Handheld Optical Coherence Tomography Research Articles

Optic nerve head morphological variation in craniosynostosis: a cohort study

To evaluate optic nerve head morphology in children with craniosynostosis versus healthy controls. Single-centre, prospective cohort study METHODS: Handheld optical coherence tomography (OCT) was performed in 110 eyes of 58 children (aged 0-13 years) with craniosynostosis. Inclusion criteria were as follows: normal intracranial pressure (ICP) on invasive overnight monitoring, or clinically stable ICP. The latter was defined as stable VA within 1 logMAR line and no papilloedema on fundoscopy for at least four months following OCT, and normal/stable visual evoked potentials. Control data for 218 eyes of 218 children were obtained from a published normative dataset. The main outcome measures were disc width, cup width, rim width and retinal nerve fibre layer (RNFL) thickness (nasal and temporal). Outcome measures were compared using three-way linear mixed model regression analysis (FGFR 1/2-associated craniosynostosis, non-FGFR 1/2-associated craniosynostosis, and controls). Out of 63 eligible children with craniosynostosis, handheld OCT imaging was successful in 110 eyes of 58 children (92%). Of these, 22 (38%) were female. Median subject age at OCT examination was 53 months (range: 2 to 157; IQR: 39 to 73). Twelve children (21%) had FGFR1/2-associated syndromes (Crouzon, n=6; Apert, n=4; Pfeiffer, n=2). Control data were available for 218 eyes of 218 healthy children. 122 controls (56%) were female. Median control age at OCT examination was 20 months (range: 0 to 163; IQR: 6 to 59). When comparing optic nerve head morphology in craniosynostosis (n=58) versus controls (n=218), disc width was 6% greater (p=0.001), temporal cup width was 13% smaller (p=0.027), rim width was 16% greater (p<0.001) and temporal RNFL was 11% smaller (p=0.027). When comparing FGFR1/2-associated syndromes (Crouzon, Apert and Pfeiffer syndromes, n=12) to the rest of the craniosynostosis group (n=46), disc width was 10% smaller (p=0.014) and temporal cup width was 38% smaller (p=0.044). This cohort demonstrated morphological differences of the optic nerve head in craniosynostosis, most markedly in Crouzon, Apert and Pfeiffer syndromes. These findings could help improve ophthalmological monitoring and surgical decision-making in children with craniosynostosis. Further work on longitudinal optic nerve head changes in syndromic and non-syndromic craniosynostosis would be valuable.

Optimization of handheld spectrally encoded coherence tomography and reflectometry for point-of-care ophthalmic diagnostic imaging.

Handheld optical coherence tomography (HH-OCT) systems enable point-of-care ophthalmic imaging in bedridden, uncooperative, and pediatric patients. Handheld spectrally encoded coherence tomography and reflectometry (HH-SECTR) combines OCT and spectrally encoded reflectometry (SER) to address critical clinical challenges in HH-OCT imaging with real-time en face retinal aiming for OCT volume alignment and volumetric correction of motion artifacts that occur during HH-OCT imaging. We aim to enable robust clinical translation of HH-SECTR and improve clinical ergonomics during point-of-care OCT imaging for ophthalmic diagnostics. HH-SECTR is redesigned with (1)optimized SER optical imaging for en face retinal aiming and retinal tracking for motion correction, (2)a modular aluminum form factor for sustained alignment and probe stability for longitudinal clinical studies, and (3)one-handed photographer-ergonomic motorized focus adjustment. We demonstrate an HH-SECTR imaging probe with micron-scale optical-optomechanical stability and use it for in vivo human retinal imaging and volumetric motion correction. This research will benefit the clinical translation of HH-SECTR for point-of-care ophthalmic diagnostics.

Retinal imaging with hand-held optical coherence tomography in older people with or without postoperative delirium after hip fracture surgery: A feasibility study.

