Feasibility of telemedicine in detecting diabetic retinopathy and age-related macular degeneration.

Seminars in Ophthalmology, Early Online, 1–15, 2013 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2013.825727

Feasibility of Telemedicine in Detecting Diabetic Retinopathy and Age-Related Macular Degeneration Kamyar Vaziri1, Darius M. Moshfeghi2, and Andrew A. Moshfeghi1

Semin Ophthalmol Downloaded from informahealthcare.com by Nyu Medical Center on 10/17/14. For personal use only.

1

Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Palm Beach Gardens, Florida, USA and 2Horngren Vitreoretinal Center, Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, California, USA

ABSTRACT Age-related macular degeneration and diabetic retinopathy are important causes of visual impairment and blindness in the world. Because of recent advances and newly available treatment modalities along with the devastating consequences associated with late stages of these diseases, much attention has been paid to the importance of early detection and improving patient access to specialist care. Telemedicine or, more specifically, digital retinal imaging utilizing telemedical technology has been proposed as an important alternative screening and management strategy to help meet this demand. In this paper, we perform a literature review and analysis that evaluates the validity and feasibility of telemedicine in detecting diabetic retinopathy and agerelated macular degeneration. Understanding both the progress and barriers to progress that have been demonstrated in these two areas is important for future telemedicine research projects and innovations in telemedicine technology. Keywords: Diabetic retinopathy, macular degeneration, telemedicine, teleretina, teleophthalmology

INTRODUCTION

compression technologies have made transferring text, voice, and images feasible via electronic links connecting one computer in one room to one in the room next door, to one in the next building, or even to one in a different country. A telemedical system can be a very simple strategy. For example, performing something as simple as consulting with a patient over the telephone is a telemedical approach, as is saving digital images and reviewing them on a computer nearby. Although we do not tend to think of these mundane, everyday clinical activities as telemedicine, they do represent a subtle form of telemedicine that can be extrapolated into a more generalizable approach to remote health care delivery and disease screening. The role of telemedicine in the field of ophthalmology — commonly referred to as teleophthalmology — has been growing. Because imaging devices and image-based information are the basis of many diagnoses in ophthalmology, the growing impact of telemedicine on this field is not surprising.

Telemedicine can be generally defined as the use of information technology (such as sending information over the Internet) and telecommunication (such as communicating over the telephone or via simultaneous dual-band audio-video communications system) to provide medical care. The potential benefits of telemedicine include providing specialist care in remote areas, creating opportunities for mass disease screening, diagnosing potentially devastating diseases at their early stages, providing expanded international clinical and research collaborations, and improving distance-learning strategies. Improvements in information technologies and improved affordability of transmitting data electronically have resulted in telemedicine being able to expand rapidly in various medical fields, including pathology, radiology, dermatology, cardiology, and ophthalmology. Readily available high-bandwidth Internet connections and advancements in digital data, audio, and video

Received 4 February 2013; accepted 12 July 2013; published online 8 October 2013 Correspondence: Andrew A. Moshfeghi, MD, MBA, Bascom Palmer Eye Institute, 7101 Fairway Drive, Palm Beach Gardens, FL 33418, USA. E-mail: [email protected]

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Teleophthalmology systems have been utilized for screening and diagnosis of many ophthalmic diseases, such as glaucoma, adnexal and orbital diseases, ocular trauma, anterior segment pathologies, retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration (AMD). Technological advances, such as digital retinal photography and the ability of saving those images and transmitting them securely through the Internet for remote evaluation, have made teleretinal techniques a viable and popular approach to increasing access of eye examinations for patients with various ophthalmic diseases (Figure 1). However, for a teleophthalmic system to be successfully implemented, it must first prove to be both a feasible and a pragmatic system. As a result, many components of such a system must be properly evaluated. In other words, teleophthalmology must prove to be accurate, reliable, cost-effective, and have adequate patient satisfaction. While telemedical technology has been studied and reviewed in other ophthalmic fields like retinopathy of prematurity,1 the focus of the present review will be on more-common retinal diseases that also have opportunities for future application in telemedicine. Despite a number of guidelines and screening recommendations, diabetic retinopathy and AMD are two of the most prevalent eye diseases and also two of the major leading causes of blindness in the United States and the world.2,3 Unfortunately, their prevalence will only increase with the rising elderly population. It is estimated that, by 2020, approximately nine million people in the United States will have age-related macular degeneration-related vision loss4 and it is

also estimated that, by the year 2020, 6.1 million people will suffer from diabetic retinopathy in the United States.5 The projected increased prevalence in these two diseases, along with the vision loss associated with these diseases if left untreated, has focused public health attention on finding alternative methods of mass screening and early detection, such as telemedicine. The purpose of paper is to summarize and review the current evaluation data on the feasibility of telemedicine in screening for and diagnosis of two very common retinal diseases: diabetic retinopathy and AMD.

