arXiv subjects

Layla Parast

Publications and source records attributed to Layla Parast.

17 recordsLinked to original sources

arXiv2026

Meta-Analysis of High-Dimensional Surrogate Markers

When direct measurement of a clinically relevant primary endpoint in a clinical trial is infeasible, a surrogate endpoint may be used instead to infer treatment effects. Trial-level surrogates predict the average treatment effect on the primary endpoint and may be evaluated within the meta-analytic framework. However, traditional methods are ill-suited to the complex high-dimensional data now increasingly collected in modern trials, such as omics data. Although methods for high-dimensional surrogate evaluation exist, they have largely been developed for single-trial settings and therefore cannot assess surrogate generalisability. Here, we propose RISE-Meta, an approach for evaluating trial-level surrogate markers in the multi-trial, high-dimensional setting. In the first stage, an existing nonparametric method is applied to individual participant data to derive study-level surrogacy metrics for each candidate marker. Next, random-effects meta-analysis combines these metrics across studies, and equivalence testing provides operational criteria for surrogate validity. Finally, a subset of candidates is combined into a composite signature through a weighting scheme to improve surrogacy relative to any individual candidate. We evaluate RISE-Meta in both simulation studies and real data applications. In an application to high-dimensional data, we analyse gene expression as trial-level surrogate markers for the antibody response to seasonal influenza vaccination, while in a low-dimensional application we compare RISE-Meta to a reference meta-analytic approach and observe strong agreement between the two.

stat.ME↗

arXiv2026

A Functional-Class Meta-Analytic Framework for Quantifying Surrogate Resilience

A surrogate marker is a biomarker or other physical measurement used to replace a primary outcome in clinical trials to evaluate a treatment effect when the primary outcome of interest is costly, invasive, or takes a long time to observe. However, replacing a primary outcome with a surrogate can lead to the "surrogate paradox," in which a treatment appears beneficial based on the surrogate but is actually harmful with respect to the primary outcome. In this paper, we propose a functional class-based method to assess resilience to the surrogate paradox in a meta-analytic setting. Our method leverages data from K completed studies in which the surrogate marker and primary outcome have been measured to make inference on a new study in which only the surrogate is measured. We do not assume direct transportability of the conditional mean function from the completed studies to the new study; instead, we consider deviations of functions from those observed in the completed studies to estimate the "resilience probability" i.e., the probability of the surrogate paradox in the new study. We investigate the performance of our proposed method through a simulation study and apply our method to data from clinical trials in schizophrenia.

stat.ME↗

arXiv2026

A Causal Framework for Evaluating Jointly Longitudinal Outcomes and Surrogate Markers: A State-Space Approach

Surrogate markers offer the potential to reduce the burden of data collection by replacing costly or invasive primary outcomes with more accessible measurements, provided that they can faithfully indicate the effectiveness of a treatment. However, appropriate evaluation of a surrogate is particularly complex in longitudinal studies, where both outcomes and surrogates can evolve dynamically over time and interest lies not only in the treatment effect at one time, but rather treatment effects that may vary along the entire trajectory. In this paper, we develop a statistical framework for surrogate evaluation when both the surrogate and primary outcome are measured over time. Specifically, within the potential outcomes framework, we propose a formal causal definition of the proportion of the treatment effect on the longitudinal primary outcome that is explained by the treatment effect on the longitudinal surrogate. For estimation, we leverage state-space models, together with the Kalman filter and smoother, enabling efficient estimation of treatment effects under realistic conditions of temporal evolution and patient-level variability. We introduce a nonparametric bootstrap strategy for state-space models, a temporal homogeneity test, and demonstrate the finite-sample performance of our proposed methods via a simulation study and application to a diabetes clinical trial.

stat.ME↗

arXiv2026

Correcting for Missing Data When Evaluating Surrogate Markers in a Clinical Trial

