Progression from preplus to plus disease in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study: incidence, timing, and predictors.

PURPOSE: To determine the incidence of and timing and predictors for progression from pre-plus to plus disease, based on evaluation of images. METHODS: Two trained readers independently evaluated posterior pole images of infants from 13 North American centers for pre-plus/plus disease, stage, and zone of retinopathy of prematurity (ROP). Discrepancies between readers were adjudicated. To be eligible for analysis, eyes had to have at least two imaging sessions, the earlier one with pre-plus disease. RESULTS: Of 681 eyes of 444 infants with pre-plus first detected at mean postmenstrual age (PMA) of 35.5 ± 2.1 weeks, 54 (7.9%) progressed to plus disease at a mean PMA of 37.6 ± 2.4 weeks with the mean interval for progression of 2.7 weeks (range, 0.4-8.9 weeks). Progression rate was higher for eyes with larger number of quadrants of pre-plus (44% for eyes with four quadrants vs 4% with one quadrant [P < 0.0001]), earlier PMA with pre-plus (18% for 32 weeks' PMA vs 3% for PMA of >37 weeks [P = 0.02]), higher ROP stage (12% for stage 3, 2.5% for no ROP [P < 0.0001]), lower ROP zone (24% for zone I, 6% for zone II or no ROP [P < 0.0001]) at the time of first pre-plus detection. CONCLUSIONS: Based on image evaluation, 8% of eyes progressed from pre-plus to plus disease at a mean interval of 3 weeks. Pre-plus in multiple quadrants, higher stages of ROP, and lower zones of ROP were associated with higher risk of progression. Image evaluation for pre-plus may help in the identification of high-risk eyes for developing plus disease.

Asymmetry of Retinopathy of Prematurity Border in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity Study.

PURPOSE: To measure the location of the retinopathy of prematurity (ROP) border in a sample of premature infants developed ROP and to determine the location for predicting subsequent development of referral-warranted ROP (defined as stage 3 ROP, zone I ROP, or plus disease) or treated ROP. DESIGN: Secondary analysis of data from an observational cohort study, the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity study. PARTICIPANTS: Infants with birth weight (BW) of less than 1251 g with at least 1 examination and imaging session at 34 weeks postmenstrual age (PMA) or younger with ROP not meeting referral-warranted ROP and at least 1 subsequent examination at 36 weeks PMA or older. METHODS: The 5-image set from the first imaging session for each eligible eye was mosaicked, and measurements of the ROP border were made using Image J. Measurements were compared among 3 groups of eyes with ROP: (1) those that never developed referral-warranted ROP or received treatment, (2) those that developed referral-warranted ROP but did not receive treatment, and (3) those that received treatment. MAIN OUTCOME MEASURES: Referral-warranted ROP and treated ROP. RESULTS: Three hundred seventeen eyes from 217 infants with mean BW of 755 g, mean gestational age (GA) of 25 weeks, and mean PMA of 33 weeks at first examination met study criteria. Of 211 eyes (66.6%) with sufficient-quality images for grading, 147 (69.7%) did not develop referral-warranted ROP or receive treatment, 36 (17.1%) developed referral-warranted ROP not requiring treatment, and 28 (13.3%) received treatment for ROP. Among all eyes, the disc-to-ROP border distance followed a consistent pattern, with nasal less than inferior less than superior less than temporal. In multivariate analysis adjusted by BW and GA, nasal ROP border distance was a significant predictor of the subsequent development of ROP that was treated (odds ratio, 0.86 for every 10-pixel increase in distance; P = 0.002). CONCLUSIONS: Retinopathy of prematurity is located asymmetrically around the optic disc and is closest to the optic disc nasally. Location of ROP nasally at first imaging is a significant predictor for subsequent development of ROP that was treated.

Plus Disease in Telemedicine Approaches to Evaluating Acute-Phase ROP (e-ROP) Study: Characteristics, Predictors, and Accuracy of Image Grading.

