Journal of Pediatric Ophthalmology and Strabismus

Original Article 

Pediatric Corneal Structural Development During Childhood Characterized by Ultrasound Biomicroscopy

Snehaa Maripudi, BS; Julia Byrd, MD; Azam Qureshi, MD; Gianna Stoleru, MD; Moran Roni Levin, MD; Osamah J. Saeedi, MD; Wuqaas Munir, MD; Marlet Bazemore, MD; Bethany Karwoski, MD; Camilo Martinez, COA; Mohamad S. Jaafar, MD; William P. Madigan, MD; Janet Leath Alexander, MD

Abstract

Purpose:

To quantitatively describe the structural corneal changes from infancy to early adulthood using ultrasound biomicroscopy.

Methods:

In this prospective study, 168 ultrasound biomicroscopy images were obtained from 24 healthy eyes of 24 patients who consented and enrolled in the Pediatric Anterior Segment Imaging Innovation Study. Their ages ranged from birth to 26 years. An established ultrasound biomicroscopy imaging protocol including seven views of one eye per patient were obtained and measured using ImageJ software (National Institutes of Health). Twelve corneal structural parameters were measured. Means were compared between younger and older groups.

Results:

Among the 12 measured structures, 5 demonstrated statistically significant differences (P < .05) between patients younger than 1 year and patients older than 1 year. The mean values for corneal cross-sectional width and length, central corneal thickness, and radii of curvature (anterior and posterior) were significantly different in patients younger than 1 year. Curvature and limbus-to-limbus dimensions changed more dramatically than thickness and tissue density. When comparing the youngest to oldest subgroups, anterior curvature flattened (6.14 to 7.55 radius), posterior curvature flattened (5.53 to 6.72 radius), angle-to-angle distance increased (8.93 to 11.40 mm), and endothelial cross-sectional distance increased (10.63 to 13.61 mm).

Conclusions:

Pediatric corneal structures change with age. The most significant changes occur in the first months of life, with additional changes later in childhood. This study further demonstrates the importance of age in pediatric corneal imaging analysis.

[J Pediatr Ophthalmol Strabismus. 2020;57(4):238–245.]

Abstract

Purpose:

To quantitatively describe the structural corneal changes from infancy to early adulthood using ultrasound biomicroscopy.

Methods:

In this prospective study, 168 ultrasound biomicroscopy images were obtained from 24 healthy eyes of 24 patients who consented and enrolled in the Pediatric Anterior Segment Imaging Innovation Study. Their ages ranged from birth to 26 years. An established ultrasound biomicroscopy imaging protocol including seven views of one eye per patient were obtained and measured using ImageJ software (National Institutes of Health). Twelve corneal structural parameters were measured. Means were compared between younger and older groups.

Results:

Among the 12 measured structures, 5 demonstrated statistically significant differences (P < .05) between patients younger than 1 year and patients older than 1 year. The mean values for corneal cross-sectional width and length, central corneal thickness, and radii of curvature (anterior and posterior) were significantly different in patients younger than 1 year. Curvature and limbus-to-limbus dimensions changed more dramatically than thickness and tissue density. When comparing the youngest to oldest subgroups, anterior curvature flattened (6.14 to 7.55 radius), posterior curvature flattened (5.53 to 6.72 radius), angle-to-angle distance increased (8.93 to 11.40 mm), and endothelial cross-sectional distance increased (10.63 to 13.61 mm).

Conclusions:

Pediatric corneal structures change with age. The most significant changes occur in the first months of life, with additional changes later in childhood. This study further demonstrates the importance of age in pediatric corneal imaging analysis.

[J Pediatr Ophthalmol Strabismus. 2020;57(4):238–245.]

Introduction

Ultrasound biomicroscopy was developed by Pavlin in 1991. Although initially used to quantify structural features of the iris, lens, and trabecular angle, ultrasound biomicroscopy has since been recognized to have numerous clinical ophthalmic applications.1 Early ultrasound biomicroscopy researchers described several anterior segment parameters, none of which included the cornea. More recently, corneal structural assessment using ultrasound biomicroscopy has become particularly relevant. In the past 15 years, development of novel procedures to treat corneal disease (eg, anterior lamellar keratoplasty, endothelial keratoplasty, and corneal cross-linking) expanded clinical applications for corneal imaging technology.

