arXiv subjects

Haoda Fu

Publications and source records attributed to Haoda Fu.

At least 19 recordsLinked to original sources

arXiv2026

Longitudinal Random Forests for Sparse and Irregular Response Trajectories

Longitudinal studies often collect data at sparse, irregular, and unequally spaced time points. Such heterogeneity is often driven by subject-specific covariates, yet existing methods have been restricted to a scalar endpoint value, completely neglecting the underlying response trajectories. We propose a novel Longitudinal Random Forest (LRF) framework that leverages tree-based ensemble machine learning with adaptive node-wise longitudinal trajectory estimation. The LRF framework makes five methodological contributions. it captures each subject's individual response trajectory while simultaneously accommodating within-node correlation, between-node heterogeneity, and nonlinear and interactive covariate effects. It introduces a novel trajectory-based splitting criterion that maximizes trajectory separation while incorporating a size-weighted penalty; it provides two variants, Principal Analysis by Conditional Expectation (LRF-PACE) and adaptive linear mixed-effects models (LRF-adaptiveLMM), which employ nonparametric and semiparametric node-wise smoothers, respectively, while learning covariate effects in a data-driven manner. It provides a comprehensive interpretation of covariates using both the classical trajectory-based permutation variable importance measure (PVIM) and a newly proposed finite-way interaction frequency count, and it not only predicts entire trajectories for new subjects but also forecasts future trajectories for existing subjects. Extensive simulation studies demonstrate that LRF achieves superior performance over several competing methods, even under severe sparsity. The practical significance of the LRF framework lies in its ability to address five important clinical questions.

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arXiv2026

Unobserved Heterogeneity in Threshold Regression Based on the Hitting Times of a Reflected Brownian Motion for Recurrent Hypoglycemia

Analyses of recurrent hypoglycemia are critical for effective treatment management in diabetic patients. Typically, within-subject dependency in such analyses is captured through subject-level frailty. Recent research has modeled recurrent hypoglycemia using the first hitting times of a reflected Brownian motion. A close examination of this approach reveals that it does not adequately account for varying frailties among individuals, which indicate notable heterogeneity. To address this gap, we propose a finite mixture model of the first hitting time distribution of the reflected Brownian motion. This model allows for component-specific regression coefficients and frailty parameters, providing nuanced insights into how risk factors differently affect patient subgroups. We employ a Bayesian framework for inference, utilizing Markov chain Monte Carlo for estimation. Model selection is conducted using the Deviance Information Criterion and the Logarithm of the Pseudo-Marginal Likelihood. The effectiveness of these criteria is assessed through simulation studies. Application to recurrent hypoglycemia modeling revealed two subgroups with different risk profiles, as reflected in their volatilities. Bayesian model comparison criteria favor the model with component specific regression coefficients for volatilities. The subgroup with lower volatility exhibits a larger variance and, hence, a greater level of heterogeneity.

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arXiv2025

Integrating RCTs, RWD, AI/ML and Statistics: Next-Generation Evidence Synthesis

Randomized controlled trials (RCTs)have been the cornerstone of clinical evidence; however, their cost, duration, and restrictive eligibility criteria limit power and external validity. Studies using real-world data (RWD), historically considered less reliable for establishing causality, are now recognized as an important source of real-world evidence (RWE). In parallel, artificial intelligence and machine learning (AI/ML) are increasingly used throughout the drug development process, providing scalability and flexibility but also presenting challenges in interpretability and statistical rigor. This Perspective argues that the future of evidence generation will not depend on RCTs versus RWD, or statistics versus AI/ML, but on their principled integration under a statistical evidence framework that clarifies estimands, evaluates data fitness, controls bias, quantifies uncertainty, and determines when evidence is strong enough to support decisions. Building on the Causal Roadmap for high-quality real-world evidence, we present a six-step statistical roadmap for integrative evidence synthesis and organize the discussion around five core questions that statisticians must confront: when RWD is fit for causal use and when it is not; what AI genuinely contributes across the evidence lifecycle; what remains distinctly statistical and indispensable; how to build trustworthy end-to-end evidence systems in pharmaceutical, regulatory, and industry settings; and how statistical training should evolve.