PURPOSE: To describe characteristics and predictors of plus disease, and the accuracy of image grading for plus disease in the e-ROP Study. DESIGN: Secondary analyses of data from 13 North American centers. PARTICIPANTS: Premature infants with birth weight (BW) <1251 g. METHODS: Infants underwent regularly scheduled diagnostic examinations by ophthalmologists and digital imaging by trained imagers using a wide-field digital camera. Two masked nonphysician trained readers independently evaluated images for posterior pole abnormality (normal, preplus, plus), with discrepancies adjudicated by a reading supervisor. Logistic regression models were used to determine predictors for plus disease. The sensitivity and specificity of image grading for plus disease were calculated using the clinical examination finding as reference standard. MAIN OUTCOME MEASURES: Odds ratios (OR), sensitivity, and specificity. RESULTS: Among 1239 infants (mean BW 864 g, mean gestational age [GA] 27 weeks), 129 infants (10%) (226 eyes, 75% bilateral) had plus disease from clinical examination. When plus disease was first diagnosed in clinical examination at median postmenstrual age (PMA) of 36 weeks (range: 32-43 weeks), 94% to 96% of plus occurred in the superior or inferior temporal quadrant. Significant predictors for plus disease from multivariate analysis were as follows: GA (OR = 3.2 for ≤24 vs. ≥28 weeks, P = 0.004), race (OR = 2.4 for white vs. black, P = 0.01), respiratory support (OR = 7.1, P = 0.006), weight gain (OR = 1.5 for weight gain ≤12 vs. >18 g/day, P = 0.03), and image findings at the first image session, including presence of preplus/plus disease (OR = 2.7, P = 0.003), ROP stage (OR = 4.2 for stage 3 ROP vs. no ROP, P = 0.006), and blot hemorrhage (OR = 3.1, P = 0.003). These features predicted plus disease with an area under the receiver operating characteristic curve of 0.89 (95% confidence interval [CI]: 0.85-0.92). The image grading using preplus as the cut point had sensitivity of 94% (95% CI: 90%-97%) and specificity of 81% (95% CI: 79%-82%) for detecting plus disease in an eye. CONCLUSIONS: Among e-ROP infants, plus disease developed in 10% of infants at a median PMA of 37 weeks, with the majority being bilateral and mostly in the superior or inferior temporal quadrant. GA, race, respiratory support, postnatal weight gain, image findings of the posterior pole, and ROP predict development of plus disease. Nonphysician image grading can detect almost all plus disease with good specificity.

Factors in Premature Infants Associated With Low Risk of Developing Retinopathy of Prematurity.

Importance: Most premature infants will not develop retinopathy of prematurity (ROP) of clinical relevance, yet screening evaluations often continue beyond hospital discharge, even for those infants without ROP. Objectives: To identify the characteristics of infants at low risk for ROP, for whom further postdischarge screening may be of limited value. Design, Setting, and Participants: This study took place in North American neonatal intensive care units where clinicians had expertise in ROP. Infants with birth weight less than 1251 g who were born at or transferred into an Telemedicine Approaches to Evaluating Acute-Phase ROP (e-ROP) study center were enrolled. The study included post hoc analysis of prospectively collected in-hospital ROP examination results among infants enrolled in the e-ROP study. We characterized infants without ROP and performed logistic regression on the subset of infants who were 27 to 33 weeks' gestational age to determine characteristics associated with the absence of ROP during all in-hospital examinations. Main Outcomes and Measures: The main measure was the absence of ROP prior to hospital discharge; the main outcome was treatment for ROP. Results: A total of 1257 infants born at 22 to 35 weeks' gestation (median [interquartile range (IQR)], 26 [25-28] weeks) with birth weights less than 1251 g (median [IQR], 860 [690-1040] g) underwent 4113 ROP examinations between 31 and 47 weeks' postmenstrual age. Overall, 1153 examinations (38%) showed no ROP, and 456 infants (36%) did not have ROP prior to study center discharge or study end point. Among infants without ROP during examinations at 32 and 33 weeks' postmenstrual age, 16 (9.4%) and 14 (5.3%) subsequently underwent ROP treatment, respectively. At hospital discharge, there was no ROP in 59% of infants of 27 to 33 weeks' gestational age, compared with 15% of those who were less than 27 weeks' gestational age (difference, 44% [95% CI, 38.5%-48.1%]; P ≤ .001). With more than 85% follow-up among infants without ROP by 37 weeks' postmenstrual age, none (95% CI, 0%-0.98%) were treated for ROP. In multivariate analysis of infants born at 27 to 33 weeks' gestation, larger birth weight (OR, 4.1 [95% CI, 1.6-10.3]) and higher gestational age (OR, 4.0 [95% CI, 1.5-10.8]) were significantly associated with absence of ROP. Conclusions and Relevance: These findings suggest that, for infants of 27 weeks' gestational age or greater and birth weights larger than 750 g, if no ROP has been detected by discharge at near-term postmenstrual age, then further ROP surveillance has limited value. Studies of all infants at risk are needed to develop more specific, objective criteria for termination of ROP surveillance and focus resources on infants at higher risk of ROP. Trial Registration: ClinicalTrials.gov Identifier: NCT01264276.

Single grading vs double grading with adjudication in the telemedicine approaches to evaluating acute-phase retinopathy of prematurity (e-ROP) study.

