Sample size re‐estimation in clinical trials

Adaptive clinical trials are becoming very popular because of their flexibility in allowing mid‐stream changes of sample size, endpoints, populations, etc. At the same time, they have been regarded with mistrust because they can produce bizarre results in very extreme settings. Understanding the advantages and disadvantages of these rapidly developing methods is a must. This paper reviews flexible methods for sample size re‐estimation when the outcome is continuous.     

Improved Logrank-Type Tests for Survival Data Using Adaptive Weights

Summary .  For testing for treatment effects with time-to-event data, the logrank test is the most popular choice and has some optimality properties under proportional hazards alternatives. It may also be combined with other tests when a range of nonproportional alternatives are entertained. We introduce some versatile tests that use adaptively weighted logrank statistics. The adaptive weights utilize the hazard ratio obtained by fitting the model of Yang and Prentice (2005,  Biometrika   92 , 1–17). Extensive numerical studies have been performed under proportional and nonproportional alternatives, with a wide range of hazard ratios patterns. These studies show that these new tests typically improve the tests they are designed to modify. In particular, the adaptively weighted logrank test maintains optimality at the proportional alternatives, while improving the power over a wide range of nonproportional alternatives. The new tests are illustrated in several real data examples.     

Informed Consent in Cross-cultural Perspective: Clinical Research in the Tibetan Autonomous Region, PRC

Procedures of Informed Consent are considered a high priority for international biomedical research. However, informed consent protocols are not necessarily transferable across cultural, national or ethnic groups. Recent debates identify the need for balancing ethical universals with practical and local conditions and paying attention to questions of cultural competence when it comes to the Informed Consent process for clinical biomedical research. This article reports on the results of a two-year effort to establish a culturally appropriate Informed Consent process for biomedical research in the Tibet Autonomous Region in the People's Republic of China. A team of Tibetan and American researchers, physicians, health professionals and medical anthropologists conducted the research. The Informed Consent was specifically for undertaking a triple-blind, double placebo-controlled randomized clinical trial of a Tibetan medicine compared with Misoprostol for reducing postpartum blood loss. The findings suggest greater need for flexibility and cooperation in establishing Informed Consent protocols across cultures and nations.     

Quantile regression for longitudinal data using the asymmetric Laplace distribution

In longitudinal studies, measurements of the same individuals are taken repeatedly through time. Often, the primary goal is to characterize the change in response over time and the factors that influence change. Factors can affect not only the location but also more generally the shape of the distribution of the response over time. To make inference about the shape of a population distribution, the widely popular mixed-effects regression, for example, would be inadequate, if the distribution is not approximately Gaussian. We propose a novel linear model for quantile regression (QR) that includes random effects in order to account for the dependence between serial observations on the same subject. The notion of QR is synonymous with robust analysis of the conditional distribution of the response variable. We present a likelihood-based approach to the estimation of the regression quantiles that uses the asymmetric Laplace density. In a simulation study, the proposed method had an advantage in terms of mean squared error of the QR estimator, when compared with the approach that considers penalized fixed effects. Following our strategy, a nearly optimal degree of shrinkage of the individual effects is automatically selected by the data and their likelihood. Also, our model appears to be a robust alternative to the mean regression with random effects when the location parameter of the conditional distribution of the response is of interest. We apply our model to a real data set which consists of self-reported amount of labor pain measurements taken on women repeatedly over time, whose distribution is characterized by skewness, and the significance of the parameters is evaluated by the likelihood ratio statistic.     

Life history and host range of Alagoasa extrema (Coleoptera: Chrysomelidae: Alticinae), a potential biological control agent of Lantana spp. (Verbenaceae) in Australia

The life history and host range of the lantana beetle, Alagoasa extrema, a potential biocontrol agent for Lantana spp. were investigated in a quarantine unit at the Alan Fletcher Research Station, Brisbane, Australia. Adults feed on leaves and females lay batches of about 17 eggs on the soil surface around the stems of plants. The eggs take 16 days to hatch and newly emerged larvae move up the stem to feed on young leaves. Larvae feed for about 23 days and there are three instars. There is a prepupal non-feeding stage that lasts about 12 days and the pupal stage, which occurs in a cocoon in the soil, lasts 16 days. Teneral adults remain in the cocoon for 3 days to harden prior to emergence. Males live for about 151 days while females live for about 127 days. The pre-oviposition period is 19 days. In no-choice larval feeding trials, nine plant species, representing three families, supported development to adult. Three species, Aloysia triphylla, Citharexylum spinosum and Pandorea pandorana were able to support at least two successive generations. These results confirm those reported in South Africa and suggest that A. extrema is not sufficiently specific for release in Australia. Furthermore, it is not recommended for release in any other country which is considering biological control of lantana.     

Introduction to placebo effects in medicine: mechanisms and clinical implications

The field of placebo research has made considerable progress in the last years and it has become a major focus of interest. We know now that the placebo effect is a real neurobiological phenomenon and that the brain's 'inner pharmacy' is a critical determinant for the occurrence of psychobiological and behavioural changes relevant to healing processes and well-being. However, harnessing the advantages of placebo effects in healthcare is still a challenge. The first part of the theme issue summarizes and discusses the various kinds of placebo mechanisms across medical fields, thereby not only focusing on two main explanatory models-expectation and conditioning theory-but also taking into account empathy and social learning, emotion and motivation, spirituality and the healing ritual. The second part of the issue focuses on questions related to transferring knowledge from placebo research into clinical practice and discusses implications for the design and interpretation of clinical trials, for the therapeutic settings in daily patient care, and for future translational placebo research.