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Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis

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Background: Numerous population-based studies of age-related macular degeneration have been reported around the world, with the results of some studies suggesting racial or ethnic differences in disease prevalence. Integrating these resources to provide summarised data to establish worldwide prevalence and to project the number of people with age-related macular degeneration from 2020 to 2040 would be a useful guide for global strategies. Methods: We did a systematic literature review to identify all population-based studies of age-related macular degeneration published before May, 2013. Only studies using retinal photographs and standardised grading classifications (the Wisconsin age-related maculopathy grading system, the international classification for age-related macular degeneration, or the Rotterdam staging system) were included. Hierarchical Bayesian approaches were used to estimate the pooled prevalence, the 95% credible intervals (CrI), and to examine the difference in prevalence by ethnicity (European, African, Hispanic, Asian) and region (Africa, Asia, Europe, Latin America and the Caribbean, North America, and Oceania). UN World Population Prospects were used to project the number of people affected in 2014 and 2040. Bayes factor was calculated as a measure of statistical evidence, with a score above three indicating substantial evidence. Findings: Analysis of 129 664 individuals (aged 30–97 years), with 12 727 cases from 39 studies, showed the pooled prevalence (mapped to an age range of 45–85 years) of early, late, and any age-related macular degeneration to be 8·01% (95% CrI 3·98–15·49), 0·37% (0·18–0·77), and 8·69% (4·26–17·40), respectively. We found a higher prevalence of early and any age-related macular degeneration in Europeans than in Asians (early: 11·2% vs 6·8%, Bayes factor 3·9; any: 12·3% vs 7·4%, Bayes factor 4·3), and early, late, and any age-related macular degeneration to be more prevalent in Europeans than in Africans (early: 11·2% vs 7·1%, Bayes factor 12·2; late: 0·5% vs 0·3%, 3·7; any: 12·3% vs 7·5%, 31·3). There was no difference in prevalence between Asians and Africans (all Bayes factors
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106
Articles
Global prevalence of age-related macular degeneration and
disease burden projection for 2020 and 2040: a systematic
review and meta-analysis
Wan Ling Wong*, Xinyi Su*, Xiang Li, Chui Ming G Cheung, Ronald Klein, Ching-Yu Cheng, Tien Yin Wong
Summary
Background Numerous population-based studies of age-related macular degeneration have been reported around the
world, with the results of some studies suggesting racial or ethnic diff erences in disease prevalence. Integrating these
resources to provide summarised data to establish worldwide prevalence and to project the number of people with
age-related macular degeneration from 2020 to 2040 would be a useful guide for global strategies.
Methods We did a systematic literature review to identify all population-based studies of age-related macular
degeneration published before May, 2013. Only studies using retinal photographs and standardised grading
classifi cations (the Wisconsin age-related maculopathy grading system, the international classifi cation for age-related
macular degeneration, or the Rotterdam staging system) were included. Hierarchical Bayesian approaches were used
to estimate the pooled prevalence, the 95% credible intervals (CrI), and to examine the diff erence in prevalence by
ethnicity (European, African, Hispanic, Asian) and region (Africa, Asia, Europe, Latin America and the Caribbean,
North America, and Oceania). UN World Population Prospects were used to project the number of people aff ected in
2014 and 2040. Bayes factor was calculated as a measure of statistical evidence, with a score above three indicating
substantial evidence.
Findings Analysis of 129 664 individuals (aged 30–97 years), with 12 727 cases from 39 studies, showed the pooled
prevalence (mapped to an age range of 45–85 years) of early, late, and any age-related macular degeneration to be
8·01% (95% CrI 3·98–15·49), 0·37% (0·18–0·77), and 8·69% (4·26–17·40), respectively. We found a higher
prevalence of early and any age-related macular degeneration in Europeans than in Asians (early: 11·2% vs 6·8%,
Bayes factor 3·9; any: 12·3% vs 7·4%, Bayes factor 4·3), and early, late, and any age-related macular degeneration to
be more prevalent in Europeans than in Africans (early: 11·2% vs 7·1%, Bayes factor 12·2; late: 0·5% vs 0·3%, 3·7;
any: 12·3% vs 7·5%, 31·3). There was no diff erence in prevalence between Asians and Africans (all Bayes factors <1).
Europeans had a higher prevalence of geographic atrophy subtype (1·11%, 95% CrI 0·53–2·08) than Africans (0·14%,
0·04–0·45), Asians (0·21%, 0·04–0·87), and Hispanics (0·16%, 0·05–0·46). Between geographical regions, cases of
early and any age-related macular degeneration were less prevalent in Asia than in Europe and North America (early:
6·3% vs 14.3% and 12·8% [Bayes factor 2·3 and 7·6]; any: 6·9% vs 18·3% and 14·3% [3·0 and 3·8]). No signifi cant
gender eff ect was noted in prevalence (Bayes factor <1·0). The projected number of people with age-related macular
degeneration in 2020 is 196 million (95% CrI 140–261), increasing to 288 million in 2040 (205–399).
Interpretation These estimates indicate the substantial global burden of age-related macular degeneration.
Summarised data provide information for understanding the eff
ect of the condition and provide data towards
designing eye-care strategies and health services around the world.
Funding National Medical Research Council, Singapore.
Introduction
Age-related macular degeneration accounts for 8·7% of
all blindness worldwide and is the most common cause
of blindness in developed countries,1–5 particularly in
people older than 60 years. Its prevalence is likely to
increase as a consequence of exponential population
ageing. There have been signifi cant advances in the
management of exudative or so-called wet age-related
macular degeneration with the introduction of anti-
angiogenesis therapy, and patients now have eff ective
treatment options that can prevent blindness and, in
many cases, restore vision.6–10 However, these treatments
are expensive and not available to all patients in many
countries.11–14 Thus, understanding the prevalence,
burden, and population impact is essential for adequate
health care planning and provision, which require
both precise and contemporary estimates of disease
prevalence.
