arXiv subjects

Ilya Lipkovich

Publications and source records attributed to Ilya Lipkovich.

12 recordsLinked to original sources

arXiv2026

Estimating optimal interpretable individualized treatment regimes from a classification perspective using adaptive LASSO

Real-world data (RWD) gains growing interests to provide a representative sample of the population for selecting the optimal treatment options. However, existing complex black box methods for estimating individualized treatment rules (ITR) from RWD have problems in interpretability and convergence. Providing an interpretable and sparse ITR can be used to overcome the limitation of existing methods. We developed an algorithm using Adaptive LASSO to predict optimal interpretable linear ITR in the RWD. To encourage sparsity, we obtain an ITR by minimizing the risk function with various types of penalties and different methods of contrast estimation. Simulation studies were conducted to select the best configuration and to compare the novel algorithm with the existing state-of-the-art methods. The proposed algorithm was applied to RWD to predict the optimal interpretable ITR. Simulations show that adaptive LASSO had the highest rates of correctly selected variables and augmented inverse probability weighting with Super Learner performed best for estimating treatment contrast. Our method had a better performance than causal forest and R-learning in terms of the value function and variable selection. The proposed algorithm can strike a balance between the interpretability of estimated ITR (by selecting a small set of important variables) and its value.

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arXiv2025

Doubly Robust Fusion of Many Treatments for Policy Learning

Individualized treatment rules/recommendations (ITRs) aim to improve patient outcomes by tailoring treatments to the characteristics of each individual. However, when there are many treatment groups, existing methods face significant challenges due to data sparsity within treatment groups and highly unbalanced covariate distributions across groups. To address these challenges, we propose a novel calibration-weighted treatment fusion procedure that robustly balances covariates across treatment groups and fuses similar treatments using a penalized working model. The fusion procedure ensures the recovery of latent treatment group structures when either the calibration model or the outcome model is correctly specified. In the fused treatment space, practitioners can seamlessly apply state-of-the-art ITR learning methods with the flexibility to utilize a subset of covariates, thereby achieving robustness while addressing practical concerns such as fairness. We establish theoretical guarantees, including consistency, the oracle property of treatment fusion, and regret bounds when integrated with multi-armed ITR learning methods such as policy trees. Simulation studies show superior group recovery and policy value compared to existing approaches. We illustrate the practical utility of our method using a nationwide electronic health record-derived de-identified database containing data from patients with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma.

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arXiv2025

Doubly protected estimation for survival outcomes utilizing external controls for randomized clinical trials

Censored survival data are common in clinical trials, but small control groups can pose challenges, particularly in rare diseases or where balanced randomization is impractical. Recent approaches leverage external controls from historical studies or real-world data to strengthen treatment evaluation for survival outcomes. However, using external controls directly may introduce biases due to data heterogeneity. We propose a doubly protected estimator for the treatment-specific restricted mean survival time difference that is more efficient than trial-only estimators and mitigates biases from external data. Our method adjusts for covariate shifts via doubly robust estimation and addresses outcome drift using the DR-Learner for selective borrowing. The approach can incorporate machine learning to approximate survival curves and detect outcome drifts without strict parametric assumptions, borrowing only comparable external controls. Extensive simulation studies and a real-data application evaluating the efficacy of Galcanezumab in mitigating migraine headaches have been conducted to illustrate the effectiveness of our proposed framework.

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arXiv2025

Overview and practical recommendations on using Shapley Values for identifying predictive biomarkers via CATE modeling

In recent years, two parallel research trends have emerged in machine learning, yet their intersections remain largely unexplored. On one hand, there has been a significant increase in literature focused on Individual Treatment Effect (ITE) modeling, particularly targeting the Conditional Average Treatment Effect (CATE) using meta-learner techniques. These approaches often aim to identify causal effects from observational data. On the other hand, the field of Explainable Machine Learning (XML) has gained traction, with various approaches developed to explain complex models and make their predictions more interpretable. A prominent technique in this area is Shapley Additive Explanations (SHAP), which has become mainstream in data science for analyzing supervised learning models. However, there has been limited exploration of SHAP application in identifying predictive biomarkers through CATE models, a crucial aspect in pharmaceutical precision medicine. We address inherent challenges associated with the SHAP concept in multi-stage CATE strategies and introduce a surrogate estimation approach that is agnostic to the choice of CATE strategy, effectively reducing computational burdens in high-dimensional data. Using this approach, we conduct simulation benchmarking to evaluate the ability to accurately identify biomarkers using SHAP values derived from various CATE meta-learners and Causal Forest.

