arXiv subjects

Ivan Diaz

Publications and source records attributed to Ivan Diaz.

At least 19 recordsLinked to original sources

arXiv2026

Data-Adaptive and Model-Robust Covariate Adjustment for Time-to-Event Outcomes in Stratified Randomized Trials

Time-to-event outcomes are commonly used as primary endpoints in randomized clinical trials. Despite this, relatively little work incorporates baseline covariate information while also accounting for stratified randomization, a common form of randomization. Moreover, leveraging efficiency gains using these approaches typically requires pre-specifying a subset of covariates that are most predictive of the outcome -- a challenging task in practice, as most trials collect dozens of potentially prognostic baseline variables. In this work, we build on existing literature to propose a data-adaptive and model-robust covariate adjustment method for time-to-event outcomes. Our approach, based on targeted minimum loss-based estimation, allows for data-adaptive covariate selection and model-robust efficient inference on functionals of the survival curve while accounting for stratification. Through extensive simulations and analysis, we showcase the simplicity and improved precision of our method when the covariate set is not known a priori.

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arXiv2026

crumble: A comprehensive framework for modern causal mediation analysis with intermediate confounding

Causal mediation analysis is widely used to investigate how causal effects operate through specific pathways linking treatments or exposures to outcomes. Recently, \texttt{crumble} was developed to enable nonparametric estimation of several mediation parameters, even when mediators are continuous and/or multi-dimensional or when treatments are non-binary. But a practical and accessible guide to using \texttt{crumble} -- one that does not require deep familiarity with mediation analysis or semiparametric theory -- is currently lacking. This tutorial aims to an accessible introduction to \texttt{crumble} while minimizing technical complexity. We first review the mediation parameters implemented in \texttt{crumble} -- natural direct and indirect effects, randomized interventional effects, and recanting-twin effects. For each, we give the definition, interpretation, identification assumptions, and suitability in the presence or absence of intermediate confounding. Then, we demonstrate the usage of \texttt{crumble} by examining an example configuration. Next, we describe how \texttt{crumble} accommodates non-binary treatments through modified treatment policies. Finally, we illustrate the practical use of \texttt{crumble} through two case studies -- one with a binary treatment and one with a non-binary treatment -- based on the Job Search Intervention Study data.

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arXiv2025

Everything all at once: On choosing an estimand for multi-component environmental exposures

Many research questions -- particularly those in environmental health -- do not involve binary exposures. In environmental epidemiology, this includes multivariate exposure mixtures with nondiscrete components. Causal inference estimands and estimators to quantify the relationship between an exposure mixture and an outcome are relatively few. We propose an approach to quantify a relationship between a shift in the exposure mixture and the outcome -- either in the single timepoint or longitudinal setting. The shift in the exposure mixture can be defined flexibly in terms of shifting one or more components, including examining interaction between mixture components, and in terms of shifting the same or different amounts across components. The estimand we discuss has a similar interpretation as a main effect regression coefficient. First, we focus on choosing a shift in the exposure mixture supported by observed data. We demonstrate how to assess extrapolation and modify the shift to minimize reliance on extrapolation. Second, we propose estimating the relationship between the exposure mixture shift and outcome completely nonparametrically, using machine learning in model-fitting. This is in contrast to other current approaches, which employ parametric modeling for at least some relationships, which we would like to avoid because parametric modeling assumptions in complex, nonrandomized settings are tenuous at best. We are motivated by longitudinal data on pesticide exposures among participants in the CHAMACOS Maternal Cognition cohort. We examine the relationship between longitudinal exposure to agricultural pesticides and risk of hypertension. We provide step-by-step code to facilitate the easy replication and adaptation of the approaches we use.

