arXiv subjects

James M. S. Wason

Publications and source records attributed to James M. S. Wason.

At least 19 recordsLinked to original sources

arXiv2026

Optimal Biological Dose Combination Finding: A Design Roadmap and Robust Cross-Indication Bayesian Borrowing

Early-phase combination oncology trials increasingly seek the optimal biological dose combination (OBDC) rather than a maximum tolerated dose combination, in line with the FDA's Project Optimus initiative. Existing Bayesian OBDC designs span rule-based, model-assisted, and model-based paradigms, but no unified framework exists for choosing among them, and none supports borrowing information across indications sharing a combination regimen. We propose a corrected three-by-two taxonomy of OBDC designs by mechanism and objective, a rule-based design (Ji3+3-Comb) closing a documented gap in transparent, model-free combination dose-finding, and a Bayesian Hierarchical Utility-based Cross-indication (BHUC) design that borrows information across indications via a robust mixture prior while discounting non-exchangeable information. We derive the shared utility function as the Bayes-optimal decision under a linear clinical loss, and prove that BHUC's mixture-prior posterior weight automatically vanishes as two indications' true rates become discordant, formalizing its robustness to non-exchangeable borrowing, and complement this asymptotic guarantee with an exact, sample-size-free ceiling on borrowed influence that holds even before any own-indication data accrue. A roadmap links trial features to design choice, and a 5000-replication simulation study, sensitivity analyses, and a case study built from a published phase Ib trial show that model-assisted designs offer the most robust safety-efficacy trade-off, while BHUC improves correct selection over independent per-indication designs even under discordance. We conclude with concrete, protocol-actionable recommendations for pharmaceutical and trial biostatisticians, and directions for future methodological and computational development.

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arXiv2026

Comparing Bayesian Dynamic Borrowing and Synthetic Control Methods: Apples to Oranges?

Bayesian dynamic borrowing (BDB) and synthetic control methods (SCM) are strategies to incorporate historical data in clinical trial design when control recruitment is a challenge. While both methods aim to improve efficiency, they differ in conceptual approach: BDB adjusts borrowing based on prior-data conflict, whereas SCM synthesizes individual-level control outcomes. This study aims to conduct a comparison BDB (using meta-analytic predictive prior (MAP)) and SCM using a case study of Pediatric Atopic Dermatitis. Six historical randomised control trials were selected for use in both the creation of the MAP prior and synthetic control arm. BDB MAP prior produced a mean response rate (historical control response probability) of 0.22 (posterior 95% credible interval: 0.11-0.36) (0.22 and 0.11-0.37 robustified), a power of 0.58, a type 1 error rate of 0.03, bias of 0.0007 (0.0008 robustified), a coverage of 0.96 (0.94 robustified) and prior ESS of 8.9 (3.32 robustified). SCM produced a mean response rate of 0.26 (95% confidence interval: 0.17-0.36), a power of 0.75, type 1 error rate of 0.013, bias of -0.0002, and coverage of 0.97; when adjusted to match the BDB ESS, SCM reported a similar mean response rate (0.27 and 0.13-0.46). a lower power (0.54), type 1 error rate (0.002) and bias(-0.0006), and the same coverage rate (0.97) to the initial SCM results. For this case study, the sample size adjusted SCM model produced a relatively similar power and type 1 error rate to the BDB MAP prior method. However, direct comparisons between these two methods fail to capture the true relationship due to how the data is handled differently and the purpose of each method. Method selection should consider trial-specific constraints, prior-data heterogeneity, and the desired balance between efficiency and robustness.

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arXiv2026

Evaluating Efficiency of Platform Trials Under Delayed Outcomes Using Treatment Throughput

Background: Platform trials improve efficiency by enabling early stopping of ineffective arms, shared controls, and addition of new treatments without compromising statistical properties. However, delays in observing primary outcomes may reduce these benefits. Investigators must either pause recruitment, delaying identification of effective treatments, or continue recruitment, potentially enrolling participants who cannot benefit from interim decisions. We assess the impact of outcome delay on platform trial efficiency using a novel metric. Methods: We propose Expected Throughput (ET), defined as the expected number of treatment arms evaluated per 1000 participants. ET accounts for participants recruited while awaiting outcomes. We consider a multi-stage sequential design for each treatment arm and assess ET across different outcome delays, assuming uniform patient accrual. Results: Outcome delays substantially reduce platform trial efficiency, with the impact dependent on recruitment rate and delay length. At a recruitment rate of 10 patients per month, severe losses occur when delays exceed 12 months. When outcome delay exceeds two-thirds of the time required to recruit a single arm, substantially fewer treatment arms are evaluated than anticipated. Conclusion: Outcome delay can markedly reduce platform trial efficiency. Recruitment rates and expected outcome delays should therefore be considered during trial planning.

