Biometrical Journal最新文献

Borrowing analyses are increasingly important in clinical trials. We develop a method for using robust mixture priors in multivariate dynamic borrowing. The method was motivated by a desire to produce causally valid, long-term treatment effect estimates of a continuous endpoint from a single active-arm open-label extension study following a randomized clinical trial by dynamically incorporating prior beliefs from a long-term external control arm. The proposed method is a generally applicable Bayesian dynamic borrowing analysis for estimates of multivariate summary metrics based on a multivariate normal likelihood function for various parameter models, some of which we describe. There are important connections to estimation incorporating a prior belief for a hypothetical estimand strategy, that is, had the event not occurred, for intercurrent events which lead to missing data.

Decreasing costs and new technologies have led to an increase in the amount of data available to plant breeding programs. High-throughput phenotyping (HTP) platforms routinely generate high-dimensional datasets of secondary features that may be used to improve genomic prediction accuracy. However, integration of these data comes with challenges such as multicollinearity, parameter estimation in $��p�>�n�$ settings, and the computational complexity of many standard approaches. Several methods have emerged to analyze such data, but interpretation of model parameters often remains challenging. We propose genetic latent factor best linear unbiased prediction (glfBLUP), a prediction pipeline that reduces the dimensionality of the original secondary HTP data using generative factor analysis. In short, glfBLUP uses redundancy filtered and regularized genetic and residual correlation matrices to fit a maximum likelihood factor model and estimate genetic latent factor scores. These latent factors are subsequently used in multitrait genomic prediction. Our approach performs better than alternatives in extensive simulations and a real-world application, while producing easily interpretable and biologically relevant parameters. We discuss several possible extensions and highlight glfBLUP as the basis for a flexible and modular multitrait genomic prediction framework.

In contemporary research, online error control is often required, where an error criterion, such as familywise error rate (FWER) or false discovery rate (FDR), shall remain under control while testing an a priori unbounded sequence of hypotheses. The existing online literature mainly considered large-scale studies and constructed powerful but rigid algorithms for these. However, smaller studies, such as platform trials, require high flexibility and easy interpretability to take study objectives into account and facilitate the communication. Another challenge in platform trials is that due to the shared control arm some of the $�p$-values are dependent and significance levels need to be prespecified before the decisions for all the past treatments are available. We propose adaptive-discarding-Graphs (ADDIS-Graphs) with FWER control that due to their graphical structure perfectly adapt to such settings and provably uniformly improve the state-of-the-art method. We introduce several extensions of these ADDIS-Graphs, including the incorporation of information about the joint distribution of the $�p$-values and a version for FDR control.

Phase I dose escalation trials in oncology generally aim to find the maximum tolerated dose. However, with the advent of molecular-targeted therapies and antibody drug conjugates, dose-limiting toxicities are less frequently observed, giving rise to the concept of optimal biological dose (OBD), which considers both efficacy and toxicity. The estimand framework presented in the addendum of the ICH E9(R1) guidelines strengthens the dialogue between different stakeholders by bringing in greater clarity in the clinical trial objectives and by providing alignment between the targeted estimand under consideration and the statistical analysis methods. However, there is a lack of clarity in implementing this framework in early-phase dose optimization studies. This paper aims to discuss the estimand framework for dose optimization trials in oncology, considering efficacy and toxicity through utility functions. Such trials should include pharmacokinetics data, toxicity data, and efficacy data. Based on these data, the analysis methods used to identify the optimized dose/s are also described. Focusing on optimizing the utility function to estimate the OBD, the population-level summary measure should reflect only the properties used for estimating this utility function. A detailed strategy recommendation for intercurrent events has been provided using a real-life oncology case study. Key recommendations regarding the estimand attributes include that in a seamless phase I/II dose optimization trial, the treatment attribute should start when the subject receives the first dose. We argue that such a framework brings in additional clarity to dose optimization trial objectives and strengthens the understanding of the drug under consideration, which would enable the correct dose to move to phase II of clinical development.