arXiv subjects

Mireille E. Schnitzer

Publications and source records attributed to Mireille E. Schnitzer.

At least 19 recordsLinked to original sources

arXiv2026

Assumption-Lean Differential Variance Inference for Heterogeneous Treatment Effect Detection

The conditional average treatment effect (CATE) is frequently estimated in clinical studies to refute a homogeneous treatment effect hypothesis. Under this regime, all patients making up the population experience identical benefit from a given treatment relative to a comparator. Uncovering heterogeneous treatment effects through inference about the CATE, however, requires that covariates truly modifying the treatment effect be reliably collected at baseline. CATE-based techniques will necessarily fail to detect violations when effect modifiers are omitted from the data due to, for example, resource constraints. Severe measurement error has a similar impact. Clinical decision makers can be misled as a result. To address these limitations, we prove that a practical homogeneous treatment effect hypothesis can be gauged through inference about contrasts of the potential outcomes' variances even when effect modifiers are missing from the data. We derive causal machine learning estimators of these contrasts and study their asymptotic properties. We establish that these estimators are doubly robust and asymptotically linear under mild conditions, permitting formal hypothesis testing about treatment effect heterogeneity. Numerical experiments demonstrate that these estimators' asymptotic guarantees are approximately achieved in finite-sample randomized and observational study data alike. These inference procedures are then used to detect heterogeneous treatment effects in the re-analysis of randomized controlled trials investigating targeted temperature management in cardiac arrest patients.

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arXiv2026

Causal inference via propensity scores for case-control studies

Propensity score methods for causal inference are increasingly being used in cohort and experimental designs, but their development and uptake in outcome-dependent sampling schemes, such as case-control studies, remains limited. Case-control studies involve the sampling of individuals with and without an outcome of interest with the goal of estimating the effects of past exposures. When the design is observational, statistical adjustment for confounding bias is necessary. In case-control studies, propensity score models can be fit using control data under the assumption that the controls are representative of the source population with respect to their exposure distribution conditional on covariates ("control exchangeability"). In this paper, we first demonstrate that relative effects, such as causal risk ratios, are estimable under three different case-control design variants using control-fitted propensity scores. We appropriate two existing estimators for these designs: inverse probability of treatment weighting and an efficient and doubly robust estimator. We also introduce a novel two-step propensity score caliper-matching procedure for case-control designs. We introduce novel diagnostic tools to verify two necessary types of overlap. We then contrast our estimators using simulated data and apply them to examine the association between regular aspirin use and ovarian cancer risk.

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arXiv2026

The positivity assumption in causal mediation analyses? Checked!

Causal mediation analyses are increasingly used in psychological sciences. Among the required assumptions, positivity is unfortunately seldom mentioned, likely due to the lack of tools for checking it. Mediational positivity is more complex than positivity in standard, non-mediated exposure effect analysis, because it requires positivity for both the exposure and the mediator, and because the specific form of the positivity assumption depends on the mediation estimand of interest. We propose an extension of the Positivity Regression Trees (PoRT) algorithm -- which was recently designed to check positivity in non-mediated settings without requiring assumptions about the modeling or the data-generating process -- to controlled, natural and interventional mediational effects. We illustrate its use through an application in mental health and have made it accessible through the port R package and a related notebook available at github.com/ArthurChatton/dePoRT-notebook. Finally, we discuss consequences and provide recommendations for when positivity violations are identified.

