Testing for bioequivalence of highly variable drugs from TR‐RT crossover designs with heterogeneous residual variances

Traditional bioavailability studies assess average bioequivalence (ABE) between the test (T) and reference (R) products under the crossover design with TR and RT sequences. With highly variable (HV) drugs whose intrasubject coefficient of variation in pharmacokinetic measures is 30% or greater, assertion of ABE becomes difficult due to the large sample sizes needed to achieve adequate power. In 2011, the FDA adopted a more relaxed, yet complex, ABE criterion and supplied a procedure to assess this criterion exclusively under TRR‐RTR‐RRT and TRTR‐RTRT designs. However, designs with more than 2 periods are not always feasible. This present work investigates how to evaluate HV drugs under TR‐RT designs. A mixed model with heterogeneous residual variances is used to fit data from TR‐RT designs. Under the assumption of zero subject‐by‐formulation interaction, this basic model is comparable to the FDA‐recommended model for TRR‐RTR‐RRT and TRTR‐RTRT designs, suggesting the conceptual plausibility of our approach. To overcome the distributional dependency among summary statistics of model parameters, we develop statistical tests via the generalized pivotal quantity (GPQ). A real‐world data example is given to illustrate the utility of the resulting procedures. Our simulation study identifies a GPQ‐based testing procedure that evaluates HV drugs under practical TR‐RT designs with desirable type I error rate and reasonable power. In comparison to the FDA's approach, this GPQ‐based procedure gives similar performance when the product's intersubject standard deviation is low (≤0.4) and is most useful when practical considerations restrict the crossover design to 2 periods.     

A simulation study of methods for selecting subgroup‐specific doses in phase 1 trials

Patient heterogeneity may complicate dose‐finding in phase 1 clinical trials if the dose‐toxicity curves differ between subgroups. Conducting separate trials within subgroups may lead to infeasibly small sample sizes in subgroups having low prevalence. Alternatively,it is not obvious how to conduct a single trial while accounting for heterogeneity. To address this problem,we consider a generalization of the continual reassessment method on the basis of a hierarchical Bayesian dose‐toxicity model that borrows strength between subgroups under the assumption that the subgroups are exchangeable. We evaluate a design using this model that includes subgroup‐specific dose selection and safety rules. A simulation study is presented that includes comparison of this method to 3 alternative approaches,on the basis of nonhierarchical models,that make different types of assumptions about within‐subgroup dose‐toxicity curves. The simulations show that the hierarchical model‐based method is recommended in settings where the dose‐toxicity curves are exchangeable between subgroups. We present practical guidelines for application and provide computer programs for trial simulation and conduct.     

Trajectory of problem behaviours of Korean adopted children: using piecewise hierarchical linear growth modelling

This study examined the trajectory of problem behaviours in domestically adopted children in South Korea as they aged. This study used the Panel Study on Korean Adopted Children's longitudinal, three‐wave data (2006, 2008 and 2010). Although data were collected at three time points, our data consisted of six time points, which covered the 5–10 years age range of the adopted children at the time of survey. One hundred sixty‐four children were included in the analysis, 75 of whom contributed to one time point, 74 to two time points and 15 to three time points. The trajectory of the problem behaviours of adopted children was examined using a piecewise hierarchical linear growth model. Because the initial exploration of the data suggested non‐linear changes in behaviour problems over time, we split the growth trajectory into two time periods: Time 1 (5–7 years) and Time 2 (7–10 years). A two‐rate model was used to estimate separate slopes for the two time periods. Results showed that the externalizing and internalizing problems of adopted children have different trajectories. Internalizing problems did not show significant changes after 5 years of age, while externalizing problems increased until 7 years of age and decreased significantly thereafter.     

Exploring how the social model of disability can be re-invigorated: in response to Mike Oliver

In his 2013 article in Disability & Society, Oliver recommended that the social model should either be replaced or re-invigorated. I argue here that the social model’s current emphasis reflects the social conditions in which it was introduced, and that the model’s impact on disabled people’s lives would increase if its emphasis was to more accurately reflect the current social conditions in the geographical regions in which it is applied. In order to help foster its re-invigoration, I ask five questions for discussion on the way forward for the social model. I identified my questions through examining published writing on the scope of the social model and on the model’s relationship with other models of disability.     