MATERIALS AND LITERATURE SEARCH METHODS A literature review of peer-reviewed articles published in the years 2000 through October of 2012 was performed on the Pubmed Internet website available from the National Library of Medicine. The resulting articles were initially screened based on the content of their abstracts. The full texts of articles with abstracts that gave indications that the paper would have the desired relevance and level of scientific evidence were then obtained and reviewed as part of a secondary screening for the final article selection. Articles mentioned in the references section of other articles were also reviewed and were included if considered relevant. Only articles in the English language were included in this paper. All the papers analyzed in this review needed to demonstrate that they utilized a type of telemedical technology that is ‘‘storeand-forward,’’ ‘‘real-time,’’ or a mixture of the two

FIGURE 1. Process of teleretinal digital imaging: After patients to be screened are selected based on risk factors and review of medical and ophthalmic history, digital retinal images of these patients are acquired. Afterwards, digital images will be saved on a hard drive or on a server, depending on the facility’s telemedical system. These images will then be electronically sent to a reading center or review station that will have computers and monitors suitable for viewing the digital images. The reading center can be within the same facility or at a different facility. At the reading center or review station, these images will be loaded and reviewed by retina specialists or trained graders. Based on findings on these images, management decisions will be made as to which referrals or future follow-ups are warranted. Seminars in Ophthalmology


Telemedicine for Macular Degeneration and Diabetic Retinopathy telemedicine approaches. ‘‘Store-and-forward’’ telemedicine is defined as the capturing of diagnostic information at an examination site, then electronically stored, and then sent via the Internet or other method to a different center or station within the same facility or another facility for the purposes of later evaluation, grading, and to come to a decision as to whether further management is warranted. ‘‘Real-time’’ telemedicine is defined as the provision of a medical evaluation and care with a patient via a real-time and simultaneous telecommunication (i.e., telephone, e-mail, webcam, or similar device.) so that those same goals can be achieved in real time, not at a later time from the patient’s encounter. The search terms used included ‘‘diabetic retinopathy’’ or ‘‘age-related macular degeneration,’’ used with the following search terms compiled in various combinations: ‘‘telemedicine,’’ ‘‘teleretinal,’’ ‘‘telecommunication,’’ ‘‘web based,’’ ‘‘Internet,’’ ‘‘remote,’’ ‘‘digital imaging,’’ ‘‘retinal imaging,’’ ‘‘teleophthalmology,’’ ‘‘tele,’’ ‘‘patient satisfaction,’’ ‘‘consumer satisfaction,’’ ‘‘cost analysis,’’ ‘‘cost effectiveness’’ and ‘‘cost benefit.’’ For reliability calculations, if the reviewed articles did not provide the statistical agreement value (kappa statistics) but did provide the raw data for such a calculation, we calculated the agreement kappa value by utilizing SPSS version 21 statistical analysis software (SPSS Inc., Armonk, NY, USA).

DIABETIC RETINOPATHY AND TELEMEDICINE Background Diabetic retinopathy is the leading cause of adult blindness and most common microvascular manifestation of diabetes mellitus.2,6 It is estimated that there are 4.1 million U.S adults over the age of 40 and 91 million people worldwide with diabetic retinopathy.2,3 Current diabetic eye-care guidelines and treatment modalities supported by a growing number of clinical studies have been very effective in preventing the vision loss secondary to diabetic retinopathy. Decades of clinical studies have shown evidence for the role of focal laser photocoagulation, scatter laser photocoagulation, intensive glycemic control, blood pressure control,7 vitrectomy,8,9 and intravitreal anti-VEGF injections10,11 in slowing or stopping the progression of diabetic retinopathy and associated macular edema. Based on this evidence and the fact that diabetic retinopathy is often asymptomatic until its late stages, the American Association of Ophthalmology recommends annual retinal screening for diabetic patients.12 However, despite these screening and evidence-based practice guidelines, less than 50% of patients with diabetes mellitus have an !

2013 Informa Healthcare USA, Inc.

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annual eye exam and only about 60% of diabetic patients receive vision-saving treatments which would benefit them.13,14 There are a number of factors that contribute to these non-adherence rates. Limited access to eye care and ophthalmologists seems to be one of the most important of these factors which stems from geographic, economic, educational, and other reasons.15–17 One of the growing solutions to address limited access to eye care and patient non-compliance to screening guidelines has been the utilization of telemedicine in screening and diagnosis of diabetic retinopathy. With the development of digital ophthalmic imaging and the opportunity of saving and sending these images electronically to different centers or different buildings within the same center, telemedicine can be a potentially valuable tool in diagnosing diabetic retinopathy. However, for a telemedical technology to be successful in screening for and diagnosis of diabetic retinopathy, it must prove to be accurate, reliable, cost-effective, and must have high satisfaction rates among patients and staff. In this next section, we review the relevant articles on the topic of telemedicine and diabetic retinopathy that have assessed the aforementioned components of this technology.

