arXiv subjects

Erica E. M. Moodie

Publications and source records attributed to Erica E. M. Moodie.

At least 37 records · Page 2Linked to original sources

arXiv2024

An adaptive enrichment design using Bayesian model averaging for selection and threshold-identification of tailoring variables

Precision medicine stands as a transformative approach in healthcare, offering tailored treatments that can enhance patient outcomes and reduce healthcare costs. As understanding of complex disease improves, clinical trials are being designed to detect subgroups of patients with enhanced treatment effects. Biomarker-driven adaptive enrichment designs, which enroll a general population initially and later restrict accrual to treatment-sensitive patients, are gaining popularity. Current practice often assumes either pre-trial knowledge of biomarkers defining treatment-sensitive subpopulations or a simple, linear relationship between continuous markers and treatment effectiveness. Motivated by a trial studying rheumatoid arthritis treatment, we propose a Bayesian adaptive enrichment design which identifies important tailoring variables out of a larger set of candidate biomarkers. Our proposed design is equipped with a flexible modelling framework where the effects of continuous biomarkers are introduced using free knot B-splines. The parameters of interest are then estimated by marginalizing over the space of all possible variable combinations using Bayesian model averaging. At interim analyses, we assess whether a biomarker-defined subgroup has enhanced or reduced treatment effects, allowing for early termination due to efficacy or futility and restricting future enrollment to treatment-sensitive patients. We consider pre-categorized and continuous biomarkers, the latter of which may have complex, nonlinear relationships to the outcome and treatment effect. Using simulations, we derive the operating characteristics of our design and compare its performance to two existing approaches.

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arXiv2024

Joint mixed-effects models for causal inference in clustered network-based observational studies

Causal inference on populations embedded in social networks poses technical challenges, since the typical no interference assumption frequently does not hold. Existing methods developed in the context of network interference rely upon the assumption of no unmeasured confounding. However, when faced with multilevel network data, there may be a latent factor influencing both the exposure and the outcome at the cluster level. We propose a Bayesian inference approach that combines a joint mixed-effects model for the outcome and the exposure with direct standardization to identify and estimate causal effects in the presence of network interference and unmeasured cluster confounding. In simulations, we compare our proposed method with linear mixed and fixed effects models and show that unbiased estimation is achieved using the joint model. Having derived valid tools for estimation, we examine the effect of maternal college education on adolescent school performance using data from the National Longitudinal Study of Adolescent Health.

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arXiv2024

Bayesian Optimization for Personalized Dose-Finding Trials with Combination Therapies

Identification of optimal dose combinations in early phase dose-finding trials is challenging, due to the trade-off between precisely estimating the many parameters required to flexibly model the possibly non-monotonic dose-response surface, and the small sample sizes in early phase trials. This difficulty is even more pertinent in the context of personalized dose-finding, where patient characteristics are used to identify tailored optimal dose combinations. To overcome these challenges, we propose the use of Bayesian optimization for finding optimal dose combinations in standard ("one size fits all") and personalized multi-agent dose-finding trials. Bayesian optimization is a method for estimating the global optima of expensive-to-evaluate objective functions. The objective function is approximated by a surrogate model, commonly a Gaussian process, paired with a sequential design strategy to select the next point via an acquisition function. This work is motivated by an industry-sponsored problem, where focus is on optimizing a dual-agent therapy in a setting featuring minimal toxicity. To compare the performance of the standard and personalized methods under this setting, simulation studies are performed for a variety of scenarios. Our study concludes that taking a personalized approach is highly beneficial in the presence of heterogeneity.