Evaluating treatment effects is critical in clinical trials but sometimes involves lengthy, invasive, or costly follow-up procedures. In these cases, surrogate markers, which provide intermediate measures of the long-term treatment effect, allow clinicians to obtain results faster and more efficiently than would have otherwise been possible. Prior to adoption, it is vital that the utility of surrogate markers (i.e., their ability to capture the treatment effect on the primary outcome) is statistically validated. Many frameworks for evaluating surrogate markers have been proposed, but they do not account for missing data. Instead, they rely on complete cases (the subset of patients without missing data), which can be inefficient and biased. To improve on this, we propose methods to accommodate missing data in nonparametric and parametric surrogate evaluation via inverse probability weighting (IPW) and semiparametric maximum likelihood estimation (SMLE). Through simulation studies, we demonstrate that the proposed methods remain unbiased under a broader range of missing data mechanisms than complete case analysis and can help retain the statistical precision of the full trial. We illustrate their practical utility through an application to a diabetes clinical trial. Moreover, our missing data corrections have complementary strengths with respect to computational ease, robustness, and statistical efficiency. All methods are implemented in the MissSurrogate R package.

stat.ME↗

arXiv2026

A Bayesian Critique of Rank-Based Methods for Surrogate Marker Evaluation

Surrogate markers are often employed in clinical trials to replace primary outcomes that may be difficult, expensive, or time-consuming to measure directly. These markers can accelerate the evaluation of new treatments, provided they reliably capture the causal relationship between treatment and true clinical benefit. Parast et al. (2024) recently proposed a rank-based approach for evaluating surrogate markers, characterized by its nonparametric nature and minimal assumptions. While this method is useful in small-sample model-agnostic settings, it has several limitations, including a lack of clear causal interpretation, low statistical power, and insufficient robustness to different data-generating mechanisms. In this paper, we propose a Bayesian approach that addresses these shortcomings by focusing on causal treatment effect estimands and, in doing so, improves power through covariate adjustment. We demonstrate the advantages of our proposed method through a simulation study designed to highlight gains in both accuracy and power.

stat.ME↗

arXiv2025

Resilience Measures for the Surrogate Paradox

Surrogate markers are often used in clinical trials to evaluate treatment effects when primary outcomes are costly, invasive, or take a long time to observe. However, reliance on surrogates can lead to the surrogate paradox, where a treatment appears beneficial based on the surrogate but is actually harmful with respect to the primary outcome. In this paper, we propose formal measures to assess resilience against the surrogate paradox. Our setting assumes an existing study in which the surrogate marker and primary outcome have been measured (Study A) and a new study (Study B) in which only the surrogate is measured. Rather than assuming transportability of the conditional mean functions across studies, we consider a class of functions for Study B that deviate from those in Study A. Using these, we estimate the distribution of potential treatment effects on the unmeasured primary outcome and define resilience measures including a resilience probability, resilience bound, and resilience set. Our approach complements traditional surrogate validation methods by quantifying the plausibility of the surrogate paradox under controlled deviations from what is known from Study A. We investigate the performance of our proposed measures via a simulation study and application to two distinct HIV clinical trials.

stat.ME↗

arXiv2025

Efficient Testing Using Surrogate Information

In modern clinical trials, there is immense pressure to use surrogate markers in place of an expensive or long-term primary outcome to make more timely decisions about treatment effectiveness. However, using a surrogate marker to test for a treatment effect can be difficult and controversial. Existing methods tend to either rely on fully parametric methods where strict assumptions are made about the relationship between the surrogate and the outcome, or assume the surrogate marker is valid for the entire study population. In this paper, we develop a fully nonparametric method for efficient testing using surrogate information (ETSI). Our approach is specifically designed for settings where there is heterogeneity in the utility of the surrogate marker, i.e., the surrogate is valid for certain patient subgroups and not others. ETSI enables treatment effect estimation and hypothesis testing via kernel-based estimation for a setting where the surrogate is used in place of the primary outcome for individuals for whom the surrogate is valid, and the primary outcome is purposefully only measured in the remaining patients. In addition, we provide a framework for future study design with power and sample size estimates based on our proposed testing procedure. We demonstrate the performance of our methods via a simulation study and application to two distinct HIV clinical trials.

