September 2014
Volume 55, Issue 9
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Glaucoma  |   September 2014
Choroidal Thickness and Primary Open-Angle Glaucoma: A Cross-Sectional Study and Meta-Analysis
Author Notes
  • Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, People's Republic of China 
  • Correspondence: Xiulan Zhang, Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, 54 S. Xianlie Road, Guangzhou, China 510060; zhangxl2@mail.sysu.edu.cn
Investigative Ophthalmology & Visual Science September 2014, Vol.55, 6007-6014. doi:10.1167/iovs.14-14996
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      Wei Wang, Xiulan Zhang; Choroidal Thickness and Primary Open-Angle Glaucoma: A Cross-Sectional Study and Meta-Analysis. Invest. Ophthalmol. Vis. Sci. 2014;55(9):6007-6014. doi: 10.1167/iovs.14-14996.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: The purpose of this study was to examine the choroidal thickness of patients with POAG using enhanced depth imaging optical coherence tomography (EDI-OCT) and compare them with healthy subjects. We first conducted a cross-sectional study and then performed a meta-analysis to address this issue further.

Methods.: Enhanced depth imaging optical coherence tomography was used to measure the macular choroidal thickness of the POAG and healthy eyes. Univariate and multivariate linear regression analyses were performed to assess the association between choroidal thickness and clinical factors. The meta-analysis was managed with Stata 12.0 software.

Results.: Seventy-six healthy and 52 POAG subjects were recruited for this study. Age and axial length were the significant factors associated with subfoveal choroidal thickness in each group. There were no significant differences in choroidal thickness at any of the nine points between the POAG and healthy eyes after adjusting for IOP, age, and axial length (all P > 0.05). Similarly, there was no association between choroidal thickness and visual field defects (all P > 0.05). Our cross-sectional study indicated no significant difference in choroidal thickness between the POAG and healthy eyes, consistent with the results of the further meta-analysis involving 875 patients and 871 controls (weighted mean difference [WMD] for subfoveal choroidal thickness = −7.36 [95% confidence interval (CI): −24.39 to 9.67], WMD for mean macular choroidal thickness = 6.67 [95% CI: −2.45 to 15.79]). Six studies also provided data on average peripapillary choroidal thickness, and the pooled estimate was −8.15 (95% CI: −16.16 to −0.13, P = 0.046). However, considering that the precision of the OCT was 10 μm, this difference could have been caused by instrument error.

Conclusions.: Our study of Chinese POAG patients, along with the meta-analysis, suggested that POAG was not significantly associated with a marked thinning or thickening of the choroid based on EDI-OCT measurements.

