arXiv subjects

Alexander W. Levis

Publications and source records attributed to Alexander W. Levis.

15 recordsLinked to original sources

arXiv2026

Targeted Data Fusion for Region-Specific Survival Effects in the AMP HIV Prevention Trials

The Antibody Mediated Prevention (AMP) trials opened a new scientific frontier by showing that passively administered monoclonal broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition. Conducted across multiple geographic regions, including the United States, Brazil, Peru, Switzerland, and sub-Saharan Africa, the AMP trials revealed substantial regional heterogeneity in treatment efficacy. These differences, together with privacy and regulatory limits on central data pooling, call for methods that borrow strength across regions without sharing individual-level data. To estimate region- and treatment-specific survival curves under distributional heterogeneity, we develop a federated learning approach that combines site-specific estimators via an L1-regularized criterion that downweights data sources not aligned with the target. We further extend the framework to a general class of causal contrasts, including the risk difference (RD), survival ratio (SR), and restricted mean survival time (RMST) difference. Through extensive simulations and an analysis of the AMP trials under different target populations, we show that the proposed approach provides privacy-preserving, region-adaptive inference with improved precision.

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arXiv2026

History-Aware Conformal Prediction Sets for Censored Time-to-Event Outcomes

Existing conformal prediction methods for time-to-event outcomes leverage only baseline covariates, producing prediction intervals that are insufficiently informative to facilitate decision making. We propose History-Aware Prediction Sets (HAPS), a conformal framework that constructs prediction sets for individual event times using covariate histories observed up to a decision time, targeting coverage among individuals who have survived to this time. HAPS handles right censoring adjusted for time-varying confounders via inverse probability of censoring weighting. When the censoring weights are consistently estimated, it achieves PAAC (probably asymptotically approximately correct) coverage among survivors. We further propose two doubly robust extensions of HAPS to weaken reliance on consistent estimation of the censoring distribution. In simulations, HAPS and its extensions reduce median prediction interval length by up to 75\% relative to baseline comparators while maintaining close to nominal coverage. On two public benchmark data sets, HAPS reduces the median interval length by up to 60\% for predictions at year 5, compared to the baseline comparators.

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arXiv2026

Robust Causal Inference for EHR-based Studies of Point Exposures with Missingness in Eligibility Criteria

Missingness in variables that define study eligibility criteria is a seldom addressed challenge in electronic health record (EHR)-based settings. It is typically the case that patients with incomplete eligibility information are excluded from analysis without consideration of (implicit) assumptions that are being made, leaving study conclusions subject to potential selection bias. In an effort to ascertain eligibility for more patients, researchers may look back further in time prior to study baseline, and in using outdated values of eligibility-defining covariates may inappropriately be including individuals who, unbeknownst to the researcher, fail to meet eligibility at baseline. To the best of our knowledge, however, very little work has been done to mitigate these concerns. We propose a robust and efficient estimator of the causal average treatment effect on the treated, defined in the study eligible population, in cohort studies where eligibility-defining covariates are missing at random. The approach facilitates the use of flexible machine-learning strategies for component nuisance functions while maintaining appropriate convergence rates for valid asymptotic inference. This method is directly motivated by, and applied throughout to EHR data from Kaiser Permanente to analyze differences between two common bariatric surgical interventions for long-term weight and glycemic outcomes among a cohort of severely obese patients with type II diabetes mellitus.

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arXiv2026

A Statistical Framework for Understanding Causal Effects that Vary by Treatment Initiation Time in EHR-based Studies

Standard practice in electronic health record (EHR)-based studies evaluating the comparative effectiveness of bariatric surgery relative to no surgery is to estimate and report a constant treatment effect across calendar time. However, real-world treatment strategies can evolve, particularly when comparators include standard of care or surgical procedures where techniques may improve, making it clinically important to ascertain whether efficacy of bariatric surgery has changed over time. Efforts to determine whether treatment efficacy itself is evolving are complicated by changing patient populations, with potential covariate shift in key effect modifiers. Through a comprehensive analysis of EHR data from Kaiser Permanente following two bariatric surgical procedures compared to standard of care, we develop a statistical framework to estimate calendar time-specific average treatment effects and describe both how and why effects vary across treatment initiation time in EHR-based studies. Our approach projects doubly robust, time-specific treatment effect estimates onto candidate marginal structural models and uses a model selection procedure to best describe how effects vary by treatment initiation time. We further introduce a novel summary metric, based on standardization analysis, to quantify the role of covariate shift in explaining observed effect changes and disentangle changes in treatment effects from changes in the patient population receiving treatment.

