Search

This paper proposes a Workflow for Assessing Treatment effeCt Heterogeneity (WATCH) in clinical drug development targeted at clinical trial sponsors. The workflow is designed to address the challenges of investigating treatment effect heterogeneity (TEH) in randomized clinical trials, where sample size and multiplicity limit the reliability of findings. The proposed workflow includes four steps: Analysis Planning, Initial Data Analysis and Analysis Dataset Creation, TEH Exploration, and Multidisciplinary Assessment. The workflow aims to provide a systematic approach to explore treatment effect heterogeneity in the exploratory setting, taking into account external evidence and best scientific understanding.

TorchSurv is a Python package that serves as a companion tool to perform deep survival modeling within the PyTorch environment. Unlike existing libraries that impose specific parametric forms, TorchSurv enables the use of custom PyTorch-based deep survival models. With its lightweight design, minimal input requirements, full PyTorch backend, and freedom from restrictive survival model parameterizations, TorchSurv facilitates efficient deep survival model implementation and is particularly beneficial for high-dimensional and complex input data scenarios., Comment: https://opensource.nibr.com/torchsurv/

We present the motivation, experience and learnings from a data challenge conducted at a large pharmaceutical corporation on the topic of subgroup identification. The data challenge aimed at exploring approaches to subgroup identification for future clinical trials. To mimic a realistic setting, participants had access to 4 Phase III clinical trials to derive a subgroup and predict its treatment effect on a future study not accessible to challenge participants. 30 teams registered for the challenge with around 100 participants, primarily from Biostatistics organisation. We outline the motivation for running the challenge, the challenge rules and logistics. Finally, we present the results of the challenge, the participant feedback as well as the learnings, and how these learnings can be translated into statistical practice.

In Oncology, trials evaluating drug combinations are becoming more common. While combination therapies bring the potential for greater efficacy, they also create unique challenges for ensuring drug safety. In Phase-I dose escalation trials of drug combinations, model-based approaches enable efficient use of information gathered, but the models need to account for trial complexities: appropriate modeling of interactions becomes increasingly important with growing numbers of drugs being tested simultaneously in a given trial. In principle, we can use data from multiple arms testing varying combinations to jointly estimate toxicity of the drug combinations. However, such efforts have highlighted limitations when modelling drug-drug interactions in the Bayesian Logistic Regression Model (BLRM) framework used to ensure patient safety. Previous models either do not account for non-monotonicity due to antagonistic toxicity, or exhibit the fundamental flaw of exponentially overpowering the contributions of the individual drugs in the dose-response. This specifically leads to issues when drug combinations exhibit antagonistic toxicity, in which case the toxicity probability gets vanishingly small as doses get very large. We put forward additional constraints inspired by Paracelsus' intuition of "the dose makes the poison" which avoid this flaw and present an improved interaction model which is compatible with these constraints. We create instructive data scenarios that showcase the improved behavior of this more constrained drug-drug interaction model in terms of preventing further dosing at overly toxic dose combinations and more sensible dose-finding under antagonistic drug toxicity. This model is now available in the open-source OncoBayes2 R package that implements the BLRM framework for an arbitrary number of drugs and trial arms., Comment: 14 pages, 3 figures

Sharing data from clinical studies can facilitate innovative data-driven research and ultimately lead to better public health. However, sharing biomedical data can put sensitive personal information at risk. This is usually solved by anonymization, which is a slow and expensive process. An alternative to anonymization is sharing a synthetic dataset that bears a behaviour similar to the real data but preserves privacy. As part of the collaboration between Novartis and the Oxford Big Data Institute, we generate a synthetic dataset based on COSENTYX (secukinumab) Ankylosing Spondylitis clinical study. We apply an Auxiliary Classifier GAN to generate synthetic MRIs of vertebral units. The images are conditioned on the VU location (cervical, thoracic and lumbar). In this paper, we present a method for generating a synthetic dataset and conduct an in-depth analysis on its properties along three key metrics: image fidelity, sample diversity and dataset privacy., Comment: v2

Knockoffs provide a general framework for controlling the false discovery rate when performing variable selection. Much of the Knockoffs literature focuses on theoretical challenges and we recognize a need for bringing some of the current ideas into practice. In this paper we propose a sequential algorithm for generating knockoffs when underlying data consists of both continuous and categorical (factor) variables. Further, we present a heuristic multiple knockoffs approach that offers a practical assessment of how robust the knockoff selection process is for a given data set. We conduct extensive simulations to validate performance of the proposed methodology. Finally, we demonstrate the utility of the methods on a large clinical data pool of more than $2,000$ patients with psoriatic arthritis evaluated in 4 clinical trials with an IL-17A inhibitor, secukinumab (Cosentyx), where we determine prognostic factors of a well established clinical outcome. The analyses presented in this paper could provide a wide range of applications to commonly encountered data sets in medical practice and other fields where variable selection is of particular interest., Comment: 24 pages, 6 figures

Evidence synthesis models that combine multiple datasets of varying design, to estimate quantities that cannot be directly observed, require the formulation of complex probabilistic models that can be expressed as graphical models. An assessment of whether the different datasets synthesised contribute information that is consistent with each other, and in a Bayesian context, with the prior distribution, is a crucial component of the model criticism process. However, a systematic assessment of conflict suffers from the multiple testing problem, through testing for conflict at multiple locations in a model. We demonstrate the systematic use of conflict diagnostics, while accounting for the multiple hypothesis tests of no conflict at each location in the graphical model. The method is illustrated by a network meta-analysis to estimate treatment effects in smoking cessation programs and an evidence synthesis to estimate HIV prevalence in Poland.

Complex stochastic models represented by directed acyclic graphs (DAGs) are increasingly employed to synthesise multiple, imperfect and disparate sources of evidence, to estimate quantities that are difficult to measure directly. The various data sources are dependent on shared parameters and hence have the potential to conflict with each other, as well as with the model. In a Bayesian framework, the model consists of three components: the prior distribution, the assumed form of the likelihood and structural assumptions. Any of these components may be incompatible with the observed data. The detection and quantification of such conflict and of data sources that are inconsistent with each other is therefore a crucial component of the model criticism process. We first review Bayesian model criticism, with a focus on conflict detection, before describing a general diagnostic for detecting and quantifying conflict between the evidence in different partitions of a DAG. The diagnostic is a p-value based on splitting the information contributing to inference about a "separator" node or group of nodes into two independent groups and testing whether the two groups result in the same inference about the separator node(s). We illustrate the method with three comprehensive examples: an evidence synthesis to estimate HIV prevalence; an evidence synthesis to estimate influenza case-severity; and a hierarchical growth model for rat weights., Comment: Published in at http://dx.doi.org/10.1214/13-STS426 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org)