PURPOSE: To evaluate the sensitivity and specificity of single, independent, nonphysician trained reader (TR) gradings in the Telemedicine Approaches to Evaluating Acute-phase Retinopathy of Prematurity (e-ROP) study. METHODS: Secondary analyses of image grading results from 1,235 infants of birth weights <1251 g. Two of three TRs independently graded image sets; discrepancies were adjudicated by the reading center director (an ophthalmologist) to reach final grading. Sensitivity and specificity of each TR grading and final grading was calculated by comparing gradings to clinical examination results. RESULTS: Of 7,808 double graded image sets, TR1 graded 5,165; TR2, 3,787; and TR3, 6,664. Compared to final grading for referral warranted retinopathy of prematurity (RW-ROP), two TRs had relatively lower sensitivity (TR1, 75% vs 79% [P = 0.03]; TR2, 73% vs 77% [P = 0.02]) and specificity (TR1, 80% vs 83% [P < 0.001]; TR2, 82% vs 83% [P = 0.09]). TR3 had similar sensitivity (83% vs 83% [P = 0.78]) and specificity (83% vs 84% [P = 0.02]). Compared to final grading, TR1 had lower sensitivity for zone I ROP (47% vs 56% [P = 0.04]) and stage ≥3 ROP (71% vs 77% [P = 0.002]); TR2 had lower sensitivity for stage ≥3 ROP (69% vs 77% [P < 0.001]) and lower specificity for all three components (P < 0.001); TR3 had lower sensitivity for detecting plus disease (23% vs 35% [P < 0.001]) and similar sensitivity for zone I ROP and stage ≥3 ROP. CONCLUSIONS: There is a small but significant decrease in the sensitivity and specificity for RW-ROP when single-reader grading is compared to double adjudicated grading.

Intereye Agreement of Retinopathy of Prematurity from Image Evaluation in the Telemedicine Approaches to Evaluating of Acute-Phase ROP (e-ROP) Study.

PURPOSE: To determine the symmetry on retinal image grading of fellow eyes for retinopathy of prematurity (ROP) features (stage, zone and plus disease) and severity, to provide the basis for the within subject comparison for ROP trials. DESIGN: Secondary analyses of data from the Telemedicine Approaches to Evaluating of Acute-Phase ROP (e-ROP) Study. SUBJECTS: Infants with birth weight less than 1251g. METHODS: Infants underwent serial retinal imaging sessions in both eyes by certified imagers starting at 32-weeks postmenstrual age (PMA). Two trained non-physician readers graded each eye independently for ROP features in a 5 retinal-image set from each session. Discrepancies were adjudicated by a reading center supervisor. Readers were masked to all eye examination results, previous gradings of both eyes, current grading of the fellow eye, and demographic data. MAIN OUTCOME MEASURES: The inter-eye agreement assessed using percent exact agreement and weighted kappa (Kw ) for stage, zone, plus, referral-warranted ROP (RW-ROP, defined as presence of stage 3 or above, plus disease, or zone I ROP), and severity of ROP. RESULTS: Among 3918 image sessions in 1235 infants, the percent agreement (Kw ) between paired eyes was 75.3% (0.65) for stage of ROP, 82.3% (0.68) for zone of ROP, 78.7% (0.51) for plus disease, 84.7% (0.56) for RW-ROP, and 72.7% (0.63) for severity of ROP. Similar inter-eye agreements were found when considering ROP features at the first image session, at the last image session, at any image session. Based on image evaluations from all sessions, 412 (33.4%) infants had ROP stage 3 or above, 148 (12.0%) had zone I ROP, 70 (5.7%) had plus disease, and 419 (33.9%) had RW-ROP in one or both eyes; symmetrical findings were present in 71.4% for ROP stage 3 or above, 56.8% for zone I ROP, 50.0% for plus disease, and 73.7% for RW-ROP. CONCLUSIONS: Masked image evaluations by trained readers showed good inter-eye agreement in ROP characteristics, consistent with the high inter-eye agreement in ROP from clinical examinations by ophthalmologists in other studies. These data confirm that acute ROP is typically symmetrical and supports within subject comparison in ROP trials.

Detection of Potentially Severe Retinopathy of Prematurity by Remote Image Grading.

Importance: Telemedicine in retinopathy of prematurity (ROP) has the potential for delivering timely care to premature infants at risk for serious ROP. Objective: To describe the characteristics of eyes at risk for ROP to provide insights into what types of ROP are most easily detected early by image grading. Design, Setting, and Participants: Secondary analysis of eyes with referral-warranted (RW) ROP (stage 3 ROP, zone I ROP, plus disease) on diagnostic examination from the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) study was conducted from May 1, 2011, to October 31, 2013, in 1257 premature infants with birth weights less than 1251 g in 13 neonatal units in North America. Data analysis was performed between February 1, 2016, and June 5, 2017. Interventions: Serial imaging sessions with concurrent diagnostic examinations for ROP. Main Outcomes and Measures: Time of detecting RW-ROP on image evaluation compared with clinical examination. Results: In the e-ROP study, 246 infants (492 eyes) were included in the analysis; 138 (56.1%) were male. A total of 447 eyes had RW-ROP on diagnostic examination. Image grading in 123 infants (mean [SD] gestational age, 24.8 [1.4] weeks) detected RW-ROP earlier than diagnostic examination (early) in 191 (42.7%) eyes by about 15 days and detected RW-ROP in 123 infants (mean [SD] gestational age, 24.6 [1.5] weeks) at the same time (same) in 200 (44.7%) eyes. Most of the early eyes (153 [80.1%]) interpreted as being RW-ROP positive on imaging evaluation agreed with examination findings when the examination subsequently documented RW-ROP. At the sessions in which RW-ROP was first found by examination, stage 3 or more in 123 infants (mean [SD] gestational age, 24.8 [1.4] weeks) ROP was noted earlier on image evaluation in 151 of 191 early eyes (79.1%) and in 172 of 200 of same eyes (86.0%) (P = .08); the presence of zone I ROP was detected in 57 of 191 (29.8%) early eyes vs 64 of 200 (32.0%) same eyes (P = .90); and plus disease was noted in 30 of 191 (15.7%) early eyes and 45 of 200 (22.5%) same eyes (P = .08). Conclusions and Relevance: In both early and same eyes, zone I and/or stage 3 ROP determined a significant proportion of RW-ROP; plus disease played a relatively minor role. In most early RW-ROP eyes, the findings were consistent with clinical examination and/or image grading at the next session. Because ROP telemedicine is used more widely, development of standard approaches and protocols is essential.

