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Figure 1.  Measurement of Parapapillary Choroidal Vessel Density (VD)
Measurement of Parapapillary Choroidal Vessel Density (VD)

A, The en face image of the choroidal map yielded by optical coherence tomography angiography was used. The boundaries of the optic disc and β-zone parapapillary atrophy (PPA) were delineated (yellow line) using ImageJ software. B, Then, a binary slab was created according to the mean threshold algorithm of ImageJ, which automatically computed the threshold value as the mean of the local grayscale distribution. After assigning white pixels as vessels and black pixels as background, parapapillary choroidal VD was measured as a percentage of vessel pixels within the β-zone PPA region relative to the total area of the β-zone PPA (within the yellow shaded region).

Figure 2.  A Representative Case
A Representative Case

A, The measured baseline parapapillary choroidal vessel density (VD) was 39.2% within the β-zone parapapillary atrophy area in a 54-year-old woman with open-angle glaucoma. B, The mean deviation of the visual field (VF) showed fast progression. C, The retinal nerve fiber layer (RNFL) thickness showed fast progression.

Table 1.  Demographics and Clinical Characteristics
Demographics and Clinical Characteristics
Table 2.  Factors Associated With Progression of Glaucoma as Measured With VF Using Logistic Regression Analysis
Factors Associated With Progression of Glaucoma as Measured With VF Using Logistic Regression Analysis
Table 3.  Factors Associated With Progression of Glaucoma as Measured With VF Using Cox Proportional Hazard Analysis
Factors Associated With Progression of Glaucoma as Measured With VF Using Cox Proportional Hazard Analysis
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Original Investigation
March 28, 2019

Association Between Parapapillary Choroidal Vessel Density Measured With Optical Coherence Tomography Angiography and Future Visual Field Progression in Patients With Glaucoma

Author Affiliations
  • 1Department of Ophthalmology, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
JAMA Ophthalmol. 2019;137(6):681-688. doi:10.1001/jamaophthalmol.2019.0422
Key Points

Question  Is parapapillary choroidal vessel density within the β-zone peripapillary atrophy as measured by optical coherence tomography angiography at baseline associated with future glaucoma progression?

Findings  In this cohort study of 108 patients with open-angle glaucoma, baseline parapapillary choroidal vessel density was associated with progression of glaucoma as measured by visual field using Cox proportional hazard regression analysis, as was older age and poorer mean deviation of the visual field.

Meaning  These data suggest that lower parapapillary choroidal vessel density within the β-zone peripapillary atrophy at baseline among individuals with glaucoma could play a role in the risk of progression of glaucoma as measured by the visual field.

Abstract

Importance  Investigating the vascular risk factors of glaucoma progression is important to individualize treatment; however, few studies have investigated these factors because the available methods have proven insufficient to evaluate the vascular features of patients with glaucoma. Recently, the advent of optical coherence tomography angiography (OCT-A) allowed both qualitative and quantitative microvascular data to be obtained, to in turn evaluate the perfusion status of different retinal layers.

Objective  To determine whether baseline parapapillary choroidal vessel density (VD) as measured by OCT-A was associated with future glaucoma progression.

Design, Setting, and Participants  A prospective, observational, comparative study was conducted at Seoul St Mary’s Hospital of The Catholic University of Korea from March 1, 2016, to December 31, 2018, for 108 glaucomatous eyes in which the retinal nerve fiber layer thickness and mean deviation were measured by at least 5 serial OCT and visual field (VF) examinations. The participants underwent OCT-A at baseline. Vessel density was measured using the en face image of the choroidal map of OCT-A within the β-zone parapapillary atrophy region.

Main Outcomes and Measures  Parapapillary choroidal VD, retinal nerve fiber layer thinning rate, mean deviation rate, and progression of glaucoma as measured by OCT and VF.

