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Mélanie Prague

Publications and source records attributed to Mélanie Prague.

9 recordsLinked to original sources

Bayesian Nonparametric Mixed-Effect ODEs with Gaussian Processes

Dynamical modelling in pharmacometrics, systems biology, and epidemiology often involves subjects with related but distinct dynamics, observed through temporally sparse and irregular measurements. Classical nonlinear mixed-effects ODE models represent this heterogeneity but rely on parametric vector fields, making them vulnerable to structural misspecification. Existing nonparametric ODE methods typically assume shared dynamics rather than an explicit mixed-effect hierarchy. We propose MEGPODE, a Bayesian nonparametric mixed-effect ODE model that decomposes each subject's vector field into a shared population component and a subject-specific deviation, both endowed with Gaussian process priors. To avoid repeated ODE solves during training, we represent latent trajectories with state-space GP priors and penalize discrepancies between their derivatives and the vector fields on a finite time grid. A single variational objective enables approximate joint inference over trajectories and vector fields, accounting for state uncertainty and dependence between population and subject-specific dynamics. Across heterogeneous oscillatory and biomedical ODE benchmarks, MEGPODE improves population-field recovery and subject-level trajectory prediction relative to strong baselines.

cs.LG↗

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

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.

stat.ML↗

Variational autoencoder for inference of nonlinear mixed effect models based on ordinary differential equations

We propose a variational autoencoder (VAE) approach for parameter estimation in nonlinear mixed-effects models based on ordinary differential equations (NLME-ODEs) using longitudinal data from multiple subjects. In moderate dimensions, likelihood-based inference via the stochastic approximation EM algorithm (SAEM) is widely used, but it relies on Markov Chain Monte-Carlo (MCMC) to approximate subject-specific posteriors. As model complexity increases or observations per subject are sparse and irregular, performance often deteriorates due to a complex, multimodal likelihood surface which may lead to MCMC convergence difficulties. We instead estimate parameters by maximizing the evidence lower bound (ELBO), a regularized surrogate for the marginal likelihood. A VAE with a shared encoder amortizes inference of subject-specific random effects by avoiding per-subject optimization and the use of MCMC. Beyond pointwise estimation, we quantify parameter uncertainty using observed-information-based variance estimator and verify that practical identifiability of the model parameters is not compromised by nuisance parameters introduced in the encoder. We evaluate the method in three simulation case studies (pharmacokinetics, humoral response to vaccination, and TGF-$β$ activation dynamics in asthmatic airways) and on a real-world antibody kinetics dataset, comparing against SAEM baselines.

stat.ME↗

Leveraging Contact Network Information in Clustered Randomized Studies of Contagion Processes

In a randomized study, leveraging covariates related to the outcome (e.g. disease status) may produce less variable estimates of the effect of exposure. For contagion processes operating on a contact network, transmission can only occur through ties that connect affected and unaffected individuals; the outcome of such a process is known to depend intimately on the structure of the network. In this paper, we investigate the use of contact network features as efficiency covariates in exposure effect estimation. Using augmented generalized estimating equations (GEE), we estimate how gains in efficiency depend on the network structure and spread of the contagious agent or behavior. We apply this approach to simulated randomized trials using a stochastic compartmental contagion model on a collection of model-based contact networks and compare the bias, power, and variance of the estimated exposure effects using an assortment of network covariate adjustment strategies. We also demonstrate the use of network-augmented GEEs on a clustered randomized trial evaluating the effects of wastewater monitoring on COVID-19 cases in residential buildings at the the University of California San Diego.

stat.AP↗

Robust and Efficient Optimization Using a Marquardt-Levenberg Algorithm with R Package marqLevAlg

Implementations in R of classical general-purpose algorithms for local optimization generally have two major limitations which cause difficulties in applications to complex problems: too loose convergence criteria and too long calculation time. By relying on a Marquardt-Levenberg algorithm (MLA), a Newton-like method particularly robust for solving local optimization problems, we provide with marqLevAlg package an efficient and general-purpose local optimizer which (i) prevents convergence to saddle points by using a stringent convergence criterion based on the relative distance to minimum/maximum in addition to the stability of the parameters and of the objective function; and (ii) reduces the computation time in complex settings by allowing parallel calculations at each iteration. We demonstrate through a variety of cases from the literature that our implementation reliably and consistently reaches the optimum (even when other optimizers fail), and also largely reduces computational time in complex settings through the example of maximum likelihood estimation of different sophisticated statistical models.

stat.CO↗

Parameter estimation in nonlinear mixed effect models based on ordinary differential equations: an optimal control approach

