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Bhramar Mukherjee

Publications and source records attributed to Bhramar Mukherjee.

At least 19 recordsLinked to original sources

Nonparametric heterogeneous causal mediation with orthogonal machine learning

Causal mediation analysis decomposes the total effect of an intervention on an outcome into a direct pathway and an indirect pathway transmitted through a mediator, but standard methods typically summarize these pathways using population average effects. In many applications, however, the indirect effect may vary substantially across individual profiles. We propose an orthogonal statistical learning framework for estimating heterogeneous causal mediation effects conditional on individual characteristics. The method constructs a class of weighted Neyman orthogonal losses motivated by influence function representations of weighted population average effects. These losses directly target conditional mediation estimands whose minimizers are locally insensitive to nuisance estimation errors. We implement the resulting learners under a two-stage meta-learning framework with regularized linear sieves as second-stage smoothers, and introduce a combination of targeted learning and orthogonal learning designed to improve stability when mediator density ratios are unstable. We establish $L^2$ and uniform limit theory and develop pointwise and uniform confidence bands. Simulation studies show that the proposed orthogonal learners reduce the mean integrated squared error by more than $50\%$ compared with existing model-based methods and provide computationally efficient inference in nonlinear settings. The CARDIA, PSACR, and STAR analyses reveal heterogeneous mediated effects across cardiometabolic, psychological, and educational settings.

stat.ME

Data Integration for Estimating Subgroup-Specific Conditional Average Treatment Effects (CATEs) Using Coarsened External Information in Randomized Trials

Randomized controlled trials (RCTs) are often underpowered to detect treatment heterogeneity in subgroups defined by cross-classifications of multiple covariates, due to sparse sample sizes in some strata. External RCT data can help, but typically provide treatment effect estimates at a coarser level (e.g., by sex or race) rather than for the finer subgroups of interest (e.g., race-by-sex). We propose a novel James-Stein (JS)-type estimator that borrows strength from such coarsened external estimates to improve estimation of finer subgroup-specific conditional average treatment effects (CATEs) in an internal study, while accommodating potential incompatibility in marginal CATEs across populations. Based on asymptotic theory, we derive a practical analytic variance estimator for the JS estimator that exhibits acceptable empirical performance. Under mild conditions, we show that the proposed estimator uniformly dominates the ordinary least squares (OLS) estimator based on internal data regarding a weighted quadratic loss. Simulation studies demonstrate favorable performance compared with existing shrinkage methods, including empirical Bayes and generalized ridge estimators. We illustrate our method by estimating race-by-sex subgroup CATEs in a tirzepatide weight-loss trial (SURMOUNT-1), borrowing sex-specific and race-specific estimates from two previous semaglutide trials (STEP 1 and STEP 2). The proposed method detects a significantly larger treatment effect on percentage weight loss in the female-White subgroup than in the female-Asian subgroup, a difference not detected using internal data alone.

stat.ME

Data (in)equities in data science: Dissecting systemic and systematic biases in pulse oximetry

Data equity is an emerging framework for responsible data science. However, its core concepts, including fairness, representativeness, and information bias, remain largely abstract and general, lacking the mathematical specificity needed for practical implementation. In this paper, we demonstrate how statisticians can operationalize data equity by translating its tenets into precise, testable formulations tailored to a given problem. Using the well-documented case of differential measurement error across racial groups in pulse oximetry, we first adopt an oracle approach, tracing how a single upstream violation of information bias compounds through the analytic pipeline into treatment disparities, fairness violations, and adverse health outcomes. We then demonstrate the inverse: starting from an observed outcome disparity, the data equity framework provides a principled structure for systematically identifying its statistical sources. Our exposition underscores how data equity, prediction equity, and decision equity are distinct requirements with distinct evaluation and policy needs--a nuance that highlights both the unique role of statisticians in the era of artificial intelligence as well as the necessity of interdisciplinary collaboration.

stat.AP

The Epidemiology of Artificial Intelligence

Artificial intelligence (AI) systems increasingly shape how people access health information, make medical decisions, and receive care -- yet epidemiology lacks frameworks for measuring AI exposure or studying its health effects at the population level. Here we argue that AI now functions as a determinant of health and propose a conceptual framework, borrowed from environmental epidemiology, for studying it. We distinguish ambient AI exposure -- algorithmic curation and AI-mediated institutional decisions that affect populations regardless of individual choice -- from personal AI exposure -- direct, volitional use of AI tools. We characterize AI's possible causal roles in epidemiological models, show that existing experimental approaches are inadequate for capturing chronic, population-level effects, and illustrate these ideas with nationally representative US survey data. We discuss implications for study design, health equity, and AI governance.