stat.ME↗

arXiv2025

Assessing Surrogate Heterogeneity in Real World Data Using Meta-Learners

Surrogate markers are most commonly studied within the context of randomized clinical trials. However, the need for alternative outcomes extends beyond these settings and may be more pronounced in real-world public health and social science research, where randomized trials are often impractical. Research on identifying surrogates in real-world non-randomized data is scarce, as available statistical approaches for evaluating surrogate markers tend to rely on the assumption that treatment is randomized. While the few methods that allow for non-randomized treatment/exposure appropriately handle confounding individual characteristics, they do not offer a way to examine surrogate heterogeneity with respect to patient characteristics. In this paper, we propose a framework to assess surrogate heterogeneity in real-world, i.e., non-randomized, data and implement this framework using various meta-learners. Our approach allows us to quantify heterogeneity in surrogate strength with respect to patient characteristics while accommodating confounders through the use of flexible, off-the-shelf machine learning methods. In addition, we use our framework to identify individuals for whom the surrogate is a valid replacement of the primary outcome. We examine the performance of our methods via a simulation study and application to examine heterogeneity in the surrogacy of hemoglobin A1c as a surrogate for fasting plasma glucose.

stat.ME↗

arXiv2025

RISE: Two-Stage Rank-Based Identification of High-Dimensional Surrogate Markers Applied to Vaccinology

In vaccine trials with long-term participant follow-up, it is of great importance to identify surrogate markers that accurately infer long-term immune responses. These markers offer practical advantages such as providing early, indirect evidence of vaccine efficacy, and can accelerate vaccine development while identifying potential biomarkers. High-throughput technologies like RNA-sequencing have emerged as promising tools for understanding complex biological systems and informing new treatment strategies. However, these data are high-dimensional, presenting unique statistical challenges for existing surrogate marker identification methods. We introduce Rank-based Identification of high-dimensional SurrogatE Markers (RISE), a novel approach designed for small sample, high-dimensional settings typical in modern vaccine experiments. RISE employs a non-parametric univariate test to screen variables for promising candidates, followed by surrogate evaluation on independent data. Our simulation studies demonstrate RISE's desirable properties, including type one error rate control and empirical power under various conditions. Applying RISE to a clinical trial for inactivated influenza vaccination, we sought to identify genes whose expression could serve as a surrogate for the induced immune response. This analysis revealed a signature of genes appearing to function as a reasonable surrogate for the neutralising antibody response. Pathways related to innate antiviral signalling and interferon stimulation were strongly represented in this derived surrogate, providing a clear immunological interpretation.

stat.ME↗

arXiv2024

Semiparametric Joint Modeling to Estimate the Treatment Effect on a Longitudinal Surrogate with Application to Chronic Kidney Disease Trials

In clinical trials where long follow-up is required to measure the primary outcome of interest, there is substantial interest in using an accepted surrogate outcome that can be measured earlier in time or with less cost to estimate a treatment effect. For example, in clinical trials of chronic kidney disease (CKD), the effect of a treatment is often demonstrated on a surrogate outcome, the longitudinal trajectory of glomerular filtration rate (GFR). However, estimating the effect of a treatment on the GFR trajectory is complicated by the fact that GFR measurement can be terminated by the occurrence of a terminal event, such as death or kidney failure. Thus, to estimate this effect, one must consider both the longitudinal outcome of GFR, and the terminal event process. Available estimation methods either impose restrictive parametric assumptions with corresponding maximum likelihood estimation that is computationintensive or other assumptions not appropriate for the GFR setting. In this paper, we build a semiparametric framework to jointly model the longitudinal outcome and the terminal event, where the model for the longitudinal outcome is semiparametric, and the relationship between the longitudinal outcome and the terminal event is nonparametric. The proposed semiparametric joint model is flexible and can be extended to include nonlinear trajectory of the longitudinal outcome easily. An estimating equation based method is proposed to estimate the treatment effect on the slope of the longitudinal outcome (e.g., GFR slope). Theoretical properties of the proposed estimators are derived. Finite sample performance of the proposed method is evaluated through simulation studies. We illustrate the proposed method using data from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trail to examine the effect of Losartan on GFR slope.

stat.ME↗

arXiv2024

Model-free Approach to Evaluate a Censored Intermediate Outcome as a Surrogate for Overall Survival