Although there have been many population-based
studies of age-related macular degeneration around the
world, there are no summarised data to guide global
strategies. Furthermore, studies have suggested
substantial racial or ethnic diff erences in disease
prevalence. In the Baltimore Eye Study, people of
European (white) ancestry were more likely to have early
and late-stage disease than were those of African
Lancet Glob Health 2014;
2: e106–16
Published Online
January 3, 2014
http://dx.doi.org/10.1016/
S2214-109X(13)70145-1
See Comment page e65
*These authors contributed
equally
†These authors contributed
equally
Copyright © Wong et al. Open
Access article distributed under
the terms of CC BY-NC-ND
Singapore Eye Research
Institute, Singapore National
Eye Centre, Singapore
(W L Wong MBiostat, X Su MD,
X Li BSc, C M G Cheung, MD,
C-Y Cheng MD,
Prof T Y Wong MBBS);
Department of
Ophthalmology, Yong Loo Lin
School of Medicine, National
University of Singapore and
National University Health
System, Singapore (W L Wong,
X Su, C-Y Cheng, Prof T Y Wong);
Department of Statistics and
Applied Probability, National
University of Singapore,
Singapore (X Li); Department
of Ophthalmology and Visual
Sciences, University of
Wisconsin, Madison, WI, USA
(R Klein MD); Saw Swee Hock
School of Public Health,
National University of
Singapore and National
University Health System,
Singapore (C-Y Cheng); and
Centre for Quantitative
Medicine, Offi ce of Clinical
Sciences, Duke-NUS Graduate
Medical School, Singapore
(C-Y Cheng)
Correspondence to:
Dr Ching-Yu Cheng, Department
of Ophthalmology, National
University Health System, 1E
Kent Ridge Road, NUHS Tower
Block Level 7, Singapore 119228
ching-yu_cheng@nuhs.edu.sg
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ancestry.15,16 Two meta-analyses done in populations of
European17 and Asian ancestry4 suggest that, in people
aged 40–79 years, the age-specifi c prevalence of late age-
related macular degeneration in Asians (0·56%) was
similar to that in Europeans (0·59%), but early signs
were less common in Asians (6·8%) than in Europeans
(8·8%). No studies had systematically compared the
prevalence of the condition across geographical regions.
To address this gap, we did a systematic review of the
literature to estimate the prevalence of age-related
macular degeneration, and assess diff erences by
ethnicity, region, and sex, and to project the number of
individuals aff ected worldwide by the condition in
2020 and 2040.
Methods
Search strategy
We systematically reviewed publications that reported
prevalence of age-related macular degeneration by
searching the electronic databases of PubMed, Web of
Science, and Embase for relevant papers published up to
May, 2013, with the following search terms (formatted for
PubMed search): (“Macular Degeneration”[Mesh] AND
(“Prevalence”[Mesh] OR “Epidemiology”[Mesh] OR
“Cross-Sectional Studies” [Mesh] OR “Cohort
Studies”[Mesh])); ((“age-related maculopathy”[All Fields]
OR “age-related maculopathy”[All Fields] OR “age-related
macular degeneration”[All Fields] OR “age related
macular degeneration”[All Fields] OR “macular degen-
eration”[All Fields]) AND (“prevalence”[All Fields] OR
“incidence”[All Fields] OR “epidemiology”[All Fields] OR
“risk factors”[All Fields])).
The strategy identifi ed all articles used in previous
reviews.4,17 Reference lists of identifi ed reports were also
scanned to identify other relevant studies. The initial
search was scrutinised in detail by clinician scientist XS
and reviewed by senior clinician scientist C-YC. Data
were checked by statisticians (WLW, XL). Disagreements
were resolved by discussion.
Inclusion and exclusion criteria
Our meta-analysis was done according to the Meta-
analysis Of Observational Studies in Epidemiology
(MOOSE) guidelines.18 The full texts of potentially
relevant articles were reviewed to identify studies that
met the inclusion and exclusion criteria. The two criteria
for inclusion were: a population-based study from a
defi ned geographic area; and a standardised photographic
assessment of age-related macular degeneration.
Population-based studies were included if they
quantifi ed the prevalence (including early, late, and
exudative or neovascular age-related macular
degeneration, and geographic atrophy) in population-
based samples, with clearly defi ned methods of sampling.
A response rate of 50% or higher was considered
adequate for inclusion,19 with the exception of the
European Eye Study (EUREYE) study20 since it was a
large population study (45%); sensitivity analysis showed
almost no eff ect on our robust model estimates (appendix
p 9). Surveys or audits of hospital eye departments or
clinics were excluded. Studies inviting non-specifi c
volunteers or particular professions were excluded, as
were studies that relied on self-reported diagnoses or did
fundus examinations only in those with reduced vision.
For the standardised photographic assessment, we
included studies that had used retinal photography and
standardised grading methods to diagnose and classify
lesions (ie, grading of retinal photographs following
either the Wisconsin age-related maculopathy grading
system,21 the international classifi cation for age-related
macular degeneration,22 or the Rotterdam staging
system23) with reproducible grading results.
Studies fulfi lling any one of the following were
excluded: use of only clinical examination by
ophthalmoscopy or slit-lamp biomicroscopy for diagnosis
(ie, lack of any grading reproducibility assessment);
reports of number of eyes with age-related macular
degeneration as opposed to the number of individuals;
studies in which determination of prevalence was not
one of the primary study objectives (eg, studies
determining risk factors); and studies not population-
based, but were interview-based or audits of hospital eye
departments. Although we did not specifi cally exclude
non-English literature, the studies included in the fi nal
analysis were all in English.
The classifi cation systems used to defi ne those with
early, late, and any age-related macular degeneration
(geographic atrophy and neovascular age-related macular
degeneration) in each study were recorded with the
Wisconsin age-related maculopathy grading system21 or
the international classifi cation.22 Early disease was
defi ned as either any soft drusen (distinct or indistinct)
and pigmentary abnormalities or large soft drusen
125 μm or more in diameter with a large drusen area
(>500 μm diameter circle) or large soft indistinct drusen
in the absence of signs of late-stage disease. Late age-
related macular degeneration was defi ned as the presence
of any of the following: geographic atrophy or pigment
epithelial detachment, subretinal haemorrhage or visible
subretinal new vessel, or subretinal fi brous scar or laser
treatment scar.