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arXiv2024

Revisiting the Effects of Maternal Education on Adolescents' Academic Performance: Doubly Robust Estimation in a Network-Based Observational Study

In many contexts, particularly when study subjects are adolescents, peer effects can invalidate typical statistical requirements in the data. For instance, it is plausible that a student's academic performance is influenced both by their own mother's educational level as well as that of their peers. Since the underlying social network is measured, the Add Health study provides a unique opportunity to examine the impact of maternal college education on adolescent school performance, both direct and indirect. However, causal inference on populations embedded in social networks poses technical challenges, since the typical no interference assumption no longer holds. While inverse probability-of-treatment weighted (IPW) estimators have been developed for this setting, they are often highly unstable. Motivated by the question of maternal education, we propose doubly robust (DR) estimators combining models for treatment and outcome that are consistent and asymptotically normal if either model is correctly specified. We present empirical results that illustrate the DR property and the efficiency gain of DR over IPW estimators even when the treatment model is misspecified. Contrary to previous studies, our robust analysis does not provide evidence of an indirect effect of maternal education on academic performance within adolescents' social circles in Add Health.

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arXiv2023

The impact of directly observed therapy on the efficacy of Tuberculosis treatment: A Bayesian multilevel approach

We propose and discuss a Bayesian procedure to estimate the average treatment effect (ATE) for multilevel observations in the presence of confounding. We focus on situations where the confounders may be latent (e.g., spatial latent effects). This work is motivated by an interest in determining the causal impact of directly observed therapy (DOT) on the successful treatment of Tuberculosis (TB); the available data correspond to individual-level information observed across different cities in a state in Brazil. We focus on propensity score regression and covariate adjustment to balance the treatment (DOT) allocation. We discuss the need to include latent local-level random effects in the propensity score model to reduce bias in the estimation of the ATE. A simulation study suggests that accounting for the multilevel nature of the data with latent structures in both the outcome and propensity score models has the potential to reduce bias in the estimation of causal effects.

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arXiv2023

Bayesian inference for optimal dynamic treatment regimes in practice

In this work, we examine recently developed methods for Bayesian inference of optimal dynamic treatment regimes (DTRs). DTRs are a set of treatment decision rules aimed at tailoring patient care to patient-specific characteristics, thereby falling within the realm of precision medicine. In this field, researchers seek to tailor therapy with the intention of improving health outcomes; therefore, they are most interested in identifying optimal DTRs. Recent work has developed Bayesian methods for identifying optimal DTRs in a family indexed by $ψ$ via Bayesian dynamic marginal structural models (MSMs) (Rodriguez Duque et al., 2022a); we review the proposed estimation procedure and illustrate its use via the new BayesDTR R package. Although methods in (Rodriguez Duque et al., 2022a) can estimate optimal DTRs well, they may lead to biased estimators when the model for the expected outcome if everyone in a population were to follow a given treatment strategy, known as a value function, is misspecified or when a grid search for the optimum is employed. We describe recent work that uses a Gaussian process ($GP$) prior on the value function as a means to robustly identify optimal DTRs (Rodriguez Duque et al., 2022b). We demonstrate how a $GP$ approach may be implemented with the BayesDTR package and contrast it with other value-search approaches to identifying optimal DTRs. We use data from an HIV therapeutic trial in order to illustrate a standard analysis with these methods, using both the original observed trial data and an additional simulated component to showcase a longitudinal (two-stage DTR) analysis.

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arXiv2023

A time-dependent Poisson-Gamma model for recruitment forecasting in multicenter studies

Forecasting recruitments is a key component of the monitoring phase of multicenter studies. One of the most popular techniques in this field is the Poisson-Gamma recruitment model, a Bayesian technique built on a doubly stochastic Poisson process. This approach is based on the modeling of enrollments as a Poisson process where the recruitment rates are assumed to be constant over time and to follow a common Gamma prior distribution. However, the constant-rate assumption is a restrictive limitation that is rarely appropriate for applications in real studies. In this paper, we illustrate a flexible generalization of this methodology which allows the enrollment rates to vary over time by modeling them through B-splines. We show the suitability of this approach for a wide range of recruitment behaviors in a simulation study and by estimating the recruitment progression of the Canadian Co-infection Cohort (CCC).

