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Derivation of pediatric sepsis phenotypes using machine learning applied to clinical, functional and genomic data from the swiss pediatric sepsis study

Lay summary

Content and aims of the research proposal:
Sepsis kills more children every year than road traffic accidents or than diseases such as childhood cancer. Yet, our understanding of why some children become extremely unwell or die doe to sepsis remains limited.

The landmark Swiss Pediatric Sepsis Study is a prospective national observational multicenter cohort study including all 10 major Swiss children`s hospitals and has recruited 1204 children with blood culture-proven bacterial sepsis over the past years. The study has highlighted the high burden of sepsis in children.

Using this world-wide largest study on blood culture-confirmed sepsis in children we will now perform additional genetic and functional analyses, so called “OMICs”. Using novel innovative computational methods (“artificial intelligence”) we seek to discover patterns which explain why some children become severely ill in the course of sepsis.

Scientific and societal context of the research project:

Sepsis represents a leading cause of childhood mortality and morbidity in Switzerland, and globally. This study will benefit from a unique cohort and is building on the combined expertise in pediatrics, genomics, immunology, and computational science across a high performing Swiss research network. The study findings are expected to improve our understanding of sepsis in children, and to help to develop novel approaches to the disease.

Abstract

Sepsis is severe infection, leading to life-threatening shutdown of organs. Sepsis represents a leading cause of death and disability in children: Over three million children die each year due to sepsis and one out of three childhood sepsis survivors will suffer from ongoing health problems. In fact, the risk of acquiring sepsis is never as high as during early childhood. A recent resolution by the WHO endorsed by Switzerland highlighted that sepsis is a global threat, demanding urgent actions to improve understanding and therapy of sepsis. While it is well known that bacteria and other pathogens such as viruses cause infections, the mechanisms underlying the severe response of the body to infection which ultimatively results in sepsis are not well understood. There is a need for studies in children with sepsis which investigate the genetic and immunologic features of the disease.

The landmark Swiss Pediatric Sepsis Study is a national observational multicenter cohort study including all 10 major children`s hospitals which recruited 1204 children with bacterial sepsis in Switzerland. The purpose of the new project is to investigate the clinical, genomic, and functional information from this unique study. We suspect that different children develop different patterns of their body`s response to infection. Using new methods, such as Artificial Intelligence, we aim to find groups of children which are particularly unwell due to sepsis, and which are more likely to one day benefit from specific interventions. For this purpose, we will investigate the genes involved, as well as markers of the body`s response to infection.

As a first objective, we will explore the role of genetic variation to understand why some children are very vulnerable to sepsis. As a second objective, we will then compare how the immune system of different children responds to sepsis. It is possible that we may find that some children with sepsis suffer from underlying alterations in their immune system, which makes them more susceptible to sepsis.Finally, using new computational methods, so called machine learning, we will try to integrate the wealth of genetic, clinical, and functional data to gain a completely new perspective on why some children become severely unwell due to sepsis.

This world-wide largest contemporary study on bacterial sepsis in children has the potential to identify key mechanisms determining sepsis risk and sepsis outcomes in children. Our hope is that it can thereby improve our understanding of the progression from infection to sepsis. Ultimately, we hope to gain a better understanding of the individual susceptibility to sepsis. Thereby, we hope to help to enable better treatment of children with sepsis in the future, for example through personalized medicine.

Last updated:06.03.2022

Luregn Schlapbach
Christoph Aebi
Eric Giannoni
  Prof.Karsten Borgwardt
Johannes Trück