Non-Linear And Cross-Interaction Analyses of SOFA Subscores As Predictive Markers For Sepsis: A Nationwide Retrospective Study

Abstract Background: The Sequential Organ Failure Assessment (SOFA) score is predominantly used to assess the severity of organ dysfunction in sepsis and is definitely proved to be associated with mortality. However, differences in prognostic value between SOFA subscores have not been sufficiently evaluated so far, and detailed evaluation of subscores is required to verify the clinical significance of the SOFA score. The present study aimed to evaluate the non-linear prognostic association of SOFA subscores and the cross-interaction effects on mortality when SOFA subscores were simultaneously increased.Methods: This retrospective observational study used a part of a large-scale database containing about 30 million patients. Among them, we included all adult patients requiring unplanned hospital admission and were diagnosed as having sepsis by Sepsis-3 criteria from February 2006 to December 2019. A proven/suspected infection was defined as having any of the ICD-10 codes for infection. Associations between the SOFA components and in-hospital mortality were examined using linear and non-linear logistic regression analyses. We also evaluated two-way interaction effects on mortality between an increase of one SOFA subscore and another.Results: The final study cohort included 38,869 patients with sepsis. Restricted cubic spline analyses showed that an increase in total SOFA score was sharply and linearly associated with increased mortality. However, the prognostic association of SOFA subscores was non-linear and varied widely by biomarker: platelet count showed a J-shaped association, creatinine showed an inverted J-shaped association, and bilirubin showed only a weak association with mortality. The mortality odds ratios of SOFA scores were synergistically increased when another SOFA subscore was higher than 2 points, and the effect modifications were statistically significant in almost all subgroups. Especially in patients with cardiovascular or hepatic subscores of ≥ 2 points, odds ratios of the other SOFA subscores were remarkably increased (double to triple) compared to those in the whole study population.Conclusion: Despite the widely varied prognostic associations of SOFA subscores, total SOFA score was sharply and almost linearly associated with increased mortality. Cross-interactions between subscores synergistically enhanced its prognostic associations and might be responsible for the high prognostic accuracy of the total SOFA score.