Graphical abstract

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Highlights

     * •
       Gestational age significantly influences neonatal peripheral blood
       gene expression
     * •
       Whole blood transcriptomics reveal that interferon pathways are
       central to NARDS
     * •
       Neonates born before 34 weeks exhibit weaker immune responses to
       ARDS
     * •
       Blood ALOX15 and PTGDR2 are potential biomarkers and therapeutic
       targets for NARDS
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   Transcriptomics; Machine learning

Introduction

   Acute respiratory distress syndrome (ARDS) is a life-threatening
   condition caused by various etiologies, and was first described in
   1967.[44]^1 Since then, diagnostic criteria of ARDS have been
   established for adults[45]^2 and children,[46]^3 respectively; however,
   these criteria do not apply to neonates. Neonatal ARDS (NARDS) remained
   poorly understood for decades until 2017, when the Montreux
   Criteria[47]^4 were specifically proposed to address the unique
   perinatal factors associated with neonates. Recent international
   multicenter researches[48]^5^,[49]^6 on NARDS have begun to uncover its
   basic clinical characteristics. NARDS occurs in 1.44%–1.5% of
   admissions, with mortality rates ranging from 12.6% to 24%. Disparities
   in the immaturity of pulmonary and immune system and different
   perinatal triggering factors may contribute to the heterogeneity of
   NARDS.[50]^6^,[51]^7 Early identification remains challenging due to
   the distinct physiological characteristics of neonatal lungs and immune
   systems. Respiratory distress, a common yet nonspecific manifestation,
   affecting 7% of deliveries.[52]^8 In addition to ARDS, which can occur
   in neonates born at every gestational age (GA), common causes of
   respiratory distress primarily include neonatal respiratory distress
   syndrome (NRDS) due to primary surfactant (PS) deficiency in preterm
   infants, and transient tachypnea of the neonate (TTN) in later period.
   The Montreux definition explicitly stated that the diagnosis of NARDS
   requires the exclusion of NRDS, TTN, or other primary acute respiratory
   conditions, while suggesting that a response to PS therapy and lung
   recruitment should be considered in confirming the diagnosis.[53]^4 No
   specific treatments are currently available for NARDS, while patients
   typically require longer courses of antibiotic therapy, mechanical
   ventilation and higher mortality compared to those with NRDS or
   TTN.[54]^5^,[55]^9

   Currently, blood transcriptomics has provided valuable insights into
   the heterogeneity of both adult and pediatric ARDS, facilitating the
   identification of novel biomarkers and construction prediction
   model,[56]^10 classifying disease sub phenotypes,[57]^11^,[58]^12 and
   uncovering the underlying pathophysiological processes[59]^13 that may
   lead to more effective therapies.[60]^14 However, this field remains
   blank in NARDS. Our study seeks to bridge this gap by establishing a
   cohort of respiratory distress across various GA. We will integrate
   high-throughput sequencing and machine learning techniques to identify
   novel predictive biomarkers and offer new perspectives and references