arXiv subjects

Malka Gorfine

Publications and source records attributed to Malka Gorfine.

At least 19 recordsLinked to original sources

arXiv2026

Efficient Cumulative Incidence Estimation in Biobank Studies Using All Prevalent and Incident Events

Population-based biobanks, now established in many countries, offer opportunities for large-scale studies investigating the incidence of various diseases. Biobank data is typically collected from a study cohort recruited over a defined calendar period, with subjects entering the study at various ages falling between $R_L$ and $R_U$. This work focuses on biobank data that includes individuals in whom onset of the disease of interest occurred before recruitment, termed prevalent cases, along with individuals initially recruited as disease-free in whom disease onset occurred during the follow-up period. We propose a novel cumulative incidence function (CIF) estimator that goes beyond existing methods in that it incorporates all disease cases, both prevalent and incident, irrespective of their subsequent life course. In particular, the new method can handle situations involving diseases that can occur at young ages with long survival after disease onset. Asymptotic properties of the new method are established and a simulation study is presented examining the performance of the method. We illustrate the use of the method and highlight its advantages over existing methods with an application to cancer data from the UK biobank.

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arXiv2026

SpARCD: A Spectral Graph Framework for Revealing Differential Functional Connectivity in fMRI Data

Identifying brain regions that exhibit altered functional connectivity between cognitive or emotional states is a fundamental problem in neuroscience. We propose SpARCD (Spectral Analysis for Revealing Connectivity Differences), a statistical framework for detecting detecting condition-specific patterns of functional connectivity. SpARCD uses distance correlation, a dependence measure sensitive to both linear and nonlinear associations, to construct weighted region-wise connectivity graphs for each condition. A differential operator obtained through spectral filtering is then used to identify connectivity changes via its leading eigenvectors. To assess statistical significance, we develop a permutation-based testing procedure that yields interpretable region-level significance maps. We establish finite-sample validity of the permutation test and derive asymptotic guarantees for the stability of the resulting region rankings. Simulation studies demonstrate improved power relative to conventional edge-wise and univariate approaches, particularly in settings with nonlinear dependence structures. We applied SpARCD to fMRI data from 113 individuals with early-stage PTSD and 42 controls during emotional and neutral task conditions. The method identified distinct connectivity networks associated with visual processing in both PTSD and control participants. Resting-state comparisons between PTSD and control participants highlighted similar visual networks. SpARCD provides a statistically rigorous and computationally efficient framework for comparing high-dimensional connectivity patterns.

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arXiv2026

Cox Regression on the Plane

The Cox proportional hazards model is the most widely used regression model in univariate survival analysis, yet extensions to bivariate survival data remain scarce. We propose two novel extensions based on a Lehmann-type representation of the survival function. The first, the simple Lehmann model, is a direct extension that retains a straightforward structure. The second, the generalized Lehmann model, allows greater flexibility by incorporating three distinct regression parameters and includes the simple Lehmann model as a special case. The models admit a direct interpretation in terms of survival probabilities, providing a transparent, fully semiparametric framework for assessing covariate effects on both marginal survival probabilities and their dependence, without requiring specification of a copula or frailty distribution. To estimate the regression parameters, we build on a pseudo-observation-based approach for bivariate survival data and extend it to the generalized model via a two-step procedure. We establish consistency and asymptotic normality of the resulting estimators. The proposed approach is illustrated through simulation studies and an application to data from the Global Retinoblastoma Outcome Study.

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arXiv2026

Flexible Deep Neural Networks for Partially Linear Survival Data: Estimation and Survival Inference

We propose a flexible deep neural network (DNN) framework for modeling survival data within a partially linear regression structure. The approach preserves interpretability through a parametric linear component for covariates of primary interest, while a nonparametric DNN component captures complex time-covariate interactions among nuisance variables. We refer to the method as FLEXI-Haz, a FLEXIble Hazard model with a partially linear structure. In contrast to existing DNN approaches for partially linear Cox models, FLEXI-Haz does not rely on the proportional hazards assumption. We establish theoretical guarantees: the neural network component attains minimax-optimal convergence rates over composite Hölder classes, the linear estimator is sqrt-n-consistent, asymptotically normal, and semiparametrically efficient, and we develop a cross-fitted one-step estimator of the cumulative hazard and survival function for a new subject, together with pointwise asymptotic confidence intervals. To the best of our knowledge, this is the first frequentist asymptotic pointwise inference result for a survival function in a DNN survival model, with or without a linear component. Simulations and real-data analyses demonstrate the utility of FLEXI-Haz as a principled and interpretable alternative to methods based on proportional hazards.