Introduction
Glaucoma is one of the leading causes of blindness in developed and developing countries. Quigley and Brodman 1 estimated that 60.5 million people would suffer from glaucoma in 2010, increasing to 79.6 million by 2020, and that three-quarters of them would have POAG. The choroid serves many physiologic functions, including oxygen and metabolite delivery to the RPE, retina, and prelaminar optic nerve, in addition to being a light and heat sink. 2 Choroidal blood flow is the highest blood flow per tissue mass in the human body. Indocyanine green angiography has been used in patients with glaucoma to demonstrate slow choroidal filling and sluggish movement of blood into and out of the choroid. 3 Slowing has also been shown specifically in normal-tension glaucoma (NTG) patients. 4 In studies conducted using histomorphometric techniques and ultrasound tomography, choroidal changes have been documented in POAG cases, suggesting that choroidal abnormalities may be involved in the pathogenesis of POAG. 5,6  
Optical coherence tomography (OCT) is another method used to study the morphology of the choroid. With the enhanced depth imaging (EDI) technique of OCT instruments, the images of the choroid have improved. An increasing number of investigators have studied choroidal thickness in healthy and diseased eyes. 7,8 Recently, several studies using EDI-OCT were conducted to compare choroidal thickness in patients with POAG and controls and to convey conflicting results. Several researchers have reported on the thinning of the macular or peripapillary choroid in patients with POAG or NTG. 913 However, other studies have found that healthy, POAG, and NTG subjects have comparable choroidal thickness, suggesting a lack of relationship between choroidal thickness and POAG. 1418 Thus, the possible association between choroidal thickness and POAG remains unclear, which justifies the need for more studies on this issue. 
In this study, we first decided to evaluate macular choroidal thickness (MCT) in Chinese POAG patients and healthy subjects, and to determine the correlation with clinical factors. Then, given the accumulating data and to shed some light on current uncertain claims, we sought to conduct a comprehensive meta-analysis of the relationship between choroidal thickness and POAG. 
Methods
Subjects and Procedures
In this cross-sectional study, all participants were examined at the Zhongshan Ophthalmic Center of Sun Yat-sen University from March 2013 until April 2014. The ethics committee of Zhongshan Ophthalmic Center approved the study protocol. All participants were informed and provided written informed consent before entering the study. All of the subjects were from a Chinese Han population. All clinical investigations conducted in this study conformed to the tenets of the Declaration of Helsinki. 
Inclusion criteria for all participants were age older than 40 years, open angles, reliable visual fields, spherical equivalent less than ±6 diopters (D), absence of diabetes and other systemic diseases, and no corneal or lens opacity that interfered with clinical evaluation or OCT examination. Primary open-angle glaucoma subjects were included if they had an established diagnosis of POAG made by a glaucoma specialist based on two reliable and repeatable visual fields (Humphrey Visual Field analysis using the SITA 24-2 perimetry) with the glaucoma hemifield test outside normal limits and pattern standard deviation (PSD) cluster criteria (P < 0.05) corresponding with documented neuroretinal rim narrowing or notching on stereophotographs. 16 The heathy subjects were volunteers from health examinations. One eye of each heathy subject was randomly selected. The eyes classified as heathy controls did not have any pathology other than mild to moderate cataracts. The other criteria for heathy subjects were best-corrected Snellen visual acuity of 0.5 or better, IOP less than 21 mm Hg, and normal optic disc appearance. Exclusion criteria for all subjects included history of retinal disease, any retinal or RPE abnormality detectable with OCT, use of systemic corticosteroids or any intravitreal medications, and poor image quality. Subjects with congenital glaucoma, angle-closure glaucoma, and secondary glaucoma were also excluded. 
Ophthalmic Examination
All of the participants underwent comprehensive ophthalmologic examinations, which included visual acuity assessment, slit-lamp inspection, Goldmann applanation tonometry, gonioscopy, indirect dilated ophthalmoscopy, standard automated perimetry, ultrasound biomicroscopy (UBM), and B-scanning. They also underwent a refractive error examination with an auto refractometer (KR-8900 version 1.07; Topcon Corporation, Tokyo, Japan). The following ocular biometric parameters were measured by A-mode ultrasonography (CINESCAN; Quantel Medical, Cedex, France): central anterior chamber depth (from the anterior corneal surface to the anterior crystalline lens surface), lens thickness (from the anterior to the posterior lens surface), vitreous chamber depth (from the posterior lens surface to the inner limiting membrane), and axial length (from the anterior corneal surface to the inner limiting membrane). 
Choroid Imaging
All subjects were examined with Spectralis HRA-OCT with EDI mode (Heidelberg Engineering, Heidelberg, Germany). The method of this system has been reported in detail in our previous reports. 19,20 Briefly, the choroid was imaged by positioning a spectral-domain (SD) OCT machine close enough to the eye to obtain a clear image. One vertical and one horizontal 9-mm line scan intersecting at the fovea was taken of each eye. Each image was averaged from 100 scans using the automated averaging and eye-tracking features provided by the Spectralis. Built-in electronic calibers (Heidelberg Eye Explorer Version 1.6.4.0; Heidelberg Engineering) were used to measure choroidal thickness via the method described previously. 19,20 In short, choroidal thickness was defined as the distance between the RPE (outermost hyper reflective line) to the inner margin of the sclera. Choroidal thickness was measured at nine points: subfoveal choroidal thickness (SFCT) and choroidal thickness at 1- and 3-mm nasal, temporal, superior, and inferior to the fovea. The average MCT was calculated by averaging the choroidal thicknesses at the nine points. All measurements were taken by a single experienced technician who was masked to the identity of the subjects and was not involved in the data analysis. To avoid diurnal variation in choroidal thickness, all EDI-OCT examinations were performed at approximately 10 and 12 AM. 
Statistical Analysis
The statistical analyses were performed using SPSS 20.0 (SPSS, Inc., Chicago, IL, USA). The normality of the data distribution for continuous variables was verified by the Kolmogorov-Smirnov test. Regarding continuous variables, Student's t-test was used for normally distributed variables and the Mann-Whitney U test was used for nonnormally distributed variables. Fisher's exact test was performed for categorical variables. Univariate and multivariate regression analysis was used to evaluate the potential factors associated with SFCT in POAG and healthy subjects. Univariate regression analyses were performed separately for each variable. Variables with a probability value less than or equal to 0.10 in univariate analyses were included in the multivariate analysis by a stepwise method. Analysis of covariance was used to calculate and compare choroidal thickness after adjusting for other variables for the POAG and healthy subjects. For all the tests, P values less than 0.05 were considered statistically significant. 
Meta-Analysis
This meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline. 21  
Relevant studies were identified by systematically searching the PubMed, Embase, Web of Science, and Chinese Biomedicine databases from its inception up to April 2014. The websites of professional associations (American Association of Ophthalmology and ARVO) were also searched. The following keywords were used: glaucoma, ocular hypertension, choroidal thickness, choroid, optical coherence tomography, enhanced depth imaging, OCT. The search results were supplemented by reviews of reference lists for all relevant studies and review articles. No minimum number of patients was required for the meta-analysis. 
Studies qualified for the study if they met the following criteria: (1) cross-sectional or case-control design, (2) choroidal thickness measured by OCT, (3) differences in choroidal thickness between patients with POAG and controls reported, and (4) include at least one of the following outcomes: SFCT, MCT, and average peripapillary choroidal thickness (PCT). In studies of the same population, only the latest or the most complete studies were included. Reviews or letters to the editor without original data, editorials, case reports, and studies with important data unavailable were excluded. Two reviewers read the identified articles carefully and assessed them independently. Discrepancies regarding eligibility were discussed and decided via consensus. For each paper, the following information was extracted into a table: first author, year of publication, number of glaucoma patients and controls, and difference in choroidal thickness. Where possible, data regarding the maximally adjusted differences in choroidal thickness were extracted. 
To arrive at a conservative estimate of the effect of potential population differences among the studies, the random effects model was used to calculate pooled WMDs in the meta-analysis. 22 Between-study heterogeneity was assessed by χ2 test and I2 statistics. For the χ2 test, a P value less than 0.10 was considered statistically significant for heterogeneity; for the I2 statistic, values of 25%, 50%, and 75% represented mild, moderate, and severe heterogeneity, respectively. 23 To explore the source of heterogeneity, subgroup analyses according to instrument used, type of glaucoma, source of controls, and levels of adjustment were conducted. To assess the influence of individual studies on the pooled result, sensitivity analyses were performed by excluding each study, one by one, and recalculating the combined estimates based on the remaining studies. Potential publication bias was evaluated using funnel plots, Begg's test, and Egger's test at the P less than 0.1 level of statistical significance. All other levels of statistical significance were set at 0.05, except as noted. All meta-analyses were performed using Stata SE 12.0 (StataCorp LP, College Station, TX, USA). 
Results
Demographic Data of Subjects
A total of 52 patients with POAG and 76 healthy subjects were included in the study. All of the subjects had clear images of the sclerochoroidal junction, and no image was excluded due to indeterminate posterior border of the choroid. The mean age of the healthy subjects was 56.6 ± 11.5 years, and that of the POAG patients was 58.19 ± 11.75 years (P = 0.446). The mean number of topical antiglaucomatous drugs was 4.1 ± 1.3 for POAG patients. As expected, the patients with POAG had higher IOP at imaging, a greater cup to disc (C/D) ratio, and more severe mean deviation (MD) or PSD compared with healthy subjects. The demographics and clinical characteristics of the study population are summarized in Table 1. No significant differences were noted in spherical equivalent, diastolic blood pressure (BP), systolic ocular perfusion pressure (OPP), axial length, anterior chamber depth, lens thickness, or vitreous chamber depth between the healthy and POAG patients. However, there were significant differences in systolic BP, mean BP, diastolic OPP, and mean OPP. 
Table 1
 
