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A community approach to mortality prediction in sepsis via gene expression analysis.

ABSTRACT: Improved risk stratification and prognosis prediction in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here, we present prognostic models for 30-day mortality generated independently by three scientific groups by using 12 discovery cohorts containing transcriptomic data collected from primarily community-onset sepsis patients. Predictive performance is validated in five cohorts of community-onset sepsis patients in which the models show summary AUROCs ranging from 0.765-0.89. Similar performance is observed in four cohorts of hospital-acquired sepsis. Combining the new gene-expression-based prognostic models with prior clinical severity scores leads to significant improvement in prediction of 30-day mortality as measured via AUROC and net reclassification improvement index These models provide an opportunity to develop molecular bedside tests that may improve risk stratification and mortality prediction in patients with sepsis.

SUBMITTER: Sweeney TE

PROVIDER: S-EPMC5814463 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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A community approach to mortality prediction in sepsis via gene expression analysis.

Sweeney Timothy E TE Perumal Thanneer M TM Henao Ricardo R Nichols Marshall M Howrylak Judith A JA Choi Augustine M AM Bermejo-Martin Jesús F JF Almansa Raquel R Tamayo Eduardo E Davenport Emma E EE Burnham Katie L KL Hinds Charles J CJ Knight Julian C JC Woods Christopher W CW Kingsmore Stephen F SF Ginsburg Geoffrey S GS Wong Hector R HR Parnell Grant P GP Tang Benjamin B Moldawer Lyle L LL Moore Frederick E FE Omberg Larsson L Khatri Purvesh P Tsalik Ephraim L EL Mangravite Lara M LM Langley Raymond J RJ

Nature communications 20180215 1

Improved risk stratification and prognosis prediction in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here, we present prognostic models for 30-day mortality generated independently by three scientific groups by using 12 discovery cohorts containing transcriptomic data collected from primarily community-onset s ...[more]

PMID: 29449546

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Project description:BackgroundSepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, has become one of the major causes of death in Intensive Care Units (ICUs). The heterogeneity and complexity of this syndrome lead to the absence of golden standards for its diagnosis, treatment, and prognosis. The early prediction of in-hospital mortality for sepsis patients is not only meaningful to medical decision making, but more importantly, relates to the well-being of patients.MethodsIn this paper, a rule discovery and analysis (rule-based) method is used to predict the in-hospital death events of 2021 ICU patients diagnosed with sepsis using the MIMIC-III database. The method mainly includes two phases: rule discovery phase and rule analysis phase. In the rule discovery phase, the RuleFit method is employed to mine multiple hidden rules which are capable to predict individual in-hospital death events. In the rule analysis phase, survival analysis and decomposition analysis are carried out to test and justify the risk prediction ability of these rules. Then by leveraging a subset of these rules, we establish a prediction model that is both more accurate at the in-hospital death prediction task and more interpretable than most comparable methods.ResultsIn our experiment, RuleFit generates 77 risk prediction rules, and the average area under the curve (AUC) of the prediction model based on 62 of these rules reaches 0.781 ([Formula: see text]) which is comparable to or even better than the AUC of existing methods (i.e., commonly used medical scoring system and benchmark machine learning models). External validation of the prediction power of these 62 rules on another 1468 sepsis patients not included in MIMIC-III in ICU provides further supporting evidence for the superiority of the rule-based method. In addition, we discuss and explain in detail the rules with better risk prediction ability. Glasgow Coma Scale (GCS), serum potassium, and serum bilirubin are found to be the most important risk factors for predicting patient death.ConclusionOur study demonstrates that, with the rule-based method, we could not only make accurate prediction on in-hospital death events of sepsis patients, but also reveal the complex relationship between sepsis-related risk factors through the rules themselves, so as to improve our understanding of the complexity of sepsis as well as its population.