Comparison of strategies for grading retinal images of premature infants for referral warranted retinopathy of prematurity.

PURPOSE: To determine the accuracy of identifying referral-warranted retinopathy of prematurity (RW-ROP, defined as any zone I ROP, stage 3 or worse, or plus disease) from retinal image sets using three grading protocols: a single optic disk-centered image, a set of 3 horizontal images, and a 5-image set. METHODS: In this secondary analysis of images from the e-ROP study, a weighted sample of 250 image sets from 250 infants (125 with RW-ROP and 125 without RW-ROP) was randomly selected. The sensitivities and specificities for detecting RW-ROP and its components from a single disk center image, along with nasal and temporal retinal images, were calculated and compared with the e-ROP grading of RW-ROP of all 5 retinal images (disk center and nasal, temporal, superior, and inferior retinal images). RESULTS: RW-ROP was identified with a sensitivity of 11.2% (95% CI, 6.79%-17.9%) using a single disk center image, with a sensitivity of 70.4% (95% CI, 61.9%-77.9%) using 3 horizontal images, and a statistically higher sensitivity of 82.4% (95% CI, 75.0%-89.0%) using all 5 images (P = 0.002). The specificities were 100%, 86.4%, and 90.4%, respectively. For grading using 3 horizontal images, sensitivity was 14.3% for plus disease, 25% for zone I ROP, and 71.2% for stage 3 or worse compared to 40.8%, 50%, and 79.8% for grading using 5-image sets, respectively. CONCLUSIONS: Both a single, disk-centered, posterior pole image and 3 horizontal images were less effective than a 5-image set in determining the presence of RW-ROP on qualitative grading by trained readers.

A Tiered Approach to Retinopathy of Prematurity Screening (TARP) Using a Weight Gain Predictive Model and a Telemedicine System.

IMPORTANCE: The Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study telemedicine system of remote fundus image grading and The Children's Hospital of Philadelphia Retinopathy of Prematurity (CHOP-ROP) postnatal weight gain predictive model are 2 approaches for improving ROP screening efficiency. Current screening has low specificity for severe ROP. OBJECTIVE: To describe a tiered approach to ROP screening (TARP) for identifying children who develop severe ROP using telemedicine and a predictive model synergistically. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a post hoc analysis of a cohort in the e-ROP Study (a multicenter prospective telemedicine study) and the Postnatal Growth and Retinopathy of Prematurity (G-ROP) Study (a multicenter retrospective cohort study). The setting was neonatal intensive care units at The Children's Hospital of Philadelphia and the Hospital of the University of Pennsylvania. Participants in the e-ROP Study were premature infants with a birth weight less than 1251 g and a known ROP outcome enrolled between May 25, 2011, and October 31, 2013. The G-ROP Study enrolled all infants undergoing ROP examinations with a known ROP outcome who were born between January 1, 2006, and December 31, 2011. MAIN OUTCOMES AND MEASURES: The mean outcomes were the sensitivity for type 1 ROP, reductions in infants requiring imaging or examinations, numbers of imaging sessions and examinations, and total clinical encounters (imaging sessions and examinations combined). The following 4 screening approaches were evaluated: ROUTINE (only diagnostic examinations by an ophthalmologist), CHOP-ROP (birth weight and gestational age, with weekly weight gain initiating examinations when the risk cut point is surpassed), e-ROP IMAGING (trained reader grading of type 1 or 2 ROP initiates diagnostic examinations), and TARP (CHOP-ROP alarm initiates imaging, and imaging finding of severe ROP initiates diagnostic examinations). RESULTS: A total of 242 infants were included in the study, with a median birth weight of 858 g (range, 690-1035 g). The median gestational age was 27 weeks (range, 25-29 weeks). Fifty-one percent (124 of 242) were female, and 49% (118 of 242) were male. The race/ethnicity was 27.3% (66 of 242) white, 56.2% (136 of 242) black, 2.1% (5 of 242) Native American, 1.7% (4 of 242) Asian, and 12.8% (31 of 242) other. The sensitivity for detecting type 1 ROP (32 infants) was 100% (95% CI, 89.3%-100%) with each approach. With ROUTINE, 242 infants had 877 examinations; with CHOP-ROP, 184 infants had 730 examinations; with e-ROP IMAGING, 242 infants had 532 imaging sessions, and 94 infants had 345 examinations (877 patient encounters); and with TARP, 182 infants had 412 imaging sessions, and 87 infants had 322 examinations (734 patient encounters). CONCLUSIONS AND RELEVANCE: The tiered approach to ROP screening was associated with a reduced number of examinations and imaging sessions compared with the other approaches. Applying a postnatal growth model and telemedicine system in a tiered approach may reduce the number of clinical ROP interventions more than either approach alone.