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arXiv2025

Constructing targeted minimum loss/maximum likelihood estimators: a simple illustration to build intuition

Use of machine learning to estimate nuisance functions (e.g. outcomes models, propensity score models) in estimators used in causal inference is increasingly common, as it can mitigate bias due to model misspecification. However, it can be challenging to achieve valid inference (e.g., estimate valid confidence intervals). The efficient influence function (EIF) provides a recipe to go from a statistical estimand relevant to our causal question, to an estimator that can validly incorporate machine learning. Our companion paper, Renson et al. 2025 (arXiv:2502.05363), provides a thorough but approachable description of the EIF, along with a guide through the steps to go from a unique statistical estimand to development of one type of EIF-based estimator, the so-called one-step estimator. Another commonly used estimator based on the EIF is the targeted maximum likelihood/minimum loss estimator (TMLE). Construction of TMLEs is well-discussed in the statistical literature, but there remains a gap in translation to a more applied audience. In this letter, which supplements Renson et al., we provide a more accessible illustration of how to construct a TMLE.

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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

Transporting results from a trial to an external target population when trial participation impacts adherence

Randomized clinical trials are considered the gold standard for informing treatment guidelines, but results may not generalize to real-world populations. Generalizability is hindered by distributional differences in baseline covariates and treatment-outcome mediators. Approaches to address differences in covariates are well established, but approaches to address differences in mediators are more limited. Here we consider the setting where trial activities that differ from usual care settings (e.g., monetary compensation, follow-up visits frequency) affect treatment adherence. When treatment and adherence data are unavailable for the real-world target population, we cannot identify the mean outcome under a specific treatment assignment (i.e., mean potential outcome) in the target. Therefore, we propose a sensitivity analysis in which a parameter for the relative difference in adherence to a specific treatment between the trial and the target, possibly conditional on covariates, must be specified. We discuss options for specification of the sensitivity analysis parameter based on external knowledge including setting a range to estimate bounds or specifying a probability distribution from which to repeatedly draw parameter values (i.e., use Monte Carlo sampling). We introduce two estimators for the mean counterfactual outcome in the target that incorporates this sensitivity parameter, a plug-in estimator and a one-step estimator that is double robust and supports the use of machine learning for estimating nuisance models. Finally, we apply the proposed approach to the motivating application where we transport the risk of relapse under two different medications for the treatment of opioid use disorder from a trial to a real-world population.

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arXiv2025

Exploring Robustness of Cortical Morphometry in the presence of white matter lesions, using Diffusion Models for Lesion Filling

Cortical thickness measurements from magnetic resonance imaging, an important biomarker in many neurodegenerative and neurological disorders, are derived by many tools from an initial voxel-wise tissue segmentation. White matter (WM) hypointensities in T1-weighted imaging, such as those arising from multiple sclerosis or small vessel disease, are known to affect the output of brain segmentation methods and therefore bias cortical thickness measurements. These effects are well-documented among traditional brain segmentation tools but have not been studied extensively in tools based on deep-learning segmentations, which promise to be more robust. In this paper, we explore the potential of deep learning to enhance the accuracy and efficiency of cortical thickness measurement in the presence of WM lesions, using a high-quality lesion filling algorithm leveraging denoising diffusion networks. A pseudo-3D U-Net architecture trained on the OASIS dataset to generate synthetic healthy tissue, conditioned on binary lesion masks derived from the MSSEG dataset, allows realistic removal of white matter lesions in multiple sclerosis patients. By applying morphometry methods to patient images before and after lesion filling, we analysed robustness of global and regional cortical thickness measurements in the presence of white matter lesions. Methods based on a deep learning-based segmentation of the brain (Fastsurfer, DL+DiReCT, ANTsPyNet) exhibited greater robustness than those using classical segmentation methods (Freesurfer, ANTs).

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arXiv2025

Learning from spatially inhomogenous data: resolution-adaptive convolutions for multiple sclerosis lesion segmentation

In the setting of clinical imaging, differences in between vendors, hospitals and sequences can yield highly inhomogeneous imaging data. In MRI in particular, voxel dimension, slice spacing and acquisition plane can vary substantially. For clinical applications, therefore, algorithms must be trained to handle data with various voxel resolutions. The usual strategy to deal with heterogeneity of resolution is harmonization: resampling imaging data to a common (usually isovoxel) resolution. This can lead to loss of fidelity arising from interpolation artifacts out-of-plane and downsampling in-plane. We present in this paper a network architecture designed to be able to learn directly from spatially heterogeneous data, without resampling: a segmentation network based on the e3nn framework that leverages a spherical harmonic, rather than voxel-grid, parameterization of convolutional kernels, with a fixed physical radius. Networks based on these kernels can be resampled to their input voxel dimensions. We trained and tested our network on a publicly available dataset assembled from three centres, and on an in-house dataset of Multiple Sclerosis cases with a high degree of spatial inhomogeneity. We compared our approach to a standard U-Net with two strategies for handling inhomogeneous data: training directly on the data without resampling, and resampling to a common resolution of 1mm isovoxels. We show that our network is able to learn from various combinations of voxel sizes and outperforms classical U-Nets on 2D testing cases and most 3D testing cases. This shows an ability to generalize well when tested on image resolutions not seen during training. Our code can be found at: http://github.com/SCAN-NRAD/e3nn\_U-Net.