Results  Among 108 patients (74 women and 34 men; mean [SD] age, 59.2 [13.1] years), 38 (35.2%) showed progression of glaucoma as measured by OCT and 34 (31.5%) showed progression of glaucoma as measured by VF at the last follow-up. The mean (SD) follow-up duration was 2.6 [2.3] years. The presence of disc hemorrhage (odds ratio, 5.57; 95% CI, 3.18-8.29; P = .001), baseline mean deviation (odds ratio, 0.83; 95% CI, 0.71-0.97; P = .02), and parapapillary choroidal VD (odds ratio, 1.18; 95% CI, 1.09-1.28; P = .01) were associated with progression of glaucoma as measured by VF, but not with progression of glaucoma as measured by OCT. Baseline parapapillary choroidal VD (β, 1.08; 95% CI, 1.02-1.13; P < .001) was associated with progression of glaucoma as measured by VF using Cox proportional hazards regression analysis.

Conclusions and Relevance  These data suggest that lower parapapillary choroidal VD within the β-zone parapapillary atrophy at baseline among individuals with glaucoma could play some role in the risk of progression of glaucoma as measured by VF. The findings suggest that patients with glaucoma with lower parapapillary choroidal VD within the β-zone parapapillary atrophy at baseline warrant careful monitoring for progression of glaucoma as measured by VF.

Introduction

Glaucoma is a progressive optic neuropathic condition characterized by a distinct visual field (VF) defect. Patients with glaucoma use glaucoma medication to slow the rate of progression; however, the rate of progression varies among patients. Identifying risk factors associated with the progression of glaucoma is therefore important because these factors may determine the amount of medication required and the follow-up intervals during management. Investigating the clinical features associated with progression of glaucoma may help to individualize treatment. However, there have been few studies investigating the vascular factors associated with progression of glaucoma because the available methods have proven insufficient to evaluate the vascular features of patients with glaucoma.1,2

Recently, the advent of optical coherence tomography angiography (OCT-A) allowed both qualitative and quantitative microvascular data to be obtained, to in turn evaluate the perfusion status of different retinal layers. Studies have reported that focal loss in the choroidal microvasculature was associated with progressive glaucoma in eyes with disc hemorrhage (DH), and reduced choroidal microvasculature within the β-zone parapapillary atrophy (PPA) was associated with the laterality of glaucomatous VF damage in myopic eyes3,4; these findings show the clinical relevance of OCT-A in glaucoma evaluation. The purpose of this study was therefore to determine whether the vessel density (VD) as measured on OCT-A was associated with the future rate of progression of glaucoma in terms of retinal nerve fiber layer (RNFL) thinning and changes in the VF parameter.

Methods
Participants

This study was a component of the Catholic Medical Center Glaucoma Progression Study, which began March 1, 2009, at Seoul St Mary’s Hospital, Seoul, Republic of Korea. The study was approved by the institutional review board of Seoul St Mary’s Hospital and it followed all relevant tenets of the Declaration of Helsinki.5 We enrolled all consecutive eligible patients who were willing to participate, and all patients provided written informed consent.

All patients with open-angle glaucoma (OAG) who were enrolled in the Catholic Medical Center Glaucoma Progression Study underwent a complete ophthalmic examination, including a review of their medical history, measurement of best-corrected visual acuity, refraction assessment, slitlamp biomicroscopy, gonioscopy, Goldmann applanation tonometry, measurement of central corneal thickness via ultrasound pachymetry (Tomey), measurement of axial length using ocular biometry (IOL Master; Carl Zeiss Meditec), dilated stereoscopic examination of the optic disc, red-free fundus photography (Canon), OCT examination (Cirrus OCT; Carl Zeiss Meditec), and Humphrey VF examination using the Swedish interactive threshold Standard 24-2 algorithm (Carl Zeiss Meditec). In addition, patients underwent OCT-A examinations starting March 1, 2016, and ending December 31, 2018 (for this study).

Data on patients with OAG who were followed up for at least 2 years with at least 5 serial OCT and VF examinations, and who underwent baseline OCT-A imaging, were reviewed by 2 of us (H.Y.-L.P. and S.J.J.). Open-angle glaucoma was defined by the presence of a glaucomatous optic disc exhibiting diffuse or localized rim thinning; a notch in the rim or a vertical cup-disc ratio 0.2 or greater than that of the other eye; a VF pattern consistent with glaucoma (a cluster of ≥3 nonedge points on the pattern deviation plot with a probability of <5% that of the normal population, and with 1 of these points having a probability of <1%); a pattern SD with P < .05, or a Glaucoma Hemifield Test result consistently outside the normal range on 2 VF examinations, as confirmed by 2 glaucoma specialists (H.Y.-L.P. and C.K.P.); and an open angle evident on results of gonioscopy. All DHs occurring during follow-up visits were recorded from the disc photographs. The intraocular pressure was recorded at each visit. The mean intraocular pressure during the entire follow-up period was calculated by averaging all of the measurements.