Clinical Characteristics of the Participants
Table 1
 
Clinical Characteristics of the Participants
Characteristics Healthy, n = 76 POAG, n = 52 P
Age, y 56.6 ± 11.5 58.2 ± 11.8 0.446
IOP at imaging, mm Hg 15.2 ± 3.6 30.8 ± 12.1 <0.001
Spherical equivalent, D 0.3 ± 1.7 0.5 ± 1.7 0.062
Systolic BP, mm Hg 122.5 ± 16.6 133.2 ± 14.3 0.017
Diastolic BP, mm Hg 75.1 ± 8.3 78.1 ± 8.9 0.194
Mean BP, mm Hg 90.9 ± 9.5 96.4 ± 10.2 0.036
Systolic OPP,* mm Hg 107.2 ± 15.8 101.9 ± 22.5 0.258
Diastolic OPP,† mm Hg 59.8 ± 8.7 46.7 ± 20.1 <0.001
Mean OPP,‡ mm Hg 75.6 ± 9.3 65.1 ± 20.5 0.002
Axial length, mm 23.1 ± 0.9 23.2 ± 0.9 0.640
Anterior chamber depth, mm 3.13 ± 0.54 3.12 ± 0.57 0.935
Lens thickness, mm 4.4 ± 0.7 4.4 ± 0.7 0.732
Vitreous chamber depth, mm 16.8 ± 0.8 16.4 ± 1.6 0.068
C/D 0.3 ± 0.04 0.8 ± 0.2 <0.001
MD, dB −1.7 ± 1.2 −22.0 ± 11.6 <0.001
PSD, dB 1.9 ± 0.5 5.6 ± 3.6 0.025
Factors Associated With SFCT
Univariate and multivariate regression analyses were performed to determine the factors associated with SFCT in healthy subjects and POAG patients. The results of these analyses are shown in Table 2. The variables associated significantly with SFCT by univariate regression were age, sex, axial length, lens thickness, diastolic OPP, and mean OPP for all participants; age, sex, axial length, lens thickness, systolic OPP, diastolic OPP, and mean OPP for healthy subjects; and age and axial length for patients with POAG. These associative variables were then entered into a multivariate regression analysis. Independent factors of choroidal thinning were age and axial length (all P < 0.05). 
Table 2
 
