用神经微分方程增强混合效应模型,自动捕捉随时间变化的健康影响模式。
Neural ODE enhanced linear mixed effect models for estimating complex association patterns of time-varying covariates with the marker trajectory

- 用神经微分方程学习协变量在连续时间中的动态轨迹,替代预设函数形式。
- 在3,324人队列中发现体重指数与血糖轨迹对认知衰退有依赖轨迹的影响。
- 适合研究长期暴露与健康结局关系的科研人员,尤其关注复杂时变效应者。
纵向队列研究产生重复测量数据,可用于评估暴露因素与健康结局之间的时变关联模式。经典线性混合效应模型(LMM)虽能处理不规则、部分缺失的测量,但需预先设定暴露史与结局的函数形式。本文提出神经微分方程-线性混合效应模型(Neural ODE-LMM),将神经微分方程嵌入线性混合效应框架:通过学习的向量场将协变量轨迹编码为连续时间潜状态,驱动固定效应和随机效应设计,同时保留标准LMM观测模型。该方法保持经典似然推断能力,灵活学习复杂且可能具有累积性的协变量效应。所有参数通过最大化惩罚边际似然估计。为量化协变量效应,引入反事实预测对比,并用delta法估计方差。模拟结果显示,该模型无需预设函数形式即可恢复瞬时与累积负担效应。应用于包含7,324名参与者的大规模Trois-Cités(3C)队列研究,揭示了体重指数(BMI)和空腹血糖轨迹与认知衰退的轨迹依赖性关联。
原文摘要 · Abstract (English)
Longitudinal cohort studies produce repeated data that enable the assessment of time-varying association patterns between exposures and health outcomes. Classical linear mixed-effects models (LMMs) can accommodate a large variety of association patterns while accounting for the irregularly spaced, partially observed measurement. But they require the analyst to pre-specify the functional form linking the exposure history to the outcome. We propose the Neural ODE-LMM, which embeds a Neural Ordinary Differential Equation (Neural ODE) within the linear mixed-effects framework: a learned vector field encodes covariate trajectories into a continuous-time latent state that drives both the fixed- and random-effect design, while preserving the standard LMM observation model. This retains classical likelihood-based inference while learning complex, potentially cumulative, covariate effects flexibly. All parameters are estimated by maximising a penalised marginal likelihood. To quantify covariate effects, we introduce contrasts of counterfactual predictions that compare the expected outcome under alternative covariate trajectories with variance estimated via the delta method. In simulations, the model recovers both instantaneous and cumulative-burden effects without prior specification of the functional form. Applied to the Trois-Cités (3C) cohort, a population-based study of 7{,}324 participants, the method reveals trajectory-dependent associations of BMI and fasting glucose with cognitive decline.
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