Non-linear and Interaction Analyses of Biomarkers for Organ Dysfunctions as Predictive Markers for Sepsis: A Nationwide Retrospective Study

The Sequential Organ Failure Assessment (SOFA) score is predominantly used to assess the severity of organ dysfunction in sepsis. However, differences in prognostic value between SOFA subscores have not been sufficiently evaluated. This retrospective observational study used a large-scale database containing about 30 million patients. Among them, we included 38,869 adult patients with sepsis from 2006 to 2019. The cardiovascular and neurological subscores were calculated by a modified method. Associations between the biomarkers of the SOFA components and mortality were examined using restricted cubic spline analyses, which showed that an increase in the total modified SOFA score was linearly associated with increased mortality. However, the prognostic association of subscores varied widely: platelet count showed a J-shaped association, creatinine showed an inverted J-shaped association, and bilirubin showed only a weak association. We also evaluated interaction effects on mortality between an increase of one subscore and another. The joint odds ratios on mortality of two modified SOFA subscores were synergistically increased compared to the sum of the single odds ratios, especially in cardiovascular-neurological, coagulation-hepatic, and renal-hepatic combinations. In conclusion, total modified SOFA score was associated with increased mortality despite the varied prognostic associations of the subscores, possibly because interactions between subscores synergistically enhanced prognostic accuracy.