- Email: [email protected]
Colorado Retinopathy of Prematurity Screening Algorithm (CO-ROP): a validation study at a tertiary care center
Accepted Manuscript Colorado Retinopathy of Prematurity Screening Algorithm (CO-ROP): a validation Study at a Tertiary Care Center Jason M. Huang, MD, Xihui Lin, MD, Yu-Guang He, MD, Jennifer H. Cao, MD PII:
S1091-8531(17)30219-7
DOI:
10.1016/j.jaapos.2017.03.009
Reference:
YMPA 2580
To appear in:
Journal of AAPOS
Please cite this article as: Huang JM, Lin X, He Y-G, Cao JH, Colorado Retinopathy of Prematurity Screening Algorithm (CO-ROP): a validation Study at a Tertiary Care Center, Journal of AAPOS (2017), doi: 10.1016/j.jaapos.2017.03.009. 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 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.
ACCEPTED MANUSCRIPT
Colorado Retinopathy of Prematurity Screening Algorithm (CO-ROP): a validation study at a tertiary care center Jason M. Huang, MD, Xihui Lin, MD, Yu-Guang He, MD, Jennifer H. Cao, MD
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Author affiliations: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas.
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Research supported in part by an unrestricted research grant from Research to Prevent Blindness Inc, New York, New York as well as a Core research grant from the University of Texas Southwestern Medical School. The funding organizations had no role in the design or conduct of this research. Submitted September 10, 2016. Revision accepted January 15, 2017.
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Correspondence: Jennifer H. Cao, MD, 5323 Harry Hines Boulevard, Dallas, TX 75390 (email: [email protected]).
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Word count: 2,323 Abstract only: 207
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Abstract Purpose The Colorado Retinopathy of Prematurity Screening Algorithm (CO-ROP) recommends
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screening for infants meeting the following criteria for retinopathy of prematurity (ROP):
gestational age ≤30 weeks, birth weight of ≤1500 g, and net weight gain of ≤650 g between birth and 4 weeks of age. This study was performed to evaluate the validity of CO-ROP in a tertiary
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referral county hospital. Methods
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CO-ROP was used to retrospectively analyze the data from consecutive newborns screened for ROP using national screening guidelines at Parkland Hospital, Dallas, Texas, between April 1, 2009, to August 30, 2013. Sensitivities and specificities for identifying ROP were calculated. Results
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A total of 374 infants were included, of whom 29 (7.8%) developed type 1 ROP and 12 (3.2%) developed type 2 ROP. The CO-ROP model would have decreased number of infants screened by 34% compared to current national screening criteria. CO-ROP had sensitivity of 93.1% (95%
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CI, 77.2-99.1) and 92.7% (95% CI, 61.5-99.8) for identifying type 1 and type 2 ROP, respectively. Of 29 patients who developed type 1 ROP, 2 were not identified using CO-ROP.
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Conclusions
The CO-ROP model significantly reduced total number screened but failed to detect 2 infants with type 1 ROP, suggesting the need for further modification of the algorithm.
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Retinopathy of prematurity (ROP) is one of the most common ocular diseases in premature infants and is characterized by abnormal development of retinal blood vessels in the immature retina.1 Left untreated, it can lead to neovascularization, retinal detachment, amblyopia, and/or
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blindness. Therefore, appropriate screening and timely treatment are important to prevent blinding complications.2,3
The incidence of ROP among all births in the United States is just 0.17%, and only about
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7%-16% of affected eyes have severe disease.4,5 The current US screening guidelines
recommend that infants are screened if they meet the following criteria: birth weight of ≤1500 g,
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gestational age of ≤30 weeks, or select infants with a birth weight of 1500–2000 g or gestational age >30 weeks with an unstable clinical course believed to be at high risk for ROP.6 Although these guidelines have high sensitivity for identifying ROP, <10% of infants identified by these guidelines eventually require treatment.7-9 As a result, many alternate screening models have
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been proposed in an attempt to decrease the number of infants screened while maintaining a high sensitivity in the identification of ROP.7,10-12
Developed using a population of infants from Colorado, the novel Colorado ROP
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Screening Algorithm (CO-ROP)13 recommends screening infants meeting all of the following criteria: gestational age of ≤30 weeks, birth weight of ≤1500 g, and net weight gain of ≤650 g
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between birth and 4 weeks of age. This model has been retrospectively evaluated in a total of 1,347 patients at 5 US academic institutions and found to be an efficient and reliable screening model.13,14 As with any new screening algorithm however, the CO-ROP model must be evaluated in different populations and hospital settings in order to validate its overall efficacy. The present study evaluated CO-ROP at Parkland Memorial Hospital (PMH), the tertiary referral hospital for Dallas County in Dallas, Texas.