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arXiv2022

The role of exchangeability in causal inference

Though the notion of exchangeability has been discussed in the causal inference literature under various guises, it has rarely taken its original meaning as a symmetry property of probability distributions. As this property is a standard component of Bayesian inference, we argue that in Bayesian causal inference it is natural to link the causal model, including the notion of confounding and definition of causal contrasts of interest, to the concept of exchangeability. Here we propose a probabilistic between-group exchangeability property as an identifying condition for causal effects, relate it to alternative conditions for unconfounded inferences (commonly stated using potential outcomes) and define causal contrasts in the presence of exchangeability in terms of posterior predictive expectations for further exchangeable units. While our main focus is on a point treatment setting, we also investigate how this reasoning carries over to longitudinal settings.

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arXiv2022

Estimation of Optimal Dynamic Treatment Regimes using Gaussian Process Emulation

In precision medicine, identifying optimal sequences of decision rules, termed dynamic treatment regimes (DTRs), is an important undertaking. One approach investigators may take to infer about optimal DTRs is via Bayesian dynamic Marginal Structural Models (MSMs). These models represent the expected outcome under adherence to a DTR for DTRs in a family indexed by a parameter $ ψ$; the function mapping regimes in the family to the expected outcome under adherence to a DTR is known as the value function. Models that allow for the straightforward identification of an optimal DTR may lead to biased estimates. If such a model is computationally tractable, common wisdom says that a grid-search for the optimal DTR may obviate this difficulty. In a Bayesian context, computational difficulties may be compounded if a posterior mean must be calculated at each grid point. We seek to alleviate these inferential challenges by implementing Gaussian Process ($ \mathcal{GP} $) optimization methods for estimators for the causal effect of adherence to a specified DTR. We examine how to identify optimal DTRs in settings where the value function is multi-modal, which are often not addressed in the DTR literature. We conclude that a $ \mathcal{GP} $ modeling approach that acknowledges noise in the estimated response surface leads to improved results. Additionally, we find that a grid-search may not always yield a robust solution and that it is often less efficient than a $ \mathcal{GP} $ approach. We illustrate the use of the proposed methods by analyzing a clinical dataset with the aim of quantifying the effect of different patterns of HIV therapy.

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arXiv2022

Estimating Individualized Treatment Rules in Longitudinal Studies with Covariate-Driven Observation Times

The sequential treatment decisions made by physicians to treat chronic diseases are formalized in the statistical literature as dynamic treatment regimes. To date, methods for dynamic treatment regimes have been developed under the assumption that observation times, i.e., treatment and outcome monitoring times, are determined by study investigators. That assumption is often not satisfied in electronic health records data in which the outcome, the observation times, and the treatment mechanism are associated with patients' characteristics. The treatment and observation processes can lead to spurious associations between the treatment of interest and the outcome to be optimized under the dynamic treatment regime if not adequately considered in the analysis. We address these associations by incorporating two inverse weights that are functions of a patient's covariates into dynamic weighted ordinary least squares to develop optimal single stage dynamic treatment regimes, known as individualized treatment rules. We show empirically that our methodology yields consistent, multiply robust estimators. In a cohort of new users of antidepressant drugs from the United Kingdom's Clinical Practice Research Datalink, the proposed method is used to develop an optimal treatment rule that chooses between two antidepressants to optimize a utility function related to the change in body mass index.

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arXiv2022

Monte Carlo Sensitivity Analysis for Unmeasured Confounding in Dynamic Treatment Regimes

Data-driven methods for personalizing treatment assignment have garnered much attention from clinicians and researchers. Dynamic treatment regimes formalize this through a sequence of decision rules that map individual patient characteristics to a recommended treatment. Observational studies are commonly used for estimating dynamic treatment regimes due to the potentially prohibitive costs of conducting sequential multiple assignment randomized trials. However, estimating a dynamic treatment regime from observational data can lead to bias in the estimated regime due to unmeasured confounding. Sensitivity analyses are useful for assessing how robust the conclusions of the study are to a potential unmeasured confounder. A Monte Carlo sensitivity analysis is a probabilistic approach that involves positing and sampling from distributions for the parameters governing the bias. We propose a method for performing a Monte Carlo sensitivity analysis of the bias due to unmeasured confounding in the estimation of dynamic treatment regimes. We demonstrate the performance of the proposed procedure with a simulation study and apply it to an observational study examining tailoring the use of antidepressants for reducing symptoms of depression using data from Kaiser Permanente Washington (KPWA).