Statistical analysis
Because intrinsic diffi culties exist when undertaking a
meta-analysis of data from varied studies with diff ering
characteristics such as disease defi nition, age dis-
tribution of the sample, and prevalence estimates
stratifi ed by age and sex versus single prevalence
estimates, we constructed statistical models to best
describe and fi t our extracted data. Heterogeneity issues
were addressed in our pooled meta-analysis using a
hierarchical Bayesian approach to establish the
worldwide prevalence of age-related macular
degeneration. This approach models the hierarchical
See Online for appendix
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structure of data extracted, taking into account the
diff erence in age distribution across the studies and the
eff ects of ethnicity, sex, and region, to ensure greater
precision in prevalence estimates.
Meta-analyses can be described in a hierarchical
Bayesian model. The number of people with age-related
macular degeneration (yij) can be specifi ed as binomially
distributed: yij ~ Binomial(nij,pij), where nij is the total
number of participants and pij is the prevalence of age-
related macular degeneration in ith the study of the jth
category of the varying covariate (eg, each study might
consist of more than one ethnicity).
In the Bayesian approach, prevalence pij is considered
as a random variable (that has a probability density
distribution) by contrast with a fi xed unknown parameter
(an unknown value) in the classical approach. Hence, the
logit transformation of pij follows a normal distribution:
logit(pij) = uij and uij ~ Normal(uij,σ²), where σ² = 1 / τ.
To investigate and account for the heterogeneity within
and between studies, we modelled uij as a linear
combination of covariates that varies across studies (ie,
age, sex, ethnicity, and regions). Hence, our base model
to pool the overall prevalence of age-related macular
degeneration was: uij = β0 + β1 * agelij + β2 * ageuij + β3 * ageuij,
where agelij and ageuij are the centred and standardised
lower and upper bounds of the age group range for
participants of each study and ageuiij is a right censoring
indicator for studies with right-censored age range data
for the upper bound (eg, 80 or more years). The lower
bound of age range was centred to 45 years and the upper
bound was 85 years, and then standardised by dividing
by their respective standard deviations to ensure that
pooled estimates were comparable since they were being
mapped onto the same age range (45–85 years). Sex,
ethnicity, and region covariates were then individually
added to the base model to establish their eff ect and for
covariate-specifi c pooled prevalence. The percentage of
variability in prevalence estimates due to various sources
of heterogeneity compared with chance alone were
examined (appendix pp 1–3).
Finally, non-informative prior (to represent ignorance)
was specifi ed for residual variability τ using the
conjugate gamma distribution: Gamma(0·01, 0·01).
Gamma distribution is applicable to unknown
quantities that take values between 0 and infi nity. All
age coeffi cients and intercept in the model were
specifi ed with non-informative normal priors—ie,
β~Normal(0, 0·0001).
The Gibbs sampler algorithm, an iterative Markov-
chain Monte Carlo technique, was used to estimate the
posterior distributions of our random variables using the
R and JAGS program.24,25 We used the JAGS software
(version 3.3.0), running from R version 3.0.2
(R Development Core Team, 2013) to implement the
Gibbs sampler, using specifi c marginal posterior
densities.24,25 Convergence estimation was assessed by
calculating the Gelman–Rubin convergence statistics.24,25
Ethnicity, region, and gender eff ects
Bayesian hypothesis testing was done to examine the
eff ect of ethnicity, geographic regions, and sex on the
prevalence of any, early, and late age-related macular
degeneration. Bayes factors were used to compare
hypotheses of diff erences between groups, implementing
the Gibbs variable selection as proposed by Dellaportas
and colleagues26 using the JAGS software. The
comparison of the posterior probabilities of hypothesis is
given by:
where H₀ is the null hypothesis and H₁ is the alternative
hypothesis. Jeff reys27 proposed an interpretation scheme
for the magnitude of Bayes factors in terms of weak
(1–3), substantial (3–10), strong (10–30), very strong
(30–100), and decisive (>100) for H₁, whereas Bayes
factors of less than 1 suggest support for the null
hypothesis.
We assessed four major ethnic groups (European
ancestry populations [Europeans], African ancestry
populations [Africans], Asians, and Hispanics) and six
geographic regions (Africa, Asia, Europe, Latin America
and the Caribbean, northern America, and Oceania).
Publication year was also tested to assess the trend of
prevalence over the years for consideration in projection
estimates.
Because the random eff ect model is the most frequently
used meta-analytical method to account for the
heterogeneity between the studies by incorporating a
random eff ect estimate of between-study variation in the
weighting, we did a simulation study to assess and
compare the hierarchical Bayesian approach and the
random eff ect methods (appendix pp 1–3, 9).
Projection estimates
Model μijk = β0k + β1k * ageij + β2 * ageuiij + β3 * studyi was used
to estimate the prevalence for each year increase in age
for the kth region. Global and region eff ects were
incorporated as fi xed and random eff ects in β0k and β1k.
Age-specifi c prevalence was often reported as an interval
(eg, 40–49 years) or censored (eg, 80 years or more) age
range in the published papers, and hence the median of
interval was used to represent the age interval, and
censored age range was taken as the age with a censoring
indicator in the analysis model. The estimated prevalence
was used to calculate the global and region-specifi c total
number of individuals with age-related macular
degeneration in 2020 and 2040 by multiplying the age-
specifi c and region-specifi c estimated prevalence rates to
the UN World Population Prospects data.28 Age-group-
specifi c prevalence rates were assumed to remain
constant for our global projection to 2040, since Bayesian
P(data|H1)
P(data|H0)
P(H1)
(posterior
odds)
(Bayes
factor)
(prior
odds)
P(H0)
P(H1|data)
P(H0|data)
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Figure 1: Overall and race-specifi ed pooled prevalence of early age-related macular degeneration (AMD)
Dashed line refers to the overall pooled prevalence estimate presented in bold. See appendix (p 7, 8) for study references.