Accuracy and Reliability of Telemedical Technology in Detection of Diabetic Retinopathy Telemedical approaches in ophthalmology often use digital imaging photography, as this method provides the ability to save the images on computer systems and to send them through the Internet to a remote grader (e.g., ‘‘store and forward’’ telemedical approach). Both the American Academy of Ophthalmology and the American Telemedicine Association have indicated the importance of validating any programs, including telemedical strategies, that are designed to assess and screen for diabetic retinopathy.18,19 For a telemedical approach to be considered successful and feasible in screening for and in the detection of diabetic retinopathy, it must be compared against the gold standard procedure for detecting this disease. Currently, the gold standard for detection and classification of diabetic retinopathy is considered to be the Early Treatment Diabetic Retinopathy Study (ETDRS) mydriatic fundus photographs utilizing 30-degree field of view, seven standard-fields acquired, and with the developing of stereoscopic 35-mm-color film slides.20 To assess the validity of telemedical digital imaging in detecting and screening for diabetic retinopathy, a number of studies have compared the accuracy and reliability of digital imaging to that of gold standard

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TABLE 1. Characteristics of validity studies comparing telemedical digital retinal imaging with ETDRS-style film-based fundus photography for diabetic retinopathy. # of Eyes/ Patients

Study Bursell et al. (2001)24

108/54

Fransen et al. (2001)22 Lin et al. (2002)23

Digital Imaging Operator

Digital Image Grader

3-field 45 stereoscopic nonmydriatic

Not Specified

Not Specified

290/549

7-field 30 stereoscopic mydriatic

Ophthalmic photographer

Non-physician expert readers

–a

1-field 45 non-mydriatic

Trained research associate

Trained and certified reader

29

222\111

15-field 55-60 non-mydriatic, monochromatic

Ophthalmic Photographer

Retina Specialist

Rudinsky et al. (2006)25

204/102



Readers trained in ETDRS grading

Vujosevic et al. (2009)30

108/55

1-field 45 non-mydriatic and 3-field 45 non-mydriatic

Trained nurse

Retinal specialists

Li et al. (2010)28

85/152



Not Specified

Schiffman et al. (2005)


Digital Imaging Technique

\197

Hubbard et al. (2011)68

–/319



Certified Grader

Silva et al. (2012)27

206/103

1-field 100 ultra-wide stereoscopic non-mydriatic


Optometrist

Kernt et al. (2012)33

212/144

1-field ultra-wide (180-200 ) non-mydriatic


Unspecified

ETDRS = Early Treatment Diabetic Retinopathy Study Dashed lines indicate unavailable data.

a

mydriatic seven-field 35-mm film fundus photography for the evaluation of diabetic retinopathy. It is important to note that these studies may differ from each other with regard to the used number of digital image fields, field angles, evaluated outcome measures and diagnostic levels, varying use of mydriatic and non-mydriatic cameras, and skill level of the digital image photographers and graders (Table 1).

Accuracy of Telemedical Digital Imaging in Detecting Diabetic Retinopathy The accuracy of a diagnostic test describes how well the test measures or detects what it was intended to measure or detect and this result is achieved by comparing its diagnostic results against a gold standard. Accuracy is often measured by sensitivity and specificity of the diagnostic test being evaluated. The sensitivity of a diagnostic test is the proportion of patients already known to have the disease who also have a positive diagnostic test result. A diagnostic test with perfect sensitivity would have a score of 100%. The specificity of a diagnostic test refers to the proportion of patients already known to be free of the disease who also have a negative diagnostic test result. A diagnostic test with perfect specificity would have a score of 100%. Several studies have evaluated the accuracy of digital imaging in detecting diabetic retinopathy compared with the gold standard ETDRS seven-field 35-mm fundus photography. Most studies

focused on the accuracy of digital imaging in detecting diabetic retinopathy based on the diagnostic levels defined by ETDRS21 (Table 2), but, in addition, a number studies also evaluated how well digital imaging detected specific lesions associated with diabetic retinopathy (Table 3). Fransen and colleagues22 and Lin and co-workers23 performed telemedical validation studies which evaluated the accuracy of digital fundus imaging in detecting patients who require a referral to a retina specialist. Fransen and colleagues compared the Inoveon’s DR-3DT digital imaging system with the film fundus photography as the gold standard using a referral threshold of ETDRS level 53 (severe nonproliferative diabetic retinopathy or worse) and found a sensitivity of 92% and specificity of 90%. Lin et al. compared a non-mydriatic, monochromatic widefield digital retina image against the gold standard for detection of diabetic retinopathy using a referral threshold of ETDRS level 35 (mild non-proliferative diabetic retinopathy or worse) as the primary outcome and calculated a sensitivity and specificity of 78% and 86%, respectively. Bursell et al.24 and Rudinskey and colleagues25 evaluated the accuracy of digital images for detecting different levels of diabetic retinopathy as defined by ETDRS extension of the modified Airlie House grading protocols.20,26 Bersell et al. compared threefield, 45-degree stereoscopic non-mydriatic telemedical retinal imaging technique developed at Beetham Eye Institute of the Joslin Diabetes Center against the Seminars in Ophthalmology

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TABLE 2. Diabetic retinopathy severity level grading accuracy: Telemedical digital retinal imaging compared with ETDRS-style film-based fundus photographs. ETDRS DR Severity Level Outcome Measures

Study

Sensitivity (%)

Specificity (%)

No DR Mild NPDR Moderate NDPR Severe NPDR Very Severe NPDR PDR

76 59 59 46 40 89

94 80 89 97 99 97

Fransen et al.22

ETDRS level 53

92

90

Lin et al.23

ETDRS level 35

78

86

Schiffman et al.

