Deep learning-based clustering robustly identified two classes of sepsis with both prognostic and predictive values

BACKGROUND: Sepsis is a heterogenous syndrome and individualized management strategy is the key to successful treatment. Genome wide expression profiling has been utilized for identifying subclasses of sepsis, but the clinical utility of these subclasses was limited because of the classification instability, and the lack of a robust class prediction model with extensive external validation. The study aimed to develop a parsimonious class model for the prediction of class membership and validate the model for its prognostic and predictive capability in external datasets. METHODS: The Gene Expression Omnibus (GEO) and ArrayExpress databases were searched from inception to April 2020. Datasets containing whole blood gene expression profiling in adult sepsis patients were included. Autoencoder was used to extract representative features for k-means clustering. Genetic algorithms (GA) were employed to derive a parsimonious 5-gene class prediction model. The class model was then applied to external datasets (n = 780) to evaluate its prognostic and predictive performance. FINDINGS: A total of 12 datasets involving 1613 patients were included. Two classes were identified in the discovery cohort (n = 685). Class 1 was characterized by immunosuppression with higher mortality than class 2 (21.8% [70/321] vs. 12.1% [44/364]; p < 0.01 for Chi-square test). A 5-gene class model (C14orf159, AKNA, PILRA, STOM and USP4) was developed with GA. In external validation cohorts, the 5-gene class model (AUC: 0.707; 95% CI: 0.664 – 0.750) performed better in predicting mortality than sepsis response signature (SRS) endotypes (AUC: 0.610; 95% CI: 0.521 – 0.700), and performed equivalently to the APACHE II score (AUC: 0.681; 95% CI: 0.595 – 0.767). In the dataset E-MTAB-7581, the use of hydrocortisone was associated with increased risk of mortality (OR: 3.15 [1.13, 8.82]; p = 0.029) in class 2. The effect was not statistically significant in class 1 (OR: 1.88 [0.70, 5.09]; p = 0.211). INTERPRETATION: Our study identified two classes of sepsis that showed different mortality rates and responses to hydrocortisone therapy. Class 1 was characterized by immunosuppression with higher mortality rate than class 2. We further developed a 5-gene class model to predict class membership. FUNDING: The study was funded by the National Natural Science Foundation of China (Grant No. 81,901,929).