Project description:To study the dysregulated host immune response to infection in sepsis, gene expression profiles from the Gene Expression Omnibus (GEO) datasets GSE54514, GSE57065, GSE64456, GSE95233, GSE66099 and GSE72829 were selected. From the Kyoto Encyclopedia of Genes and Genomes (KEGG) immune system pathways, 998 unique genes were selected, and genes were classified as follows based on gene annotation from KEGG, Gene Ontology, and Reactome: adaptive immunity, antigen presentation, cytokines and chemokines, complement, hematopoiesis, innate immunity, leukocyte migration, NK cell activity, platelet activity, and signaling. After correlation matrix formation, correlation coefficient of 0.8 was selected for network generation and network analysis. Total transcriptome was analyzed for differentially expressed genes (DEG), followed by gene set enrichment analysis. The network topological structure revealed that adaptive immunity tended to form a prominent and isolated cluster in sepsis. Common genes within the cluster from the 6 datasets included CD247, CD8A, ITK, LAT, and LCK. The clustering coefficient and modularity parameters were increased in 5/6 and 4/6 datasets in the sepsis group that seemed to be associated with functional aspect of the network. GSE95233 revealed that the nonsurvivor group showed a prominent and isolated adaptive immunity cluster, whereas the survivor group had isolated complement-coagulation and platelet-related clusters. T cell receptor signaling (TCR) pathway and antigen processing and presentation pathway were down-regulated in 5/6 and 4/6 datasets, respectively. Complement and coagulation, Fc gamma, epsilon related signaling pathways were up-regulated in 5/6 datasets. Altogether, network and gene set enrichment analysis showed that adaptive-immunity-related genes along with TCR pathway were down-regulated and isolated from immune the network that seemed to be associated with unfavorable prognosis. Prominence of platelet and complement-coagulation-related genes in the immune network was associated with survival in sepsis. Complement-coagulation pathway was up-regulated in the sepsis group that was associated with favorable prognosis. Network and gene set enrichment analysis supported elucidation of sepsis pathogenesis.

Project description:BackgroundNovel biomarkers are needed to progress toward individualized patient care in sepsis. The immune profiling panel (IPP) prototype has been designed as a fully-automated multiplex tool measuring expression levels of 26 genes in sepsis patients to explore immune functions, determine sepsis endotypes and guide personalized clinical management. The performance of the IPP gene set to predict 30-day mortality has not been extensively characterized in heterogeneous cohorts of sepsis patients.MethodsPublicly available microarray data of sepsis patients with widely variable demographics, clinical characteristics and ethnical background were co-normalized, and the performance of the IPP gene set to predict 30-day mortality was assessed using a combination of machine learning algorithms.ResultsWe collected data from 1,801 arrays sampled on sepsis patients and 598 sampled on controls in 17 studies. When gene expression was assayed at day 1 following admission (1,437 arrays sampled on sepsis patients, of whom 1,161 were alive and 276 (19.2%) were dead at day 30), the IPP gene set showed good performance to predict 30-day mortality, with an area under the receiving operating characteristics curve (AUROC) of 0.710 (CI 0.652-0.768). Importantly, there was no statistically significant improvement in predictive performance when training the same models with all genes common to the 17 microarray studies (n = 7,122 genes), with an AUROC = 0.755 (CI 0.697-0.813, p = 0.286). In patients with gene expression data sampled at day 3 following admission or later, the IPP gene set had higher performance, with an AUROC = 0.804 (CI 0.643-0.964), while the total gene pool had an AUROC = 0.787 (CI 0.610-0.965, p = 0.811).ConclusionUsing pooled publicly-available gene expression data from multiple cohorts, we showed that the IPP gene set, an immune-related transcriptomics signature conveys relevant information to predict 30-day mortality when sampled at day 1 following admission. Our data also suggests that higher predictive performance could be obtained when assaying gene expression at later time points during the course of sepsis. Prospective studies are needed to confirm these findings using the IPP gene set on its dedicated measurement platform.

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A community approach to mortality prediction in sepsis via gene expression analysis.

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A community approach to mortality prediction in sepsis via gene expression analysis.

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