions: Tadalafil is effective for both male LUTS and ED. It is also shown that tadalafil improves baPWV, which we can conclude that higher vessels elasticity has been obtained. This major finding of this study shows that tadalafil has the potency to improve vessels endothelial dysfunction in patients with BPH.     

Group sequential monitoring based on the weighted log‐rank test statistic with the Fleming–Harrington class of weights in cancer vaccine studies

In recent years, immunological science has evolved, and cancer vaccines are now approved and available for treating existing cancers. Because cancer vaccines require time to elicit an immune response, a delayed treatment effect is expected and is actually observed in drug approval studies. Accordingly, we propose the evaluation of survival endpoints by weighted log‐rank tests with the Fleming–Harrington class of weights. We consider group sequential monitoring, which allows early efficacy stopping, and determine a semiparametric information fraction for the Fleming–Harrington family of weights, which is necessary for the error spending function. Moreover, we give a flexible survival model in cancer vaccine studies that considers not only the delayed treatment effect but also the long‐term survivors. In a Monte Carlo simulation study, we illustrate that when the primary analysis is a weighted log‐rank test emphasizing the late differences, the proposed information fraction can be a useful alternative to the surrogate information fraction, which is proportional to the number of events. Copyright © 2016 John Wiley & Sons, Ltd.     

Using GIS in community design charrettes: Lessons from a Japan–U.S. collaboration in earthquake recovery and mitigation planning for Kobe

Charrettes have become popular in the urban design field, especially for use among multidisciplinary teams of professionals and non-professional community stakeholders seeking to incorporate a rich array of expertise in short visioning activities. Geographic Information Systems are among the technologies with potential to provide sophisticated spatial information to charrette participants efficiently. This article reports on a charrette carried out jointly by teams from Kobe University and the University of Washington, Seattle, USA, using GIS to inform urban design in three neighborhoods affected by the Great Hanshin–Awaji Earthquake of 1995 in Kobe, Japan. The article describes the charrette itself, and discusses the utility of GIS, given the challenges of disaster recovery in a context of undeveloped institutions for public participation, and with participants of different linguistic and educational backgrounds. In combination with electronically storable drawing technology, GIS proved useful in enlarging the multidisciplinary and cross-cultural reach of urban design; in incorporating new layers of pre-prepared expert data, and in combining such data with dynamically-generated “advice maps” and design ideas. For GIS-based charrettes to become more widely useful in community-scale design in Japan, however, additional property-scale data need to be available.     

Using the community of inquiry for interviewing children: theory and practice

Involvement of children in research processes requires various ethical considerations. In particular, while interviewing children, a researcher needs to take into consideration the power imbalance between a researcher and children as well as among children. This article suggests a possible way of mitigating potential risks, drawing on the idea and practice of the Community of Inquiry (CoI) as an interview method. CoI is the practice of group dialog for knowledge-making, where participants talk about a common topic by sharing their lived experiences in a cooperative manner. This article shows that CoI allows children to act as both interviewers and interviewees, which helps children in reflective knowledge-making while at the same time mitigating the ethical concerns of interviewing. To illustrate how CoI can help achieve these goals, this article draws on the empirical research conducted with a group of junior high school students in Japan.     

Enabling children’s deliberation in deliberative systems: schools as a mediating space

In recent years, there has been a growing scholarly interest in conceptualising schools beyond their educational functions, as sites and agents of democracy. Yet this interest is often underpinned by a narrow conception of democracy, focusing solely on schools’ public and social aspects. To capture the democratic potential of schools more fully, this article suggests adopting a deliberative systems approach, which conceptualises democracy as differentiated yet linked sites of democratic communications and views schools as one such site. Using this approach as a broader framework and drawing on the fieldwork conducted in two Japanese schools, this article identifies the condition under which schools can become a meaningful part of deliberative systems. It reveals that schools contribute to deliberative systems when they serve as a bridge between children’s everyday practices and deliberative actions in the public space. In light of the findings, this article suggests conceptualising schools as a ‘mediating space’.     

Coaching für japanische Migranten in Deutschland

Compared to other minority groups, Japanese migrants in Germany are regarded as privileged and homogeneous. The author argues against the stereotype of homogeneity and closely analyses this particular migrant group and its situational, heterogeneous necessities and objectives which motivate the use of diverse coaching methods. In addition, the author discusses traditional hierarchical values in the home culture which tends to project a role model in a coach. The mixture of Japanese migrants’ heterogeneous needs in coaching and their hierarchically homogeneous values cannot be adequately addressed by the application of conventional coaching methods in Germany.     

Restricted mean survival time as a summary measure of time‐to‐event outcome

Many clinical research studies evaluate a time‐to‐event outcome, illustrate survival functions, and conventionally report estimated hazard ratios to express the magnitude of the treatment effect when comparing between groups. However, it may not be straightforward to interpret the hazard ratio clinically and statistically when the proportional hazards assumption is invalid. In some recent papers published in clinical journals, the use of restricted mean survival time (RMST) or τ ‐year mean survival time is discussed as one of the alternative summary measures for the time‐to‐event outcome. The RMST is defined as the expected value of time to event limited to a specific time point corresponding to the area under the survival curve up to the specific time point. This article summarizes the necessary information to conduct statistical analysis using the RMST, including the definition and statistical properties of the RMST, adjusted analysis methods, sample size calculation, information fraction for the RMST difference, and clinical and statistical meaning and interpretation. Additionally, we discuss how to set the specific time point to define the RMST from two main points of view. We also provide developed SAS codes to determine the sample size required to detect an expected RMST difference with appropriate power and reconstruct individual survival data to estimate an RMST reference value from a reported survival curve.     

An extended formulation of Arrow's theorem for k-social welfare functions

Past studies in social choice theory are generally based on the assumption that any two alternatives must be incompatible. We are concerned with the concept, k-social choice based on the assumption that just k alternatives out of p (1kp–1) are compatible. The purpose of this paper is to show an extended formulation of Arrow's theorem for k-social welfare functions.     

Sleep disturbance as a clinical sign for severe hypogonadism: efficacy of testosterone replacement therapy on sleep disturbance among hypogonadal men without obstructive sleep apnea

Objective: The present subanalysis of the EARTH study investigates the effects of one year testosterone replacement therapy (TRT) on sleep disturbance among hypogonadal men without obstructive sleep apnea.

Methods: Sleep disturbance was defined as three or more points in question 4 of the aging males symptoms (AMS) questionnaire. All participants completed the AMS scale, International Prostatic Symptoms Score (IPSS), Sexual Health Inventory for Men (SHIM) and Short Form 36 (SF-36) health survey at baseline and after 12?months. Sexual symptoms were also evaluated based on three AMS subscores (Q15, 16 and 17).

Results: We identified 100 patients with sleep disturbance, of whom 48 (24 each in the TRT and control groups) were ultimately included for analysis. All SF-36 categories , AMS scale, IPSS and SHIM score subdomains were significantly worse in patients with sleep disturbance than in those without disturbance. Statistically significant differences in sleep disturbance, erectile symptoms, sexual desire and some domains of the SF-36 were observed between the TRT and control groups after 12?months.

Conclusion: Sleep disturbance may be one of the clinical signs for severe hypogonadism. Moreover, TRT improved sleep conditions, sexual function and quality of life among hypogonadal men with sleep disturbance.