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arXiv2026

Valid post-selection inference for penalized G-estimation

Understanding treatment effect heterogeneity is important for decision making in medical and clinical practices, or handling various engineering and marketing challenges. When dealing with high-dimensional covariates or when the effect modifiers are not predefined and need to be discovered, data-adaptive selection approaches become essential. However, with data-driven model selection, the quantification of statistical uncertainty is complicated by post-selection inference due to difficulties in approximating the sampling distribution of the target estimator. Data-driven model selection tends to favor models with strong effect modifiers with an associated cost of inflated type I errors. Although several frameworks and methods for valid statistical inference have been proposed for ordinary least squares regression following data-driven model selection, fewer options exist for valid inference for effect modifier discovery in causal modeling contexts. In this article, we extend two different methods to develop valid inference for penalized G-estimation that investigates effect modification of proximal treatment effects within the structural nested mean model framework. We show the asymptotic validity of the proposed methods. Using extensive simulation studies, we evaluate and compare the finite sample performance of the proposed methods and the naive inference based on a sandwich variance estimator. Our work is motivated by the study of hemodiafiltration for treating patients with end-stage renal disease at the Centre Hospitalier de l'Université de Montréal. We apply these methods to draw inference about the effect heterogeneity of dialysis facility on the repeated session-specific hemodiafiltration outcomes.

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arXiv2026

Robust Mendelian Randomization Estimation using Weighted Quantile Regression

In Mendelian randomization (MR) studies, genetic variants are used as instrumental variables (IVs) to investigate causal relationships between exposures and outcomes based on observational data. However, numerous genetic studies have shown the pervasive pleiotropy of genetic variants, meaning that many, if not most, variants are associated with multiple traits, potentially violating the core assumptions of IV estimation. Uncorrelated pleiotropy occurs when genetic variants have a direct effect on the outcome that is not mediated by the exposure, while correlated pleiotropy occurs when genetic variants affect the exposure and outcome via shared heritable confounders. In this work, we propose a novel MR method, called MR-Quantile, based on weighted quantile regression (WQR) that is robust to both correlated and uncorrelated pleiotropy. We propose a procedure for selecting the optimal quantile of the ratio estimates through a likelihood-based formulation of WQR using the asymmetric Laplace distribution. Monte Carlo simulations demonstrate the empirical performance of the proposed method, especially in settings with many invalid IVs with weak pleiotropic effects. Finally, we apply our method to study the causal effect of resting heart rate on atrial fibrillation. Genetic variants associated with heart rate were identified in a genome-wide association study of 425,748 individuals from the VA Million Veteran Program, and used as instruments in a two-sample MR analysis with summary statistics from a genetic meta-analysis of 228,926 AF cases across eight studies.

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arXiv2025

Sex at birth could well be a biological coin toss.... Beware of conditioning on post-baseline information

Wang et al. (2025) use statistics to argue that sex at birth is not a biological coin toss, by noticing that repeated patterns such as Male Male Male and Female Female Female occur in the Nurses Health Study more often than patterns like Male Female Male, Male Female Female, Female Male Female, or Female Male Male. This letter shows that this over-representation is likely due to a statistical artifact, arising from parent preferences for mixed-sex children. As noticed in Angrist and Evans (1998) and supported by the data in Wang et al. (2025), parents are more likely to have a third child if their first two children are of the same sex. We show mathematically and statistically that mixed-sex preferences lead to the over-representation of patterns like Male Male Male and Female Female Female. In fact, the patterns seen in the Nurses Health Study are perfectly consistent with sex at birth being a random coin toss.

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arXiv2025

Is checking for sequential positivity violations getting you down? Try sPoRT!

Background: Sequential positivity is often a necessary assumption for drawing causal inferences, such as through marginal structural modeling. Unfortunately, verification of this assumption can be challenging because it usually relies on multiple parametric propensity score models, unlikely all correctly specified. Therefore, we propose a new algorithm, called sequential Positivity Regression Tree (sPoRT), to overcome this issue and identify the subgroups found to be violating this assumption, allowing for insights about the nature of the violations and potential solutions. Methods: We present different versions of sPoRT based on either stratifying or pooling over time under static or dynamic treatment strategies. This methodological development was motivated by a real-life application of the impact of the timing of initiation of HIV treatment with and without smoothing over time, which we also use to demonstrate the method. Results: The illustration of sPoRT demonstrates its easy use and the interpretability of the results for applied epidemiologists. Furthermore, an R notebook showing how to use sPoRT in practice is available at github.com/ArthurChatton/sPoRT-notebook. Conclusions: The sPoRT algorithm provides interpretable subgroups violating the sequential positivity violation, allowing patterns and trends in the confounders to be easily identified. We finally provided practical implications and recommendations when positivity violations are identified.