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arXiv2022

Using Pilot Data to Size Observational Studies for the Estimation of Dynamic Treatment Regimes

There has been significant attention given to developing data-driven methods for tailoring patient care based on individual patient characteristics. Dynamic treatment regimes formalize this through a sequence of decision rules that map patient information to a suggested treatment. The data for estimating and evaluating treatment regimes are ideally gathered through the use of Sequential Multiple Assignment Randomized Trials (SMARTs) though longitudinal observational studies are commonly used due to the potentially prohibitive costs of conducting a SMART. These studies are typically sized for simple comparisons of fixed treatment sequences or, in the case of observational studies, a priori sample size calculations are often not performed. We develop sample size procedures for the estimation of dynamic treatment regimes from observational studies. Our approach uses pilot data to ensure a study will have sufficient power for comparing the value of the optimal regime, i.e. the expected outcome if all patients in the population were treated by following the optimal regime, with a known comparison mean. Our approach also ensures the value of the estimated optimal treatment regime is within an a priori set range of the value of the true optimal regime with a high probability. We examine the performance of the proposed procedure with a simulation study and use it to size a study for reducing depressive symptoms using data from electronic health records.

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arXiv2022

Causal inference under mis-specification: adjustment based on the propensity score

We study Bayesian approaches to causal inference via propensity score regression. Much of the Bayesian literature on propensity score methods have relied on approaches that cannot be viewed as fully Bayesian in the context of conventional `likelihood times prior' posterior inference; in addition, most methods rely on parametric and distributional assumptions, and presumed correct specification. We emphasize that causal inference is typically carried out in settings of mis-specification, and develop strategies for fully Bayesian inference that reflect this. We focus on methods based on decision-theoretic arguments, and show how inference based on loss-minimization can give valid and fully Bayesian inference. We propose a computational approach to inference based on the Bayesian bootstrap which has good Bayesian and frequentist properties.

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arXiv2022

New designs for Bayesian adaptive cluster-randomized trials

Adaptive approaches, allowing for more flexible trial design, have been proposed for individually randomized trials to save time or reduce sample size. However, adaptive designs for cluster-randomized trials in which groups of participants rather than individuals are randomized to treatment arms are less common. Motivated by a cluster-randomized trial designed to assess the effectiveness of a machine-learning based clinical decision support system for physicians treating patients with depression, two Bayesian adaptive designs for cluster-randomized trials are proposed to allow for early stopping for efficacy at pre-planned interim analyses. The difference between the two designs lies in the way that participants are sequentially recruited. Given a maximum number of clusters as well as maximum cluster size allowed in the trial, one design sequentially recruits clusters with the given maximum cluster size, while the other recruits all clusters at the beginning of the trial but sequentially enrolls individual participants until the trial is stopped early for efficacy or the final analysis has been reached. The design operating characteristics are explored via simulations for a variety of scenarios and two outcome types for the two designs. The simulation results show that for different outcomes the design choice may be different. We make recommendations for designs of Bayesian adaptive cluster-randomized trial based on the simulation results.

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arXiv2021

Causal Inference for Quantile Treatment Effects

Analyses of environmental phenomena often are concerned with understanding unlikely events such as floods, heatwaves, droughts or high concentrations of pollutants. Yet the majority of the causal inference literature has focused on modelling means, rather than (possibly high) quantiles. We define a general estimator of the population quantile treatment (or exposure) effects (QTE) -- the weighted QTE (WQTE) -- of which the population QTE is a special case, along with a general class of balancing weights incorporating the propensity score. Asymptotic properties of the proposed WQTE estimators are derived. We further propose and compare propensity score regression and two weighted methods based on these balancing weights to understand the causal effect of an exposure on quantiles, allowing for the exposure to be binary, discrete or continuous. Finite sample behavior of the three estimators is studied in simulation. The proposed methods are applied to data taken from the Bavarian Danube catchment area to estimate the 95% QTE of phosphorus on copper concentration in the river.