Additional inclusion criteria were as follows: a best-corrected visual acuity of 20/40 or greater, a spherical refraction within ±6.0 diopters (D), cylinder correction within ±3.0 D, at least 5 reliable VF measurements (false negatives <15%, false positives <15%, and fixation losses <20%), and a mean deviation (MD) better than –20.00 dB. The exclusion criteria were as follows: a history of any retinal disease, including diabetic or hypertensive retinopathy; a history of eye trauma or surgery, with the exception of uncomplicated cataract surgery; any optic nerve disease except glaucoma; and a history of systemic or neurologic disease that might affect the VF. If incisional or laser glaucoma treatment was performed during follow-up, only the data obtained prior to treatment were analyzed. If both eyes of an enrolled patient met all inclusion and exclusion criteria, 1 eye was randomly chosen for study.

Optical Coherence Tomography Angiography

The DRI OCT Triton system used a swept source laser with a wavelength of 1050 nm and scan speed of 100 000 A-scans per second, using the Topcon OCT angiography ratio analysis algorithm. Optical coherence tomography angiography of the DRI OCT generated en face images via automated layer segmentation around the optic nerve head into 4 layers; the deep layer parapapillary choroidal microvasculature in the relevant region was evaluated using en face images generated via automated layer segmentation of signals from the retinal pigment epithelium that extended to the outer border of the sclera. Only clear images with quality scores greater than 30 that did not exhibit blurring attributable to motion were analyzed. For the measurement of choroidal VD, the boundaries of the optic disc and β-zone PPA were delineated (Figure 1, yellow line) using ImageJ software (National Institutes of Health). Eyes in which the optic disc or β-zone PPA could not be clearly delineated, as well as eyes without β-zone PPA on the en face mages, were excluded. An 8-bit binary slab was then created according to the mean threshold algorithm of ImageJ, which automatically computed the threshold value as the mean of the local grayscale distribution. After assigning white pixels as vessels and black pixels as background, parapapillary choroidal VD was defined as a percentage of vessel pixels within the β-zone PPA region relative to the total area of the β-zone PPA (Figure 1, yellow shaded region). Two independent observers (H.Y.-L.P. and S.J.J.) blinded to clinical data independently measured parapapillary choroidal VD using the en face images from the choroidal map of OCT-A, then averaged the data, which were used in the final analyses.

Definition of Progression of Glaucoma as Measured by OCT and VF

Mean RNFL thickness was measured using the optic disc cube scan mode of the Cirrus OCT. After creating an RNFL thickness map from the cube data set, the built-in software automatically determined the center of the disc and next extracted a circumpapillary circle (radius, 1.73 mm) from the data set, prior to calculation of RNFL thickness measurements. All accepted images exhibited a centered optic disc, were well focused with even and adequate illumination, exhibited no eye motion within the measurement circle and no segmentation error, and had a signal strength of 7 or greater.

Progression of glaucoma as measured by OCT was determined using the Cirrus Guided Progression Analysis (GPA) software, with the data analyzed in the optic disc cube 200 × 200 mode. Using the mean RNFL thickness, progression was identified if the observed change from baseline to a test value exceeded the test-retest variability of the system. We considered that likely loss reflected progression of glaucoma as measured by OCT.

Progression of glaucoma as measured by VF was determined by event-based analysis using the GPA software from the Humphrey Field Analyzer. For each individual VF test location, the GPA compared the sensitivity on follow-up testing with that for the same location obtained from averaging 2 baseline tests. Progression of glaucoma as measured by VF was defined as a significant decrease from baseline (2 VFs) pattern deviation at 3 or more of the same test points on 3 or 3 consecutive VF tests. The software classified VF progression as possible progression or likely progression. Only the likely progression condition was defined as progression of glaucoma as measured by VF.

