REVIEW ARTICLE
Artificial Intelligence in Diabetic Eye Disease Screening
Carol Y. Cheung, PhD,* Fangyao Tang, PhD,* Daniel Shu Wei Ting, MD, PhD,†
Gavin Siew Wei Tan, MD,† and Tien Yin Wong, MD, PhD†
Abstract: Systematic or national screening programs for diabetic
retinopathy (DR) and diabetic macular edema (DME), using digital
fundus photography and optical coherence tomography (OCT), are
currently implemented at primary care level, aiming to provide timely
referral for vision-threatening DR and DME to ophthalmologists for
Downloaded from http://journals.lww.com/apjoo by BhDMf5ePHKbH4TTImqenVFpRRqarA4WBo19OZATH64c0vutF+167Hc8QOeWVQUEbdtXf1GZF1KE= on 12/08/2019
timely treatment and vision loss prevention. However, interpretation of
retinal images requires specialized knowledge and expertise in diabetic
eye disease. Furthermore, current DR screening programs are capital- and
labor-intensive, which makes it difficult to rapidly scale up and expand
diabetic eye screening to meet the needs of this growing global epidemic.
Deep learning (DL), a new branch of machine learning technology
under the broad term of artificial intelligence (AI), has made remarkable
breakthrough in medical imaging in particular for pattern recognition and
image classification. In ophthalmology, AI and DL technology has been
developed from big image datasets in assessment of retinal photographs
for detection and screening of DR as well as the segmentation and
assessment of OCT images for diagnosis and screening of DME. This
review aimed to summarize the current progress and the development of
using AI and DL technology for diabetic eye disease screening as well
as current challenges in the actual implementation of DL in screening
programs, and translating DL research into direct clinical applications of
screening in a community setting.
Key Words: artificial intelligence, deep learning, diabetic retinopathy,
optical coherence tomography, screening
(Asia Pac J Ophthalmol (Phila) 2019;8:158–164)
A rtificial intelligence (AI) using deep learning (DL) algorithms
or systems has been identified as a major ‘disruptive
innovation’ in medicine and healthcare. In ophthalmology, AI
and DL technology has been developed in several areas, with the
two most prominent being in assessment of retinal photographs
for detection and screening of diabetic retinopathy (DR),1–6
From the *Department of Ophthalmology and Visual Sciences, The Chinese
University of Hong Kong, Hong Kong; and †Singapore Eye Research Institute,
Singapore National Eye Centre, Singapore.
Submitted March 25, 2019; accepted April 8, 2019.
Supported by the Research Grants Council – General Research Fund, Hong
Kong (Ref: 14102418); National Medical Research Council, Singapore (Ref:
NMRC/STaR/0016/2013). D.S.W.T. and T.Y.W. are co-inventors of a patent on
a deep learning system.
Reprints: Tien Y. Wong, Singapore National Eye Center, 11 Third Hospital Avenue,
Singapore 168751. E-mail: wong.tien.yin@snec.com.sg.
Copyright © 2019 by Asia-Pacific Academy of Ophthalmology
ISSN: 2162-0989
DOI: 10.22608/APO.201976
158 | www.apjo.org
Copyright © 2019 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
age-related macular degeneration (AMD),7–9 glaucoma,10,11 and
retinopathy of prematurity,12,13 as well as the segmentation and
assessment of optical coherence tomography (OCT) images for
diagnosis and screening of major retinal diseases.14–16
For DR screening, DL has made remarkable breakthrough
with some of the first few landmark studies in this area, as
well as approval and registration of a fundus camera device for
DR screening using DL technology by the US Food and Drug
Administration (FDA).17 A study by Google Health, in particular,
has drawn substantial media publicity, showing extremely high
sensitivity and specificity in detecting referable DR from fundus
photographs.3 These developments have been cited in mainstream
media and editorials in non-ophthalmology literature.18–21
Despite the promise and hype, there remains significant
challenges in the actual implementation of DL in DR screening,
and translating DL research into direct clinical applications of
screening in a community setting. This review will focus on
the current progress and the development of using AI and DL
technology for DR screening.
WHY IT IS IMPORTANT TO SCREEN FOR DR?
Screening for DR is based on a high level of evidence. By
2040, 642 million people worldwide is projected to have diabetes
mellitus (DM).22 This is a global epidemic with heavy health
burden to individuals and societies across the world, affecting
populations not only in highly developed countries, but also
increasingly in developing countries.22–24 Of note, DR is already
the most specific microvascular complication of DM that leads to
progressive visual impairment and even blindness. The prevalence
of DR ranges from 30% to 45%, with 10% having vision-
threatening DR (VTDR), defined as severe non-proliferative
DR, proliferative DR, and diabetic macular edema (DME).25–28
Diabetes is estimated to account for 11.6% of the annual healthcare
budgets in most countries.29 The cost of care for patients with DR
is higher than those without DR, and increasing with severity.30
With a projected increase in the incidence of DM, increased life
expectancy and an aging population, it is anticipated that the
impact of vision impairment associated with DR will inevitably
increase in the coming years. Early identification of eyes at risk
of VTDR and timely treatment has been shown to be effective
in preventing the onset of visual impairment.25 Recent results of
randomized controlled trials have also shown that intraocular
injections of drugs targeting vascular endothelial growth factor or
inflammation in DME can lead to better visual outcomes.31 Early
detection through regular surveillance by clinical examination or
grading of retinal photographs is, therefore, the key to prevent
vision loss and even blindness.
