Using Bayesian modeling in frequentist adaptive enrichment designs.
Ontology highlight
ABSTRACT:
SUBMITTER: Simon N
PROVIDER: S-EPMC6075009 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Based on a Bayesian decision theoretic approach, we optimize frequentist single- and adaptive two-stage trial designs for the development of targeted therapies, where in addition to an overall population, a pre-defined subgroup is investigated. In such settings, the losses and gains of decisions can be quantified by utility functions that account for the preferences of different stakeholders. In particular, we optimize expected utilities from the perspectives both of a commercial sponsor, maximizing the net present value, and also of the society, maximizing cost-adjusted expected health benefits of a new treatment for a specific population. We consider single-stage and adaptive two-stage designs with partial enrichment, where the proportion of patients recruited from the subgroup is a design parameter. For the adaptive designs, we use a dynamic programming approach to derive optimal adaptation rules. The proposed designs are compared to trials which are non-enriched (i.e. the proportion of patients in the subgroup corresponds to the prevalence in the underlying population). We show that partial enrichment designs can substantially improve the expected utilities. Furthermore, adaptive partial enrichment designs are more robust than single-stage designs and retain high expected utilities even if the expected utilities are evaluated under a different prior than the one used in the optimization. In addition, we find that trials optimized for the sponsor utility function have smaller sample sizes compared to trials optimized under the societal view and may include the overall population (with patients from the complement of the subgroup) even if there is substantial evidence that the therapy is only effective in the subgroup.
| S-EPMC6613177 | biostudies-literature
Project description:We consider the problem of designing experiments for estimating a target parameter in regression analysis when there is uncertainty about the parametric form of the regression function. A new optimality criterion is proposed that chooses the experimental design to minimize the asymptotic mean squared error of the frequentist model averaging estimate. Necessary conditions for the optimal solution of a locally and Bayesian optimal design problem are established. The results are illustrated in several examples, and it is demonstrated that Bayesian optimal designs can yield a reduction of the mean squared error of the model averaging estimator by up to 45%.
| S-EPMC6690170 | biostudies-literature
Project description:BackgroundBayesian adaptive designs can improve the efficiency of trials, and lead to trials that can produce high quality evidence more quickly, with fewer patients and lower costs than traditional methods. The aim of this work was to determine how Bayesian adaptive designs can be constructed for phase III clinical trials in critical care, and to assess the influence that Bayesian designs would have on trial efficiency and study results.MethodsWe re-designed the High Frequency OSCillation in Acute Respiratory distress syndrome (OSCAR) trial using Bayesian adaptive design methods, to allow for the possibility of early stopping for success or futility. We constructed several alternative designs and studied their operating characteristics via simulation. We then performed virtual re-executions by applying the Bayesian adaptive designs using the OSCAR data to demonstrate the practical applicability of the designs.ResultsWe constructed five alternative Bayesian adaptive designs and identified a preferred design based on the simulated operating characteristics, which had similar power to the original design but recruited fewer patients on average. The virtual re-executions showed the Bayesian sequential approach and original OSCAR trial yielded similar trial conclusions. However, using a Bayesian sequential design could have led to a reduced sample size and earlier completion of the trial.ConclusionsUsing the OSCAR trial as an example, this case study found that Bayesian adaptive designs can be constructed for phase III critical care trials. If the OSCAR trial had been run using one of the proposed Bayesian adaptive designs, it would have terminated at a smaller sample size with fewer deaths in the trial, whilst reaching the same conclusions. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials.Trial registrationOSCAR Trial registration ISRCTN, ISRCTN10416500 . Retrospectively registered 13 June 2007.
