Abstract
Our understanding of the host component of sepsis has made significant progress. However, detailed study of the microorganisms causing sepsis, either as single pathogens or microbial assemblages, has received far less attention. Metagenomic data offer opportunities to characterize the microbial communities found in septic and healthy individuals. In this study we apply gradient-boosted tree classifiers and a novel computational decontamination technique built upon SHapley Additive exPlanations (SHAP) to identify microbial hallmarks which discriminate blood metagenomic samples of septic patients from that of healthy individuals. Classifiers had high performance when using the read assignments to microbial genera [area under the receiver operating characteristic (AUROC=0.995)], including after removal of species ‘culture-confirmed’ as the cause of sepsis through clinical testing (AUROC=0.915). Models trained on single genera were inferior to those employing a polymicrobial model and we identified multiple co-occurring bacterial genera absent from healthy controls. While prevailing diagnostic paradigms seek to identify single pathogens, our results point to the involvement of a polymicrobial community in sepsis. We demonstrate the importance of the microbial component in characterising sepsis, which may offer new biological insights into the aetiology of sepsis, and ultimately support the development of clinical diagnostic or even prognostic tools.
Highlights
Sepsis poses a significant challenge to public health and was listed as a global health priority by the World Health Organisation (WHO) in 2017
Our work demonstrates a clear polymicrobial signal in sepsis, where multiple, co-occuring, genera can be used to discriminate blood metagenomes of septic patients from that of healthy controls
The high performance of the Karius-Only model highlights that genera containing ‘culture-confirmed’ pathogens were very useful in delineating septic from healthy samples
Summary
Sepsis poses a significant challenge to public health and was listed as a global health priority by the World Health Organisation (WHO) in 2017. 48.9 million cases of sepsis and 11 million deaths were recorded worldwide [1], having a particular impact in low- and low-to-m iddle income countries [2]. Current research efforts have predominately focused on understanding the host’s response to sepsis. All contemporary definitions of sepsis focus on the host’s response and resulting systemic complications. The 2016 Sepsis-3 definition sought to differentiate between mild and severe cases of dysregulated host responses, describing sepsis as a life-threatening organ dysfunction as a result of infection [5]. Significant progress has been made in understanding how dysregulation occurs [6] and the long-term impacts of sepsis [7, 8]. The focus on the host component of sepsis may overlook the important role of microbial composition in the pathogenesis of the disease
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