Asia-Pacific Journal of Ophthalmology • Volume 8, Number 2, March/April 2019
Asia-Pacific Journal of Ophthalmology • Volume 8, Number 2, March/April 2019
CURRENT CHALLENGES IN DR SCREENING
PROGRAMS
While the rationale to screen for DR among patients with
DM is clear, there are significant challenges in designing and
sustaining a DR screening program in many communities and
countries.
Systematic or national screening programs for DR using
2-dimensional (2D) non-stereoscopic digital fundus photography
are currently implemented at primary care level in many
countries, aiming to provide timely referral for more severe
levels of DR to ophthalmologists for timely treatment and vision
loss prevention.32–34 Diagnosis of DME requires identification of
thickening of the macula; therefore, screening for DME using
non-stereoscopic fundus photographs is bound to a very high
false-positive rate (eg, >86% in Hong Kong35 and >79% in the
UK36). Currently, spectral-domain optical coherence tomography
(SD-OCT), which provides 3D volumetric data cube of the
layered retinal structures, is being piloted to add in different DR
screening programs in the UK, China and Singapore, aiming to
reduce the false-positive rate of DME detection from fundus
photography.37–39 When signs of referable DR or other referable
eye diseases are identified from retinal photographs and SD-
OCT, patients are referred to eye clinics at tertiary eye hospitals
for clinical examination and management to prevent vision loss.
However, interpretation of both retinal photographs and SD-
OCT requires specialized knowledge and expertise in diabetic
eye diseases and retinal imaging. Inter-individual differences
in interpretation as well as potential of missing important
retinal pathologies, especially with the engagement of non-
ophthalmologist graders of varying skills and experience, are
always concerned. Furthermore, current DR screening programs
are capital- and labor-intensive, which makes it difficult to rapidly
scale up and expand diabetic eye screening to meet the needs of
this growing global epidemic.40 Given that the number of DM is
expected to rise rapidly, manual grading of DR and DME from
retinal images in DR screening programs will not be sustainable.
THE CASE FOR “AUTOMATED” MACHINE-BASED
ASSESSMENT OF DR
In view of the challenges associated with DR screening, an
automated program to assess DR from photographs has significant
potential of increasing efficiency, reproducibility, and coverage
of screening programs, and at the same time reducing cost and
barriers to access, and improving patient outcomes by providing
early detection and treatment.
Image interpretation using AI has been developed in the
field of medicine. Over the last 2 decades, automated analysis
of retinal photographs for DR has been studied using traditional
machine learning methods based on feature extraction or pattern
recognition specified by experts manually for DR characterization
and classification.41–43 However, the detection of DR is a complex
image-interpretation task. Based on feature extraction or pattern
recognition using traditional machine learning algorithms, these
systems still cannot reach a good level of specificity. Furthermore,
traditional machine learning algorithms typically plateau in
performance after it reaches a threshold of training data.
Recently, DL has been applied in the field of ophthalmology
to outstrip the ceiling performance of prior technology, and has
revolutionized the detection of DR/DME from retinal photographs
© 2019 Asia-Pacific Academy of Ophthalmology
Copyright © 2019 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
AI in Diabetic Eye Disease Screening
and SD-OCT to achieve excellent diagnostic performance.
DL AS THE BREAKTHROUGH IN AI TECHNOLOGY
Deep learning is a new branch of machine learning
technology under the broad term of AI. The concept is that
DL permits software algorithms to be trained through a large
mathematical function with millions of parameters on vast
amounts of data called convolutional neural network (CNN). Such
network is inspired by the ability of brains to learn complicated
patterns in data by changing the strengths of synaptic connections
between neurons. Deep learning uses deep networks with many
intermediate layers of artificial “neurons” between the input and
the output, and, like the visual cortex, these artificial neurons learn
a hierarchy of progressively more complex feature detectors.44 In
recent years, AI-DL with CNNs has been developed rapidly and
has demonstrated strengths in intricate pattern recognition from
big datasets in the medical field. For example, it is shown that
the performance of automated classification for DR,1–5 retinal
diseases,14–16 glaucoma10,11 as well as other medical conditions
including malignant melanoma,45 tuberculosis,46 and lung
cancer47 by DL systems are equal to or better than board-certified
specialists. These studies underscoring the ability of automated
image interpretation using DL are promising.