The most commonly evaluated clinical corneal parameters are diameter, central thickness, and anterior curvature. These corneal measurements play an essential role in the diagnosis of and prognosis for several pediatric diseases, such as congenital glaucoma and keratoconus. Qualitative and quantitative corneal structural morphology assessments also aid in diagnosis and treatment decisions for corneal dystrophies, anterior segment dysgenesis, intraocular lens selection, aniridia, and cataracts.1

In neonates, ultrasound biomicroscopy has been used to understand the microstructure of the anterior eye and the cornea in the setting of congenital corneal staphyloma.2 In patients with macular corneal dystrophy, ultrasound biomicroscopy was shown to disclose deeper pathologies than anterior segment optical coherence tomography (AS-OCT), including opacities and focal protrusions of the posterior cornea. Ultrasound biomicroscopy provided valuable information when choosing the best surgical option for these patients.3 These examples suggest that ultrasound biomicroscopy can improve our understanding of the pathology and progression of numerous conditions as they relate to the pediatric cornea, particularly due to the ability of this imaging tool to visualize structural features to determine whether a relative or absolute corneal opacity is present, or if a clinician requires structural assessment of the iris, lens, and ciliary body.

Various age groups are known to respond differently to surgeries involving the cornea, and their corneas have different mechanical properties, which may be directly related to tissue density.4–6 To our knowledge, the corneal tissue density related to age has not previously been studied in healthy children using ultrasound biomicroscopy. Quantitative analysis of the corneal tissue density has theoretical clinical applications. Prior to future evaluation of these potentially relevant clinical correlations, normative corneal tissue density characteristics in infants and children are required.

This study aimed to identify and describe the corneal changes, including structural and tissue density measurements, with physiologic corneal growth in the first few decades of life. These features may help us better understand the unique mechanical properties and disease progression patterns observed in children.

Patients and Methods

Ultrasound biomicroscopy images were obtained from 24 healthy eyes of 24 participants enrolled in the Pediatric Anterior Segment Imaging Innovation Study (PASIIS) at the University of Maryland, Baltimore, Maryland. A total of 168 images (7 from each eye) were obtained. Participant ages ranged from birth to age 26 years (7 participants younger than than 1 year, 4 patients between 1 and 3 years, 5 patients between 3 and 18 years, and 7 patients between 18 and 26 years). Patients in the young adult age group (18 to 26 years) were included as an external cohort to quantify the endpoint of pediatric ocular growth for each parameter. Consent for participation in ultrasound biomicroscopy imaging and analysis was obtained from the parents or participants, depending on the participant's age.

Participants younger than 18 years were imaged during examination under anesthesia, concurrent with the clinically indicated procedure (strabismus surgery, contralateral trauma repair, or oculoplastic procedure). Adult participants were imaged while awake with topical anesthesia. Participants older than 18 years were recruited following a normal dilated eye examination with an optometrist and compensated for time and travel. Young adult eyes were included to serve as a comparison group for the pediatric patients to provide perspective as an endpoint of pediatric ocular growth. One eye per participant was enrolled. Exclusion criteria included eyes with abnormal visual function for age, previous intraocular surgery, history of traumatic injury, past or current ocular anomaly, abnormal gonioscopy, refractive error greater than 4.00 diopters (D) of hyperopia or myopia, or more than 2.00 D of astigmatism. Premature infants were not excluded. Corrected age was used for premature infants in the age group younger than 1 year. Exclusion criteria were applied after imaging such that excluded patients may remain eligible for enrollment in other PASII studies.

This study adhered to the ethical principles outlined in the Declaration of Helsinki as amended in 2013. The institutional review board of the University of Maryland has approved the above referenced protocol and the associated consent forms. Collection and evaluation of protected health information was compliant with the Health Insurance Portability and Accountability Act of 1996.

Imaging

Ultrasound biomicroscopy imaging was performed using the Aviso Ultrasound Platform A/B ultrasound biomicroscopy with a 50-MHz linear transducer (Quantel Medical). The orientation of seven distinct images that were obtained in each eye have been previously described by Qureshi et al.4 One additional cross-sectional image in focus at the corneal plane was added to the Qureshi imaging protocol. The seven views obtained from each eye included two cross-sections of the eye (horizontal and vertical) centered at the pupil center, four images at the intersection of the cornea and iris (angles at the 12-, 3-, 6-, and 9-o'clock positions) centered at the trabecular-iris angle, and one dedicated central corneal image. All images were deidentified and measured by a masked observer (SM).

