RESUME JURNAL

Judul : Derajat Miopia dan Resiko Glaukoma: Meta-Analisis Dosis-Respon

Latar Belakang : Glaukoma adalah penyebab utama kebutaan permanen diseluruh dunia,
dan OAG adalah bentuk glaukoma yang paling umum. Miopia adalah
faktor risiko kuat untuk OAG, hubungan antara mereka telah diselidiki
secara menyeluruh.
Tujuan : Memverifikasi hubungan dosis-respons antara derajat miopia dan risiko
glaukoma sudut terbuka (OAG)
Metodologi : Menelusuri database PubMed, EMBASE, dan Cochrane Library untuk
studi berbasis populasi yang diterbitkan hingga 30 November 2020, dan
melaporkan miopia dan OAG. Model efek acak menghasilkan rasio
odds gabungan (OR) dan 95% CI. Kekokohan hasil dikonfirmasi oleh
analisis pengaruh dan subkelompok. Meta-analisis dosis-respons 2
tahap menghitung risiko OAG per unit dosis miopia (spherical
equivalent [SE] penurunan 1 diopter [D]) dan memeriksa pola
hubungan.
Hasil : Meta-analisis terdiri dari 24 studi di 11 negara (514.265 individu). OR
yang dikumpulkan dari asosiasi derajat miopia dengan OAG adalah
1,88 (95% CI, 1,66- 2,13;I2=53%). Perbedaan OR berdasarkan etnis
(Asia vs Barat) atau 5 wilayah geografis tidak signifikan secara statistik
(P=.80 danP=.06, masing-masing). OR gabungan dari hubungan antara
miopia rendah, sedang, sedang hingga tinggi, tinggi, dan OAG adalah
1,50 (95% CI, 1,29-1,76), 1,69 (95% CI, 1,33-2,15), 2,27 (95% CI ,
1,74-2,96), dan 4,14 (95% CI, 2.57-6.69), masing-masing. Menurut
meta-analisis dosis-respons, gabungan OR (per perubahan SE 1-D)
adalah 1,21 (95% CI, 1,15- 1,28). Risiko OAG dipercepat kira-kira− 6
D, dan selanjutnya dipercepat dari−8 D, menunjukkan kemiringan ke
atas cekung nonlinier (P=.03).
Kesimpulan : Untuk setiap unit (1-D) peningkatan miopia, risiko glaukoma
meningkat sekitar 20%. Risiko lebih tajam meningkat pada miopia
derajat tinggi, mewakili hubungan nonlinear yang signifikan
Rangkuman dan : Masih terdapat keterbatasan pada penelitian ini berupa kriteria
Hasil Pembelajaran diagnostik OAG bervariasi di seluruh studi yang disertakan, sebagian
besar studi yang dianalisis menganggap usia dan tekanan intraokular
sebagai faktor perancu, meskipun terdapat variasi antarstudi dalam
penanganan kovariat. Kemudian kelainan refraksi itu sendiri tidak
membedakan antara komponen refraksi aksial, kornea, dan lentikular.
Dari sudut pandang kesehatan masyarakat, miopia dan glaukoma
adalah penyakit mata yang paling umum dan meningkat pesat yang
menyebabkan gangguan penglihatan dan kebutaan secara global. Harus
ada peningkatan kesadaran glaukoma di antara individu dengan miopia,
terlepas dari derajatnya. Yang penting, pemantauan yang lebih waspada
diperlukan pada miopia yang lebih buruk dari −6 D, mengingat risiko
yang meningkat tajam pada miopia tingkat tinggi.
 Degree of Myopia and Glaucoma Risk: A
Dose-Response Meta-analysis
AHNUL HA1, CHUNG YOUNG KIM1, SUNG RYUL SHIM, IN BOEM CHANG2, AND YOUNG KOOK KIM2
• PURPOSE: To verify the dose-response relation between
the degree of myopia and open-angle glaucoma (OAG)
risk
• DESIGN: Dose-response meta-analysis.
• METHODS: We searched the PubMed, EMBASE, and
Cochrane Library databases for population-based studies
published until November 30, 2020, and reporting on
both myopia and OAG. Random-effect models generated
pooled odds ratios (OR) and 95% CIs. Results robust-
ness was confirmed by influence and subgroup analyses. A
2-stage dose-response meta-analysis calculated the OAG
risk per unit dose of myopia (spherical equivalent [SE]
decrease of 1 diopter [D]) and examined the relationship
pattern.
• RESULTS: The meta-analysis comprised 24 studies in 11
countries (514,265 individuals). The pooled OR of any
myopia degree’s association with OAG was 1.88 (95%
CI, 1.66-2.13; I2 = 53%). The OR differences based on
ethnicity (Asians vs Westerners) or 5 geographic areas
were not statistically significant (P = .80 and P = .06, re-
spectively). The pooled ORs of the associations between
low, moderate, moderate-to-high, high myopia, and OAG
were 1.50 (95% CI, 1.29-1.76), 1.69 (95% CI, 1.33-
2.15), 2.27 (95% CI, 1.74-2.96), and 4.14 (95% CI,
2.57-6.69), respectively. According to the dose-response
meta-analysis, the pooled OR (per SE 1-D change) was
1.21 (95% CI, 1.15-1.28). The OAG risk accelerated at
approximately −6 D, and further accelerated from −8 D,
showing a nonlinear concave upward slope (P = .03).
Supplemental Material available at AJO.com.
Accepted for publication October 6, 2021.
From the Department of Ophthalmology (A.H., Y.K.K.), Seoul Na-
tional University College of Medicine, Seoul, South Korea; Depart-
ment of Ophthalmology (A.H.), Jeju National University Hospital, Jeju-
si, South Korea; Seogwipo Public Health Center (C.Y.K.), Seogwipo-
si, South Korea; Department of Preventive Medicine (S.R.S.), Korea
University College of Medicine, Seoul, South Korea; Kim Kisoo Soo
Eye Clinic (I.B.C.), Jeju-si, South Korea; Department of Ophthalmology
(Y.K.K.), Seoul National University Hospital, Seoul, South Korea.
In Boem Chang, Kim Kisoo Soo Eye Clinic, Ido 2-dong, Jungang-ro 286,
Jeju-si, Jeju-do 63206, South Korea.; e-mail: ibeyebe0515@gmail.com
Inquiries to Young Kook Kim, Department of Ophthalmology, Seoul
National University Hospital, Seoul National University College of
Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, South Korea.; e-mail:
md092@naver.com
1 Dr. Ha and Dr. Kim contributed equally to this study as co-first authors.