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arXiv2024

Identification and estimation of causal effects using non-concurrent controls in platform trials

Platform trials are multi-arm designs that simultaneously evaluate multiple treatments for a single disease within the same overall trial structure. Unlike traditional randomized controlled trials, they allow treatment arms to enter and exit the trial at distinct times while maintaining a control arm throughout. This control arm comprises both concurrent controls, where participants are randomized concurrently to either the treatment or control arm, and non-concurrent controls, who enter the trial when the treatment arm under study is unavailable. While flexible, platform trials introduce the challenge of using non-concurrent controls, raising questions about estimating treatment effects. Specifically, which estimands should be targeted? Under what assumptions can these estimands be identified and estimated? Are there any efficiency gains? In this paper, we discuss issues related to the identification and estimation assumptions of common choices of estimand. We conclude that the most robust strategy to increase efficiency without imposing unwarranted assumptions is to target the concurrent average treatment effect (cATE), the ATE among only concurrent units, using a covariate-adjusted doubly robust estimator. Our studies suggest that, for the purpose of obtaining efficiency gains, collecting important prognostic variables is more important than relying on non-concurrent controls. We also discuss the perils of targeting ATE due to an untestable extrapolation assumption that will often be invalid. We provide simulations illustrating our points and an application to the ACTT platform trial, resulting in a 20% improvement in precision compared to the naive estimator that ignores non-concurrent controls and prognostic variables.

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arXiv2024

Associations between pain-management treatments and opioid use disorder risk among Medicaid patients

Introduction: Chronic pain patients are at increased risk of opioid-misuse. Less is known about the unique risk conferred by each pain-management treatment, as treatments are typically implemented together, confounding their independent effects. We estimated the extent to which pain-management strategies were associated with risk of incident opioid use disorder (OUD) for those with chronic pain, controlling for baseline demographic and clinical confounding variables and holding other pain-management treatments at their observed levels. Methods: We used data from two chronic pain subgroups within a cohort of non-pregnant Medicaid patients aged 35-64 years, 2016-2019, from 25 states: 1) those with a chronic pain condition co-morbid with physical disability (N=6,133) or 2) those with chronic pain without disability (N=67,438). We considered 9 pain-management treatments: prescription opioid i) dose and ii) duration; iii) number of opioid prescribers; opioid co-prescription with iv) benzodiazepines, v) muscle relaxants, and vi) gabapentinoids; vii) non-opioid pain prescription, viii) physical therapy, and ix) other pain treatment modality. Our outcome was incident OUD. Results: Having an opioid and gabapentin co-prescription or an opioid and benzodiazepine co-prescription was statistically significantly associated with a 16-46% increased risk of OUD. Opioid dose and duration also were significantly associated with increased risk of OUD. Physical therapy was significantly associated with an 11% decreased risk of OUD in the subgroup with chronic pain but no disability. Conclusions: Co-prescription of opioids with either gabapentin or benzodiazepines may substantially increase risk of OUD. More positively, physical therapy may be a relatively accessible and safe pain-management strategy.