Image Analysis

The PASIIS standardized protocol was developed to extract quantitative data from both ultrasound biomicroscopy and AS-OCT images. The manual image analysis protocol uses ImageJ 1.48v (National Institutes of Health), a Java-based open access image processing program. Reliability and repeatability analysis of the current imaging and analysis protocol has been previously published.4 Twelve specific corneal parameters were measured in each ultrasound biomicroscopy image using ImageJ. An average value for each parameter was calculated for each participant from the measurements taken on each one of their seven eye images.

The 12 prospectively defined measurements shown in Figure 1 include three distances, five measurements of corneal thickness, two measurements of corneal curvature, and two measurements of image pixel density. The distances include: (1) AA-D, the linear distance from angle to angle in cross-sectional view of the anterior chamber; (2) A-SS-D, the linear distance between the angle and the scleral spur; and (3) ECS-D, the curved distance following the corneal endothelium from angle to angle. The corneal thicknesses included central, peripheral (at 3 and 6 mm, respectively), endothelial, and epithelial. The corneal curvatures were anterior and posterior and integrated pixel densities were measured for the cornea and sclera.

Sample ultrasound biomicroscopy image illustrating measurement technique for each parameter. (A) Angle-to-angle distance. (B) Angle-to-scleral spur distance. (C) Endothelial cross-sectional distance. (D) Central corneal thickness. (E) Three-millimeter paracentral corneal thickness. (F) Six-millimeter peripheral corneal thickness. (G) Epithelial thickness. (H) Endothelial thickness. (I) Anterior corneal radius of curvature. (J) Posterior corneal radius of curvature. (K) Corneal pixel integrated density. (L) Scleral pixel integrated density. Parameters ending in “−D” correspond to linear distance, “−T” correspond to thickness, “−C” correspond to curvature, and “−ID” correspond to integrated density.

Figure 1.

Sample ultrasound biomicroscopy image illustrating measurement technique for each parameter. (A) Angle-to-angle distance. (B) Angle-to-scleral spur distance. (C) Endothelial cross-sectional distance. (D) Central corneal thickness. (E) Three-millimeter paracentral corneal thickness. (F) Six-millimeter peripheral corneal thickness. (G) Epithelial thickness. (H) Endothelial thickness. (I) Anterior corneal radius of curvature. (J) Posterior corneal radius of curvature. (K) Corneal pixel integrated density. (L) Scleral pixel integrated density. Parameters ending in “−D” correspond to linear distance, “−T” correspond to thickness, “−C” correspond to curvature, and “−ID” correspond to integrated density.

Statistical analysis was performed with Microsoft Excel (2019 version; Microsoft Corporation). Each parameter was plotted against age to observe trends. Means and standard deviations for each parameter were determined in each age group. Age groups were defined as: infants younger than 1 year (younger infants and older infants were further separated as age 0 to 6 months and 6 to 12 months, respectively), toddlers between 1 and 3 years, children between 3 and 18 years, and adults between 18 and 26 years. Analysis of variance of a single factor was conducted to compare means in age groups. The two-sample t test was performed to test the hypothesis that the means of the younger and older groups are different. P values were two-sided. Differences were considered statistically significant when the P value was less than .05.

Results

For 7 of the 12 parameters including angle-to-scleral spur distance, 3- and 6-mm peripheral thicknesses, epithelial thickness, endothelial thickness, and integrated density of the cornea and sclera, there was no significant difference between age groups. The other five parameters (angle-to-angle distance, endothelial cross-sectional distance, central corneal thickness, and anterior and posterior curvatures) had statistically significant differences in participants younger than 1 year compared to older participants. Results are displayed in Table 1.

Parameters and Mean Measurements Among Participant Groups

Table 1:

Parameters and Mean Measurements Among Participant Groups

Each parameter is presented in scatter plot with age on the horizontal axis in Figure 2A. Figure 2B summarizes results of analysis of variance of a single factor and two sample t tests between groups. As shown in Figure 2, the means for AA-D, ECS-D, ACR-C, and PCR-C are lower in infants compared to older participants and mean CC-T is greater in infants compared to older participants.