No DR vs. Any DR (values averaged between left and right eyes)

99.3

96

Rudinsky et al.25

No DR Mild NPDR Moderate NPDR Severe NDPR PDR 5HRC PDR with HRC

93 79 80 25 94 80

93 92 93 100 98 99

Vujosevic et al.30

1-Field: No DR Mild NDPR Moderate NDPR Severe NDPR PDR 3-Field: No DR Mild NPDR Moderate NPDR Severe NPDR PDR

100 67 87 52 54

99 96 75 86 99

100 78 87 66 73

99 99 84 89 98

Bursell et al.

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29

Li et al.28

Mild NPDR Moderate NPDR Moderately Severe NPDR Severe NPDR Mild PDR Moderate PDR High-risk PDR

98 96 88 91 97 100 100

94 91 58 92 98 99 99

Hubbard et al.68

Any retinopathy Mild NPDR or worse Moderate NDPR or worse Severe NPDR or worse PDR or worse

97 88 75 96 98

72 84 92 99 99

Silva et al.27

No DR vs. DR present Absent or mild DR vs. moderate or worse NDPR Severe NDPR or better vs PDR

99 95 73

100 94 99

ETDRS = Early Treatment Diabetic Retinopathy Study; DR = Diabetic Retinopathy NPDR = Non-proliferative diabetic retinopathy; PDR = Proliferative diabetic retinopathy.

gold standard. The sensitivity for detecting mild or moderate non-proliferative diabetic retinopathy (NPDR) was 86%, while it was just 57% for detecting severe or very severe NPDR. The specificity of digital retinal imaging, however, was close to 100% for detecting severe NPDR, very severe NDPR, and was 100% for proliferative diabetic retinopathy (PDR) with high-risk characteristics. Rudinskey and colleagues used the ETDRS diabetic retinopathy grading levels to evaluate the accuracy of seven-field 30 stereoscopic mydriatic digital fundus imaging. Except for severe !


NPDR, which had a sensitivity of 25%, the sensitivities for the remainder of the metrics were high, ranging from 79% for mild NDPR to 94% for PDR without high-risk characteristics. Silva and co-workers27 examined the accuracy of one-field ultra-wide non-mydriatic digital retina imaging (Optos, Dunfermline, Scottland, UK), which was found to have an overall sensitivity of 99% and specificity of 100% for detecting diabetic retinopathy. In another study, Li and colleagues28 compared the seven-field 35-mm stereoscopic mydriatic digital

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TABLE 3. Agreement between digital retinal imaging and ETDRS-style film-based fundus photography for detecting diabetic retinopathy severity levels.


Study Bursell et al.24 Fransen et al.22 Lin et al.23 Rudinsky et al.25 Li et al.28 Kernt et al.33 (results based on one grader only) Hubbard et al.68 Vujosevic et al.30 3F-NMb 1F-NMc

Exact Agreement (%)

(un-weighted)

(weighted)

61.9 85.77 59.1 71.7 67.8 84.0

0.53 0.78 0.44 0.65 0.62 0.79

0.694 0.90 0.90 0.87 0.86 0.89

–

0.74

0.69 0.56

– –

63 –a –

ETDRS == Early Treatment Diabetic Retinopathy Study Dashed lines = represent unavailable data b 3F-NM = 3-field non-mydriatic digital imaging c 1F-NM = 1-field non-mydriatic digital imaging. a

fundus imaging gold standard film imaging and found that their digital imaging technique had sensitivities and specificities exceeding 90% for all ETDRS-scale thresholds except for moderately severe NDPR or worse category, which had a sensitivity of 88% and specificity of 58%. Schiffman and colleagues29 demonstrated very high mean sensitivities and specificities for their telemedical digital retina camera (DigiScope, EyeTel Imaging, Inc., Columbia, MD) in both eyes in distinguishing between no diabetic retinopathy and any diabetic retinopathy (99.5% and 96%, respectively). While most of the reviewed articles evaluated the accuracy of a single digital imaging technique of choice, Vujosevic and colleagues30 directly compared the accuracy of both one- and three-field nonmydriatic digital fundus images against the mydriatic gold standard with film-based fundus photography. The results showed that for detection of referralwarranted diabetic retinopathy, the sensitivity was 71% and specificity was 96% for one-field digital imaging and 82% and 92% for three-field digital imaging, respectively. In addition to evaluating the accuracy of digital imaging in telemedicine in determining diabetic retinopathy severity levels, a number of studies have also examined the accuracy of digital imaging in detecting specific lesions associated with diabetic retinopathy. Lesions included were based on the modified Airlie House classification of diabetic retinopathy.31 In general, these studies found lower levels of sensitivity in detecting new vessels elsewhere (NVE), intraretinal microvascular abnormalities (IRMA), and venous beading (VB), and higher levels of sensitivity for detecting retinal hemorrhages,

microaneurysms, or both. Specificities were close to 100% for new vessels on the disc (NVD) and new vessels elsewhere (NVE) in these studies (Table 3).24,27,28

