Objective-To combine mathematical modeling of salivary gene expression microarray data and systems biology annotation with RT-qPCR amplification to identify (phase I) and validate (phase II) salivary biomarker analysis for the prediction of oral feeding readiness in preterm infants.Study design-Comparative whole transcriptome microarray analysis from 12 preterm newborns pre-and post-oral feeding success was used for computational modeling and systems biology analysis to identify potential salivary transcripts associated with oral feeding success (phase I). Selected gene expression biomarkers (15 from computational modeling; 6 evidencebased; and 3 reference) were evaluated by RT-qPCR amplification on 400 salivary samples from successful (n=200) and unsuccessful (n=200) oral feeders (phase II). Genes, alone and in combination, were evaluated by a multivariate analysis controlling for sex and post-conceptional age (PCA) to determine the probability that newborns achieved successful oral feeding.Results-Advancing post-conceptional age (p < 0.001) and female sex (p = 0.05) positively predicted an infant's ability to feed orally. A combination of five genes, NPY2R (hunger signaling), AMPK (energy homeostasis), PLXNA1 (olfactory neurogenesis), NPHP4 (visual behavior) and WNT3 (facial development), in addition to PCA and sex, demonstrated good accuracy for determining feeding success (AUROC = 0.78). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The authors declare no conflicts of interest. Conclusions-We have identified objective and biologically relevant salivary biomarkers that noninvasively assess a newborn's developing brain, sensory and facial development as they relate to oral feeding success. Understanding the mechanisms that underlie the development of oral feeding readiness through translational and computational methods may improve clinical decision making while decreasing morbidities and health care costs. NIH Public AccessPreterm births affect an estimated 11.5% of all pregnancies in the United States resulting in medical costs exceeding $26 billion annually 1 . Prior to discharge, each infant must demonstrate mature oral feeding skills in accordance to the American Academy of Pediatrics' guidelines 2 . The determination of oral feeding readiness in the preterm newborn remains a significant clinical challenge 3 . Oral feeding is a complex developmental task requiring maturation and integration of the nervous, gastrointestinal, sensory, skeletal muscular and hypothalamic systems 4 . Disruption or delayed maturation in one or several of these developmental syst...