arXiv subjects

Zachary R. McCaw

Publications and source records attributed to Zachary R. McCaw.

7 recordsLinked to original sources

arXiv2026

Pseudo-value Based Mean Cumulative Count Regression

The mean cumulative function (MCF) summarizes how events accumulate over time for a recurrent or multi-component endpoint. The MCF, and its integral over a given time horizon, the area under the MCF (AUMCF), provide interpretable summaries of recurrent-event burden in the presence of right-censoring and terminal events. Existing approaches for these estimands have focused primarily on nonparametric treatment comparisons, covariate-adjusted augmentation, and linearized test statistics. Herein, we propose a pseudo-value-based regression approach for estimating covariate effects on the MCF and AUMCF at a fixed truncation time. The proposed method uses influence-function-based pseudo-values as regression outcomes, allowing estimation with standard generalized estimating equation machinery and, under an identity link, ordinary least squares. Through simulation studies, we evaluate estimation accuracy, confidence interval coverage, type I error control, and power across a range of recurrent-event settings. We demonstrate the utility of the proposed covariate adjustment procedure through an application to the ORATORIO clinical trial, evaluating the safety and efficacy of ocrelizumab for the treatment of primary progressive multiple sclerosis. Overall, pseudo-value-based regression provides a simple and interpretable framework for modeling covariate effects on cumulative recurrent-event burden over time.

stat.ME↗

arXiv2026

Nonparametric estimation of the total treatment effect with multiple outcomes in the presence of terminal events

As standards of care advance, patients are living longer and once-fatal diseases are becoming manageable. Clinical trials increasingly focus on reducing disease burden, which can be quantified by the timing and occurrence of multiple non-fatal clinical events. Most existing methods for the analysis of multiple event-time data require stringent modeling assumptions that can be difficult to verify empirically, leading to treatment efficacy estimates that forego interpretability when the underlying assumptions are not met. Moreover, many methods do not appropriately account for informative terminal events, such as premature treatment discontinuation or death, which prevent the occurrence of subsequent events. To address these limitations, we derive and validate estimation and inference procedures for the area under the mean cumulative function (AUMCF), an extension of the restricted mean survival time to the multiple event-time setting. The AUMCF is clinically interpretable, properly accounts for terminal competing risks, and can be estimated nonparametrically. To enable covariate adjustment, we also develop an augmentation estimator that provides efficiency at least equaling, and often exceeding, the unadjusted estimator. The utility and interpretability of the AUMCF are illustrated with extensive simulation studies and through an analysis of multiple heart-failure-related endpoints using data from the Beta-Blocker Evaluation of Survival Trial (BEST) clinical trial. Our open-source R package MCC makes conducting AUMCF analyses straightforward and accessible.

stat.ME↗

arXiv2026

Another look at statistical inference with machine learning-imputed data

From structural biology to epidemiology, predictions from machine learning (ML) models increasingly complement costly gold-standard data, enabling faster, more affordable, and scalable scientific inquiry. In response, prediction-based (PB) inference has emerged to support statistical analysis that combines a large volume of predicted data with a small amount of gold-standard data. The goals of PB inference are twofold: (i) to mitigate bias arising from prediction error and (ii) to improve efficiency relative to classical inference based solely on gold-standard data. While early PB inference methods primarily focused on bias mitigation, improving efficiency remains an active area of research. Motivated by connections between PB inference and longstanding problems in statistics and related fields, we draw on the two-phase sampling literature to introduce an approach for Z-estimation with ML-imputed outcomes that is guaranteed to match or exceed the efficiency of classical inference, regardless of prediction quality. We demonstrate the utility of our approach through theoretical and numerical analyses as well as an application to UK Biobank data. We further establish new connections between existing PB inference approaches and foundational and contemporary statistical methods.

stat.ML↗

arXiv2026

Revealing the Truth: Calculating True Values in Causal Inference Simulation Studies via Gaussian Quadrature