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arXiv2025

Double Machine Learning Methods for Estimating Average Treatment Effects: A Comparative Study

Observational cohort studies are increasingly being used for comparative effectiveness research to assess the safety of therapeutics. Recently, various doubly robust methods have been proposed for average treatment effect estimation by combining the treatment model and the outcome model via different vehicles, such as matching, weighting, and regression. The key advantage of doubly robust estimators is that they require either the treatment model or the outcome model to be correctly specified to obtain a consistent estimator of average treatment effects, and therefore lead to a more accurate and often more precise inference. However, little work has been done to understand how doubly robust estimators differ due to their unique strategies of using the treatment and outcome models and how machine learning techniques can be combined to boost their performance, which we call double machine learning estimators. Here we examine multiple popular doubly robust methods and compare their performance using different treatment and outcome modeling via extensive simulations and a real-world application. We found that incorporating machine learning with doubly robust estimators such as the targeted maximum likelihood estimator gives the best overall performance. Practical guidance on how to apply doubly robust estimators is provided.

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arXiv2024

Improving randomized controlled trial analysis via data-adaptive borrowing

In recent years, real-world external controls have grown in popularity as a tool to empower randomized placebo-controlled trials, particularly in rare diseases or cases where balanced randomization is unethical or impractical. However, as external controls are not always comparable to the trials, direct borrowing without scrutiny may heavily bias the treatment effect estimator. Our paper proposes a data-adaptive integrative framework capable of preventing unknown biases of the external controls. The adaptive nature is achieved by dynamically sorting out a comparable subset of the external controls via bias penalization. Our proposed method can simultaneously achieve (a) the semiparametric efficiency bound when the external controls are comparable and (b) selective borrowing that mitigates the impact of the existence of incomparable external controls. Furthermore, we establish statistical guarantees, including consistency, asymptotic distribution, and inference, providing type-I error control and good power. Extensive simulations and two real-data applications show that the proposed method leads to improved performance over the trial-only estimator across various bias-generating scenarios.

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arXiv2024

Modern approaches for evaluating treatment effect heterogeneity from clinical trials and observational data

In this paper we review recent advances in statistical methods for the evaluation of the heterogeneity of treatment effects (HTE), including subgroup identification and estimation of individualized treatment regimens, from randomized clinical trials and observational studies. We identify several types of approaches using the features introduced in Lipkovich, Dmitrienko and D'Agostino (2017) that distinguish the recommended principled methods from basic methods for HTE evaluation that typically rely on rules of thumb and general guidelines (the methods are often referred to as common practices). We discuss the advantages and disadvantages of various principled methods as well as common measures for evaluating their performance. We use simulated data and a case study based on a historical clinical trial to illustrate several new approaches to HTE evaluation.

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arXiv2024

A unified Bayesian framework for interval hypothesis testing in clinical trials

The American Statistical Association (ASA) statement on statistical significance and P-values \cite{wasserstein2016asa} cautioned statisticians against making scientific decisions solely on the basis of traditional P-values. The statement delineated key issues with P-values, including a lack of transparency, an inability to quantify evidence in support of the null hypothesis, and an inability to measure the size of an effect or the importance of a result. In this article, we demonstrate that the interval null hypothesis framework (instead of the point null hypothesis framework), when used in tandem with Bayes factor-based tests, is instrumental in circumnavigating the key issues of P-values. Further, we note that specifying prior densities for Bayes factors is challenging and has been a reason for criticism of Bayesian hypothesis testing in existing literature. We address this by adapting Bayes factors directly based on common test statistics. We demonstrate, through numerical experiments and real data examples, that the proposed Bayesian interval hypothesis testing procedures can be calibrated to ensure frequentist error control while retaining their inherent interpretability. Finally, we illustrate the improved flexibility and applicability of the proposed methods by providing coherent frameworks for competitive landscape analysis and end-to-end Bayesian hypothesis tests in the context of reporting clinical trial outcomes.

