Model-based Decision Support for Sepsis Endotypes

Sepsis is a high mortality syndrome characterized by organ dysfunction due to a severe and dysregulated acute inflammatory response to infection. Research into therapies for this syndrome has historically ended in failure, which has largely been attributed to the elevated levels of subject heterogeneity. What may have been previously attributed to variability in sepsis may be due to mechanistic differences between patients. Endotypes are distinct subtypes of disease, where underlying causes such as mechanistic or pathway related differences manifest into phenotypes of disease. The lack of mechanistic understanding of immune mediator dynamics and the responses they trigger necessitates a mathematical modeling approach to analyze its complexities. A transfer function model is proposed to describe and cluster the dynamics of key inflammatory mediators. Five sepsis endotypes were discovered and revealed motifs of overwhelming inflammation, various levels of immunosuppression, sustained inflammation, and immunodeficiency. An accurate clinical tool was proposed to classify subjects into endotypes using six-hour trajectories of clinical data. A physiological ordinary differential equation model of sepsis is proposed that characterizes the interactions of inflammatory signaling molecules, neutrophils, and macrophages across the bone, blood, and tissue compartments of the body. This model used to generate individual subject fits against human sepsis data. Population-level parameter analysis implicated macrophage cell death and cytokine half- dynamics in endotype-level differences. Several proof-of-concept statistical models were introduced to demonstrate that it is possible to estimate the pre-hospital time of sepsis subjects and to quantify their sepsis-induced systemic tissue damage. A nearest-neighbor-based method was verified against animal and human data and revealed that identifying infection time-zero of sepsis patients can be quickly estimated with high accuracy using commonly measured clinical features. A logistic regression ensemble model demonstrated revealed early organ dysfunction were significant contributors to systemic damage and mortality. Knowledge of time-zero and systemic damage levels, in combination with an endotype classifier, provides clinicians with a clear depiction of where a subject is located on their sepsis trajectory. Such a decision support system enables therapy timing, early organ support, and targeted therapies to guide personalized treatment and shift patients towards better outcomes in sepsis.