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Subjects and Methods This study was approved by the Institutional Review Board of Parkland Hospital and the University of Texas Southwestern Medical Center. A retrospective cohort study was performed
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of all neonates screened for ROP using national screening guidelines at PMH from April 1, 2009, to August 30, 2013. Data collection included demographics, gestational age, birth weight, weight at age 28 days, systemic comorbidities, ROP severity, and if applicable, treatment received. All
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screened neonates were reevaluated to determine whether they met CO-ROP screening criteria (gestational age ≤30 weeks, birth weight ≤1500 g, and net weight gain ≤650 g at 4 weeks of age).
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All screening examinations were performed by a pediatric retina specialist. Infants had their first screening examination at 30-32 weeks or 4-6 weeks after birth, whichever was later. ROP was graded using the International Classification of ROP criteria.15 For the purposes of this study, ROP severity was defined as the maximum grade of ROP (highest stage and lowest zone
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of ROP) at any time point during the screening period. Patients with type 1 ROP (any stage in zone I with plus disease, stage 3 in zone I with no plus disease, or stage 2 or 3 in zone II with plus disease) and type 2 ROP (stage 1 or 2 in zone I without plus disease or stage 3 in zone II
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without plus disease) were defined as “high-grade” ROP. Any other infant who developed ROP but did not meet high-grade criteria were defined as “low-grade” ROP. All infants with type 1
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ROP were treated with laser photocoagulation in accordance with the Early Treatment of Retinopathy of Prematurity (ETROP) trial or with bevacizumab intravitreal injections in accordance with the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) trial.3,16 The CO-ROP model was evaluated by calculating sensitivities and specificities for detection of high-grade ROP, low-grade ROP, and overall ROP. The 95% confidence intervals
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were calculated using exact Clopper-Pearson confidence limits for binomial proportions. Means and uncorrected sample standard deviations were calculated. Statistical analyses were performed using SAS software edition 9.4 (SAS Institute Inc, Cary, NC).
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Results
A total of 375 premature infants met national guidelines for screening. One chart was excluded due to lack of weight documentation at 28 days of life. This infant did not develop ROP and
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would not have been screened by CO-ROP criteria because of a gestational age of 32 weeks and birth weight of 2545 g. Of the remaining 374 patients, 194 (51.9%) were male. Mean gestational
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age was 28.5 ± 2.4 weeks (range 24-36 weeks). Mean birth weight was 1201 ± 366 g (range, 548–3010 g). Demographic data are listed in Table 1. Infants gained an average weight of 433.5 ± 185.8 g in the first 28 days of life, with a mean net weight gain of 272 g, 343 g, 377 g, and 491 g for infants with type 1, type 2, low-grade, and no ROP, respectively (Figure 1).
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All patients had their initial ROP screening examination at least 28 days after birth. Out of 374 infants included in the study, 158 (42.2%) developed ROP in at least one eye. Of these patients, 29 (7.8%) developed type 1 ROP and 12 (3.2%) developed type 2 ROP, for a total of 41
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patients (11.0%) with high-grade ROP. All patients with type 1 ROP were treated with either laser photocoagulation or intravitreal bevacizumab injection. One patient received both
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treatments because of continued proliferative disease with insufficient response to the initial laser photocoagulation treatment.
Of the 374 patients identified by current national screening criteria, 338 (90.4%) were
identified for ROP screening due to gestational age ≤30 weeks or birth weight ≤1500 g. Of these 338 patients, 150 developed ROP (28 with type 1 ROP). An additional 36 infants (9.6%) were screened due to an unstable clinical course despite having gestational age >30 weeks and birth
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weight >1500 g. Eight patients developed ROP (1 with type 1 ROP) in this latter group. When infants were reevaluated using CO-ROP screening criteria, 246 (65.8%) infants met criteria for screening, whereas 128 (34.2%) infants did not meet CO-ROP screening criteria.
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Hence, the CO-ROP model would have reduced the total number of infants screened by 34.2% compared to the current screening guidelines and the number of infants screened with no ROP by 48.1%.
