March 2024 Dynamic risk prediction for cervical precancer screening with continuous and binary longitudinal biomarkers
Siddharth Roy, Anindya Roy, Megan A. Clarke, Ana Gradissimo, Robert D. Burk, Nicolas Wentzensen, Paul S. Albert, Danping Liu
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Ann. Appl. Stat. 18(1): 246-265 (March 2024). DOI: 10.1214/23-AOAS1788


Dynamic risk prediction that incorporates longitudinal measurements of biomarkers is useful in identifying high-risk patients for better clinical management. Our work is motivated by the prediction of cervical precancers. Currently, Pap cytology is used to identify HPV-positive (HPV+) women at high-risk of cervical precancer, but cytology lacks accuracy and reproducibility. Molecular markers, like HPV DNA methylation, that are closely linked to the carcinogenic process show promise of improved risk stratification. We are interested in developing a dynamic risk model that uses all longitudinal biomarker information to improve precancer risk estimation. We propose a joint model to link both the continuous methylation biomarker and a binary cytology biomarker to the time to precancer outcome using shared random effects. The model uses a discretization of the time scale to allow for closed-form likelihood expressions, thereby avoiding potential high dimensional integration of the random effects. The method handles an interval-censored time-to-event outcome, due to intermittent clinical visits, incorporates sampling weights to deal with stratified sampling data and can provide immediate and five-year risk estimates that may inform clinical decision-making. Applying the method to longitudinally measured HPV methylation data improves risk stratification for triage of HPV+ women.

Funding Statement

This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NIH). This work utilized the computational resources of the NIH HPC Biowulf cluster (


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Siddharth Roy. Anindya Roy. Megan A. Clarke. Ana Gradissimo. Robert D. Burk. Nicolas Wentzensen. Paul S. Albert. Danping Liu. "Dynamic risk prediction for cervical precancer screening with continuous and binary longitudinal biomarkers." Ann. Appl. Stat. 18 (1) 246 - 265, March 2024.


Received: 1 November 2021; Revised: 1 June 2023; Published: March 2024
First available in Project Euclid: 31 January 2024

Digital Object Identifier: 10.1214/23-AOAS1788

Keywords: Cervical precancer , dynamic risk prediction , joint model , longitudinal biomarkers , shared random effects

Rights: Copyright © 2024 Institute of Mathematical Statistics


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Vol.18 • No. 1 • March 2024
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