(A) Individual data points plotted against age. Trendlines were not statistically significant and are not displayed. (B) Comparison among 4 age groups. Infants are younger than 1 year (n = 7), toddlers are aged 1 to 3 years (n = 4), children are aged 3 to 18 years (n = 5), and adults are aged 18 to 26 years (n = 7). Asterisk (*) marks the parameters that had statistically significantly different means among infants compared to the combined older participants. A–D = linear distance from angle to angle (cross-sectional width); ECS-D = curved distance along the endothelium in cross-section; CC-T = central corneal thickness; 3 mm-T = paracentral corneal thickness at a 3-mm radius from corneal center; 6 mm-T = peripheral corneal thickness at a 6-mm radius from corneal center; Epi-T = thickness of the corneal epithelium; Endo-T = thickness of the corneal endothelium; ACR-C = anterior corneal radius of curvature; PCR-C = posterior corneal radius of curvature; C-ID = corneal integrated density; S-ID = scleral integrated density

Figure 2.

(A) Individual data points plotted against age. Trendlines were not statistically significant and are not displayed. (B) Comparison among 4 age groups. Infants are younger than 1 year (n = 7), toddlers are aged 1 to 3 years (n = 4), children are aged 3 to 18 years (n = 5), and adults are aged 18 to 26 years (n = 7). Asterisk (*) marks the parameters that had statistically significantly different means among infants compared to the combined older participants. A–D = linear distance from angle to angle (cross-sectional width); ECS-D = curved distance along the endothelium in cross-section; CC-T = central corneal thickness; 3 mm-T = paracentral corneal thickness at a 3-mm radius from corneal center; 6 mm-T = peripheral corneal thickness at a 6-mm radius from corneal center; Epi-T = thickness of the corneal epithelium; Endo-T = thickness of the corneal endothelium; ACR-C = anterior corneal radius of curvature; PCR-C = posterior corneal radius of curvature; C-ID = corneal integrated density; S-ID = scleral integrated density

Discussion

This study analyzed 12 corneal parameters, two of which are well studied and routinely measured in clinical care: central corneal thickness and anterior corneal curvature.5,6 Using high-resolution imaging, we introduced 10 novel corneal parameters to further characterize corneal shape in the pediatric population. The lack of studies on these novel parameters is likely due to no gold standard measurement tools or techniques, and unknown clinical relevance.

Distance

As expected, the distances that spanned the entire eye (AA-D and ECS-D) increased significantly with age. AA-D, a one-dimensional width of the anterior chamber, is geometrically related to corneal diameter. The limbus is not a discrete visible feature on ultrasound biomicroscopy images, yet the angle is easily identified, so this measurement was more appropriate to evaluate and assess corneal size based on ultrasound biomicroscopy images. Studies have shown the angle to be a more reliable landmark on ultrasound biomicroscopy imaging compared to the scleral spur and limbus.4 The trends in AA-D were consistent with known patterns of growth for the corneal diameter, namely expected growth of 2 mm from birth to adulthood.5,6

The absolute distance between the angle and scleral spur (A-SS-D) was small, standard deviations were large, and results were variable. The A-SS-D was measured as a negative distance in half of the participants in infants younger than 1 year (meaning the scleral spur was posterior to the angle), due to a physiologically shallow anterior chamber and narrow angle. None of the participants older than year had a negative A-SS-D. This measurement may be better evaluated using AS-OCT, given the need for very high resolution to determine relative locations of very small structures and crowded orientation in infants' trabecular-iris angle.

Clinical correlations using the endothelial cross-sectional distance (ECS-D), or corneal arc length, have not been previously reported. This novel parameter is introduced because the landmarks for measurement are easily identified using ultrasound biomicroscopy, and because this parameter incorporates a two-dimensional corneal measurement, accounting for both the horizontal and the vertical dimensions of the cornea.

Thickness

Total cornea and sublayer thicknesses measured included CC-T, paracentral (at 3 mm and 6 mm from the center), epithelium, and endothelium. CC-T in premature infants is 691 µm, and decreases to 564 µm at birth,6 and decreases further to 553 µm (range: 548 to 558 µm) among children.7–9 Our study confirmed that young infant corneas tended to be thicker in all regions compared to older participants. The mean CC-T among all participants was 570 µm, with a mean of 600 µm among infants and 561 µm among young adults. In general, the central thickness was less than the peripheral thickness, with one exception in the 6-mm thickness in the infants younger than 6 months. Only two infants in this young infant subgroup had eyes of sufficient size to measure the thickness at 6 mm, due to their age-appropriate small corneal diameter.

