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.     

Principal stratum strategy: Potential role in drug development

A randomized trial allows estimation of the causal effect of an intervention compared to a control in the overall population and in subpopulations defined by baseline characteristics. Often, however, clinical questions also arise regarding the treatment effect in subpopulations of patients, which would experience clinical or disease related events post-randomization. Events that occur after treatment initiation and potentially affect the interpretation or the existence of the measurements are called intercurrent events in the ICH E9(R1) guideline. If the intercurrent event is a consequence of treatment, randomization alone is no longer sufficient to meaningfully estimate the treatment effect. Analyses comparing the subgroups of patients without the intercurrent events for intervention and control will not estimate a causal effect. This is well known, but post-hoc analyses of this kind are commonly performed in drug development. An alternative approach is the principal stratum strategy, which classifies subjects according to their potential occurrence of an intercurrent event on both study arms. We illustrate with examples that questions formulated through principal strata occur naturally in drug development and argue that approaching these questions with the ICH E9(R1) estimand framework has the potential to lead to more transparent assumptions as well as more adequate analyses and conclusions. In addition, we provide an overview of assumptions required for estimation of effects in principal strata. Most of these assumptions are unverifiable and should hence be based on solid scientific understanding. Sensitivity analyses are needed to assess robustness of conclusions.     

Young Black women's resistance to the Canadian settler colonial state apparatus: Negotiating the complexities of “being part of the system that oppresses”

Young Black peoples encounter racism and discriminatory practices and policies through formal education and in the larger society (Creese, 2013; Dei & James, 1998; Kelly, 1998). As the experiences of the research participants—young Black women between the ages of 18 and 30—highlight, a formal education system that is structured to benefit and perpetuate the settler colonial state apparatus marginalizes Black youth, including those who are deemed “successful” through their acceptance into higher education as formal education and the labour market are structured according to the logic of settler colonialism. As such, these systems operate by imposing Euro-Western systems of knowledge, justice, and community on racialized peoples, and in particular, Black peoples. Yet, the research also shows that while injustice is the reality for young Black people, so too is resistance through a small yet powerful contingent who are refusing to remain complicit in perpetuating settler colonialism.     

Evaluating surrogate variables for improving microarray multiple testing inference

The use of surrogate variables has been proposed as a means to capture, for a given observed set of data, sources driving the dependency structure among high-dimensional sets of features and remove the effects of those sources and their potential negative impact on simultaneous inference. In this article we illustrate the potential effects of latent variables on testing dependence and the resulting impact on multiple inference, we briefly review the method of surrogate variable analysis proposed by Leek and Storey (PNAS 2008; 105:18718-18723), and assess that method via simulations intended to mimic the complexity of feature dependence observed in real-world microarray data. The method is also assessed via application to a recent Merck microarray data set. Both simulation and case study results indicate that surrogate variable analysis can offer a viable strategy for tackling the multiple testing dependence problem when the features follow a potentially complex correlation structure, yielding improvements in the variability of false positive rates and increases in power.     

Kinship capital: young mothers,kinship networks and support in urban South Africa

ABSTRACT

In this paper, I explore kinship and other networks of support for young mothers and their babies after an unintended, ex-nuptial pregnancy in a resource-poor urban setting. I draw on in-depth interviews conducted with 30 young mothers aged 18 to 20 years old and follow up interviews conducted with 9 of them. The interviews focused on three main areas: pregnancy and birth, education and income generation, and support networks. I present three cases that reflect variability in support and kinship network patterns. I use genograms and kinship network maps to identify sources of support and kinship networks within and outside households. Paying attention to the location and distribution of networks, I engage with the role of kinship capital and other forms of support in mitigating some of the negative consequences of early, unplanned motherhood. I show how young mothers draw on support from kinship networks which in turn adapt and reconfigure to provide support, allowing young mothers to exercise agency in relation to aspirations around educational attainment and income generation.     

Happiness,wellbeing and ecosocialism – a radical humanist perspective

ABSTRACT

The GDP growth paradigm has come under increased scrutiny in recent years, with the rising threats of global social inequality, poverty, and environmental degradation. New thinking around ecosocialism, degrowth, happiness and the wellbeing economy insist on keeping alive the utopian imagination. It seeks to break through the constraints of traditional state-or-market development debates, by searching for ways to subordinate both the state and market to society, in harmony with non-human nature. Pioneering work on alternative development indicators has been done in recent times, the most notable being the Gross National Happiness Index, currently in practice within the small Buddhist mountain state of Bhutan. The happiness/wellbeing perspectives do not have an explicit critique of capitalism, and avoid any mention of ‘socialism’ or ‘ecosocialism'. Is there a Chinese Wall between the Buddha and Marx – or can these perspectives be harmonized, as part of building a broader counter-hegemonic movement?     

Calculation of Phase 2 dose-finding study sample size for reliable Phase 3 dose selection

Sample sizes of Phase 2 dose-finding studies, usually determined based on a power requirement to detect a significant dose–response relationship, will generally not provide adequate precision for Phase 3 target dose selection. We propose to calculate the sample size of a dose-finding study based on the probability of successfully identifying the target dose within an acceptable range (e.g., 80%–120% of the target) using the multiple comparison and modeling procedure (MCP-Mod). With the proposed approach, different design options for the Phase 2 dose-finding study can also be compared. Due to inherent uncertainty around an assumed true dose–response relationship, sensitivity analyses to assess the robustness of the sample size calculations to deviations from modeling assumptions are recommended. Planning for a hypothetical Phase 2 dose-finding study is used to illustrate the main points. Codes for the proposed approach is available at https://github.com/happysundae/posMCPMod .     

Home range and habitat use of feral cats in an urban mosaic in Pietermaritzburg,KwaZulu-Natal,South Africa

Feral cats (Felis catus) are one of the world’s worst invasive species with continuing expanding populations, particularly in urban areas. Effects of anthropogenic changing land-use, especially urbanisation, can alter distribution and behaviour of feral cats. Additionally, resource availability can influence home range and habitat use. Therefore, we investigated home range and habitat use of feral cats (n?=?11) in an urban mosaic with varying degrees of urbanisation and green spaces in Pietermaritzburg, KwaZulu-Natal, South Africa. Using global positioning cellular trackers, individual feral cats were followed for a minimum of six months. Minimum convex polygons (MCP) and kernel density estimates (KDE) were used to determine their home range, core area size, and habitat use. Mean home range (± SE) for feral cats was relatively small (95% MCP 6.2?±?4.52 ha) with no significant difference between male and female home ranges, nor core areas. There was individual variation in home ranges despite supplemental feeding in the urban mosaic. Generally supplemental resources were the primary driver of feral cat home ranges where these feeding sites were within the core areas of individuals. However, the ecological consequences of feeding feral cats can increase their survival, and reduce their home ranges and movement as found in other studies.     

The Challenge of Partnerships Between the State,Capital, and Civil Society: The Case of the Media Development and Diversity Agency in South Africa

VOLUNTAS: International Journal of Voluntary and Nonprofit Organizations - Inspired by “extra-market” initiatives to ensure media diversity in social-demo- cratic Northern Europe, the...     

Anxious urbanity: xenophobia,the native subject and the refugee camp

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