Simulation studies are used to understand the properties of statistical methods. A key luxury in many simulation studies is knowledge of the true value (i.e. the estimand) being targeted. With this oracle knowledge in-hand, the researcher conducting the simulation study can assess across repeated realizations of the data how well a given method recovers the truth. In causal inference simulation studies, the truth is rarely a simple parameter of the statistical model chosen to generate the data. Instead, the estimand is often an average treatment effect, marginalized over the distribution of confounders and/or mediators. Luckily, these variables are often generated from common distributions such as the normal, uniform, exponential, or gamma. For all these distributions, Gaussian quadratures provide efficient and accurate calculation for integrands with integral kernels that stem from known probability density functions. We demonstrate through four applications how to use Gaussian quadrature to accurately and efficiently compute the true causal estimand. We also compare the pros and cons of Gauss-Hermite quadrature to Monte Carlo integration approaches, which we use as benchmarks. Overall, we demonstrate that the Gaussian quadrature is an accurate tool with negligible computation time, yet is underused for calculating the true causal estimands in simulation studies.

stat.ME↗

arXiv2025

What is Fair? Defining Fairness in Machine Learning for Health

Ensuring that machine learning (ML) models are safe, effective, and equitable across all patients is critical for clinical decision-making and for preventing the amplification of existing health disparities. In this work, we examine how fairness is conceptualized in ML for health, including why ML models may lead to unfair decisions and how fairness has been measured in diverse real-world applications. We review commonly used fairness notions within group, individual, and causal-based frameworks. We also discuss the outlook for future research and highlight opportunities and challenges in operationalizing fairness in health-focused applications.

cs.LG↗

arXiv2025

Simplifying Causal Mediation Analysis for Time-to-Event Outcomes using Pseudo-Values

Mediation analysis for survival outcomes is challenging. Most existing methods quantify the treatment effect using the hazard ratio (HR) and attempt to decompose the HR into the direct effect of treatment plus an indirect, or mediated, effect. However, the HR is not expressible as an expectation, which complicates this decomposition, both in terms of estimation and interpretation. Here, we present an alternative approach which leverages pseudo-values to simplify estimation and inference. Pseudo-values take censoring into account during their construction, and once derived, can be modeled in the same way as any continuous outcome. Thus, pseudo-values enable mediation analysis for a survival outcome to fit seamlessly into standard mediation software (e.g. CMAverse in R). Pseudo-values are easy to calculate via a leave-one-observation-out procedure (i.e. jackknifing) and the calculation can be accelerated when the influence function of the estimator is known. Mediation analysis for causal effects defined by survival probabilities, restricted mean survival time, and cumulative incidence functions - in the presence of competing risks - can all be performed within this framework. Extensive simulation studies demonstrate that the method is unbiased across 324 scenarios/estimands and controls the type-I error at the nominal level under the null of no mediation. We illustrate the approach using data from the PARADIGMS clinical trial for the treatment of pediatric multiple sclerosis using fingolimod. In particular, we evaluate whether an imaging biomarker lies on the causal path between treatment and time-to-relapse, which aids in justifying this biomarker as a surrogate outcome. Our approach greatly simplifies mediation analysis for survival data and provides a decomposition of the total effect that is both intuitive and interpretable.

stat.ME↗

arXiv2020

Large-scale machine learning-based phenotyping significantly improves genomic discovery for optic nerve head morphology

Genome-wide association studies (GWAS) require accurate cohort phenotyping, but expert labeling can be costly, time-intensive, and variable. Here we develop a machine learning (ML) model to predict glaucomatous optic nerve head features from color fundus photographs. We used the model to predict vertical cup-to-disc ratio (VCDR), a diagnostic parameter and cardinal endophenotype for glaucoma, in 65,680 Europeans in the UK Biobank (UKB). A GWAS of ML-based VCDR identified 299 independent genome-wide significant (GWS; $P\leq5\times10^{-8}$) hits in 156 loci. The ML-based GWAS replicated 62 of 65 GWS loci from a recent VCDR GWAS in the UKB for which two ophthalmologists manually labeled images for 67,040 Europeans. The ML-based GWAS also identified 92 novel loci, significantly expanding our understanding of the genetic etiologies of glaucoma and VCDR. Pathway analyses support the biological significance of the novel hits to VCDR, with select loci near genes involved in neuronal and synaptic biology or known to cause severe Mendelian ophthalmic disease. Finally, the ML-based GWAS results significantly improve polygenic prediction of VCDR and primary open-angle glaucoma in the independent EPIC-Norfolk cohort.

q-bio.GN↗