African ancestry
ARIC
BES
CHS
Kenya
MESA
NHANES05–08
NHANESIII
Overall
Asian
Beijing
CIEMS
Funagata
Handan
Hisayama
INDEYE
MESA
Shihpai
SiMES
Thailand
Overall
European ancestry
ARIC
BDES
BMES
BOSS
CHS
Crete
MESA
NHANES05–08
NHANESIII
Oslo
Oulu
RS
SEE
Speedwell
Tromso
VIP
Overall
Hispanic
LALES
MESA
NHANES05–08
NHANESIII
VER
Overall
Globally overall
Early AMD
93/2548
561/3344
32/363
366/3304
34/1583
33/1114
172/1992
1291/14
248
63/4376
215/4544
8/1625
200/6581
178/1486
77/1101
25/691
97/1060
160/3265
294/10
788
1317/35
517
462/8984
773/4771
423/3654
95/2810
334/1998
46/777
111/2299
187/2947
495/4008
197/459
160/478
170/1022
225/2132
486/934
1524/2631
865/5167
6553/45
071
551/5875
51/1274
58/848
165/1834
676/2776
1501/12
607
10
662/107
443
n/N
48–72
40–80+
69–97
50–80+
45–84
40–60+
40–60+
40–75+
30–80+
35–75+
30–70+
50–80+
50–79
45–84
65–85+
40–80
50–80+
48–72
43–75+
49–85+
21–84
69–97
40–80+
45–84
40–60+
40–75+
51–90
70–90+
50–80+
65–80+
65–75+
65–87
40–90+
40–80+
45–84
40–60+
40–60+
50–80+
Age range
(years)
7·06, 95% CrI (3·41–13·15)
6·81, 95% CrI (3·14–13·94)
11·19, 95% CrI (5·63–20·39)
9·87, 95% CrI (4·97–18·90)
8·01, 95% CrI (3·95–15·49)
0 5 10 15 20 25 30 35 40 45 50 55 60
Prevalence (%)
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Figure 2: Overall and race-specifi ed pooled prevalence of late age-related macular degeneration
Dashed line refers to the overall pooled prevalence estimate presented in bold.
African ancestry
ARIC
Baltimore
BES
CHS
Kenya
MESA
NHANES05–08
NHANESIII
Overall
Asian
Beijing
CIEMS
Funagata
Handan
Hisayama
INDEYE
MESA
Shihpai
SiMES
Thailand
Overall
European ancestry
ARIC
Baltimore
BDES
BMES
CHS
Crete
EUREYE
MESA
NHANES05–08
NHANESIII
Oslo
Oulu
RS
SEE
Speedwell
Tromso
VIP
Overall
Hispanic
LALES
MESA
NHANES05–08
NHANESIII
VER
Overall
Globally overall
Late AMD
1/2548
4/1843
19/3344
1/363
38/3304
4/1583
1/1114
4/1992
72/16
091
9/4376
7/4544
8/1625
4/6581
13/1486
15/1101
7/691
20/1060
23/3265
27/10
788
133/35
517
15/8984
31/2518
79/4771
101/3654
29/1998
15/777
165/4753
13/2299
1/2947
12/4008
13/459
39/478
32/1022
11/2132
5/934
92/2631
76/5167
729/49
532
25/5875
3/1274
1/848
2/1834
15/2776
46/12
607
980/113
747
n/N
48–72
40–80+
40–80+
69–97
50–80+
45–84
40–60+
40–60+
40–75+
30–80+
35–75+
30–70+
50–80+
50–79
45–84
65–85+
40–80
50–80+
48–72
40–80+
43–75+
49–85+
69–97
40–80+
65–80+
45–84
40–60+
40–75+
51–90
70–90+
50–80+
65–80+
65–75+
65–87
40–90+
40–80+
45–84
40–60+
40–60+
50–80+
Age range
(years)
0·28, 95% CrI (0·12–0·63)
0·37, 95% CrI (0·17–0·85)
0·50, 95% CrI (0·26–1·08)
0·32, 95% CrI (0·13–0·75)
0·37, 95% CrI (0·18–0·77)
024681012
Prevalence (%)
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Figure 3: Overall and race-specifi ed pooled prevalence of any age-related macular degeneration
Dashed line refers to the overall pooled prevalence estimate presented in bold.
African ancestry
ARIC
BES
CHS
Kenya
MESA
NHANES05–08
NHANESIII
Overall
Asian
APEDS
Beijing
CIEMS
Funagata
Handan
Hisayama
INDEYE
Londrina
MESA
Shihpai
SiMES
SP2
Thailand
Overall
European ancestry
ARIC
BDES
BMES
CHS
Crete
MESA
NHANES05–08
NHANESIII
Oslo
Oulu
RS
Salandra
SEE
Speedwell
Tromso
VIP
Overall
Hispanic
LALES
MESA
NHANES05–08
NHANESIII
VER
Overall
Globally overall
Any AMD
94/2548
580/3344
33/363
404/3304
38/1583
34/1114
176/1992
1359/14
248
71/3722
72/4376
222/4544
16/1625
204/6581
191/1486
92/1101
72/506
32/691
117/1060
183/3265
211/3172
321/10
788
1804/42
917
477/8984
852/4771
524/3654
363/1998
61/777
124/2299
188/2947
507/4008
210/459
199/478
202/1022
147/310
236/2132
491/934
1616/2631
941/5167
7138/42
571
576/5875
54/1274
59/848
167/1834
691/2776
1547/12
607
11
848/112
343
n/N
48–72
40–80+
69–97
50–80+
45–84
40–60+
40–60+
40–70+
40–75+
30–80+
35–75+
30–70+
50–80+
50–79
60–80+
45–84
65–85+
40–80
40–80+
50–80+
48–72
43–75+
49–85+
69–97
40–80+
45–84
40–60+
40–75+
51–90
70–90+
50–80+
60–75+
65–80+
65–75+
65–87
40–90+
40–80+
45–84
40–60+
40–60+
50–80+
Age range
(years)
7·53, 95% CrI (3·80–14·89)
7·38, 95% CrI (3·40–14·46)
12·33, 95% CrI (6·46–22·75)
1
10·43, 95% CrI (5·27–20·01)
8·69, 95% CrI (4·26–17·40)
0 5 10 15 20 25 30 35 40 45 50 55 60 65
Prevalence (%)
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hypothesis testing of the publication year covariate in our
review showed no trend for prevalence from 1989 to2013.