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arXiv2025

Comparing Methods of Expert Elicitation for Treatment Effect or Borrowing Parameters in Standard and Rare Disease Clinical Trials: A Systematic Mapping Study

Expert elicitation is an invaluable tool for gaining insights into the degree of clinical knowledge surrounding parameters of interest when designing, or supplementing trial data when analysing, a clinical trial. Elicitation is considered particularly useful in cases where limited data are available, such as in rare diseases. This study aims to identify methods of expert elicitation and aggregation for treatment effect or borrowing parameters that are used in the design or analysis stages of clinical trials. A comprehensive review of statistical and non-statistical literature was conducted by database searching, and reference list screening of older, relevant literature reviews. The search took place in October 2024 and identified 366 potentially relevant publications. Of these, 126 were selected for full-text review based on review of titles and abstracts, and 41 publications were deemed eligible for inclusion after a full reading. For each included publication, data were extracted on methods of elicitation and aggregation, the types of parameters elicited, the resulting distributions, the number of experts used, and any training provided to experts. Publication characteristics such as contribution type, journal type, and application to the rare disease setting was also noted. A narrative description of the selected publications was produced, detailing 6 unique methods for expert elicitation and 10 unique methods for aggregation. We discuss the most popular methods used across standard and rare disease clinical trials, along with any strengths and limitations. Overall, there is no formal framework for expert elicitation in clinical trials, and more general methods are applied with little consideration into the specific context and trial designs. This review identifies the methodological gaps in current practice, providing a foundation for future development.

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arXiv2025

Evaluating the impact of outcome delay on the efficiency of two-arm group-sequential trials

Adaptive designs(AD) are a broad class of trial designs that allow preplanned modifications based on patient data providing improved efficiency and flexibility. However, a delay in observing the primary outcome variable can harm this added efficiency. In this paper, we aim to ascertain the size of such outcome delay that results in the realised efficiency gains of ADs becoming negligible compared to classical fixed sample RCTs. We measure the impact of delay by developing formulae for the no. of overruns in 2 arm GSDs with normal data, assuming different recruitment models. The efficiency of a GSD is usually measured in terms of the expected sample size (ESS), with GSDs generally reducing the ESS compared to a standard RCT. Our formulae measures the efficiency gain from a GSD in terms of ESS reduction that is lost due to delay. We assess whether careful choice of design (e.g., altering the spacing of the IAs) can help recover the benefits of GSDs in presence of delay. We also analyse the efficiency of GSDs with respect to time to complete the trial. Comparing the expected efficiency gains, with and without consideration of delay, it is evident GSDs suffer considerable losses due to delay. Even a small delay can have a significant impact on the trial's efficiency. In contrast, even in the presence of substantial delay, a GSD will have a smaller expected time to trial completion in comparison to a simple RCT. Greater efficiency is lost with increase in the no. of stages. The timing of IAs also can impact the efficiency of a GSDs with delay. Particularly, for unequally spaced IAs, conducting IAs too early in the trial can be harmful for the design with delay.

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arXiv2024

Bayesian sample size determination using robust commensurate priors with interpretable discrepancy weights

Randomized controlled clinical trials provide the gold standard for evidence generation in relation to the efficacy of a new treatment in medical research. Relevant information from previous studies may be desirable to incorporate in the design and analysis of a new trial, with the Bayesian paradigm providing a coherent framework to formally incorporate prior knowledge. Many established methods involve the use of a discounting factor, sometimes related to a measure of `similarity' between historical and the new trials. However, it is often the case that the sample size is highly nonlinear in those discounting factors. This hinders communication with subject-matter experts to elicit sensible values for borrowing strength at the trial design stage. Focusing on a commensurate predictive prior method that can incorporate historical data from multiple sources, we highlight a particular issue of nonmonotonicity and explain why this causes issues with interpretability of the discounting factors (hereafter referred to as `weights'). We propose a solution for this, from which an analytical sample size formula is derived. We then propose a linearization technique such that the sample size changes uniformly over the weights. Our approach leads to interpretable weights that represent the probability that historical data are (ir)relevant to the new trial, and could therefore facilitate easier elicitation of expert opinion on their values. Keywords: Bayesian sample size determination; Commensurate priors; Historical borrowing; Prior aggregation; Uniform shrinkage.

