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.     

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.     

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.     

Money-metric utilitarianism

We discuss a method of ranking allocations in economic environments which applies when we do not know the names or preferences of individual agents. We require that two allocations can be ranked with the knowledge only of agents present, their aggregate bundles, and community indifference sets—a condition we refer to as aggregate independence. We also postulate a basic Pareto and continuity property, and a property stating that when two disjoint economies and allocations are put together, the ranking in the large economy should be consistent with the rankings in the two smaller economies (reinforcement). We show that a ranking method satisfies these axioms if and only if there is a probability measure over the strictly positive prices for which the rule ranks allocations on the basis of the random-price money-metric utilitarian rule. This is a rule which computes the money-metric utility for each agent at each price, sums these, and then takes an expectation according to the probability measure.     

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.     

The Possibility of Mixed-Mode Surveys in Sociological Studies

Abstract:  This paper explores the possibility of the mixed-mode survey in Japan in order to ensure a wider range of respondents, focusing on the specific type of mixture that is designed to make contact with a respondent by more than one mode and in which a respondent can choose an alternative mode convenient for him or her. The dataset mainly used comes from the survey Study on the Social Composition of the Urban Local Community conducted in Shinagawa Ward of Tokyo in 1999. Three other studies are introduced for additional information. As an indicator of the effectiveness of a mixed-mode design, the response rates of four studies are examined and some improvement in the response rates is observed, compared to that of a single-mode design. Another indicator is the representativeness of a sample and it is evaluated using the data of the Shinagawa survey. When the discrepancy between valid respondents and the population on some demographic characteristics is regarded as representation bias, a mixed-mode design is found to reduce the bias. An inherent problem in a mixed-mode design is "mode effect." In order to control for the mode effect in analyses, the inclusion of an additional variable indicating "mode" in the model is recommended. It is further suggested that the interaction effects between the "mode" and the respondents' traits should be checked, on the assumption that the survey mode affects respondents differently. The attempts are made and discussed in this paper using two variables drawn from the Shinagawa survey.     

The compensation of national union presidents: Moderating effects of union size

Over the last forty years numerous reseachers from the fields of economics, finance, and human resources management have proposed and empirically evaluated a number of models in efforts to identify determinants of executive compensation. Recently, similar research efforts have been undertaken to identify compensation determinants for union officers, both at the local and national levels. As an extension of these works, this study found measures of union financial strength, job complexity, performance and tenure in office to be directly related to national union presidents’ compensation. Although union income and relative union member earnings were the strongest determinants of officer compensation for the sample of unions as a whole, analyses of three subgroups of unions based on size revealed very different findings for large as opposed to small and medium-sized unions.     

Linking Decision Theory and Quantitative Microbial Risk Assessment: Tradeoffs Between Compliance and Efficacy for Waterborne Disease Interventions

Achieving health gains from the U.N. Sustainable Development Goals of universal coverage for water and sanitation will require interventions that can be widely adopted and maintained. Effectiveness—how an intervention performs based on actual use—as opposed to efficacy will therefore be central to evaluations of new and existing interventions. Incomplete compliance—when people do not always use the intervention and are therefore exposed to contamination—is thought to be responsible for the lower‐than‐expected risk reductions observed from water, sanitation, and hygiene interventions based on their efficacy at removing pathogens. We explicitly incorporated decision theory into a quantitative microbial risk assessment model. Specifically, we assume that the usability of household water treatment (HWT) devices (filters and chlorine) decreases as they become more efficacious due to issues such as taste or flow rates. Simulations were run to examine the tradeoff between device efficacy and usability. For most situations, HWT interventions that trade lower efficacy (i.e., remove less pathogens) for higher compliance (i.e., better usability) contribute substantial reductions in diarrheal disease risk compared to devices meeting current World Health Organization efficacy guidelines. Recommendations that take into account both the behavioral and microbiological properties of treatment devices are likely to be more effective at reducing the burden of diarrheal disease than current standards that only consider efficacy.     

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.