Role of the funding source
The sponsors of this study had no role in study design,
data collection, data analysis, data interpretation, or
writing of the report, or in the decision to submit for
publication. The corresponding author had full access to
all the data in the study and had fi nal responsibility for
the decision to submit for publication.
Results
2751 published original research articles, letters,
abstracts, and review articles based on abstracts and titles
were identifi ed as of May, 2013, from our literature search
(appendix pp 4–8). After initial abstract review,
54 potentially eligible articles were retrieved for
assessment. Of these, we applied the inclusion and
exclusion criteria and identifi ed 39 eligible articles
reporting on 39 population-based studies (12 727 cases in
129 664 participants and fi ve ethnic ancestry groups;
appendix pp 4–8). Data from patients with early, late, and
any age-related macular degeneration were pooled
separately. Of the study participants, 43·5% were of
European ancestry, 12·4% were of African ancestry,
33·1% were Asian, 9·7% Hispanic, and 1·3% other.
Figure 1–3 shows the overall and ethnic-specifi c pooled
prevalence of age-related macular degeneration. The lack
of overlap in credible intervals from graphical inspection
of forest plots suggests the presence of heterogeneity.
Further analysis showed that heterogeneity in ethnicity
and geographic regions for any stage were 99·5%
(95% CrI 99·2–99·8) and 99·7% (99·5–99·9),
respectively (appendix p 11). The pooled global
prevalences (accounting for various sources of
heterogeneity) of early and late-stage disease in adult
populations were 8·01% (95% CrI 3·95–15·49) and
0·37% (0·18–0·77), respectively. The overall prevalence
of any age-related macular degeneration was 8·69%
(95% CrI 4·26–17·40). Detailed estimated prevalence by
subtypes, ethnicity, and age groups from meta-analysis
using the hierarchical Bayesian approach are provided in
the appendix (pp 12,13).
Early age-related macular degeneration was more
prevalent in populations of European ancestry (11·2%)
than in Asians (6·8%), with a Bayes factor of 3·9,
suggesting substantial evidence for the diff erence
between groups (appendix p 10). Likewise, any age-
related macular degeneration was more prevalent in
populations of European ancestry than Asian (12·3% vs
7·4%; Bayes factor 4·3). Compared with African ancestry
populations, people of European ancestry had higher
prevalence of early, late, or any age-related macular
degeneration (late: 12·3% vs 7·5%; Bayes factor 31·3,
suggesting very strong evidence). Geographically, early
and any disease were less prevalent in Asia than in
Europe and northern America (all Bayes factors >2;
gure 4 and appendix p 10). There was no evidence of
diff erence in the prevalence of early, late, or any age-
related macular degeneration between sexes (all Bayes
factors <0·05, appendix p 10). Eight (21%) of the
39 studies provided information on geographic atrophy
and neovascular subtypes. Subgroup analysis showed
similar overall prevalence of geographic atrophy (0·44%,
95% CrI 0·15–1·36) and neovascular age-related macular
degeneration (0·46%, 0·18–1·08). Europeans had a
higher prevalence of geographic atrophy (1·11%, 95% CrI
0·53–2·08) than Africans (0·14%, 0·04–0·45), Asians
(0·21%, 0·04–0·87), and Hispanics (0·16%, 0·05–0·46).
There was no diff erence in prevalence of neovascular
age-related macular degeneration between ethnicities.
The prevalence of early and late disease increased with
age in each of the ethnic groups and regions (fi gure 5).
Prevalence of late disease in populations with European
ancestry increased most rapidly after age 75 years, with a
similar trend seen in Europe and Oceania regions.
Figure 4: Prevalence of age-related macular degeneration (AMD) by ethnic group (A) and (B) geographical region
Error bars=95% CrI.
African ancestry
Asian
European ancestry
Hispanic
Any Early
0
10
20
30
40
50
Prevalence (%) of any or early AMD
Late
0
1
2
3
4
5
Prevalence (%) of late AMD
Any Early
0
20
40
60
80
100
ABPrevalence (95% CrI) Prevalence (95% CrI)
Prevalence (%) of any or early AMD
Late
0
2
4
6
8
10
Prevalence (%) of late AMD
Africa
Asia
Europe
Latin America and Caribbean
North America
Oceania
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The projected number of people with age-related
macular degeneration by region in the years 2014, 2020,
and 2040 are shown in fi gure 6 and the appendix
(pp 14–16). In the year 2020, global projected cases of any
age-related macular degeneration are 196 million
(95% CrI 140–261), rising to 288 million (205–399) in
2040, with the largest number of cases in Asia (113 million
[60–203] in 2040). Europe is expected to be second to Asia
in the number of projected cases (69 million [40–109] in
2040), followed by Africa (39 million [12–93]), Latin
America and the Caribbean (39 million [15–82]), North
America (25 million [15–38]), and Oceania (2 million
[1–5]). Pairwise comparison between geographical
regions showed statistical evidence for the larger
projected number of people with any age-related macular
degeneration in 2040 in Asia compared with Latin
America and the Caribbean, northern America, and
Oceania, and up to 2038 for Africa (appendixpp 17,18).