| S-EPMC6515675 | biostudies-literature
Project description:In order to have confidence in model-based phylogenetic methods, such as maximum likelihood (ML) and Bayesian analyses, one must use an appropriate model of molecular evolution identified using statistically rigorous criteria. Although model selection methods such as the likelihood ratio test and Akaike information criterion are widely used in the phylogenetic literature, model selection methods lack the ability to reject all models if they provide an inadequate fit to the data. There are two methods, however, that assess absolute model adequacy, the frequentist Goldman-Cox (GC) test and Bayesian posterior predictive simulations (PPSs), which are commonly used in conjunction with the multinomial log likelihood test statistic. In this study, we use empirical and simulated data to evaluate the adequacy of common substitution models using both frequentist and Bayesian methods and compare the results with those obtained with model selection methods. In addition, we investigate the relationship between model adequacy and performance in ML and Bayesian analyses in terms of topology, branch lengths, and bipartition support. We show that tests of model adequacy based on the multinomial likelihood often fail to reject simple substitution models, especially when the models incorporate among-site rate variation (ASRV), and normally fail to reject less complex models than those chosen by model selection methods. In addition, we find that PPSs often fail to reject simpler models than the GC test. Use of the simplest substitution models not rejected based on fit normally results in similar but divergent estimates of tree topology and branch lengths. In addition, use of the simplest adequate substitution models can affect estimates of bipartition support, although these differences are often small with the largest differences confined to poorly supported nodes. We also find that alternative assumptions about ASRV can affect tree topology, tree length, and bipartition support. Our results suggest that using the simplest substitution models not rejected based on fit may be a valid alternative to implementing more complex models identified by model selection methods. However, all common substitution models may fail to recover the correct topology and assign appropriate bipartition support if the true tree shape is difficult to estimate regardless of model adequacy.
| S-EPMC2981515 | biostudies-literature
Project description:Clinical trials in the era of precision cancer medicine aim to identify and validate biomarker signatures which can guide the assignment of individually optimal treatments to patients. In this article, we propose a group sequential randomized phase II design, which updates the biomarker signature as the trial goes on, utilizes enrichment strategies for patient selection, and uses Bayesian response-adaptive randomization for treatment assignment. To evaluate the performance of the new design, in addition to the commonly considered criteria of type I error and power, we propose four new criteria measuring the benefits and losses for individuals both inside and outside of the clinical trial. Compared with designs with equal randomization, the proposed design gives trial participants a better chance to receive their personalized optimal treatments and thus results in a higher response rate on the trial. This design increases the chance to discover a successful new drug by an adaptive enrichment strategy, i.e., identification and selective enrollment of a subset of patients who are sensitive to the experimental therapies. Simulation studies demonstrate these advantages of the proposed design. It is illustrated by an example based on an actual clinical trial in non-small-cell lung cancer.
| S-EPMC8132854 | biostudies-literature
Project description:Quantitative analysis of magnetic resonance imaging (MRI) scans of the brain requires accurate automated segmentation of anatomical structures. A desirable feature for such segmentation methods is to be robust against changes in acquisition platform and imaging protocol. In this paper we validate the performance of a segmentation algorithm designed to meet these requirements, building upon generative parametric models previously used in tissue classification. The method is tested on four different datasets acquired with different scanners, field strengths and pulse sequences, demonstrating comparable accuracy to state-of-the-art methods on T1-weighted scans while being one to two orders of magnitude faster. The proposed algorithm is also shown to be robust against small training datasets, and readily handles images with different MRI contrast as well as multi-contrast data.
| S-EPMC8117726 | biostudies-literature
Project description:We design two-stage confirmatory clinical trials that use adaptation to find the subgroup of patients who will benefit from a new treatment, testing for a treatment effect in each of two disjoint subgroups. Our proposal allows aspects of the trial, such as recruitment probabilities of each group, to be altered at an interim analysis. We use the conditional error rate approach to implement these adaptations with protection of overall error rates. Applying a Bayesian decision-theoretic framework, we optimize design parameters by maximizing a utility function that takes the population prevalence of the subgroups into account. We show results for traditional trials with familywise error rate control (using a closed testing procedure) as well as for umbrella trials in which only the per-comparison type 1 error rate is controlled. We present numerical examples to illustrate the optimization process and the effectiveness of the proposed designs.