For image interpretation, DL is superior to traditional
machine learning. In traditional machine learning, features need
to be extracted manually, before they are fed in the machine
learning algorithm. Using DL, the features are automatically
learnt by neural networks in the feature extraction stage and then
fed into a classifier for classification. No lesion-based features
need to be specified in DL, and thus steps of traditional feature
calculation or lesion segmentation machine learning algorithms
can be skipped which required considerable domain expertise and
careful engineering. Furthermore, such DL approach may identify
“different features” that are associated with the desired classifi-
cation and unknown to humans previously. Table 1 summarizes
recent DL systems for screening DR and DME.1–6,14,15,48,49
DL IN RETINAL PHOTOGRAPH FOR DETECTING DR
There have been several DL systems developed by different
groups for detecting DR and VTDR from retinal photographs.
1. Abràmoff et al2 was the first to use a DL-enhanced algorithm
for the automated detection of referable DR and VTDR
using 1748 retinal photographs from Messidor-2 dataset.
They found that the sensitivity of the DL system was not
statistically different from their previously published
algorithm based on traditional machine learning methods, but
with a significantly better specificity.50 The DL system has
recently been evaluated using data collected prospectively
from 819 subjects recruited from 10 primary care sites in the
US with high sensitivity (87.2%) and specificity (90.7%).48
The DL system has also been evaluated in primary care
setting outside the US.51,52 In April 2018, the DL algorithm
developed by Abramoff et al, called IDx-DR, has received
the first approval from the FDA for detecting more-than-
mild DR in adults who have DM using DL without assisted
interpretation by a clinician.17 The case of IDx-DR highlights
one of the earliest successes of a DL-based screening tool in
completing the regulatory process.
www.apjo.org | 159
 TABLE 1. A Summary of Recent Deep Learning Systems for Screening DR and DME

Size of Dataset
Cheung et al

Output(s) of DR/ Deep Learning Size of Dataset for for External Sensitivity for Specificity for AUC for Output of
Study Year Imaging DME Techniques Development Validation Other Outputs Output of DR/DME Output of DR/DME DR/DME

Abràmoff et 2016, Fundus mtmDR (defined AlexNet and Messidor-2: 1748 819 subjects Sufficient image 87.2% 90.7% Not reported

160 | www.apjo.org
al2,48 2018 photograph as ETDRS level VGG network images recruited from 10 quality: yes/no
≥35 and/or DME architectures primary care sites
present)
Gulshan et al3 2016 Fundus Referable DR Inception-V3 128,175 images EyePACS-1: 9963 All-cause referable EyePACS-1: 97.5% EyePACS-1: 93.4% EyePACS-1: 0.991
photograph architecture images Messidor-2: 96.1% Messidor-2: 93.9% Messidor-2: 0.990
Messidor-2: 1748
images
Gargeya and 2017 Fundus Any stage of DR, Customized CNNs 75,137 images Messidor-2: 1748 Nil Messidor-2 (no DR Messidor-2 (no DR Messidor-2 (no DR
Leng4 photograph mild DR images vs any stage of DR): vs any stage of DR): vs any stage of DR):
E-Ophtha: 405 93% 87% 0.94
images Messidor-2 (no DR Messidor-2 (no DR Messidor-2 (no DR
vs mild DR): 74% vs mild DR): 80% vs mild DR): 0.83
E-Ophtha (no DR vs E-Ophtha (no DR vs E-Ophtha (no DR vs
mild DR): 90% mild DR): 94% mild DR): 0.95
Ting et al1 2017 Fundus Referable DR and Adapted VGGNet DR: 76,370 images Primary: 71,896 Referable possible Referable DR: Referable DR: Referable DR:
photograph VTDR architecture Possible glaucoma: images glaucoma 90.5% 91.6% 0.936
125,189 images 10 additional Referable AMD VTDR: 100% VTDR: 91.1% VTDR: 0.958
AMD: 72,610 datasets: 40,752
images images
Li et al5 2018 Fundus Vision-threatening Inception V3 71,043 images 35,201 images Nil 92.5% 98.5% 0.955
photograph referable DR architecture
Kanagasingam 2018 Fundus DR Inception V3 30,000 images 193 subjects Nil 100% 92% Nil
et al6 photograph architecture
Kermany et al14 2018 OCT DME Inception V3 108,312 images 1000 images CNV; drusen; Multiclass model: Multiclass model: Multiclass model:
architecture and urgent referral 97.8% 97.4% 0.999
transfer learning Limited model: Limited model: Limited model:
96.6% 94.0% 0.988
Binary model: Binary model: Binary model:
96.8% 99.6% 0.999
De Fauw et al15 2018 OCT Diagnosis 3D U-Net 877 segmented 997 subjects Referral suggestion, Not reported Not reported 0.990
probability of architecture for scans for the tissue volume
macular edema segmentation segmentation of drusen and
network network; 14,884 epiretinal
Customized CNNs scans with membrane,
for classification diagnoses and and diagnosis

Copyright © 2019 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
network referral decisions probability of
for classification other retinal
network abnormalities
Li et al49 2019 OCT DME VGG-16 network 109,312 images 1000 images CNV; drusen 98.8% 98.8% 0.999
architecture

AMD indicates age-related macular degeneration; AUC, area under the curve; CNN, convolutional neural network; CNV, choroidal neovascularization; DME, diabetic macular edema; DR, diabetic retinopathy; ETDRS,
Early Treatment Diabetic Retinopathy Study; mtmDR, more-than-mild diabetic retinopathy; OCT, optical coherence tomography; VGG, Visual Geometry Group; VTDR, vision-threatening diabetic retinopathy.

