Learning Surrogate Equations for the Analysis of an Agent-Based Cancer Model

In this paper, we adapt a two species agent-based cancer model that describes the interaction between cancer cells and healthy cells on a uniform grid to include the interaction with a third species -- namely immune cells. We run six different scenarios to explore the competition between cancer and immune cells and the initial concentration of the immune cells on cancer dynamics. We then use coupled equation learning to construct a population-based reaction model for each scenario. We show how they can be unified into a single surrogate population-based reaction model, whose underlying three coupled ordinary differential equations are much easier to analyse than the original agent-based model. As an example, by finding the single steady state of the cancer concentration, we are able to find a linear relationship between this concentration and the initial concentration of the immune cells. This then enables us to estimate suitable values for the competition and initial concentration to reduce the cancer substantially without performing additional complex and expensive simulations from an agent-based stochastic model. The work shows the importance of performing equation learning from agent-based stochastic data for gaining key insights about the behaviour of complex cellular dynamics.

Towards Learning Stochastic Population Models by Gradient Descent

Increasing effort is put into the development of methods for learning mechanistic models from data. This task entails not only the accurate estimation of parameters, but also a suitable model structure. Recent work on the discovery of dynamical systems formulates this problem as a linear equation system. Here, we explore several simulation-based optimization approaches, which allow much greater freedom in the objective formulation and weaker conditions on the available data. We show that even for relatively small stochastic population models, simultaneous estimation of parameters and structure poses major challenges for optimization procedures. Particularly, we investigate the application of the local stochastic gradient descent method, commonly used for training machine learning models. We demonstrate accurate estimation of models but find that enforcing the inference of parsimonious, interpretable models drastically increases the difficulty. We give an outlook on how this challenge can be overcome.

Automatic Gradient Estimation for Calibrating Crowd Models with Discrete Decision Making

Recently proposed gradient estimators enable gradient descent over stochastic programs with discrete jumps in the response surface, which are not covered by automatic differentiation (AD) alone. Although these estimators' capability to guide a swift local search has been shown for certain problems, their applicability to models relevant to real-world applications remains largely unexplored. As the gradients governing the choice in candidate solutions are calculated from sampled simulation trajectories, the optimization procedure bears similarities to metaheuristics such as particle swarm optimization, which puts the focus on the different methods' calibration progress per function evaluation. Here, we consider the calibration of force-based crowd evacuation models based on the popular Social Force model augmented by discrete decision making. After studying the ability of an AD-based estimator for branching programs to capture the simulation's rugged response surface, calibration problems are tackled using gradient descent and two metaheuristics. As our main insights, we find 1) that the estimation's fidelity benefits from disregarding jumps of large magnitude inherent to the Social Force model, and 2) that the common problem of calibration by adjusting a simulation input distribution obviates the need for AD across the Social Force calculations, allowing gradient descent to excel.

Smoothing Methods for Automatic Differentiation Across Conditional Branches

Programs involving discontinuities introduced by control flow constructs such as conditional branches pose challenges to mathematical optimization methods that assume a degree of smoothness in the objective function's response surface. Smooth interpretation (SI) is a form of abstract interpretation that approximates the convolution of a program's output with a Gaussian kernel, thus smoothing its output in a principled manner. Here, we combine SI with automatic differentiation (AD) to efficiently compute gradients of smoothed programs. In contrast to AD across a regular program execution, these gradients also capture the effects of alternative control flow paths. The combination of SI with AD enables the direct gradient-based parameter synthesis for branching programs, allowing for instance the calibration of simulation models or their combination with neural network models in machine learning pipelines. We detail the effects of the approximations made for tractability in SI and propose a novel Monte Carlo estimator that avoids the underlying assumptions by estimating the smoothed programs' gradients through a combination of AD and sampling. Using DiscoGrad, our tool for automatically translating simple C++ programs to a smooth differentiable form, we perform an extensive evaluation. We compare the combination of SI with AD and our Monte Carlo estimator to existing gradient-free and stochastic methods on four non-trivial and originally discontinuous problems ranging from classical simulation-based optimization to neural network-driven control. While the optimization progress with the SI-based estimator depends on the complexity of the programs' control flow, our Monte Carlo estimator is competitive in all problems, exhibiting the fastest convergence by a substantial margin in our highest-dimensional problem.