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arXiv2025

Penalized G-estimation for effect modifier selection in a structural nested mean model for repeated outcomes

Effect modification occurs when the impact of the treatment on an outcome varies based on the levels of other covariates known as effect modifiers. Modeling these effect differences is important for etiological goals and for purposes of optimizing treatment. Structural nested mean models (SNMMs) are useful causal models for estimating the potentially heterogeneous effect of a time-varying exposure on the mean of an outcome in the presence of time-varying confounding. A data-adaptive selection approach is necessary if the effect modifiers are unknown a priori and need to be identified. Although variable selection techniques are available for estimating the conditional average treatment effects using marginal structural models or for developing optimal dynamic treatment regimens, all of these methods consider a single end-of-follow-up outcome. In the context of an SNMM for repeated outcomes, we propose a doubly robust penalized G-estimator for the causal effect of a time-varying exposure with a simultaneous selection of effect modifiers and prove the oracle property of our estimator. We conduct a simulation study for the evaluation of its performance in finite samples and verification of its double-robustness property. Our work is motivated by the study of hemodiafiltration for treating patients with end-stage renal disease at the Centre Hospitalier de l'Université de Montréal. We apply the proposed method to investigate the effect heterogeneity of dialysis facility on the repeated session-specific hemodiafiltration outcomes.

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arXiv2024

Personalised dynamic super learning: an application in predicting hemodiafiltration convection volumes

Obtaining continuously updated predictions is a major challenge for personalised medicine. Leveraging combinations of parametric regressions and machine learning approaches, the personalised online super learner (POSL) can achieve such dynamic and personalised predictions. We adapt POSL to predict a repeated continuous outcome dynamically and propose a new way to validate such personalised or dynamic prediction models. We illustrate its performance by predicting the convection volume of patients undergoing hemodiafiltration. POSL outperformed its candidate learners with respect to median absolute error, calibration-in-the-large, discrimination, and net benefit. We finally discuss the choices and challenges underlying the use of POSL.

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arXiv2024

trajmsm: An R package for Trajectory Analysis and Causal Modeling

The R package trajmsm provides functions designed to simplify the estimation of the parameters of a model combining latent class growth analysis (LCGA), a trajectory analysis technique, and marginal structural models (MSMs) called LCGA-MSM. LCGA summarizes similar patterns of change over time into a few distinct categories called trajectory groups, which are then included as "treatments" in the MSM. MSMs are a class of causal models that correctly handle treatment-confounder feedback. The parameters of LCGA-MSMs can be consistently estimated using different estimators, such as inverse probability weighting (IPW), g-computation, and pooled longitudinal targeted maximum likelihood estimation (pooled LTMLE). These three estimators of the parameters of LCGA-MSMs are currently implemented in our package. In the context of a time-dependent outcome, we previously proposed a combination of LCGA and history-restricted MSMs (LCGA-HRMSMs). Our package provides additional functions to estimate the parameters of such models. Version 0.1.3 of the package is currently available on CRAN.

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arXiv2024

Integrating complex selection rules into the latent overlapping group Lasso for constructing coherent prediction models

The construction of coherent prediction models holds great importance in medical research as such models enable health researchers to gain deeper insights into disease epidemiology and clinicians to identify patients at higher risk of adverse outcomes. One commonly employed approach to developing prediction models is variable selection through penalized regression techniques. Integrating natural variable structures into this process not only enhances model interpretability but can also %increase the likelihood of recovering the true underlying model and boost prediction accuracy. However, a challenge lies in determining how to effectively integrate potentially complex selection dependencies into the penalized regression. In this work, we demonstrate how to represent selection dependencies mathematically, provide algorithms for deriving the complete set of potential models, and offer a structured approach for integrating complex rules into variable selection through the latent overlapping group Lasso. To illustrate our methodology, we applied these techniques to construct a coherent prediction model for major bleeding in hypertensive patients recently hospitalized for atrial fibrillation and subsequently prescribed oral anticoagulants. In this application, we account for a proxy of anticoagulant adherence and its interaction with dosage and the type of oral anticoagulants in addition to drug-drug interactions.