stat.OT

Prediction-based Inference in Electronic Health Record (EHR)-linked Biobanks with Clinically Informative Outcomes

Electronic health record (EHR)-linked biobank data hold tremendous promise for large-scale discoveries via genome-wide association study (GWAS) on diverse phenotypic traits and biomarkers routinely captured in the EHR. However, heterogeneous missingness in biomarkers compromises the validity and efficiency of statistical analyses. Prediction-based (PB) inference methods meet this challenge by using external machine learning (ML) predictions to impute missing biomarker outcomes, thereby improving statistical power and estimation accuracy in association analyses. Yet, their suitability remains unclear when outcomes are subject to clinically informative observation processes, that is, when laboratory tests are ordered based on both measured and unmeasured patient- and health system-level characteristics. In this paper, we review the statistical underpinnings of popular PB methods and then evaluate nine methods, including four PB methods and five traditional missing-data approaches, under an encompassing set of outcome observation processes for continuous and binary outcomes. PB methods can substantially improve statistical power and estimation efficiency when the missing-data mechanism is correctly specified. Under misspecification, however, these gains require both conditional independence between the covariates of interest and the missingness mechanism and independence between imputation error and the missingness mechanism. Using All of Us (AoU) data, we perform GWAS of six laboratory biomarkers and demonstrate that PB methods can replicate known genetic associations while improving efficiency relative to (weighted) complete-case analysis (CCA). Their performance in replicating existing GWAS results in AoU also depends on imputation quality and the underlying missingness mechanism.

stat.AP

Joint Modeling of Longitudinal EHR Data with Shared Random Effects for Informative Visiting and Observation Processes

Longitudinal electronic health record (EHR) data offer opportunities to study biomarker trajectories; however, association estimates-the primary inferential target-from standard models designed for regular observation times may be biased by a two-stage hierarchical missingness mechanism. The first stage is the visiting process (informative presence), where encounters occur at irregular times driven by patient health status; the second is the observation process (informative observation), where biomarkers are selectively measured during visits. To address these mechanisms, we propose a unified semiparametric joint modeling framework that simultaneously characterizes the visiting, biomarker observation, and longitudinal outcome processes. Central to this framework is a shared subject-specific Gaussian latent variable that captures unmeasured frailty and induces dependence across all components. We develop a three-stage estimation procedure and establish the consistency and asymptotic normality of our estimators. We also introduce a sequential procedure that imputes missing biomarkers prior to adjusting for irregular visiting and examine its performance. Simulation results demonstrate that our method yields unbiased estimates under this mechanism, whereas existing approaches can be substantially biased; notably, methods adjusting only for irregular visiting may exhibit even greater bias than those ignoring both mechanisms. We apply our framework to data from the All of Us Research Program to investigate associations between neighborhood-level socioeconomic status indicators and six blood-based biomarker trajectories, providing a robust tool for outpatient settings where irregular monitoring and selective measurement are prevalent.

stat.ME

Upgrading survival models with CARE

Clinical risk prediction models are regularly updated as new data, often with additional covariates, become available. We propose CARE (Convex Aggregation of relative Risk Estimators) as a general approach for combining existing "external" estimators with a new data set in a time-to-event survival analysis setting. Our method initially employs the new data to fit a flexible family of reproducing kernel estimators via penalised partial likelihood maximisation. The final relative risk estimator is then constructed as a convex combination of the kernel and external estimators, with the convex combination coefficients and regularisation parameters selected using cross-validation. We establish high-probability bounds for the $L_2$-error of our proposed aggregated estimator, showing that it achieves a rate of convergence that is at least as good as both the optimal kernel estimator and the best external model. Empirical results from simulation studies align with the theoretical results, and we illustrate the improvements our methods provide for cardiovascular disease risk modelling. Our methodology is implemented in the Python package care-survival.

stat.ME

A Doubly Robust Framework for Addressing Outcome-Dependent Selection Bias in Multi-Cohort EHR Studies

