arXiv subjects

Chixiang Chen

Publications and source records attributed to Chixiang Chen.

At least 19 recordsLinked to original sources

arXiv2026

A Novel Tool for Evaluating Effect Modification in Older Adults with ADRD Using Medicare Claims

Studying consequences following baseline exposures has become increasingly important for advancing comparative effectiveness research using real-world data. This case study evaluates the impact of hospital-acquired conditions (HAC) during hospitalization for hip fracture on post-discharge recovery trajectories among older adults living with Alzheimer Disease and Related Dementia, a population particularly vulnerable to high post-hospital mortality. To appropriately account for truncation of recovery trajectory due to death and to explore heterogeneity in effect modification by patient demographics, we introduce a novel pseudo data-based robust (PD-Robust) analysis strategy, accompanied by an R package and detailed usage guidance to inform real data analysis. Grounded in an interpretable estimand via principal stratification under principal ignorability and a structural working model, PD-Robust accommodates truncation by death, provides model diagnosis and robustness check against assumption violation, and facilitates the characterization of patient profiles among the principal stratum. Applied to Medicare claims data, where better recovery is defined as more days at home (DAH) over six months post-discharge, PD-Robust reveals heterogeneity in HAC effects, with males under the age of 85 years as a high-risk subgroup experiencing up to 23 fewer DAH, comparing HAC to no HAC. This exceeds the 8-day threshold regarded as clinically meaningful difference in DAH due to any exposure. Moreover, simulation studies further demonstrate that PD-Robust achieves low estimation bias and accurate statistical inference, supporting its utility in real-world data applications.

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arXiv2026

Trustworthy AI/ML Regression and Unbiased Causal Inference for Real-World Data

Real-World Data (RWD), with its large sample sizes and rich clinical detail, offers a compelling alternative to randomized controlled trials (RCTs) for studying treatment effects in diverse and complex patient populations. However, its observational nature introduces confounding that prevents straightforward comparative effectiveness research. Target trial emulation leverages RWD to estimate average treatment effects (ATE) at the population scale and diversity that RCTs cannot achieve, yet its validity depends critically on unbiased ATE estimation under high-dimensional confounding. Many causal inference pipelines address high-dimensional confounding through machine learning and artificial intelligence (ML/AI) outcome regression. However, commonly used ML/AI regression models exhibit systematic prediction bias, with predicted outcomes shrinking toward the marginal outcome mean. This structural bias propagates into ATE estimation and cannot be corrected by cross-fitting, ensemble methods, or any standard ML practice. In this work, we first quantitatively characterize how systematic prediction bias in ML/AI outcome regression leads to biased ATE estimates in causal inference models. We further propose an unbiased ML/AI regression-based causal inference framework to ensure unbiased ATE estimation for observational studies. We demonstrate our approach by studying the effects of opioids on cardiovascular health in patients with chronic pain using UK Biobank data.

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arXiv2025

A New Targeted-Federated Learning Framework for Estimating Heterogeneity of Treatment Effects: A Robust Framework with Applications in Aging Cohorts

Analyzing data from multiple sources offers valuable opportunities to improve the estimation efficiency of causal estimands. However, this analysis also poses many challenges due to population heterogeneity and data privacy constraints. While several advanced methods for causal inference in federated settings have been developed in recent years, many focus on difference-based averaged causal effects and are not designed to study effect modification. In this study, we introduce a novel targeted-federated learning framework to study the heterogeneity of treatment effects (HTEs) for a targeted population by proposing a projection-based estimand. This HTE framework integrates information from multiple data sources without sharing raw data, while accounting for covariate distribution shifts among sources. Our proposed approach is shown to be doubly robust, conveniently supporting both difference-based estimands for continuous outcomes and odds ratio-based estimands for binary outcomes. Furthermore, we develop a communication-efficient bootstrap-based selection procedure to detect non-transportable data sources, thereby enhancing robust information aggregation without introducing bias. The superior performance of the proposed estimator over existing methods is demonstrated through extensive simulation studies, and the utility of our approach has been shown in a real-world data application using nationwide Medicare-linked data.