Postoperative delirium in older people may result from the interaction between intrinsic brain vulnerability (e.g. neurodegeneration) and precipitating factors (e.g. surgery induced cytokines). Intrinsic brain vulnerability may be overt (e.g. Alzheimer's disease) or preclinical. In cognitively intact older people presenting for surgery, identification of preclinical neurodegeneration using bedside tools could aid postoperative delirium risk stratification. Thinning of the circumpapillary retinal nerve fibre layer thickness is associated with neurodegenerative disorders e.g. Alzheimer's disease. We propose that thinning of the retinal nerve fibre layer may be present some older people with postoperative delirium due to preclinical neurodegeneration, albeit to a lesser extent than in overt dementia. The primary objective: Feasibility of acquiring usable retinal images with the hand-held optical coherence device, at the bedside of older, hip fracture surgery patients. Secondary objective: Comparison of the circumpapillary retinal nerve fibre layer thickness between people who did/did not have postoperative delirium. Proportion of exclusions due to retinal pathology. Feasibility study involving 30, cognitively intact, older people recovering from hip fracture surgery. Retinal images were obtained using the hand-held optical coherence tomography device at the participants' bedside. Imaging was deferred in participants who had postoperative delirium. Retinal images that could be assessed for circumpapillary retinal nerve fibre layer thickness were obtained in 26 participants (22 no postoperative delirium, 4 postoperative delirium). The mean circumpapillary retinal nerve fibre layer thickness was lower in the participants who had postoperative delirium compared to those who did not experience postoperative delirium (Mean (95% CI) of 76.50 (62.60-90.40) vs 89.19 (85.41-92.97) respectively). Retinal imaging at the patient's bedside, using hand-held OCT is feasible. Our data suggests that the circumpapillary retinal nerve fibre layer may be thinner in older people who experience postoperative delirium compared to those who do not. Further studies are required.

A Novel Small Form-Factor Handheld Optical Coherence Tomography Probe for Oral Soft Tissue Imaging.

Tissue imaging is crucial in oral cancer diagnostics. Imaging techniques such as X-ray imaging, magnetic resonance imaging, optical coherence tomography (OCT) and computed tomography (CT) enable the visualization and analysis of tissues, aiding in the detection and diagnosis of cancers. A significant amount of research has been conducted on designing OCT probes for tissue imaging, but most probes are either heavy, bulky and require external mounting or are lightweight but straight. This study addresses these challenges, resulting in a curved lightweight, low-voltage and compact handheld imaging probe for oral soft tissue examination. To the best of our knowledge, this is the first curved handheld OCT probe with its shape optimized for oral applications. This probe features highly compact all-fiber optics with a diameter of 125 μm and utilizes innovative central deflection magnetic actuation for controlled beam scanning. To ensure vertical stability while scanning oral soft tissues, the fiber was secured through multiple narrow slits at the probe's distal end. This apparatus was encased in a 3D-printed angular cylinder tube (15 mm outer diameter, 12 mm inner diameter and 160 mm in length, weighing < 20 g). An angle of 115° makes the probe easy to hold and suitable for scanning in space-limited locations. To validate the feasibility of this probe, we conducted assessments on a multi-layered imaging phantom and human tissues, visualizing microstructural features with high contrast.

Improved feasibility of handheld optical coherence tomography in children with craniosynostosis.

Improved feasibility of handheld optical coherence tomography in children with craniosynostosis.

Modernizing the evaluation of infantile nystagmus: the role of handheld optical coherence tomography

BackgroundInfantile nystagmus syndrome can be associated with an afferent problem (anterior or posterior segment) or constitute an isolated idiopathic disorder. With a normal ophthalmic examination, current guidelines recommend electroretinography (ERG) rather than magnetic resonance (MRI) for preliminary workup. Given the limited use of optical coherence tomography (OCT) in preverbal children, the purpose of this study was to evaluate the role of handheld OCT (HH-OCT) in the initial diagnostic evaluation of infantile nystagmus. MethodsIn this cross-sectional case series, the medical records of all children with infantile nystagmus and HH-OCT imaging at the Duke Eye Center from August 2016 to July 2021 were retrospectively reviewed. Children with anterior segment disorders or obvious retina/optic nerve structural pathology, bilateral ophthalmoplegia, or Down syndrome were excluded. Two masked pediatric ophthalmologists graded HH-OCT images for optic nerve head and macular abnormalities. A neuro-ophthalmologist reviewed clinical findings of each patient’s presenting visit and recommended appropriate testing (MRI vs ERG), initially without, and again with HH-OCT image review. ResultsA total of 39 cases were included, with mean presenting age of 1.3 years. Final diagnoses included retinal or foveal abnormalities (7), optic nerve pathology (13), idiopathic (10), or unknown (9). HH-OCT findings included optic nerve hypoplasia (1), optic nerve elevation (3), persistence of the inner layers at the fovea (9), thin ganglion cell layer (8), ellipsoid zone abnormality (3), and thin choroid (1). HH-OCT findings altered initial clinical-only management in 16 cases (41%), including avoiding MRI (5) and ERG (10) testing. ConclusionsOur results suggest that HH-OCT has the potential to augment and streamline the evaluation of infantile nystagmus.