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The CO-ROP model had a 93.1% sensitivity (95% CI, 77.2-99.1) for identifying type 1 ROP and a 92.7% sensitivity (95% CI, 61.5-99.8) for identifying high-grade ROP (Table 2). Of
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27 patients with type 1 ROP, 2 were not identified by CO-ROP; of 11 patients with type 2 ROP, 1 was not identified. One of the patients with type 1 ROP missed by CO-ROP had gestational age of 32 weeks, birth weight of 1949 g, and net weight gain of 331 g at 4 weeks. The other missed patient with type 1 ROP had gestational age of 30 weeks, birth weight of 1549 g, and net
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weight gain of 501 g at 4 weeks. The missed patient with type 2 ROP was born at 28 weeks, 1729 g, with net weight gain of 201 g at 4 weeks. Discussion
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In the original CO-ROP study of 499 infants, sensitivity was 100% for detecting high-grade ROP and 96.4% for detecting all grades of ROP. The number of infants requiring screening was
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reduced by 23.7% compared to the 2013 screening guidelines.13 In a subsequent validation study of 858 infants performed at 4 large, academic referral centers, sensitivity was 98.1% for highgrade ROP and 95% for all grades of ROP, and there was a 23.9% reduction in number of infants screened by CO-ROP compared to the 2013 screening guidelines. One infant with type 1 ROP was missed by the CO-ROP model in this validation study due to nonphysiologic weight gain at 28 days of life. This infant had significant edema requiring ongoing diuresis and resultant weight
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fluctuations.14 The present study, performed at a tertiary referral county hospital, found 92.7% sensitivity for identifying high-grade ROP and 84.8% sensitivity for identifying all grades of
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ROP. The number of infants requiring screening was reduced by 34.2% compared to the 2013 screening guidelines. The CO-ROP model identified 27 out of 29 infants with type 1 ROP (93.1% sensitivity).
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The 2 infants with type 1 ROP missed by CO-ROP had unstable clinical courses
requiring pressors for sepsis prior to their initial ROP screening examination. Patient 1 was born
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at 32 weeks’ gestation (estimated by 15 week ultrasound) and had a birthweight of 1949 g. This infant gained 331 g in the first 28 days of life. At the time of 28 days of life this patient had developed necrotizing enterocolitis with sepsis and was receiving fluid support; his weight gain was not physiologic. However, due to his large birthweight he would not have been captured by
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the CO-ROP model, regardless of possibly inaccurate dating and nonphysiologic weight gain at 28 days of life. Patient 1 was found to have stage 3, zone 2 with plus disease in both eyes at the initial screening examination at 38 weeks’ gestation and subsequently received laser
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photocoagulation.
Patient 2 was born at 30 weeks, 1549 g, and had weight gain of 501 g at 28 days. At
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delivery, the patient was nonvigorous with poor spontaneous respiratory effort requiring positive pressure ventilation. Blood culture was positive for group B streptococci, and chest X-ray was concerning for pneumonia. She was treated with ampicillin, and she ultimately required oxygen for 43 days. She developed stage 2, zone II ROP in both eyes with plus disease in the right eye at 36 weeks’ gestational age. Laser photocoagulation was performed on both eyes. In a subanalysis of data from the multicenter study by Cao and colleagues,14 the statistics
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suggested that the birthweight cutoff be increased to 1650 g but did not reach statistical significance for improving sensitivity of detecting high-grade ROP (data: JHC). The outcome of patient 2 suggests that a higher weight cutoff may indeed be beneficial for identifying more
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infants that eventually develop treatment-requiring ROP. By increasing the weight cutoff to 1650 g, however, reduction in infants screened would be smaller, at 29.7% as opposed to 34.2%.
Development of a new, more efficient screening algorithm is a challenge because missing
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even a single infant with treatment-requiring ROP is unacceptable. While the 2013 screening guidelines include a modifier to screen infants with an unstable clinical course, this modifier is
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not included in the CO-ROP model in an effort use simple, objective criteria to identify all infants with severe ROP. In our study, 2 infants that eventually required treatment for ROP had unstable clinical courses and were missed by CO-ROP. These 2 omissions from the CO-ROP screening algorithm highlight the need for further modifications.
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One potential modification would be to screen all patients that developed sepsis in addition to those captured by CO-ROP. Further analysis of the data shows that there were 48 patients diagnosed with sepsis during their hospital course. Eight of these patients, including
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patients 1 and 2 above, were not screened by CO-ROP criteria. If these 8 patients were included in the screening, sensitivity for identifying type 1 ROP would increase from 93.1% to 100%, and
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the number of infants requiring screening would be reduced by 32.1% as opposed to 34.2% by CO-ROP criteria alone. Inclusion of patients with sepsis in screening would identify all patients with type 1 ROP in our cohort with a small decrease the number of reduced examinations. Further studies are required to see if this modification to the CO-ROP model would maintain validity in other populations. This study was limited by the small number of patients with treatment-requiring ROP.