© 2019 Asia-Pacific Academy of Ophthalmology

Asia-Pacific Journal of Ophthalmology • Volume 8, Number 2, March/April 2019
Asia-Pacific Journal of Ophthalmology • Volume 8, Number 2, March/April 2019
2. A major development in DL for DR detection was the study
by Gulshan et al3 from Google Healthcare which developed
a DL system for detecting referable DR using 128,175
retinal photographs which were graded 3 to 7 times for DR,
DME, and image gradability by a panel of 54 US-licensed
ophthalmologists and ophthalmology senior residents. The
DL algorithm achieved a high sensitivity (≥87%), specificity
(≥90%) and area under the receiver operating characteristic
curve (AUC) (≥0.99) in the external validation using 2
public databases (EyePACS-1: n = 9963 and Messidor-2:
n = 1748); both graded by at least 7 US board-certified
ophthalmologists.3 Other groups have reported similar
results. Gargeya and Leng4 developed a DL algorithm for
detecting DR (any DR and mild DR) using 75,137 retinal
photographs obtained from the EyePACS public dataset.
The DL algorithm has further been evaluated using 2 other
public databases (Messidor-2: n = 1748 and E-Ophtha: n =
405) with a sensitivity of ≥74%, specificity of ≥80%, and
AUC of ≥0.83.4 Li et al5 developed another DL algorithm
and internally validated it using 71,043 retinal photographs
acquired from a total of 36 hospital ophthalmology
departments, optometry clinics, and screening settings
in China. In the external validation, the DL algorithm
was evaluated using 35,201 retinal photographs from
population-based cohorts of Malay, Caucasian Australians,
and Indigenous Australians with a sensitivity of 92.5%, a
specificity of 98.5% and an AUC of 0.955.5 Kanagasingam
et al6 developed a DL algorithm based on several training
dataset including DiaRetDB1, EyePACS, and the Australian
Tele-eye care DR database. They deployed the DL algorithm
prospectively and evaluated the performance in 193 patients
at a primary care clinic in Australia with a specificity of 92%
and a positive predictive value of just 12% driven by the low
incidence of DR in their cohort (2 of 193).6
3. A third major development addresses a major gap in
previous studies in which the DL algorithms were not trained
to detect other common sight-threatening eye conditions,
such as glaucoma and AMD. To address this gap, Ting et al1
developed a DL system to screen for possible glaucoma and
AMD, in addition to referable DR and VTDR. The DL system
was composed of 8 CNNs, all using an adaptation of the
VGGNet architecture: (i) an ensemble of 2 networks for the
classification of DR severity; (ii) an ensemble of 2 networks
for the identification of referable possible glaucoma; (iii) an
ensemble of 2 networks for the identification of referable
AMD; (iv) 1 network to assess image quality; and (v) 1
network to reject invalid non-retinal images. The DL system
was validated using retinal photographs collected from
the Singapore Integrated Diabetic Retinopathy Program
(SIDRP) and from 10 additional multiethnic datasets from
different countries with diverse community- and clinic-
based populations with DM.1 In the primary validation
dataset of 71,896 images from 17,974 patients, the AUC
of the DL system was 0.936 for referable DR, 0.958 for
VTDR, 0.941 for glaucoma suspect, and 0.931 for referable
AMD. The DL system had AUCs between 0.889 and 0.983
for referable DR on 10 additional datasets (n = 40,752
images). In the secondary validation datasets, the DL system
had AUCs between 0.889 and 0.983 for referable DR (n =
40,752 images). The DL system could also achieve high
© 2019 Asia-Pacific Academy of Ophthalmology
Copyright © 2019 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
AI in Diabetic Eye Disease Screening
sensitivity (>90%), specificity (>73.3%) and AUC (>0.89)
for identifying other referable eye conditions.