Clinical trials or studies oftentimes require long-term and/or costly follow-up of participants to evaluate a novel treatment/drug/vaccine. There has been increasing interest in the past few decades in using short-term surrogate outcomes as a replacement of the primary outcome i.e., in using the surrogate outcome, which can potentially be observed sooner, to make inference about the treatment effect on the long-term primary outcome. Very few of the available statistical methods to evaluate a surrogate are applicable to settings where both the surrogate and the primary outcome are time-to-event outcomes subject to censoring. Methods that can handle this setting tend to require parametric assumptions or be limited to assessing only the restricted mean survival time. In this paper, we propose a non-parametric approach to evaluate a censored surrogate outcome, such as time to progression, when the primary outcome is also a censored time-to-event outcome, such as time to death, and the treatment effect of interest is the difference in overall survival. Specifically, we define the proportion of the treatment effect on the primary outcome that is explained (PTE) by the censored surrogate outcome in this context, and estimate this proportion by defining and deriving an optimal transformation of the surrogate information. Our approach provides the added advantage of relaxed assumptions to guarantee that the true PTE is within (0,1), along with being model-free. Finite sample performance of our estimators are illustrated via extensive simulation studies and a real data application examining progression-free survival as a surrogate for overall survival for patients with metastatic colorectal cancer.

stat.ME↗

arXiv2024

Group Sequential Testing of a Treatment Effect Using a Surrogate Marker

The identification of surrogate markers is motivated by their potential to make decisions sooner about a treatment effect. However, few methods have been developed to actually use a surrogate marker to test for a treatment effect in a future study. Most existing methods consider combining surrogate marker and primary outcome information to test for a treatment effect, rely on fully parametric methods where strict parametric assumptions are made about the relationship between the surrogate and the outcome, and/or assume the surrogate marker is measured at only a single time point. Recent work has proposed a nonparametric test for a treatment effect using only surrogate marker information measured at a single time point by borrowing information learned from a prior study where both the surrogate and primary outcome were measured. In this paper, we utilize this nonparametric test and propose group sequential procedures that allow for early stopping of treatment effect testing in a setting where the surrogate marker is measured repeatedly over time. We derive the properties of the correlated surrogate-based nonparametric test statistics at multiple time points and compute stopping boundaries that allow for early stopping for a significant treatment effect, or for futility. We examine the performance of our testing procedure using a simulation study and illustrate the method using data from two distinct AIDS clinical trials.

stat.ME↗

arXiv2024

Robust Evaluation of Longitudinal Surrogate Markers with Censored Data

The development of statistical methods to evaluate surrogate markers is an active area of research. In many clinical settings, the surrogate marker is not simply a single measurement but is instead a longitudinal trajectory of measurements over time, e.g., fasting plasma glucose measured every 6 months for 3 years. In general, available methods developed for the single-surrogate setting cannot accommodate a longitudinal surrogate marker. Furthermore, many of the methods have not been developed for use with primary outcomes that are time-to-event outcomes and/or subject to censoring. In this paper, we propose robust methods to evaluate a longitudinal surrogate marker in a censored time-to-event outcome setting. Specifically, we propose a method to define and estimate the proportion of the treatment effect on a censored primary outcome that is explained by the treatment effect on a longitudinal surrogate marker measured up to time $t_0$. We accommodate both potential censoring of the primary outcome and of the surrogate marker. A simulation study demonstrates good finite-sample performance of our proposed methods. We illustrate our procedures by examining repeated measures of fasting plasma glucose, a surrogate marker for diabetes diagnosis, using data from the Diabetes Prevention Program (DPP).

stat.ME↗

arXiv2022

Using a Surrogate with Heterogeneous Utility to Test for a Treatment Effect

The primary benefit of identifying a valid surrogate marker is the ability to use it in a future trial to test for a treatment effect with shorter follow-up time or less cost. However, previous work has demonstrated potential heterogeneity in the utility of a surrogate marker. When such heterogeneity exists, existing methods that use the surrogate to test for a treatment effect while ignoring this heterogeneity may lead to inaccurate conclusions about the treatment effect, particularly when the patient population in the new study has a different mix of characteristics than the study used to evaluate the utility of the surrogate marker. In this paper, we develop a novel test for a treatment effect using surrogate marker information that accounts for heterogeneity in the utility of the surrogate. We compare our testing procedure to a test that uses primary outcome information (gold standard) and a test that uses surrogate marker information, but ignores heterogeneity. We demonstrate the validity of our approach and derive the asymptotic properties of our estimator and variance estimates. Simulation studies examine the finite sample properties of our testing procedure and demonstrate when our proposed approach can outperform the testing approach that ignores heterogeneity. We illustrate our methods using data from an AIDS clinical trial to test for a treatment effect using CD4 count as a surrogate marker for RNA.