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arXiv2025

Estimate Time-Varying Exposure Effects via Ensemble Learning-based Marginal Structural Model with Application to Adolescent Cognitive Development Study

Evaluating the effects of time-varying exposures is essential for longitudinal studies. The effect estimation becomes increasingly challenging when dealing with hundreds of time-dependent confounders. We propose a Marginal Structure Ensemble Learning Model (MASE) to provide a marginal structure model (MSM)-based robust estimator under the longitudinal setting. The proposed model integrates multiple machine learning algorithms to model propensity scores and a sequence of conditional outcome means such that it becomes less sensitive to model mis-specification due to any single algorithm and allows many confounders with potential non-linear confounding effects to reduce the risk of inconsistent estimation. Extensive simulation analysis demonstrates the superiority of MASE over benchmark methods (e.g., MSM, G-computation, Targeted maximum likelihood), yielding smaller estimation bias and improved inference accuracy. We apply MASE to the adolescent cognitive development study to investigate the time-varying effects of sleep insufficiency on cognitive performance. The results reveal an aggregated negative impact of insufficient sleep on cognitive development among youth.

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arXiv2025

Prior-Aligned Meta-RL: Thompson Sampling with Learned Priors and Guarantees in Finite-Horizon MDPs

We study meta-reinforcement learning in finite-horizon MDPs where related tasks share similar structures in their optimal action-value functions. Specifically, we posit a linear representation $Q^*_h(s,a)=\Phi_h(s,a)\,\theta^{(k)}_h$ and place a Gaussian meta-prior $ \mathcal{N}(\theta^*_h,\Sigma^*_h)$ over the task-specific parameters $\theta^{(k)}_h$. Building on randomized value functions, we propose two Thompson-style algorithms: (i) MTSRL, which learns only the prior mean and performs posterior sampling with the learned mean and known covariance; and (ii) $\text{MTSRL}^{+}$, which additionally estimates the covariance and employs prior widening to control finite-sample estimation error. Further, we develop a prior-alignment technique that couples the posterior under the learned prior with a meta-oracle that knows the true prior, yielding meta-regret guarantees: we match prior-independent Thompson sampling in the small-task regime and strictly improve with more tasks once the prior is learned. Concretely, for known covariance we obtain $\tilde{O}(H^{4}S^{3/2}\sqrt{ANK})$ meta-regret, and with learned covariance $\tilde{O}(H^{4}S^{3/2}\sqrt{AN^3K})$; both recover a better behavior than prior-independent after $K \gtrsim \tilde{O}(H^2)$ and $K \gtrsim \tilde{O}(N^2H^2)$, respectively. Simulations on a stateful recommendation environment (with feature and prior misspecification) show that after brief exploration, MTSRL/MTSRL$^+$ track the meta-oracle and substantially outperform prior-independent RL and bandit-only meta-baselines. Our results give the first meta-regret guarantees for Thompson-style RL with learned Q-priors, and provide practical recipes (warm-start via RLSVI, OLS aggregation, covariance widening) for experiment-rich settings.

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arXiv2025

A New Integrative Learning Framework for Integrating Multiple Secondary Outcomes into Primary Outcome Analysis: A Case Study on Liver Health

In the era of big data, secondary outcomes have become increasingly important alongside primary outcomes. These secondary outcomes, which can be derived from traditional endpoints in clinical trials, compound measures, or risk prediction scores, hold the potential to enhance the analysis of primary outcomes. Our method is motivated by the challenge of utilizing multiple secondary outcomes, such as blood biochemistry markers and urine assays, to improve the analysis of the primary outcome related to liver health. Current integration methods often fall short, as they impose strong model assumptions or require prior knowledge to construct over-identified working functions. This paper addresses these statistical challenges and potentially opens a new avenue in data integration by introducing a novel integrative learning framework that is applicable in a general setting. The proposed framework allows for the robust, data-driven integration of information from multiple secondary outcomes, promotes the development of efficient learning algorithms, and ensures optimal use of available data. Extensive simulation studies demonstrate that the proposed method significantly reduces variance in primary outcome analysis, outperforming existing integration approaches. Additionally, applying this method to UK Biobank (UKB) reveals that cigarette smoking is associated with increased fatty liver measures, with these effects being particularly pronounced in the older adult cohort.

