DOI: 10.5061/dryad.612jm649r
title: Data from: Plane wave Doppler determination of blood flow in retinopathy of prematurity

description: Retinopathy of prematurity (ROP) is a disorder affecting low birthweight,
 preterm neonates. In the preterm eye, the retina is not fully developed
 and neovascularization may occur at the margin between the developed
 vascular retina and undeveloped avascular retina. Without timely treatment
 by laser or intravitreal anti-vascular endothelial growth factor (VEGF)
 therapy, this can lead to tractional retinal detachment and blindness.
 Visualization of the retina in regular examinations by indirect
 ophthalmoscopy is hence the current standard of care, but the exams are
 stressful and interpretation of images is subjective. The upregulation of
 VEGF in ROP would suggest an increase in ocular blood flow. In this
 report, we evaluate the potential of ultrafast plane-wave Doppler
 ultrasound (PWU) to detect increased flow velocities in the orbital
 vessels supplying the eye in a gentle exam with objective findings. We
 imaged both eyes of 50 low-birthweight preterm neonates using 18 MHz PWU.
 Flow velocity in the central retinal artery (CRA) and vein (CRV), and the
 short posterior ciliary arteries were determined and values at each ROP
 Stage compared. We found significantly increased velocities in the CRA and
 CRV in Stage 3 ROP eyes, where intervention would be considered. We
 compared multivariate models for identifying Stage 3 eyes comprised solely
 of clinical factors, solely of Doppler parameters, and clinical plus
 Doppler parameters. The respective models provided areas under their
 respective ROC curves of 0.760, 0.812, and 0.904.  PWU Doppler
 represents a gentle, objective means for identifying neonates at risk for
 ROP that could complement ophthalmoscopy.
description: Neonate subjects were inpatients in the neonatal intensive care
 unit (NICU). Inclusion criteria: Neonates with a birth
 weight of ≤1500g or a gestational age of ≤30 weeks.
 Exclusion criteria: Presence of other congenital ophthalmic
 disease or cardiovascular disease; prior treatment with laser or
 intravitreal anti-VEGF agents. A total of 50
 low-birthweight, preterm neonates (100 eyes) were examined. 30 had
 follow-up exams approximately 2 weeks after their initial exam.
 ROP Stage, Zone, and presence of plus disease in each eye were
 determined by an experienced retinal specialist by indirect
 ophthalmoscopic examination as defined by the International Committee for
 the Classification of Retinopathy of Prematurity while masked to the PWU
 results. We performed PWU using a Vantage-128
 (Verasonics, Inc., Kirkland, WA)  research ultrasound system<strong>
 </strong>with a Verasonics L22-14vXLF linear array probe. The probe
 had an 18-MHz center frequency, 128 piezoelectric elements, a 12.8 mm
 aperture, and an elevation focal length of approximately 18 mm.
 Scanning was performed at cribside in the NICU with the
 assistance of neonatal ophthalmic nurses. Exams were performed by a single
 person experienced in the performance of clinical ophthalmic
 ultrasonography. During the exam, the probe was placed in a viral barrier
 sheath (Sheathes3D; Sheathing Technologies, Inc., Morgan Hill, CA) filled
 with a cm of water, and coupled to the upper eyelid with GenTeal (Alcon
 Laboratories, Inc., Fort Worth, TX) gel with minimal pressure. Scans were
 performed in a horizontal plane encompassing the optic nerve. B-mode
 color-flow images were displayed in real time. Once the optic nerve and
 posterior vasculature were satisfactorily displayed, the system was
 triggered to acquire PWU compound data from six angled transmits over ±9
 degrees. Data were acquired continuously for 1.5 seconds at 3,000 compound
 scans per second, and the stack of 4,500 phase-resolved images stored for
 post-processing. We acquired three scans of each eye, repeating scans as
 necessary if degraded by eye or head movement. Examination of both eyes
 would typically take about 15 minutes. Acoustic
 intensity was compliant with FDA guidelines for ophthalmic diagnostic
 ultrasound standards. Doppler analysis was performed as
 follows: A singular value decomposition filter and a 10 Hz high-pass
 filter was applied to the data to suppress stationary or slowly moving
 structures, leaving only blood flow. This information was then used to
 produce a color flow image from which the CRA, CRV and short posterior
 ciliary arteries (SPCAs) were identified. We then sampled each vessel to
 produce spectrograms depicting flow pulsatile flow velocity over the 1.5
 seconds of each scan. From this, after correcting for vessel angle with
 respect to the acoustic axis, we measured peak systolic velocity (PSV),
 end diastolic velocity (EDV) and mean velocity (MV), and computed the
 pulsatile index, PI = (PSV – EDV)/VM and resistive index, RI = (PSV-
 EDV)/PSV. Statistical analysis was performed using IBM
 SPSS Version 29 (IBM Corp., Armonk, NY). ANOVA, with
 post-hoc Dunnett’s test, was used to compare Doppler parameters between
 ROP Stages for each vessel. Because each eye was classified and imaged
 separately, we treated each eye as a separate case. However, recognizing
 that eyes of a given subject tend to be correlated, we additionally
 performed the analysis separately for right and left eyes.
