The Male to Female Ratio in Treatment-Warranted Retinopathy of Prematurity: A Systematic Review and Meta-analysis.

Importance: Literature and anecdotal evidence suggest a relationship between male sex and retinopathy of prematurity (ROP). It is not known whether a difference, if present, is sex-related pathophysiologic predisposition or sex difference in meeting ROP screening criteria. Objective: To evaluate the association of sex with the development of treatment-warranted ROP. Data Sources: PubMed, Embase, and Web of Science databases were searched from 2000 to 2022. The search strategy used keywords including retinopathy of prematurity or ROP or retrolental fibroplasia and treatment or anti-VEGF or bevacizumab or ranibizumab or aflibercept or conbercept or laser or cryotherapy and gender or sex or male or female and medical subject headings terms. Study Selection: All studies reporting on treatment with anti-vascular endothelial growth factor, laser photocoagulation, and/or cryotherapy for ROP were identified. Studies reporting sex distribution in the treatment group were included in the meta-analysis. Exclusion criteria included case reports, case series of fewer than 10 treated patients, systematic reviews, conference abstracts, letters to the editor, animal studies, and non-English records. Data Extraction and Synthesis: Two reviewers independently screened and extracted the data following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The proportions of treated male and female infants were combined using random-effects meta-analysis. Main Outcomes and Measures: Numbers and percentages of male and female infants treated for ROP. Results: Of 11 368 identified studies, 316 met inclusion criteria, yielding a total of 31 026 treated patients. A higher percentage of male infants were treated for ROP (55% [95% CI, 0.54%-0.55%]), with low heterogeneity between studies (I2 = 34%; P < .001). Thirty-eight studies reported sex distribution in the screened population (170 053 patients; 92 612 [53%] male vs 77 441 [47%] female). There was no significant difference in the odds of receiving treatment between screened male and female infants (pooled odds ratio, 1.04 [95% CI, 0.91-1.18]; P = .67). Conclusions and Relevance: More male infants are treated for ROP than female infants. This could be due to a known relative pathophysiological fragility of preterm male infants in addition to a difference in ROP screening rates, with more male infants meeting the criteria than female infants. These findings have implications for future studies and may prompt more careful clinical monitoring of male neonates.

Longitudinal Examination of Fellow-Eye Vascular Anomalies in Coats' Disease With Widefield Fluorescein Angiography: A Multicenter Study.

BACKGROUND AND OBJECTIVE: Retinovascular anomalies in the fellow eyes of patients with Coats' disease have been described, but the clinical significance is unknown, as well as whether these lesions progress over time. PATIENTS AND METHODS: This is an international, multicenter, retrospective, observational cohort study of fellow-eye abnormalities on widefield fluorescein angiography in patients with Coats' disease. RESULTS: Three hundred fifty eyes of 175 patients with Coats' disease were analyzed. A total of 33 patients (18.8%) demonstrated abnormal fellow-eye findings: 14 (42.4%) telangiectasias, 18 (54.5%) aneurysms, six (18.2%) segmental non-perfusion, six (18.2%) leakage, and two (6.0%) vascular tortuosity. All eyes were asymptomatic, and none of the lesions progressed over time. There was no association between fellow-eye findings with severity of Coats' disease (P = .16), patient age (P = .16), or presence of systemic vascular disease (P = .16). CONCLUSIONS: The vascular abnormalities in fellow eyes of patients with Coats' disease did not progress over time. Observation is a reasonable initial management strategy. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:221-227.].

Experimental Evidence Behind Clinical Trial Outcomes in Retinopathy of Prematurity.

Treatment of severe retinopathy of prematurity (ROP) has evolved over the last decade. This article reviews recent clinical trials and experimental evidence that supports clinical outcomes and observations, including the efficacy of anti-vascular endothelial growth factor (VEGF) agents in reducing the vascular activity of severe ROP, and the mechanisms behind recurrent stage 3 ROP and plus disease in some infants treated with anti-VEGF agents. Also discussed will be current imaging modalities that link experimental models of ROP with longitudinal human studies and which provide exciting future opportunities to enhance the understanding of pathophysiology of ROP and improve treatments. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:228-234.].

A Dosing Study of Bevacizumab for Retinopathy of Prematurity: Late Recurrences and Additional Treatments.