2 Dr. Chang and Dr. Kim contributed equally to this study as co-
corresponding authors.
© 2021 THE AUTHORS. PUBLISHED BY ELSEVIER INC.
0002-9394/$36.00 THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE
https://doi.org/10.1016/j.ajo.2021.10.007 (HTTP://CREATIVECOMMONS.ORG/LICENSES/BY-NC-ND/4.0/).
• CONCLUSIONS: For each unit (1-D) increase in
myopia, the risk of glaucoma increases by approxi-
mately 20%. The risk more steeply increases in high-
degree myopia, representing a significant nonlinear re-
lationship. (Am J Ophthalmol 2022;236: 107–119.
© 2021 The Authors. Published by Elsevier Inc.
This is an open access article under the CC BY-NC-
ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/))
M
yopia is a public health issue of increasing
concern, particularly in East Asia, where it is al-
ready at a pandemic level.1 Estimates are that by
2050, the worldwide prevalence of myopia and high my-
opia will have increased substantially to nearly 5 billion
and 1 billion people, respectively. 2 Uncorrected refractive
errors not only impose a socioeconomic burden but also
can present the following severe, myopia-associated and
sight-threatening complications that may negatively affect
quality of life: macular degeneration, retinal detachment,
cataract, and open-angle glaucoma (OAG).3
Glaucoma is the leading cause of irreversible blindness
worldwide, and OAG is the most prevalent form of glau-
coma.4 Myopia is a well-established risk factor for OAG,
5–7
the association between them having been thoroughly
investigated. The evidence on the association of myopia de-
gree with increased risk of OAG, however, is contradictory.
According to some studies, an association exists between
myopia of any degree and OAG, 8 , 9 whereas other inves-
tigations have reported links only with high myopia. 10 , 11
The initial meta-analysis of the myopia/glaucoma associa-
tion was published in 2011. 7 Marcus and associates 7 an-
alyzed 13 population-based studies accounting for 48,161
individuals and reported that myopic individuals are at in-
creased risk of OAG and that the odds of developing that
disease are slightly increased in myopia of higher degrees.
They had classified myopia into only 2 groups (low and
high, cutoff value: −3 diopters [D]) though, and moreover,
their studies, individuals, and races/ethnicities were rela-
tively small in number.
Clearer understanding of the myopia/OAG risk associ-
ation calls for wider and deeper investigation, particularly
given its significant public health urgency. In the current
analysis, we extended the scope of Marcus and associates
in quantity and quality and updated the pool of selected
107
studies in seeking to identify a dose-response relationship
between myopia degree and OAG risk.
METHODS
• SEARCH STRATEGY AND SELECTION CRITERIA: We
systematically searched the PubMed, EMBASE, and
Cochrane Library databases to find relevant studies. Our
search strategies were developed with assistance from an
academic librarian with expertise in systematic review and
based on established terminology using the extensive Med-
ical Subject Headings and EMBASE search terms, when
available. The keywords included were glaucoma, open-
angle glaucoma, myopia, refractive error, risk factor, deter-
minant, and association. All of the database search details
are included in Supplemental Table 1. Two investigators
(A.H. and C.Y.K.) searched the literature in an indepen-
dent and masked fashion, with any inconsistencies resolved
by discussion and consensus or, if needed, adjudication by
a third investigator (Y.K.K.). We also manually reviewed
the reference lists from the retrieved articles and identified
additional relevant studies. The databases were searched
for any relevant reports published through November 30,
2020. Non–English-language reports were assessed by a sin-
gle individual who was a native or fluent speaker of the
language. Full-text articles from eligible studies were in-
cluded according to the following inclusion and exclusion
criteria.
The inclusion criteria were (1) population-based study,
(2) myopia reported as covariate, (3) OAG as outcome
measure, (4) measure of association reported as odds ratios
(ORs) with 95% CIs, or the allowed calculation from the
data presented in the article.
The exclusion criteria were (1) not conducted with hu-
mans or adults, (2) narrative and/or systematic reviews,
commentaries, case reports, (3) involving secondary glau-
coma or angle-closure glaucoma, and (4) lacking detailed
definition of OAG or without clear description of myopia
assessment. In situations where multiple publications were
available for the same study population, we included only
the study with the largest cohort (after checking for dupli-
cate analyses).
We conducted this study according to a pre-specified
protocol, and its methods adhered to both the Meta-
analysis Of Observational Studies in Epidemiology
(MOOSE) 12 and Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA)
guidelines. 13 The protocol was registered in the PROS-
PERO database (CRD42021227804).
• DATA EXTRACTION AND QUALITY ASSESSMENT: Two
investigators (A.H. and C.Y.K) extracted data in an inde-
pendent and masked manner using a standardized method
of data extraction based on the ones used by the Cochrane
108 AMERICAN JOURNAL OF OPHTHALMOLOGY
Library’s Database of Systematic Reviews (The Cochrane
Collaboration: Review Manager 4.1.1. Nepean, 2000). Ex-