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arXiv2024

Efficient Human-in-the-Loop Active Learning: A Novel Framework for Data Labeling in AI Systems

Modern AI algorithms require labeled data. In real world, majority of data are unlabeled. Labeling the data are costly. this is particularly true for some areas requiring special skills, such as reading radiology images by physicians. To most efficiently use expert's time for the data labeling, one promising approach is human-in-the-loop active learning algorithm. In this work, we propose a novel active learning framework with significant potential for application in modern AI systems. Unlike the traditional active learning methods, which only focus on determining which data point should be labeled, our framework also introduces an innovative perspective on incorporating different query scheme. We propose a model to integrate the information from different types of queries. Based on this model, our active learning frame can automatically determine how the next question is queried. We further developed a data driven exploration and exploitation framework into our active learning method. This method can be embedded in numerous active learning algorithms. Through simulations on five real-world datasets, including a highly complex real image task, our proposed active learning framework exhibits higher accuracy and lower loss compared to other methods.

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arXiv2024

Recurrent Events Modeling Based on a Reflected Brownian Motion with Application to Hypoglycemia

Patients with type 2 diabetes need to closely monitor blood sugar levels as their routine diabetes self-management. Although many treatment agents aim to tightly control blood sugar, hypoglycemia often stands as an adverse event. In practice, patients can observe hypoglycemic events more easily than hyperglycemic events due to the perception of neurogenic symptoms. We propose to model each patient's observed hypoglycemic event as a lower-boundary crossing event for a reflected Brownian motion with an upper reflection barrier. The lower-boundary is set by clinical standards. To capture patient heterogeneity and within-patient dependence, covariates and a patient level frailty are incorporated into the volatility and the upper reflection barrier. This framework provides quantification for the underlying glucose level variability, patients heterogeneity, and risk factors' impact on glucose. We make inferences based on a Bayesian framework using Markov chain Monte Carlo. Two model comparison criteria, the Deviance Information Criterion and the Logarithm of the Pseudo-Marginal Likelihood, are used for model selection. The methodology is validated in simulation studies. In analyzing a dataset from the diabetic patients in the DURABLE trial, our model provides adequate fit, generates data similar to the observed data, and offers insights that could be missed by other models.

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arXiv2023

Multi-Label Residual Weighted Learning for Individualized Combination Treatment Rule

Individualized treatment rules (ITRs) have been widely applied in many fields such as precision medicine and personalized marketing. Beyond the extensive studies on ITR for binary or multiple treatments, there is considerable interest in applying combination treatments. This paper introduces a novel ITR estimation method for combination treatments incorporating interaction effects among treatments. Specifically, we propose the generalized $\psi$-loss as a non-convex surrogate in the residual weighted learning framework, offering desirable statistical and computational properties. Statistically, the minimizer of the proposed surrogate loss is Fisher-consistent with the optimal decision rules, incorporating interaction effects at any intensity level - a significant improvement over existing methods. Computationally, the proposed method applies the difference-of-convex algorithm for efficient computation. Through simulation studies and real-world data applications, we demonstrate the superior performance of the proposed method in recommending combination treatments.

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arXiv2023

Fast Approximation of the Shapley Values Based on Order-of-Addition Experimental Designs

Shapley value is originally a concept in econometrics to fairly distribute both gains and costs to players in a coalition game. In the recent decades, its application has been extended to other areas such as marketing, engineering and machine learning. For example, it produces reasonable solutions for problems in sensitivity analysis, local model explanation towards the interpretable machine learning, node importance in social network, attribution models, etc. However, its heavy computational burden has been long recognized but rarely investigated. Specifically, in a $d$-player coalition game, calculating a Shapley value requires the evaluation of $d!$ or $2^d$ marginal contribution values, depending on whether we are taking the permutation or combination formulation of the Shapley value. Hence it becomes infeasible to calculate the Shapley value when $d$ is reasonably large. A common remedy is to take a random sample of the permutations to surrogate for the complete list of permutations. We find an advanced sampling scheme can be designed to yield much more accurate estimation of the Shapley value than the simple random sampling (SRS). Our sampling scheme is based on combinatorial structures in the field of design of experiments (DOE), particularly the order-of-addition experimental designs for the study of how the orderings of components would affect the output. We show that the obtained estimates are unbiased, and can sometimes deterministically recover the original Shapley value. Both theoretical and simulations results show that our DOE-based sampling scheme outperforms SRS in terms of estimation accuracy. Surprisingly, it is also slightly faster than SRS. Lastly, real data analysis is conducted for the C. elegans nervous system and the 9/11 terrorist network.