Selection bias can hinder accurate estimation of association parameters in binary disease risk models using non-probability samples like electronic health records (EHRs). The issue is compounded when participants are recruited from multiple clinics/centers with varying selection mechanisms that may depend on the disease/outcome of interest. Traditional inverse-probability-weighted (IPW) methods, based on constructed parametric selection models, often struggle with misspecifications when selection mechanisms vary across cohorts. This paper introduces a new Joint Augmented Inverse Probability Weighted (JAIPW) method, which integrates individual-level data from multiple cohorts collected under potentially outcome-dependent selection mechanisms, with data from an external probability sample. JAIPW offers double robustness by incorporating a flexible auxiliary score model to address potential misspecifications in the selection models. We outline the asymptotic properties of the JAIPW estimator, and our simulations reveal that JAIPW achieves up to six times lower relative bias and five times lower root mean square error (RMSE) compared to the best performing joint IPW methods under scenarios with misspecified selection models. Applying JAIPW to the Michigan Genomics Initiative (MGI), a multi-clinic EHR-linked biobank, combined with external national probability samples, resulted in cancer-sex association estimates closely aligned with national benchmark estimates. We also analyzed the association between cancer and polygenic risk scores (PRS) in MGI to illustrate a situation where the exposure variable is not measured in the external probability sample.

stat.ME

"Rebuilding" Statistics in the Age of AI: A Town Hall Discussion on Culture, Infrastructure, and Training

This article presents the full, original record of the 2024 Joint Statistical Meetings (JSM) town hall, "Statistics in the Age of AI," which convened leading statisticians to discuss how the field is evolving in response to advances in artificial intelligence, foundation models, large-scale empirical modeling, and data-intensive infrastructures. The town hall was structured around open panel discussion and extensive audience Q&A, with the aim of eliciting candid, experience-driven perspectives rather than formal presentations or prepared statements. This document preserves the extended exchanges among panelists and audience members, with minimal editorial intervention, and organizes the conversation around five recurring questions concerning disciplinary culture and practices, data curation and "data work," engagement with modern empirical modeling, training for large-scale AI applications, and partnerships with key AI stakeholders. By providing an archival record of this discussion, the preprint aims to support transparency, community reflection, and ongoing dialogue about the evolving role of statistics in the data- and AI-centric future.

stat.ML

A Unified Framework for Inference with General Missingness Patterns and Machine Learning Imputation

Pre-trained machine learning (ML) predictions have been increasingly used to complement incomplete data to enable downstream scientific inquiries, but their naive integration risks biased inferences. Recently, multiple methods have been developed to provide valid inference with ML imputations regardless of prediction quality and to enhance efficiency relative to complete-case analyses. However, existing approaches are often limited to missing outcomes under a missing-completely-at-random (MCAR) assumption, failing to handle general missingness patterns (missing in both the outcome and exposures) under the more realistic missing-at-random (MAR) assumption. This paper develops a novel method that delivers a valid statistical inference framework for general Z-estimation problems using ML imputations under the MAR assumption and for general missingness patterns. The core technical idea is to stratify observations by distinct missingness patterns and construct an estimator by appropriately weighting and aggregating pattern-specific information through a masking-and-imputation procedure on the complete cases. We provide theoretical guarantees of asymptotic normality of the proposed estimator and efficiency dominance over weighted complete-case analyses. Practically, the method affords simple implementations by leveraging existing weighted complete-case analysis software. Extensive simulations are carried out to validate theoretical results. A real data example is provided to further illustrate the practical utility of the proposed method. The paper concludes with a brief discussion on practical implications, limitations, and potential future directions.

stat.ME

What's the Weight? Estimating Controlled Outcome Differences in Complex Surveys for Health Disparities Research

In this work, we are motivated by the problem of estimating racial disparities in health outcomes, specifically the average controlled difference (ACD) in telomere length between Black and White individuals, using data from the National Health and Nutrition Examination Survey (NHANES). To do so, we build a propensity for race to properly adjust for other social determinants while characterizing the controlled effect of race on telomere length. Propensity score methods are broadly employed with observational data as a tool to achieve covariate balance, but how to implement them in complex surveys is less studied - in particular, when the survey weights depend on the group variable under comparison (as the NHANES sampling scheme depends on self-reported race). We propose identification formulas to properly estimate the ACD in outcomes between Black and White individuals, with appropriate weighting for both covariate imbalance across the two racial groups and generalizability. Via extensive simulation, we show that our proposed methods outperform traditional analytic approaches in terms of bias, mean squared error, and coverage when estimating the ACD for our setting of interest. In our data, we find that evidence of racial differences in telomere length between Black and White individuals attenuates after accounting for confounding by socioeconomic factors and utilizing appropriate propensity score and survey weighting techniques. Software to implement these methods and code to reproduce our results can be found in the R package svycdiff, available through the Comprehensive R Archive Network (CRAN) at cran.r-project.org/web/packages/svycdiff/, or in a development version on GitHub at github.com/salernos/svycdiff.