tracted data, after being entered into a dedicated database,
were rechecked by a third investigator (I.B.C). The fol-
lowing study data were extracted: (1) name of the first au-
thor, (2) year of publication, (3) race/ethnicity of the study
population, (4) country of study, (5) number of partici-
pants, (6) ages and sexes of participants, (7) OAG diag-
nostic criteria, (8) definition of myopia, (9) reported mea-
sures of association (ORs) with corresponding 95% CIs ac-
cording to degree of myopia, and (10) adjusted confounding
factors.
To assess the methodologic quality of studies, we applied
the Newcastle-Ottawa Scale for assessment of comparative
nonrandomized study quality. 14 We additionally evaluated
studies to determine the risk of selection, comparability, ex-
posure/outcome, or any other form of bias.
• STATISTICAL ANALYSIS: Most of the studies included in
this meta-analysis reported both an OR for any myopia and
ORs for stratified myopias. For studies reporting only strat-
ified ORs, we pooled those results to obtain an overall es-
timate for any myopia. According to the stratification, and
as was the case in most of the studies included in the anal-
ysis, myopia was stratified into low-, moderate-, moderate-
to-high–, and high-degree categories, as based on spherical
equivalent (SE) refractive error up to −3 D, between −6 D
and −3 D, lower than −3 D, and lower than −6 D, respec-
tively. For studies reporting data on the association of axial
length (AXL) with OAG risk, we analyzed the pooled OR
for 1-mm increments in AXL and OAG risk.
The fully adjusted, study-specific ORs were combined to
estimate the pooled OR with 95% CI based on a random
effects model. We quantified interstudy heterogeneity us-
ing the I2 statistic representing the interstudy variation per-
centage attributable to heterogeneity (not to sampling er-
ror). 15 , 16 Values of approximately 25%, 50%, and 75% rep-
resent low, medium, and high heterogeneity, respectively.
To determine whether any study or studies in a meta-
analysis exerted a very high influence on the overall results,
we performed influence analyses to investigate more deeply
than by simple outlier removal. Such techniques are based
on the so-called leave-one-out-method, by which the re-
sults of our meta-analysis were recalculated multiple times,
leaving out one study each time. We also used an even more
sophisticated means of exploring the effect-size patterns and
heterogeneity in our data; namely, graphic display of hetero-
geneity (GOSH) plot analysis, 17 which uses 3 clustering al-
gorithms (also known as unsupervised machine-learning al-
gorithms): k-means clustering, 18 density-based spatial clus-
tering of applications with noise (DBSCAN), 19 and Gaus-
sian mixture models. 20 On those plots, we fit exactly the
same meta-analysis model to all of the possible subsets of
our included studies. If, for example, the effect sizes in a
sample were homogeneous, the GOSH plot would form a
symmetric distribution with 1 peak. Finally, we used a sen-
APRIL 2022
FIGURE 1. Flow diagram shows the selection process for inclusion of studies in the meta-analysis.
sitivity analysis to determine what happens in the event of
rerunning the meta-analysis after removing the studies that
could potentially contribute to cluster imbalance.
Another source of between-study heterogeneity possi-
bly making an effect-size estimate less precise is study-
population difference. So, in subgroup analyses by the ran-
dom effects model for between-subgroup differences, 21 we
looked at subgroups differing by ethnicity and geographic
area, because ethnic differences have been found in my-
opia prevalence and optic nerve head (ONH) structures.
22 , 23
Also, in the cases of studies reporting categorized ORs
according to myopia degree, we calculated pooled OR for
each of the 4 different myopia groups (ie, mild, moderate,
moderate-to-high, and high myopia) to estimate the strati-
fied trends of risk.
Finally, for confirmation of the dose-response relation-
ship between myopia and OAG risk, we identified stud-
VOL. 236 MYOPIA DEGREE AND GLAUCOMA RISK
ies categorizing myopia degree into 3 or more groups, in-
cluding the reference group. We then performed a dose-
response meta-analysis (DRMA) using a random effects
meta-regression model based on a nonlinear dose-response
relationship framework that provides the best-fitting 2-
term fractional polynomial model. 24 This method pro-
ceeds via a 2-stage process. First, 2-term fractional poly-
nomial models are fitted within each study included in
the meta-analysis, taking into account the correlation be-
tween the reported estimates for different exposure levels.
25
Thus, OAG risk per unit dose of myopia (SE change of
1 D) is calculated in consideration of the P value of the
goodness-of-fit.
Second, the pooled dose-response relationship is esti-
mated according to the between-studies heterogeneity us-
ing a bivariate random effects model. That is, we exam-
ined the potential for a nonlinear relationship by testing
109
the null hypothesis: that the coefficients of the second and
third spline are all equal to 0 (ie, the Wald test). 26
We evaluated publication bias (1) qualitatively by funnel
plot, 27 the best means of visualizing whether small stud-
ies having small effect sizes are missing, and (2) quantita-
tively by the Begg and Mazumdar adjusted rank correlation