 ANOVA was also performed to evaluate the presence of preplus
 disease and Zone on flow. Stepwise linear discriminant
 analysis was used to produce multivariate classification models to
 distinguish Stage 3 with respect to Stages 0-2. <em>A priori
 </em>probabilities for group membership were set equal.
 Classification accuracy was assessed and validated by a leave-one-out
 procedure. Receiver operator characteristic (ROC) analysis was performed
 to evaluate the effectiveness of classification functions.
 We first produced a stepwise clinical model by entering sex,
 blood pressure (systolic, diastolic, mean, pulse pressure), GA and BW into
 the analysis (Model 1). Next, we produced a model using stepwise variable
 selection of all Doppler parameters (Model 2). Lastly, we produced a
 stepwise model simultaneously considering both clinical and Doppler
 parameters (Model 3).
description: # Data from: Plane wave Doppler determination of blood flow in retinopathy
 of prematurity Statistical analysis was performed using IBM SPSS Version
 29 (IBM Corp., Armonk, NY). ANOVA, with post-hoc Dunnett’s test, was used
 to compare Doppler parameters between ROP Stages for each vessel. Because
 each eye was classified and imaged separately, we treated each eye as a
 separate case. However, recognizing that eyes of a given subject tend to
 be correlated, we additionally performed the analysis separately for right
 and left eyes. ANOVA was also performed to evaluate the presence of
 preplus disease and Zone on flow. Stepwise linear discriminant analysis
 was used to produce multivariate classification models to distinguish
 Stage 3 with respect to Stages 0-2. *A priori *probabilities for group
 membership were set equal. Classification accuracy was assessed and
 validated by a leave-one-out procedure. Receiver operator characteristic
 (ROC) analysis was performed to evaluate the effectiveness of
 classification functions. We first produced a stepwise clinical model by
 entering sex, blood pressure (systolic, diastolic, mean, pulse pressure),
 GA and BW into the analysis (Model 1). Next, we produced a model using
 stepwise variable selection of all Doppler parameters (Model 2). Lastly,
 we produced a stepwise model simultaneously considering both clinical and
 Doppler parameters (Model 3). Description of variables Patient # Exam #
 Days days between initial and followup exams BWg birthweight (g) Gaw
 gestational age, weeks BPM heartbeats per minute Systolic blood pressure
 (mmHg) Diastolic blood pressure (mmHg) MAP mean arterial pressure (mmHg)
 PP pulse pressure Eye 0=right, 1=left Stage ROP stage* Zone ROP zone**
 Plus 0=none, 1=preplus, 2=plus** VmaxCRA Central retinal artery (CRA)
 systolic velocity; (0=missing) VminCRA CRA diastolic velocity; (0=missing)
 VmeanCRA CRA mean velocity; (0=missing) RICRA CRA resistive index;
 (0=missing) PICRA CRA pulsatility index; (0=missing) VmaxCRV Central
 retinal vein (CRV) systolic velocity; (0=missing) VminCRV CRV diastolic
 velocity; (0=missing) VmeanCRV CRV mean velocity; (0=missing) RICRV CRV
 resistive index; (0=missing) PICRV CRV pulsatility index; (0=missing)
 VmaxSPCA Short posterior ciliary artery (SPCA) )msystolic velocity;
 (0=missing) VminSPCA SPCA diastolic velocity; (0=missing) VmeanSPCA SPCA
 mean velocity; (0=missing) RISPCA SPCA resistive index; (0=missing) PISPCA
 SPCA pulsatility index; (0=missing) All Doppler velocities are in mm/sec.
 \* Stage: 0 = No clear demarcation line between vascularized and
 non-vascularized retina; 1 = Demarcation line is visible; 2 = Demarcation
 line has developed into a ridge; 3=Blood vessels are visible at the ridge
 \**Zone: 1 is small area surrounding the optic nerve; 2 covers the middle
 of the retina; 3 runs along the retina's outer edge. \***Plus disease
 indicates presence of dilated, tortuous retinal vessels. Preplus is an
 intermediate stage between normal and plus disease. Missing values in
 Doppler velocity fields occur when a vessel was not adequately imaged.