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Further study on larger, diverse patient populations is needed to validate the CO-ROP model in order to further refine this screening model. Our study population was primarily composed of Hispanic and black infants and hence the results may not be generalizable to other populations.
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Nevertheless, this study provides valuable information regarding the validity of CO-ROP in a significant number of patients from a new geographic location within the United States. We do not believe that retrospective data collection is a major limitation, because all of the information
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necessary for the study was available in the medical record, and none of the data were degraded in quality. Larger-scale prospective studies will be needed to refine the algorithm; nevertheless,
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CO-ROP is useful in further stratifying infants at risk for developing high-grade ROP. It should not, however, be used as a standalone screening tool.
Using infants at a tertiary referral county hospital, the CO-ROP model was found to maintain a high sensitivity for ROP while significantly reducing the number of infants screened
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compared to the 2013 screening criteria. However, 2 infants that required treatment for ROP were missed. In its current formulation, the model can be used in addition to current screening
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guidelines to identify infants at high risk for developing significant ROP.
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References 1.
Hellstrom A, Smith LE, Dammann O. Retinopathy of prematurity. Lancet 2013;382(9902):1445-57. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of
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2.
cryotherapy for retinopathy of prematurity: Snellen visual acuity and structural outcome at 5 1/2 years after randomization. Arch Ophthalmol 1996;114:417-24.
Good WV; Early Treatment for Retinopathy of Prematurity Cooperative Group. Final
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3.
results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial.
4.
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Trans Am Ophthalmol Soc 2004;102:233-48; discussion 248-50.
Horbar JD, Carpenter JH, Badger GJ, et al. Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009. Pediatrics 2012;129:1019-26.
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Lad EM, Hernandez-Boussard T, Morton JM, Moshfeghi DM. Incidence of retinopathy
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of prematurity in the United States: 1997 through 2005. Am J Ophthalmol 2009;148:4518. 6.
Fierson, WM; American Academy of Pediatrics Section on Ophthalmology; American
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Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists. Screening examination of
7.
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premature infants for retinopathy of prematurity. Pediatrics 2013;131:189-95.
Binenbaum G, Ying GS, Quinn GE, et al. The CHOP postnatal weight gain, birth weight,
and gestational age retinopathy of prematurity risk model. Arch Ophthalmol 2012;130:1560-65.
8.
Wu C, Vanderveen DK, Hellström A, Löfqvist C, Smith LE. Longitudinal postnatal weight measurements for the prediction of retinopathy of prematurity. Arch Ophthalmol
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2010;128:443-7. 9.
Binenbaum G. Algorithms for the prediction of retinopathy of prematurity based on postnatal weight gain. Clin Perinatol 2013;40:261-70. Hellström A, Hård AL, Engström E, et al. Early weight gain predicts retinopathy in
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preterm infants: new, simple, efficient approach to screening. Pediatrics 2009;123:e63845.
Hutchinson AK, Melia M, Yang MB, VanderVeen DK, Wilson LB, Lambert SR. Clinical
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11.
models and algorithms for the prediction of retinopathy of prematurity: a report by the
12.
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American Academy of Ophthalmology. Ophthalmology 2016;123:804-16. Wilson CM, Ells AL, Fielder AR. The challenge of screening for retinopathy of prematurity. Clin Perinatol 2013;40:241-59. 13.
Cao JH, Wagner BD, McCourt EA, et al. The Colorado-retinopathy of prematurity model
14.
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(CO-ROP): postnatal weight gain screening algorithm. J AAPOS 2016;20:19-24. Cao JH, Wagner BD, Cerda A, et al., Colorado retinopathy of prematurity model: a multi-institutional validation study. J AAPOS 2016;20:220-25. International Committee for the Classification of Retinopathy of Prematurity. The
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15.
International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol
16.
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2005;123:991-9.
Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011;364:603-15.
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Legends
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FIG 1. Weight gain by retinopathy of prematurity grade (g, mean ± standard deviation).
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Characteristic Value Female, n (%) 180 (48.1) Race, n (%) Hispanic 261 (69.8) White, non-Hispanic 20 (5.4) Black 77 (20.6) Asian or Pacific Islander 8 (2.1) American Indian 2 (0.5) GA, weeks, median (IQR) 29 (27-30) BW, g, median (IQR) 1200 (900-1430) Net weight gain 28 days, g, median (IQR) 440 (290-560) ROP type, n (%) High-grade 41 (11) Low-grade 117 (31.3) No ROP 216 (57.8)
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Table 1. Patient demographics
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BW, birth weight; GA, gestational age; IQR, interquartile range; ROP, retinopathy of prematurity.