test (a direct statistical analog of the visual funnel graph).
The Begg and Mazumdar test determined whether any sig-
nificant correlation existed between the effect estimates
and their variances. 28 The absence of any such correla-
tion suggested that studies had been selected in an unbiased
way.
The data handling and statistical analyses were the re-
sponsibility of a single investigator (Y.K.K.) under the su-
pervision of a statistician (S.R.S.) with expertise in meta-
analysis. All of the 95% CI and P values were 2-sided, and
P < .05 was considered to represent statistical significance.
All of the statistical analyses other than DRMA were per-
formed with R 4.0.4 software (The R Foundation for Statis-
tical Computing). The 2-stage random effects DRMA was
run using Stata 14.2 software (StataCorp).
RESULTS
• SEARCH RESULTS: Our systematic search identified 1595
articles, specifically 1166 from PubMed and 429 from Em-
base (not in PubMed), among which 79 were full-text re-
viewed. After a thorough review, the final analyses pro-
ceeded with 24 studies (Figure 1). The Newcastle-Ottawa
Scale was applied to all of the included studies to assess the
methodologic quality. The median score was 8 of 9, with a
minimum of 6 and a maximum of 9 (Supplemental Table
2).
The 24 studies, with a total study population of 514,265
individuals, had been conducted in 11 countries: 4 studies
in the United States, 29–32 4 in India, 33–36 3 in China, 37–39 2
in Japan, 40 , 41 2 in South Korea, 42 , 43 2 in Australia, 44 , 45
3 in Singapore (Malay, 46 Indian, 47 and Chinese 48 ), and
1 study each in Myanmar, 49 Sri Lanka, 50 Greece, 51 and
Barbados. 52 In 13 of those studies, 33 , 34 , 36 , 37 , 39 , 43 , 45–50 , 52
myopia was defined based on an SE of −0.5 D, and 7 others
29–32 , 41 , 44 , 51
reported myopia of SE less than −1.0 D. The
characteristics of all of the included studies are summarized
in Table 1. Supplemental Tables 3 and 4, meanwhile, show
the diagnostic criteria for OAG along with the covariates
that had been adjusted in each study.
• OVERALL SUMMARY MEASUREMENT: A total of 21 stud-
ies 29–34 , 36–39 , 41 , 43–52 reported data on myopia’s association
with OAG risk based on SE; the pooled OR for any my-
opia (ie, SE less than −0.5 D or −1.0 D) and OAG risk was
1.878 (95% CI, 1.658-2.126) with medium heterogeneity
(I2 = 53%; P < .01). Nine studies 30 , 35 , 36 , 39 , 40 , 42 , 47 , 49 , 50 re-
ported data on the association between 1-mm increment of
110 AMERICAN JOURNAL OF OPHTHALMOLOGY
AXL and OAG risk (Supplemental Table 5). The pooled
OR was 1.395 (95% CI, 1.266-1.537) with low heterogene-
ity (I2 = 16%; P = .30). Figure 2 provides the relevant forest
plots.
• SUBGROUP ANALYSES: We performed subgroup analyses
using a random effects model of between-subgroup differ-
ences to investigate the potential sources (ie, ethnicity and
geographic area) of between-study heterogeneity. The OR
difference between studies including Asians (OR, 1.945;
95% CI, 1.570-2.409) and Westerners (OR, 1.868; 95%
CI, 1.497-2.331) did not reflect any statistical significance
(Q = 0.07, P = .80).
The subgroup analysis according to geographic area (ie,
5 continents) showed relatively higher ORs for Australia
(OR, 2.220; 95% CI 1.429-3.449), Northeast Asia (OR,
2.190; 95% CI, 1.703-2.816), and Southeast Asia (OR,
2.172; 95% CI, 1.197-3.944) compared with South Asia
(OR, 1.681; 95% CI, 0.971-2.909) or North America (OR,
1.601; 95% CI, 1.549-1.655), with borderline significance
(Q = 8.87, P = .06). The detailed results are plotted in Sup-
plemental Figure 1.
• INFLUENCE ANALYSES: All of the pooled estimates, af-
ter omitting 1 study at a time according to the leave-one-
out analysis, were still within the 95% CI of the over-
all estimate. The lowest I2 heterogeneity was reached by
omitting the studies of Qiu and associates 31 and Xu and
associates 37 however, which fact indicated their possible
distorting influence on the pooled effect (Supplemental
Figure 2). Then, based on the method proposed by Viecht-
bauer and Cheung, 53 we identified potential outliers ex-
erting a strong influence on the overall results. The cut-
off values indicated that the study by Qiu and associates
31
was an influential case. There were 3 spikes in most plots,
whereas the other studies had similar values. Given this
structure, the studies Sia and associates 50 and Xu and as-
sociates 37 were also identified as influential (Supplemental
Figure 3).
Further, we used GOSH plot analysis to explore the ro-
bustness of our meta-analysis results (Supplemental Figure
4). Two peaks suggesting asymmetric effect size heterogene-
ity patterns were shown. Three clustering algorithms for de-
tection of different clusters in the GOSH plot data were
applied, which detected 5 studies possibly contributing to
cluster imbalance: Qiu and associates, 31 Sia and associates,
50
Xu and associates, 37 Garudadri and associates, 34 and
Shen and associates. 32 These studies seemed to almost fully
account for the second high effect size, high heterogeneity
cluster we found. The potential outliers that we identified
by the influence analyses and GOSH diagnostics are sum-
marized in Supplemental Table 6.
Sensitivity Analysis
After excluding the 5 potential outliers, we repeated the
meta-analysis and obtained 1.759 (95% CI, 1.582-1.955),
APRIL 2022
 TABLE 1. Characteristics of Studies Included in the Meta-Analysis