Panretinal handheld OCT angiography for pediatric retinal imaging

Comprehensive visualization of retina morphology is essential in the diagnosis and management of retinal diseases in pediatric populations. Conventional imaging techniques often face challenges in effectively capturing the peripheral retina, primarily due to the limitations in current optical designs, which lack the necessary field of view to characterize the far periphery. To address this gap, our study introduces a novel ultra-widefield optical coherence tomography angiography (OCTA) system. This system, specifically tailored for pediatric applications, incorporates an ultrahigh-speed 800 kHz swept-source laser. The system’s innovative design achieves a 140° field of view while maintaining excellent optical performance. Over the last 15 months, we have conducted 379 eye examinations on 96 babies using this system. It demonstrates marked efficacy in the diagnosis of retinopathy of prematurity, providing detailed and comprehensive peripheral retinal angiography. The capabilities of the ultra-widefield handheld OCTA system in enhancing the clarity and thoroughness of retina vascularization assessments have significantly improved the precision of diagnoses and the customization of treatment strategies. Our findings underscore the system’s potential to advance pediatric ophthalmology and broaden the scope of retinal imaging.

Handheld contact-type OCT and color fundus system for retinal imaging.

We present proof of concept for a handheld contact-type system capable of simultaneous optical coherence tomography (OCT) imaging of the retina and wide-field digital fundus color photography. The study focuses on demonstrating the feasibility of the proposed approach, particularly for eventual use in pediatric patients during examination under anesthesia in the operating room and in the neonatal intensive care unit. Direct contact of the probe with the cornea allows the photographer to maintain a stable position during imaging, reducing motion artifacts in the OCT images. Additionally, it simplifies the alignment process and increases the field of view of the optics. By integrating OCT and fundus imaging into a single device, the proposed compact modular design eliminates the need for separate, space-consuming systems dedicated to each imaging modality.

USE OF HAND-HELD OPTICAL COHERENCE TOMOGRAPHY DURING RETINOPATHY OF PREMATURITY SCREENING DEMONSTRATES AN INCREASED OUTER RETINA FROM EARLY POSTMENSTRUAL AGE IN PRETERM INFANTS WITH RETINOPATHY OF PREMATURITY.

To identify structural markers of active retinopathy of prematurity (ROP) in foveal and parafoveal retinal layers using hand-held optical coherence tomography. Hand-held optical coherence tomography images (n = 278) were acquired from a prospective mixed cross-sectional longitudinal observational study of 87 participants (23-36 weeks gestational age; n = 30 with ROP, n = 57 without ROP) between 31 and 44 weeks postmenstrual age excluding treated ROP and features of cystoid macular edema. Six retinal layer thicknesses from the fovea to the parafovea were analyzed at five locations up to 1,000 µ m, temporally and nasally. The mean outer retinal thickness during active ROP increased at the fovea and parafovea from postmenstrual age 33 weeks to 39 weeks ( P < 0.001), whereas the parafoveal inner nuclear layer and retinal nerve fiber layer reduced ( P < 0.001). Outer retinal thickness at the fovea from 33 weeks to 39 weeks postmenstrual age was consistently thicker in infants with ROP across all levels of prematurity (gestational age). Increased foveal and parafoveal outer retina measured using hand-held optical coherence tomography shows potential as a marker for ROP screening.

Development of handheld optical coherence tomography based on commercial intra‐oral scanner shape for extended clinical utility in dentistry

AbstractThe main objective of this study is to develop a handheld dental optical coherence tomography (OCT) system capable of imaging the target area of the teeth in the oral cavity and demonstrate the applicability of the developed system to in vivo dental disease diagnosis based on a user‐friendly scanner form. The design of the developed system is based on mimicking the shape of a commonly used commercial intra‐oral scanner (IOS) so that the system users do not feel awkward when using it. A microelectromechanical system (MEMS) scanning unit was used to optimize the overall size of the system, and the optical axis was designed in a Z‐shape to maximize the beam size reflected by the MEMS mirror. A pre‐study of in vivo oral scanning was performed to demonstrate the enhanced clinical feasibility of the developed system. Furthermore, the main experiment classified teeth with worn cervical regions into two groups according to the cervical abrasion shape. The developed dental OCT system produced a three‐dimensional image of the scanning area and quantitatively analyzed the margin gap through an A‐scan profile based on cross‐sectional images. This study confirms the effectiveness of the developed handheld dental OCT system in actual dental clinical practice, and we expect our system to be utilized for various dental diseases, not only for diagnosing a cervical abrasions.