PURPOSE: Intravitreal bevacizumab is increasingly used to treat severe retinopathy of prematurity (ROP), but it enters the bloodstream, and there is concern that it may alter development of other organs. Previously we reported short-term outcomes of 61 infants enrolled in a dose de-escalation study, and we report the late recurrences and additional treatments. DESIGN: Masked, multicenter, dose de-escalation study. PARTICIPANTS: A total of 61 premature infants with type 1 ROP. METHODS: If type 1 ROP was bilateral at enrollment, then the study eye was randomly selected. In the study eye, bevacizumab intravitreal injections were given at de-escalating doses of 0.25 mg, 0.125 mg, 0.063 mg, or 0.031 mg; if needed, fellow eyes received 1 dose level higher: 0.625 mg, 0.25 mg, 0.125 mg, or 0.063 mg, respectively. After 4 weeks, additional treatment was at the discretion of the investigator. MAIN OUTCOME MEASURES: Early and late ROP recurrences, additional treatments, and structural outcomes after 6 months. RESULTS: Of 61 study eyes, 25 (41%; 95% confidence interval [CI], 29%-54%) received additional treatment: 3 (5%; 95% CI, 1%-14%) for early failure (within 4 weeks), 11 (18%; 95% CI, 9%-30%) for late recurrence of ROP (after 4 weeks), and 11 (18%; 95% CI, 9%-30%) for persistent avascular retina. Re-treatment for early failure or late recurrence occurred in 2 of 11 eyes (18%; 95% CI, 2%-52%) treated with 0.25 mg, 4 of 16 eyes (25%; 95% CI, 7%-52%) treated with 0.125 mg, 8 of 24 eyes (33%; 95% CI, 16%-55%) treated with 0.063 mg, and 0 (0%; 95% CI, 0%-31%) of 10 eyes treated with 0.031 mg. By 6 months corrected age, 56 of 61 study eyes had regression of ROP with normal posterior poles, 1 study eye had developed a Stage 5 retinal detachment, and 4 infants had died of preexisting medical conditions. CONCLUSIONS: Retinal structural outcomes are very good after low-dose bevacizumab treatment for ROP, although many eyes received additional treatment.

Erythropoietin Signaling Increases Choroidal Macrophages and Cytokine Expression, and Exacerbates Choroidal Neovascularization.

Erythropoietin (EPO) is recognized for neuroprotective and angiogenic effects and has been associated with aging and neovascular age-related macular degeneration (AMD). We hypothesized that systemic EPO facilitates the development of choroidal neovascularization (CNV). Wild type mice expressed murine EPOR (mWtEPOR) in RPE/choroids at baseline and had significantly increased serum EPO after laser treatment. To test the role of EPO signaling, we used human EPOR knock-in mice with the mWtEPOR gene replaced by either the human EPOR gene (hWtEPOR) or a mutated human EPOR gene (hMtEPOR) in a laser-induced choroidal neovascularization (LCNV) model. Loss-of-function hWtEPOR mice have reduced downstream activation, whereas gain-of-function hMtEPOR mice have increased EPOR signaling. Compared to littermate controls (mWtEPOR), hMtEPOR with increased EPOR signaling developed larger CNV lesions. At baseline, hMtEPOR mice had increased numbers of macrophages, greater expression of macrophage markers F4/80 and CD206, and following laser injury, had greater expression of cytokines CCL2, CXCL10, CCL22, IL-6, and IL-10 than mWtEPOR controls. These data support a hypothesis that injury from age- and AMD-related changes in the RPE/choroid leads to choroidal neovascularization through EPOR-mediated cytokine production.

Assessment of Lower Doses of Intravitreous Bevacizumab for Retinopathy of Prematurity: A Phase 1 Dosing Study.