DL IN OCT FOR DETECTING DME
A major issue in DR screening is the detection of
DME, which is not easily captured from 2-dimensional (2D)
fundus photographs.35,38 Thus, recent studies have focused on
demonstrating that DL algorithms can be trained using OCT
images to detect DME and other retinal diseases. Kermany et al14
firstly applied DL and transfer learning techniques in the detection
of DME as well as choroidal neovascularization, drusen, and
normal from 2D OCT images. Two models (multiclass model
and binary model) were firstly developed using a training dataset
of 108,312 2D OCT images and a “limited model” was further
trained using 1000 2D OCT images randomly selected from each
class during training to compare transfer learning performance
using limited data compared with results using a large dataset.14
In the validation, they evaluated the performance of the models
of a dataset of 1000 2D OCT images and found that both models
achieved high performance even in the limited model (sensitivity
≥96%, specificity ≥94%, and AUC ≥0.99).14 This study
highlighted the application of transfer learning in conditions with
small datasets.
Another major study was performed by Google’s Deepmind
in collaboration with Moorfields Eye Hospital, where the group
applied a combined 3D segmentation and classification networks
for interpreting 3D OCT images in predicting tissue volumes and
identifying and referring different retinal abnormalities.15 They
developed the DL algorithm using 877 segmented scans for
the segmentation network and 14,884 scans from 7621 patients
with multiple clinical diagnoses and referral decisions for
classification network. The classification network learned to map
a segmentation map to 4 referral decisions (urgent, semi-urgent,
routine, and observation only) and 10 different retinal pathologies
(macular retinal edema, choroidal neovascularization, full-
thickness macular hole, partial-thickness macular hole, epiretinal
membrane, geographic atrophy, drusen, vitreomacular traction,
central serous retinopathy, and normal). Their framework
(predicting tissue volumes, identifying retinal abnormalities,
and providing referral suggestions) closely matched the clinical
decision-making process, separating judgments about the scan
itself from the subsequent referral decision, allowing a clinician
to inspect and visualize an interpretable segmentation, rather than
simply being presented with a diagnosis and referral suggestion.
VISUALIZING DL AND EXPLAINABILITY
A key challenge for clinical adoption of DL algorithms is
a major mindset shift in how clinicians entrust clinical care to
machines. The issue of ‘black box’ problem has been identified as
an impediment to the application of DL in healthcare.53 Previous
reports have already performed visualization heat map analysis to
represent intuitively the learning procedure of the CNNs for DR
and DME.4,14 Recently, Keel et al54 conducted a study to analyze
the CNN learning procedure for 2 validated DL systems including
one for the detection of referable DR. They developed and applied
a CNN-independent adaptive kernel visualization technique for
visualizing the learning procedure of the networks. Using this
method, discriminative image regions were highlighted when the
www.apjo.org | 161
Cheung et al
classification possibility output of being diagnosed was greater
than 70%, and a heat map was then generated highlighting highly
prognostic regions in the input image. They found that typical
referable DR lesions (retinal hemorrhage, exudate, intraretinal
microvascular abnormality, venous beading) could be identified
as the most important prognostic regions in 96% of true-positive
referable DR cases whereas nontraditional fundus regions (eg,
optic disc and fundus areas adjacent to vessels) were identified in
85% of false-positive referable DR cases. This study may further
promote the clinical adoption of using DL algorithm and enable
clinicians to understand important exposure variables in real time.
HOW DOES DL FIT IN CURRENT DR SCREENING
STRATEGY?
A critical question in the conceptualization of using DL
technology for DR screening is “where does the DL system
fit?”. Deep learning systems could potentially be deployed in
2 different settings.1,18 Figure 1 illustrates the 2 proposed DL-
based screening models for DR, compared with an existing
model. First, the DL system could be incorporated in existing DR
screening programs such as in the UK and Singapore to assist
human assessors in centralized reading centers (a semi-automated
model).1,55,56 The retinal images can be firstly analyzed by the DL
system and the human assessors only review images flagged as
“referable” or “ungradable” by the DL system (2nd screening) for
further confirmation. This model not only decreases the massive
workload to read those non-referable retinal images but also
avoids those false-positive cases referring to ophthalmologists
(Fig. 1A). Second, the DL system could be a fully automated
model in that all retinal images can be analyzed by the DL system
which will be useful in communities without any existing DR
A B
FIGURE 1. Two artificial intelligence–based screening models for diabetic eye diseases have been proposed. A, A semi-automated model that retinal
images will be firstly analyzed by the deep learning systems. The images will be read by doctors or trained graders (2nd screening) if it is flagged by
the deep learning systems. B, A fully automated model that retinal images will be analyzed by the deep learning systems. C, Existing model by human
assessors.
162 | www.apjo.org
Copyright © 2019 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Asia-Pacific Journal of Ophthalmology • Volume 8, Number 2, March/April 2019
screening programs (Fig. 1B). By using this screening model, the
sensitivity of the DL system may need to be set higher in order to
minimalize false-negative cases.
CURRENT CHALLENGES
The performance of DL algorithms is extremely promising
as seen from current literature. However, there are still several
challenges and complexities that limit the ability to move forward
quickly.