Association Between Subfoveal Choroidal Thickness With Other Factors
Table 2
 
Association Between Subfoveal Choroidal Thickness With Other Factors
Factors All Healthy POAG
β P β P β P
Univariate regression
 Age, y −2.6 <0.001 −2.9 <0.001 −2.3 <0.001
 Sex (male vs. female) 24.9 0.006 36.1 0.003 8.6 0.516
 IOP at imaging, mm Hg 0.3 0.446 4.7 0.446 −0.1 0.822
 Spherical equivalent, D 2.9 0.340 0.1 0.989 5.2 0.170
 Axial length, mm −39.8 <0.001 −45.5 <0.001 −32.3 <0.001
 Anterior chamber depth, mm 7.5 0.389 7.5 0.525 7.6 0.558
 Lens thickness, mm −14.7 0.041 −19.4 0.044 −6.9 0.530
 Vitreous chamber depth, mm −4.1 0.354 −4.3 0.565 −4.7 0.373
 MD, dB −0.1 0.828 15.9 0.539 −0.2 0.792
 PSD, dB 1.9 0.338 −17.6 0.801 2.3 0.301
 Systolic BP, mm Hg −0.1 0.724 −0.4 0.322 0.4 0.478
 Diastolic BP, mm Hg −0.8 0.267 −1.3 0.113 0.7 0.488
 Mean BP, mm Hg −0.5 0.402 −1.1 0.132 0.6 0.463
 Systolic OPP, mm Hg −0.5 0.167 −0.7 0.082 0.5 0.203
 Diastolic OPP, mm Hg −0.9 0.030 −2.1 0.005 0.6 0.212
 Mean OPP, mm Hg −0.9 0.038 −1.9 0.006 0.6 0.199
Multivariate regression
 Axial length, mm −33.3 <0.001 −36.1 <0.001 −33.2 <0.001
 Age, y −1.6 <0.001 −1.4 0.004 −2.5 <0.001
Adjusted Choroidal Thickness Compared Between POAG and Healthy Subjects
The choroid was found to be thickest beneath the fovea and thinner nasally, temporally, superiorly, and inferiorly. This pattern was observed in healthy subjects and patients with POAG, in agreement with previous studies. Table 3 shows the choroidal thickness at each location after adjusting for IOP, age, and axial length. There were no significant differences in choroidal thickness between the healthy subjects and patients with POAG at any of the locations (all P > 0.05). 
Table 3
 
Choroidal Thickness in Healthy and POAG Subjects After Adjusting Axial Length, Age, and IOP
Table 3
 
Choroidal Thickness in Healthy and POAG Subjects After Adjusting Axial Length, Age, and IOP
Location Healthy POAG P*
SFCT 257.8 ± 37.9 255.9 ± 38.3 0.776
T3, mm 211.9 ± 26.3 215.0 ± 26.8 0.532
T1, mm 242.5 ± 44.4 238.3 ± 44.8 0.611
N1, mm 230.6 ± 47.9 221.1 ± 48.6 0.291
N3, mm 150.1 ± 35.2 148.8 ± 35.6 0.840
I3, mm 197.8 ± 49.1 204.4 ± 49.9 0.469
I1, mm 230.1 ± 57.4 225.6 ± 57.9 0.674
S1, mm 252.2 ± 56.2 247.3 ± 57.1 0.643
S3, mm 249.3 ± 41.4 239.9 ± 42.3 0.227
MCT 224.1 ± 43.7 221.5 ± 44.1 0.747
Eligible Articles for Meta-Analysis
To obtain more information about the results of other similar studies, a meta-analysis was performed. The initial search yielded 104 potentially relevant articles. After applying the inclusion/exclusion criteria, 16 studies (Ciechanowski PP, et al. IOVS 2011;50: ARVO E-Abstract 3501; and Refs. 9–18, 24–28) were eligible for inclusion. The retrieved studies, published between 2011 and 2014, included 14 published full-text studies 918,24,25,26,28 and two meeting abstracts (Ciechanowski PP, et al. IOVS 2011;50: ARVO E-Abstract 3501 and Ref. 27). 
Characteristics of the Studies Included in the Meta-Analysis
Table 4 summarizes the characteristics of the previous studies on differences in choroidal thickness between POAG patients and controls, using an OCT device. Sixteen separate studies plus the present study, encompassing a total of 875 patients with POAG and 871 controls, were finally meta-analyzed, with seven studies conducted on Asians, five on Caucasians, and five on multiracial composition of the population. Fourteen studies reported adjusted differences in choroidal thickness between patients and controls. All the studies performed the choroid imaging using Spectralis, with the exception of scanning laser ophthalmoscope-OCT in Cennamo et al. 26 and swept source-OCT in Usui et al. 11 The report by Usui et al. 11 differed from the others in that it included younger high-myopia NTG patients. All but two studies were in agreement that there were no significant differences in optic nerve parameters. Macular parameters did not show such consistency, but not all of the authors investigated them. 
Table 4
 