Author, Study Population, Sample Size Age, y Female, Definition of Odds Ratio (95%
Country % Myopia (SE in CI)
Diopters)

Wu et al 52 Black, 4036 58.2 ± 11.7 57 < −0.5 1.48 (1.12-1.95)a

The Barbados Eye Study Barbados (40-84)
(1999)
Mitchell et al 44 Australians, 3654 49-97 57 ≤ −1.0 2.4 (1.5-4.0)a , b
The Blue Mountains Australia −3.0 < to ≤ −1.0 2.3 (1.3-4.1)c
Eye Study (1999) ≤ −3.0 3.3 (1.7-6.4)d
Weih et al 45 Diverse, 4498 59 ± 12 53 ≤ −0.5 1.6 (0.91-6.7)a
The Visual Impairment Project Australia
(2001)
Wong et al 29 White, 4670 61.5 ± 11.0 56 ≤ −1.0 1.6 (1.1-2.3)a
The Beaver Dam USA (43-86) −3.0 < to ≤ −1.0 1.6 (1.1-2.4)c
Eye Study (2003) ≤ −3.0 1.5 (0.8-2.6)d
Ramakrishnan et al 33 Indians, 5150 40-90 55 < −0.5 2.8 (1.7-4.6)a , b
The Aravind Comprehensive India Milde 2.9 (1.3-6.9)c
Eye Survey (2003) Moderatee 2.1 (1.0-4.6)f
Severee 3.9 (1.6-9.5)g
Suzuki et al 41 Japanese, 2874 58.4 ± 11.8 56 < −1.0 2.2 (1.5-3.3)a , b
The Tajimi Study (2006) Japan −3.0 < to < −1.0 1.9 (1.0-3.3)c
≤ −3.0 2.6 (1.6-4.4)d
Xu et al 37 Chinese, 4319 55.8 ± 10.3 56 < −0.5 3.8 (2.1-6.7)a , b
The Beijing Eye Study (2007) China (40-90) −3.0 < to < −0.5 0.61 (0.25-1.48)c
−6.0 < to < −3.0 0.56 (0.20-1.57)f
< −6.0 4.67 (1.75-12.46)g
Casson et al 49 Diverse, 2076 56.2 ± 12.0 NA < −0.5 2.74 (1.00-7.48)a
The Meiktila Eye Study (2007) Myanmar
Garudadri et al 34 Indian, 3724 Urban: 53.2 ± 53 ≤ −0.5 1.0 (0.6-1.6)a , b
The Andhra Pradesh India 10.9
Eye Disease Study (2010) Rural: 54.7 ±
10.4
Perera et al 46 Malay, 3109 58.2 ± 10.9 52 < −0.5 1.8 (0.9-3.7)a , b
The Singapore Singapore (40-80) −4.0 ≤ to < −0.5 1.3 (0.6-2.7)c
Malay Eye Study (2010) < −4.0 2.8 (1.1-7.4)d
Kuzin et al 30 Latino, 5927 54.9 ± 10.8 58 ≤ −1.0 1.8 (1.2-2.8)a
The Los Angeles USA −3.0 < to -1.0 1.6 (0.9-2.6)c
Latino Eye Study (2010) ≤ −3.0 2.0 (1.1-3.7)d
Sia et al 50 Singhalese, 1244 57.0 ± 10.6 60 < −0.5 4.71 (2.13-10.39)a
The Kandy Eye Study (2010) Sri Lanka
Topouzis et al 51 Greek, 1991 68.7 ± 5.7 47 < −1 2.05
The Thessaloniki Eye Study Greece (PEX (1.18-3.54)a , b
(2011) excluded) −3 < to −1 1.97 (0.96-4.03)c
≤ −3 2.16 (0.92-5.06)d
Liang et al 39 Chinese, 6716 54.4 ± 10.8 53 < −0.5 2.05
The Handan Eye Study (2011) China (1.19-3.55)a , b
−3.0 < to < −0.51 1.5 (0.8-3.0)c
−6.0 < to < −3.1 4.7 (1.6-13.5)f
−8.0 < to < −6.1 0
< −8.1 1.8 (0.17-19.3)g
Kim et al 42 Korean, 1464 64.1 ± 11.5 58 NA NA
The Namil study (2012) South Korea
Qiu et al 31 Diverse, 5277 ≥40 50 ≤ −1.00 2.89
Study on the United States USA (2.00-4.18)a , b
Population (2013) −2.99 < to < 2.02 (1.28-3.19)c
−1.00
−5.99 < to < 3.09 (1.42-6.72)f
−3.00
< −6.00 14.43
(5.13-40.61)g
(continued on next page)

