PROJECT SUMMARY/ABSTRACT The current standard measure of OSA, the apnea-hypopnea index (AHI) underestimates women’s OSA severity compared to men, which may lead to missed diagnoses, thus increasing women’s risk for cardiovascular disease, metabolic and mood disorders, and poor daytime functioning. Most of the early evidence to support the use of AHI as a measure of OSA severity has been validated in men. There is a pressing need to identify a reliable biomarker of OSA severity in order to minimize sex and gender inequities in in diagnosis and management of OSA. We propose to assess night-to-night variability in novel OSA severity metrics and assess their impact on day-to-day sleepiness, fatigue, mood, and stress towards characterization of reliable biomarkers of disease severity. The proposed study will leverage cutting-edge sleep monitoring technology (Cerebra Sleep System) supporting the data collection in the participant’s home over 7 nights. The study will also collect daytime functioning information several times per day via ecological momentary assessments (EMA). We will enroll participants from two Sleep Medicine Centers associated with the University of Pittsburgh and the University of Kansas Medical Center which will allow for a robust recruitment of 300 participants, 100 men, and 200 women balanced by menopausal status. Using available multiple night recordings, we will assess the within- and between-subject variability of key sleep-disordered breathing physiological traits (total and sleep stage-specific AHI, hypoxic burden, and pulse rate responses to respiratory events and to arousals) and determine the role of sex as a potential contributor of between-subject variability in these traits (Aim 1). Next, we will assess the temporal relationship between novel OSA severity parameters, sleep traits and daytime function using key objective (sleep duration, architecture, depth, microstructure) and self-reported sleep traits, as well as EMA of daytime sleepiness, fatigue, mood, and stress (Aim 2). We will assess the temporal effects of OSA severity parameters on daytime function, determine whether these effects are mediated by objective sleep traits, and establish whether sex and gender moderate these associations. Our central hypothesis is that men and women require distinct definitions of OSA severity, because the mechanisms explaining how sleep disordered breathing impact daytime functioning will be different between sexes. This study has the potential to create a new paradigm in OSA research that will lead to novel approaches to OSA severity definitions and improve long term health outcomes for women and men.