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arXiv2025

PyDTS: A Python Package for Discrete-Time Survival Analysis with Competing Risks and Optional Penalization

Time-to-event (survival) analysis models the time until a pre-specified event occurs. When time is measured in discrete units or rounded into intervals, standard continuous-time models can yield biased estimators. In addition, the event of interest may belong to one of several mutually exclusive types, referred to as competing risks, where the occurrence of one event prevents the occurrence or observation of the others. PyDTS is an open-source Python package for analyzing discrete-time survival data with competing-risks. It provides regularized estimation methods, model evaluation metrics, variable screening tools, and a simulation module to support research and development.

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arXiv2025

Heterogeneous Treatment Effect in Time-to-Event Outcomes: Harnessing Censored Data with Recursively Imputed Trees

Tailoring treatments to individual needs is a central goal in fields such as medicine. A key step toward this goal is estimating Heterogeneous Treatment Effects (HTE) - the way treatments impact different subgroups. While crucial, HTE estimation is challenging with survival data, where time until an event (e.g., death) is key. Existing methods often assume complete observation, an assumption violated in survival data due to right-censoring, leading to bias and inefficiency. Cui et al. (2023) proposed a doubly-robust method for HTE estimation in survival data under no hidden confounders, combining a causal survival forest with an augmented inverse-censoring weighting estimator. However, we find it struggles under heavy censoring, which is common in rare-outcome problems such as Amyotrophic lateral sclerosis (ALS). Moreover, most current methods cannot handle instrumental variables, which are a crucial tool in the causal inference arsenal. We introduce Multiple Imputation for Survival Treatment Response (MISTR), a novel, general, and non-parametric method for estimating HTE in survival data. MISTR uses recursively imputed survival trees to handle censoring without directly modeling the censoring mechanism. Through extensive simulations and analysis of two real-world datasets-the AIDS Clinical Trials Group Protocol 175 and the Illinois unemployment dataset we show that MISTR outperforms prior methods under heavy censoring in the no-hidden-confounders setting, and extends to the instrumental variable setting. To our knowledge, MISTR is the first non-parametric approach for HTE estimation with unobserved confounders via instrumental variables.

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arXiv2025

An Overview and Recent Developments in the Analysis of Multistate Processes

Multistate models offer a powerful framework for studying disease processes and can be used to formulate intensity-based and more descriptive marginal regression models. They also represent a natural foundation for the construction of joint models for disease processes and dynamic marker processes, as well as joint models incorporating random censoring and intermittent observation times. This article reviews the ways multistate models can be formed and fitted to life history data. Recent work on pseudo-values and the incorporation of random effects to model dependence on the process history and between-process heterogeneity are also discussed. The software available to facilitate such analyses is listed.

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arXiv2025

Discrete-time Competing-Risks Regression with or without Penalization

Many studies employ the analysis of time-to-event data that incorporates competing risks and right censoring. Most methods and software packages are geared towards analyzing data that comes from a continuous failure time distribution. However, failure-time data may sometimes be discrete either because time is inherently discrete or due to imprecise measurement. This paper introduces a new estimation procedure for discrete-time survival analysis with competing events. The proposed approach offers a major key advantage over existing procedures and allows for straightforward integration and application of widely used regularized regression and screening-features methods. We illustrate the benefits of our proposed approach by a comprehensive simulation study. Additionally, we showcase the utility of the proposed procedure by estimating a survival model for the length of stay of patients hospitalized in the intensive care unit, considering three competing events: discharge to home, transfer to another medical facility, and in-hospital death. A Python package, PyDTS, is available for applying the proposed method with additional features.

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arXiv2024

Cost-Effectiveness Analysis for Disease Prevention -- A Case Study on Colorectal Cancer Screening

Cancer Screening has been widely recognized as an effective strategy for preventing the disease. Despite its effectiveness, determining when to start screening is complicated, because starting too early increases the number of screenings over lifetime and thus costs but starting too late may miss the cancer that could have been prevented. Therefore, to make an informed recommendation on the age to start screening, it is necessary to conduct cost-effectiveness analysis to assess the gain in life years relative to the cost of screenings. As more large-scale observational studies become accessible, there is growing interest in evaluating cost-effectiveness based on empirical evidence. In this paper, we propose a unified measure for evaluating cost-effectiveness and a causal analysis for the continuous intervention of screening initiation age, under the multi-state modeling with semi-competing risks. Extensive simulation results show that the proposed estimators perform well in realistic scenarios. We perform a cost-effectiveness analysis of the colorectal cancer screening, utilizing data from the large-scale Women's Health Initiative. Our analysis reveals that initiating screening at age 50 years yields the highest quality-adjusted life years with an acceptable incremental cost-effectiveness ratio compared to no screening, providing real-world evidence in support of screening recommendation for colorectal cancer.