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arXiv2024

Shape-restricted transfer learning analysis for generalized linear regression model

Transfer learning has emerged as a highly sought-after and actively pursued research area within the statistical community. The core concept of transfer learning involves leveraging insights and information from auxiliary datasets to enhance the analysis of the primary dataset of interest. In this paper, our focus is on datasets originating from distinct yet interconnected distributions. We assume that the training data conforms to a standard generalized linear model, while the testing data exhibit a connection to the training data based on a prior probability shift assumption. Ultimately, we discover that the two-sample conditional means are interrelated through an unknown, nondecreasing function. We integrate the power of generalized estimating equations with the shape-restricted score function, creating a robust framework for improved inference regarding the underlying parameters. We theoretically establish the asymptotic properties of our estimator and demonstrate, through simulation studies, that our method yields more accurate parameter estimates compared to those based solely on the testing or training data. Finally, we apply our method to a real-world example.

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arXiv2024

Exploring causal effects of hormone- and radio-treatments in an observational study of breast cancer using copula-based semi-competing risks models

Breast cancer patients may experience relapse or death after surgery during the follow-up period, leading to dependent censoring of relapse. This phenomenon, known as semi-competing risk, imposes challenges in analyzing treatment effects on breast cancer and necessitates advanced statistical tools for unbiased analysis. Despite progress in estimation and inference within semi-competing risks regression, its application to causal inference is still in its early stages. This article aims to propose a frequentist and semi-parametric framework based on copula models that can facilitate valid causal inference, net quantity estimation and interpretation, and sensitivity analysis for unmeasured factors under right-censored semi-competing risks data. We also propose novel procedures to enhance parameter estimation and its applicability in real practice. After that, we apply the proposed framework to a breast cancer study and detect the time-varying causal effects of hormone- and radio-treatments on patients' relapse-free survival and overall survival. Moreover, extensive numerical evaluations demonstrate the method's feasibility, highlighting minimal estimation bias and reliable statistical inference.

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arXiv2024

Advancing Information Integration through Empirical Likelihood: Selective Reviews and a New Idea

Information integration plays a pivotal role in biomedical studies by facilitating the combination and analysis of independent datasets from multiple studies, thereby uncovering valuable insights that might otherwise remain obscured due to the limited sample size in individual studies. However, sharing raw data from independent studies presents significant challenges, primarily due to the need to safeguard sensitive participant information and the cumbersome paperwork involved in data sharing. In this article, we first provide a selective review of recent methodological developments in information integration via empirical likelihood, wherein only summary information is required, rather than the raw data. Following this, we introduce a new insight and a potentially promising framework that could broaden the application of information integration across a wider spectrum. Furthermore, this new framework offers computational convenience compared to classic empirical likelihood-based methods. We provide numerical evaluations to assess its performance and discuss various extensions in the end.

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arXiv2024

Modeling Interconnected Modules in Multivariate Outcomes: Evaluating the Impact of Alcohol Intake on Plasma Metabolomics

Alcohol consumption has been shown to influence cardiovascular mechanisms in humans, leading to observable alterations in the plasma metabolomic profile. Regression models are commonly employed to investigate these effects, treating metabolomics features as the outcomes and alcohol intake as the exposure. Given the latent dependence structure among the numerous metabolomic features (e.g., co-expression networks with interconnected modules), modeling this structure is crucial for accurately identifying metabolomic features associated with alcohol intake. However, integrating dependence structures into regression models remains difficult in both estimation and inference procedures due to their large or high dimensionality. To bridge this gap, we propose an innovative multivariate regression model that accounts for correlations among outcome features by incorporating an interconnected community structure. Furthermore, we derive closed-form and likelihood-based estimators, accompanied by explicit exact and explicit asymptotic covariance matrix estimators, respectively. Simulation analysis demonstrates that our approach provides accurate estimation of both dependence and regression coefficients, and enhances sensitivity while maintaining a well-controlled discovery rate, as evidenced through benchmarking against existing regression models. Finally, we apply our approach to assess the impact of alcohol intake on $249$ metabolomic biomarkers measured using nuclear magnetic resonance spectroscopy. The results indicate that alcohol intake can elevate high-density lipoprotein levels by enhancing the transport rate of Apolipoproteins A1.