First, as mentioned above, the “black box” approach is still
unacceptable. Deep learning uses millions of image features most
predictive for classification rather than explicitly detecting clinical
features that physicians are familiar with (eg, microaneurysms,
hard exudates). It is unclear exactly what the machine “thinks”
and “sees”.18 Transparency of DL algorithm is required in order
to let users understand the basis to justify a particular diagnosis,
treatment recommendation, or outcome prediction that the DL
algorithm offered, and also allow examination for any potential
bias.57
Second, AI most likely succeeds when it is used with
high-quality “labeled” input data validated by multiple medical
specialists for learning and classifying images in relation to
outcomes. Also, DL algorithms are highly data hungry, often
requiring millions of observations to reach acceptable performance
levels.58 Moreover, training using single clinical dataset is always
limited by potential biases (eg, same ethnicity, same device)
which may affect both performance and generalizability.59,60
Using dataset from diverse settings and populations for training
DL algorithm is ideal. Nevertheless, the availability of such
dataset is very limited and it is very costly.
Third, “real-world” experiments are essential in the
C
© 2019 Asia-Pacific Academy of Ophthalmology
Asia-Pacific Journal of Ophthalmology • Volume 8, Number 2, March/April 2019
validation of DL algorithm. For example, prospective study
design in appropriate clinical settings and testing DL algorithm
using independent validation datasets under different settings and
conditions that played no role in model development are critical
to evaluate the performance of DL algorithms. Several recent
studies have already reported the performance of DL algorithm
using a prospective study design.6,48,61
Fourth, a continuous data supply is necessary for ongoing
improvement and refinement of the DL algorithms and data
may need to be shared across multiple centers for widespread
implementation. However, the current healthcare environment
holds little incentive for data sharing.57
Lastly, before DL algorithms or systems can be deployed
in the clinical workflow of diabetic eye disease screening
programs, there are still more questions need to be addressed. For
example, “If a patient suffers an adverse event due to an AI-based
technology, who is responsible?”.57 In addition, more rigorous
scientific evidence on safety, validity, reproducibility, reliability,
usability, and patient and clinician acceptability is also critical,
before the clinical deployment.
CONCLUSIONS
In summary, AI and DL are entering the mainstream of clinical
medicine. This technology can augment human intelligence to
improve decision making and operational processes. Screening of
DR is almost an ideal task for AI in health care. Looking forward,
AI will become ubiquitous and indispensable for the screening,
with expectation to improve the efficiency and accessibility of
screening programs, and therefore will be able to prevent visual
loss and blindness from this devastating disease.
REFERENCES
1. Ting DSW, Cheung CY, Lim G, et al. Development and validation of a
deep learning system for diabetic retinopathy and related eye diseases
using retinal images from multiethnic populations with diabetes. JAMA.
2017;318:2211–2223.
2. Abràmoff MD, Lou Y, Erginay A, et al. Improved automated detection of
diabetic retinopathy on a publicly available dataset through integration of
deep learning. Invest Ophthalmol Vis Sci. 2016;57:5200–5206.
3. Gulshan V, Peng L, Coram M, et al. Development and validation of a deep
learning algorithm for detection of diabetic retinopathy in retinal fundus
photographs. JAMA. 2016;316:2402–2410.
4. Gargeya R, Leng T. Automated identification of diabetic retinopathy using
deep learning. Ophthalmology. 2017;124:962–969.
5. Li Z, Keel S, Liu C, et al. An automated grading system for detection of
vision-threatening referable diabetic retinopathy on the basis of color fundus
photographs. Diabetes Care. 2018;41:2509–2516.
6. Kanagasingam Y, Xiao D, Vignarajan J, et al. Evaluation of artificial
intelligence-based grading of diabetic retinopathy in primary care. JAMA
Netw Open. 2018;1:e182665.
7. Burlina PM, Joshi N, Pacheco KD, et al. Assessment of deep generative
models for high-resolution synthetic retinal image generation of age-related
macular degeneration. JAMA Ophthalmol. 2019 Jan 10. Epub ahead of print.
8. Peng Y, Dharssi S, Chen Q, et al. DeepSeeNet: A deep learning model for
automated classification of patient-based age-related macular degeneration
severity from color fundus photographs. Ophthalmology. 2019;126:565–575.
9. Burlina PM, Joshi N, Pacheco KD, et al. Use of deep learning for detailed
severity characterization and estimation of 5-year risk among patients with
© 2019 Asia-Pacific Academy of Ophthalmology
Copyright © 2019 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
AI in Diabetic Eye Disease Screening
age-related macular degeneration. JAMA Ophthalmol. 2018;136:1359–1366.
10. Li Z, He Y, Keel S, et al. Efficacy of a deep learning system for detecting
glaucomatous optic neuropathy based on color fundus photographs.
Ophthalmology. 2018;125:1199–1206.
11. Medeiros FA, Jammal AA, Thompson AC. From machine to machine:
An OCT-trained deep learning algorithm for objective quantification of
glaucomatous damage in fundus photographs. Ophthalmology. 2019;126:
513–521.