The corneal endothelium is histologically a single layer of cells, whereas the epithelium is 5 to 7 cells thick with an average thickness of approximately 50 µm (48 to 60 µm) among participants of all ages with a non-uniform thickness profile.10,11 Our findings were relatively consistent with these known values and relationships. In this study, the epithelial thicknesses were thicker than endothelial thicknesses. Interest in epithelial thickness profiles has gained popularity recently due to the role the epithelial layer plays in corneal power, refractive shifts, and relevant anatomic changes in refractive surgery, corneal remodeling, contact lens wear, keratoconus, other ectatic diseases, and limbal stem cell deficiency.10–12 For all measurements, the epithelial thickness was greater than 50 µm. It is not clear if this is due to a systematic bias in measurement or if this is a true unique feature of young eyes. We suspect an ultrasound artifact called speckle noise may have contributed to the overestimation of thickness at this prominent tissue interface. Among infants, both endothelial and epithelial thicknesses were greater than they were in older participants, but this difference was not statistically significant.

Curvature

Anterior and posterior corneal curvatures were determined by fitting a circle to the curve of the anterior and posterior corneal cross-section. To our knowledge, this precise technique has not been previously described; however, analogous techniques have been well described using AS-OCT.13,14 Some preliminary work correlating ultrasound biomicroscopy images with keratometry has also demonstrated accuracy.15 Comparison of anterior and posterior curvature was found to be consistent with physiologic expectation that the posterior cornea is steeper than the anterior cornea and data were consistent with published normative values for anterior corneal.5,6 Among our data, values for ACR-C stabilized at 1 year, whch is the established expected trend for pediatric corneal curvature.5,6,16 Normative values for keratometry are 52.00 D (6.49 radians) at birth, 46.00 D (7.34 radians) at 6 months, and 44.00 D (7.67 radians) in adults.5 Although our data set was small, our findings were consistent with these normative values, suggesting our measurement technique of approximating corneal curvatures by circle-fitting cross-sectional ultrasound biomicroscopy images warrants further study.

Integrated Density

Studies have established that tissue density can be accurately determined using ultrasound, and measured quantitatively using ImageJ.17,18 Integrated density is a quantifiable image feature and an established proxy for tissue density19 and therefore likely an appropriate proxy for corneal and scleral stromal tissue density. Integrated density is defined as the product of area and mean gray value (the sum of the gray values in all pixels divided by the number of pixels). This tool has been used widely in ophthalmology to systematically quantify image features.20,21 Our findings demonstrated greater sonographic density in the sclera compared to the cornea, and a trend toward less dense corneal and scleral tissue in infants compared to older participants. This may explain pediatric corneal surgical experiences, particularly with penetrating keratoplasty, that younger patients have reduced corneal tissue rigidity and more elastic biomechanical corneal properties.

Structural features of the cornea that have been previously reported include corneal diameter, central corneal thickness, and anterior corneal curvature. Novel features of this study include measurement of corneal curvatures from ultrasound biomicroscopy images using circle-fitting, and measurement of integrated density. Previously demonstrated patterns for corneal changes with age were reproduced in this study. Some features that changed most significantly with age were the width of the anterior chamber (AA-D), the curved distance of the corneal endothelium cross-section (ECS-D), and the anterior and posterior corneal curvatures. Non-significant trends in peripheral corneal thicknesses, epithelial and endothelial thicknesses, and tissue density were noted.

Our results were consistent with previous reports that the most significant corneal growth occurs before age 1 year. Evaluation of multiple corneal parameters is possible with an imaging modality that captures the entire cross-sectional span of the cornea, which is a key advantage to ultrasound biomicroscopy or AS-OCT imaging. The consistency of our data with known values, where available, supports ultrasound biomicroscopy as an adequate tool to evaluate corneal growth among many quantifiable structural corneal parameters.

There were limitations and assumptions inherent to this study. We used averages from multiple images at multiple identical clock hour locations in four quadrants to determine a final value for each parameter. This technique optimized our ability to determine an accurate average measurement and purposely disregarded the known differences between horizontal and vertical corneal structural features.22 Our assumption that the cornea is spherical and symmetric, which is known to be incorrect, was deemed appropriate for the purposes of this study for several reasons. The relative difference between two axes is small compared to the differences observed in different age groups, the ratio of horizontal vertical corneal asymmetry is stable from prenatal years to adulthood, only average values of equal measurements in each quadrant were calculated, and participants with greater than 2.00 D of corneal astigmatism were excluded.