Erratum in: Feasibility and Repeatability of Handheld Optical Coherence Tomography in Children With Craniosynostosis.

Erratum in: Feasibility and Repeatability of Handheld Optical Coherence Tomography in Children With Craniosynostosis.

In vivo optical coherence tomography attenuation imaging of the breast surgical cavity using a handheld probe

Approximately 20–30% of breast-conserving surgery (BCS) patients require follow-up re-excision surgery due to inadequate cancer resection. To aid cancer detection and resection, we present a handheld optical coherence tomography (OCT) probe and attenuation imaging method to enable in vivo imaging of the surgical cavity during BCS. The attenuation imaging method incorporates three-dimensional correction of system factors in the probe, namely, confocal function and sensitivity roll-off function, demonstrating accurate and repeatable attenuation imaging of phantoms, validated using the Mie scattering model. To assess the imaging performance of the probe prior to in vivo imaging, ex vivo attenuation imaging of breast specimens from eight mastectomy patients was performed and the results compared to those acquired using a benchtop imaging system, showing consistent tissue contrast in attenuation images. In vivo imaging of breast tissue in the surgical cavity of seven patients was subsequently performed during BCS. The results demonstrate the potential of attenuation imaging to delineate cancer in vivo in the surgical cavity. Attenuation imaging provides an additional tissue contrast mechanism to complement OCT imaging, potentially contributing to more complete identification and resection of cancer during BCS.

MACULAR NEUROVASCULAR ABNORMALITIES IN A CHILD WITH INCONTINENTIA PIGMENTI ON HANDHELD OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

To report macular neurovascular abnormalities in a child with incontinentia pigmenti using handheld optical coherence tomography (OCT) and OCT angiography (OCT-A). An eye of a child with incontinentia pigmenti enrolled in BabySTEPS was imaged using an investigational noncontact, handheld swept-source OCT device during examination under anesthesia. Custom MATLAB scripts were used to generate depth-resolved vascular slabs, B-scans with flow overlay, and retinal thickness maps. Depth-resolved OCT and OCT-A imaging demonstrated focal areas of decreased capillary flow that corresponded to areas of both inner retinal and outer retinal thinning on retinal thickness maps. Atypical diving of superficial retinal vessels occurred as they traversed from thin retina to normal-thickness retina. Depth-resolved OCT and OCT-A identified retinal vascular abnormalities that were not evident on fundus photography or fluorescein angiography. This case depicted concurrent, localized abnormalities in retinal thickness and microvasculature in an eye with incontinentia pigmenti.

Determining relative thickness of inner retinal layers on single-line foveal optical coherence tomography (OCT) in healthy pediatric eyes—normative data for handheld OCT

Handheld optical coherence tomography (HH-OCT) lacks integrated segmentation/analysis software. Optic neuropathies cause ganglion cell layer (GCL) thinning, with normal to thickened inner nuclear layer (INL), suggesting the potential value of estimating the GCL/INL ratio on single-line foveal HH-OCT scans. This study determines this ratio in macular scans from healthy eyes of young children using HH-OCT and overhead-mounted OCT. Macular OCT scans were obtained using either HH-OCT or overhead-mounted Spectralis FLEX-OCT in children ages 0-5 years undergoing clinically indicated anesthesia/sedation. Exclusion criteria included gestational age <37 weeks, neurologic disease, amblyopia, ocular disease, or large refractive error (spherical equivalent beyond -3.00 D to +8.00 D). For HH-OCT, the GCL and INL were manually measured in pixels from single-line macular scans at the thickest point nasal and temporal to the fovea. For FLEX-OCT images, measurements were aided by automated software. HH-OCT was obtained on 38 eyes (38 children, mean age 2.4 ± 1.8 years) and FLEX-OCT on 56 eyes (56 children, mean age 2.3 ± 1.5 years). Mean nasal GCL/INL was 1.24 ± 0.18 (min/max = 0.92/1.75) for HH-OCT and 1.29 ± 0.18 (min/max = 0.96/1.66) for FLEX-OCT (P = 0.11). Mean temporal GCL/INL was 1.22 ± 0.24 (min/max = 0.66/1.70) for HH-OCT and 1.19 ± 0.16 (min/max = 0.86/1.47) for FLEX-OCT (P = 0.47). Mean normative GCL/INL ratios were approximately 1.2 at the thickest macular areas both nasal and temporal to the fovea, with either HH-OCT or FLEX-OCT in young children's eyes. These values may prove useful when HH-OCT is used to assess optic neuropathies, in which the GCL/INL ratio is expected to be decreased.