Discussion
This systematic review and meta-analysis has shown that
8·7% of the worldwide population has age-related
macular degeneration, and the projected number of
people with the disease is around 196 million in 2020,
increasing to 288 million in 2040. We found substantial
evidence that early age-related macular degeneration was
more prevalent in Europe than in Asia, but that rates of
late onset were similar. These results confi rm those of
previous meta-analyses4 and multiethnic population-
based studies.15 Asian (Chinese) people might be more
Figure 5: Age trends of prevalence of age-related macular degeneration (AMD) by ethnicity (A and B) and region (C and D)
0
10
20
30
40
50
Prevalence (%)
0
2
4
6
8
10
ABEarly AMD Late AMD
45 55 65 75 85
0
10
20
30
40
50
Prevalence (%)
Age (years)
45 55 65 75 85
0
2
4
6
8
10
CDEarly AMD Late AMD
Age (years)
African ancestry
Asian
European ancestry
Hispanic
Total
Africa
Asia
Europe
Latin America and Caribbean
North America
Oceania
Total
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114
likely to develop exudative or neovascular age-related
macular degeneration than white people,15,29 but our
subgroup analysis suggests no evidence for ethnicity
diff erence. Also, most population-based studies were
unable to reliably diagnose polypoidal choroidal
vasculopathy, which often manifests like exudative age-
related macular degeneration. Taking into consideration
that polypoidal choroidal vasculopathy is markedly more
common in Asians than in Europeans, we could be
overestimating the true prevalence of late disease in
Asians.30–32 Our study also provides strong evidence that
early, late, and any age-related macular degeneration is
more prevalent in people of European ancestry than
those of African ancestry, which validates observations
derived from previous individual studies, such as the
Baltimore Eye Study.15,16 These patterns are in line with a
previous multiethnic population-based study in the USA,
whereby the prevalence of early disease was highest in
people of European ancestry, compared with Hispanics,
Asians (Chinese), and African Americans.15
Our meta-analysis updates two earlier reviews focused
on single ethnicities, one in Europeans by Rudnicka and
colleagues17 and one in Asians by Kawasaki and
colleagues.4 In our study, compared with the Asian meta-
analysis, we included four additional Asian studies
published after 2010, including the Handan Eye
Study,33 the Central India Eye and Medical Study,34 one
multiethnic Asian cohort study in Singapore,35 and one
study in Thailand.36 Unlike Rudnicka and colleagues, six
studies published between 1970 and 1990 were excluded
since they relied only on eye examinations, without taking
fundus photos, and used study-specifi c defi nitions.29,37–41 We
included only participants with internationally recog-
nised defi nitions of age-related macular degen-
eration21,22 confi rmed using retinal photographs.
Analysis of pooled prevalence by geographical regions
showed greater variability, indicated by the larger 95%
credible intervals compared with prevalence pooled by
ethnic ancestry groups. This fi nding could be due to
heterogeneity contributed by various ethnic groups
within each region, and lends further support to the
hypothesis that inherited genetic factors determined by
ethnic ancestry play a substantial part in age-related
macular degeneration,42–44 in addition to established
environmental risk factors such as smoking. Northern
America and Europe had a higher pooled prevalence of
early and any age-related macular degeneration than in
Asia, in accordance with the higher prevalence in people
of European ancestry than in Asians, as reported both in
the literature and substantiated in our meta-analysis.
Female gender was considered a weak risk factor, with
inconsistent association for late age-related macular
degeneration.45,46 In our meta-analysis, there was no
evidence of gender diff erence in both early and late
prevalence. This fi nding is consistent with previous
reviews in people of European ancestry, where no
signifi cant gender diff erence was found in the prevalence
of neovascular age-related macular degeneration or
geographic atrophy.47 Similarly in Asians, men do not
have a higher prevalence of late disease than women
after adjusting for risk factors such as smoking.48–50
Figure 6: Projection of number of people with early and late age-related
macular degeneration (AMD) by regions in 2014, 2020, and 2040
0
50
100
150
Number (milions)
AEarly AMD
Africa
Asia
Europe
Latin America and Caribbean
North America
Oceania
0
5
10
15
Number (milions)
BLate AMD
0
50
100
150
Number (milions)
CAny AMD
2014 2020 2030
Year
2040
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Asia accounts for more than 60% of the world population
and hence will see the largest projected number of cases
of age-related macular degeneration (a third of the cases
globally), and is expected to increase more rapidly than
other regions over the years, despite having the lowest
estimated prevalence currently. Europe, being the third
most populous region (11%) with the highest prevalence
of age-related macular degeneration, follows after Asia in
the number of projected cases, with a moderate increase
over the years. The trends and diff erences between regions
are mainly aff ected by the demographic progression in
population structure (ie, an ageing population) of the
regions based on UN population projection data.28 These
ndings are important, since more than two-thirds of
aff ected patients in Asia, Africa, and Latin America might
not have access to expensive anti-angiogenesis therapies
now widely used in North America and Europe.
The strength of our study is that we pooled data that
used fundus photography and standardised protocols to
assess age-related macular degeneration. Our study was
limited by the fact that, despite the large number of studies
included in this meta-analysis, our subgroup analysis on
the prevalence of late disease subtypes (ie, neovascular age-
related macular degeneration vs geographic atrophy) by
ethnicity used data from only eight studies. Moreover,
there is evidence that without harmonisation of class-
ifi cation systems and defi nitions of lesions, estimates of
early age-related macular degeneration might sub stantially
vary due to several factors. These include varying
defi nitions used for grading the disease and inconsistencies
in quality of images.51 Although there are inherent
disadvantages in undertaking a meta-analysis based on
datasets pooled together from disparate population
studies, we have attempted to circumvent this issue by
only including studies in which standard protocols are
used to grade fundus photos.
There is substantial evidence for higher prevalence of
early disease in people of European ancestry than in
Asians, and early and late disease in people of European
ancestry than in those of African ancestry. We noted that
late prevalence increases rapidly after age 75 years,
especially in people of European ethnicity and in Europe
and Oceania regions, but Asia will see the largest number
of people with the condition despite currently having the
lowest prevalence. These data provide important infor-
mation for the design and implementation of eye care
programmes for both specifi c ethnic groups and
geographical regions, as well as worldwide.
Contributors
XS and C-YC reviewed the literature. WLW and XL checked and analysed
the data. XS and WLW drafted the manuscript. C-YC, RK, CMGC, and
TYW did the critical revision.
Confl icts of interest
We declare that we have no confl icts of interest.
Acknowledgments
C-YC is supported by an award from National Medical Research Council
(CSA/033/2012), Singapore.
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... Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly of the Western world. Currently, more than 196 million people worldwide have AMD, and global aging will increase the number of affected persons to 288 million by the year 2040 [1,2]. The prevalence of early and intermediate AMD is~20% in people aged over 65 years. ...
