Hazard-Based Targeted Maximum Likelihood Estimation for Survival in Resampling Designs

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Main Authors: Landsiedel, Kirsten E., Phillips, Rachael V., Petersen, Maya L., van der Laan, Mark J.
Format: Preprint
Published: 2025
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author Landsiedel, Kirsten E.
Phillips, Rachael V.
Petersen, Maya L.
van der Laan, Mark J.
author_facet Landsiedel, Kirsten E.
Phillips, Rachael V.
Petersen, Maya L.
van der Laan, Mark J.
contents Survival is a key metric for evaluating standards of care for people living with HIV. In resource-limited settings, high rates of loss to follow-up (LTFU) often result in underestimation of mortality when only observed deaths are considered. Resampling, which tracks a subset of LTFU patients to ascertain their outcomes, mitigates bias and improves survival estimates. However, common estimators for survival in resampling designs, such as weighted Kaplan-Meier (KM), fail to leverage covariate information collected during repeated clinic visits, even though this information is highly predictive of survival. We propose a Targeted Maximum Likelihood Estimator (TMLE) for survival in resampling designs, which addresses these limitations by leveraging baseline and longitudinal covariates to achieve greater efficiency. Our TMLE is a plug-in estimator and is robust to misspecification of the initial model for the conditional hazard of death, guaranteeing consistency of our estimator due to known resampling probabilities. We present: (1) a fully efficient TMLE for data from resampling studies with fixed follow-up time for all participants and (2) an inverse probability of censoring weighted (IPCW) TMLE that accounts for varied follow-up times by stratifying on patients with sufficient follow-up to evaluate survival. This IPCW-TMLE can be made highly efficient through nonparametric or targeted estimation of the follow-up censoring mechanism. In simulations, our TMLE reduced variance by up to 55% compared with the commonly used weighted KM estimator while preserving nominal confidence interval coverage. These findings demonstrate the potential of our TMLE to improve survival estimation in resampling designs, offering a robust and resource-efficient framework for HIV research. Keywords: Resampling designs, Survival analysis, Targeted Maximum Likelihood Estimation, Inverse probability weighting
format Preprint
id arxiv_https___arxiv_org_abs_2511_15045
institution arXiv
publishDate 2025
record_format arxiv
spellingShingle Hazard-Based Targeted Maximum Likelihood Estimation for Survival in Resampling Designs
Landsiedel, Kirsten E.
Phillips, Rachael V.
Petersen, Maya L.
van der Laan, Mark J.
Methodology
Survival is a key metric for evaluating standards of care for people living with HIV. In resource-limited settings, high rates of loss to follow-up (LTFU) often result in underestimation of mortality when only observed deaths are considered. Resampling, which tracks a subset of LTFU patients to ascertain their outcomes, mitigates bias and improves survival estimates. However, common estimators for survival in resampling designs, such as weighted Kaplan-Meier (KM), fail to leverage covariate information collected during repeated clinic visits, even though this information is highly predictive of survival. We propose a Targeted Maximum Likelihood Estimator (TMLE) for survival in resampling designs, which addresses these limitations by leveraging baseline and longitudinal covariates to achieve greater efficiency. Our TMLE is a plug-in estimator and is robust to misspecification of the initial model for the conditional hazard of death, guaranteeing consistency of our estimator due to known resampling probabilities. We present: (1) a fully efficient TMLE for data from resampling studies with fixed follow-up time for all participants and (2) an inverse probability of censoring weighted (IPCW) TMLE that accounts for varied follow-up times by stratifying on patients with sufficient follow-up to evaluate survival. This IPCW-TMLE can be made highly efficient through nonparametric or targeted estimation of the follow-up censoring mechanism. In simulations, our TMLE reduced variance by up to 55% compared with the commonly used weighted KM estimator while preserving nominal confidence interval coverage. These findings demonstrate the potential of our TMLE to improve survival estimation in resampling designs, offering a robust and resource-efficient framework for HIV research. Keywords: Resampling designs, Survival analysis, Targeted Maximum Likelihood Estimation, Inverse probability weighting
title Hazard-Based Targeted Maximum Likelihood Estimation for Survival in Resampling Designs
topic Methodology
url https://arxiv.org/abs/2511.15045