Developing a model of disability that focuses on the actions of disabled people

Disabled people, writers on disability and disability activists stress the importance of disabled people being included in all aspects of society. I argue that a major omission from this inclusiveness is that no current model of disability focuses on the impact of the actions of disabled people on disability. Disabled people are not passive bystanders, powerless to reduce the restrictions of disability. On the contrary, we are central to actively limiting its constraints. I develop a model of disability, called ‘active’, which focuses on the effects on disability of the individual and collective actions of disabled people. I describe published findings which indicate that engaging in self-help, using support groups and deploying assistive technology can all reduce the limitations of disability. Recent increases in the number of disability support groups and developments in assistive technology have substantially augmented the potential for disabled people to combat the effects of disability.     

Exploring how the social model of disability can be re-invigorated for autism: in response to Jonathan Levitt

Levitt argues that the social model of disability needs to be re-invigorated, potentially by adapting the tool for separate countries. The social model has been successfully applied for some disabled groups in the United Kingdom. However, the social model is not implemented for neurodivergent labels such as autism, through the negative language of autism, causing severe problems for autistic individuals’ daily lives. The social model can be re-invigorated for autism, removing social barriers by changing non-autistic people’s attitudes towards autism through ensuring positive language of autism, preventing the categorisation of autism and fully enacting The Autism Act 2009 and The Equality Act 2010.     

The relationship between the community participation of disabled youth and socioeconomic factors: mixed-methods approach in rural Sri Lanka

Mixed methods were applied to examine the association of community participation by disabled youth with socioeconomic factors in rural Sri Lanka. There was a significant association between community participation and socioeconomic factors in the quantitative survey (n = 116): participants living in socioeconomically disadvantaged conditions had lower levels of community participation than those living without these disadvantages. Consistent with the findings of the survey, previous educational experiences, household economic conditions, and perceived resource information were common themes in the qualitative study (n = 26). The dynamics of these factors, including marginalisation of disabled youth within the household, were also observed.     

Employee communication,job engagement,and organizational commitment: A study of members of the Millennial Generation

The purpose of this study was to explore the relationship between job engagement and two key components of employee-organization relationships (EOR). Findings from a survey of members of the Millennial Generation (N = 539) in the United States indicate that job engagement mediates the relationship between employee communication and organizational commitment. It is concluded that when employees are engaged in their work, their commitment to the organization is strengthened and the likelihood of them leaving the organization decreases. Furthermore, an argument is made in light of the study’s findings that engagement and commitment work in concert to strengthen EORs overall. To foster engagement, organizations should remove obstacles to internal information flow and provide ongoing feedback to employees about individual and organizational issues.     

Sociolinguistic interaction and identity construction: The view from game‐theoretic pragmatics

Understanding the dynamics that characterize interaction between conversational participants is a fundamental goal of most theories of socially conditioned language use and identity construction through language. In this paper, I outline a class of formal tools that, I suggest, can be helpful in making progress towards this goal. More precisely, this paper explores how Bayesian signalling game models can be used to formalize key aspects of current sociolinguistic theories, and, in doing so, contribute to our knowledge of how speakers use their linguistic resources to communicate information and carve out their place in the social world. The Bayesian framework has become increasingly popular for the analysis of pragmatic phenomena of many different types, and, more generally, these models have become a dominant paradigm for the explanation of non‐linguistic cognitive processes. As such, I argue that this approach has the potential to yield a formalized theory of personal and social identity construction and to situate the study of sociolinguistic interaction within a broader theory of rationalistic cognition.     

Youth studies,citizenship and transitions: towards a new research agenda

A key goal in youth studies is to gain holistic understandings of what it means to be young. However, a significant impediment to achieving this has been the tendency of youth studies to develop along siloed and stratified subfields. In keeping with the goal of creating more productive dialogue between subfields in youth studies, this paper examines the intersections between research in youth citizenship and youth transitions to consider the fresh insights and cross fertilisations that such an analysis may yield. This examination reveals a sense of dissatisfaction in both subfields with traditional normative and linear models of citizenship and transitions which rely on step-wise and sequential notions of time. In response, the paper advances a new research agenda which posits more temporally, spatially and relationally-sensitive understandings of youth citizenship and transition. Drawing on Ingold (2007. Lines: A brief history. London: Routledge), this agenda proposes the use of three alternative metaphors – genealogical, wayfaring and threads – which could hold the potential to unsettle the normativity and linearity of previous youth transitions and citizenship frameworks, and thus provide deeper insights into what it means to live and to be young citizens in times of transition.