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Current retinopathy of prematurity (ROP) guidelines, which are based on studies of high-risk infants and expert opinion, have low specificity for disease requiring treatment. Postnatal weight gain–based models improve specificity but have been limited by complexity and small development cohorts, which results in model overfitting and resultant decreased sensitivity in validation studies.To develop a birth weight (BW), gestational age (GA), and weight gain (WG) prediction model using data from a broad-risk cohort of premature infants.The Postnatal Growth and ROP Study was a retrospective multicenter cohort study conducted in 29 hospitals in the United States and Canada from 2006 to 2012 that included 7483 premature infants at risk for ROP with a known ROP outcome. A hybrid modeling approach was used that combined BW/GA criteria, weight comparison with expected growth from infants without ROP, multiple growth-interval assessments, consideration of nonphysiological WG, and user-friendly screening criteria. Numerous BW/GA levels, postnatal age periods, time intervals, and WG percentile thresholds were evaluated to identify the most robust parameters.Sensitivity for Early Treatment of ROP Study type 1 ROP and potential reduction in infants who require examinations.Of 7483 infants, the median (SD) BW was 1099 (359) g, the median GA was 28 weeks (range, 22-35), 3575 (47.8%) were female, 3615 (48.4%) were white, 2310 (30.9%) were black, 233 (3.1%) were Asian, 93 (1.2%) were Pacific Islander, and 40 (0.5%) were American Indian/Alaskan Native. Infants who met any of 6 criteria would undergo examinations: (1) a GA of younger than 28 weeks; (2) a BW of less than 1051 g; a WG of less than 120 g, 180 g, or 170 g during ages 10 to 19, 20 to 29, or 30 to 39 days, respectively; or hydrocephalus. These criteria predicted 459 of 459 (100%) type 1 (sensitivity, 100%; 95% CI, 99.2%-100%), 524 of 524 (100%) treated, and 466 of 472 (98.7%) type 2 cases while reducing the number of infants who required examinations by 2269 (30.3%).This cohort study, broadly representative of infants who are undergoing ROP examinations, provides evidence-based screening criteria. With validation, the Postnatal Growth and ROP Study criteria could be incorporated into ROP screening guidelines to reduce the number of infants who require examinations in North America.