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arXiv2024

Confidence Intervals and Simultaneous Confidence Bands Based on Deep Learning

Deep learning models have significantly improved prediction accuracy in various fields, gaining recognition across numerous disciplines. Yet, an aspect of deep learning that remains insufficiently addressed is the assessment of prediction uncertainty. Producing reliable uncertainty estimators could be crucial in practical terms. For instance, predictions associated with a high degree of uncertainty could be sent for further evaluation. Recent works in uncertainty quantification of deep learning predictions, including Bayesian posterior credible intervals and a frequentist confidence-interval estimation, have proven to yield either invalid or overly conservative intervals. Furthermore, there is currently no method for quantifying uncertainty that can accommodate deep neural networks for survival (time-to-event) data that involves right-censored outcomes. In this work, we provide a valid non-parametric bootstrap method that correctly disentangles data uncertainty from the noise inherent in the adopted optimization algorithm, ensuring that the resulting point-wise confidence intervals or the simultaneous confidence bands are accurate (i.e., valid and not overly conservative). The proposed ad-hoc method can be easily integrated into any deep neural network without interfering with the training process. The utility of the proposed approach is illustrated by constructing simultaneous confidence bands for survival curves derived from deep neural networks for survival data with right censoring.

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arXiv2024

Mastering Rare Event Analysis: Optimal Subsample Size in Logistic and Cox Regressions

In the realm of contemporary data analysis, the use of massive datasets has taken on heightened significance, albeit often entailing considerable demands on computational time and memory. While a multitude of existing works offer optimal subsampling methods for conducting analyses on subsamples with minimized efficiency loss, they notably lack tools for judiciously selecting the optimal subsample size. To bridge this gap, our work introduces tools designed for choosing the optimal subsample size. We focus on three settings: the Cox regression model for survival data with rare events and logistic regression for both balanced and imbalanced datasets. Additionally, we present a novel optimal subsampling procedure tailored for logistic regression with imbalanced data. The efficacy of these tools and procedures is demonstrated through an extensive simulation study and meticulous analyses of two sizable datasets.

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arXiv2024

Cumulative Incidence Function Estimation Based on Population-Based Biobank Data

Many countries have established population-based biobanks, which are being used increasingly in epidemiolgical and clinical research. These biobanks offer opportunities for large-scale studies addressing questions beyond the scope of traditional clinical trials or cohort studies. However, using biobank data poses new challenges. Typically, biobank data is collected from a study cohort recruited over a defined calendar period, with subjects entering the study at various ages falling between $c_L$ and $c_U$. This work focuses on biobank data with individuals reporting disease-onset age upon recruitment, termed prevalent data, along with individuals initially recruited as healthy, and their disease onset observed during the follow-up period. We propose a novel cumulative incidence function (CIF) estimator that efficiently incorporates prevalent cases, in contrast to existing methods, providing two advantages: (1) increased efficiency, and (2) CIF estimation for ages before the lower limit, $c_L$.

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arXiv2023

Unveiling Challenges in Mendelian Randomization for Gene-Environment Interaction

Many diseases and traits involve a complex interplay between genes and environment, generating significant interest in studying gene-environment interaction through observational data. However, for lifestyle and environmental risk factors, they are often susceptible to unmeasured confounding factors and as a result, may bias the assessment of the joint effect of gene and environment. Recently, Mendelian randomization (MR) has evolved into a versatile method for assessing causal relationships based on observational data to account for unmeasured confounders. This approach utilizes genetic variants as instrumental variables (IVs) and aims to offer a reliable statistical test and estimation of causal effects. MR has gained substantial popularity in recent years largely due to the success of large-scale genome-wide association studies in identifying genetic variants associated with lifestyle and environmental factors. Many methods have been developed for MR; however, little work has been done for evaluating gene-environment interaction. In this paper, we focus on two primary IV approaches: the 2-stage predictor substitution (2SPS) and the 2-stage residual inclusion (2SRI), and extend them to accommodate gene-environment interaction under both the linear and logistic regression models for the continuous and binary outcomes, respectively. Extensive simulation and analytical derivations show that finding solutions in the linear regression model setting is relatively straightforward; however, the logistic regression model is significantly more complex and demands additional effort.