stat.ME

A Tutorial on Conducting Mediation Analysis with Exposure Mixtures

Causal mediation analysis is a powerful tool in environmental health research, allowing researchers to uncover the pathways through which exposures influence health outcomes. While traditional mediation methods have been widely applied to individual exposures, real-world scenarios often involve complex mixtures. Such mixtures introduce unique methodological challenges, including multicollinearity, sparsity of active exposures, and potential nonlinear and interactive effects. This paper provides an overview of several commonly used approaches for mediation analysis under exposure mixture settings with clear strategies and code for implementation. The methods include: single exposure mediation analysis (SE-MA), principal component-based mediation analysis, environmental risk score-based mediation analysis, and Bayesian kernel machine regression causal mediation analysis. While SE-MA serves as a baseline that analyzes each exposure individually, the other methods are designed to address the correlation and complexity inherent in exposure mixtures. For each method, we aim to clarify the target estimand and the assumptions that each method is making to render a causal interpretation of the estimates obtained. We conduct a simulation study to systematically evaluate the operating characteristics of these four methods to estimate global indirect effects and to identify individual exposures contributing to the global mediation under varying sample sizes, effect sizes, and exposure-mediator-outcome structures. We also illustrate their real-world applicability by examining data from the PROTECT birth cohort, specifically analyzing the relationship between prenatal exposure to phthalate mixtures and neonatal head circumference Z-score, with leukotriene E4 as a mediator. This example offers practical guidance for conducting mediation analysis in complex environmental contexts.

stat.ME

Towards Enhancing Data Equity in Public Health Data Science

Data-driven decisions shape public health policies and practice, yet persistent disparities in data representation skew insights and undermine interventions. To address this, we advance a structured roadmap that integrates public health data science with computer science and is grounded in reflexivity. We adopt data equity as a guiding concept: ensuring the fair and inclusive representation, collection, and use of data to prevent the introduction or exacerbation of systemic biases that could lead to invalid downstream inference and decisions. To underscore urgency, we present three public health cases where non-representative datasets and skewed knowledge impede decisions across diverse subgroups. These challenges echo themes in two literatures: public health highlights gaps in high-quality data for specific populations, while computer science and statistics contribute criteria and metrics for diagnosing bias in data and models. Building on these foundations, we propose a working definition of public health data equity and a structured self-audit framework. Our framework integrates core computational principles (fairness, accountability, transparency, ethics, privacy, confidentiality) with key public health considerations (selection bias, representativeness, generalizability, causality, information bias) to guide equitable practice across the data life cycle, from study design and data collection to measurement, analysis, interpretation, and translation. Embedding data equity in routine practice offers a practical path for ensuring that data-driven policies, artificial intelligence, and emerging technologies improve health outcomes for all. Finally, we emphasize the critical understanding that, although data equity is an essential first step, it does not inherently guarantee information, learning, or decision equity.

stat.AP

Generating Synthetic Electronic Health Record Data: a Methodological Scoping Review with Benchmarking on Phenotype Data and Open-Source Software

We conduct a scoping review of existing approaches for synthetic EHR data generation, and benchmark major methods with proposed open-source software to offer recommendations for practitioners. We search three academic databases for our scoping review. Methods are benchmarked on open-source EHR datasets, MIMIC-III/IV. Seven existing methods covering major categories and two baseline methods are implemented and compared. Evaluation metrics concern data fidelity, downstream utility, privacy protection, and computational cost. 42 studies are identified and classified into five categories. Seven open-source methods covering all categories are selected, trained on MIMIC-III, and evaluated on MIMIC-III or MIMIC-IV for transportability considerations. Among them, GAN-based methods demonstrate competitive performance in fidelity and utility on MIMIC-III; rule-based methods excel in privacy protection. Similar findings are observed on MIMIC-IV, except that GAN-based methods further outperform the baseline methods in preserving fidelity. A Python package, "SynthEHRella", is provided to integrate various choices of approaches and evaluation metrics, enabling more streamlined exploration and evaluation of multiple methods. We found that method choice is governed by the relative importance of the evaluation metrics in downstream use cases. We provide a decision tree to guide the choice among the benchmarked methods. Based on the decision tree, GAN-based methods excel when distributional shifts exist between the training and testing populations. Otherwise, CorGAN and MedGAN are most suitable for association modeling and predictive modeling, respectively. Future research should prioritize enhancing fidelity of the synthetic data while controlling privacy exposure, and comprehensive benchmarking of longitudinal or conditional generation methods.

cs.LG

A new statistical approach for joint modeling of longitudinal outcomes measured in electronic health records with clinically informative presence and observation processes