12. Redd TK, Campbell JP, Brown JM, et al. Evaluation of a deep learning
image assessment system for detecting severe retinopathy of prematurity. Br
J Ophthalmol. 2018 Nov 23. Epub ahead of print.
13. Brown JM, Campbell JP, Beers A, et al. Automated diagnosis of plus
disease in retinopathy of prematurity using deep convolutional neural
networks. JAMA Ophthalmol. 2018;136:803–810.
14. Kermany DS, Goldbaum M, Cai W, et al. Identifying medical diagnoses
and treatable diseases by image-based deep learning. Cell. 2018;172:
1122–1131.e9.
15. De Fauw J, Ledsam JR, Romera-Paredes B, et al. Clinically applicable deep
learning for diagnosis and referral in retinal disease. Nat Med. 2018;24:
1342–1350.
16. Schlegl T, Waldstein SM, Bogunovic H, et al. Fully automated detection and
quantification of macular fluid in OCT using deep learning. Ophthalmology.
2018;125:549–558.
17. FDA permits marketing of artificial intelligence-based device to detect
certain diabetes-related eye problems [news release]. US Food & Drug
Administration; April 11, 2018. https://www.fda.gov/NewsEvents/
Newsroom/PressAnnouncements/ucm604357.htm?fbclid=IwAR2h4qBp
SAD6vx8EErts2nhhundX8654ZUL3xwvVahXyLxnSYSxCAOMEias.
Accessed February 24, 2019.
18. Wong TY, Bressler NM. Artificial intelligence with deep learning
technology looks into diabetic retinopathy screening. JAMA. 2016;316:
2366–2367.
19. Beam AL, Kohane IS. Translating artificial intelligence into clinical care.
JAMA. 2016;316:2368–2369.
20. Google AI matches diabetic retinopathy screens [medical news]. Medscap;
November 30, 2016. https://www.medscape.com/viewarticle/872555.
Accessed February 24, 2019.
21. Metz C. India fights diabetic blindness with help from A.I. New York
Times. March 10, 2019: https://www.nytimes.com/2019/03/10/technology/
artificial-intelligence-eye-hospital-india.html. Accessed March 12, 2019.
22. Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas:
Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes
Res Clin Pract. 2017;128:40–50.
23. Chan JC, Malik V, Jia W, et al. Diabetes in Asia: epidemiology, risk factors,
and pathophysiology. JAMA. 2009;301:2129–2140.
24. Chan JC, Zhang Y, Ning G. Diabetes in China: a societal solution for a
personal challenge. Lancet Diabetes Endocrinol. 2014;2:969–979.
25. Wong TY, Cheung CM, Larsen M, et al. Diabetic retinopathy. Nat Rev Dis
Primers. 2016;2:16012.
26. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376:
124–136.
27. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk
factors of diabetic retinopathy. Diabetes Care. 2012;35:556–564.
28. Cheung CY, Ikram MK, Klein R, et al. The clinical implications of recent
studies on the structure and function of the retinal microvasculature in
diabetes. Diabetologia. 2015;58:871–885.
29. Zhang P, Zhang X, Brown JB, et al. In: Economic Impact of Diabetes. IDF
Diabetes Atlas. 4th ed. International Diabetes Federation; 2010.
30. Zhang X, Low S, Kumari N, et al. Direct medical cost associated with
diabetic retinopathy severity in type 2 diabetes in Singapore. PLoS One.
www.apjo.org | 163
Cheung et al
2017;12:e0180949.
31. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR,
et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.
N Engl J Med. 2015;372:1193–1203.
32. Wang LZ, Cheung CY, Tapp RJ, et al. Availability and variability in
guidelines on diabetic retinopathy screening in Asian countries. Br J
Ophthalmol. 2017;101:1352–1360.
33. Bhargava M, Cheung CY, Sabanayagam C, et al. Accuracy of diabetic
retinopathy screening by trained non-physician graders using non-mydriatic
fundus camera. Singapore Med J. 2012;53:715–719.
34. Wong TY, Sun J, Kawasaki R, et al. Guidelines on Diabetic Eye Care:
The International Council of Ophthalmology Recommendations for
Screening, Follow-up, Referral, and Treatment Based on Resource Settings.
Ophthalmology. 2018;125:1608–1622.
35. Wong RL, Tsang CW, Wong DS, et al. Are we making good use of
our public resources? The false-positive rate of screening by fundus
photography for diabetic macular oedema. Hong Kong Med J. 2017;23:
356–364.
36. Jyothi S, Elahi B, Srivastava A, et al. Compliance with the quality standards
of National Diabetic Retinopathy Screening Committee. Prim Care
Diabetes. 2009;3:67–72.
37. Olson J, Sharp P, Goatman K, et al. Improving the economic value of
photographic screening for optical coherence tomography-detectable
macular oedema: a prospective, multicentre, UK study. Health Technol
Assess. 2013;17:1–142.