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Table 2. Sensitivities for detecting retinopathy of prematurity using CO-ROP model
93.1% (77.2%-99.1%)
c
Type 2 ROP Low-grade ROP (n = 117) (n = 12) a b a b Alarm No alarm Alarm No Alarm 11 1 96 21 Sensitivity (95% CI) 91.7% (61.5%-99.8%) 82.1% (73.9%-88.5%)
Any ROP (n = 158) a b Alarm No alarm 134 24 70.9% (63.1%-77.8%)
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Type 1 ROP (n = 29) a b Alarm No alarm 27 2
CI, confidence interval; CO-ROP, Colorado Retinopathy of Prematurity Screening Algorithm; ROP, retinopathy of prematurity. a
Infants who met CO-ROP screening criteria. Infants who did not meet CO-ROP screening criteria. c Infant who developed any grade of ROP that did not meet type 1 or type 2 criteria.
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b
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S1091-8531(17)30219-7
DOI:
10.1016/j.jaapos.2017.03.009
Reference:
YMPA 2580
To appear in:
Journal of AAPOS
Please cite this article as: Huang JM, Lin X, He Y-G, Cao JH, Colorado Retinopathy of Prematurity Screening Algorithm (CO-ROP): a validation Study at a Tertiary Care Center, Journal of AAPOS (2017), doi: 10.1016/j.jaapos.2017.03.009. 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 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.
ACCEPTED MANUSCRIPT
Colorado Retinopathy of Prematurity Screening Algorithm (CO-ROP): a validation study at a tertiary care center Jason M. Huang, MD, Xihui Lin, MD, Yu-Guang He, MD, Jennifer H. Cao, MD
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Author affiliations: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas.
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Research supported in part by an unrestricted research grant from Research to Prevent Blindness Inc, New York, New York as well as a Core research grant from the University of Texas Southwestern Medical School. The funding organizations had no role in the design or conduct of this research. Submitted September 10, 2016. Revision accepted January 15, 2017.
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Correspondence: Jennifer H. Cao, MD, 5323 Harry Hines Boulevard, Dallas, TX 75390 (email: [email protected]).
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Word count: 2,323 Abstract only: 207
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Abstract Purpose The Colorado Retinopathy of Prematurity Screening Algorithm (CO-ROP) recommends
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screening for infants meeting the following criteria for retinopathy of prematurity (ROP):
gestational age ≤30 weeks, birth weight of ≤1500 g, and net weight gain of ≤650 g between birth and 4 weeks of age. This study was performed to evaluate the validity of CO-ROP in a tertiary
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referral county hospital. Methods
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CO-ROP was used to retrospectively analyze the data from consecutive newborns screened for ROP using national screening guidelines at Parkland Hospital, Dallas, Texas, between April 1, 2009, to August 30, 2013. Sensitivities and specificities for identifying ROP were calculated. Results
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A total of 374 infants were included, of whom 29 (7.8%) developed type 1 ROP and 12 (3.2%) developed type 2 ROP. The CO-ROP model would have decreased number of infants screened by 34% compared to current national screening criteria. CO-ROP had sensitivity of 93.1% (95%
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CI, 77.2-99.1) and 92.7% (95% CI, 61.5-99.8) for identifying type 1 and type 2 ROP, respectively. Of 29 patients who developed type 1 ROP, 2 were not identified using CO-ROP.
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Conclusions
The CO-ROP model significantly reduced total number screened but failed to detect 2 infants with type 1 ROP, suggesting the need for further modification of the algorithm.
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Retinopathy of prematurity (ROP) is one of the most common ocular diseases in premature infants and is characterized by abnormal development of retinal blood vessels in the immature retina.1 Left untreated, it can lead to neovascularization, retinal detachment, amblyopia, and/or
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blindness. Therefore, appropriate screening and timely treatment are important to prevent blinding complications.2,3
The incidence of ROP among all births in the United States is just 0.17%, and only about
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7%-16% of affected eyes have severe disease.4,5 The current US screening guidelines
recommend that infants are screened if they meet the following criteria: birth weight of ≤1500 g,
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gestational age of ≤30 weeks, or select infants with a birth weight of 1500–2000 g or gestational age >30 weeks with an unstable clinical course believed to be at high risk for ROP.6 Although these guidelines have high sensitivity for identifying ROP, <10% of infants identified by these guidelines eventually require treatment.7-9 As a result, many alternate screening models have
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been proposed in an attempt to decrease the number of infants screened while maintaining a high sensitivity in the identification of ROP.7,10-12
Developed using a population of infants from Colorado, the novel Colorado ROP
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Screening Algorithm (CO-ROP)13 recommends screening infants meeting all of the following criteria: gestational age of ≤30 weeks, birth weight of ≤1500 g, and net weight gain of ≤650 g
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between birth and 4 weeks of age. This model has been retrospectively evaluated in a total of 1,347 patients at 5 US academic institutions and found to be an efficient and reliable screening model.13,14 As with any new screening algorithm however, the CO-ROP model must be evaluated in different populations and hospital settings in order to validate its overall efficacy. The present study evaluated CO-ROP at Parkland Memorial Hospital (PMH), the tertiary referral hospital for Dallas County in Dallas, Texas.