Importance: Intravitreous bevacizumab (0.25 to 0.625 mg) is increasingly used to treat type 1 retinopathy of prematurity (ROP), but there remain concerns about systemic toxicity. A much lower dose may be effective while reducing systemic risk. Objective: To find a dose of intravitreous bevacizumab that was lower than previously used for severe ROP, was effective in this study, and could be tested in future larger studies. Design, Setting, and Participants: Between May 2015 and September 2016, 61 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, phase 1 dose de-escalation study. One eye of 10 to 14 infants received 0.25 mg of intravitreous bevacizumab. If successful, the dose was reduced for the next group of infants (to 0.125 mg, then 0.063 mg, and finally 0.031 mg). Diluted bevacizumab was delivered using 300 µL syringes with 5/16-inch, 30-gauge fixed needles. Interventions: Bevacizumab injections at 0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg. Main Outcomes and Measures: Success was defined as improvement in preinjection plus disease or zone I stage 3 ROP by 5 days after injection or sooner, and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks. Results: Fifty-eight of 61 enrolled infants had 4-week outcomes completed; mean birth weight was 709 g and mean gestational age was 24.9 weeks. Success was achieved in 11 of 11 eyes at 0.25 mg, 14 of 14 eyes at 0.125 mg, 21 of 24 eyes at 0.063 mg, and 9 of 9 eyes at 0.031 mg. Conclusions and Relevance: A dose of bevacizumab as low as 0.031 mg was effective in 9 of 9 eyes in this phase 1 study and warrants further investigation. Identifying a lower effective dose of bevacizumab may reduce the risk for neurodevelopmental disability or detrimental effects on other organs.

Advances in understanding and management of retinopathy of prematurity.

The understanding, diagnosis, and treatment of retinopathy of prematurity have changed in the 70 years since the original description of retrolental fibroplasia associated with high oxygenation. It is now recognized that retinopathy of prematurity differs in appearance worldwide and as ever smaller and younger premature infants survive. New methods are being evaluated to image the retina, diagnose severe retinopathy of prematurity, and determine windows of time for treatment to save eyes and improve visual and neural outcomes. New treatments to promote physiologic retinal vascular development, vascular repair, and inhibit vasoproliferation by regulating proteins involved in vascular endothelial growth factor, insulin-like growth factor, or erythropoietin signaling. Reducing excessive oxidative/nitrosative stress and understanding progenitor cells and neurovascular and glial vascular interactions are being studied.

Ophthalmologist-patient communication, self-efficacy, and glaucoma medication adherence.

OBJECTIVE: To examine the associations of provider-patient communication, glaucoma medication adherence self-efficacy, and outcome expectations with glaucoma medication adherence. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Two hundred seventy-nine patients with glaucoma who were newly prescribed or taking glaucoma medications were recruited at 6 ophthalmology clinics. METHODS: Patients' visits were video recorded and communication variables were coded using a detailed coding tool developed by the authors. Adherence was measured using Medication Event Monitoring Systems for 60 days after their visits. MAIN OUTCOME MEASURES: The following adherence variables were measured for the 60-day period after their visits: whether the patient took 80% or more of the prescribed doses, percentage of the correct number of prescribed doses taken each day, and percentage of the prescribed doses taken on time. RESULTS: Higher glaucoma medication adherence self-efficacy was associated positively with better adherence with all 3 measures. Black race was associated negatively with percentage of the correct number of doses taken each day (ß = -0.16; P < 0.05) and whether the patient took 80% or more of the prescribed doses (odds ratio, 0.37; 95% confidence interval, 0.16-0.86). Physician education about how to administer drops was associated positively with percentage of the correct number of doses taken each day (ß = 0.18; P < 0.01) and percentage of the prescribed doses taken on time (ß = 0.15; P < 0.05). CONCLUSIONS: These findings indicate that provider education about how to administer glaucoma drops and patient glaucoma medication adherence self-efficacy are associated positively with adherence.

Real-time, computer-assisted quantification of plus disease in retinopathy of prematurity at the bedside.

BACKGROUND AND OBJECTIVE: Plus disease is the primary indication for retinopathy of prematurity (ROP) treatment, but in borderline cases ophthalmologists may struggle to judge whether it is present. ROPtool is a semi-automated computer program that objectively assesses plus disease by measuring retinal vascular tortuosity and width. This study determined ROPtool's bedside diagnostic accuracy concurrent with ROP screening. PATIENTS AND METHODS: ROP screening examinations were recorded using Keeler video indirect ophthalmoscopy. A masked operator traced images in ROPtool at the bedside, comparing ROPtool's plus diagnosis to the examiner's clinical judgment. RESULTS: Four hundred sixty-four examinations (129 eyes of 65 infants) were performed. ROPtool's sensitivity, specificity, and area under the receiver operating characteristic curve for plus diagnosis was 71% (CI: 38%-100%), 93% (CI: 89%-98%) and 0.87, and for pre-plus or worse was 68% (CI: 51%-85%), 82% (CI: 77%-86%) and 0.81, respectively. CONCLUSION: ROPtool can provide a real-time second opinion of plus disease at the bedside. Image enhancement technologies may further improve ROPtool's diagnostic accuracy.