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arXiv2024

Optimal Bayesian stepped-wedge cluster randomised trial designs for binary outcome data

Under a generalised estimating equation analysis approach, approximate design theory is used to determine Bayesian D-optimal designs. For two examples, considering simple exchangeable and exponential decay correlation structures, we compare the efficiency of identified optimal designs to balanced stepped-wedge designs and corresponding stepped-wedge designs determined by optimising using a normal approximation approach. The dependence of the Bayesian D-optimal designs on the assumed correlation structure is explored; for the considered settings, smaller decay in the correlation between outcomes across time periods, along with larger values of the intra-cluster correlation, leads to designs closer to a balanced design being optimal. Unlike for normal data, it is shown that the optimal design need not be centro-symmetric in the binary outcome case. The efficiency of the Bayesian D-optimal design relative to a balanced design can be large, but situations are demonstrated in which the advantages are small. Similarly, the optimal design from a normal approximation approach is often not much less efficient than the Bayesian D-optimal design. Bayesian D-optimal designs can be readily identified for stepped-wedge cluster randomised trials with binary outcome data. In certain circumstances, principally ones with strong time period effects, they will indicate that a design unlikely to have been identified by previous methods may be substantially more efficient. However, they require a larger number of assumptions than existing optimal designs, and in many situations existing theory under a normal approximation will provide an easier means of identifying an efficient design for binary outcome data.

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arXiv2024

Developing a predictive signature for two trial endpoints using the cross-validated risk scores method

The existing cross-validated risk scores (CVRS) design has been proposed for developing and testing the efficacy of a treatment in a high-efficacy patient group (the sensitive group) using high-dimensional data (such as genetic data). The design is based on computing a risk score for each patient and dividing them into clusters using a non-parametric clustering procedure. In some settings it is desirable to consider the trade-off between two outcomes, such as efficacy and toxicity, or cost and effectiveness. With this motivation, we extend the CVRS design (CVRS2) to consider two outcomes. The design employs bivariate risk scores that are divided into clusters. We assess the properties of the CVRS2 using simulated data and illustrate its application on a randomised psychiatry trial. We show that CVRS2 is able to reliably identify the sensitive group (the group for which the new treatment provides benefit on both outcomes) in the simulated data. We apply the CVRS2 design to a psychology clinical trial that had offender status and substance use status as two outcomes and collected a large number of baseline covariates. The CVRS2 design yields a significant treatment effect for both outcomes, while the CVRS approach identified a significant effect for the offender status only after pre-filtering the covariates.

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arXiv2023

Online multiple hypothesis testing

Modern data analysis frequently involves large-scale hypothesis testing, which naturally gives rise to the problem of maintaining control of a suitable type I error rate, such as the false discovery rate (FDR). In many biomedical and technological applications, an additional complexity is that hypotheses are tested in an online manner, one-by-one over time. However, traditional procedures that control the FDR, such as the Benjamini-Hochberg procedure, assume that all p-values are available to be tested at a single time point. To address these challenges, a new field of methodology has developed over the past 15 years showing how to control error rates for online multiple hypothesis testing. In this framework, hypotheses arrive in a stream, and at each time point the analyst decides whether to reject the current hypothesis based both on the evidence against it, and on the previous rejection decisions. In this paper, we present a comprehensive exposition of the literature on online error rate control, with a review of key theory as well as a focus on applied examples. We also provide simulation results comparing different online testing algorithms and an up-to-date overview of the many methodological extensions that have been proposed.

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arXiv2022

Bayesian sample size determination in basket trials borrowing information between subsets

Basket trials are increasingly used for the simultaneous evaluation of a new treatment in various patient subgroups under one overarching protocol. We propose a Bayesian approach to sample size determination in basket trials that permit borrowing of information between commensurate subsets. Specifically, we consider a randomised basket trial design where patients are randomly assigned to the new treatment or a control within each trial subset (`subtrial' for short). Closed-form sample size formulae are derived to ensure each subtrial has a specified chance of correctly deciding whether the new treatment is superior to or not better than the control by some clinically relevant difference. Given pre-specified levels of pairwise (in)commensurability, the subtrial sample sizes are solved simultaneously. The proposed Bayesian approach resembles the frequentist formulation of the problem in yielding comparable sample sizes for circumstances of no borrowing. When borrowing is enabled between commensurate subtrials, a considerably smaller trial sample size is required compared to the widely implemented approach of no borrowing. We illustrate the use of our sample size formulae with two examples based on real basket trials. A comprehensive simulation study further shows that the proposed methodology can maintain the true positive and false positive rates at desired levels.