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Subjects and Methods This study was approved by the Institutional Review Board of Parkland Hospital and the University of Texas Southwestern Medical Center. A retrospective cohort study was performed
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of all neonates screened for ROP using national screening guidelines at PMH from April 1, 2009, to August 30, 2013. Data collection included demographics, gestational age, birth weight, weight at age 28 days, systemic comorbidities, ROP severity, and if applicable, treatment received. All
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screened neonates were reevaluated to determine whether they met CO-ROP screening criteria (gestational age ≤30 weeks, birth weight ≤1500 g, and net weight gain ≤650 g at 4 weeks of age).
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All screening examinations were performed by a pediatric retina specialist. Infants had their first screening examination at 30-32 weeks or 4-6 weeks after birth, whichever was later. ROP was graded using the International Classification of ROP criteria.15 For the purposes of this study, ROP severity was defined as the maximum grade of ROP (highest stage and lowest zone
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of ROP) at any time point during the screening period. Patients with type 1 ROP (any stage in zone I with plus disease, stage 3 in zone I with no plus disease, or stage 2 or 3 in zone II with plus disease) and type 2 ROP (stage 1 or 2 in zone I without plus disease or stage 3 in zone II
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without plus disease) were defined as “high-grade” ROP. Any other infant who developed ROP but did not meet high-grade criteria were defined as “low-grade” ROP. All infants with type 1
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ROP were treated with laser photocoagulation in accordance with the Early Treatment of Retinopathy of Prematurity (ETROP) trial or with bevacizumab intravitreal injections in accordance with the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) trial.3,16 The CO-ROP model was evaluated by calculating sensitivities and specificities for detection of high-grade ROP, low-grade ROP, and overall ROP. The 95% confidence intervals
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were calculated using exact Clopper-Pearson confidence limits for binomial proportions. Means and uncorrected sample standard deviations were calculated. Statistical analyses were performed using SAS software edition 9.4 (SAS Institute Inc, Cary, NC).
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Results
A total of 375 premature infants met national guidelines for screening. One chart was excluded due to lack of weight documentation at 28 days of life. This infant did not develop ROP and
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would not have been screened by CO-ROP criteria because of a gestational age of 32 weeks and birth weight of 2545 g. Of the remaining 374 patients, 194 (51.9%) were male. Mean gestational
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age was 28.5 ± 2.4 weeks (range 24-36 weeks). Mean birth weight was 1201 ± 366 g (range, 548–3010 g). Demographic data are listed in Table 1. Infants gained an average weight of 433.5 ± 185.8 g in the first 28 days of life, with a mean net weight gain of 272 g, 343 g, 377 g, and 491 g for infants with type 1, type 2, low-grade, and no ROP, respectively (Figure 1).
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All patients had their initial ROP screening examination at least 28 days after birth. Out of 374 infants included in the study, 158 (42.2%) developed ROP in at least one eye. Of these patients, 29 (7.8%) developed type 1 ROP and 12 (3.2%) developed type 2 ROP, for a total of 41
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patients (11.0%) with high-grade ROP. All patients with type 1 ROP were treated with either laser photocoagulation or intravitreal bevacizumab injection. One patient received both
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treatments because of continued proliferative disease with insufficient response to the initial laser photocoagulation treatment.
Of the 374 patients identified by current national screening criteria, 338 (90.4%) were
identified for ROP screening due to gestational age ≤30 weeks or birth weight ≤1500 g. Of these 338 patients, 150 developed ROP (28 with type 1 ROP). An additional 36 infants (9.6%) were screened due to an unstable clinical course despite having gestational age >30 weeks and birth
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weight >1500 g. Eight patients developed ROP (1 with type 1 ROP) in this latter group. When infants were reevaluated using CO-ROP screening criteria, 246 (65.8%) infants met criteria for screening, whereas 128 (34.2%) infants did not meet CO-ROP screening criteria.