Provider use of collaborative goal setting with glaucoma patients.

PURPOSE: The purpose of this preliminary study was to describe the extent to which providers used collaborative goal setting and individualized assessment with patients who were newly prescribed glaucoma medications. METHODS: English-speaking glaucoma suspect patients from six ophthalmology clinics who were newly prescribed glaucoma medications had their medical visits videotaped and were interviewed after the visits. The videotapes were transcribed and coded to examine provider use of collaborative goal setting and individualized assessment. RESULTS: Fifty-one patients seeing 12 ophthalmologists participated. Providers gave patients glaucoma treatment options during 37% of the visits; only five providers gave patients treatment options Providers asked for patient treatment preferences in less than 20% of the visits; only two providers asked for patient treatment preferences. Providers were significantly more likely to ask African American patients for their preferences or ideas concerning treatment than non-African American patients (Pearson χ² = 4.1, p = 0.04). Providers were also significantly more likely to ask African American patients about their confidence in using glaucoma medication regularly than non-African American patients (Pearson χ² = 8.2, p = 0.004). Providers asked about patient views about glaucoma in less than 20% of the visits; five providers asked patients their views on glaucoma and its treatment. Providers were significantly more likely to ask African American patients about their views on glaucoma than non-African American patients (Pearson χ² = 5.62, p = 0.02). CONCLUSIONS: Eye care providers often did not use collaborative goal setting or conduct individualized assessments of patient views on glaucoma when prescribing treatment for the first time.

Baseline predictors of visual acuity and retinal thickness outcomes in patients with retinal vein occlusion: Standard Care Versus COrticosteroid for REtinal Vein Occlusion Study report 10.

OBJECTIVE: To investigate baseline factors associated with visual acuity and central retinal thickness outcomes in patients with macular edema secondary to retinal vein occlusion in the Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study. DESIGN: Two multicenter, randomized clinical trials: one evaluating participants with central retinal vein occlusion (CRVO) and one evaluating participants with branch retinal vein occlusion (BRVO). PARTICIPANTS: Participants with follow-up data of 1 year or more, including 238 with CRVO and 367 with BRVO. METHODS: Visual acuity was measured by the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) method, and central retinal thickness was measured by optical coherence tomography (OCT). Regression analysis related these outcomes to 20 baseline measures. Multiple P values were adjusted to control the false discovery rate. MAIN OUTCOME MEASURES: Outcome measures of visual acuity letter score included absolute change from baseline, a gain of ≥ 15 from baseline, and a loss of ≥ 15 from baseline. Outcome measures of center point thickness included absolute change from baseline, a measurement of ≤ 250 µm, and a measurement of ≥ 500 µm. Outcomes were assessed at 1 and 2 years. RESULTS: For CRVO and BRVO, younger age was associated with improved visual acuity and central retinal thickness outcomes. For CRVO, triamcinolone treatment and less severe anatomic abnormalities of the retina (center point thickness and areas of retinal hemorrhage, thickening, and fluorescein leakage) were predictive of better visual acuity outcomes. For BRVO, no history of coronary artery disease was predictive of improved visual acuity outcomes. For center point thickness outcomes, shorter duration of macular edema was associated with improvement in both disease entities. For CRVO, higher baseline visual acuity letter score was predictive of favorable OCT outcomes. For BRVO, lower baseline visual acuity letter score, presence of dense macular hemorrhage, and no prior grid photocoagulation were predictive of favorable OCT outcomes. CONCLUSIONS: Several factors were predictive of better visual acuity outcomes and more favorable OCT outcomes, including younger age and shorter duration of macular edema, respectively. These factors may assist clinicians in predicting disease course for patients with CRVO and BRVO.

