Adding new experimental arms to randomised clinical trials: Impact on error rates

Background: Experimental treatments pass through various stages of development. If a treatment passes through early-phase experiments, the investigators may want to assess it in a late-phase randomised controlled trial. An efficient way to do this is adding it as a new research arm to an ongoing trial while the existing research arms continue, a so-called multi-arm platform trial. The familywise type I error rate is often a key quantity of interest in any multi-arm platform trial. We set out to clarify how it should be calculated when new arms are added to a trial some time after it has started. / Methods: We show how the familywise type I error rate, any-pair and all-pairs powers can be calculated when a new arm is added to a platform trial. We extend the Dunnett probability and derive analytical formulae for the correlation between the test statistics of the existing pairwise comparison and that of the newly added arm. We also verify our analytical derivation via simulations. / Results: Our results indicate that the familywise type I error rate depends on the shared control arm information (i.e. individuals in continuous and binary outcomes and primary outcome events in time-to-event outcomes) from the common control arm patients and the allocation ratio. The familywise type I error rate is driven more by the number of pairwise comparisons and the corresponding (pairwise) type I error rates than by the timing of the addition of the new arms. The familywise type I error rate can be estimated using Šidák’s correction if the correlation between the test statistics of pairwise comparisons is less than 0.30. / Conclusions: The findings we present in this article can be used to design trials with pre-planned deferred arms or to add new pairwise comparisons within an ongoing platform trial where control of the pairwise error rate or familywise type I error rate (for a subset of pairwise comparisons) is required

Models for Paired Comparison Data: A Review with Emphasis on Dependent Data

Thurstonian and Bradley-Terry models are the most commonly applied models in the analysis of paired comparison data. Since their introduction, numerous developments have been proposed in different areas. This paper provides an updated overview of these extensions, including how to account for object- and subject-specific covariates and how to deal with ordinal paired comparison data. Special emphasis is given to models for dependent comparisons. Although these models are more realistic, their use is complicated by numerical difficulties. We therefore concentrate on implementation issues. In particular, a pairwise likelihood approach is explored for models for dependent paired comparison data, and a simulation study is carried out to compare the performance of maximum pairwise likelihood with other limited information estimation methods. The methodology is illustrated throughout using a real data set about university paired comparisons performed by students.Comment: Published in at http://dx.doi.org/10.1214/12-STS396 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Emergence of a stable cortical map for neuroprosthetic control.

Cortical control of neuroprosthetic devices is known to require neuronal adaptations. It remains unclear whether a stable cortical representation for prosthetic function can be stored and recalled in a manner that mimics our natural recall of motor skills. Especially in light of the mixed evidence for a stationary neuron-behavior relationship in cortical motor areas, understanding this relationship during long-term neuroprosthetic control can elucidate principles of neural plasticity as well as improve prosthetic function. Here, we paired stable recordings from ensembles of primary motor cortex neurons in macaque monkeys with a constant decoder that transforms neural activity to prosthetic movements. Proficient control was closely linked to the emergence of a surprisingly stable pattern of ensemble activity, indicating that the motor cortex can consolidate a neural representation for prosthetic control in the presence of a constant decoder. The importance of such a cortical map was evident in that small perturbations to either the size of the neural ensemble or to the decoder could reversibly disrupt function. Moreover, once a cortical map became consolidated, a second map could be learned and stored. Thus, long-term use of a neuroprosthetic device is associated with the formation of a cortical map for prosthetic function that is stable across time, readily recalled, resistant to interference, and resembles a putative memory engram

Disentangling the effects of geographic and ecological isolation on genetic differentiation

Populations can be genetically isolated both by geographic distance and by differences in their ecology or environment that decrease the rate of successful migration. Empirical studies often seek to investigate the relationship between genetic differentiation and some ecological variable(s) while accounting for geographic distance, but common approaches to this problem (such as the partial Mantel test) have a number of drawbacks. In this article, we present a Bayesian method that enables users to quantify the relative contributions of geographic distance and ecological distance to genetic differentiation between sampled populations or individuals. We model the allele frequencies in a set of populations at a set of unlinked loci as spatially correlated Gaussian processes, in which the covariance structure is a decreasing function of both geographic and ecological distance. Parameters of the model are estimated using a Markov chain Monte Carlo algorithm. We call this method Bayesian Estimation of Differentiation in Alleles by Spatial Structure and Local Ecology (BEDASSLE), and have implemented it in a user-friendly format in the statistical platform R. We demonstrate its utility with a simulation study and empirical applications to human and teosinte datasets