# Joint modeling of longitudinal biomarker and survival outcomes with the presence of competing risk in the nested case–control studies with application to the TEDDY microbiome dataset

## TL;DR

This paper introduces a new statistical framework for analyzing longitudinal biomarker data and survival outcomes in nested case-control studies, particularly when competing risks are present.

## Contribution

The novel contribution is a joint modeling framework (JM-NCC) that handles non-normal biomarkers and competing risks in nested case-control designs.

## Key findings

- The proposed JM-NCC framework demonstrates robustness and efficiency in simulation studies.
- Application to the TEDDY microbiome dataset validates the framework's practical utility.

## Abstract

Large-scale prospective cohort studies collect longitudinal biospecimens alongside time-to-event outcomes to investigate biomarker dynamics in relation to disease risk. The nested case–control (NCC) design provides a cost-effective alternative to full cohort biomarker studies while preserving statistical efficiency. Despite advances in joint modeling for longitudinal and time-to-event outcomes, few approaches address the unique challenges posed by NCC sampling, non-normally distributed biomarkers, and competing survival outcomes.

Motivated by the TEDDY study, we propose “JM-NCC”, a joint modeling framework designed for NCC studies with competing events. It integrates a generalized linear mixed-effects model for potentially non-normally distributed biomarkers with a cause-specific hazard model for competing risks. Two estimation methods are developed. fJM-NCC leverages NCC sub-cohort longitudinal biomarker data and full cohort survival and clinical metadata, while wJM-NCC uses only NCC sub-cohort data. Both simulation studies and an application to TEDDY microbiome dataset demonstrate the robustness and efficiency of the proposed methods.

Software is available at https://github.com/Zhaoyn-oss/JMNCC and archived on Zenodo at https://zenodo.org/records/18199759 (DOI: 10.5281/zenodo.18199759).