Utilizing the Heterogeneity of Clinical Data for Model Refinement and Rule Discovery Through the Application of Genetic Algorithms to Calibrate a High-Dimensional Agent-Based Model of Systemic Inflammation.

Accounting for biological heterogeneity represents one of the greatest challenges in biomedical research. Dynamic computational and mathematical models can be used to enhance the study and understanding of biological systems, but traditional methods for calibration and validation commonly do not account for the heterogeneity of biological data, which may result in overfitting and brittleness of these models. Herein we propose a machine learning approach that utilizes genetic algorithms (GAs) to calibrate and refine an agent-based model (ABM) of acute systemic inflammation, with a focus on accounting for the heterogeneity seen in a clinical data set, thereby avoiding overfitting and increasing the robustness and potential generalizability of the underlying simulation model. Agent-based modeling is a frequently used modeling method for multi-scale mechanistic modeling. However, the same properties that make ABMs well suited to representing biological systems also present significant challenges with respect to their construction and calibration, particularly with respect to the selection of potential mechanistic rules and the large number of associated free parameters. We have proposed that machine learning approaches (such as GAs) can be used to more effectively and efficiently deal with rule selection and parameter space characterization; the current work applies GAs to the challenge of calibrating a complex ABM to a specific data set, while preserving biological heterogeneity reflected in the range and variance of the data. This project uses a GA to augment the rule-set for a previously validated ABM of acute systemic inflammation, the Innate Immune Response ABM (IIRABM) to clinical time series data of systemic cytokine levels from a population of burn patients. The genome for the GA is a vector generated from the IIRABM's Model Rule Matrix (MRM), which is a matrix representation of not only the constants/parameters associated with the IIRABM's cytokine interaction rules, but also the existence of rules themselves. Capturing heterogeneity is accomplished by a fitness function that incorporates the sample value range ("error bars") of the clinical data. The GA-enabled parameter space exploration resulted in a set of putative MRM rules and associated parameterizations which closely match the cytokine time course data used to design the fitness function. The number of non-zero elements in the MRM increases significantly as the model parameterizations evolve toward a fitness function minimum, transitioning from a sparse to a dense matrix. This results in a model structure that more closely resembles (at a superficial level) the structure of data generated by a standard differential gene expression experimental study. We present an HPC-enabled machine learning/evolutionary computing approach to calibrate a complex ABM to complex clinical data while preserving biological heterogeneity. The integration of machine learning, HPC, and multi-scale mechanistic modeling provides a pathway forward to more effectively representing the heterogeneity of clinical populations and their data.