Statistical Analysis

The interobserver reproducibility of measurements of parapapillary choroidal VD was evaluated by having 2 observers (H.Y.-L.P. and S.J.J.) measure this parameter in 30 randomly selected eyes, to calculate the intraclass correlation coefficients and their CIs. We used the t test to compare continuous variables and the χ2 test to compare categorical variables between progression and stable groups. Possible associations between the parapapillary choroidal VD and ocular parameters were analyzed by calculating Pearson correlations. Correlation coefficient from the Pearson correlation analysis was graded using the guideline by Evans6: 0 to 0.19 as very weak, 0.20 to 0.39 as weak, 0.40 to 0.59 as moderate, 0.60 to 0.79 as strong, and 0.80 to 1.00 as very strong correlation. Linear regression analysis against time was performed for the mean RNFL thickness or the MD of the VF for each patient, to determine the rate of change in terms of mean RNFL thickness (expressed in micrometers per year) and MD (expressed in decibels per year). Univariate and multivariate logistic regression analyses were used to identify factors associated with progression of glaucoma as measured by OCT and VF. The dependent variable was likely loss of RNFL thickness or likely progression of glaucoma as measured by VF determined on GPA analysis. Hazard ratios for an association between potential risk factors and progression of glaucoma as measured by VF was obtained using a Cox proportional hazards regression analysis. Independent variables yielding P < .20 in the univariate model were included in the multivariate model. All P values were from 2-sided tests and results were deemed statistically significant at P < .05. All statistical analyses were performed with SPSS for Windows statistical software, version 16.0 (SPSS Inc).

Results

A total of 122 eyes of 122 patients with OAG who met the inclusion and exclusion criteria were included. Of the 122 eyes, 12 (9.8%) were excluded from further analyses because the OCT-A images were of poor quality or had motion artifacts. Two (1.6%) were excluded because the optic disc or β-zone PPA could not be clearly delineated. The remaining 108 eyes of 108 patients with OAG were further analyzed. The mean (SD) follow-up duration was 2.6 [2.3] years. The measurement of parapapillary choroidal VD showed excellent interobserver agreement (intraclass correlation coefficient, 0.91; 95% CI, 0.90-0.93).

Baseline characteristics of all 108 patients are in Table 1. The measured mean (SD) VD within the PPA area was 51.2% (9.8%). Among these patients, 38 (35.2%) showed progression of glaucoma as measured by OCT and 34 (31.5%) showed progression of glaucoma as measured by VF. Sixteen of 108 eyes (14.8%) showed progression of glaucoma as measured by both OCT and VF. Comparisons between eyes with progression of glaucoma and stable eyes with OCT revealed that eyes with progression of glaucoma as measured by OCT showed lower mean (SD) RNFL thicknesses at baseline compared with the stable group (82.97 [8.73] vs 89.00 [6.29] μm; P < .001; eTable 1 in the Supplement). Mean (SD) parapapillary choroidal VD was similar between the group with progression as measured by OCT and the stable group (49.2% [11.7%] vs 51.8% [8.3%]; P = .26). Data on the comparison between progression and stable eyes on VF are shown in Table 1. The presence of DH (odds ratio, 5.57; 95% CI, 3.18-8.29; P = .001), baseline MD (odds ratio, 0.83; 95% CI, 0.71-0.97; P = .02), and parapapillary choroidal VD (odds ratio, 1.18; 95% CI, 1.09-1.28; P = .01) were associated with progression of glaucoma as measured by VF, but not with progression of glaucoma as measured by OCT. The mean (SD) parapapillary choroidal VD was reduced in the group with progression as measured by VF (47.0% [6.5%]) compared with the stable group (52.5% [10.4%]; P = .001).

We determined correlations between clinical characteristics and the parapapillary choroidal VD (eTable 2 in the Supplement). The refractive error (R = 0.57; P < .001) and axial length (R = –0.56; P < .001) showed moderate correlations with the parapapillary choroidal VD. Peripapillary atrophy area (R = –0.28; P = .01), baseline mean RNFL thickness (R = 0.35; P < .001), baseline MD of the VF (R = 0.402; P < .001), and rate of change in both the mean RNFL thickness (R = 0.47; P < .001) and the MD of the VF (R = 0.21; P = .03) showed weak to moderate correlations with the parapapillary choroidal VD.