Impact of number and quality of retinal images in a telemedicine screening program for ROP: results from the e-ROP study.

BACKGROUND: Telemedicine for the detection of retinopathy of prematurity (ROP) is becoming increasingly common; however, obtaining the required multiple retinal images from an infant can be challenging. This secondary analysis from the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) study evaluated the detection of referral-warranted ROP (RW-ROP) by trained readers when a full set of 5 retinal images could not be obtained. METHODS: A total of 7,905 image sets from 1,257 infants in the study were evaluated. Retinal location of images and image quality were recorded. Sensitivity and specificity of RW-ROP detection by trained readers were calculated by comparing findings in incomplete image sets to the findings on standard eye examination. RESULTS: The majority of image sets contained all 5 retinal images (92.8%). The disk center view was the image most likely to be present and to be of acceptable image quality (96.8%). The nasal retina was the most difficult to obtain with acceptable image quality (83.4%). Sensitivity of detection of RW-ROP was 82.1% when 5 retinal images of acceptable quality were submitted for grading, 67.2% when 4 acceptable images were submitted, and 66.7% for 3 or fewer acceptable images (P = 0.02), with corresponding specificity of 82.2%, 89.0%, and 81.7% respectively (P < 0.0001). When images of any quality were evaluated, sensitivity was not increased (P = 0.74). CONCLUSIONS: The likelihood of detecting RW-ROP by telemedicine screening is decreased when a full set of retinal images is not obtained.

Timely implementation of a retinopathy of prematurity telemedicine system.

PURPOSE: To examine the feasibility of a retinopathy of prematurity (ROP) telemedicine evaluation system of providing timely feedback to a neonatal intensive care unit (NICU) with at-risk premature infants. METHODS: This was a prospective observational study of premature infants with birth weights of <1251 g in five NICUs in the United States. Infants scheduled for clinically indicated ROP evaluations underwent indirect ophthalmoscopic examinations and digital imaging on the same day. Imaging was performed by nonphysician retinal imagers. Times required were determined from obtaining digital images of both eyes to submission via web-based system to a secure server for grading by trained readers at a central reading center to sending back grading results to the clinical center. RESULTS: A total of 1,642 image sets of eyes of 292 infants were obtained, from 823 imaging sessions. The mean turnaround time from submission of image sets of both eyes to return of the grading results to the clinical center was 10.1 ± 11.3 hours (standard deviation), with a median of 12.0 hours (1st quartile, 0.9 hours; 3rd quartile, 16 hours). Overall, 95.5% of gradings (95% CI, 93.9%-96.7%) were returned within 24 hours. Subgroup analyses found, for image sets submitted to the reading center before 2 p.m. Eastern Standard Time, median time to report was 1.7 hours (1st quartile, 0.7 hours; 3rd quartile, 15.5 hours) compared with those submitted after 2pm (median, 14.1 hours; 1st quartile, 11.2, hours; 3rd quartile, 16.3 hours). CONCLUSIONS: An ROP telemedicine approach can provide timely feedback to the NICU regarding the detection of potentially serious ROP and thus referral to an ophthalmologist for examination and consideration of treatment.

Risk Score for Predicting Treatment-Requiring Retinopathy of Prematurity (ROP) in the Telemedicine Approaches to Evaluating Acute-Phase ROP Study.