Studies on the pathogenesis of avascular retina and neovascularization into the vitreous in peripheral severe retinopathy of prematurity (an american ophthalmological society thesis).

PURPOSE: To study vascular endothelial growth factor (VEGF) regulation in the development of intravitreous neovascularization and peripheral avascular retina in peripheral severe retinopathy of prematurity (ROP). METHODS: The rat 50/10 model of ROP mimics zone II, stage 3 severe ROP and recreates fluctuations in transcutaneous oxygen levels in preterm infants. On postnatal (p) day ages p0, p8, p11-p14, and p18, retinas from the model or room-air (RA) age-matched pups were analyzed for mRNA of VEGF splice variants and receptors using real-time polymerase chain reaction or VEGF protein using enzyme-linked immunosorbent assay. RESULTS: On p14, when retinas were only 70% vascularized in the model but fully vascularized in RA, VEGF164 expression was threefold greater in the model compared to RA. On p18, intravitreous neovascularization was associated with a 5-fold increase in VEGF164 mRNA in the model compared to RA. By analysis of variance, VEGF164 and VEGFR2 mRNAs were up-regulated in association with increasing developmental age (P<.0001 for both comparisons) or exposure to the model compared to RA (P<.0001 and P=.0247, respectively), whereas increasing developmental age was associated only with up-regulated VEGF120 (P=.0006), VEGF188 (P=.0256), and VEGFR1 (P<.0001) mRNAs. VEGF protein increased significantly in the model and on p14 and p18 compared to RA (P<.0001). CONCLUSIONS: The model mimics contemporary severe ROP in the United States unlike other models of oxygen-induced retinopathy. Compared to RA retinas, VEGF significantly increased in association with avascular retina and intravitreous neovascularization. A hypothesis is proposed that VEGF up-regulation plays a role in the development of both important features.

Reduction in endothelial tip cell filopodia corresponds to reduced intravitreous but not intraretinal vascularization in a model of ROP.

To determine the effect of a vascular endothelial growth factor receptor 2 tyrosine kinase (VEGFR2) inhibitor on intravitreous neovascularization (IVNV), endothelial tip cell filopodia, and intraretinal vascularization in a rat model of retinopathy of prematurity (ROP). Within 4h of birth, newborn Sprague-Dawley rat pups and their mothers were cycled between 50% and 10% oxygen daily until postnatal day (p)12. Pups were given intravitreous injections of VEGFR2 inhibitor, SU5416, or control (dimethyl sulfoxide, DMSO) and returned to oxygen cycling until p14, then placed into room air. Intravitreous neovascularization (IVNV), avascular/total retinal areas, and endothelial tip cell filopodial number and length were determined in lectin-labeled neurosensory retinal flat mounts. Cryosections or fresh tissue were analyzed for phospho-VEGFR1, phospho-VEGFR2, activated caspase-3, or phospho-beta3 integrin. Human umbilical venous (HUVECs) and human choroidal endothelial cells (ECs) were treated with VEGFR2 inhibitor to determine effect on VEGFR2 phosphorylation and on directed EC migration toward a VEGF gradient. Filopodial length and number of migrated ECs were also measured. Compared to control, the VEGFR2 inhibitor reduced VEGFR2 phosphorylation in HUVECs in vitro and clock hours and areas of IVNV but not percent avascular retina in vivo. Filopodial length and number of filopodia/EC tip cell were reduced in retinal flat mounts at doses that inhibited IVNV, whereas at lower doses, only a reduction in filopodial length/EC tip cell was found. There was no difference in phosphorylated beta3 integrin and cleaved caspase-3 labeling in VEGFR2 inhibitor-treated compared to control in vivo. Doses of the VEGFR2 inhibitor that reduced filopodial length and number of filopodia/migrating EC corresponded to reduced EC migration in in vitro models. VEGFR2 inhibitor reduced IVNV and filopodial number and length/EC tip cell without interfering with intraretinal vascularization. Reducing the number and length of filopodia/endothelial tip cell may reduce guidance cues for endothelial cells to migrate into the vitreous without interfering with migration into the retina toward a VEGF gradient.

Comparison of time-domain OCT and fundus photographic assessments of retinal thickening in eyes with diabetic macular edema.