Reliability (Reproducibility) of Telemedical Digital Imaging in Detecting Diabetic Retinopathy Reliability refers to consistency and reproducibility or, in other words, the level of agreement with respect to the results of different diagnostic tests. There are several types of reliabilities (agreements) that are evaluated in assessing experimental diagnostic or interventional strategies including inter-method reliability, inter-grader reliability, and intra-grader reliability. Often the level of reliability or agreement is calculated using kappa statistics. Kappa statistics assess the level of agreement between categorical data that is not attributable to chance. Interpretation of kappa statistic values are defined as follows: 0 to 0.20 indicates slight agreement, 0.21 to 0.40 indicates fair agreement, and 0.41 to 0.60 indicates moderate agreement, and values greater than 0.81 indicate almost perfect agreement.32 Inter-method reliability refers to the degree with which the results are consistent when two different methods are used to analyze the same data. Intermethod reliability is determined by calculating agreement levels between these two methods using kappa statistics. Several studies have assessed the intermethod reliability between digital imaging used in telemedicine and the gold standard fundus photography with mydriatic seven-field ETDRS film imaging (Table 4). Exact agreements between these two methods for detecting various diabetic retinopathy severity levels ranged from 61%-86%, with weighted kappa statistics ranging from 0.70 to 0.90 (moderate to almost excellent reproducibility). One study compared both one-field and three-field digital imaging to the gold standard and determined inter-method reliability kappa values of 0.56 and 0.69 for one-field and three-field digital imaging, respectively.30 Inter-grader reliability or agreement describes the extent to which the diabetic retinopathy severity level or diabetic retinopathy associated lesion detection was consistent when the same images were reviewed by different image graders. In one study, inter-grader agreement for diabetic retinopathy levels was better (k = 0.86) for three-field non-mydriatic digital imaging and equal for one-field non-mydriatic digital imaging ( = 75) when compared to mydriatic ETDRS film ( = 0.76) images of the retina.30 In another study, inter-grader agreements were assessed for detecting diabetic retinopathy-associated ocular lesions using three-field 45 stereoscopic non-mydriatic digital retinal imaging, which was found to have a higher Seminars in Ophthalmology

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TABLE 4. Accuracy of digital retinal imaging for detection of diabetic retinopathy related lesions compared with ETDRS-style film-based fundus photographs.


Li et al.28

Bursell et al.24

Silva et al.27

Lesion

SE

SP

SE

SP

SE

SP

RH MA HMA IRMA HE VB NVE NVD

0.98 0.98 – 0.76 0.98 0.77 0.96 0.67

0.89 0.96 – 0.83 0.97 0.94 0.98 0.99

– – 0.86 0.67 0.78 0.65 0.53 0.56

– – 0.73 0.90 0.91 0.87 0.99 0.99

– – 0.90 0.63 0.79 0.71 0.39 0.80

– – 0.83 0.86 0.89 0.78 0.99 0.99

SE = Sensitivity; SP = Specificity; RH = retinal hemorrhage; MA = microaneurysm; HMA = hemorrhage, microaneurysm or both; IRMA = intraretinal microvascular abnormality; HE = hard exudate; VB = venous bleeding; NVE = neovascularization elsewhere; NVD = neovascularization on the disc.

inter-grader agreement for detecting hard exudates but lower inter-grader agreement for detecting hemorrhages, microaneurysms, or both, and NVD when compared to gold standard 35-mm ETDRS films.24 Kernt and co-workers33 found comparable intergrader agreements for diabetic retinopathy level grading between telemedical digital imaging and seven-field photography. Intra-grader reliability refers to the agreement grading done on the same set of data by the same grader at different times. The Joslin Vision Network (JVN) study24 assessed telemedical intra-grader agreement in detecting diabetic retinopathy by having the two graders re-evaluate the telemedical digital retinal images from 10 patients selected randomly and also re-evaluate gold standard 35-mm film fundus photographs of 10 randomly selected patients. It was found that for grader 1, intra-grader agreement ranged from substantial to almost perfect for telemedical digital imaging (JVN imaging network), while intra-grader agreement ranged between moderate for hemorrhage, microaneurysms, or both, IRMA, VBV, and substantial to almost perfect for rest of the evaluated diabetic retinopathy associated lesions. For grader 2, intragrader agreement was almost perfect for both telemedical digital images and ETDRS 35-mm photographs. Schiffman and colleagues29 reported that intragrader agreement was perfect ( = 1) for both telemedical digital imaging and standard film photographs in distinguishing between no retinopathy and any level of retinopathy.

AGE-RELATED MACULAR DEGENERATION AND TELEMEDICINE Background Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in older population in the industrialized world.2,34 It is estimated !


that more than eight million Americans or 6.5% of Americans aged 40 or older suffer from this condition.2,35,36 A recent epidemiological study showed that the prevalence of late-stage age-related macular degeneration in US population 40 years of age or older is estimated to be 0.8%, and another study estimated a 3.1% 15-year cumulative incidence for the late stage of this disease.37,38 Until only recently, there were no effective vision-preserving treatments available for neovascular AMD. Today, however, several preventative and therapeutic modalities have proven to be efficacious in both disease mitigation and therapeutic management of AMD, which include smoking cessation,39 antioxidants and minerals in dry AMD and thermal laser photocoagulation, photodynamic therapy, and intravitreal anti-VEGF injections in neovascular AMD.40 Availability of these innovative treatments now makes early detection crucial. While there are no accepted screening guidelines specifically for age-related macular degeneration, the American Academy of Ophthalmology recommends individuals 65 years old or older to have comprehensive eye examinations every 1–2 years.41 These general recommendations can be very important for detecting age-related macular degeneration as the prevalence of this disease dramatically increases after the age of 65, reaching 12% and 18.5% for individuals older than the age of 70 and 85, respectively.42,43 Despite these general recommendations, similar to diabetic retinopathy, many elderly individuals and individuals living in remote areas do not have access to specialist care for the purposes of screening and early detection. It is estimated that 6.05 million adults in the United States are unaware of their age-related macular degeneration. A study using data from the 2005–2008 National Health and Nutritional Examination Survey (NHANES) showed that 84% of individuals with age-related macular degeneration did not know about their condition. Of this unaware population, 95% had early or moderate levels of