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arXiv2023

Optimal Individualized Treatment Rule for Combination Treatments Under Budget Constraints

The individualized treatment rule (ITR), which recommends an optimal treatment based on individual characteristics, has drawn considerable interest from many areas such as precision medicine, personalized education, and personalized marketing. Existing ITR estimation methods mainly adopt one of two or more treatments. However, a combination of multiple treatments could be more powerful in various areas. In this paper, we propose a novel Double Encoder Model (DEM) to estimate the individualized treatment rule for combination treatments. The proposed double encoder model is a nonparametric model which not only flexibly incorporates complex treatment effects and interaction effects among treatments, but also improves estimation efficiency via the parameter-sharing feature. In addition, we tailor the estimated ITR to budget constraints through a multi-choice knapsack formulation, which enhances our proposed method under restricted-resource scenarios. In theory, we provide the value reduction bound with or without budget constraints, and an improved convergence rate with respect to the number of treatments under the DEM. Our simulation studies show that the proposed method outperforms the existing ITR estimation in various settings. We also demonstrate the superior performance of the proposed method in PDX data that recommends optimal combination treatments to shrink the tumor size of the colorectal cancer.

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arXiv2022

Learning Optimal Dynamic Treatment Regimens Subject to Stagewise Risk Controls

Dynamic treatment regimens (DTRs) aim at tailoring individualized sequential treatment rules that maximize cumulative beneficial outcomes by accommodating patients' heterogeneity in decision-making. For many chronic diseases including type 2 diabetes mellitus (T2D), treatments are usually multifaceted in the sense that aggressive treatments with a higher expected reward are also likely to elevate the risk of acute adverse events. In this paper, we propose a new weighted learning framework, namely benefit-risk dynamic treatment regimens (BR-DTRs), to address the benefit-risk trade-off. The new framework relies on a backward learning procedure by restricting the induced risk of the treatment rule to be no larger than a pre-specified risk constraint at each treatment stage. Computationally, the estimated treatment rule solves a weighted support vector machine problem with a modified smooth constraint. Theoretically, we show that the proposed DTRs are Fisher consistent, and we further obtain the convergence rates for both the value and risk functions. Finally, the performance of the proposed method is demonstrated via extensive simulation studies and application to a real study for T2D patients.

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arXiv2021

Stabilized Direct Learning for Efficient Estimation of Individualized Treatment Rules

In recent years, the field of precision medicine has seen many advancements. Significant focus has been placed on creating algorithms to estimate individualized treatment rules (ITR), which map from patient covariates to the space of available treatments with the goal of maximizing patient outcome. Direct Learning (D-Learning) is a recent one-step method which estimates the ITR by directly modeling the treatment-covariate interaction. However, when the variance of the outcome is heterogeneous with respect to treatment and covariates, D-Learning does not leverage this structure. Stabilized Direct Learning (SD-Learning), proposed in this paper, utilizes potential heteroscedasticity in the error term through a residual reweighting which models the residual variance via flexible machine learning algorithms such as XGBoost and random forests. We also develop an internal cross-validation scheme which determines the best residual model amongst competing models. SD-Learning improves the efficiency of D-Learning estimates in binary and multi-arm treatment scenarios. The method is simple to implement and an easy way to improve existing algorithms within the D-Learning family, including original D-Learning, Angle-based D-Learning (AD-Learning), and Robust D-Learning (RD-Learning). We provide theoretical properties and justification of the optimality of SD-Learning. Head-to-head performance comparisons with D-Learning methods are provided through simulations, which demonstrate improvement in terms of average prediction error (APE), misclassification rate, and empirical value, along with data analysis of an AIDS randomized clinical trial.