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arXiv2024

A general framework for formulating structured variable selection

In variable selection, a selection rule that prescribes the permissible sets of selected variables (called a "selection dictionary") is desirable due to the inherent structural constraints among the candidate variables. Such selection rules can be complex in real-world data analyses, and failing to incorporate such restrictions could not only compromise the interpretability of the model but also lead to decreased prediction accuracy. However, no general framework has been proposed to formalize selection rules and their applications, which poses a significant challenge for practitioners seeking to integrate these rules into their analyses. In this work, we establish a framework for structured variable selection that can incorporate universal structural constraints. We develop a mathematical language for constructing arbitrary selection rules, where the selection dictionary is formally defined. We demonstrate that all selection rules can be expressed as combinations of operations on constructs, facilitating the identification of the corresponding selection dictionary. Once this selection dictionary is derived, practitioners can apply their own user-defined criteria to select the optimal model. Additionally, our framework enhances existing penalized regression methods for variable selection by providing guidance on how to appropriately group variables to achieve the desired selection rule. Furthermore, our innovative framework opens the door to establishing new l0 norm-based penalized regression techniques that can be tailored to respect arbitrary selection rules, thereby expanding the possibilities for more robust and tailored model development.

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arXiv2024

Structured Learning in Time-dependent Cox Models

Cox models with time-dependent coefficients and covariates are widely used in survival analysis. In high-dimensional settings, sparse regularization techniques are employed for variable selection, but existing methods for time-dependent Cox models lack flexibility in enforcing specific sparsity patterns (i.e., covariate structures). We propose a flexible framework for variable selection in time-dependent Cox models, accommodating complex selection rules. Our method can adapt to arbitrary grouping structures, including interaction selection, temporal, spatial, tree, and directed acyclic graph structures. It achieves accurate estimation with low false alarm rates. We develop the sox package, implementing a network flow algorithm for efficiently solving models with complex covariate structures. sox offers a user-friendly interface for specifying grouping structures and delivers fast computation. Through examples, including a case study on identifying predictors of time to all-cause death in atrial fibrillation patients, we demonstrate the practical application of our method with specific selection rules.

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arXiv2022

The Delta-Method and Influence Function in Medical Statistics: a Reproducible Tutorial

Approximate statistical inference via determination of the asymptotic distribution of a statistic is routinely used for inference in applied medical statistics (e.g. to estimate the standard error of the marginal or conditional risk ratio). One method for variance estimation is the classical Delta-method but there is a knowledge gap as this method is not routinely included in training for applied medical statistics and its uses are not widely understood. Given that a smooth function of an asymptotically normal estimator is also asymptotically normally distributed, the Delta-method allows approximating the large-sample variance of a function of an estimator with known large-sample properties. In a more general setting, it is a technique for approximating the variance of a functional (i.e., an estimand) that takes a function as an input and applies another function to it (e.g. the expectation function). Specifically, we may approximate the variance of the function using the functional Delta-method based on the influence function (IF). The IF explores how a functional $ϕ(θ)$ changes in response to small perturbations in the sample distribution of the estimator and allows computing the empirical standard error of the distribution of the functional. The ongoing development of new methods and techniques may pose a challenge for applied statisticians who are interested in mastering the application of these methods. In this tutorial, we review the use of the classical and functional Delta-method and their links to the IF from a practical perspective. We illustrate the methods using a cancer epidemiology example and we provide reproducible and commented code in R and Python using symbolic programming. The code can be accessed at https://github.com/migariane/DeltaMethodInfluenceFunction

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arXiv2021

Doubly Robust Adaptive LASSO for Effect Modifier Discovery

Effect modification occurs when the effect of the treatment on an outcome differs according to the level of a third variable (the effect modifier, EM). A natural way to assess effect modification is by subgroup analysis or include the interaction terms between the treatment and the covariates in an outcome regression. The latter, however, does not target a parameter of a marginal structural model (MSM) unless a correctly specified outcome model is specified. Our aim is to develop a data-adaptive method to select effect modifying variables in an MSM with a single time point exposure. A two-stage procedure is proposed. First, we estimate the conditional outcome expectation and propensity score and plug these into a doubly robust loss function. Second, we use the adaptive LASSO to select the EMs and estimate MSM coefficients. Post-selection inference is then used to obtain coverage on the selected EMs. Simulations studies are performed in order to verify the performance of the proposed methods.