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arXiv2023

Implementation of ICH E9 (R1): a few points learned during the COVID-19 pandemic

The current COVID-19 pandemic poses numerous challenges for ongoing clinical trials and provides a stress-testing environment for the existing principles and practice of estimands in clinical trials. The pandemic may increase the rate of intercurrent events (ICEs) and missing values, spurring a great deal of discussion on amending protocols and statistical analysis plans to address these issues. In this article we revisit recent research on estimands and handling of missing values, especially the ICH E9 (R1) on Estimands and Sensitivity Analysis in Clinical Trials. Based on an in-depth discussion of the strategies for handling ICEs using a causal inference framework, we suggest some improvements in applying the estimand and estimation framework in ICH E9 (R1). Specifically, we discuss a mix of strategies allowing us to handle ICEs differentially based on reasons for ICEs. We also suggest ICEs should be handled primarily by hypothetical strategies and provide examples of different hypothetical strategies for different types of ICEs as well as a road map for estimation and sensitivity analyses. We conclude that the proposed framework helps streamline translating clinical objectives into targets of statistical inference and automatically resolves many issues with defining estimands and choosing estimation procedures arising from events such as the pandemic.

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arXiv2022

Using principal stratification in analysis of clinical trials

The ICH E9(R1) addendum (2019) proposed principal stratification (PS) as one of five strategies for dealing with intercurrent events. Therefore, understanding the strengths, limitations, and assumptions of PS is important for the broad community of clinical trialists. Many approaches have been developed under the general framework of PS in different areas of research, including experimental and observational studies. These diverse applications have utilized a diverse set of tools and assumptions. Thus, need exists to present these approaches in a unifying manner. The goal of this tutorial is threefold. First, we provide a coherent and unifying description of PS. Second, we emphasize that estimation of effects within PS relies on strong assumptions and we thoroughly examine the consequences of these assumptions to understand in which situations certain assumptions are reasonable. Finally, we provide an overview of a variety of key methods for PS analysis and use a real clinical trial example to illustrate them. Examples of code for implementation of some of these approaches are given in supplemental materials.

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arXiv2022

Assessing the commonly used assumptions in estimating the principal causal effect in clinical trials

In clinical trials, it is often of interest to understand the principal causal effect (PCE), the average treatment effect for a principal stratum (a subset of patients defined by the potential outcomes of one or more post-baseline variables). Commonly used assumptions include monotonicity, principal ignorability, and cross-world assumptions of principal ignorability and principal strata independence. In this article, we evaluate these assumptions through a 2$\times$2 cross-over study in which the potential outcomes under both treatments can be observed, provided there are no carry-over and study period effects. From this example, it seemed the monotonicity assumption and the within-treatment principal ignorability assumptions did not hold well. On the other hand, the assumptions of cross-world principal ignorability and cross-world principal stratum independence conditional on baseline covariates seemed reasonable. With the latter assumptions, we estimated the PCEs, defined by whether the blood glucose standard deviation increased in each treatment period, without relying on the cross-over feature, producing estimates close to the results when exploiting the cross-over feature. To the best of our knowledge, this article is the first attempt to evaluate the plausibility of commonly used assumptions for estimating PCEs using a cross-over trial.

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arXiv2021

Selection bias in the treatment effect for a principal stratum

Estimation of treatment effect for principal strata has been studied for more than two decades. Existing research exclusively focuses on the estimation, but there is little research on forming and testing hypotheses for principal stratification-based estimands. In this brief report, we discuss a phenomenon in which the true treatment effect for a principal stratum may not equal zero even if the two treatments have the same effect at patient level which implies an equal average treatment effect for the principal stratum. We explain this phenomenon from the perspective of selection bias. This is an important finding and deserves attention when using and interpreting results based on principal stratification. There is a need to further study how to form the null hypothesis for estimands for a principal stratum.

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