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arXiv2022

Online error control for platform trials

Platform trials evaluate multiple experimental treatments under a single master protocol, where new treatment arms are added to the trial over time. Given the multiple treatment comparisons, there is the potential for inflation of the overall type I error rate, which is complicated by the fact that the hypotheses are tested at different times and are not all necessarily pre-specified. Online error control methodology provides a possible solution to the problem of multiplicity for platform trials where a relatively large number of hypotheses are expected to be tested over time. In the online testing framework, hypotheses are tested in a sequential manner, where at each time-step an analyst decides whether to reject the current null hypothesis without knowledge of future tests but based solely on past decisions. Methodology has recently been developed for online control of the false discovery rate as well as the familywise error rate (FWER). In this paper, we describe how to apply online error control to the platform trial setting, present extensive simulation results, and give some recommendations for the use of this new methodology in practice. We show that the algorithms for online error rate control can have a substantially lower FWER than uncorrected testing, while still achieving noticeable gains in power when compared with the use of a Bonferroni procedure. We also illustrate how online error control would have impacted a currently ongoing platform trial.

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arXiv2021

Two-Stage Penalized Regression Screening to Detect Biomarker-Treatment Interactions in Randomized Clinical Trials

High-dimensional biomarkers such as genomics are increasingly being measured in randomized clinical trials. Consequently, there is a growing interest in developing methods that improve the power to detect biomarker-treatment interactions. We adapt recently proposed two-stage interaction detecting procedures in the setting of randomized clinical trials. We also propose a new stage 1 multivariate screening strategy using ridge regression to account for correlations among biomarkers. For this multivariate screening, we prove the asymptotic between-stage independence, required for family-wise error rate control, under biomarker-treatment independence. Simulation results show that in various scenarios, the ridge regression screening procedure can provide substantially greater power than the traditional one-biomarker-at-a-time screening procedure in highly correlated data. We also exemplify our approach in two real clinical trial data applications.

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arXiv2020

Bayesian sample size determination using commensurate priors to leverage pre-experimental data

This paper develops Bayesian sample size formulae for experiments comparing two groups. We assume the experimental data will be analysed in the Bayesian framework, where pre-experimental information from multiple sources can be represented into robust priors. In particular, such robust priors account for preliminary belief about the pairwise commensurability between parameters that underpin the historical and new experiments, to permit flexible borrowing of information. Averaged over the probability space of the new experimental data, appropriate sample sizes are found according to criteria that control certain aspects of the posterior distribution, such as the coverage probability or length of a defined density region. Our Bayesian methodology can be applied to circumstances where the common variance in the new experiment is known or unknown. Exact solutions are available based on most of the criteria considered for Bayesian sample size determination, while a search procedure is described in cases for which there are no closed-form expressions. We illustrate the application of our Bayesian sample size formulae in the setting of designing a clinical trial. Hypothetical data examples, motivated by a rare-disease trial with elicitation of expert prior opinion, and a comprehensive performance evaluation of the proposed methodology are presented.

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arXiv2020

Conditional Power and Friends: The Why and How of (Un)planned, Unblinded Sample Size Recalculations in Confirmatory Trials

Adapting the final sample size of a trial to the evidence accruing during the trial is a natural way to address planning uncertainty. Designs with adaptive sample size need to account for their optional stopping to guarantee strict type-I error-rate control. A variety of different methods to maintain type-I error-rate control after unplanned changes of the initial sample size have been proposed in the literature. This makes interim analyses for the purpose of sample size recalculation feasible in a regulatory context. Since the sample size is usually determined via an argument based on the power of the trial, an interim analysis raises the question of how the final sample size should be determined conditional on the accrued information. Conditional power is a concept often put forward in this context. Since it depends on the unknown effect size, we take a strict estimation perspective and compare assumed conditional power, observed conditional power, and predictive power with respect to their properties as estimators of the unknown conditional power. We then demonstrate that pre-planning an interim analysis using methodology for unplanned interim analyses is ineffective and naturally leads to the concept of optimal two-stage designs. We conclude that unplanned design adaptations should only be conducted as reaction to trial-external new evidence, operational needs to violate the originally chosen design, or post hoc changes in the objective criterion. Finally, we show that commonly discussed sample size recalculation rules can lead to paradoxical outcomes and propose two alternative ways of reacting to newly emerging trial-external evidence.