We present a parameter estimation method for nonlinear mixed effect models based on ordinary differential equations (NLME-ODEs). The method presented here aims at regularizing the estimation problem in presence of model misspecifications, practical identifiability issues and unknown initial conditions. For doing so, we define our estimator as the minimizer of a cost function which incorporates a possible gap between the assumed model at the population level and the specific individual dynamic. The cost function computation leads to formulate and solve optimal control problems at the subject level. This control theory approach allows to bypass the need to know or estimate initial conditions for each subject and it regularizes the estimation problem in presence of poorly identifiable parameters. Comparing to maximum likelihood, we show on simulation examples that our method improves estimation accuracy in possibly partially observed systems with unknown initial conditions or poorly identifiable parameters with or without model error. We conclude this work with a real application on antibody concentration data after vaccination against Ebola virus coming from phase 1 trials. We use the estimated model discrepancy at the subject level to analyze the presence of model misspecification.

stat.ME↗

EpidemiOptim: A Toolbox for the Optimization of Control Policies in Epidemiological Models

Epidemiologists model the dynamics of epidemics in order to propose control strategies based on pharmaceutical and non-pharmaceutical interventions (contact limitation, lock down, vaccination, etc). Hand-designing such strategies is not trivial because of the number of possible interventions and the difficulty to predict long-term effects. This task can be cast as an optimization problem where state-of-the-art machine learning algorithms such as deep reinforcement learning, might bring significant value. However, the specificity of each domain -- epidemic modelling or solving optimization problem -- requires strong collaborations between researchers from different fields of expertise. This is why we introduce EpidemiOptim, a Python toolbox that facilitates collaborations between researchers in epidemiology and optimization. EpidemiOptim turns epidemiological models and cost functions into optimization problems via a standard interface commonly used by optimization practitioners (OpenAI Gym). Reinforcement learning algorithms based on Q-Learning with deep neural networks (DQN) and evolutionary algorithms (NSGA-II) are already implemented. We illustrate the use of EpidemiOptim to find optimal policies for dynamical on-off lock-down control under the optimization of death toll and economic recess using a Susceptible-Exposed-Infectious-Removed (SEIR) model for COVID-19. Using EpidemiOptim and its interactive visualization platform in Jupyter notebooks, epidemiologists, optimization practitioners and others (e.g. economists) can easily compare epidemiological models, costs functions and optimization algorithms to address important choices to be made by health decision-makers.

cs.LG↗

Effects of interventions and optimal strategies in the stochastic system approach to causality

We consider the problem of defining the effect of an intervention on a time-varying risk factor or treatment for a disease or a physiological marker; we develop here the latter case. So, the system considered is $(Y,A,C)$, where $Y=(Y_t)$, is the marker process of interest, $A=A_t$ the treatment. A realistic case is that the treatment can be changed only at discrete times. In an observational study the treatment attribution law is unknown; however, the physical law can be estimated without knowing the treatment attribution law, provided a well-specified model is available. An intervention is specified by the treatment attribution law, which is thus known. Simple interventions will simply randomize the attribution of the treatment; interventions that take into account the past history will be called "strategies". The effect of interventions can be defined by a risk function $R^{\intr}=\Ee_{\intr}[L(\bar Y_{t_J}, \bar A_{t_{J}},C)]$, where $L(\bar Y_{t_J}, \bar A_{t_{J}},C)$ is a loss function, and contrasts between risk functions for different strategies can be formed. Once we can compute effects for any strategy, we can search for optimal or sub-optimal strategies; in particular we can find optimal parametric strategies. We present several ways for designing strategies. As an illustration, we consider the choice of a strategy for containing the HIV load below a certain level while limiting the treatment burden. A simulation study demonstrates the possibility of finding optimal parametric strategies.

stat.ME↗

Modeling CD4+ T cells dynamics in HIV-infected patients receiving repeated cycles of exogenous Interleukin 7

Combination Antiretroviral Therapy (cART) succeeds to control viral replication in most HIV infected patients. This is normally followed by a reconstitution of the CD4$^+$ T cells pool; however, this does not happen for a substantial proportion of patients. For these patients, an immunotherapy based on injections of Interleukin 7 (IL-7) has been recently proposed as a co-adjutant treatment in the hope of obtaining long-term reconstitution of the T cells pool. Several questions arise as to the long-term efficiency of this treatment and the best protocol to apply. We develop a model based on a system of ordinary differential equations and a statistical model of variability and measurement. We can estimate key parameters of this model using the data from INSPIRE, INSPIRE 2 $\&$ INSPIRE 3 trials. In all three studies, cycles of three injections have been administered; in the last two studies, for the first time, repeated cycles of exogenous IL-7 have been administered. Our aim was to estimate the possible different effects of successive injections in a cycle, to estimate the effect of repeated cycles and to assess different protocols. The use of dynamical models together with our complex statistical approach allow us to analyze major biological questions. We found a strong effect of IL-7 injections on the proliferation rate; however, the effect of the third injection of the cycle appears to be much weaker than the first ones. Also, despite a slightly weaker effect of repeated cycles with respect to the initial one, our simulations show the ability of this treatment of maintaining adequate CD4$^+$ T cells count for years. We were also able to compare different protocols, showing that cycles of two injections should be sufficient in most cases. %Finally, we also explore the possibility of adaptive protocols.

stat.AP↗