PURPOSE: To develop a risk score for predicting treatment-requiring retinopathy of prematurity (TR-ROP) in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) study. DESIGN: Second analyses of an observational cohort study. PARTICIPANTS: Infants with birth weight (BW) <1251 g who had ≥1 imaging session by 34 weeks of postmenstrual age (PMA) and ≥1 subsequent retinopathy of prematurity (ROP) examination for determining TR-ROP by study-certified ophthalmologists. METHODS: Nonphysician trained readers evaluated wide-field retinal image sets for characteristics of ROP, pre-plus/plus disease, and retinal hemorrhage. Risk score points for predicting TR-ROP were derived from the regression coefficients of significant predictors in a multivariate logistic regression model. MAIN OUTCOME MEASURES: TR-ROP. RESULTS: Eighty-five of 771 infants (11.0%) developed TR-ROP. In a multivariate model, significant predictors for TR-ROP were gestational age (GA) (odds ratio [OR], 5.7; 95% confidence interval [CI], 1.7-18.9 for ≤25 vs. ≥28 weeks), need for respiratory support (OR, 7.0; 95% CI, 1.3-37.1 for high-frequency oscillatory ventilation vs. no respiratory support), slow weight gain (OR, 2.4; 95% CI, 1.2-4.6 for weight gain ≤12 g/day vs. >15 g/day), and image findings at the first image session including number of quadrants with pre-plus (OR, 3.8; 95% CI, 1.5-9.7 for 4 pre-plus quadrants vs. no pre-plus), stage and zone of ROP (OR, 4.7; 95% CI, 2.1-11.8 for stage 1-2 zone I, OR, 5.9; 95% CI, 2.1-16.6 for stage 3 zone I vs. no ROP), and presence of blot hemorrhage (OR, 3.1; 95% CI, 1.4-6.7). Image findings predicted TR-ROP better than GA (area under receiver operating characteristic curve [AUC] = 0.82 vs. 0.75, P = 0.03). The risk of TR-ROP steadily increased with higher risk score and predicted TR-ROP well (AUC = 0.88; 95% CI, 0.85-0.92). Risk score ≥3 points for predicting TR-ROP had a sensitivity of 98.8%, specificity of 40.1%, and positive and negative predictive values of 17.0% and 99.6%, respectively. CONCLUSIONS: Image characteristics at 34 PMA weeks or earlier independently predict TR-ROP. If externally validated in other infants, risk score, calculated from image findings, GA, weight gain, and respiratory support, enables early identification of infants in need of increased surveillance for TR-ROP.

Training retinal imagers for retinopathy of prematurity (ROP) screening.

PURPOSE: To report the training/certification process of nonphysician imagers, image quality, and factors that affected image quality in the National Eye Institute sponsored multicentered e-ROP study. METHODS: Nonphysician imagers underwent rigorous training and certification in obtaining retinal images, with attention to clarity, focus, and optic disk placement. Image readers measured pupil size in pupil image and graded posterior pole, temporal, nasal, superior, and inferior retinal images and classified them as good, adequate, poor, or missing. Good and adequate images were deemed acceptable. RESULTS: In 4,003 image sessions of 1,257 infants, 3,453 (86.8%) were complete. Of 39,550 retinal images, 91.7% had acceptable quality, 5.6% poor, and 2.7% were missing. Inadequate pupil dilation negatively affected acceptable image quality: 54% acceptable images for pupil <5 mm versus 93% for >6 mm (P < 0.0001). When ventilatory equipment obstructed access to imaged infant, the percent of acceptable image quality decreased: 94% for no support versus 66.6% for oscillatory ventilation (P < 0.0001). Acceptable image quality rates improved from 87% to 90% (P = 0.03) from first 6 months to last 6 months at low patient volume centers, while high patient volume centers remained stable at 95%. CONCLUSIONS: Nonphysicians successfully obtained acceptable quality images for ROP evaluation. Skills improved with experience. Image quality was negatively affected by inadequate pupil dilation and the presence of obstructive ventilatory equipment.

A Comparison of Strategies for Retinopathy of Prematurity Detection.

BACKGROUND AND OBJECTIVES: Delayed detection of type 1 retinopathy of prematurity (ROP) can lead to permanent visual impairment. Providing ROP examinations is challenging because of the limited ophthalmology workforce. This study compares digital imaging-based ROP detection strategies versus serial ROP examinations. METHODS: We conducted an individual-level microsimulation study of a hypothetical cohort of 650 infants with gestational age from 23 to 30 weeks. Infants were evaluated by using strategies based on indirect ophthalmoscopy or digital imaging beginning at 32 weeks' postmenstrual age (PMA) and continuing to discharge, transfer, or 40 weeks' PMA. ROP status and the accuracy of digital imaging were based on the e-ROP (Telemedicine Approaches to Evaluating Acute-Phase ROP) study, which enrolled high-risk infants. RESULTS: Within the hypothetical NICU, the strategy of ROP examinations identified an average of 45.8 cases of type 1 ROP by discharge, transfer, or 40 weeks' PMA, and another 1.9 cases were included in the group of infants recommended to have later follow-up. Digital imaging with an ROP examination at discharge identified all 47.7 cases of type 1 ROP. On average, the ROP examination-only strategy required 1745.7 ROP examinations, whereas digital imaging with a discharge examination required 1065.5 ROP examinations and 1786.2 digital imaging sessions. CONCLUSIONS: Although digital imaging decreased the number of ROP examinations per infant, there was an increase in the total number of interventions (ie, ROP examinations and imaging sessions). Providing an ROP examination at the time of NICU discharge can significantly reduce the number of infants who require follow-up.

Safety of Retinopathy of Prematurity Examination and Imaging in Premature Infants.