Handheld common-path swept-source optical coherence tomography angiography.

This study develops a handheld optical coherence tomography angiography (OCTA) system that uses a high-speed (200 kHz) swept laser with a dual-reference common-path configuration for stable and fast imaging. The common-path design automatically avoids polarization and dispersion mismatches by using one circulator as the primary system element, ensuring a cost-effective and compact design for handheld probe use. With its stable envelope (i.e., sub-µm shifts) and phase variation (corresponding to nm changes in axial displacement), the minimum detectable flow velocity is ∼ 0.08 mm/s in our experiment, which gives the common-path setup a high potential for application in a handheld OCTA system for clinical skin screening. In vivo skin structures and microvasculature networks on the dorsum of the hand and cheek of a healthy human are imaged successfully.

Longitudinal Choroidal Development in Preterm Infants

To characterize changes in subfoveal choroidal thickness in preterm infants from 30 to 60 weeks' postmenstrual age (PMA). The prospective, observational Study of Eye Imaging in Preterm infantS (BabySTEPS) enrolled infants eligible for retinopathy of prematurity screening per the American Association of Pediatrics guidelines. Infants imaged with an investigational, handheld OCT at ≥ 4 distinct imaging sessions between 30 to 60 weeks' PMA as part of BabySTEPS. Average choroidal thickness across the central subfoveal 1 mm in each eye at each time point was measured using custom segmentation software, and errors were manually corrected by a trained grader. We prospectively collected birth history data. A segmented mixed model was used to analyze the change in choroidal thickness as a function of PMA, birth weight, and gestational age (GA). Characterization of normative subfoveal choroidal thickness values and choroidal growth rate between 30 to 60 weeks' PMA. We included 592 imaging sessions of 79 preterm infants (152 eyes). Mean (± standard deviation) GA was 27.5 ± 2.5 weeks. Mean choroidal thickness was 141.4 ± 34.5 μm at 30 weeks, 272.2 ± 83.9 μm at 38 weeks, and 306.2 ± 77.4 μm between 56 and 60 weeks. Between 30 and 60 weeks' PMA, choroidal growth followed a biphasic model, with a linear growth rate of 14.8 μm per week (95% confidence interval [CI], 13.6-16.0) from 30 until 38.4 weeks, then cessation of growth, with a growth rate of 0.3 μm per week (95% CI,-1.1 to 1.6) from 38.4 to 60 weeks. Infants with extremely low birth weight (ELBW; < 1000 g) and extremely preterm (GA < 28 weeks) infants had significantly slower initial growth rates compared with very low and low birth weight and very preterm and preterm infants (ELBW 13.0 vs. 21.0 μm per week; P < 0.0001 and extremely preterm 13.2 vs. 18.0 μm per week; P= 0.003). Preterm infant choroidal thickness experiences rapid linear growth from 30 to 38 weeks' PMA, at which time growth nearly stops. These foundational measurements and identification of the impact of extremes of low birth weight and prematurity on choroidal development will be essential as researchers begin to understand the role of choroidal development in ocular and retinal health in human infants. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

BC05 Technological and clinical demonstration of a skin ageing analysis prototype

Abstract The skin undergoes intrinsic and extrinsic ageing, with extrinsic ageing caused by environmental factors including inadequate sleep. Preliminary studies have suggested a link between sleep quality and skin ageing. Noninvasive devices have been developed that are able to measure and quantify markers of skin ageing, such as collagen levels and wrinkle formation. A handheld optical coherence tomography (OCT) test, sourced from Industrial Technology Research Institute, is one such device that allows for the measurement of dermal collagen levels. We describe a pilot study to assess the feasibility of combining several methods to quantify skin ageing in those with and without sleep disturbance, to understand which specific markers of skin ageing are affected by poor sleep. Questionnaires were distributed to 10 female workers and completed by each participant to understand their sleep and sun protection habits. There were two groups: women working fixed day shifts (aged 41–53 years) or fixed night shifts (aged 22–63 years). Skin swabs, VISIA® and OCT were used to measure markers of skin ageing of both cheeks: DNA amplification, wrinkles (percentile) and collagen (percentage), respectively. The entire testing could be completed by each participant within 15 minutes. The results were then compared between the different groups. The testing was well tolerated in this small sample. There was a statistically significant difference between day and night workers in their percentile of wrinkles using the VISIA (left cheek: P = 0.039; right cheek: P = 0.015), with night workers showing fewer signs of wrinkle formation. No statistically significant difference in DNA amplification was observed between day and night workers using skin swabs (left cheek: P = 0.27; right cheek: P = 0.32). Using OCT, no statistically significant difference was observed in collagen percentage between day and night workers (left cheek: P = 0.73; right cheek: P = 0.98). Skin swabs, OCT and VISIA were well tolerated, with no adverse events seen. The VISIA showed a significant difference in markers of skin ageing between day and night workers. Night shift workers may have shown fewer signs of wrinkle formation due to confounding factors such as age and smoking. No significant difference was observed with skin swabs and OCT, which may be related to the small sample size. The skin swabs, VISIA and OCT together can be quickly used to test the impact of sleep or any other extrinsic factor on skin ageing. This study has provided useful pilot data that can be scaled for future, larger studies.