VOL. 236 MYOPIA DEGREE AND GLAUCOMA RISK 111

 TABLE 1. (continued)

Author, Study Population, Sample Size Age, y Female, Definition of Odds Ratio (95%
Country % Myopia (SE in CI)
Diopters)
Pan et al 47 Indians, 3400 58.6 ± 10.3 50 < −0.5 1.20 (0.50-2.89)a
The Singapore Indian Eye Singapore −3.0 ≤ to < −0.5 0.62 (0.27-1.45)c
Study (2013) −6.0 ≤ to < −3.0 1.10 (0.23-5.36)f
< −6.0 6.97 (2.20-22.16)g
Nangia et al 35 Indians, 4711 49.5 ± 13.4 54 NA NA
The Central India Eye and India (30-100)
Medical Study (2013)
Yamamoto et al 40 Japanese, 3762 61.8 ± 14.0 51 NA NA
The Kumejima Study (2014) Japan
Vijaya et al 36 Indians, 4316 58.4 ± 9.7 55 < −0.5 1.7 (1.1-2.5)a
The Chennai Eye Disease India
Incidence Study (2014)
He et al 38 Chinese, 2528 63.5 ± 8.8 58 All myopiae 1.94 (1.01-3.75)a
Pudong, Shanghai study (2015) China (50-106)
Baskaran et al 48 Chinese, 3353 59.7 ± 9.9 50 ≤ −0.5 1.57 (0.89-2.74)a
The Singapore Chinese Eye Singapore
Study (2015)
Kim et al 43 Korean, 13,831 55.1 ± 0.2 57 < − 0.5 1.60
Korea National Health and South Korea (1.31-1.95)a , b
Nutrition Examination Survey − 6.0 < to < − 0.5 1.45 (1.17-1.79)c , f
(2016) ≤ − 6.0 3.35 (1.87-5.99)g
Shen et al 32 Diverse, 417,635 POAG: 67.4 ± 51 < − 1.00 1.60
Kaiser Permanente Northern USA 11.3, NTG: (1.55-1.65)a , b
California Health Plan Study 66.8 ± 10.9 −2.99 < to < 1.30
(2016) −1.00 (1.24-1.36)b , c
−5.99 < to < 1.67 (1.60-1.80)b , f
−3.00
≤ −6.00 2.48
(2.29-2.67)b , g

NA = not available; NTG = normal-tension glaucoma; PEX = pseudoexfoliation; POAG = primary open-angle glaucoma; SE = spherical
equivalent; USA = United States of America.
a
Included in the analysis as all myopia.
b
Calculated from data contained in the article.
c
Included in the analysis as low myopia.
d
Included in the analysis as moderate-to-high myopia.
e
Severity of myopia was not defined in the article.
f
Included in the analysis as moderate hyopia.
g
Included in the analysis as high myopia.