In this study, 24 participants were observed so few individuals represented an entire age group. The small sample size was presumed valid given the consistency with previously published data, when available. Heterogenous demographics were present among our pediatric participants. A similarly heterogenous group of healthy adult volunteers for the participant group 18 to 26 years old was recruited. It has been well established that ethnicity differences exist in corneal structural parameters in both pediatric and adult patients.23–25 This study provides non-demographic-specific data and represents a range of age-based values that may apply to children and young adults.

Corneal image analysis allows for a quantified comparison of the specific structural features in different age groups. Although ultrasound biomicroscopy images can be examined in a highly organized and systematic way, the process of quantification is relatively labor intensive, and the direct clinical benefit is not yet known. This study focuses on normal pediatric eyes. Further studies on normal and anomalous corneal structural features in pediatric patients are needed.

References

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Parameters and Mean Measurements Among Participant Groups

Parameter With DescriptionAll AgesAge 0 to 6 Months (Young Infants)Age 6 to 12 Months (Older Infants)Age 1 to 3 Years (Toddlers)Age 3 to 18 Years Children)Age 18 to 26 Years (Young Adults)
AA-D (mm)10.69 ± 1.248.93 ± 1.389.97 ± 0.3411.22 ± 0.3311.32 ± 0.5111.40 ± 0.25
A-SS-D (mm)0.07 ± 0.20−0.12 ± 0.460.15 ± 0.120.17 ± 0.120.13 ± 0.0890.094 ± 0.076
ECS-D (mm)12.83 ± 1.6610.63 ± 1.9612.42 ± 0.0013.42 ± 0.6913.66 ± 0.7713.61 ± 0.45
CC-T (mm)0.58 ± 0.040.620 ± 0.0410.584 ± 0.0140.569 ± 0.0300.555 ± 0.0190.561 ± 0.022
3 mm-T (mm)0.61 ± 0.040.633 ± 0.0490.676 ± 0.0450.591 ± 0.0210.587 ± 0.0250.600 ± 0.027
6 mm-T (mm)0.75 ± 0.120.580 ± 0.0680.867 ± 0.0210.709 ± 0.1540.770 ± 0.0620.805 ± 0.050
Epi-T (mm)0.09 ± 0.030.115 ± 0.0270.090 ± 0.0180.089 ± 0.0260.092 ± 0.0340.087 ± 0.020
Endo-T (mm)0.07 ± 0.020.087 ± 0.0230.068 ± 0.0110.063 ± 0.0160.068 ± 0.0300.060 ± 0.015
ACR-C (rad)7.27 ± 1.096.14 ± 0.586.42 ± 1.117.94 ± 1.077.83 ± 0.777.55 ± 0.75
PCR-C (rad)6.43 ± 0.905.53 ± 0.705.41 ± 0.617.14 ± 0.606.74 ± 0.656.72 ± 0.62
C-ID (pixel/mm2)3.34 ± 1.063.12 ± 1.141.92 ± 0.133.27 ± 0.483.24 ± 1.204.02 ± 0.72
S-ID (pixel/mm2)8.25 ± 1.828.02 ± 1.485.97 ± 3.008.77 ± 0.948.54 ± 1.578.57 ± 1.63
Authors

From the Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, Maryland (SM, AQ, GS, MRL, OJS, WM, JLA); and the Department of Ophthalmology, Children's National Health System, Washington, DC (JB, MB, BK, CM, MSJ, WPM).

Ms. Maripudi received funding support from the Proposed Research Initiated by Students and Mentors (PRISM) Program from the University of Maryland. Dr. Alexander received funding support from the Knights Templar Eye Foundation Career Starter Grant and the UMB ICTR/Clinical Science and Translational Science KL2 Award 1KL2TR003099-01. The remaining authors have no financial or proprietary interest in the materials presented herein.

The authors thank Steven Bernstein, MD, PhD, and Laurence S. Magder, PhD, for their help in preparing this manuscript. The authors also thank University of Maryland, Baltimore, Institute for Clinical & Translational Research (ICTR), and the National Center for Advancing Translational Sciences (NCATS) Clinical Translational Science Award (CTSA) (Grant No. 1UL1TR003098), for their support.

Correspondence: Janet Leath Alexander, MD, 419 West Redwood Street, Suite 479, Baltimore, MD 21201. Email: jalexander@som.umaryland.edu

Received: January 03, 2020
Accepted: April 14, 2020

10.3928/01913913-20200506-01

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