Characteristics of the Studies Included in the Meta-Analysis
Table 4
 
Characteristics of the Studies Included in the Meta-Analysis
Author, y Location CT Instrument Glaucoma Sample Size Age Adjusting
Mwanza et al.,16 2011 USA SFCT Spectralis POAG 76/38 60.1/73.8 Age, Axl, IOP
MCT NTG
Arora et al.,24 2012 USA MCT Spectralis POAG 106/40 67.8/65.7 Age, Axl, IOP, CCT
POAGS
Rhew et al.,25 2014 Korea SFCT Spectralis NTG 32/35 53.0/45.7 Age
Hirooka et al.,13 2012 Japan SFCT Spectralis NTG 45/62 67.0/63.8 Age, SE
Ciechanowskiet et al.,* 2011 Switzerland SFCT Spectralis POAG 21/41 Age
Maul et al.,18 2011 USA MCT Spectralis OAG 30/23 66.5/63.1 Age, Axl, CCT, DOPP, sex, race
PCT
Cennamo et al.,26 2012 Italy SFCT SD-SLO/OCT POAG 10/14 51/49 None
Usui, 2012 Japan SFCT SS-OCT PM-NTG 12/12 33.6/31.2 Age, Axl, SE
PCT
Mwanza et al.,15 2012 USA SFCT Spectralis POAG 24/24 69.6 Age, Axl, IOP
Steinmetz and Jonas,27 2013 Germany SFCT Spectralis OAG 71/228 Age, SE
Park et al.,9 2014 Korea MCT Spectralis POAG 108/48 63.5/57.8 None
PCT NTG
Suh et al.,28 2014 Korea PCT Spectralis NTG 61/61 52.6 Age, Axl, IOP, MD, PSD, CCT, systemic disease, sex, SE
Li et al.,14 2013 China PCT Spectralis POAG 31/31 57.2/57.9 Age, sex
Hirooka,12 2012 Japan PCT Spectralis NTG 52/50 66.2/62.4 None
Roberts et al.,10 2012 Canada PCT Spectralis OAG 89/76 71.1/56.1 Age
Ehrlich et al.,17 2011 USA PCT Spectralis POAG 31/39 62.6/59.6 Age, PPA
Present China SFCT Spectralis POAG 76/52 58.2/56.6 Age, Axl, IOP
MCT
Meta-Analysis Results
After combining all of the qualified studies, no significant differences in MCT were observed between the POAG and healthy subjects, with pooled WMDs of −7.36 (95% confidence interval [CI]: −24.40 to 9.67; P = 0.397) for SFCT and 6.67 (95 CI%: −2.45 to 15.79; P = 0.152) for MCT (Fig.). The heterogeneities were found to be severe for SFCT and zero for MCT. Regarding PCT, the pooled estimate from six studies was −8.15 (95% CI: −16.16 to −0.13, P = 0.046), with nil heterogeneity (Fig.). Considering that the precision of the OCT was 10 μm, this difference could have been caused by instrument error. Subgroup analyses were performed to evaluate whether the pooled estimates were different according to type of instrument, type of glaucoma, source of controls, and levels of adjustment (Table 5). Restricting analysis to studies that measured SFCT using Spectralis, the heterogeneity became very small; thus, the studies by Cennamo et al. 26 and Usui et al. 11 were the source of the heterogeneity. Similar findings were obtained in other subgroup analyses, indicating the robustness of our results (Table 5). 
Figure
 
Forest figure of all studies comparing SFCT, mean macular thickness, and average PCT in POAG and those in controls.
Figure
 
Forest figure of all studies comparing SFCT, mean macular thickness, and average PCT in POAG and those in controls.
Table 5
 