38. Goh JK, Cheung CY, Sim SS, et al. Retinal imaging techniques for diabetic
retinopathy screening. J Diabetes Sci Technol. 2016;10:282–294.
39. Leal J, Luengo-Fernandez R, Stratton IM, et al. Cost-effectiveness of digital
surveillance clinics with optical coherence tomography versus hospital eye
service follow-up for patients with screen-positive maculopathy. Eye (Lond).
2018 Nov 30. Epub ahead of print.
40. Scanlon PH, Aldington SJ, Leal J, et al. Development of a cost-effectiveness
model for optimisation of the screening interval in diabetic retinopathy
screening. Health Technol Assess. 2015;19:1–116.
41. Abràmoff MD, Reinhardt JM, Russell SR, et al. Automated early detection
of diabetic retinopathy. Ophthalmology. 2010;117:1147–1154.
42. Tufail A, Rudisill C, Egan C, et al. Automated diabetic retinopathy image
assessment software: diagnostic accuracy and cost-effectiveness compared
with human graders. Ophthalmology. 2017;124:343–351.
43. Fleming AD, Goatman KA, Philip S, et al. Automated grading for diabetic
retinopathy: a large-scale audit using arbitration by clinical experts. Br J
Ophthalmol. 2010;94:1606–1610.
44. LeCun Y, Bengio Y, Hinton G. Deep learning. Nature. 2015;521:436–444.
45. Esteva A, Kuprel B, Novoa RA, et al. Dermatologist-level classification of
164 | www.apjo.org
Copyright © 2019 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Asia-Pacific Journal of Ophthalmology • Volume 8, Number 2, March/April 2019
skin cancer with deep neural networks. Nature. 2017;542:115–118.
46. Lakhani P, Sundaram B. Deep learning at chest radiography: automated
classification of pulmonary tuberculosis by using convolutional neural
networks. Radiology. 2017;284:574–582.
47. Yu KH, Zhang C, Berry GJ, et al. Predicting non-small cell lung cancer
prognosis by fully automated microscopic pathology image features. Nat
Commun. 2016;7:12474.
48. Abràmoff MD, Lavin PT, Birch M, et al. Pivotal trial of an autonomous AI-
based diagnostic system for detection of diabetic retinopathy in primary
care offices. NPJ Digit Med. 2018;1:39.
49. Li F, Chen H, Liu Z, et al. Fully automated detection of retinal disorders by
image-based deep learning. Graefes Arch Clin Exp Ophthalmol. 2019;257:
495–505.
50. Abràmoff MD, Folk JC, Han DP, et al. Automated analysis of retinal
images for detection of referable diabetic retinopathy. JAMA Ophthalmol.
2013;131:351–357.
51. Verbraak FD, Abramoff MD, Bausch GCF, et al. Diagnostic accuracy of a
device for the automated detection of diabetic retinopathy in a primary care
setting. Diabetes Care. 2019;42:651–656.
52. van der Heijden AA, Abramoff MD, Verbraak F, et al. Validation of
automated screening for referable diabetic retinopathy with the IDx-DR
device in the Hoorn Diabetes Care System. Acta Ophthalmol. 2018;96:
63–68.
53. Castelvecchi D. Can we open the black box of AI? Nature. 2016;538:20–23.
54. Keel S, Wu J, Lee PY, et al. Visualizing deep learning models for
the detection of referable diabetic retinopathy and glaucoma. JAMA
Ophthalmol. 2018 Dec 20. Epub ahead of print.
55. Nguyen HV, Tan GS, Tapp RJ, et al. Cost-effectiveness of a National
Telemedicine Diabetic Retinopathy Screening Program in Singapore.
Ophthalmology. 2016;123:2571–2580.
56. Scanlon PH. The English National Screening Programme for diabetic
retinopathy 2003-2016. Acta Diabetol. 2017;54:515–525.
57. He J, Baxter SL, Xu J, et al. The practical implementation of artificial
intelligence technologies in medicine. Nat Med. 2019;25:30–36.
58. Obermeyer Z, Emanuel EJ. Predicting the future – big data, machine
learning, and clinical medicine. N Engl J Med. 2016;375:1216–1219.
59. Gianfrancesco MA, Tamang S, Yazdany J, et al. Potential biases in machine
learning algorithms using electronic health record data. JAMA Intern Med.
2018;178:1544–1547.
60. Zou J, Schiebinger L. AI can be sexist and racist – it’s time to make it fair.
Nature. 2018;559:324–326.
61. Keel S, Lee PY, Scheetz J, et al. Feasibility and patient acceptability of a
novel artificial intelligence-based screening model for diabetic retinopathy
at endocrinology outpatient services: a pilot study. Sci Rep. 2018;8:4330.
© 2019 Asia-Pacific Academy of Ophthalmology