2024-10-28 カナダ・ブリティッシュコロンビア大学(UBC)
<関連情報>
- https://news.ubc.ca/2024/10/tool-to-predict-sepsis-in-apparently-healthy-newborns/
- https://www.sciencedirect.com/science/article/pii/S235239642400447X
新生児敗血症を臨床症状の前に診断する遺伝子発現予測シグネチャーを開発 Predictive gene expression signature diagnoses neonatal sepsis before clinical presentation
Andy Y. An, Erica Acton, Olubukola T. Idoko, Casey P. Shannon, Travis M. Blimkie, Reza Falsafi, Oghenebrume Wariri, Abdulazeez Imam, Tida Dibbasey, Tue Bjerg Bennike, Kinga K. Smolen, Joann Diray-Arce, Rym Ben-Othman, Sebastiano Montante, Asimenia Angelidou, Oludare A. Odumade, David Martino, Scott J. Tebbutt, Ofer Levy, Hanno Steen,…Oghenebrume Wariri
eBioMedicine Available online: 28 October 2024
DOI:https://doi.org/10.1016/j.ebiom.2024.105411
Summary
Background
Neonatal sepsis is a deadly disease with non-specific clinical signs, delaying diagnosis and treatment. There remains a need for early biomarkers to facilitate timely intervention. Our objective was to identify neonatal sepsis gene expression biomarkers that could predict sepsis at birth, prior to clinical presentation.
Methods
Among 720 initially healthy full-term neonates in two hospitals (The Gambia, West Africa), we identified 21 newborns who were later hospitalized for sepsis in the first 28 days of life, split into early-onset sepsis (EOS, onset ≤7 days of life) and late-onset sepsis (LOS, onset 8–28 days of life), 12 neonates later hospitalized for localized infection without evidence of systemic involvement, and 33 matched control neonates who remained healthy. RNA-seq was performed on peripheral blood collected at birth when all neonates were healthy and also within the first week of life to identify differentially expressed genes (DEGs). Machine learning methods (sPLS-DA, LASSO) identified genes expressed at birth that predicted onset of neonatal sepsis at a later time.
Findings
Neonates who later developed EOS already had ∼1000 DEGs at birth when compared to control neonates or those who later developed a localized infection or LOS. Based on these DEGs, a 4-gene signature (HSPH1, BORA, NCAPG2, PRIM1) for predicting EOS at birth was developed (training AUC = 0.94, sensitivity = 0.93, specificity = 0.92) and validated in an external cohort (validation AUC = 0.72, sensitivity = 0.83, and specificity = 0.83). Additionally, during the first week of life, EOS disrupted expression of >1800 genes including those influencing immune and metabolic transitions observed in healthy controls.
Interpretation
Despite appearing healthy at birth, neonates who later developed EOS already had distinct whole blood gene expression changes at birth, which enabled the development of a 4-gene predictive signature for EOS. This could facilitate early recognition and treatment of neonatal sepsis, potentially mitigating its long-term sequelae.
Funding
CIHR and NIH/NIAID.
Research in context
Evidence before this study
Neonatal sepsis is a disease with high mortality and long-term developmental consequences but is difficult to diagnose due to non-specific clinical signs. There is a need for better diagnostic biomarkers that are effective as early as possible, ideally predictive biomarkers right at birth. Gene expression biomarkers are an exciting new field of diagnostics with potentially increased sensitivity and specificity. We searched PubMed for research articles published in English between Jan 1, 2010, and Mar 30, 2024, with the terms: “neonate”, “sepsis OR septic shock”, AND “transcriptomics OR multiarray OR RNAseq”. While there are several studies that investigate gene expression biomarkers in neonatal sepsis, no studies analyzed gene expression in term neonates at birth prior to neonates showing clinical signs of sepsis; instead, these existing studies analyzed neonates after they presented to hospital with signs of sepsis.
Added value of this study
In this multicentre, prospective study of term neonates born in The Gambia with a validation cohort from an external dataset in neonates from the United States, we derived and validated a four-gene expression signatures from peripheral blood for neonatal sepsis. This signature could predict, at birth when neonates were still healthy, which neonates would later develop early onset sepsis within 7 days of life. The signature had an area under the receiver operating characteristic curve (AUROC) of 0.94, sensitivity of 0.93, and specificity of 0.92 and was validated in an external cohort (validation AUROC = 0.72, sensitivity = 0.83, and specificity = 0.83).
Implications of all the available evidence
This predictive gene expression signature for neonatal sepsis can identify which neonate, at birth, would later develop early-onset sepsis, while the neonate still appeared clinically well. Our findings provide an early diagnostic tool of neonatal sepsis that could possibly be used in combination with other screening tools at birth. This would be essential in facilitating timely therapeutic interventions in order to decrease mortality and the risk of developing long-term sequelae due to neonatal sepsis.
