Defining Sepsis Phenotypes-Two Murine Models of Sepsis and Machine Learning.

Abstract

The immunobiology defining the clinically apparent differences in response to sepsis remains unclear. We hypothesize that in murine models of sepsis we can identify phenotypes of sepsis using non-invasive physiologic parameters (NIPP) early after infection to distinguish between different inflammatory states. Two murine models of sepsis were used: gram-negative pneumonia (PNA) and cecal ligation and puncture (CLP). All mice were treated with broad spectrum antibiotics and fluid resuscitation. High-risk sepsis responders (pDie) were defined as those predicted to die within 72 h following infection. Low-risk responders (pLive) were expected to survive the initial 72 h of sepsis. Statistical modeling in R was used for statistical analysis and machine learning. NIPP obtained at 6 and 24 h after infection of 291 mice (85 PNA and 206 CLP) were used to define the sepsis phenotypes. Lasso regression for variable selection with 10-fold cross-validation was used to define the optimal shrinkage parameters. The variables selected to discriminate between phenotypes included 6-h temperature and 24-h pulse distention, heart rate (HR), and temperature. Applying the model to fit test data (n = 55), area under the curve (AUC) for the receiver operating characteristics (ROC) curve was 0.93. Subgroup analysis of 120 CLP mice revealed a HR of <620 bpm at 24 h as a univariate predictor of pDie. (AUC of ROC curve = 0.90). Subgroup analysis of PNA exposed mice (n = 121) did not reveal a single predictive variable highlighting the complex physiological alterations in response to sepsis. In murine models with various etiologies of sepsis, non-invasive vitals assessed just 6 and 24 h after infection can identify different sepsis phenotypes. Stratification by sepsis phenotypes can transform future studies investigating novel therapies for sepsis.