| S-EPMC8251960 | biostudies-literature
Project description:BackgroundBayesian adaptive designs can be more efficient than traditional methods for multi-arm randomised controlled trials. The aim of this work was to demonstrate how Bayesian adaptive designs can be constructed for multi-arm phase III clinical trials and assess potential benefits that these designs offer.MethodsWe constructed several alternative Bayesian adaptive designs for the Collaborative Ankle Support Trial (CAST), which was a randomised controlled trial that compared four treatments for severe ankle sprain. These designs incorporated response adaptive randomisation (RAR), arm dropping, and early stopping for efficacy or futility. We studied the operating characteristics of the Bayesian designs via simulation. We then virtually re-executed the trial by implementing the Bayesian adaptive designs using patient data sampled from the CAST study to demonstrate the practical applicability of the designs.ResultsWe constructed five Bayesian adaptive designs, each of which had high power and recruited fewer patients on average than the original designs target sample size. The virtual executions showed that most of the Bayesian designs would have led to trials that declared superiority of one of the interventions over the control. Bayesian adaptive designs with RAR or arm dropping were more likely to allocate patients to better performing arms at each interim analysis. Similar estimates and conclusions were obtained from the Bayesian adaptive designs as from the original trial.ConclusionsUsing CAST as an example, this case study shows how Bayesian adaptive designs can be constructed for phase III multi-arm trials using clinically relevant decision criteria. These designs demonstrated that they can potentially generate earlier results and allocate more patients to better performing arms. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials.Trial registrationCAST study registration ISRCTN, ISRCTN37807450. Retrospectively registered on 25 April 2003.
| S-EPMC6961269 | biostudies-literature
Project description:Slow recruitment in clinical trials leads to increased costs and resource utilization, which includes both the clinic staff and patient volunteers. Careful planning and monitoring of the accrual process can prevent the unnecessary loss of these resources. We propose two hierarchical extensions to the existing Bayesian constant accrual model: the accelerated prior and the hedging prior. The new proposed priors are able to adaptively utilize the researcher's previous experience and current accrual data to produce the estimation of trial completion time. The performance of these models, including prediction precision, coverage probability, and correct decision-making ability, is evaluated using actual studies from our cancer center and simulation. The results showed that a constant accrual model with strongly informative priors is very accurate when accrual is on target or slightly off, producing smaller mean squared error, high percentage of coverage, and a high number of correct decisions as to whether or not continue the trial, but it is strongly biased when off target. Flat or weakly informative priors provide protection against an off target prior but are less efficient when the accrual is on target. The accelerated prior performs similar to a strong prior. The hedging prior performs much like the weak priors when the accrual is extremely off target but closer to the strong priors when the accrual is on target or only slightly off target. We suggest improvements in these models and propose new models for future research.
| S-EPMC4314351 | biostudies-literature
Project description:Streams and rivers are biodiverse and provide valuable ecosystem services. Maintaining these ecosystems is an important task, so organisations often monitor the status and trends in stream condition and biodiversity using field sampling and, more recently, autonomous in-situ sensors. However, data collection is often costly, so effective and efficient survey designs are crucial to maximise information while minimising costs. Geostatistics and optimal and adaptive design theory can be used to optimise the placement of sampling sites in freshwater studies and aquatic monitoring programs. Geostatistical modelling and experimental design on stream networks pose statistical challenges due to the branching structure of the network, flow connectivity and directionality, and differences in flow volume. Geostatistical models for stream network data and their unique features already exist. Some basic theory for experimental design in stream environments has also previously been described. However, open source software that makes these design methods available for aquatic scientists does not yet exist. To address this need, we present SSNdesign, an R package for solving optimal and adaptive design problems on stream networks that integrates with existing open-source software. We demonstrate the mathematical foundations of our approach, and illustrate the functionality of SSNdesign using two case studies involving real data from Queensland, Australia. In both case studies we demonstrate that the optimal or adaptive designs outperform random and spatially balanced survey designs implemented in existing open-source software packages. The SSNdesign package has the potential to boost the efficiency of freshwater monitoring efforts and provide much-needed information for freshwater conservation and management.
| S-EPMC7508409 | biostudies-literature