OBJECTIVES: To describe adverse events (AEs) and noteworthy clinical or ocular findings associated with retinopathy of prematurity (ROP) evaluation procedures. STUDY DESIGN: Descriptive analysis of predefined AEs and noteworthy findings reported in a prospective observational cohort study of infants <1251 g birth weight who had ROP study visits consisting of both binocular indirect ophthalmoscopy (BIO) and digital retinal imaging. We compared infant characteristics during ROP visits with and without AEs. We compared respiratory support, nutrition, and number of apnea, bradycardia, or hypoxia events 12 hours before and after ROP visits. RESULTS: A total of 1257 infants, mean birth weight 802 g, had 4263 BIO and 4048 imaging sessions (total 8311 procedures). No serious AEs were related to ROP visits. Sixty-five AEs were reported among 61 infants for an AE rate of 4.9% infants (61/1257) or 0.8% total procedures (65/8311 BIO + imaging). Most AEs were due to apnea, bradycardia, and/or hypoxia (68%), tachycardia (16%), or emesis (8%). At ROP visit, infants with AEs, compared with those without, were more likely to be on mechanical ventilation (26% vs 12%, P = .04) even after adjustment for weight and postmenstrual age. Noteworthy clinical findings were reported during 8% BIO and 15% imaging examinations. Respiratory and nutrition support were not significantly different before and after ROP evaluations. CONCLUSIONS: Retinal imaging by nonphysicians combined with BIO was safe. Noteworthy clinical findings occurred during both procedures. Ventilator support was a risk factor for AEs. Monitoring rates of AEs and noteworthy findings are important to the safe implementation of ROP imaging protocols. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01264276.

Retinopathy of prematurity risk prediction for infants with birth weight less than 1251 grams.

OBJECTIVE: To predict retinopathy of prematurity (ROP) exam findings among infants with birth weight <1251 g from 32-40 weeks postmenstrual age (PMA). STUDY DESIGN: Secondary analysis of 3714 eye exams from 1239 infants. RESULTS: The likelihood of developing type 1 ROP by 40 weeks PMA varied by gestational age (GA) (P < .001), from 33% for ≤25 weeks, 10% for 26 or 27 weeks, 4% for 28 or 29 weeks, and none for ≥30 weeks. By 40 weeks PMA, 51% with GA ≤27 weeks still needed subsequent exams. Previous exam findings, GA, and PMA were predictive of the development of type 1 ROP (area under the curve, 0.78) or mature retina (area under the curve, 0.85). CONCLUSIONS: This analysis provides the opportunity for development of an ROP approach to estimate resource needs in the neonatal intensive care unit and to facilitate communication with families when planning discharge or transfer.

Predictors for the development of referral-warranted retinopathy of prematurity in the telemedicine approaches to evaluating acute-phase retinopathy of prematurity (e-ROP) study.

IMPORTANCE: Detection of treatment-requiring retinopathy of prematurity (ROP) involves serial eye examinations. An ROP prediction model using predictive factors could identify high-risk infants and reduce required eye examinations. OBJECTIVE: To determine predictive factors for the development of referral-warranted (RW) ROP. DESIGN, SETTING, AND PARTICIPANTS: This multicenter observational cohort study included secondary analysis of data from the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity Study. Infants included in the study had a birth weight (BW) of less than 1251 g. EXPOSURES: Serial ROP examinations of premature infants who had 2 or more ROP examinations. MAIN OUTCOMES AND MEASURES: Incidence of RW-ROP (defined as the presence of plus disease, zone I ROP, or ROP stage 3 or greater in either eye) and associations with predictive factors. RESULTS: Among 979 infants without RW-ROP at first study-related eye examination (median postmenstrual age, 33 weeks; range, 29-40 weeks) who underwent at least 2 eye examinations, 149 (15.2%) developed RW-ROP. In a multivariate model, significant predictors for RW-ROP were male sex (odds ratio [OR], 1.80; 95% CI, 1.13-2.86 vs female), nonblack race (OR, 2.76; 95% CI, 1.50-5.08 for white vs black race and OR, 4.81; 95% CI, 2.19-10.6 for other vs black race), low BW (OR, 5.16; 95% CI, 1.12-7.20 for ≤500 g vs >1100 g), younger gestational age (OR, 9.79; 95% CI, 3.49-27.5 for ≤24 weeks vs ≥28 weeks), number of quadrants with preplus disease (OR, 7.12; 95% CI, 2.53-20.1 for 1-2 quadrants and OR, 18.4; 95% CI, 4.28-79.4 for 3-4 quadrants vs no preplus disease), stage 2 ROP (OR, 4.13; 95% CI, 2.13-8.00 vs no ROP), the presence of retinal hemorrhage (OR, 4.36; 95% CI, 1.57-12.1 vs absence), the need for respiratory support (OR, 4.99; 95% CI, 1.89-13.2 for the need for controlled mechanical ventilator; OR, 11.0; 95% CI, 2.26-53.8 for the need for high-frequency oscillatory ventilation vs no respiratory support), and slow weight gain (OR, 2.44; 95% CI, 1.22-4.89 for weight gain ≤12 g/d vs >18 g/d). These characteristics predicted the development of RW-ROP significantly better than BW and gestational age (area under receiver operating characteristic curve, 0.88 vs 0.78; P < .001). CONCLUSIONS AND RELEVANCE: When controlling for very low BW and prematurity, the presence of preplus disease, stage 2 ROP, retinal hemorrhage, and the need for ventilation at time of first study-related eye examination were strong independent predictors for RW-ROP. These predictors may help identify infants in need of timely eye examinations.