stat.ME↗

arXiv2022

Towards Optimal Use of Surrogate Markers to Improve Power

Motivated by increasing pressure for decision makers to shorten the time required to evaluate the efficacy of a treatment such that treatments deemed safe and effective can be made publicly available, there has been substantial recent interest in using an earlier or easier to measure surrogate marker, $S$, in place of the primary outcome, $Y$. To validate the utility of a surrogate marker in these settings, a commonly advocated measure is the proportion of treatment effect on the primary outcome that is explained by the treatment effect on the surrogate marker (PTE). Model based and model free estimators for PTE have also been developed. While this measure is very intuitive, it does not directly address the important questions of how $S$ can be used to make inference of the unavailable $Y$ in the next phase clinical trials. In this paper, to optimally use the information of surrogate S, we provide a framework for deriving an optimal transformation of $S$, $g_{opt}(S)$, such that the treatment effect on $g_{opt}(S)$ maximally approximates the treatment effect on $Y$ in a certain sense. Based on the optimally transformed surrogate, $g_{opt}(S)$, we propose a new measure to quantify surrogacy, the relative power (RP), and demonstrate how RP can be used to make decisions with $S$ instead of $Y$ for next phase trials. We propose nonparametric estimation procedures, derive asymptotic properties, and compare the RP measure with the PTE measure. Finite sample performance of our estimators is assessed via a simulation study. We illustrate our proposed procedures using an application to the Diabetes Prevention Program (DPP) clinical trial to evaluate the utility of hemoglobin A1c and fasting plasma glucose as surrogate markers for diabetes.

stat.ME↗

arXiv2020

Doubly-robust evaluation of high-dimensional surrogate markers

When evaluating the effectiveness of a treatment, policy, or intervention, the desired measure of effectiveness may be expensive to collect, not routinely available, or may take a long time to occur. In these cases, it is sometimes possible to identify a surrogate outcome that can more easily/quickly/cheaply capture the effect of interest. Theory and methods for evaluating the strength of surrogate markers have been well studied in the context of a single surrogate marker measured in the course of a randomized clinical study. However, methods are lacking for quantifying the utility of surrogate markers when the dimension of the surrogate grows and/or when study data are observational. We propose an efficient nonparametric method for evaluating high-dimensional surrogate markers in studies where the treatment need not be randomized. Our approach draws on a connection between quantifying the utility of a surrogate marker and the most fundamental tools of causal inference -- namely, methods for estimating the average treatment effect. We show that recently developed methods for incorporating machine learning methods into the estimation of average treatment effects can be used for evaluating surrogate markers. This allows us to derive limiting asymptotic distributions for key quantities, and we demonstrate their good performance in simulation.

stat.ME↗

arXiv2016

Evaluating Surrogate Marker Information using Censored Data

Given the long follow-up periods that are often required for treatment or intervention studies, the potential to use surrogate markers to decrease the required follow-up time is a very attractive goal. However, previous studies have shown that using inadequate markers or making inappropriate assumptions about the relationship between the primary outcome and surrogate marker can lead to inaccurate conclusions regarding the treatment effect. Currently available methods for identifying and validating surrogate markers tend to rely on restrictive model assumptions and/or focus on uncensored outcomes. The ability to use such methods in practice when the primary outcome of interest is a time-to-event outcome is difficult due to censoring and missing surrogate information among those who experience the primary outcome before surrogate marker measurement. In this paper, we propose a novel definition of the proportion of treatment effect explained by surrogate information collected up to a specified time in the setting of a time-to-event primary outcome. Our proposed approach accommodates a setting where individuals may experience the primary outcome before the surrogate marker is measured. We propose a robust nonparametric procedure to estimate the defined quantity using censored data and use a perturbation-resampling procedure for variance estimation. Simulation studies demonstrate that the proposed procedures perform well in finite samples. We illustrate the proposed procedures by investigating two potential surrogate markers for diabetes using data from the Diabetes Prevention Program.

stat.ME↗