Subgroup Analysis of SFCT in POAG Subjects Compared With Healthy Eyes
Table 5
 
Subgroup Analysis of SFCT in POAG Subjects Compared With Healthy Eyes
Group N Studies WMD (95% CI) I2 P heterogeneity P overall
All 9 −7.4 (−24.4, 9.7) 84.6% <0.001 0.397
Instrument
 Spectralis 7 −7.3 (−13.0, −1.5) 0.0% 0.879 0.014
 Other 2 −19.6 (−193.2, 154.0) 97.5% <0.001 0.825
Type of glaucoma
 POAG 4 8.8 (−19.7, 37.3) 90.2% <0.001 0.547
 NTG 2 −15.6 (−39.3, 8.2) 0.0% 0.751 0.199
Source of control
 Healthy 7 1.7 (−18.2, 21.6) 81.4% <0.001 0.867
 Glaucoma-suspects 2 −55.5 (−155.5, 44.6) 94.1% <0.001 0.277
Adjusting factors
 Age 2 −9.7 (−19.8, 0.3) 0.0% 0.540 0.058
 Age, SE 2 −18.4 (−47.5, 10.6) 0.0% 0.556 0.213
 Age, Axl, IOP 3 −5.3 (−12.5, 2.0) 0.0% 0.744 0.152
Publication Bias
A one-way sensitivity analysis was conducted to evaluate the stability of the meta-analysis, and the results were not altered when any single study was omitted. A funnel plot was created to access the potential publication bias of the literature, and the arrangement of the data points did not reveal any evidence of obvious asymmetry. In addition, Begg's tests and Egger's tests confirmed that the results did not show any evidence of publication bias (all P > 0.05). 
Discussion
Glaucoma is a multifactorial optic neuropathy, and it has been suggested that the choroid is associated with the development and progression of glaucomatous optic neuropathy and visual field loss. 29 Several studies have demonstrated that blood flow to the choroid is diminished in patients with POAG, and some previous histologic reports have suggested that the choroid might be thinner in eyes with glaucoma than in nonglaucoma pathology specimens. 3,30 In contrast, some researchers have detected significant thickening of the choroid in POAG cases. However, histologic studies have not reflected the choroid in vivo and have not controlled for the confounding effects of age, axial length, IOP, and so on. Enhanced depth imaging OCT is a reliable and repeatable technique that has evaluated both the macular and PCT in vivo. 18 Since the first report by Spaide et al., 31 there has been growing interest in the relationship between choroidal thickness and POAG in recent years. Although great efforts have been made, the association between POAG and choroidal thickness is still controversial. With the increase of OCT studies, synthesizing the available data to resolve persistent difficulties in obtaining robust, replicable results is highly encouraged. 
In this study, we observed that choroidal thickness was similar in the glaucomatous eyes and the controls. After a systematic search of several databases, we reviewed 16 studies, plus ours, that compared choroidal thickness in patients with POAG with that of controls. The data from these papers were combined, as they had similar study designs and methods. Our findings of nonsignificance were also reflected in the meta-analysis, even across different subgroups, which are less prone to chance results, indicating the robustness of our findings. As far as we known, this is the first report of MCT in Chinese patients with POAG, and the first meta-analysis on this topic. 
Several strengths distinguishing the present investigation merit adequate consideration. First, to date, this is the first synthesis exploring the association of choroidal thickness with POAG. Second, the results of the present cross-sectional study were in line with that of the corresponding meta-analysis, and restricting the analysis to studies on POAG or NTG generated similar findings. Third, our results are less prone to selection bias, in view of the low probability of publication bias. Fourth, The Beijing Eye Study, which included 3468 participants, found that SFCT was associated with age and axial length, and not with BP, OPP, IOP, or arterial hypertension. 32 Our findings agree with this large study. 
Some limitations should be considered when interpreting our findings. First, only two studies with a mode sample size provided data on NTG; therefore, further pragmatic studies are needed to evaluate the association between choroidal thickness and NTG. Second, choroidal thickness was measured manually; thus, the determination of the scleral border may be subjective in part, and poorly reproducible. However, several studies have reported that choroidal thickness measurement by EDI-OCT is highly reproducible and repeatable. 33,34 Third, the use of topical and systemic medications could affect choroidal thickness. Several studies have confirmed that some antiglaucomatous agents, such as topical α-2 agonists and carbonic anhydrase inhibitors, can increase choroidal blood flow. 3537 Intravenous acetazolamide also increases choroidal thickness, and there are a number of other vasoactive substances that could potential influence the choroid. 3840 However, in studies by EDI-OCT, other reseachers 18,41 found that antiglaucomatous agents weren't likely to influence choroidal thickness. Fourth, substantial heterogeneity among studies regarding the relationship between SFCT and POAG was observed. However, our subgroup analysis found that the heterogeneity predominantly derived from two studies that had not used Spectralis. After omitting those studies, there was no heterogeneity across our analyses. Fifth, residual confounding is of concern. Many factors can produce effects on choroidal thickness. Although most studies have controlled for various known confounding factors, the possibility of residual or unmeasured confounding cannot be ruled out. Finally, we focused on only several locations in macular and average PCT, and we did not cover the choroid in other areas. Given these limitations, we cannot jump to any conclusions until further verification of our findings in vitro, in vivo, and in large prospective studies. 
In conclusion, this cross-sectional study of Chinese POAG patients, along with the comprehensive meta-analysis, failed to confirm the association of choroidal thickness with POAG, even across different subgroups. Nevertheless, the results should be interpreted cautiously, as the relevant evidence remains limited, and the findings must be confirmed through future larger research studies. 
Acknowledgments
This study was supported by the National Natural Science Foundation of China (81170849, 81371008; Beijing, Beijing, China), the Science and Technology Planning Project of Guangdong Province, China (No. 2012B031800353; Guangzhou, Guangdong, China). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 
Disclosure: W. Wang, None; X. Zhang, None 
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Figure
 