Biobanks with genetics-linked electronic health records (EHR) have opened up opportunities to study associations between genetic, social, or environmental factors and longitudinal lab biomarkers. However, in EHRs, the timing of patient visits and the recording of lab tests often depend on patient health status, referred to as informative presence (IP) and informative observation (IO), which can bias exposure-biomarker associations. Two gaps remain in EHR-based research: (1) the performance of existing IP-aware methods is unclear in real-world EHR settings, and (2) no existing methods handle IP and IO simultaneously. To address these challenges, we first conduct extensive simulation studies tailored to EHR-specific IP patterns to assess existing methods. We then propose a joint modeling framework, EHRJoint, that simultaneously models the visiting, observation, and longitudinal biomarker processes to address both IP and IO. We develop a computationally efficient estimation procedure based on estimating equations and provide asymptotically valid inference. Simulations show that EHRJoint yields unbiased exposure effect estimates under both IP and IO, while existing methods fail. We apply EHRJoint to the Michigan Genomics Initiative data to examine associations between repeated glucose measurements and two exposures: genetic variants and educational disadvantage.

stat.ME

Doubly robust causal inference through penalized bias-reduced estimation: combining non-probability samples with designed surveys

Causal inference on the average treatment effect (ATE) using non-probability samples, such as electronic health records (EHR), faces challenges from sample selection bias and high-dimensional covariates. This requires considering a selection model alongside treatment and outcome models that are typical ingredients in causal inference. This paper considers integrating large non-probability samples with external probability samples from a design survey, addressing moderately high-dimensional confounders and variables that influence selection. In contrast to the two-step approach that separates variable selection and debiased estimation, we propose a one-step plug-in doubly robust (DR) estimator of the ATE. We construct a novel penalized estimating equation by minimizing the squared asymptotic bias of the DR estimator. Our approach facilitates ATE inference in high-dimensional settings by ignoring the variability in estimating nuisance parameters, which is not guaranteed in conventional likelihood approaches with non-differentiable L1-type penalties. We provide a consistent variance estimator for the DR estimator. Simulation studies demonstrate the double robustness of our estimator under misspecification of either the outcome model or the selection and treatment models, as well as the validity of statistical inference under penalized estimation. We apply our method to integrate EHR data from the Michigan Genomics Initiative with an external probability sample.

stat.ME

Patient Recruitment Using Electronic Health Records Under Selection Bias: a Two-phase Sampling Framework

Electronic health records (EHRs) are increasingly recognized as a cost-effective resource for patient recruitment in clinical research. However, how to optimally select a cohort from millions of individuals to answer a scientific question of interest remains unclear. Consider a study to estimate the mean or mean difference of an expensive outcome. Inexpensive auxiliary covariates predictive of the outcome may often be available in patients' health records, presenting an opportunity to recruit patients selectively which may improve efficiency in downstream analyses. In this paper, we propose a two-phase sampling design that leverages available information on auxiliary covariates in EHR data. A key challenge in using EHR data for multi-phase sampling is the potential selection bias, because EHR data are not necessarily representative of the target population. Extending existing literature on two-phase sampling design, we derive an optimal two-phase sampling method that improves efficiency over random sampling while accounting for the potential selection bias in EHR data. We demonstrate the efficiency gain from our sampling design via simulation studies and an application to evaluating the prevalence of hypertension among US adults leveraging data from the Michigan Genomics Initiative, a longitudinal biorepository in Michigan Medicine.

stat.ME

A Framework for Understanding Selection Bias in Real-World Healthcare Data

Using administrative patient-care data such as Electronic Health Records (EHR) and medical/ pharmaceutical claims for population-based scientific research has become increasingly common. With vast sample sizes leading to very small standard errors, researchers need to pay more attention to potential biases in the estimates of association parameters of interest, specifically to biases that do not diminish with increasing sample size. Of these multiple sources of biases, in this paper, we focus on understanding selection bias. We present an analytic framework using directed acyclic graphs for guiding applied researchers to dissect how different sources of selection bias may affect estimates of the association between a binary outcome and an exposure (continuous or categorical) of interest. We consider four easy-to-implement weighting approaches to reduce selection bias with accompanying variance formulae. We demonstrate through a simulation study when they can rescue us in practice with analysis of real world data. We compare these methods using a data example where our goal is to estimate the well-known association of cancer and biological sex, using EHR from a longitudinal biorepository at the University of Michigan Healthcare system. We provide annotated R codes to implement these weighted methods with associated inference.

stat.ME