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arXiv2023

Unlocking Retrospective Prevalent Information in EHRs -- a Pairwise Pseudolikelihood Approach

Typically, electronic health record data are not collected towards a specific research question. Instead, they comprise numerous observations recruited at different ages, whose medical, environmental and oftentimes also genetic data are being collected. Some phenotypes, such as disease-onset ages, may be reported retrospectively if the event preceded recruitment, and such observations are termed ``prevalent". The standard method to accommodate this ``delayed entry" conditions on the entire history up to recruitment, hence the retrospective prevalent failure times are conditioned upon and cannot participate in estimating the disease-onset age distribution. An alternative approach conditions just on survival up to recruitment age, plus the recruitment age itself. This approach allows incorporating the prevalent information but brings about numerical and computational difficulties. In this work we develop consistent estimators of the coefficients in a regression model for the age-at-onset, while utilizing the prevalent data. Asymptotic results are provided, and simulations are conducted to showcase the substantial efficiency gain that may be obtained by the proposed approach. In particular, the method is highly useful in leveraging large-scale repositories for replicability analysis of genetic variants. Indeed, analysis of urinary bladder cancer data reveals that the proposed approach yields about twice as many replicated discoveries compared to the popular approach.

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arXiv2022

Shared Frailty Methods for Complex Survival Data: A Review of Recent Advances

Dependent survival data arise in many contexts. One context is clustered survival data, where survival data are collected on clusters such as families or medical centers. Dependent survival data also arise when multiple survival times are recorded for each individual. Frailty models is one common approach to handle such data. In frailty models, the dependence is expressed in terms of a random effect, called the frailty. Frailty models have been used with both Cox proportional hazards model and the accelerated failure time model. This paper reviews recent developments in the area of frailty models in a variety of settings. In each setting we provide a detailed model description, assumptions, available estimation methods, and R packages.

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arXiv2022

An Accelerated Failure Time Regression Model for Illness-Death Data: A Frailty Approach

This work presents a new model and estimation procedure for the illness-death survival data where the hazard functions follow accelerated failure time (AFT) models. A shared frailty variate induces positive dependence among failure times of a subject for handling the unobserved dependency between the non-terminal and the terminal failure times given the observed covariates. Semi-parametric maximum likelihood estimation procedure is developed via a kernel smoothed-aided EM algorithm, and variances are estimated by weighted bootstrap. The model is presented in the context of existing frailty-based illness-death models, emphasizing the contribution of the current work. The breast cancer data of the Rotterdam tumor bank are analyzed using the proposed and existing illness-death models. The results are contrasted and evaluated based on a new graphical goodness-of-fit procedure. Simulation results and data analysis nicely demonstrate the practical utility of the shared frailty variate with the AFT regression model under the illness-death framework.

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arXiv2022

Revisiting the Cumulative Incidence Function With Competing Risks Data

We consider estimation of the cumulative incidence function (CIF) in the competing risks Cox model. We study three methods. Methods 1 and 2 are existing methods while Method 3 is a newly-proposed method. Method 3 is constructed so that the sum of the CIF's across all event types at the last observed event time is guaranteed, assuming no ties, to be equal to 1. The performance of the methods is examined in a simulation study, and the methods are illustrated on a data example from the field of computer code comprehension. The newly-proposed Method 3 exhibits performance comparable to that of Methods 1 and 2 in terms of bias, variance, and confidence interval coverage rates. Thus, with our newly-proposed estimator, the advantage of having the end-of-study total CIF equal to 1 is achieved with no price to be paid in terms of performance.

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arXiv2022

Optimal Cox Regression Subsampling Procedure with Rare Events

Massive sized survival datasets are becoming increasingly prevalent with the development of the healthcare industry. Such datasets pose computational challenges unprecedented in traditional survival analysis use-cases. A popular way for coping with massive datasets is downsampling them to a more manageable size, such that the computational resources can be afforded by the researcher. Cox proportional hazards regression has remained one of the most popular statistical models for the analysis of survival data to-date. This work addresses the settings of right censored and possibly left truncated data with rare events, such that the observed failure times constitute only a small portion of the overall sample. We propose Cox regression subsampling-based estimators that approximate their full-data partial-likelihood-based counterparts, by assigning optimal sampling probabilities to censored observations, and including all observed failures in the analysis. Asymptotic properties of the proposed estimators are established under suitable regularity conditions, and simulation studies are carried out to evaluate the finite sample performance of the estimators. We further apply our procedure on UK-biobank colorectal cancer genetic and environmental risk factors.

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