Forest figure of all studies comparing SFCT, mean macular thickness, and average PCT in POAG and those in controls.
Figure
 
Forest figure of all studies comparing SFCT, mean macular thickness, and average PCT in POAG and those in controls.
Table 1
 
Clinical Characteristics of the Participants
Table 1
 
Clinical Characteristics of the Participants
Characteristics Healthy, n = 76 POAG, n = 52 P
Age, y 56.6 ± 11.5 58.2 ± 11.8 0.446
IOP at imaging, mm Hg 15.2 ± 3.6 30.8 ± 12.1 <0.001
Spherical equivalent, D 0.3 ± 1.7 0.5 ± 1.7 0.062
Systolic BP, mm Hg 122.5 ± 16.6 133.2 ± 14.3 0.017
Diastolic BP, mm Hg 75.1 ± 8.3 78.1 ± 8.9 0.194
Mean BP, mm Hg 90.9 ± 9.5 96.4 ± 10.2 0.036
Systolic OPP,* mm Hg 107.2 ± 15.8 101.9 ± 22.5 0.258
Diastolic OPP,† mm Hg 59.8 ± 8.7 46.7 ± 20.1 <0.001
Mean OPP,‡ mm Hg 75.6 ± 9.3 65.1 ± 20.5 0.002
Axial length, mm 23.1 ± 0.9 23.2 ± 0.9 0.640
Anterior chamber depth, mm 3.13 ± 0.54 3.12 ± 0.57 0.935
Lens thickness, mm 4.4 ± 0.7 4.4 ± 0.7 0.732
Vitreous chamber depth, mm 16.8 ± 0.8 16.4 ± 1.6 0.068
C/D 0.3 ± 0.04 0.8 ± 0.2 <0.001
MD, dB −1.7 ± 1.2 −22.0 ± 11.6 <0.001
PSD, dB 1.9 ± 0.5 5.6 ± 3.6 0.025
Table 2
 
Association Between Subfoveal Choroidal Thickness With Other Factors
Table 2
 
Association Between Subfoveal Choroidal Thickness With Other Factors
Factors All Healthy POAG
β P β P β P
Univariate regression
 Age, y −2.6 <0.001 −2.9 <0.001 −2.3 <0.001
 Sex (male vs. female) 24.9 0.006 36.1 0.003 8.6 0.516
 IOP at imaging, mm Hg 0.3 0.446 4.7 0.446 −0.1 0.822
 Spherical equivalent, D 2.9 0.340 0.1 0.989 5.2 0.170
 Axial length, mm −39.8 <0.001 −45.5 <0.001 −32.3 <0.001
 Anterior chamber depth, mm 7.5 0.389 7.5 0.525 7.6 0.558
 Lens thickness, mm −14.7 0.041 −19.4 0.044 −6.9 0.530
 Vitreous chamber depth, mm −4.1 0.354 −4.3 0.565 −4.7 0.373
 MD, dB −0.1 0.828 15.9 0.539 −0.2 0.792
 PSD, dB 1.9 0.338 −17.6 0.801 2.3 0.301
 Systolic BP, mm Hg −0.1 0.724 −0.4 0.322 0.4 0.478
 Diastolic BP, mm Hg −0.8 0.267 −1.3 0.113 0.7 0.488
 Mean BP, mm Hg −0.5 0.402 −1.1 0.132 0.6 0.463
 Systolic OPP, mm Hg −0.5 0.167 −0.7 0.082 0.5 0.203
 Diastolic OPP, mm Hg −0.9 0.030 −2.1 0.005 0.6 0.212
 Mean OPP, mm Hg −0.9 0.038 −1.9 0.006 0.6 0.199
Multivariate regression
 Axial length, mm −33.3 <0.001 −36.1 <0.001 −33.2 <0.001
 Age, y −1.6 <0.001 −1.4 0.004 −2.5 <0.001
Table 3
 