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arXiv2024

Gerontologic Biostatistics 2.0: Developments over 10+ years in the age of data science

Background: Introduced in 2010, the sub-discipline of gerontologic biostatistics (GBS) was conceptualized to address the specific challenges in analyzing data from research studies involving older adults. However, the evolving technological landscape has catalyzed data science and statistical advancements since the original GBS publication, greatly expanding the scope of gerontologic research. There is a need to describe how these advancements enhance the analysis of multi-modal data and complex phenotypes that are hallmarks of gerontologic research. Methods: This paper introduces GBS 2.0, an updated and expanded set of analytical methods reflective of the practice of gerontologic biostatistics in contemporary and future research. Results: GBS 2.0 topics and relevant software resources include cutting-edge methods in experimental design; analytical techniques that include adaptations of machine learning, quantifying deep phenotypic measurements, high-dimensional -omics analysis; the integration of information from multiple studies, and strategies to foster reproducibility, replicability, and open science. Discussion: The methodological topics presented here seek to update and expand GBS. By facilitating the synthesis of biostatistics and data science in gerontology, we aim to foster the next generation of gerontologic researchers.

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arXiv2023

Multiple Imputation Method for High-Dimensional Neuroimaging Data

Missingness is a common issue for neuroimaging data, and neglecting it in downstream statistical analysis can introduce bias and lead to misguided inferential conclusions. It is therefore crucial to conduct appropriate statistical methods to address this issue. While multiple imputation is a popular technique for handling missing data, its application to neuroimaging data is hindered by high dimensionality and complex dependence structures of multivariate neuroimaging variables. To tackle this challenge, we propose a novel approach, named High Dimensional Multiple Imputation (HIMA), based on Bayesian models. HIMA develops a new computational strategy for sampling large covariance matrices based on a robustly estimated posterior mode, which drastically enhances computational efficiency and numerical stability. To assess the effectiveness of HIMA, we conducted extensive simulation studies and real-data analysis using neuroimaging data from a Schizophrenia study. HIMA showcases a computational efficiency improvement of over 2000 times when compared to traditional approaches, while also producing imputed datasets with improved precision and stability.

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arXiv2023

Integrative data analysis where partial covariates have complex non-linear effects by using summary information from an external data

A full parametric and linear specification may be insufficient to capture complicated patterns in studies exploring complex features, such as those investigating age-related changes in brain functional abilities. Alternatively, a partially linear model (PLM) consisting of both parametric and non-parametric elements may have a better fit. This model has been widely applied in economics, environmental science, and biomedical studies. In this paper, we introduce a novel statistical inference framework that equips PLM with high estimation efficiency by effectively synthesizing summary information from external data into the main analysis. Such an integrative scheme is versatile in assimilating various types of reduced models from the external study. The proposed method is shown to be theoretically valid and numerically convenient, and it ensures a high-efficiency gain compared to classic methods in PLM. Our method is further validated using two data applications by evaluating the risk factors of brain imaging measures and blood pressure.

stat.ME↗

arXiv2023

An Efficient Data Integration Scheme for Synthesizing Information from Multiple Secondary Datasets for the Parameter Inference of the Main Analysis

Many observational studies and clinical trials collect various secondary outcomes that may be highly correlated with the primary endpoint. These secondary outcomes are often analyzed in secondary analyses separately from the main data analysis. However, these secondary outcomes can be used to improve the estimation precision in the main analysis. We propose a method called Multiple Information Borrowing (MinBo) that borrows information from secondary data (containing secondary outcomes and covariates) to improve the efficiency of the main analysis. The proposed method is robust against model misspecification of the secondary data. Both theoretical and case studies demonstrate that MinBo outperforms existing methods in terms of efficiency gain. We apply MinBo to data from the Atherosclerosis Risk in Communities study to assess risk factors for hypertension.

