arXiv subjects

Philippe Boileau

Publications and source records attributed to Philippe Boileau.

7 recordsLinked to original sources

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.

stat.ME↗

arXiv2026

Identifying and Estimating Causal Direct Effects Under Unmeasured Confounding

Causal mediation analysis provides techniques for defining and estimating effects that may be endowed with mechanistic interpretations. With many scientific investigations seeking to address mechanistic questions, causal direct and indirect effects have garnered much attention. The natural direct and indirect effects, the most widely used among such causal mediation estimands, are limited in their practical utility due to stringent identification requirements. Accordingly, considerable effort has been invested in developing alternative direct and indirect effect decompositions with relaxed identification requirements. Such efforts often yield effect definitions with nuanced and challenging interpretations. By contrast, relatively limited attention has been paid to relaxing the identification assumptions of the natural direct and indirect effects. Motivated by a secondary aim of a recent non-randomized vaccine prospective cohort study (NCT05168813), we present a set of relaxed conditions under which the natural direct effect is identifiable in spite of unobserved baseline confounding of the exposure-mediator pathway; we use this result to investigate the effect mediated by putative immune correlates of protection. Relaxing the commonly used but restrictive cross-world counterfactual independence assumption, we discuss strategies for evaluating the natural direct effect in non-randomized settings that arise in the analysis of vaccine studies. We revisit prior studies of semi-parametric efficiency theory to demonstrate the construction of flexible, multiply robust estimators of the natural direct effect and discuss efficient estimation strategies that do not place restrictive modeling assumptions on nuisance functions.

stat.ME↗

arXiv2023

Guidance on Individualized Treatment Rule Estimation in High Dimensions

Individualized treatment rules, cornerstones of precision medicine, inform patient treatment decisions with the goal of optimizing patient outcomes. These rules are generally unknown functions of patients' pre-treatment covariates, meaning they must be estimated from clinical or observational study data. Myriad methods have been developed to learn these rules, and these procedures are demonstrably successful in traditional asymptotic settings with moderate number of covariates. The finite-sample performance of these methods in high-dimensional covariate settings, which are increasingly the norm in modern clinical trials, has not been well characterized, however. We perform a comprehensive comparison of state-of-the-art individualized treatment rule estimators, assessing performance on the basis of the estimators' accuracy, interpretability, and computational efficiency. Sixteen data-generating processes with continuous outcomes and binary treatment assignments are considered, reflecting a diversity of randomized and observational studies. We summarize our findings and provide succinct advice to practitioners needing to estimate individualized treatment rules in high dimensions. All code is made publicly available, facilitating modifications and extensions to our simulation study. A novel pre-treatment covariate filtering procedure is also proposed and is shown to improve estimators' accuracy and interpretability.

stat.ME↗

arXiv2023

A nonparametric framework for treatment effect modifier discovery in high dimensions

Heterogeneous treatment effects are driven by treatment effect modifiers, pre-treatment covariates that modify the effect of a treatment on an outcome. Current approaches for uncovering these variables are limited to low-dimensional data, data with weakly correlated covariates, or data generated according to parametric processes. We resolve these issues by developing a framework for defining model-agnostic treatment effect modifier variable importance parameters applicable to high-dimensional data with arbitrary correlation structure, deriving one-step, estimating equation and targeted maximum likelihood estimators of these parameters, and establishing these estimators' asymptotic properties. This framework is showcased by defining variable importance parameters for data-generating processes with continuous, binary, and time-to-event outcomes with binary treatments, and deriving accompanying multiply-robust and asymptotically linear estimators. Simulation experiments demonstrate that these estimators' asymptotic guarantees are approximately achieved in realistic sample sizes for observational and randomized studies alike. This framework is applied to gene expression data collected for a clinical trial assessing the effect of a monoclonal antibody therapy on disease-free survival in breast cancer patients. Genes predicted to have the greatest potential for treatment effect modification have previously been linked to breast cancer. An open-source R package implementing this methodology, unihtee, is made available on GitHub at https://github.com/insightsengineering/unihtee.

