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

ABSTRACT: 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).

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7658497 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Zhang Zhongheng Z Pan Qing Q Ge Huiqing H Xing Lifeng L Hong Yucai Y Chen Pengpeng P

EBioMedicine 20201110

<h4>Background</h4>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 va ...[more]

PMID: 33181462

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Project description:BackgroundSepsis is a heterogeneous syndrome with high morbidity and mortality. Optimal and effective classifications are in urgent need and to be developed.Methods and resultsA total of 1,936 patients (sepsis samples, n=1,692; normal samples, n=244) in 7 discovery datasets were included to conduct weighted gene co-expression network analysis (WGCNA) to filter out candidate genes related to sepsis. Then, two subtypes of sepsis were classified in the training sepsis set (n=1,692), the Adaptive and Inflammatory, using K-means clustering analysis on 90 sepsis-related features. We validated these subtypes using 617 samples in 5 independent datasets and the merged 5 sets. Cibersort method revealed the Adaptive subtype was related to high infiltration levels of T cells and natural killer (NK) cells and a better clinical outcome. Immune features were validated by single-cell RNA sequencing (scRNA-seq) analysis. The Inflammatory subtype was associated with high infiltration of macrophages and a disadvantageous prognosis. Based on functional analysis, upregulation of the Toll-like receptor signaling pathway was obtained in Inflammatory subtype and NK cell-mediated cytotoxicity and T cell receptor signaling pathway were upregulated in Adaptive group. To quantify the cluster findings, a scoring system, called, risk score, was established using four datasets (n=980) in the discovery cohorts based on least absolute shrinkage and selection operator (LASSO) and logistic regression and validated in external sets (n=760). Multivariate logistic regression analysis revealed the risk score was an independent predictor of outcomes of sepsis patients (OR [odds ratio], 2.752, 95% confidence interval [CI], 2.234-3.389, P<0.001), when adjusted by age and gender. In addition, the validation sets confirmed the performance (OR, 1.638, 95% CI, 1.309-2.048, P<0.001). Finally, nomograms demonstrated great discriminatory potential than that of risk score, age and gender (training set: AUC=0.682, 95% CI, 0.643-0.719; validation set: AUC=0.624, 95% CI, 0.576-0.664). Decision curve analysis (DCA) demonstrated that the nomograms were clinically useful and had better discriminative performance to recognize patients at high risk than the age, gender and risk score, respectively.ConclusionsIn-depth analysis of a comprehensive landscape of the transcriptome characteristics of sepsis might contribute to personalized treatments and prediction of clinical outcomes.

Project description:The identification of generalizable treatment response classes (TRC[s]) in major depressive disorder (MDD) would facilitate comparisons across studies and the development of treatment prediction algorithms. Here, we investigated whether such stable TRCs can be identified and predicted by clinical baseline items. We analyzed data from an observational MDD cohort (Munich Antidepressant Response Signature [MARS] study, N = 1017), treated individually by psychopharmacological and psychotherapeutic means, and a multicenter, partially randomized clinical/pharmacogenomic study (Genome-based Therapeutic Drugs for Depression [GENDEP], N = 809). Symptoms were evaluated up to week 16 (or discharge) in MARS and week 12 in GENDEP. Clustering was performed on 809 MARS patients (discovery sample) using a mixed model with the integrated completed likelihood criterion for the assessment of cluster stability, and validated through a distinct MARS validation sample and GENDEP. A random forest algorithm was used to identify prediction patterns based on 50 clinical baseline items. From the clustering of the MARS discovery sample, seven TRCs emerged ranging from fast and complete response (average 4.9 weeks until discharge, 94% remitted patients) to slow and incomplete response (10% remitted patients at week 16). These proved stable representations of treatment response dynamics in both the MARS and the GENDEP validation sample. TRCs were strongly associated with established response markers, particularly the rate of remitted patients at discharge. TRCs were predictable from clinical items, particularly personality items, life events, episode duration, and specific psychopathological features. Prediction accuracy improved significantly when cluster-derived slopes were modelled instead of individual slopes. In conclusion, model-based clustering identified distinct and clinically meaningful treatment response classes in MDD that proved robust with regard to capturing response profiles of differently designed studies. Response classes were predictable from clinical baseline characteristics. Conceptually, model-based clustering is translatable to any outcome measure and could advance the large-scale integration of studies on treatment efficacy or the neurobiology of treatment response.

Dataset Information

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

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

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