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arXiv2025

Nonparametric Estimation of Local Treatment Effects with Continuous Instruments

Instrumental variable methods are widely used to address unmeasured confounding, yet much of the existing literature has focused on the binary instrument setting. Extensions to continuous instruments often impose strong parametric assumptions for identification and estimation, which can be difficult to justify and may limit their applicability in complex real-world settings. In this work, we develop theory and methods for nonparametric estimation of treatment effects with a continuous instrumental variable. We introduce an estimand that, under a monotonicity assumption, quantifies the treatment effect among the maximal complier class, generalizing the local average treatment effect framework to continuous instruments. Considering this estimand and the local instrumental variable curve, we draw connections to the dose-response function and its derivative, and propose doubly robust estimation methods. We establish convergence rates and conditions for asymptotic normality, providing valuable insights into the role of nuisance function estimation when the instrument is continuous. Additionally, we present practical procedures for bandwidth selection and variance estimation. Through extensive simulations, we demonstrate the advantages of the proposed nonparametric estimators. Finally, we apply our methods to data where excess travel time is an instrument for patients' likelihood of receiving care at specialized health care facilities. We use this instrument to estimate the effect of delivering at low-quality neonatal intensive care units (NICUs) on infant mortality.

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arXiv2025

Nonparametric causal inference for optogenetics: sequential excursion effects for dynamic regimes

Optogenetics is a powerful neuroscience technique for studying how neural circuit manipulation affects behavior. Standard analysis conventions discard information and severely limit the scope of the causal questions that can be probed. To address this gap, we 1) draw connections to the causal inference literature on sequentially randomized experiments, 2) propose a non-parametric framework for analyzing "open-loop" (static regime) optogenetics behavioral experiments, 3) derive extensions of history-restricted marginal structural models for dynamic treatment regimes with positivity violations for "closed-loop" designs, and 4) propose a taxonomy of identifiable causal effects that encompass a far richer collection of scientific questions compared to standard methods. From another view, our work extends "excursion effect" methods, popularized recently in the mobile health literature, to enable estimation of causal contrasts for treatment sequences in the presence of positivity violations. We describe sufficient conditions for identifiability of the proposed causal estimands, and provide asymptotic statistical guarantees for a proposed inverse probability-weighted estimator, a multiply-robust estimator (for two intervention timepoints), a framework for hypothesis testing, and a computationally scalable implementation. Finally, we apply our framework to data from a recent neuroscience study and show how it provides insight into causal effects of optogenetics on behavior that are obscured by standard analyses.

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arXiv2025

Longitudinal weighted and trimmed treatment effects with flip interventions

Weighting and trimming are popular methods for addressing positivity violations in causal inference. While well-studied with single-timepoint data, standard methods do not easily generalize to address non-baseline positivity violations in longitudinal data, and remain vulnerable to such violations. In this paper, we extend weighting and trimming to longitudinal data via stochastic ``flip'' interventions, which maintain the treatment status of subjects who would have received the target treatment, and flip others' treatment to the target with probability equal to their weight (e.g., overlap weight, trimming indicator). We first show, in single-timepoint data, that flip interventions yield a large class of weighted average treatment effects, ascribing a novel policy interpretation to these popular weighted estimands. With longitudinal data, we then show that flip interventions provide interpretable weighting or trimming on non-baseline covariates and, crucially, yield effects that are identifiable under arbitrary positivity violations. Moreover, we demonstrate that flip interventions are policy-relevant since they could be implemented in practice. By contrast, we show that alternative approaches for weighting on non-baseline covariates fail to achieve this property. We derive flexible and efficient estimators based on efficient influence functions when the weight is a smooth function of the propensity score. Namely, we construct multiply robust-style and sequentially doubly robust-style estimators that achieve root-n consistency and asymptotic normality under nonparametric conditions. Finally, we demonstrate our methods through an analysis of the effect of union membership on earnings.