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arXiv2020

A review of Bayesian perspectives on sample size derivation for confirmatory trials

Sample size derivation is a crucial element of the planning phase of any confirmatory trial. A sample size is typically derived based on constraints on the maximal acceptable type I error rate and a minimal desired power. Here, power depends on the unknown true effect size. In practice, power is typically calculated either for the smallest relevant effect size or a likely point alternative. The former might be problematic if the minimal relevant effect is close to the null, thus requiring an excessively large sample size. The latter is dubious since it does not account for the a priori uncertainty about the likely alternative effect size. A Bayesian perspective on the sample size derivation for a frequentist trial naturally emerges as a way of reconciling arguments about the relative a priori plausibility of alternative effect sizes with ideas based on the relevance of effect sizes. Many suggestions as to how such `hybrid' approaches could be implemented in practice have been put forward in the literature. However, key quantities such as assurance, probability of success, or expected power are often defined in subtly different ways in the literature. Starting from the traditional and entirely frequentist approach to sample size derivation, we derive consistent definitions for the most commonly used `hybrid' quantities and highlight connections, before discussing and demonstrating their use in the context of sample size derivation for clinical trials.

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arXiv2020

Graphical approaches for the control of generalised error rates

When simultaneously testing multiple hypotheses, the usual approach in the context of confirmatory clinical trials is to control the familywise error rate (FWER), which bounds the probability of making at least one false rejection. In many trial settings, these hypotheses will additionally have a hierarchical structure that reflects the relative importance and links between different clinical objectives. The graphical approach of Bretz et al. (2009) is a flexible and easily communicable way of controlling the FWER while respecting complex trial objectives and multiple structured hypotheses. However, the FWER can be a very stringent criterion that leads to procedures with low power, and may not be appropriate in exploratory trial settings. This motivates controlling generalised error rates, particularly when the number of hypotheses tested is no longer small. We consider the generalised familywise error rate (k-FWER), which is the probability of making k or more false rejections, as well as the tail probability of the false discovery proportion (FDP), which is the probability that the proportion of false rejections is greater than some threshold. We also consider asymptotic control of the false discovery rate (FDR), which is the expectation of the FDP. In this paper, we show how to control these generalised error rates when using the graphical approach and its extensions. We demonstrate the utility of the resulting graphical procedures on three clinical trial case studies.

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arXiv2020

Bayesian design and analysis of external pilot trials for complex interventions

External pilot trials of complex interventions are used to help determine if and how a confirmatory trial should be undertaken, providing estimates of parameters such as recruitment, retention and adherence rates. The decision to progress to the confirmatory trial is typically made by comparing these estimates to pre-specified thresholds known as progression criteria, although the statistical properties of such decision rules are rarely assessed. Such assessment is complicated by several methodological challenges, including the simultaneous evaluation of multiple endpoints, complex multi-level models, small sample sizes, and uncertainty in nuisance parameters. In response to these challenges, we describe a Bayesian approach to the design and analysis of external pilot trials. We show how progression decisions can be made by minimising the expected value of a loss function, defined over the whole parameter space to allow for preferences and trade-offs between multiple parameters to be articulated and used in the decision making process. The assessment of preferences is kept feasible by using a piecewise constant parameterisation of the loss function, the parameters of which are chosen at the design stage to lead to desirable operating characteristics. We describe a flexible, yet computationally intensive, nested Monte Carlo algorithm for estimating operating characteristics. The method is used to revisit the design of an external pilot trial of a complex intervention designed to increase the physical activity of care home residents.

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arXiv2020

Borrowing of information across patient subgroups in a basket trial based on distributional discrepancy

Basket trials have emerged as a new class of efficient approaches in oncology to evaluate a new treatment in several patient subgroups simultaneously. In this paper, we extend the key ideas to disease areas outside of oncology, developing a robust Bayesian methodology for randomised, placebo-controlled basket trials with a continuous endpoint to enable borrowing of information across subtrials with similar treatment effects. After adjusting for covariates, information from a complementary subtrial can be represented into a commensurate prior for the parameter that underpins the subtrial under consideration. We propose using distributional discrepancy to characterise the commensurability between subtrials for appropriate borrowing of information through a spike-and-slab prior, which is placed on the prior precision factor. When the basket trial has at least three subtrials, commensurate priors for point-to-point borrowing are combined into a marginal predictive prior, according to the weights transformed from the pairwise discrepancy measures. In this way, only information from subtrial(s) with the most commensurate treatment effect is leveraged. The marginal predictive prior is updated to a robust posterior by the contemporary subtrial data to inform decision making. Operating characteristics of the proposed methodology are evaluated through simulations motivated by a real basket trial in chronic diseases. The proposed methodology has advantages compared to other selected Bayesian analysis models, for (i) identifying the most commensurate source of information, and (ii) gauging the degree of borrowing from specific subtrials. Numerical results also suggest that our methodology can improve the precision of estimates and, potentially, the statistical power for hypothesis testing.

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