Treatment Choice With Trial Data: Statistical Decision Theory Should Supplant Hypothesis Testing

Abstract

A central objective of empirical research on treatment response is to inform treatment choice. Unfortunately, researchers commonly use concepts of statistical inference whose foundations are distant from the problem of treatment choice. It has been particularly common to use hypothesis tests to compare treatments. Wald’s development of statistical decision theory provides a coherent frequentist framework for use of sample data on treatment response to make treatment decisions. A body of recent research applies statistical decision theory to characterize uniformly satisfactory treatment choices, in the sense of maximum loss relative to optimal decisions (also known as maximum regret). This article describes the basic ideas and findings, which provide an appealing practical alternative to use of hypothesis tests. For simplicity, the article focuses on medical treatment with evidence from classical randomized clinical trials. The ideas apply generally, encompassing use of observational data and treatment choice in nonmedical contexts.     

Bittersweet and Paradoxical

The American Red Cross is the most active nonprofit organization involved in disaster planning and response in the United States. The organization deployed nearly 50,000 volunteers to provide essential support to victims of some 125,000 domestic disasters, including home fires, hurricanes, wildfires, and floods, in a recent two‐year period. This study asks how American Red Cross disaster response volunteer experiences function to cultivate satisfaction and, at the other end of the spectrum, the kind of dissatisfaction that leads people to quit; it pays particular attention to ways in which volunteer management shapes dissatisfaction and fatigue because of implications for volunteer retention. Paradoxically, the Red Cross facilitates the highly satisfying act of helping victims, but volunteers feel dissatisfied when management practices get in the way of helping. The study suggests voluntary organizations that rely on skilled, long‐term volunteers to deliver services should evaluate and strengthen their communication strategies, recognition practices, and support systems for volunteers in distress.     

Enabling robust assessment of QTc prolongation in early phase clinical trials

Since the implementation of the International Conference on Harmonization (ICH) E14 guideline in 2005, regulators have required a “thorough QTc” (TQT) study for evaluating the effects of investigational drugs on delayed cardiac repolarization as manifested by a prolonged QTc interval. However, TQT studies have increasingly been viewed unfavorably because of their low cost effectiveness. Several researchers have noted that a robust drug concentration‐QTc (conc‐QTc) modeling assessment in early phase development should, in most cases, obviate the need for a subsequent TQT study. In December 2015, ICH released an “E14 Q&As (R3)” document supporting the use of conc‐QTc modeling for regulatory decisions. In this article, we propose a simple improvement of two popular conc‐QTc assessment methods for typical first‐in‐human crossover‐like single ascending dose clinical pharmacology trials. The improvement is achieved, in part, by leveraging routinely encountered (and expected) intrasubject correlation patterns encountered in such trials. A real example involving a single ascending dose and corresponding TQT trial, along with results from a simulation study, illustrate the strong performance of the proposed method. The improved conc‐QTc assessment will further enable highly reliable go/no‐go decisions in early phase clinical development and deliver results that support subsequent TQT study waivers by regulators.     

Humanitarian response and stress in Kenya: gendered problems and their implications

ABSTRACT

Stress-related conditions such as burnout and post-traumatic stress disorder are a growing concern in the humanitarian sector. Aid workers themselves report not only that mental health problems are common, but that the support they receive from their employers is insufficient. Problematically, the experience of the international aid worker – particularly those who are white and from the global North – is often foregrounded in explaining what constitutes stress and related mental health problems. This indicates a wider problem of what is required of ‘the perfect humanitarian’ – a personality that is gendered and racialised – and how this influences the different experiences and treatment of national and international staff from aid agencies. This article explores the organisational culture and working conditions of humanitarian settings and their impact on the mental health and well-being of staff. It argues that there is a structural dimension to stress that is less to do with external security threats and more to do with the specific infrastructure, policies, and practices of humanitarian operations, with implications for aid workers which cut across dimensions of race, gender, and nationality.     

A pool-adjacent-violators-algorithm approach to detect infinite parameter estimates in one-regressor dose–response models with asymptotes

Binary response models are often applied in dose–response settings where the number of dose levels is limited. Commonly, one can find cases where the maximum likelihood estimation process for these models produces infinite values for at least one of the parameters, often corresponding to the ‘separated data’ issue. Algorithms for detecting such data have been proposed, but are usually incorporated directly into in the parameter estimation. Additionally, they do not consider the use of asymptotes in the model formulation. In order to study this phenomenon in greater detail, we define the class of specifiably degenerate functions where this can occur (including the popular logistic and Weibull models) that allows for asymptotes in the dose–response specification. We demonstrate for this class that the well-known pool-adjacent-violators algorithm can efficiently pre-screen for non-estimable data. A simulation study demonstrates the frequency with which this problem can occur for various response models and conditions.     

