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.     

The Nature of the Political Reconsidered

I present an immanent, and explanatory, critique of reflections on the nature of politics and of power within political science. I argue that these reflections are problematic, to the extent that they presuppose an actualist conception of the political, and that this is generated by an empiricist way of thinking on the one hand and a constructivist way of thinking on the other. I show how re‐defining politics, power, and the political on the basis of a dialectical critical realist ontology resolves these problems and, thereby, allows us to understand the conditions for social change and the relationship between the political and the economic. My argument has two, important implications: first, that the proposal that those who study politics professionally should celebrate philosophical diversity is dangerous–at least if it makes it difficult to sustain a distinct, emancipatory form of political inquiry; and, second, that the nature of social reality justifies the need both for specialized forms of inquiry, such as politics and economics, and integrative forms of inquiry, such as political economy.     

A variable-neighbourhood search algorithm for finding optimal run orders in the presence of serial correlation

The responses obtained from response surface designs that are run sequentially often exhibit serial correlation or time trends. The order in which the runs of the design are performed then has an impact on the precision of the parameter estimators. This article proposes the use of a variable-neighbourhood search algorithm to compute run orders that guarantee a precise estimation of the effects of the experimental factors. The importance of using good run orders is demonstrated by seeking D-optimal run orders for a central composite design in the presence of an AR(1) autocorrelation pattern.     

Deconvolution methods for non-parametric inference in two-level mixed models

Summary.  We develop a general non-parametric approach to the analysis of clustered data via random effects. Assuming only that the link function is known, the regression functions and the distributions of both cluster means and observation errors are treated non-parametrically. Our argument proceeds by viewing the observation error at the cluster mean level as though it were a measurement error in an errors-in-variables problem, and using a deconvolution argument to access the distribution of the cluster mean. A Fourier deconvolution approach could be used if the distribution of the error-in-variables were known. In practice it is unknown, of course, but it can be estimated from repeated measurements, and in this way deconvolution can be achieved in an approximate sense. This argument might be interpreted as implying that large numbers of replicates are necessary for each cluster mean distribution, but that is not so; we avoid this requirement by incorporating statistical smoothing over values of nearby explanatory variables. Empirical rules are developed for the choice of smoothing parameter. Numerical simulations, and an application to real data, demonstrate small sample performance for this package of methodology. We also develop theory establishing statistical consistency.     

ESTIMATING A PARAMETER WHEN IT IS KNOWN THAT THE PARAMETER EXCEEDS A GIVEN VALUE

In some statistical problems a degree of explicit, prior information is available about the value taken by the parameter of interest, θ say, although the information is much less than would be needed to place a prior density on the parameter's distribution. Often the prior information takes the form of a simple bound, ‘θ > θ₁ ’ or ‘θ < θ₁ ’, where θ₁ is determined by physical considerations or mathematical theory, such as positivity of a variance. A conventional approach to accommodating the requirement that θ > θ₁ is to replace an estimator, , of θ by the maximum of and θ₁. However, this technique is generally inadequate. For one thing, it does not respect the strictness of the inequality θ > θ₁ , which can be critical in interpreting results. For another, it produces an estimator that does not respond in a natural way to perturbations of the data. In this paper we suggest an alternative approach, in which bootstrap aggregation, or bagging, is used to overcome these difficulties. Bagging gives estimators that, when subjected to the constraint θ > θ₁ , strictly exceed θ₁ except in extreme settings in which the empirical evidence strongly contradicts the constraint. Bagging also reduces estimator variability in the important case for which is close to θ₁, and more generally produces estimators that respect the constraint in a smooth, realistic fashion.     

Agreement and discrepancy between children,parents, and social workers on school‐based effort avoidance in child welfare services

A multiperspective approach is beneficial for obtaining reliable and multifaceted pictures of child behaviour problems. The goal of the present study is to examine interrater agreement on school‐based effort avoidance between children receiving child welfare services, parents, and social workers. Given previous findings, interrater agreement is expected to be low. Self‐reported data on school‐based effort avoidance were gathered for children and adolescents in child welfare services. Additionally, social workers (using the Teacher‐Report Checklist for social and learning behaviour) and parents (using the parallel version of the self‐rating questionnaire on school‐based effort avoidance) were asked to complete an external assessment tool to compare children's perspectives with the ratings of significant adults. The results confirmed significant discrepancies between parents' and children's ratings on effort avoidance tendencies. Furthermore, there were only small to moderate correlations between children's self‐ratings and the adults' assessments; however, the consensus between adults was higher than the interrater agreement between children and social workers. Discrepancies in ratings from multiple informants underline the importance of integrating multiple perspectives, especially children's perspectives, in the diagnostic process in order to plan and adapt appropriate care and treatment.