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disease which would potentially benefit from available preventative and treatment modalities.44 As a result, telemedicine could be a valuable tool in providing better access to specialists and increase awareness of these conditions for the purpose of early treatment and avoiding the irreversible visionloss-associated exudative stages of this disease.


Accuracy and Reliability of Telemedical Technology in Detecting Age-Related Macular Degeneration Utilization of teleretinal technology in detecting agerelated macular degeneration is in its infancy and there is a very small body of literature that has assessed this strategy for grading and detecting agerelated macular degeneration. We found just one study that performed a teleophthalmology quality evaluation study in England for patients with macular disorders. In this study, community optometrists would capture optical coherence tomography digital images and send them via secure e-mail to ophthalmologists for triage and recommendation. Authors concluded that while this teleophthalmology strategy does not replace face-to-face examination, it does assist in prioritizing patient referrals.45 The number of studies evaluating the actual validity of telemedical technologies (saving digital images and sending them via the Internet to a reading center) and comparing their feasibility in detecting agerelated macular degeneration with conventional methods has been limited. There have been a number of studies that have assessed the feasibility of screening and detecting age-related macular degeneration using digital imaging by evaluating the accuracy and reliability of digital images in detecting various stages of age-related macular degeneration as compared with the conventional gold standards, such as a dilated stereoscopic fundus exam and fluorescein angiography.46–50 Similar to telemedical feasibility studies for diabetic retinopathy, digital images acquired for evaluating age-related macular degeneration can be saved, stored, and sent to other locations within the same facility or distant facilities for remote grading and evaluation.

Accuracy of Telemedical Digital Imaging in Detecting Age-related Macular Degeneration Lim and colleagues46 were among the first to assess digital imaging for detecting lesions associated with age-related macular degeneration. In their study, they compared non-mydriatic digital macular imaging with gold standard 35-mm stereo macular slide images for detecting AMD. The results were

underwhelming. The sensitivity of digital retinal images when compared with mydriatic gold standard 35-mm film images of the macula ranged from 0% for subretinal fluid to 75% for subretinal hemorrhage. In another study by Pirbhai et al.,47 telemedical mydriatic non-stereoscopic telemedical digital macular imaging was compared with fundus fluorescein angiography and conventional clinical examination with dilated fundoscopy in identifying and classifying exudative age-related macular degeneration. They found sensitivities for digital imaging to range from 40% pigment epithelial detachment to 89.2% exudative AMD. Similarly, Jain and colleagues48 also assessed the accuracy of non-stereoscopic mydriatic digital macular imaging with the ‘‘known diagnosis’’ attained based on clinical history, conventional examination findings, and other ancillary tests. It was found that the mean sensitivity of digital imaging for detecting non-exudative AMD was 60.5% and for detecting exudative age-related macular degeneration was 76.3%. Zimmer-Galler and co-workers49 constructed a study design to evaluate the feasibility of using the ‘‘DigiScope,’’ (a mydriatic digital imaging system of the retina that was developed for telemedical screening and diagnosing diabetic retinopathy) in detecting lesions associated with age-related macular degeneration. In this study, it was found that the sensitivity of DigiScope in detecting AMD-related lesions when compared to standard 35-mm fundus film images ranged from 71% for detecting non-central geographic atrophy to 100% for detecting central geographic atrophy and choroidal neovascularization. The specificity of digital imaging DigiScope ranged from 84% for detecting intermediate drusen to 100% for presence of central geographic atrophy and non-central geographic atrophy.

Reliability (Reproducibility) of Telemedical Digital Imaging in Detecting AMD Similar to diabetic retinopathy, reliability (agreement measure) for telemedical digital imaging was divided into inter-method reliability, intra-grader reliability, and inter-grader reliability. In the reviewed studies for age-related macular degeneration, reliability or agreement measures were also calculated by using kappa statistics. Inter-method reliability was calculated by Lim et al.46 between non-mydriatic digital retinal imaging and the gold standard film images of the macula. They determined that agreement between digital macular images and 35-mm film slides of the macula were highest for detecting subretinal fibrosis ( = 0.71, exact agreement in 91% of cases) and lowest for detecting retinal pigment epithelium ( = 0.36, exact agreement in 63% of cases). Pirbhai and Seminars in Ophthalmology