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arXiv2023

Analyzing Risk Factors for Post-Acute Recovery in Older Adults with Alzheimer's Disease and Related Dementia: A New Semi-Parametric Model for Large-Scale Medicare Claims

Nearly 300,000 older adults experience a hip fracture every year, the majority of which occur following a fall. Unfortunately, recovery after fall-related trauma such as hip fracture is poor, where older adults diagnosed with Alzheimer's Disease and Related Dementia (ADRD) spend a particularly long time in hospitals or rehabilitation facilities during the post-operative recuperation period. Because older adults value functional recovery and spending time at home versus facilities as key outcomes after hospitalization, identifying factors that influence days spent at home after hospitalization is imperative. While several individual-level factors have been identified, the characteristics of the treating hospital have recently been identified as contributors. However, few methodological rigorous approaches are available to help overcome potential sources of bias such as hospital-level unmeasured confounders, informative hospital size, and loss to follow-up due to death. This article develops a useful tool equipped with unsupervised learning to simultaneously handle statistical complexities that are often encountered in health services research, especially when using large administrative claims databases. The proposed estimator has a closed form, thus only requiring light computation load in a large-scale study. We further develop its asymptotic properties that can be used to make statistical inference in practice. Extensive simulation studies demonstrate superiority of the proposed estimator compared to existing estimators.

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arXiv2023

The Effect of Alcohol intake on Brain White Matter Microstructural Integrity: A New Causal Inference Framework for Incomplete Phenomic Data

Although substance use, such as alcohol intake, is known to be associated with cognitive decline during aging, its direct influence on the central nervous system remains incompletely understood. In this study, we investigate the influence of alcohol intake frequency on reduction of brain white matter microstructural integrity in the fornix, a brain region considered a promising marker of age-related microstructural degeneration, using a large UK Biobank (UKB) cohort with extensive phenomic data reflecting a comprehensive lifestyle profile. Two major challenges arise: 1) potentially nonlinear confounding effects from phenomic variables and 2) a limited proportion of participants with complete phenomic data. To address these challenges, we develop a novel ensemble learning framework tailored for robust causal inference and introduce a data integration step to incorporate information from UKB participants with incomplete phenomic data, improving estimation efficiency. Our analysis reveals that daily alcohol intake may significantly reduce fractional anisotropy, a neuroimaging-derived measure of white matter structural integrity, in the fornix and increase systolic and diastolic blood pressure levels. Moreover, extensive numerical studies demonstrate the superiority of our method over competing approaches in terms of estimation bias, while outcome regression-based estimators may be preferred when minimizing mean squared error is prioritized.

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arXiv2023

Covariance Matrix Estimation for High-Throughput Biomedical Data with Interconnected Communities

Estimating a covariance matrix is central to high-dimensional data analysis. Empirical analyses of high-dimensional biomedical data, including genomics, proteomics, microbiome, and neuroimaging, among others, consistently reveal strong modularity in the dependence patterns. In these analyses, intercorrelated high-dimensional biomedical features often form communities or modules that can be interconnected with others. While the interconnected community structure has been extensively studied in biomedical research (e.g., gene co-expression networks), its potential to assist in the estimation of covariance matrices remains largely unexplored. To address this gap, we propose a procedure that leverages the commonly observed interconnected community structure in high-dimensional biomedical data to estimate large covariance and precision matrices. We derive the uniformly minimum-variance unbiased estimators for covariance and precision matrices in closed forms and provide theoretical results on their asymptotic properties. Our proposed method enhances the accuracy of covariance- and precision-matrix estimation and demonstrates superior performance compared to the competing methods in both simulations and real data analyses.

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arXiv2020

A Robust Consistent Information Criterion for Model Selection based on Empirical Likelihood

Conventional likelihood-based information criteria for model selection rely on the distribution assumption of data. However, for complex data that are increasingly available in many scientific fields, the specification of their underlying distribution turns out to be challenging, and the existing criteria may be limited and are not general enough to handle a variety of model selection problems. Here, we propose a robust and consistent model selection criterion based upon the empirical likelihood function which is data-driven. In particular, this framework adopts plug-in estimators that can be achieved by solving external estimating equations, not limited to the empirical likelihood, which avoids potential computational convergence issues and allows versatile applications, such as generalized linear models, generalized estimating equations, penalized regressions and so on. The formulation of our proposed criterion is initially derived from the asymptotic expansion of the marginal likelihood under variable selection framework, but more importantly, the consistent model selection property is established under a general context. Extensive simulation studies confirm the out-performance of the proposal compared to traditional model selection criteria. Finally, an application to the Atherosclerosis Risk in Communities Study illustrates the practical value of this proposed framework.

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