Late recurrence of retinopathy of prematurity after treatment with both intravitreal bevacizumab and laser.

An infant of 36 weeks' postmenstrual age (PMA) and 25 weeks' gestation received bilateral intravitreal bevacizumab injections for type 1 retinopathy of prematurity. He underwent laser photocoagulation in both eyes 5 days later, confluent except for 1 clock hour obscured by hemorrhage in the left eye. Despite initial regression, neovascularization in both vascularized and lasered retina with plus disease recurred, requiring repeat laser bilaterally at 51 weeks' PMA and vitrectomy in the left eye at 54 weeks' PMA. Whereas late recurrence is thought to occur rarely after laser treatment, infants who have received both bevacizumab injections and laser may still require long-term surveillance for recurrence. In this case, fundus photography proved valuable for appreciating recurrent plus disease because the initial treatments had resulted in marked retinal vessel attenuation.

Validity of a telemedicine system for the evaluation of acute-phase retinopathy of prematurity.

IMPORTANCE: The present strategy to identify infants needing treatment for retinopathy of prematurity (ROP) requires repeated examinations of at-risk infants by physicians. However, less than 10% ultimately require treatment. Retinal imaging by nonphysicians with remote image interpretation by nonphysicians may provide a more efficient strategy. OBJECTIVE: To evaluate the validity of a telemedicine system to identify infants who have sufficiently severe ROP to require evaluation by an ophthalmologist. DESIGN, SETTING, AND PARTICIPANTS: An observational study of premature infants starting at 32 weeks' postmenstrual age was conducted. This study involved 1257 infants with birth weight less than 1251 g in neonatal intensive care units in 13 North American centers enrolled from May 25, 2011, through October 31, 2013. INTERVENTIONS: Infants underwent regularly scheduled diagnostic examinations by an ophthalmologist and digital imaging by nonphysician staff using a wide-field digital camera. Ophthalmologists documented findings consistent with referral-warranted (RW) ROP (ie, zone I ROP, stage 3 ROP or worse, or plus disease). A standard 6-image set per eye was sent to a central server and graded by 2 trained, masked, nonphysician readers. A reading supervisor adjudicated disagreements. MAIN OUTCOMES AND MEASURES: The validity of grading retinal image sets was based on the sensitivity and specificity for detecting RW-ROP compared with the criterion standard diagnostic examination. RESULTS: A total of 1257 infants (mean birth weight, 864 g; mean gestational age, 27 weeks) underwent a median of 3 sessions of examinations and imaging. Diagnostic examination identified characteristics of RW-ROP in 18.2% of eyes (19.4% of infants). Remote grading of images of an eye at a single session had sensitivity of 81.9% (95% CI, 77.4-85.6) and specificity of 90.1% (95% CI, 87.9-91.8). When both eyes were considered for the presence of RW-ROP, as would routinely be done in a screening, the sensitivity was 90.0% (95% CI, 85.4-93.5), with specificity of 87.0% (95% CI, 84.0-89.5), negative predictive value of 97.3%, and positive predictive value of 62.5% at the observed RW-ROP rate of 19.4%. CONCLUSIONS AND RELEVANCE: When compared with the criterion standard diagnostic examination, these results provide strong support for the validity of remote evaluation by trained nonphysician readers of digital retinal images taken by trained nonphysician imagers from infants at risk for RW-ROP. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01264276.

Participant- and study-related characteristics predicting treatment completion and study retention in an adolescent smoking cessation trial.

PURPOSE: To determine which factors predict smoking cessation treatment completion and retention among adolescents. METHODS: In a multisite, randomized, controlled trial, the efficacy of motivational interviewing was compared with structured brief advice for smoking cessation and reduction in adolescents (n = 355) aged 14-18 years (55% female, 45% black, 12% Hispanic). Treatment spanned 12 weeks, with follow-up assessments at 24 weeks. Treatment completion was defined as completion of all five counseling sessions. Study retention was defined as completing the 24-week assessment. Participant and study variables served as predictors of treatment completion and retention. RESULTS: In all, 79% of participants completed all five counseling sessions and the same percent completed the 24-week assessment. Black race, precontemplation stage to cut back, and shorter length of time between the baseline assessment and the first counseling session were significantly associated with treatment completion. For every 7.5-day delay in starting treatment after the baseline visit, there was a 50% decrease in the odds of completing all five treatment sessions. Retention at 24 weeks was predicted by black race, younger age, greater maternal education, expectations of graduating college, and structured brief advice intervention. CONCLUSIONS: High rates of treatment completion and study retention can be achieved in a multisession, behavioral intervention for adolescent smoking cessation. Findings suggest that treatment should begin soon after the intake session to maximize treatment completion. Enhanced efforts to retain older adolescents and youth with lower academic goals and lower family income will be important in future studies.