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Fundus photography is indispensable for the clinical detection and management of eye diseases. Low image contrast and small field of view (FOV) are common limitations of conventional fundus photography, making it difficult to detect subtle abnormalities at the early stages of eye diseases. Further improvements in image contrast and FOV coverage are important for early disease detection and reliable treatment assessment. We report here a portable, wide FOV fundus camera with high dynamic range (HDR) imaging capability. Miniaturized indirect ophthalmoscopy illumination was employed to achieve the portable design for nonmydriatic, widefield fundus photography. Orthogonal polarization control was used to eliminate illumination reflectance artifacts. With independent power controls, three fundus images were sequentially acquired and fused to achieve HDR function for local image contrast enhancement. A 101°eye-angle (67° visual-angle) snapshot FOV was achieved for nonmydriatic fundus photography. The effective FOV was readily expanded up to 190° eye-angle (134° visual-angle) with the aid of a fixation target without the need for pharmacologic pupillary dilation. The effectiveness of HDR imaging was validated with both normal healthy and pathologic eyes, compared to a conventional fundus camera.
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Background/objectives: To examine the risk factors for poor vision-related and health-related quality of life (QoL) in patients with neovascular age-related macular degeneration (nAMD) who present for anti-vascular endothelial growth factor (anti-VEGF) therapy. Methods: In a clinic-based cohort of 547 nAMD patients who presented for treatment, the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ25), Short-Form 36 (SF-36) and EuroQoL EQ-5D-5L questionnaires were administered to assess vision-related and health-related QoL. Of these, 83 participants were followed up one-year later to provide longitudinal data. Results: Individuals with mild or moderate visual impairment or blindness at baseline had significantly lower NEI-VFQ-25 scores at follow-up. The presence of ≥3 chronic diseases was associated with lower SF-36 mental component scores (MCS) (p = 0.04) and EQ-VAS scores (p = 0.05). Depressive symptoms were associated with significantly lower MCS (p < 0.0001) and EQ-VAS scores (p = 0.02). Individuals with versus without impaired basic activities of daily living (ADLs) exhibited NEI-VFQ-25 and EQ-VAS scores that were 10.96 (p = 0.03) and 0.13 (p = 0.02) points lower. Those with impaired instrumental ADLs scored 11.62 (p = 0.02), 13.13 (p < 0.0001) and 15.8 (p = 0.0012) points lower in the NEI-VFQ-25, SF-36 physical component score and EQ-5D-5L summary score, respectively. Conclusions: The QoL of nAMD patients is affected by visual acuity as well as patients' medical history, mental health and functional status.
Article
Purpose: Automatic multilabel classification of multiple fundus diseases is of importance for ophthalmologists. This study aims to design an effective multilabel classification model that can automatically classify multiple fundus diseases based on color fundus images. Methods: We proposed a multilabel fundus disease classification model based on a convolutional neural network to classify normal and seven categories of common fundus diseases. Specifically, an attention mechanism was introduced into the network to further extract information features from color fundus images. The fundus images with eight categories of labels were applied to train, validate, and test our model. We employed the validation accuracy, area under the receiver operating characteristic curve (AUC), and F1-score as performance metrics to evaluate our model. Results: Our proposed model achieved better performance with a validation accuracy of 94.27%, an AUC of 85.80%, and an F1-score of 86.08%, compared to two state-of-the-art models. Most important, the number of training parameters has dramatically dropped by three and eight times compared to the two state-of-the-art models. Conclusions: This model can automatically classify multiple fundus diseases with not only excellent accuracy, AUC, and F1-score but also significantly fewer training parameters and lower computational cost, providing a reliable assistant in clinical screening. Translational relevance: The proposed model can be widely applied in large-scale multiple fundus disease screening, helping to create more efficient diagnostics in primary care settings.
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Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the elderly population. Neovascular AMD is the late stage, characterized by choroidal neovascularization (CNV). Non-coding RNAs have been implicated in CNV; however, the role of circular RNAs (circRNAs) has not yet been elucidated. Herein, we comprehensively investigated circRNA profiles in laser-induced CNV mouse models and patient specimens. A novel circRNA, circRNA Uxs1, was identified, and its function in CNV regulation was investigated in the present study. CircRNA Uxs1 was consistently upregulated in CNV patient specimens and CNV mouse models. Knockdown of circRNA Uxs1 interrupted the tube formation, migration, and proliferation of endothelial cells in vitro. Silencing circRNA Uxs1 in vivo alleviated neovascularization formation, as shown by the decreased size of laser spots. Mechanistically, circRNA Uxs1 functioned by binding to miR-335-5p, which further upregulated the expression of placental growth factor (PGF) gene and activated the mammalian target of rapamycin/p70 S6 Kinase (mTOR/p70 S6k) pathway. By subretinal injections of adeno-associated virus (AAV), we demonstrated the anti-angiogenic function of circRNA Uxs1 knockdown in vivo. In conclusion, circRNA Uxs1 promoted CNV by sponging miR-335-5p, which stimulated PGF expression and subsequently activated the mTOR/p70 S6k pathway. Therefore, circRNA Uxs1 may serve as a promising therapeutic target for CNV.
Article
Purpose: Individuals with central vision loss due to macular degeneration (MD) often spontaneously develop a preferred retinal locus (PRL) outside the area of retinal damage, which they use instead of the fovea. Those who develop a stable PRL are more successful at coping with their vision loss. However, it is unclear whether improvements in visual performance at the PRL are specific to that retinal location or are also observed in other parts of the retina. Perceptual learning literature suggests that the retinal specificity of these effects provides insight about the mechanisms involved. Better understanding of these mechanisms is necessary for the next generation of interventions and improved patient outcomes. Methods: To address this, we trained participants with healthy vision to develop a trained retinal locus (TRL), analogous to the PRL in patients. We trained 24 participants on a visual search task using a gaze-contingent display to simulate a central scotoma. Results: Results showed retinotopically specific improvements in visual crowding only at the TRL; however, visual acuity improved in both the TRL and in an untrained retinal locus. Conclusions: These results suggest that training with an artificial scotoma involves multiple mechanistic levels, some location-specific and some not, and that simulated scotoma training paradigms likely influence multiple mechanisms simultaneously. Eye movement analysis suggests that the non-retinotopic learning effects may be related to improvements in the capability to maintain a stable gaze during stimulus presentation. This work suggests that effective interventions promoting peripheral viewing may influence multiple mechanisms simultaneously.
