Empirical methods for the validation of time-to-event mathematical models taking into account uncertainty and variability: application to EGFR + lung adenocarcinoma.

BACKGROUND: Over the past several decades, metrics have been defined to assess the quality of various types of models and to compare their performance depending on their capacity to explain the variance found in real-life data. However, available validation methods are mostly designed for statistical regressions rather than for mechanistic models. To our knowledge, in the latter case, there are no consensus standards, for instance for the validation of predictions against real-world data given the variability and uncertainty of the data. In this work, we focus on the prediction of time-to-event curves using as an application example a mechanistic model of non-small cell lung cancer. We designed four empirical methods to assess both model performance and reliability of predictions: two methods based on bootstrapped versions of parametric statistical tests: log-rank and combined weighted log-ranks (MaxCombo); and two methods based on bootstrapped prediction intervals, referred to here as raw coverage and the juncture metric. We also introduced the notion of observation time uncertainty to take into consideration the real life delay between the moment when an event happens, and the moment when it is observed and reported. RESULTS: We highlight the advantages and disadvantages of these methods according to their application context. We have shown that the context of use of the model has an impact on the model validation process. Thanks to the use of several validation metrics we have highlighted the limit of the model to predict the evolution of the disease in the whole population of mutations at the same time, and that it was more efficient with specific predictions in the target mutation populations. The choice and use of a single metric could have led to an erroneous validation of the model and its context of use. CONCLUSIONS: With this work, we stress the importance of making judicious choices for a metric, and how using a combination of metrics could be more relevant, with the objective of validating a given model and its predictions within a specific context of use. We also show how the reliability of the results depends both on the metric and on the statistical comparisons, and that the conditions of application and the type of available information need to be taken into account to choose the best validation strategy.

Knowledge-based mechanistic modeling accurately predicts disease progression with gefitinib in EGFR-mutant lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is associated with a low survival rate at advanced stages. Although the development of targeted therapies has improved outcomes in LUAD patients with identified and specific genetic alterations, such as activating mutations on the epidermal growth factor receptor gene (EGFR), the emergence of tumor resistance eventually occurs in all patients and this is driving the development of new therapies. In this paper, we present the In Silico EGFR-mutant LUAD (ISELA) model that links LUAD patients' individual characteristics, including tumor genetic heterogeneity, to tumor size evolution and tumor progression over time under first generation EGFR tyrosine kinase inhibitor gefitinib. This translational mechanistic model gathers extensive knowledge on LUAD and was calibrated on multiple scales, including in vitro, human tumor xenograft mouse and human, reproducing more than 90% of the experimental data identified. Moreover, with 98.5% coverage and 99.4% negative logrank tests, the model accurately reproduced the time to progression from the Lux-Lung 7 clinical trial, which was unused in calibration, thus supporting the model high predictive value. This knowledge-based mechanistic model could be a valuable tool in the development of new therapies targeting EGFR-mutant LUAD as a foundation for the generation of synthetic control arms.

Integration of Heterogeneous Biological Data in Multiscale Mechanistic Model Calibration: Application to Lung Adenocarcinoma.

Mechanistic models are built using knowledge as the primary information source, with well-established biological and physical laws determining the causal relationships within the model. Once the causal structure of the model is determined, parameters must be defined in order to accurately reproduce relevant data. Determining parameters and their values is particularly challenging in the case of models of pathophysiology, for which data for calibration is sparse. Multiple data sources might be required, and data may not be in a uniform or desirable format. We describe a calibration strategy to address the challenges of scarcity and heterogeneity of calibration data. Our strategy focuses on parameters whose initial values cannot be easily derived from the literature, and our goal is to determine the values of these parameters via calibration with constraints set by relevant data. When combined with a covariance matrix adaptation evolution strategy (CMA-ES), this step-by-step approach can be applied to a wide range of biological models. We describe a stepwise, integrative and iterative approach to multiscale mechanistic model calibration, and provide an example of calibrating a pathophysiological lung adenocarcinoma model. Using the approach described here we illustrate the successful calibration of a complex knowledge-based mechanistic model using only the limited heterogeneous datasets publicly available in the literature.

Partial differential model of lactate neuro-energetics: analytic results and numerical simulations.

Interfaces play a key role on diseases development because they dictate the energy inflow of nutrients from the surrounding tissues. What is underestimated by existing mathematical models is the biological fact that cells are able to use different resources through nonlinear mechanisms. Among all nutrients, lactate appears to be a sensitive metabolic when talking about brain tumours or neurodegenerative diseases. Here we present a partial differential model to investigate the lactate exchanges between cells and the vascular network in the brain. By extending an existing kinetic model for lactate neuro-energetics, we first provide analytical proofs of the uniqueness and the derivation of precise bounds on the solutions of the problem including diffusion of lactate in a representative volume element comprising the interface between a capillary and cells. We further perform finite element simulations of the model in two test cases, discussing the relevant physical parameters governing the lactate dynamics.

Mathematical Modeling of Substrates Fluxes and Tumor Growth in the Brain.

The aim of this article is to show how a tumor can modify energy substrates fluxes in the brain to support its own growth. To address this question we use a modeling approach to explain brain nutrient kinetics. In particular we set up a system of 17 equations for oxygen, lactate, glucose concentrations and cells number in the brain. We prove the existence and uniqueness of nonnegative solutions and give bounds on the solutions. We also provide numerical simulations.

Stability analysis of a steady state of a model describing Alzheimer's disease and interactions with prion proteins.

Alzheimer's disease (AD) is a neuro-degenerative disease affecting more than 46 million people worldwide in 2015. AD is in part caused by the accumulation of A[Formula: see text] peptides inside the brain. These can aggregate to form insoluble oligomers or fibrils. Oligomers have the capacity to interact with neurons via membrane receptors such as prion proteins ([Formula: see text]). This interaction leads [Formula: see text] to be misfolded in oligomeric prion proteins ([Formula: see text]), transmitting a death signal to neurons. In the present work, we aim to describe the dynamics of A[Formula: see text] assemblies and the accumulation of toxic oligomeric species in the brain, by bringing together the fibrillation pathway of A[Formula: see text] peptides in one hand, and in the other hand A[Formula: see text] oligomerization process and their interaction with cellular prions, which has been reported to be involved in a cell-death signal transduction. The model is based on Becker-Döring equations for the polymerization process, with delayed differential equations accounting for structural rearrangement of the different reactants. We analyse the well-posedness of the model and show existence, uniqueness and non-negativity of solutions. Moreover, we demonstrate that this model admits a non-trivial steady state, which is found to be globally stable thanks to a Lyapunov function. We finally present numerical simulations and discuss the impact of model parameters on the whole dynamics, which could constitute the main targets for pharmaceutical industry.

Analysis of a mathematical model for brain lactate kinetics.

The aim of this article is to study the well-posedness and properties of a fast-slow system which is related with brain lactate kinetics. In particular, we prove the existence and uniqueness of nonnegative solutions and obtain linear stability results. We also give numerical simulations with different values of the small parameter ε and compare them with experimental data.