Choroidal Thickness in Healthy and POAG Subjects After Adjusting Axial Length, Age, and IOP
Table 3
 
Choroidal Thickness in Healthy and POAG Subjects After Adjusting Axial Length, Age, and IOP
Location Healthy POAG P*
SFCT 257.8 ± 37.9 255.9 ± 38.3 0.776
T3, mm 211.9 ± 26.3 215.0 ± 26.8 0.532
T1, mm 242.5 ± 44.4 238.3 ± 44.8 0.611
N1, mm 230.6 ± 47.9 221.1 ± 48.6 0.291
N3, mm 150.1 ± 35.2 148.8 ± 35.6 0.840
I3, mm 197.8 ± 49.1 204.4 ± 49.9 0.469
I1, mm 230.1 ± 57.4 225.6 ± 57.9 0.674
S1, mm 252.2 ± 56.2 247.3 ± 57.1 0.643
S3, mm 249.3 ± 41.4 239.9 ± 42.3 0.227
MCT 224.1 ± 43.7 221.5 ± 44.1 0.747
Table 4
 
Characteristics of the Studies Included in the Meta-Analysis
Table 4
 
Characteristics of the Studies Included in the Meta-Analysis
Author, y Location CT Instrument Glaucoma Sample Size Age Adjusting
Mwanza et al.,16 2011 USA SFCT Spectralis POAG 76/38 60.1/73.8 Age, Axl, IOP
MCT NTG
Arora et al.,24 2012 USA MCT Spectralis POAG 106/40 67.8/65.7 Age, Axl, IOP, CCT
POAGS
Rhew et al.,25 2014 Korea SFCT Spectralis NTG 32/35 53.0/45.7 Age
Hirooka et al.,13 2012 Japan SFCT Spectralis NTG 45/62 67.0/63.8 Age, SE
Ciechanowskiet et al.,* 2011 Switzerland SFCT Spectralis POAG 21/41 Age
Maul et al.,18 2011 USA MCT Spectralis OAG 30/23 66.5/63.1 Age, Axl, CCT, DOPP, sex, race
PCT
Cennamo et al.,26 2012 Italy SFCT SD-SLO/OCT POAG 10/14 51/49 None
Usui, 2012 Japan SFCT SS-OCT PM-NTG 12/12 33.6/31.2 Age, Axl, SE
PCT
Mwanza et al.,15 2012 USA SFCT Spectralis POAG 24/24 69.6 Age, Axl, IOP
Steinmetz and Jonas,27 2013 Germany SFCT Spectralis OAG 71/228 Age, SE
Park et al.,9 2014 Korea MCT Spectralis POAG 108/48 63.5/57.8 None
PCT NTG
Suh et al.,28 2014 Korea PCT Spectralis NTG 61/61 52.6 Age, Axl, IOP, MD, PSD, CCT, systemic disease, sex, SE
Li et al.,14 2013 China PCT Spectralis POAG 31/31 57.2/57.9 Age, sex
Hirooka,12 2012 Japan PCT Spectralis NTG 52/50 66.2/62.4 None
Roberts et al.,10 2012 Canada PCT Spectralis OAG 89/76 71.1/56.1 Age
Ehrlich et al.,17 2011 USA PCT Spectralis POAG 31/39 62.6/59.6 Age, PPA
Present China SFCT Spectralis POAG 76/52 58.2/56.6 Age, Axl, IOP
MCT
Table 5
 
Subgroup Analysis of SFCT in POAG Subjects Compared With Healthy Eyes
Table 5
 
Subgroup Analysis of SFCT in POAG Subjects Compared With Healthy Eyes
Group N Studies WMD (95% CI) I2 P heterogeneity P overall
All 9 −7.4 (−24.4, 9.7) 84.6% <0.001 0.397
Instrument
 Spectralis 7 −7.3 (−13.0, −1.5) 0.0% 0.879 0.014
 Other 2 −19.6 (−193.2, 154.0) 97.5% <0.001 0.825
Type of glaucoma
 POAG 4 8.8 (−19.7, 37.3) 90.2% <0.001 0.547
 NTG 2 −15.6 (−39.3, 8.2) 0.0% 0.751 0.199
Source of control
 Healthy 7 1.7 (−18.2, 21.6) 81.4% <0.001 0.867
 Glaucoma-suspects 2 −55.5 (−155.5, 44.6) 94.1% <0.001 0.277
Adjusting factors
 Age 2 −9.7 (−19.8, 0.3) 0.0% 0.540 0.058
 Age, SE 2 −18.4 (−47.5, 10.6) 0.0% 0.556 0.213
 Age, Axl, IOP 3 −5.3 (−12.5, 2.0) 0.0% 0.744 0.152
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