Neural ODE enhanced linear mixed effect models for estimating complex association patterns of time-varying covariates with the marker trajectory

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.

Dynamical modelling is central to many scientific domains, including pharmacometrics, systems biology, physiology, and epidemiology. In these settings, heterogeneity is often intrinsic: different subjects or units follow related but distinct continuous-time dynamics. Classical nonlinear mixed-effects Ordinary Differential Equation (ODE) models address this by combining population-level structure with subject-specific effects, but they rely on a parametric vector field and are therefore vulnerable to structural misspecification and unmodelled mechanisms. This motivates nonparametric approaches that can retain principled uncertainty quantification, yet existing nonparametric ODE methods typically assume a single shared dynamical system rather than an explicit mixed-effect hierarchy over subject-specific dynamics. We propose MEGPODE, a Bayesian nonparametric mixed-effect ODE model in which each subject's vector field is decomposed into a shared population component and a subject-specific deviation, both endowed with Gaussian process (GP) priors. To avoid repeated ODE solves per subject during training, we combine state-space GP trajectory priors with virtual collocation observations, yielding Kalman-smoothing trajectory updates and closed-form regressions for the vector fields. Across controlled heterogeneous ODE benchmarks spanning oscillatory, biomedical systems, MEGPODE improves population-field recovery and subject-level trajectory prediction relative to strong baselines.

Scalable Bayesian inference for generalized linear mixed models (GLMMs) provides uncertainty-aware analysis of correlated longitudinal data, but existing scalable approaches largely assume low-dimensional tabular predictors and do not directly accommodate high-dimensional modalities such as images and text. We address this limitation by learning one or more modality-specific neural encoders jointly with a GLMM objective, then performing variance-corrected stochasticgradient MCMC for the GLMM parameters conditional on the learned representation. This conditional-Bayes design combines supervised representation learning with posterior uncertainty quantification for population-level effects, subjectspecific heterogeneity, and modality-level random slopes. The resulting model preserves interpretable fixed and random effects for structured covariates and learned modalities while scaling gracefully to large longitudinal datasets. In simulation studies, our method recovers posterior means and variance estimates from full-data MCMC benchmarks after covariance correction. We further evaluate uncertainty through parameter-level interval coverage in simulations and predictive calibration on held-out data. Applications to glaucoma progression and adolescent mental health demonstrate that the framework allows nuanced assessment of the relative importance of each modality on both individual and population levels without sacrificing predictive performance.