PURPOSE: To explore the correlation between optical coherence tomography (OCT) and stereoscopic fundus photographs (FP) for the assessment of retinal thickening (RT) in diabetic macular edema (DME) within a clinical trial. METHODS: OCT, FP, and best corrected visual acuity (VA) measurements were obtained in both eyes of 263 participants in a trial comparing two photocoagulation techniques for DME. Correlation coefficients (r) were calculated comparing RT measured by OCT, RT estimated from FP, and VA. Principal variables were central subfield retinal thickness (CSRT) obtained from the OCT fast macular map and DME severity assessed by a reading center using a seven-step photographic scale combining the area of thickened retina within 1 disc diameter of the foveal center and thickening at the center. RESULTS: Medians (quartiles) for retinal thickness within the center subfield by OCT at baseline increased from 236 (214, 264) microm in the lowest level of the photographic scale to 517 (455, 598) microm in the highest level (r = 0.67). However, CSRT interquartile ranges were broad and overlapping between FP scale levels, and there were many outliers. Correlations between either modality and VA were weaker (r = 0.57 for CSRT, and r = 0.47 for the FP scale). OCT appeared to be more reproducible and more sensitive to change in RT between baseline and 1 year than was FP. CONCLUSIONS: There was a moderate correlation between OCT and FP assessments of RT in patients with DME and slightly less correlation of either measure with VA. OCT and FP provide complementary information but neither is a reliable surrogate for VA.

The Photographic Screening for Retinopathy of Prematurity Study (Photo-ROP): study design and baseline characteristics of enrolled patients.

OBJECTIVE: The Photographic Screening for Retinopathy of Prematurity Study (Photo-ROP) sought to evaluate the utility of digital wide-angle photographic fundus screening for retinopathy of prematurity (ROP) as compared to bedside indirect ophthalmoscopy. This article describes the study design and presents baseline characteristics of the subjects. DESIGN: Prospective, multicenter, masked, Internet-based clinical trial. PARTICIPANTS: Premature infants <31 weeks postmenstrual age at birth and <1000 g birthweight. INTERVENTIONS: Examinations began at 31 weeks postmenstrual age or 4 weeks postnatal age, whichever was later. Both eyes of all infants were imaged with a panoramic fundus imaging system followed by indirect ophthalmoscopic fundus examination. Images were transmitted via Internet to the Reading Center for interpretation by masked graders. Clinical interpretations based on indirect ophthalmoscopy were recorded for comparison with the Reading Center determinations. Examinations were performed weekly for 10 weeks or until an infant was discharged from the hospital. MAIN OUTCOME MEASURE: Sensitivity, specificity, and positive and negative predictive values of Reading Center image interpretations were compared to clinical impressions based on bedside indirect ophthalmoscopy. RESULTS: Enrollment began in February 2001 and was completed in February 2002. The target number of infants was 50, and 62 were enrolled. Of those enrolled, 51 infants (102 eyes) were considered eligible, and are the subject of this article. Mean postmenstrual age (+/- SD) at time of delivery was 26.80 +/- 1.73 weeks (median = 26.86 weeks, interquartile range [IQR] = 2.43 weeks). Mean postmenstrual age at first examination (+/- SD) was 32.19 +/- 2.86 weeks (median = 31.71 weeks, IQR = 2.29 weeks). Mean birthweight (+/- SD) was 830.51 +/- 219.57 g (median = 817 g, IQR = 225 g). Female infants comprised 49.02% of the patients. Race distribution was as follows: white 45.10%, African or black 39.22%, Hispanic 3.92%, Asian 9.80%, and other races 1.96%. Mean follow-up (+/- SD) was 5.73 +/- 3.22 weeks (median = 6 weeks, IQR = 5, range = [1, 15]). CONCLUSIONS: The Photo-ROP Study Cooperative Group successfully recruited and enrolled at-risk premature infants into a longitudinal, prospective clinical trial comparing two different diagnostic approaches. Technology employed in this study is comparable to that currently available. Design issues for this trial included establishing the information technology infrastructure for an ROP study based on digital imaging, defining the study endpoints, estimating event rates, defining a standardized imaging protocol, and defining standards for interpretation of image quality and clinical findings.