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arXiv2023

Studying continuous, time-varying, and/or complex exposures using longitudinal modified treatment policies

This tutorial discusses methodology for causal inference using longitudinal modified treatment policies. This method facilitates the mathematical formalization, identification, and estimation of many novel parameters, and mathematically generalizes many commonly used parameters, such as the average treatment effect. Longitudinal modified treatment policies apply to a wide variety of exposures, including binary, multivariate, and continuous, and can accommodate time-varying treatments and confounders, competing risks, loss-to-follow-up, as well as survival, binary, or continuous outcomes. Longitudinal modified treatment policies can be seen as an extension of static and dynamic interventions to involve the natural value of treatment, and, like dynamic interventions, can be used to define alternative estimands with a positivity assumption that is more likely to be satisfied than estimands corresponding to static interventions. This tutorial aims to illustrate several practical uses of the longitudinal modified treatment policy methodology, including describing different estimation strategies and their corresponding advantages and disadvantages. We provide numerous examples of types of research questions which can be answered using longitudinal modified treatment policies. We go into more depth with one of these examples--specifically, estimating the effect of delaying intubation on critically ill COVID-19 patients' mortality. We demonstrate the use of the open-source R package lmtp to estimate the effects, and we provide code on https://github.com/kathoffman/lmtp-tutorial.

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arXiv2023

Improving efficiency in transporting average treatment effects

We develop flexible, semiparametric estimators of the average treatment effect (ATE) transported to a new population ("target population") that offer potential efficiency gains. Transport may be of value when the ATE may differ across populations. We consider the setting where differences in the ATE are due to differences in the distribution of baseline covariates that modify the treatment effect ("effect modifiers"). First, we propose a collaborative one-step semiparametric estimator that can improve efficiency. This approach does not require researchers to have knowledge about which covariates are effect modifiers and which differ in distribution between the populations, but does require all covariates to be measured in the target population. Second, we propose two one-step semiparametric estimators that assume knowledge of which covariates are effect modifiers and which are both effect modifiers and differentially distributed between the populations. These estimators can be used even when not all covariates are observed in the target population; one requires that only effect modifiers are observed, and the other requires that only those modifiers that are also differentially distributed are observed. We use simulation to compare finite sample performance across our proposed estimators and an existing semiparametric estimator of the transported ATE, including in the presence of practical violations of the positivity assumption. Lastly, we apply our proposed estimators to a large-scale housing trial.

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arXiv2023

Leveraging SO(3)-steerable convolutions for pose-robust semantic segmentation in 3D medical data

Convolutional neural networks (CNNs) allow for parameter sharing and translational equivariance by using convolutional kernels in their linear layers. By restricting these kernels to be SO(3)-steerable, CNNs can further improve parameter sharing. These rotationally-equivariant convolutional layers have several advantages over standard convolutional layers, including increased robustness to unseen poses, smaller network size, and improved sample efficiency. Despite this, most segmentation networks used in medical image analysis continue to rely on standard convolutional kernels. In this paper, we present a new family of segmentation networks that use equivariant voxel convolutions based on spherical harmonics. These networks are robust to data poses not seen during training, and do not require rotation-based data augmentation during training. In addition, we demonstrate improved segmentation performance in MRI brain tumor and healthy brain structure segmentation tasks, with enhanced robustness to reduced amounts of training data and improved parameter efficiency. Code to reproduce our results, and to implement the equivariant segmentation networks for other tasks is available at http://github.com/SCAN-NRAD/e3nn_Unet

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arXiv2022

All models are wrong, but which are useful? Comparing parametric and nonparametric estimation of causal effects in finite samples

There is a long-standing debate in the statistical, epidemiological and econometric fields as to whether nonparametric estimation that uses data-adaptive methods, like machine learning algorithms in model fitting, confer any meaningful advantage over simpler, parametric approaches in real-world, finite sample estimation of causal effects. We address the question: when trying to estimate the effect of a treatment on an outcome, across a universe of reasonable data distributions, how much does the choice of nonparametric vs.~parametric estimation matter? Instead of answering this question with simulations that reflect a few chosen data scenarios, we propose a novel approach evaluating performance across thousands of data-generating mechanisms drawn from non-parametric models with semi-informative priors. We call this approach a Universal Monte-Carlo Simulation. We compare performance of estimating the average treatment effect across two parametric estimators (a g-computation estimator that uses a parametric outcome model and an inverse probability of treatment weighted estimator) and two nonparametric estimators (Bayesian additive regression trees and a targeted minimum loss-based estimator that uses an ensemble of machine learning algorithms in model fitting). We summarize estimator performance in terms of bias, confidence interval coverage, and mean squared error. We find that the nonparametric estimators nearly always outperform the parametric estimators with the exception of having similar performance in terms of bias and similar-to-slightly-worse performance in terms of coverage under the smallest sample size of N=100.