Regarding the OCT and VF, we used logistic regression analyses to identify factors associated with progression of glaucoma. Only baseline mean RNFL thickness, and not the parapapillary choroidal VD, was associated with progression of glaucoma as measured by OCT on univariate analysis (odds ratio [OR], 1.11; 95% CI, 1.04-1.17; P = .001) and multivariate analysis (OR, 1.68; 95% CI, 1.095-2.58; P = .02) (eTable 3 in the Supplement). In both univariate and multivariate analyses, the presence of DH (univariate: OR, 4.93; 1.83-13.29; P = .002; and multivariate: OR, 5.57; 95% CI, 3.18-8.28; P = .001) and parapapillary choroidal VD (univariate: OR, 1.07; 95% CI, 1.02-1.12; P < .001; and multivariate: OR, 1.18; 95% CI, 1.09-1.28; P = .01) were associated with progression of glaucoma as measured by VF (Table 2). The baseline MD of the VF was associated with progression of glaucoma as measured by VF on multivariate analysis (OR, 0.83; 95% CI, 0.71-0.97; P = .02). Because the area of β-zone PPA could affect the value of parapapillary choroidal VD, we performed logistic regression analysis using β-zone PPA area as a covariate (eTable 4 in the Supplement). The baseline MD (OR, 0.79; 95 % CI, 0.65-0.96; P = .02), presence of DH (OR, 4.88; 95% CI, 1.97-12.81; P < .001), and parapapillary choroidal VD (OR, 1.29; 95% CI, 1.11-1.49; P = .01) were associated with progression of glaucoma as measured by VF after considering β-zone PPA area.

To assess the value of baseline parameters associated with progression of glaucoma as measured by VF, we performed Cox proportional hazards regression analysis (Table 3). Older age (β, 1.19; 95% CI, 1.03-1.28; P < .001), poorer baseline MD (β, 1.88; 95% CI, 1.81-1.97; P < .001), and lower parapapillary choroidal VD (β, 1.08; 95% CI, 1.02-1.13; P < .001) within the β-zone PPA were associated with progression of glaucoma as measured by VF in multivariate analysis.

Representative cases are shown in Figure 2 and eFigure 2 in the Supplement. A 54-year-old woman with OAG had a parapapillary choroidal VD of 39.2%, showing progression of glaucoma as measured by both VF and OCT (Figure 2; eFigure 1 in the Supplement). However, a 62-year-old man with OAG had a parapapillary choroidal VD of 62.7%, showing progression of glaucoma only as measured by OCT, but not as measured by VF (eFigure 2 in the Supplement).

Discussion

In this study, we found that the parapapillary choroidal VD within the β-zone PPA at baseline was decreased in eyes with OAG, with progression of glaucoma as measured by VF. Baseline parapapillary choroidal VD was associated with progression of glaucoma as measured by VF, together with previously known risk factors for progression such as baseline MD and the presence of DH. Baseline parapapillary choroidal VD showed higher utility for determining progression of glaucoma as measured by VF than did baseline RNFL thickness or the baseline MD of the VF.

The findings of this study suggested that the baseline perfusion status of the parapapillary choroid within the β-zone PPA was an important factor associated with progression in patients with OAG. More important, baseline perfusion status of the parapapillary choroid within the β-zone PPA was associated with progression of glaucoma as measured by VF, and not as measured by OCT, and estimated further progression of glaucoma as measured by VF better than the baseline mean RNFL thickness or the MD of the VF. Eyes with a larger β-zone PPA have been reported to be more frequently associated with glaucoma than in healthy controls, including in terms of the severity of glaucoma.7,8 It has been suggested that both mechanical stress and ischemic insults within the β-zone PPA region may further influence and compromise axonal susceptibility in patients with glaucoma. Breakdown of the blood-optic nerve barrier and a reduced blood supply may also contribute to ischemic insults to the optic nerve; these could serve as vascular risk factors. In the present study, investigation of the vessels and perfusion status within the β-zone PPA via measurement of parapapillary choroidal VD indicated that the state of choroidal microcirculation determined the rate of progression, and estimated further progression, in glaucomatous eyes. Our study showed that the perfusion status within the PPA area was associated with faster progression of glaucoma, which we estimated by measuring the parapapillary choroidal VD on the choroidal map of OCT-A, rather than the extent of the β-zone PPA area itself.