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Hence, the CO-ROP model would have reduced the total number of infants screened by 34.2% compared to the current screening guidelines and the number of infants screened with no ROP by 48.1%.
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The CO-ROP model had a 93.1% sensitivity (95% CI, 77.2-99.1) for identifying type 1 ROP and a 92.7% sensitivity (95% CI, 61.5-99.8) for identifying high-grade ROP (Table 2). Of
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27 patients with type 1 ROP, 2 were not identified by CO-ROP; of 11 patients with type 2 ROP, 1 was not identified. One of the patients with type 1 ROP missed by CO-ROP had gestational age of 32 weeks, birth weight of 1949 g, and net weight gain of 331 g at 4 weeks. The other missed patient with type 1 ROP had gestational age of 30 weeks, birth weight of 1549 g, and net
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weight gain of 501 g at 4 weeks. The missed patient with type 2 ROP was born at 28 weeks, 1729 g, with net weight gain of 201 g at 4 weeks. Discussion
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In the original CO-ROP study of 499 infants, sensitivity was 100% for detecting high-grade ROP and 96.4% for detecting all grades of ROP. The number of infants requiring screening was
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reduced by 23.7% compared to the 2013 screening guidelines.13 In a subsequent validation study of 858 infants performed at 4 large, academic referral centers, sensitivity was 98.1% for highgrade ROP and 95% for all grades of ROP, and there was a 23.9% reduction in number of infants screened by CO-ROP compared to the 2013 screening guidelines. One infant with type 1 ROP was missed by the CO-ROP model in this validation study due to nonphysiologic weight gain at 28 days of life. This infant had significant edema requiring ongoing diuresis and resultant weight
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fluctuations.14 The present study, performed at a tertiary referral county hospital, found 92.7% sensitivity for identifying high-grade ROP and 84.8% sensitivity for identifying all grades of
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ROP. The number of infants requiring screening was reduced by 34.2% compared to the 2013 screening guidelines. The CO-ROP model identified 27 out of 29 infants with type 1 ROP (93.1% sensitivity).
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The 2 infants with type 1 ROP missed by CO-ROP had unstable clinical courses
requiring pressors for sepsis prior to their initial ROP screening examination. Patient 1 was born
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at 32 weeks’ gestation (estimated by 15 week ultrasound) and had a birthweight of 1949 g. This infant gained 331 g in the first 28 days of life. At the time of 28 days of life this patient had developed necrotizing enterocolitis with sepsis and was receiving fluid support; his weight gain was not physiologic. However, due to his large birthweight he would not have been captured by
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the CO-ROP model, regardless of possibly inaccurate dating and nonphysiologic weight gain at 28 days of life. Patient 1 was found to have stage 3, zone 2 with plus disease in both eyes at the initial screening examination at 38 weeks’ gestation and subsequently received laser
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photocoagulation.
Patient 2 was born at 30 weeks, 1549 g, and had weight gain of 501 g at 28 days. At
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delivery, the patient was nonvigorous with poor spontaneous respiratory effort requiring positive pressure ventilation. Blood culture was positive for group B streptococci, and chest X-ray was concerning for pneumonia. She was treated with ampicillin, and she ultimately required oxygen for 43 days. She developed stage 2, zone II ROP in both eyes with plus disease in the right eye at 36 weeks’ gestational age. Laser photocoagulation was performed on both eyes. In a subanalysis of data from the multicenter study by Cao and colleagues,14 the statistics
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suggested that the birthweight cutoff be increased to 1650 g but did not reach statistical significance for improving sensitivity of detecting high-grade ROP (data: JHC). The outcome of patient 2 suggests that a higher weight cutoff may indeed be beneficial for identifying more
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infants that eventually develop treatment-requiring ROP. By increasing the weight cutoff to 1650 g, however, reduction in infants screened would be smaller, at 29.7% as opposed to 34.2%.
Development of a new, more efficient screening algorithm is a challenge because missing
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even a single infant with treatment-requiring ROP is unacceptable. While the 2013 screening guidelines include a modifier to screen infants with an unstable clinical course, this modifier is
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not included in the CO-ROP model in an effort use simple, objective criteria to identify all infants with severe ROP. In our study, 2 infants that eventually required treatment for ROP had unstable clinical courses and were missed by CO-ROP. These 2 omissions from the CO-ROP screening algorithm highlight the need for further modifications.