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arXiv2021

Evaluating the Use of Generalized Dynamic Weighted Ordinary Least Squares for Individualized HIV Treatment Strategies

Dynamic treatment regimes (DTR) are a statistical paradigm in precision medicine which aim to optimize patient outcomes by individualizing treatments. At its simplest, a DTR may require only a single decision to be made; this special case is called an individualized treatment rule (ITR) and is often used to maximize short-term rewards. Generalized dynamic weighted ordinary least squares (G-dWOLS), a DTR estimation method that offers theoretical advantages such as double robustness of parameter estimators in the decision rules, has been recently extended to now accommodate categorical treatments. In this work, G-dWOLS is applied to longitudinal data to estimate an optimal ITR, which is demonstrated in simulations. This novel method is then applied to a population affected by HIV whereby an ITR for the administration of Interleukin 7 (IL-7) is devised to maximize the duration where the CD4 load is above a healthy threshold (500 cells/$μ$L) while preventing the administration of unnecessary injections.

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arXiv2021

Bayesian Sample Size Calculations for SMART Studies

In the management of most chronic conditions characterized by the lack of universally effective treatments, adaptive treatment strategies (ATSs) have been growing in popularity as they offer a more individualized approach, and sequential multiple assignment randomized trials (SMARTs) have gained attention as the most suitable clinical trial design to formalize the study of these strategies. While the number of SMARTs has increased in recent years, their design has remained limited to the frequentist setting, which may not fully or appropriately account for uncertainty in design parameters and hence not yield appropriate sample size recommendations. Specifically, standard frequentist formulae rely on several assumptions that can be easily misspecified. The Bayesian framework offers a straightforward path to alleviate some of these concerns. In this paper, we provide calculations in a Bayesian setting to allow more realistic and robust estimates that account for uncertainty in inputs through the `two priors' approach. Additionally, compared to the standard formulae, this methodology allows us to rely on fewer assumptions, integrate pre-trial knowledge, and switch the focus from the standardized effect size to the minimal detectable difference. The proposed methodology is evaluated in a thorough simulation study and is implemented to estimate the sample size for a full-scale SMART of an Internet-Based Adaptive Stress Management intervention based on a pilot SMART conducted on cardiovascular disease patients from two Canadian provinces.

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arXiv2021

Estimation of the marginal effect of antidepressants on body mass index under confounding and endogenous covariate-driven monitoring times

In studying the marginal effect of antidepressants on body mass index using electronic health records data, we face several challenges. Patients' characteristics can affect the exposure (confounding) as well as the timing of routine visits (measurement process), and those characteristics may be altered following a visit which can create dependencies between the monitoring and body mass index when viewed as a stochastic or random processes in time. This may result in a form of selection bias that distorts the estimation of the marginal effect of the antidepressant. Inverse intensity of visit weights have been proposed to adjust for these imbalances, however no approaches have addressed complex settings where the covariate and the monitoring processes affect each other in time so as to induce endogeneity, a situation likely to occur in electronic health records. We review how selection bias due to outcome-dependent follow-up times may arise and propose a new cumulated weight that models a complete monitoring path so as to address the above-mentioned challenges and produce a reliable estimate of the impact of antidepressants on body mass index. More specifically, we do so using data from the Clinical Practice Research Datalink in the United Kingdom, comparing the marginal effect of two commonly used antidepressants, citalopram and fluoxetine, on body mass index. The results are compared to those obtained with simpler methods that do not account for the extent of the dependence due to an endogenous covariate process.

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