Many studies have recently reported the role of OCT-A in glaucoma practice.9-12 Macular and peripapillary VDs in the superficial layer of the retina have shown similar diagnostic utility to RNFL thickness and VF parameters.13-16 In addition, VD parameters as measured with OCT-A have been reported to have strong correlations with results from VF testing.17-19 It is evident that the VD of the superficial retina, which includes the RNFL and retinal ganglion cell (RGC) layer, decreases as a result of RGC loss during the course of the disease. However, the VD of the deep layer, including the choroidal vasculature around the optic disc, may have different clinical applications. It may also be reduced during the course of the disease, affect the perfusion status of the optic nerve head, and further contribute to axonal damage in patients with glaucoma. However, a previous report showed that choroidal microvasculature dropout, which is complete focal loss of the choroidal vasculature around the optic disc, was prevalent in eyes with DH with progression of glaucoma.3 Eyes with choroidal microvasculature dropout had a poorer VF than did eyes without this finding in patients with glaucoma.20 This focal loss of choroidal microvasculature was frequently seen in glaucomatous eyes with central VF damage.21 These studies suggest that impairment in parapapillary choroidal perfusion may contribute to functional impairment of the RGC or cause vascular damage to the axons. Taken together, these data suggest that OCT-A parameters of the choroidal microvasculature could represent a valuable vascular factor in clinical practice.

There was a discrepancy between the role of parapapillary choroidal VD in progression of glaucoma as measured by OCT and VF. Choroidal VD had a stronger association with functional progression than structural progression. As shown in the representative cases, eyes with OAG with reduced parapapillary choroidal VD showed progression of glaucoma as measured by both VF and OCT. One interpretation could be that parapapillary choroidal VD was associated with the function of the RGCs. A recent study by Suh et al20 reported that structure-function associations were steeper in eyes with OAG with choroidal microvasculature dropout. They proposed that the perfusion status of the choriocapillaris or microvasculature within the PPA region may directly influence RGC function, leading to functional impairment. This finding suggests that parapapillary choroidal VD could be clinically relevant in the estimation of functional progression, even when structural progression is present in patients with glaucoma.

Limitations

Our study had several limitations. First, OCT-A imaging itself still has certain limitations. Retinal vessel signals evident on en face, deep-layer OCT-A images render it difficult to precisely measure the choroidal VD. This issue should be considered when evaluating OCT-A images. However, recent studies have reported that measurement repeatability and reproducibility were good in intrasession and intersession examinations.15,22-25 We included patients with a minimum of 5 VF tests and OCTs, and these examinations were usually performed at 6- to 12-month intervals. More frequent testing is suggested using linear regression to calculate the rate of progression or detect progression as measured with VF. Considering these issues, we analyzed both global MD rates and mean RNFL thinning, to compare the rates of progression between groups, and used the GPA program for logistic regression analyses. Last, we did not classify the PPA region using OCT in this study; further investigation may be needed to elucidate its clinical significance.26,27

Conclusions

We found that parapapillary choroidal VD within the β-zone PPA at baseline was associated with progression of glaucoma as measured with VF. Imaging the perfusion status of the choroidal microvasculature using OCT-A may be clinically relevant in managing patients with glaucoma and provides an additional tool to assess the risk of progression of glaucoma.

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Article Information

Accepted for Publication: January 31, 2019.

Corresponding Author: Chan Kee Park, MD, PhD, Department of Ophthalmology, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul 137-701, Korea (ckpark@catholic.ac.kr).

Published Online: March 28, 2019. doi:10.1001/jamaophthalmol.2019.0422

Author Contributions: Dr C. K. Park had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: H. Y.-L. Park, C. K. Park.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: H. Y.-L. Park, Jeon.

Critical revision of the manuscript for important intellectual content: H. Y.-L. Park, Shin, C. K. Park.

Statistical analysis: H. Y.-L. Park, Shin, C. K. Park.

Obtained funding: C. K. Park.

Administrative, technical, or material support: H. Y.-L. Park, Jeon, C. K. Park.

Supervision: H. Y.-L. Park, C. K. Park.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by grant NRF-2017R1D1A1B03029229 from the Ministry of Education for design and conduct of the study.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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