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One potential modification would be to screen all patients that developed sepsis in addition to those captured by CO-ROP. Further analysis of the data shows that there were 48 patients diagnosed with sepsis during their hospital course. Eight of these patients, including
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patients 1 and 2 above, were not screened by CO-ROP criteria. If these 8 patients were included in the screening, sensitivity for identifying type 1 ROP would increase from 93.1% to 100%, and
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the number of infants requiring screening would be reduced by 32.1% as opposed to 34.2% by CO-ROP criteria alone. Inclusion of patients with sepsis in screening would identify all patients with type 1 ROP in our cohort with a small decrease the number of reduced examinations. Further studies are required to see if this modification to the CO-ROP model would maintain validity in other populations. This study was limited by the small number of patients with treatment-requiring ROP.
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Further study on larger, diverse patient populations is needed to validate the CO-ROP model in order to further refine this screening model. Our study population was primarily composed of Hispanic and black infants and hence the results may not be generalizable to other populations.
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Nevertheless, this study provides valuable information regarding the validity of CO-ROP in a significant number of patients from a new geographic location within the United States. We do not believe that retrospective data collection is a major limitation, because all of the information
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necessary for the study was available in the medical record, and none of the data were degraded in quality. Larger-scale prospective studies will be needed to refine the algorithm; nevertheless,
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CO-ROP is useful in further stratifying infants at risk for developing high-grade ROP. It should not, however, be used as a standalone screening tool.
Using infants at a tertiary referral county hospital, the CO-ROP model was found to maintain a high sensitivity for ROP while significantly reducing the number of infants screened
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compared to the 2013 screening criteria. However, 2 infants that required treatment for ROP were missed. In its current formulation, the model can be used in addition to current screening
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guidelines to identify infants at high risk for developing significant ROP.
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References 1.
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results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial.
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Trans Am Ophthalmol Soc 2004;102:233-48; discussion 248-50.
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premature infants for retinopathy of prematurity. Pediatrics 2013;131:189-95.
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and gestational age retinopathy of prematurity risk model. Arch Ophthalmol 2012;130:1560-65.
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2010;128:443-7. 9.
Binenbaum G. Algorithms for the prediction of retinopathy of prematurity based on postnatal weight gain. Clin Perinatol 2013;40:261-70. Hellström A, Hård AL, Engström E, et al. Early weight gain predicts retinopathy in
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American Academy of Ophthalmology. Ophthalmology 2016;123:804-16. Wilson CM, Ells AL, Fielder AR. The challenge of screening for retinopathy of prematurity. Clin Perinatol 2013;40:241-59. 13.
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(CO-ROP): postnatal weight gain screening algorithm. J AAPOS 2016;20:19-24. Cao JH, Wagner BD, Cerda A, et al., Colorado retinopathy of prematurity model: a multi-institutional validation study. J AAPOS 2016;20:220-25. International Committee for the Classification of Retinopathy of Prematurity. The
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Legends
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FIG 1. Weight gain by retinopathy of prematurity grade (g, mean ± standard deviation).
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Characteristic Value Female, n (%) 180 (48.1) Race, n (%) Hispanic 261 (69.8) White, non-Hispanic 20 (5.4) Black 77 (20.6) Asian or Pacific Islander 8 (2.1) American Indian 2 (0.5) GA, weeks, median (IQR) 29 (27-30) BW, g, median (IQR) 1200 (900-1430) Net weight gain 28 days, g, median (IQR) 440 (290-560) ROP type, n (%) High-grade 41 (11) Low-grade 117 (31.3) No ROP 216 (57.8)
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Table 1. Patient demographics
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BW, birth weight; GA, gestational age; IQR, interquartile range; ROP, retinopathy of prematurity.
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Table 2. Sensitivities for detecting retinopathy of prematurity using CO-ROP model
93.1% (77.2%-99.1%)
c
Type 2 ROP Low-grade ROP (n = 117) (n = 12) a b a b Alarm No alarm Alarm No Alarm 11 1 96 21 Sensitivity (95% CI) 91.7% (61.5%-99.8%) 82.1% (73.9%-88.5%)
Any ROP (n = 158) a b Alarm No alarm 134 24 70.9% (63.1%-77.8%)
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Type 1 ROP (n = 29) a b Alarm No alarm 27 2
CI, confidence interval; CO-ROP, Colorado Retinopathy of Prematurity Screening Algorithm; ROP, retinopathy of prematurity. a
Infants who met CO-ROP screening criteria. Infants who did not meet CO-ROP screening criteria. c Infant who developed any grade of ROP that did not meet type 1 or type 2 criteria.
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b
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