arXiv subjects

Nikki L. B. Freeman

Publications and source records attributed to Nikki L. B. Freeman.

8 recordsLinked to original sources

arXiv2026

Backward Bayesian Outcome Weighted Learning

A central objective of precision medicine is learning optimal dynamic treatment regimes (DTRs) from data. Classification-based methods, like outcome weighted learning (OWL) for single-stage and backward OWL (BOWL) for multi-stage problems, leverage machine learning to directly learn optimal DTRs. However, these methods lack a natural way to quantify uncertainty in treatment decisions at the individual level. In this paper, we extend Bayesian OWL, a Bayesian reformulation of OWL, to the multi-stage setting. We call this method backward Bayesian outcome weighted learning (BBOWL). Like BOWL, our method directly learns an optimal DTR via backward induction, and unlike existing methods, our approach propagates uncertainty backward through the DTR learning process and provides uncertainty quantification of individualized treatment recommendations. We present a theoretical justification of BBOWL and verify its performance via a simulation study.

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arXiv2026

Bayesian Mediation Analysis for Individualized Treatment Rules

The value of an individualized treatment rule (ITR), defined as the expected outcome under treatment assignment according to the rule, is useful for assessing average clinical benefit but does not explain how the benefit of a rule is generated. We propose a causal mediation framework for decomposing the value contrast between a prespecified candidate ITR and a clinically meaningful reference rule into direct and indirect components. Using rule-specific nested potential outcomes, we define natural direct and indirect rule effects that quantify the extent to which the improvement in value arises through pathways operating directly on the outcome versus through a specified mediator. We give identification conditions under which these components are identified by a rule-level mediation g-formula. For estimation, we adapt Bayesian causal mediation forests to obtain posterior inference for the value contrast and its path-specific components. Our simulations demonstrate that the proposed estimator achieved near-nominal credible interval coverage with decreasing bias and root mean squared error as sample size increased in settings with varying direct and mediated contributions. We further illustrate the method using data from the TRIUMPH trial, decomposing the cognitive benefit of a lifestyle intervention rule through candidate neurovascular, cardiorespiratory, and behavioral mediators. The proposed framework complements optimal ITR learning with explanation using mediation, providing a natural approach for mechanistic evaluation of ITRs.

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arXiv2026

The Fidelity and Feedback Traps: The Case for Health Digital Twins as Modular Evolving Causal Systems

Digital twins for health may be used to compare treatments, project patient trajectories, and support clinical decisions. While related to mechanical digital twins, those initially developed for engineering applications, replicating the mechanical digital twin architecture and goals may fail in health for two reasons. The fidelity trap is the belief that an accurate model can answer what-if questions by virtue of its accuracy. Prediction and counterfactual reasoning are different tasks, and a twin that can fit past trajectories well may miss the mark when ranking treatments. The feedback trap arises when the twin updates on data its own recommendations helped generate. Refitting in this way can recover a biased relationship and grow more confident even as data grows thinner. We contend that health digital twins should be conceived as causally valid, modular, and evolving systems. Modularity isolates the data and models needed for interventional recommendations, causal validity supports such claims, and governed evolution updates the twin while accounting for how its recommendations reshape the data. We conclude that the standard for a health twin should be how well it supports decisions in the world it helps create, not how faithfully it reproduces the world it observes.

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arXiv2026

A Review of Methods and Practices for Missing Data in Sequential Multiple Assignment Randomized Trials (SMARTs): An Ancillary Study of a Scoping Review

Background: Missing data poses an acute threat to sequential multiple assignment randomized trial (SMART) analyses because of the sequential treatment structure and response-dependent re-randomization. Objectives: This study aimed to (1) review the current statistical methods for handling missing data in SMARTs, and (2) characterize how missing data is reported and handled in published SMARTs. Methods: We conducted a narrative review of statistical methods developed for missing data in SMARTs. Additionally, we conducted a pre-specified secondary extraction of a previously published scoping review of SMARTs focused on missing data. Extraction captured attrition rates, methods for handling missingness, and planned versus performed missing data analyses. Results: Seven methodological papers were identified; nearly all assume missing at random (MAR), and only one addresses the full set of SMART-specific missingness types. Across 30 published SMARTs, median overall attrition was 18.1% (range 0.6%-56.5%). Methods used to address missing data were described in 80% of the manuscripts; mixed-model methods were most common (30%). Among 14 studies with paired protocols, sensitivity analyses were pre-specified in 2 (14%). Conclusions: SMART-specific methodology for missing data is limited, and a substantial gap exists between available methodology and current SMART practice.