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arXiv2021

Data Integration through outcome adaptive LASSO and a collaborative propensity score approach

Administrative data, or non-probability sample data, are increasingly being used to obtain official statistics due to their many benefits over survey methods. In particular, they are less costly, provide a larger sample size, and are not reliant on the response rate. However, it is difficult to obtain an unbiased estimate of the population mean from such data due to the absence of design weights. Several estimation approaches have been proposed recently using an auxiliary probability sample which provides representative covariate information of the target population. However, when this covariate information is high-dimensional, variable selection is not a straight-forward task even for a subject matter expert. In the context of efficient and doubly robust estimation approaches for estimating a population mean, we develop two data adaptive methods for variable selection using the outcome adaptive LASSO and a collaborative propensity score, respectively. Simulation studies are performed in order to verify the performance of the proposed methods versus competing methods. Finally, we presented an anayisis of the impact of Covid-19 on Canadians.

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arXiv2021

Identifiability and estimation under the test-negative design with population controls with the goal of identifying risk and preventive factors for SARS-CoV-2 infection

Due to the rapidly evolving COVID-19 pandemic caused by the SARS-CoV-2 virus, quick public health investigations of the relationships between behaviours and infection risk are essential. Recently the test-negative design was proposed to recruit and survey participants who are symptomatic and being tested for SARS-CoV-2 infection with the goal of evaluating associations between the survey responses (including behaviours and environment) and testing positive on the test. It was also proposed to recruit additional controls who are part of the general population as a baseline comparison group in order to evaluate risk factors specific to SARS-CoV-2 infection. In this study, we consider an alternative design where we recruit among all individuals, symptomatic and asymptomatic, being tested for the virus in addition to population controls. We define a regression parameter related to a prospective risk factor analysis and investigate its identifiability under the two study designs. We review the difference between the prospective risk factor parameter and the parameter targeted in the typical test-negative design where only symptomatic and tested people are recruited. Using missing data directed acyclic graphs we provide conditions and required data collection under which identifiability of the prospective risk factor parameter is possible and compare the benefits and limitations of the alternative study designs and target parameters. We propose a novel inverse probability weighting estimator and demonstrate the performance of this estimator through simulation study.

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arXiv2019

Educational Note: Paradoxical Collider Effect in the Analysis of Non-Communicable Disease Epidemiological Data: a reproducible illustration and web application

Classical epidemiology has focused on the control of confounding but it is only recently that epidemiologists have started to focus on the bias produced by colliders. A collider for a certain pair of variables (e.g., an outcome Y and an exposure A) is a third variable (C) that is caused by both. In a directed acyclic graph (DAG), a collider is the variable in the middle of an inverted fork (i.e., the variable C in A -> C <- Y). Controlling for, or conditioning an analysis on a collider (i.e., through stratification or regression) can introduce a spurious association between its causes. This potentially explains many paradoxical findings in the medical literature, where established risk factors for a particular outcome appear protective. We use an example from non-communicable disease epidemiology to contextualize and explain the effect of conditioning on a collider. We generate a dataset with 1,000 observations and run Monte-Carlo simulations to estimate the effect of 24-hour dietary sodium intake on systolic blood pressure, controlling for age, which acts as a confounder, and 24-hour urinary protein excretion, which acts as a collider. We illustrate how adding a collider to a regression model introduces bias. Thus, to prevent paradoxical associations, epidemiologists estimating causal effects should be wary of conditioning on colliders. We provide R-code in easy-to-read boxes throughout the manuscript and a GitHub repository (https://github.com/migariane/ColliderApp) for the reader to reproduce our example. We also provide an educational web application allowing real-time interaction to visualize the paradoxical effect of conditioning on a collider http://watzilei.com/shiny/collider/.

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