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arXiv2021

Query-augmented Active Metric Learning

In this paper we propose an active metric learning method for clustering with pairwise constraints. The proposed method actively queries the label of informative instance pairs, while estimating underlying metrics by incorporating unlabeled instance pairs, which leads to a more accurate and efficient clustering process. In particular, we augment the queried constraints by generating more pairwise labels to provide additional information in learning a metric to enhance clustering performance. Furthermore, we increase the robustness of metric learning by updating the learned metric sequentially and penalizing the irrelevant features adaptively. In addition, we propose a novel active query strategy that evaluates the information gain of instance pairs more accurately by incorporating the neighborhood structure, which improves clustering efficiency without extra labeling cost. In theory, we provide a tighter error bound of the proposed metric learning method utilizing augmented queries compared with methods using existing constraints only. Furthermore, we also investigate the improvement using the active query strategy instead of random selection. Numerical studies on simulation settings and real datasets indicate that the proposed method is especially advantageous when the signal-to-noise ratio between significant features and irrelevant features is low.

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arXiv2021

Deep Neural Networks Guided Ensemble Learning for Point Estimation

In modern statistics, interests shift from pursuing the uniformly minimum variance unbiased estimator to reducing mean squared error (MSE) or residual squared error. Shrinkage based estimation and regression methods offer better prediction accuracy and improved interpretation. However, the characterization of such optimal statistics in terms of minimizing MSE remains open and challenging in many problems, for example estimating treatment effect in adaptive clinical trials with pre-planned modifications to design aspects based on accumulated data. From an alternative perspective, we propose a deep neural network based automatic method to construct an improved estimator from existing ones. Theoretical properties are studied to provide guidance on applicability of our estimator to seek potential improvement. Simulation studies demonstrate that the proposed method has considerable finite-sample efficiency gain as compared with several common estimators. In the Adaptive COVID-19 Treatment Trial (ACTT) as an important application, our ensemble estimator essentially contributes to a more ethical and efficient adaptive clinical trial with fewer patients enrolled. The proposed framework can be generally applied to various statistical problems, and can be served as a reference measure to guide statistical research.

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arXiv2021

Model-Assisted Uniformly Honest Inference for Optimal Treatment Regimes in High Dimension

This paper develops new tools to quantify uncertainty in optimal decision making and to gain insight into which variables one should collect information about given the potential cost of measuring a large number of variables. We investigate simultaneous inference to determine if a group of variables is relevant for estimating an optimal decision rule in a high-dimensional semiparametric framework. The unknown link function permits flexible modeling of the interactions between the treatment and the covariates, but leads to nonconvex estimation in high dimension and imposes significant challenges for inference. We first establish that a local restricted strong convexity condition holds with high probability and that any feasible local sparse solution of the estimation problem can achieve the near-oracle estimation error bound. We further rigorously verify that a wild bootstrap procedure based on a debiased version of the local solution can provide asymptotically honest uniform inference for the effect of a group of variables on optimal decision making. The advantage of honest inference is that it does not require the initial estimator to achieve perfect model selection and does not require the zero and nonzero effects to be well-separated. We also propose an efficient algorithm for estimation. Our simulations suggest satisfactory performance. An example from a diabetes study illustrates the real application.

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arXiv2020

Near-optimal Individualized Treatment Recommendations

Individualized treatment recommendation (ITR) is an important analytic framework for precision medicine. The goal is to assign proper treatments to patients based on their individual characteristics. From the machine learning perspective, the solution to an ITR problem can be formulated as a weighted classification problem to maximize the average benefit that patients receive from the recommended treatments. Several methods have been proposed for ITR in both binary and multicategory treatment setups. In practice, one may prefer a more flexible recommendation with multiple treatment options. This motivates us to develop methods to obtain a set of near-optimal individualized treatment recommendations alternative to each other, called alternative individualized treatment recommendations (A-ITR). We propose two methods to estimate the optimal A-ITR within the outcome weighted learning (OWL) framework. We show the consistency of these methods and obtain an upper bound for the risk between the theoretically optimal recommendation and the estimated one. We also conduct simulation studies, and apply our methods to a real data set for Type 2 diabetic patients with injectable antidiabetic treatments. These numerical studies have shown the usefulness of the proposed A-ITR framework. We develop a R package aitr which can be found at https://github.com/menghaomiao/aitr.

