Biometrical Journal最新文献

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.

Accelerated failure time (AFT) models offer an attractive alternative to Cox proportional hazards models. AFT models are collapsible and, unlike hazard ratios in proportional hazards models, the acceleration factor—a key effect measure in AFT models—is collapsible, meaning its value remains unchanged when adjusting for additional covariates. In addition, AFT models provide an intuitive interpretation directly on the survival time scale. From the recent development of smooth parametric AFT models, we identify potential issues with their applications and note several desired extensions that have not yet been implemented. To enrich this tool and its application in clinical research, we improve the AFT models within a flexible parametric framework in several ways: we adopt monotone natural splines to constrain the log cumulative hazard to be a monotonic function across its support; allow for time-varying acceleration factors, possibly include cure and accommodating more than one time-varying effect; and implement both mixture and nonmixture cure models. We implement all of these extensions in the rstpm2 package, which is publicly available on CRAN. Simulations highlight a varying success in estimating cure fractions. However, in terms of covariate-effect estimation, flexible AFT models appear to be more robust than the Cox model even when there is a high proportion of cured individuals in the data, regardless of whether cure is reached within the observed data. We also apply some of our extensions of AFT models to real-world survival data.

Partially linear models are commonly used in observational studies of the causal effect of treatment and/or exposure when there are observed confounding variables. The models are robust and asymptotically distribution-free for testing the causal null hypothesis. In this research, we investigate methods for estimating the partially linear models with data missing at random in all the variables, including the response, the treatment, and the confounding variables. We develop a general estimation method for inference in partially linear models with nonmonotone missing at random data. It proposes using partially linear working models to improve the estimation efficiency of the standard complete case method. It can be shown that the new estimator is consistent, which does not depend on the correctness of the working models. In addition, we recommend bootstrap estimates for the asymptotic variances and semiparametric models for the missing data probabilities. It is computationally simple and can be directly implemented in standard software. Simulation studies are provided to examine its performance. A real data example with sparsely observed missingness patterns is used to illustrate the method.