stat.ME↗

arXiv2022

A Flexible Approach for Predictive Biomarker Discovery

An endeavor central to precision medicine is predictive biomarker discovery; they define patient subpopulations which stand to benefit most, or least, from a given treatment. The identification of these biomarkers is often the byproduct of the related but fundamentally different task of treatment rule estimation. Using treatment rule estimation methods to identify predictive biomarkers in clinical trials where the number of covariates exceeds the number of participants often results in high false discovery rates. The higher than expected number of false positives translates to wasted resources when conducting follow-up experiments for drug target identification and diagnostic assay development. Patient outcomes are in turn negatively affected. We propose a variable importance parameter for directly assessing the importance of potentially predictive biomarkers, and develop a flexible nonparametric inference procedure for this estimand. We prove that our estimator is double-robust and asymptotically linear under loose conditions on the data-generating process, permitting valid inference about the importance metric. The statistical guarantees of the method are verified in a thorough simulation study representative of randomized control trials with moderate and high-dimensional covariate vectors. Our procedure is then used to discover predictive biomarkers from among the tumor gene expression data of metastatic renal cell carcinoma patients enrolled in recently completed clinical trials. We find that our approach more readily discerns predictive from non-predictive biomarkers than procedures whose primary purpose is treatment rule estimation. An open-source software implementation of the methodology, the uniCATE R package, is briefly introduced.

stat.ME↗

arXiv2022

A generalization of moderated statistics to data adaptive semiparametric estimation in high-dimensional biology

The widespread availability of high-dimensional biological data has made the simultaneous screening of many biological characteristics a central problem in computational biology and allied sciences. While the dimensionality of such datasets continues to grow, so too does the complexity of biomarker identification from exposure patterns in health studies measuring baseline confounders; moreover, doing so while avoiding model misspecification remains an issue only partially addressed. Efficient estimators capable of incorporating flexible, data adaptive regression techniques in estimating relevant components of the data-generating distribution provide an avenue for avoiding model misspecification; however, in the context of high-dimensional problems that require the simultaneous estimation of numerous parameters, standard variance estimators have proven unstable, resulting in unreliable Type-I error control even under standard multiple testing corrections. We present a general approach for applying empirical Bayes shrinkage to variance estimators of a family of efficient, asymptotically linear estimators of population intervention causal effects. Our generalization of shrinkage-based variance estimators increases inferential stability in high-dimensional settings, facilitating the application of these estimators for deriving nonparametric variable importance measures in high-dimensional biological datasets with modest sample sizes. The result is a data adaptive approach for robustly uncovering stable causal associations in high-dimensional data in studies with limited samples. Our generalized variance estimator is evaluated against alternative variance estimators in numerical experiments. Identification of biomarkers with the proposed methodology is demonstrated in an analysis of high-dimensional DNA methylation data from an observational study on the epigenetic effects of tobacco smoking.

stat.ME↗

arXiv2021

Cross-Validated Loss-Based Covariance Matrix Estimator Selection in High Dimensions

The covariance matrix plays a fundamental role in many modern exploratory and inferential statistical procedures, including dimensionality reduction, hypothesis testing, and regression. In low-dimensional regimes, where the number of observations far exceeds the number of variables, the optimality of the sample covariance matrix as an estimator of this parameter is well-established. High-dimensional regimes do not admit such a convenience, however. As such, a variety of estimators have been derived to overcome the shortcomings of the sample covariance matrix in these settings. Yet, the question of selecting an optimal estimator from among the plethora available remains largely unaddressed. Using the framework of cross-validated loss-based estimation, we develop the theoretical underpinnings of just such an estimator selection procedure. In particular, we propose a general class of loss functions for covariance matrix estimation and establish finite-sample risk bounds and conditions for the asymptotic optimality of the cross-validated estimator selector with respect to these loss functions. We evaluate our proposed approach via a comprehensive set of simulation experiments and demonstrate its practical benefits by application in the exploratory analysis of two single-cell transcriptome sequencing datasets. A free and open-source software implementation of the proposed methodology, the cvCovEst R package, is briefly introduced.

stat.ME↗