Improved estimation methods for unrelated question randomized response techniques

The randomized response technique (RRT) is an important tool, commonly used to avoid biased answers in survey on sensitive issues by preserving the respondents’ privacy. In this paper, we introduce a data collection method for survey on sensitive issues combining both the unrelated-question RRT and the direct question design. The direct questioning method is utilized to obtain responses to a non sensitive question that is related to the innocuous question from the unrelated-question RRT. These responses serve as additional information that can be used to improve the estimation of the prevalence of the sensitive behavior. Furthermore, we propose two new methods for the estimation of the proportion of respondents possessing the sensitive attribute under a missing data setup. More specifically, we develop the weighted estimator and the weighted conditional likelihood estimator. The performances of our estimators are studied numerically and compared with that of an existing one. Both proposed estimators are more efficient than the Greenberg's estimator. We illustrate our methods using real data from a survey study on illegal use of cable TV service in Taiwan.     

基于同城化视角的人口空间动态与区域经济发展耦合关联机理研究

人口空间动态与区域经济发展的耦合关系是同城化区域间共同面对的重要课题。本文在解构人口空间动态维度主体的基础上,将人口空间动态的诉求机制与动因机理架构于更低交易费用的利益诉求之上,解析人口空间动态的模式选择,深入探讨人口空间动态与区域经济发展的耦合关联性。在此基础上,提出引导人口流动与合理分布的策略。研究成果将有助于更好地理解同城化态势下人口空间演变的动因机理,为同城区域的经济发展、城市规划、文化交融等方面的科学设计提供重要参考。     

The duty to care and the need to split

This paper arises out of psychoanalytically oriented consultancy to teams of staff in the helping professions where there is a statutory 'duty to care'. It takes as its premise the seemingly paradoxical hypothesis that workers may need to split off part of their emotional experience in order to preserve their own mental health and provide reliable services to their clients. I argue that while a professional 'duty to care' requires us to be emotionally 'in touch', the demands of our clients together with the demands of the institutional response to the 'duty to care' cause us to split off parts of our awareness. I also argue that provided the splitting does not become extreme we are doing no more or less than the rest of society. In other words, there is a degree of 'normal splitting' which numbs our awareness of danger and destructiveness and seeks to protect us from too much anxiety and pain. Yet if professional workers are charged with the responsibility of assessing risk and acting accordingly for the protection of all concerned they need ways of being 'in touch' (re-integrating the splits) for some or enough of the time. Finally, I will describe ways of being 'in touch', illustrating the difficulty and the pain of re-integrating the splits and some of the insights that can arise out of this work with examples from my consultancy work.     

Effects of attributed responsibility and response strategies on organizational reputation: A meta-analysis of situational crisis communication theory research

Scholars utilizing situational crisis communication theory (SCCT) mainly examine how attributed responsibility affects organizational reputation and how response strategies matched with the amount of attributed responsibility protect reputation. The findings on these 2 important questions have been mixed. A meta-analysis of 35 investigations from 24 studies published between January 1990 and March 2015 was conducted to explain the mixed findings and reveal average correlations. Attributed responsibility was strongly associated with reputation at –.54, and response strategies were only weakly associated with reputation at .23. Equally important, crisis vignette choice moderated the responsibility-reputation association. Crisis clusters, reputation measurements, sample choice, and crisis vignette choice moderated the match-reputation association. Theoretical, methodological, and practical implications were discussed.     

Adaptive phase I/II clinical trials for drug combination assessment in oncology using the outcomes of each cycle

Many new anticancer agents can be combined with existing drugs, as combining a number of drugs may be expected to have a better therapeutic effect than monotherapy owing to synergistic effects. Furthermore, to drive drug development and to reduce the associated cost, there has been a growing tendency to combine these as phase I/II trials. With respect to phase I/II oncology trials for the assessment of dose combinations, in the existing methodologies in which efficacy based on tumor response and safety based on toxicity are modeled as binary outcomes, it is not possible to enroll and treat the next cohort of patients unless the best overall response has been determined in the current cohort. Thus, the trial duration might be potentially extended to an unacceptable degree. In this study, we proposed a method that randomizes the next cohort of patients in the phase II part to the dose combination based on the estimated response rate using all the available observed data upon determination of the overall response in the current cohort. We compared the proposed method to the existing method using simulation studies. These demonstrated that the percentage of optimal dose combinations selected in the proposed method is not less than that in the existing method and that the trial duration in the proposed method is shortened compared to that in the existing method. The proposed method meets both ethical and financial requirements, and we believe it has the potential to contribute to expedite drug development.