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Purpose: To describe methods to harmonize the classification of age-related macular degeneration (AMD) phenotypes across four population-based cohort studies: the Beaver Dam Eye Study (BDES), the Blue Mountains Eye Study (BMES), the Los Angeles Latino Eye Study (LALES), and the Rotterdam Study (RS). Methods: AMD grading protocols, definitions of categories, and grading forms from each study were compared to determine whether there were systematic differences in AMD severity definitions and lesion categorization among the three grading centers. Each center graded the same set of 60 images using their respective systems to determine presence and severity of AMD lesions. A common 5-step AMD severity scale and definitions of lesion measurement cutpoints and early and late AMD were developed from this exercise. Results: Applying this severity scale changed the age-sex adjusted prevalence of early AMD from 18.7% to 20.3% in BDES, from 4.7% to 14.4% in BMES, from 14.1% to 15.8% in LALES, and from 7.5% to 17.1% in RS. Age-sex adjusted prevalences of late AMD remained unchanged. Comparison of each center's grades of the 60 images converted to the consortium scale showed that exact agreement of AMD severity among centers varied from 61.0-81.4%, and one-step agreement varied from 84.7-98.3%. Conclusion: Harmonization of AMD classification reduced categorical differences in phenotypic definitions across the studies, resulted in a new 5-step AMD severity scale, and enhanced similarity of AMD prevalence among the four cohorts. Despite harmonization it may still be difficult to remove systematic differences in grading, if present.
Article
Age-related macular degeneration(AMD)is the leading cause of visual impairment among older population worldwide, and wet AMD is more threatened to vision because of the choroidal neovascularization. Some physical therapies are thought to destroy the lesions but can not improve the visual acuity. Therefore, anti-VEGF drug therapy is becoming a new approach to the management of wet AMD. Vascular endothelial growth factor(VEGF) is thought to play an important role in the complicated pathogenesis, which can be addressed by disease reduction strategies. Among the anti-VEGF drug therapies, anti-VEGF monoclonal antibodies are proved to maintain and improve visual acuity. Other therapies have been or now being developed for the treatment of neovascular AMD with the goal of inhibiting VEGF. These inhibitors include VEGF receptor decoy aflibercept, small interfering RNA-based therapies (bevasiranib) and tyrosine kinase inhibitors (vatalanib), which could offer the potential for further advances. To completely realize the active mechanism of VEGF in wet AMD is helpful for the rational use of anti-VEGF drugs.
Article
AIM To determine the prevalence of age related maculopathy (ARM) in a representative older Japanese population. METHODS 1486 residents of Hisayama town, Fukuoka, Japan, aged 50 years or older were examined and the presence of ARM was determined by grading from fundus examination by indirect ophthalmoscope, slit lamp, and colour fundus photographs. RESULTS The prevalence rate of drusen, which occurred with comparable frequency in men and women, was 9.6%. The frequency of drusen increased with age (p <0.01). Hyperpigmentation and/or hypopigmentation of the retina was present in 3.2%, geographic atrophy in 0.2%, and neovascular age related macular degeneration in 0.67%. The frequency of neovascular age related macular degeneration was significantly higher in the men (1.2% v 0.34%, p <0.01). CONCLUSIONS Early and late stage ARM is less common among Japanese people than among white people in Western countries, while late stage ARM is more common among Japanese than among black people.
Article
Background: Previous reports suggest that the outcome of age-related macular degeneration treatment is dependent on variants in the apolipoprotein E (APOE) gene. We wish to establish if variants in this gene are associated with anatomical location of fluid within the macula on optical coherence tomography imaging before and after three anti-vascular endothelial growth factor treatments. Methods: Patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration were prospectively enrolled and monitored over a 12-month period. Main outcome measures were logMAR best-corrected visual acuity and correlation of qualitative optical coherence tomography features (intraretinal fluid [IRF] and/or subretinal fluid) at baseline and after three anti-vascular endothelial growth factor injections with genetic variants of the APOE gene. Results: One hundred and eighty-six eyes of 186 patients aged 79.4 years (range, 58-103 years). Subjects with an ε2 allele were more likely to have IRF at baseline compared with the eyes without (odds ratio: 2.98, 95% confidence interval: 1.22-7.29, P = 0.02). After 3 injections, 184 eyes remained. Of these, 114 of eyes (62.0%) were classified as "dry" on optical coherence tomography, whereas 48 eyes (26.1%) still had a component of IRF, and 22 (12.0%) had subretinal fluid alone. There was no statistically significant association between APOE variants and presence of persistent IRF, although there were almost double the number of subjects with ε2 (40%) who had persistent fluid compared with those with ε3/ε4 (23%) (P = 0.06). Conclusion: In patients with neovascular age-related macular degeneration, the presence of the ε2 allele of the APOE gene was associated with having IRF at baseline. Larger studies are required to determine if a greater proportion of those with the ε2 allele retain this fluid after three initial injections.
Article
The prevalence of age-related maculopathy (ARM) varies considerably in different locations and racial/ethnic groups around the world. At present there are insufficient data to determine whether it is likely that these differences in prevalence, especially for the early forms of ARM are due to variations in genetic and environmental factors or due to variations in age of the cohorts and methods used to ascertain and define ARM. In three population-based studies of whites living in Beaver Dam, Wisconsin, Blue Mountains, Australia, and Rotterdam, The Netherlands, in which similar methods of ascertainment and classification were used to detect and define ARM, late ARM in 1.2%, 1.4%, and 1.2% of the population less than 86 years of age, respectively. While data from clinical studies suggest that late ARM associated with choroidal neovascularization is rare in blacks compared with whites, some epidemiological studies suggest that late ARM may be similar in blacks and whites. There are still too few data from various ethnic/racial groups around the world and too few population-based data in older Hispanic and Asian populations to make meaningful comparisons. There is a need for further research into the distribution of ARM and its possible causes using similar methodologies to ascertain and define the disease. Further insights will be gained when genotypes associated with ARM are discovered.