Seymour CW, et al. - In this investigation, researchers derived sepsis (defined as a dysregulated immune response to infection that leads to acute organ dysfunction) phenotypes from clinical data, assessed their reproducibility and correlation with biomarkers of host-response and clinical outcomes, and evaluated the potential causal relationship with randomized clinical trial outcomes. The derivation cohort comprised 20,189 patients with sepsis and the validation cohort involved 43,086 patients. In this retrospective analysis of data sets from sepsis patients, four novel sepsis phenotypes (α, β, γ, and δ) have been identified that link with patterns of host-response and clinical outcomes; simulations have suggested that these phenotypes may help to understand the heterogeneity of treatment effects. Of the four phenotypes identified, the δ phenotype was most strongly associated with abnormal values of host-response biomarkers and cardiovascular and liver dysfunction clinical characteristics.