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arXiv2025

Statistical Design and Rationale of the Biomarkers for Evaluating Spine Treatments (BEST) Trial

Chronic low back pain (cLBP) is a prevalent condition with profound impacts on functioning and quality of life. While multiple evidence-based treatments exist, they all have modest average treatment effects$\unicode{x2013}$potentially due to individual variation in treatment response and the diverse etiologies of cLBP. This multi-site sequential, multiple-assignment randomized trial (SMART) investigated four treatment modalities with two stages of randomization and aimed to enroll 630 protocol completers. The primary objective was to develop a precision medicine approach by estimating optimal treatment or treatment combinations based on patient characteristics and initial treatment response. The analysis strategy focuses on estimating interpretable dynamic treatment regimes and identifying subgroups most responsive to specific interventions. Broad eligibility criteria were implemented to enhance generalizability and recruitment, most notably that participants could be eligible to enroll even if they could not be assigned to one (but no more) of the study interventions. Enrolling participants with restrictions on the treatment they could be assigned necessitated modifications to standard minimization methods for balancing covariates. The BEST trial represents one of the largest SMARTs focused on clinical decision-making to date and the largest in cLBP. By collecting an extensive array of biomarker and phenotypic measures, this trial may identify potential treatment mechanisms and establish a more evidence-based approach to individualizing cLBP treatment in clinical practice.

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arXiv2024

Optimal individualized treatment regimes for survival data with competing risks

Precision medicine leverages patient heterogeneity to estimate individualized treatment regimens, formalized, data-driven approaches designed to match patients with optimal treatments. In the presence of competing events, where multiple causes of failure can occur and one cause precludes others, it is crucial to assess the risk of the specific outcome of interest, such as one type of failure over another. This helps clinicians tailor interventions based on the factors driving that particular cause, leading to more precise treatment strategies. Currently, no precision medicine methods simultaneously account for both survival and competing risk endpoints. To address this gap, we develop a nonparametric individualized treatment regime estimator. Our two-phase method accounts for both overall survival from all events as well as the cumulative incidence of a main event of interest. Additionally, we introduce a multi-utility value function that incorporates both outcomes. We develop random survival and random cumulative incidence forests to construct individual survival and cumulative incidence curves. Simulation studies demonstrated that our proposed method performs well, which we applied to a cohort of peripheral artery disease patients at high risk for limb loss and mortality.

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arXiv2024

Bayesian Outcome Weighted Learning

One of the primary goals of statistical precision medicine is to learn optimal individualized treatment rules (ITRs). The classification-based, or machine learning-based, approach to estimating optimal ITRs was first introduced in outcome-weighted learning (OWL). OWL recasts the optimal ITR learning problem into a weighted classification problem, which can be solved using machine learning methods, e.g., support vector machines. In this paper, we introduce a Bayesian formulation of OWL. Starting from the OWL objective function, we generate a pseudo-likelihood which can be expressed as a scale mixture of normal distributions. A Gibbs sampling algorithm is developed to sample the posterior distribution of the parameters. In addition to providing a strategy for learning an optimal ITR, Bayesian OWL provides a natural, probabilistic approach to estimate uncertainty in ITR treatment recommendations themselves. We demonstrate the performance of our method through several simulation studies.

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arXiv2022

Dynamic treatment regime characterization via value function surrogate with an application to partial compliance

Precision medicine is a promising framework for generating evidence to improve health and health care. Yet, a gap persists between the ever-growing number of statistical precision medicine strategies for evidence generation and implementation in real world clinical settings, and the strategies for closing this gap will likely be context dependent. In this paper, we consider the specific context of partial compliance to wound management among patients with peripheral artery disease. Through the use of a Gaussian process surrogate for the value function, we expand beyond the common precision medicine task of learning an optimal dynamic treatment regime to characterization of classes of dynamic treatment regimes and how those findings can be translated into clinical contexts.

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