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arXiv2025

Causal Quantile Treatment Effects with missing data by double-sampling

Causal weighted quantile treatment effects (WQTE) are a useful complement to standard causal contrasts that focus on the mean when interest lies at the tails of the counterfactual distribution. To-date, however, methods for estimation and inference regarding causal WQTEs have assumed complete data on all relevant factors. In most practical settings, however, data will be missing or incomplete data, particularly when the data are not collected for research purposes, as is the case for electronic health records and disease registries. Furthermore, such data sources may be particularly susceptible to the outcome data being missing-not-at-random (MNAR). In this paper, we consider the use of double-sampling, through which the otherwise missing data are ascertained on a sub-sample of study units, as a strategy to mitigate bias due to MNAR data in the estimation of causal WQTEs. With the additional data in-hand, we present identifying conditions that do not require assumptions regarding missingness in the original data. We then propose a novel inverse-probability weighted estimator and derive its asymptotic properties, both pointwise at specific quantiles and uniformly across a range of quantiles over some compact subset of (0,1), allowing the propensity score and double-sampling probabilities to be estimated. For practical inference, we develop a bootstrap method that can be used for both pointwise and uniform inference. A simulation study is conducted to examine the finite sample performance of the proposed estimators. The proposed method is illustrated with data from an EHR-based study examining the relative effects of two bariatric surgery procedures on BMI loss at 3 years post-surgery.

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arXiv2024

Stochastic interventions, sensitivity analysis, and optimal transport

Recent methodological research in causal inference has focused on effects of stochastic interventions, which assign treatment randomly, often according to subject-specific covariates. In this work, we demonstrate that the usual notion of stochastic interventions have a surprising property: when there is unmeasured confounding, bounds on their effects do not collapse when the policy approaches the observational regime. As an alternative, we propose to study generalized policies, treatment rules that can depend on covariates, the natural value of treatment, and auxiliary randomness. We show that certain generalized policy formulations can resolve the "non-collapsing" bound issue: bounds narrow to a point when the target treatment distribution approaches that in the observed data. Moreover, drawing connections to the theory of optimal transport, we characterize generalized policies that minimize worst-case bound width in various sensitivity analysis models, as well as corresponding sharp bounds on their causal effects. These optimal policies are new, and can have a more parsimonious interpretation compared to their usual stochastic policy analogues. Finally, we develop flexible, efficient, and robust estimators for the sharp nonparametric bounds that emerge from the framework.

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arXiv2024

Intervention effects based on potential benefit

Optimal treatment rules are mappings from individual patient characteristics to tailored treatment assignments that maximize mean outcomes. In this work, we introduce a conditional potential benefit (CPB) metric that measures the expected improvement under an optimally chosen treatment compared to the status quo, within covariate strata. The potential benefit combines (i) the magnitude of the treatment effect, and (ii) the propensity for subjects to naturally select a suboptimal treatment. As a consequence, heterogeneity in the CPB can provide key insights into the mechanism by which a treatment acts and/or highlight potential barriers to treatment access or adverse effects. Moreover, we demonstrate that CPB is the natural prioritization score for individualized treatment policies when intervention capacity is constrained. That is, in the resource-limited setting where treatment options are freely accessible, but the ability to intervene on a portion of the target population is constrained (e.g., if the population is large, and follow-up and encouragement of treatment uptake is labor-intensive), targeting subjects with highest CPB maximizes the mean outcome. Focusing on this resource-limited setting, we derive formulas for optimal constrained treatment rules, and for any given budget, quantify the loss compared to the optimal unconstrained rule. We describe sufficient identification assumptions, and propose nonparametric, robust, and efficient estimators of the proposed quantities emerging from our framework. Finally, we illustrate our methodology using data from a prospective cohort study in which we assess the impact of intensive care unit transfer on mortality.

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arXiv2024

Multi-Source Conformal Inference Under Distribution Shift

Recent years have experienced increasing utilization of complex machine learning models across multiple sources of data to inform more generalizable decision-making. However, distribution shifts across data sources and privacy concerns related to sharing individual-level data, coupled with a lack of uncertainty quantification from machine learning predictions, make it challenging to achieve valid inferences in multi-source environments. In this paper, we consider the problem of obtaining distribution-free prediction intervals for a target population, leveraging multiple potentially biased data sources. We derive the efficient influence functions for the quantiles of unobserved outcomes in the target and source populations, and show that one can incorporate machine learning prediction algorithms in the estimation of nuisance functions while still achieving parametric rates of convergence to nominal coverage probabilities. Moreover, when conditional outcome invariance is violated, we propose a data-adaptive strategy to upweight informative data sources for efficiency gain and downweight non-informative data sources for bias reduction. We highlight the robustness and efficiency of our proposals for a variety of conformal scores and data-generating mechanisms via extensive synthetic experiments. Hospital length of stay prediction intervals for pediatric patients undergoing a high-risk cardiac surgical procedure between 2016-2022 in the U.S. illustrate the utility of our methodology.

