DTVEM-RE: A Hierarchical Random-Effects Extension of the Differential Time-Varying Effect Model for Person-Specific Multi-Lag Estimation in Intensive Longitudinal Data

We introduce Distributed Lag Neural Additive Models (DLNAMs), neural-additive analogues of Distributed Lag Non-linear Models (DLNMs) for learning nonlinear effects distributed over lags. DLNAMs replace a prespecified spline cross-basis with neural components that learn exposure--lag response surfaces, avoiding choices of basis family, dimension, and knot placement while preserving additive interpretability and familiar distributed-lag summaries. Exp-centered input layers, smooth activations, and learned subnetwork mixtures produce smooth, locally adaptive representations; pointwise uncertainty combines a conditional last-layer Laplace approximation with between-member ensemble variation. In simulations, DLNAMs generally outperformed DLNM comparators, including penalized and treed variants, in recovering known response functions, with lower bias, stronger boundary recovery, and better-calibrated cumulative intervals; gains were largest for more demanding functions. The architecture performed consistently across sample sizes, outcome families, lag horizons, and jointly fitted multi-exposure settings, retaining recovery performance as exposures were added; fit-specific changes were largely confined to optimization, and applications recovered established empirical patterns.

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.

Longitudinal studies often collect data at sparse, irregular, and unequally spaced time points. Such heterogeneity is often driven by subject-specific covariates, yet existing methods have been restricted to a scalar endpoint value, completely neglecting the underlying response trajectories. We propose a novel Longitudinal Random Forest (LRF) framework that leverages tree-based ensemble machine learning with adaptive node-wise longitudinal trajectory estimation. The LRF framework makes five methodological contributions. it captures each subject's individual response trajectory while simultaneously accommodating within-node correlation, between-node heterogeneity, and nonlinear and interactive covariate effects. It introduces a novel trajectory-based splitting criterion that maximizes trajectory separation while incorporating a size-weighted penalty; it provides two variants, Principal Analysis by Conditional Expectation (LRF-PACE) and adaptive linear mixed-effects models (LRF-adaptiveLMM), which employ nonparametric and semiparametric node-wise smoothers, respectively, while learning covariate effects in a data-driven manner. It provides a comprehensive interpretation of covariates using both the classical trajectory-based permutation variable importance measure (PVIM) and a newly proposed finite-way interaction frequency count, and it not only predicts entire trajectories for new subjects but also forecasts future trajectories for existing subjects. Extensive simulation studies demonstrate that LRF achieves superior performance over several competing methods, even under severe sparsity. The practical significance of the LRF framework lies in its ability to address five important clinical questions.