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arXiv2020

Boosting Algorithms for Estimating Optimal Individualized Treatment Rules

We present nonparametric algorithms for estimating optimal individualized treatment rules. The proposed algorithms are based on the XGBoost algorithm, which is known as one of the most powerful algorithms in the machine learning literature. Our main idea is to model the conditional mean of clinical outcome or the decision rule via additive regression trees, and use the boosting technique to estimate each single tree iteratively. Our approaches overcome the challenge of correct model specification, which is required in current parametric methods. The major contribution of our proposed algorithms is providing efficient and accurate estimation of the highly nonlinear and complex optimal individualized treatment rules that often arise in practice. Finally, we illustrate the superior performance of our algorithms by extensive simulation studies and conclude with an application to the real data from a diabetes Phase III trial.

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arXiv2020

Multicategory Angle-based Learning for Estimating Optimal Dynamic Treatment Regimes with Censored Data

An optimal dynamic treatment regime (DTR) consists of a sequence of decision rules in maximizing long-term benefits, which is applicable for chronic diseases such as HIV infection or cancer. In this paper, we develop a novel angle-based approach to search the optimal DTR under a multicategory treatment framework for survival data. The proposed method targets maximization the conditional survival function of patients following a DTR. In contrast to most existing approaches which are designed to maximize the expected survival time under a binary treatment framework, the proposed method solves the multicategory treatment problem given multiple stages for censored data. Specifically, the proposed method obtains the optimal DTR via integrating estimations of decision rules at multiple stages into a single multicategory classification algorithm without imposing additional constraints, which is also more computationally efficient and robust. In theory, we establish Fisher consistency of the proposed method under regularity conditions. Our numerical studies show that the proposed method outperforms competing methods in terms of maximizing the conditional survival function. We apply the proposed method to two real datasets: Framingham heart study data and acquired immunodeficiency syndrome (AIDS) clinical data.

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arXiv2018

Quantile Regression Modeling of Recurrent Event Risk

Progression of chronic disease is often manifested by repeated occurrences of disease-related events over time. Delineating the heterogeneity in the risk of such recurrent events can provide valuable scientific insight for guiding customized disease management. In this paper, we present a new modeling framework for recurrent event data, which renders a flexible and robust characterization of individual multiplicative risk of recurrent event through quantile regression that accommodates both observed covariates and unobservable frailty. The proposed modeling requires no distributional specification of the unobservable frailty, while permitting the exploration of dynamic covariate effects. We develop estimation and inference procedures for the proposed model through a novel adaptation of the principle of conditional score. The asymptotic properties of the proposed estimator, including the uniform consistency and weak convergence, are established. Extensive simulation studies demonstrate satisfactory finite-sample performance of the proposed method. We illustrate the practical utility of the new method via an application to a diabetes clinical trial that explores the risk patterns of hypoglycemia in Type 2 diabetes patients.

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arXiv2018

Quantile Regression of Latent Longitudinal Trajectory Features

Quantile regression has demonstrated promising utility in longitudinal data analysis. Existing work is primarily focused on modeling cross-sectional outcomes, while outcome trajectories often carry more substantive information in practice. In this work, we develop a trajectory quantile regression framework that is designed to robustly and flexibly investigate how latent individual trajectory features are related to observed subject characteristics. The proposed models are built under modeling with usual parametric assumptions lifted or relaxed. We derive our estimation procedure by novelly transforming the problem at hand to quantile regression with perturbed responses and adapting the bias correction technique for handling covariate measurement errors. We establish desirable asymptotic properties of the proposed estimator, including uniform consistency and weak convergence. Extensive simulation studies confirm the validity of the proposed method as well as its robustness. An application to the DURABLE trial uncovers sensible scientific findings and illustrates the practical value of our proposals.

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