Response-adaptive dose-finding under model uncertainty
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Publication:641106
DOI10.1214/10-AOAS445zbMATH Open1223.62158arXiv1107.5883OpenAlexW2015987000MaRDI QIDQ641106FDOQ641106
Authors: Juan-Miguel Gracia 
Publication date: 21 October 2011
Published in: The Annals of Applied Statistics (Search for Journal in Brave)
Abstract: Dose-finding studies are frequently conducted to evaluate the effect of different doses or concentration levels of a compound on a response of interest. Applications include the investigation of a new medicinal drug, a herbicide or fertilizer, a molecular entity, an environmental toxin, or an industrial chemical. In pharmaceutical drug development, dose-finding studies are of critical importance because of regulatory requirements that marketed doses are safe and provide clinically relevant efficacy. Motivated by a dose-finding study in moderate persistent asthma, we propose response-adaptive designs addressing two major challenges in dose-finding studies: uncertainty about the dose-response models and large variability in parameter estimates. To allocate new cohorts of patients in an ongoing study, we use optimal designs that are robust under model uncertainty. In addition, we use a Bayesian shrinkage approach to stabilize the parameter estimates over the successive interim analyses used in the adaptations. This approach allows us to calculate updated parameter estimates and model probabilities that can then be used to calculate the optimal design for subsequent cohorts. The resulting designs are hence robust with respect to model misspecification and additionally can efficiently adapt to the information accrued in an ongoing study. We focus on adaptive designs for estimating the minimum effective dose, although alternative optimality criteria or mixtures thereof could be used, enabling the design to address multiple objectives.
Full work available at URL: https://arxiv.org/abs/1107.5883
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Bayesian inference (62F15) Applications of statistics to biology and medical sciences; meta analysis (62P10) Medical applications (general) (92C50)
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Cited In (18)
- A new approach towards minimizing the risk of misdosing warfarin initiation doses
- On optimal designs for clinical trials: an updated review
- Adaptive isotonic estimation of the minimum effective and peak doses in the presence of covariates
- Adaptive dose‐response studies to establish proof‐of‐concept in learning‐phase clinical trials
- Generalized multiple contrast tests in dose-response studies
- A Review of Modern Computational Algorithms for Bayesian Optimal Design
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- Statistical considerations in model-based dose finding for binary responses under model uncertainty
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- BMA‐Mod: A Bayesian model averaging strategy for determining dose‐response relationships in the presence of model uncertainty
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