Early Tracheal and Salivary miRNAs in Extremely Preterm Infants Predict Bronchopulmonary Dysplasia‐Related Pulmonary Hypertension
Tang Li, Shaoyi Zhang, Vincent Aluquin, Ann Donnelly, Heather Stephens, Shakshi Sharma, Steven D. Hicks, Dajiang Liu, Eric Austin, Roopa SiddaiahABSTRACT
Pulmonary hypertension (BPD‐PH) associated with bronchopulmonary dysplasia (BPD) in preterm infants associates with high morbidity and mortality within the first 2 years of life. In a previous unbiased study, we identified a panel of 16 miRNAs in tracheal aspirates (TA) that were differentially expressed in extremely low gestational age newborns (ELGANs) with BPD‐PH compared to those with BPD but no PH. To explore the predictive potential of these candidate miRNAs, we studied them in TA exosomes from 7‐day‐old ELGANs and through logistic regression calculated the predictive area under the receiver operating characteristic curve (AUROC) to diagnose BPD‐PH at 36 weeks post menstrual age (PMA). AUROC of TA miRNAs was 0.76 with sensitivity and specificity of 93% and 54%, respectively. Adding sex and gestational age to the variables improved the AUROC to 0.78 with sensitivity and specificity of 88% and 62%, respectively. Due to challenges of obtaining TA in noninvasively ventilated infants, we collected saliva samples from ELGANs at 7 days of age and compared the log expression of these target miRNAs in both biofluids and found a significant correlation in their expression (pearson r = 0.92, p < 0.001). We calculated the predictive AUROC of these candidate miRNAs to diagnose BPD‐PH at 36 weeks PMA. AUROC of these miRNAs in saliva was = 0.85 with sensitivity and specificity of 72% and 82%, respectively; addition of biological sex and gestational age improved AUROC to 0.86 with sensitivity and specificity of 76% and 79%, respectively. Leave‐one‐sample‐out sensitivity analysis demonstrated stable training performance with reduced performance in testing samples, supporting the need for validation in larger independent cohorts. In conclusion, early salivary miRNAs have great potential for risk stratification of ELGANs to develop BPD‐PH, while also providing the opportunity to identify target molecules and mechanisms that modulate molecular function.