which was the pooled OR for any myopia/OAG risk (Sup-
plemental Figure 5). We noted that the between-study het-
erogeneity had dropped to 0% (P = .74), indicating that the
studies we were then analyzing stemmed from 1 homoge-
neous (sub)population, which is to say, the main homony-
mous cluster in our GOSH plot.
Dose-Response Analysis
Among the 21 studies reporting the SE-based degree
of myopia, 13 reported risk estimates for low myopia.
29–33 , 37 , 39 , 41 , 43 , 44 , 46 , 47 , 51
The pooled OR was 1.504 (95%
CI, 1.285-1.762) with medium heterogeneity (I2 = 45%;
P = .040). Seven studies 31–33 , 37 , 39 , 43 , 47 reported risk
estimates for moderate myopia, and the pooled OR
there was 1.692 (95% CI, 1.334-2.146), again with
medium heterogeneity (I2 = 53%; P = .040). The
pooled OR of the 6 studies 29 , 30 , 41 , 44 , 46 , 51 reporting
risk estimates for moderate-to-high myopia was 2.268
(95% CI, 1.738-2.959) with no heterogeneity (I2 = 0%;
P = .585). Seven studies 31–33 , 37 , 39 , 43 , 47 reported risk
estimates for high myopia, and the pooled OR there
was 4.142 (95% CI, 2.567-6.685) with moderate-to-high
heterogeneity (I2 = 66%; P < .010). Figure 3 plots
the results of the meta-analysis based on myopia
degree.
We found that every category of myopia degree from low
to high was associated with an increased risk of OAG in
a dose-response manner; therefore, we subsequently per-
formed a 2-stage random effects DRMA. A total of 10 stud-
ies 29–31 , 37 , 41 , 43 , 44 , 46 , 47 , 51 supplied more than 3 data cate-
gories on myopia degree, which were required to conduct
the DRMA; the pooled OR for SE 1 D change and OAG

112 AMERICAN JOURNAL OF OPHTHALMOLOGY APRIL 2022

FIGURE 2. (Upper) Forest plot of risk estimates of association between any myopia and open-angle glaucoma. (Lower) Association
of 1-mm increment of axial length with open-angle glaucoma. The size of the box representing the point estimate for each study in
the forest plot is in proportion to the contribution of that study’s weight estimate to the summary estimate. The horizontal lines
indicate the 95% CIs. The diamond denotes the pooled odds ratio, and the lateral tips of the diamond indicate the associated CIs.
TE = total effect; SE = standard error; IV = inverse variance.

VOL. 236 MYOPIA DEGREE AND GLAUCOMA RISK 113

FIGURE 3. Association of myopia and open-angle glaucoma risk according to the degree of myopia in spherical equivalent of
refractive error. The size of the box representing the point estimate for each study in the forest plot is proportional to that study’s
weight estimate contribution to the summary estimate. The horizontal lines indicate the 95% CIs. The diamond denotes the pooled
odds ratio, and the lateral tips of the diamond indicate the associated CIs. TE = total effect; SE = standard error; IV = inverse
variance.

114 AMERICAN JOURNAL OF OPHTHALMOLOGY APRIL 2022

FIGURE 4. Dose-response meta-analysis of association between myopia and open-angle glaucoma risk. (Upper) Results from 10
studies with more than 3 data categories on myopia degree. (Lower) After 2 potential outliers identified from influence analyses
were excluded, the risk of glaucoma increased more steeply with decreasing spherical equivalent from approximately −6 diopters
(blue arrow), and increased more steeply from −8 diopters (red arrow), in both analyses. Note that the y-axis ranges of the 2 graphs
shown here are not the same. Nonlinear and linear data are plotted with dashed and long-dashed lines, respectively. The solid lines
indicate the 95% CIs.

risk was 1.212 (95% CI 1.149-1.279). The DRMA revealed
a nonlinear dose-response relationship between myopia de-
gree and OAG risk, based on the Wald test for linearity
(P = .025). After excluding the 2 potential outliers 31 , 37 in-
dentified in the influence analyses, the pooled OR for SE 1-
D change and OAG risk was 1.190 (95% CI, 1.134-1.248),
showing a similar value without removal of outliers. The
nonlinear relationship was confirmed also by Wald test for
linearity (P = .014). Figure 4 plots the association of OAG
risk with myopia degree as a continuous variable. As can
be seen, the risk more steeply increased with decreasing SE
from approximately −6 D, and it further increased, more
steeply, from −8 D, showing a concave upward slope.
Publication Bias
Supplemental Figure 6 is the funnel plot depicting publi-
cation bias. According to our meta-analysis, 2 and 3 stud-
ies were distributed on the outer left and right sides of the