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arXiv2022

Nonparametric estimators of interventional (transported) direct and indirect effects that accommodate multiple mediators and multiple intermediate confounders

Mediation analysis is appealing for its ability to improve understanding of the mechanistic drivers of causal effects, but real-world data complexities challenge its successful implementation, including: 1) the existence of post-exposure variables that also affect mediators and outcomes (thus, confounding the mediator-outcome relationship), that may also be 2) multivariate, and 3) the existence of multivariate mediators. Interventional direct and indirect effects (IDE/IIE) accommodate post-exposure variables that confound the mediator-outcome relationship, but currently, no estimator for IDE/IIE exists that allows for both multivariate mediators and multivariate post-exposure intermediate confounders. This, again, represents a significant limitation for real-world analyses. We address this gap by extending two recently developed nonparametric estimators -- one that estimates the IDE/IIE and another that estimates the IDE/IIE transported to a new, target population -- to allow for multivariate mediators and multivariate intermediate confounders simultaneously. We use simulation to examine finite sample performance, and apply these estimators to longitudinal data from the Moving to Opportunity trial. In the application, we walk through a strategy for separating indirect effects into mediator- or mediator-group-specific indirect effects, while appropriately accounting for other, possibly co-occurring intermediate variables.

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arXiv2022

When effects cannot be estimated: redefining estimands to understand the effects of naloxone access laws

Violations of the positivity assumption (also called the common support condition) challenge health policy research, and can result in significant bias, large variance, and invalid inference. We define positivity in the single- and multiple-timepoint (i.e., longitudinal) health policy evaluation setting, and discuss real-world threats to positivity. We show empirical evidence of the practical positivity violations that can result when attempting to estimate effects of health policies (in this case, Naloxone Access Laws). In such scenarios, an alternative is to estimate the effect of a shift in law enactment (e.g., the effect if enactment had been delayed by some number of years). Such an effect corresponds to what is called a modified treatment policy, and dramatically weakens the required positivity assumption, thereby offering a means to estimate policy effects even in scenarios with serious positivity problems. We apply the approach to define and estimate longitudinal effects of Naloxone Access Laws on opioid overdose rates.

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arXiv2022

Causal inference for social network data

We describe semiparametric estimation and inference for causal effects using observational data from a single social network. Our asymptotic results are the first to allow for dependence of each observation on a growing number of other units as sample size increases. In addition, while previous methods have implicitly permitted only one of two possible sources of dependence among social network observations, we allow for both dependence due to transmission of information across network ties and for dependence due to latent similarities among nodes sharing ties. We propose new causal effects that are specifically of interest in social network settings, such as interventions on network ties and network structure. We use our methods to reanalyze an influential and controversial study that estimated causal peer effects of obesity using social network data from the Framingham Heart Study; after accounting for network structure we find no evidence for causal peer effects.

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arXiv2022

Efficient and flexible estimation of natural mediation effects under intermediate confounding and monotonicity constraints

Natural direct and indirect effects are mediational estimands that decompose the average treatment effect and describe how outcomes would be affected by contrasting levels of a treatment through changes induced in mediator values (in the case of the indirect effect) or not through induced changes in the mediator values (in the case of the direct effect). Natural direct and indirect effects are not generally point-identifiable in the presence of a treatment-induced confounder, however they may still be identified if one is willing to assume monotonicity between a treatment and the treatment-induced confounder. We argue that this assumption may be reasonable in the relatively common encouragement-design trial setting where intervention is randomized treatment assignment and the treatment-induced confounder is whether or not treatment was actually taken/adhered to. We develop efficiency theory for the natural direct and indirect effects under this monotonicity assumption, and use it to propose a nonparametric, multiply robust estimator. We demonstrate the finite sample properties of this estimator using a simulation study, and apply it to data from the Moving to Opportunity Study to estimate the natural direct and indirect effects of being randomly assigned to receive a Section 8 housing voucher -- the most common form of federal housing assistance -- on risk developing any mood or externalizing disorder among adolescent boys, possibly operating through various school and community characteristics.

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