A hand-held optical coherence tomography angiography scanner based on angiography reconstruction transformer networks.

Optical coherence tomography angiography (OCTA) has successfully demonstrated its viability for clinical applications in dermatology. Due to the high optical scattering property of skin, extracting high-quality OCTA images from skin tissues requires at least six-repeated scans. While the motion artifacts from the patient and the free hand-held probe can lead to a low-quality OCTA image. Our deep-learning-based scan pipeline enables fast and high-quality OCTA imaging with 0.3-s data acquisition. We utilize a fast scanning protocol with a 60 μm/pixel spatial interval rate and introduce angiography-reconstruction-transformer (ART) for 4× super-resolution of low transverse resolution OCTA images. The ART outperforms state-of-the-art networks in OCTA image super-resolution and provides a lighter network size. ART can restore microvessels while reducing the processing time by 85%, and maintaining improvements in structural similarity and peak-signal-to-noise ratio. This study represents that ART can achieve fast and flexible skin OCTA imaging while maintaining image quality.

Vitreoretinal biomarkers of retinopathy of prematurity using handheld optical coherence tomography: a review.

Retinopathy of prematurity (ROP) is caused by abnormal retinal vascularization in premature infants that has the potential for severe long-term vision impairment. Recent advancements in handheld optical coherence tomography (OCT) have enabled noninvasive, high-resolution, cross-sectional imaging of the infant eye at the bedside. The use of handheld OCT devices in the diagnosis of ROP in premature infants has furthered our understanding of disease state and progression. This review discusses the known and novel biomarkers of ROP severity in premature infants identified through handheld OCT and potential for future directions.

Multivariate Models to Diagnose Early Referral-Warranted Retinopathy of Prematurity With Handheld Optical Coherence Tomography.

The purpose of this study was to create multivariate models predicting early referral-warranted retinopathy of prematurity (ROP) using non-contact handheld spectral-domain optical coherence tomography (OCT) and demographic data. Between July 2015 and February 2018, infants ≤1500 grams birth weight or ≤30 weeks gestational age from 2 academic neonatal intensive care units were eligible for this study. Infants were excluded if they were too unstable to participate in ophthalmologic examination (2), had inadequate image quality (20), or received prior ROP treatment (2). Multivariate models were created using demographic variables and imaging findings to identify early referral-warranted ROP (referral-warranted ROP and/or pre-plus disease) by routine indirect ophthalmoscopy. A total of 167 imaging sessions of 71 infants (45% male infants, gestational age 28.2+/-2.8 weeks, and birth weight 995.6+/-292.0 grams) were included. Twelve of 71 infants (17%) developed early referral-warranted ROP. The area under the receiver operating characteristic curve (AUC) was 0.94 for the generalized linear mixed model (sensitivity = 95.5% and specificity = 80.7%) and 0.83 for the machine learning model (sensitivity = 91.7% and specificity = 77.8%). The strongest variables in both models were birth weight, image-based Vitreous Opacity Ratio (an estimate of opacity density), vessel elevation, and hyporeflective vessels. A model using only birth weight and gestational age yielded an AUC of 0.68 (sensitivity = 77.3% and specificity = 63.4%), and a model using only imaging biomarkers yielded 0.88 (sensitivity = 81.8% and specificity = 84.8%). A generalized linear mixed model containing handheld OCT biomarkers can identify early referral-warranted ROP. Machine learning produced a less optimal model. With further validation, this work may lead to a better-tolerated ROP screening tool.