Telemedicine for Macular Degeneration and Diabetic Retinopathy colleagues47 also evaluated the reliability of digital macular imaging in detecting AMD by calculated agreement levels between these images and those of gold standard fundoscopy and fluorescein angiography. In this study, agreement measurements demonstrated excellent or almost perfect ratings for the detection of exudative AMD ( = 0.75, exact agreement 87.4%), fair agreement for and reproducibility for detecting pigment epithelial detachment ( = 0.34, exact agreement 89.2%) and moderate agreement for the presence of geographic atrophy ( = 0.50, exact agreement = 82.5%). It was also demonstrated that digital macular imaging compared with the gold standard has an exact agreement of 80.3% and kappa value of 0.59 (indicating fair agreement and reliability) when comparing recommendations made based on grading each type of images. In the study by Zimmer-Galler et al.49 where DigiScope digital macular images were compared with standard stereo film images of the macula, exact agreements for grading and detecting AMD associated lesions ranged from 60% for non-central geographic atrophy to 100% for detecting intermediate drusen and choroidal neovascularization. Jain and co-workers48 calculated inter-grader agreement between the two ophthalmic interns in charge of grading non-stereoscopic digital macular images and found moderate agreement ( = 0.54). Tien and co-workers50 designed a study where the main outcome measure was inter-grader and intraobserver agreement in detecting AMD lesions utilizing non-mydriatic digital macular imaging. The inter-observer agreement levels were moderate or almost perfect ( 60) for all AMD grading classifications.

9

Intra-observer reproducibility or agreement for AMD was also calculated by both Jain et al.47 and Tien and co-workers.50 In the study by the former authors,47 intra-observer agreement calculated by kappa statistics were 0.75 for grader 1 (moderate agreement) and 0.91 for grader 2 (almost perfect). Tien and co-workers50 found the intra-grader agreement (kappa statistics value) to be 0.95 for grader 1 and 0.92 for grader 2, both indicating almost perfect agreement.

IMAGE QUALITY AND GRADABILITY Image quality and the ability to assess and grade digital images adequately are very important factors when determining the feasibility of telemedical diagnosis of diabetic retinopathy. Several studies which examined the accuracy and reliability of telemedical digital images in screening for diabetic retinopathy also reported the proportion of the captured digital images which were ungradable ranged from 0% to 14.9%. By contrast, this proportion ranged from 0% to 11.7% for seven-field ETDRS style fundus images in the same studies (Table 5). While most of these studies did not specify reasons for the upgradability of their telemedical digital images, Lin et al.23 did attribute it to lack of proper pupillary dilation and media opacity. Other teleretinal studies have also addressed this issue and found that cataracts and inadequate dilation of the pupil are strongly associated with ungradable telemedical digital images.51,52 In the reviewed validity studies which assessed telemedical digital imaging in detecting age-related macular degeneration, the proportion of ungradable telemedical digital images

TABLE 5. Proportion of ungradable retinal digital images across various reviewed validity studies. Study

Dilation?

Diabetic Retinopathy Studies Schiffmann et al.29 No No Silva et al.27 No Lin et al.23 Yes Fransen et al.22 No Bursell et al.24 Yes Hubbard et al.68 Yes Rudinsky et al.25 Yes Li et al.28 No Vujosevic et al.30 No Kernt et al.33

Ungradable Digital Images (%)

Ungradable 7-field Film Images (%)

14.9 9.3 8.1 6.6 0.9 2.8 2.9 0

11.7 0.5 3 5.5 0.9 1.9 1.5 0

–

–

–a

Age-related Macular Degeneration Studies Tien et al.50 No Group 470 years old = 14.5

–

Not applicable

Group 455 years old = 9.1 Pirbhai et al.47 Lim et al.46

Yes No

a

Dashed lines represent unavailable data.

!


5.5 –

Not applicable Not applicable

Digital Image Photographer Ophthalmic photographer Ophthalmic photographer Trained research associate Ophthalmic photographer Not specified Ophthalmic photographer Ophthalmic photographer Ophthalmic photographer Trained nurse Ophthalmic photographer Group 470 years old = trained generologists Group 455 years old = ophthalmologists Not specified Ophthalmic photographer


10 K. Vaziri et al. ranged from 5.5% to 14.5% (Table 5). Lim et al.46 reported that 50% of their telemedical digital images were unreadable secondary to cataracts and another 20% due to presence of intraocular lens implants. Kawasaki and co-workers52 also highlighted that, in addition to aforementioned reasons, a communication problem (i.e., human error in transferring the digital images) led to the inability of ophthalmologists to grade the teleretinal digital images in 2.9% of their cases. Another factor that may affect the quality and gradability of digital images used in telemedical diabetic retinopathy is how these digital images were being compressed and the format they were saved as for the purposes of transferring to a remote reading center. Lee et al.53 concluded that digital retinal images saved as Tagged Image File Format (TIFF) and low-compression (30:1) Joint Photographic Experts Group (JPEG) formats were comparable in quality to the original images while images saved and compressed as high-compression JPEG format had a significantly degraded quality that proved unsuitable for telemedical analysis. It is unclear whether the suboptimal sensitivity and specificity ratings associated with digital images are a function of the type of digital storage format, the method or limitations of digital image acquisition (e.g., illumination, image processing, etc.), non-standardized image review modalities (e.g., monitors, brightness, contrast sensitivity), or a combination of these factors. While most imaging applications in radiology and other disciplines in medicine utilize Digital Imaging and Communications in Medicine (DICOM) standardized image output and standardized image reviewing stations, most ophthalmic imaging platforms have lagged behind this universal standard and often have variable proprietary image outputs and viewing software. In addition, non-standardized computer monitors are commonly used in most ophthalmology settings. This is certainly a limitation that will stymie the rapid expansion of telemedicine in the field of ophthalmology, especially if data from telemedicine projects will be used in large comparative studies.