VOL. 236 MYOPIA DEGREE AND GLAUCOMA RISK 115

funnel, respectively. Inside the funnel, 9 and 7 studies were
distributed to the left and right, respectively. No publica-
tion bias was evident in this visual examination of plot sym-
metry. Likewise, there was no evidence of publication bias
by the Begg and Mazumbar adjusted rank correlation test
(Z = 1.057, P = .290).
DISCUSSION
Our meta-analysis suggests that individuals with myopia
have an approximately doubled risk of developing OAG
compared with those without myopia. Additionally, the
DRMA represented the relationship of myopia with OAG
risk as a concave upward slope, the risk accelerating from
−6 D and further accelerating from −8 D.
This study, building on a previous meta-analysis that
examined the association of myopia with OAG risk, in-
cludes the greatest number of population-based studies to
date. A 2011 pooled analysis combining 13 population-
based studies (48,161 individuals) reported a comparable
OR of 1.92 (95% CI, 1.54-2.38) for any myopia and OAG
but could not confirm any significant dose-response rela-
tionship. 7 We believe there were 2 reasons for that limi-
tation. One, the degree of myopia was classified into only
2 groups (cutoff value: −3D), rendering stratified analyses
impossible; and the other was the relatively small number
of participants having moderate-to-high or high myopia in
the included studies. In the present study, we analyzed 24
population-based studies (514,265 individuals), the addi-
tional studies being mainly on Asians (n = 8 studies). That
Asian populations have higher prevalences of myopia than
do others has been well established. 54
We found that the odds of developing OAG increased
gradually from 1.504 to 4.142 with the increase of the de-
gree of myopia from low to high. This pronounced dose-
response relationship seems to suggest a possible explana-
tion for the pathogenesis of glaucomatous damage in eyes
with myopia. Because of the elongated AXL and thinner
sclera in myopic eyes, the ONH has been presumed to be
more vulnerable to the damage typically incurred in glau-
coma. 55 Additionally to the mechanical susceptibility per-
spective, vascular theory postulates that a contributory fac-
tor to glaucomatous optic neuropathy is insufficient ocular
perfusion. 56 Atrophy of the retinal pigment epithelium and
choroid in myopic eyes, furthermore, may diminish retinal
cells’ access to essential molecules along with their ability to
handle oxidative stress. 57 These changes progress with my-
opia’s course, possibly contributing to development of glau-
comatous injury.
Notably, our DRMA’s nonlinear dose-response relation-
ship of myopia with OAG showed an accelerated risk in
high myopia. The mechanisms undergirding OAG risk’s
steeper rise in higher degrees of myopia remain unclear. Ax-
ial elongation beyond the cutoff value of 26.0 or 26.5 mm
116 AMERICAN JOURNAL OF OPHTHALMOLOGY
has been shown to lead to significant histologic changes
to the ONH. 55 Whereas ONH alterations in mild-to-
moderate myopia, typically are confined to ovalization
of optic disc shape and enlargement of the parapapillary
gamma zone; in high myopia, further morphometric alter-
ations frequently are observed, such as enlargement of the
Bruch membrane opening, elongation of the peripapillary
scleral flange, as well as thinning and/or elongation of the
laminar cribrosa. 58 Such marked changes of the ONH’s
biomechanical properties might be one explanation for the
greatly increased susceptibility to glaucomatous damage in
cases of high myopia.
There are various established risk factors for OAG. De-
tailed subgroup analyses that could comprehensively de-
termine the impact of such covariates on the relation be-
tween myopia and OAG, however, proved impossible in
the present study. Analysis of subgroups stratified by age
or ethnicity would be especially important, because myopia
affects glaucomatous change differently in different demo-
graphics. Age indeed might modulate the myopia/OAG as-
sociation, especially considering that mechanical strain in
the course of axial elongation decreases after the develop-
mental period. And as for ethnic differences, they are found
in myopia prevalence, ONH structures, and peripapillary
tissues. 22 , 23 The borderline statistical significance revealed
by our geographic area–based subgroup analysis might have
been owed to the relatively limited number of studies ana-
lyzed. Unfortunately, the data were not sufficiently granular
for us to conduct meaningful subgroup analyses, but we in-
tend to do so in an update to this review after more evidence
has become available in the literature.
This systematic review and meta-analysis affords the
most updated and most comprehensive summary estimates
of the dose-response relationship between myopia and
OAG risk. The strengths of our meta-analyses include a
pool of individuals that is large as well as diverse, thus ren-
dering the present findings generalizable to the global pop-
ulation, and the current study’s dose-response design pro-
viding for better quantification of associations between a
specified degree of myopia and OAG risk. We included
population-based studies only to minimize any potential in-
fluence of selection bias, and we performed subgroup meta-
analyses, influence analyses, and, finally, a sensitivity anal-
ysis to ensure the robustness of results.
Nevertheless, study limitations remain. First, the OAG-
diagnostic criteria varied across the included studies. Al-
though 22 studies (92%) evaluated both ONH and vi-
sual field, the detailed methods were heterogeneous. Since
evaluation of glaucoma for a myopic eye requires a multi-
modal approach that considers the limitations, and poten-
tial sources of error, of each test, our summary estimate is
limited by the differences in diagnostic approaches among
the studies.
Second, most of the studies analyzed considered age and
intraocular pressure as confounding factors, although there
was interstudy variety in the handling of covariates.
APRIL 2022
 Third, refractive error itself does not differentiate among
axial, corneal, and lenticular refractive components. Also,
AXL actually is not synonymous with axial elongation; an
eye showing a high AXL may simply be large in proportion
with the other optical components. 59 Future studies per-
forming ideal structural evaluation of myopic eyes should
consider refractive error and AXL along with features of the
ONH.
Fourth, evaluation of glaucomatous structural change in
the ONH can be challenging in myopic eyes because of
morphologic characteristics such as tilted disc, peripapillary
atrophy, and larger diameters of optic disc. 60 , 61 Nonglauco-
matous optic nerve damage also can accompany high my-
opia. 55 Thus, the fact that overdiagnosis of glaucoma in
Funding/Support: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Financial Disclosures: The authors indicate no financial support or conflicts of interest. All authors attest that they meet the current ICMJE criteria for
authorship.
Authorship: Drs Ha and C.Y. Kim contributed equally to this study as co-first authors. Drs Chang and Y.K. Kim contributed equally to this study as
co-corresponding authors.
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