On optimal designs for clinical trials: An updated review

Optimization of clinical trial designs can help investigators achieve higher qualityresults for the given resource constraints. The present paper gives an overviewof optimal designs for various important problems that arise in different stages ofclinical drug development, including phase I dose–toxicity studies; phase I/II studiesthat consider early efficacy and toxicity outcomes simultaneously; phase IIdose–response studies driven by multiple comparisons (MCP), modeling techniques(Mod), or their combination (MCP–Mod); phase III randomized controlled multiarmmulti-objective clinical trials to test difference among several treatment groups;and population pharmacokinetics–pharmacodynamics experiments. We find thatmodern literature is very rich with optimal design methodologies that can be utilizedby clinical researchers to improve efficiency of drug development

Modeling Dependence with C- and D-Vine Copulas: The R Package CDVine

Flexible multivariate distributions are needed in many areas. The popular multivariate Gaussian distribution is however very restrictive and cannot account for features like asymmetry and heavy tails. Therefore dependence modeling using copulas is nowadays very common to account for such patterns. The use of copulas is however challenging in higher dimensions, where standard multivariate copulas suffer from rather inflexible structures. Vine copulas overcome such limitations and are able to model complex dependency patterns by benefiting from the rich variety of bivariate copulas as building blocks. This article presents the R package CDVine which provides functions and tools for statistical inference of canonical vine (C-vine) and D-vine copulas. It contains tools for bivariate exploratory data analysis and for bivariate copula selection as well as for selection of pair-copula families in a vine. Models can be estimated either sequentially or by joint maximum likelihood estimation. Sampling algorithms and graphical methods are also included

Copula models for epidemiological research and practice

Investigating associations between random variables (rvs) is one of many topics in the heart of statistical science. Graphical displays show emerging patterns between rvs, and the strength of their association is conventionally quantified via correlation coefficients. When two or more of these rvs are thought of as outcomes, their association is governed by a joint probability distribution function (pdf). When the joint pdf is bivariate normal, scalar correlation coefficients will produce a satisfactory summary of the association, otherwise alternative measures are needed. Local dependence functions, together with their corresponding graphical displays, quantify and show how the strength of the association varies across the span of the data. Additionally, the multivariate distribution function can be explicitly formulated and explored. Copulas model joint distributions of varying shapes by combining the separate (univariate) marginal cumulative distribution functions of each rv under a specified correlation structure. Copula models can be used to analyse complex relationships and incorporate covariates into their parameters. Therefore, they offer increased flexibility in modelling dependence between rvs. Copula models may also be used to construct bivariate analogues of centiles, an application for which few references are available in the literature though it is of particular interest for many paediatric applications. Population centiles are widely used to highlight children or adults who have unusual univariate outcomes. Whilst the methodology for the construction of univariate centiles is well established there has been very little work in the area of bivariate analogues of centiles where two outcomes are jointly considered. Conditional models can increase the efficiency of centile analogues in detection of individuals who require some form of intervention. Such adjustments can be readily incorporated into the modelling of the marginal distributions and of the dependence parameter within the copula model