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arXiv2024

Nonparametric identification and efficient estimation of causal effects with instrumental variables

Instrumental variables are widely used in econometrics and epidemiology for identifying and estimating causal effects when an exposure of interest is confounded by unmeasured factors. Despite this popularity, the assumptions invoked to justify the use of instruments differ substantially across the literature. Similarly, statistical approaches for estimating the resulting causal quantities vary considerably, and often rely on strong parametric assumptions. In this work, we compile and organize structural conditions that nonparametrically identify conditional average treatment effects, average treatment effects among the treated, and local average treatment effects, with a focus on identification formulae invoking the conditional Wald estimand. Moreover, we build upon existing work and propose nonparametric efficient estimators of functionals corresponding to marginal and conditional causal contrasts resulting from the various identification paradigms. We illustrate the proposed methods on an observational study examining the effects of operative care on adverse events for cholecystitis patients, and a randomized trial assessing the effects of market participation on political views.

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arXiv2023

Covariate-assisted bounds on causal effects with instrumental variables

When an exposure of interest is confounded by unmeasured factors, an instrumental variable (IV) can be used to identify and estimate certain causal contrasts. Identification of the marginal average treatment effect (ATE) from IVs relies on strong untestable structural assumptions. When one is unwilling to assert such structure, IVs can nonetheless be used to construct bounds on the ATE. Famously, Balke and Pearl (1997) proved tight bounds on the ATE for a binary outcome, in a randomized trial with noncompliance and no covariate information. We demonstrate how these bounds remain useful in observational settings with baseline confounders of the IV, as well as randomized trials with measured baseline covariates. The resulting bounds on the ATE are non-smooth functionals, and thus standard nonparametric efficiency theory is not immediately applicable. To remedy this, we propose (1) under a novel margin condition, influence function-based estimators of the bounds that can attain parametric convergence rates when the nuisance functions are modeled flexibly, and (2) estimators of smooth approximations of these bounds. We propose extensions to continuous outcomes, explore finite sample properties in simulations, and illustrate the proposed estimators in an observational study targeting the effect of higher education on wages.

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arXiv2023

Doubly robust machine learning for an instrumental variable study of surgical care for cholecystitis

Comparative effectiveness research frequently employs the instrumental variable design since randomized trials can be infeasible for many reasons. In this study, we investigate and compare treatments for emergency cholecystitis -- inflammation of the gallbladder. A standard treatment for cholecystitis is surgical removal of the gallbladder, while alternative non-surgical treatments include managed care and pharmaceutical options. As randomized trials are judged to violate the principle of equipoise, we consider an instrument for operative care: the surgeon's tendency to operate. Standard instrumental variable estimation methods, however, often rely on parametric models that are prone to bias from model misspecification. We outline instrumental variable estimation methods based on the doubly robust machine learning framework. These methods enable us to employ various machine learning techniques for nuisance parameter estimation and deliver consistent estimates and fast rates of convergence for valid inference. We use these methods to estimate the primary target causal estimand in an IV design. Additionally, we expand these methods to develop estimators for heterogeneous causal effects, profiling principal strata, and a sensitivity analyses for a key instrumental variable assumption. We conduct a simulation study to demonstrate scenarios where more flexible estimation methods outperform standard methods. Our findings indicate that operative care is generally more effective for cholecystitis patients, although the benefits of surgery can be less pronounced for key patient subgroups.

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arXiv2023

Double sampling for informatively missing data in electronic health record-based comparative effectiveness research

Missing data arise in most applied settings and are ubiquitous in electronic health records (EHR). When data are missing not at random (MNAR) with respect to measured covariates, sensitivity analyses are often considered. These post-hoc solutions, however, are often unsatisfying in that they are not guaranteed to yield concrete conclusions. Motivated by an EHR-based study of long-term outcomes following bariatric surgery, we consider the use of double sampling as a means to mitigate MNAR outcome data when the statistical goals are estimation and inference regarding causal effects. We describe assumptions that are sufficient for the identification of the joint distribution of confounders, treatment, and outcome under this design. Additionally, we derive efficient and robust estimators of the average causal treatment effect under a nonparametric model and under a model assuming outcomes were, in fact, initially missing at random (MAR). We compare these in simulations to an approach that adaptively estimates based on evidence of violation of the MAR assumption. Finally, we also show that the proposed double sampling design can be extended to handle arbitrary coarsening mechanisms, and derive nonparametric efficient estimators of any smooth full data functional.

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