PATIENT SATISIFACTION WITH TELERETINAL TECHNOLOGY Patient satisfaction is another component important component for assessing the feasibility of teleretinal services. No matter how accurate or reliable this technology might be for detecting retinal diseases remotely, patient reluctance to use this type of healthcare technology can make it a lot less effective in increasing the ease of access to retina specialists and similar health care providers. Boucher and colleagues assessed the application of telemedical non-mydriatic cameras for diabetic retinopathy screening and found that close to 99% of participants were satisfied with a

telemedical system as a way to perform screening eye examinations and 95% would prefer a telemedical screening exam for their next screening instead of a conventional face-to-face in-office clinical examination by an ophthalmologist.54 Another study evaluated the adherence of diabetic patients to annual eye examinations using non-mydriatic teleretinal imaging.51 Participants in this study had a mean satisfaction score of 1.1 on a scale of 1 to 4, 1 being very satisfied with telemedical retinal imaging. Also, in the same study it was shown that participants who had received teleretinal imaging were more likely to adhere to their follow-up dilated eye screening examinations. Pradeep et al.55 implemented a teleophthalmology consultation system in rural India and found that close to 98% of participants were satisfied. Furthermore, no association was found between age, gender, or occupation with the level of satisfaction. A search of literature did not yield any studies that evaluated patient satisfaction with regards to telemedical approaches for detecting age-related macular degeneration.

ECONOMIC CONSIDERATIONS One of the most important factors that determine if a new technology or methodology is feasible is whether it is cost-effective when compared with conventional and already established retinal screening and diagnostic strategies. One of the potential advantages of telemedicine is that it could provide better eye care access to populations residing in remote areas where patients have to travel from or specialists have to travel to for the purpose of receiving and proving care, respectively. Maberley et al.56 performed a costeffectiveness analysis for retinopathy screening in Canada’s First Nations population using retinal photography via a portable telemedical digital camera versus utilizing traveling ophthalmologists. It was found that the teleretinal approach not only saved more site visits as compared with specialist-based onsite services (67 versus 56) over the five-year study period, but also was more cost-effective than providing traveling retina specialist services (C$3900 versus C$9800 per sight year, respectively, and C$15,000 versus C$37,000 per quality-adjusted life year, respectively). In a unique study by Aoki and co-workers,57 a cost-effectiveness analysis of telemedical services in screening and detecting diabetic retinopathy was performed in a prison population. This study’s authors concluded that the teleophthalmic strategy was less costly and resulted in higher quality-adjusted life years (QALY) gains. Whitted and colleagues58 evaluated the cost benefits of Joslin Vision Network’s (JVN) non-mydriatic teleophthalmology system for detecting proliferative diabetic retinopathy in three federal agencies: the Seminars in Ophthalmology


Telemedicine for Macular Degeneration and Diabetic Retinopathy Department of Veterans’ Affairs, the Department of Defense, and the Indian Health Service. In all three agencies, digital teleretinal services proved to be more cost-effective when compared with in-person screening with mydriatic ophthalmoscopy. For example, in the Department of Veterans Affairs, the use of teleophthalmology could detect an additional 96 cases of proliferative diabetic retinopathy and decrease costs by close to $3,000,000 compared with conventional means. In the Department of Defense, compared with ophthalmoscopy, teleretinal technology could detect an additional 165 cases of proliferative diabetic retinopathy and decrease costs by $129,000. In the Indian Health Service, it was shown that utilization of teleophthalmology detected an additional 148 cases of PDR while saving close to $526,000 when compared against conventional ophthalmoscopy. In another cost-benefit analysis study done by Rein and co-workers,59 the cost-effectiveness of teleretinal strategy was compared with conventional annual and biennial eye evaluations by retina specialists. It was found that in screening of people with no diabetic retinopathy or early diabetic retinopathy, teleretinal screening was the most costeffective when detecting only diabetic retinopathy was the goal. Not all studies, however, have found teleretinal strategies to be cost-effective. Gomez-Ulla and coworkers60 performed a cost analysis study comparing telemedical digital imaging with direct fundus examination for the detection of diabetic retinopathy in Spain’s public health care system. This study found that, with regard to the burdens on the health care system, direct fundus examination was more costeffective than the telemedical approach, primarily due to the higher costs associated with purchasing and maintaining the equipment required for a teleretinal system. However, from a patient’s perspective, when factoring in the travel costs and the loss of income secondary to traveling by retina specialists for an inoffice examination, the teleretinal strategy was more cost-effective. Once again, our search of literature did not yield any studies that have specifically assessed the costeffectiveness of telemedical approaches in detecting age-related macular degeneration.

DISCUSSION Diabetic retinopathy and age-related macular degeneration (AMD) are two leading causes of blindness in the United States and around the world. Diabetic retinopathy is the leading cause of blindness in the working population of developed countries and agerelated macular degeneration is the leading cause of irreversible blindness in developed nations among individuals older than 65 years of age.61 Both of these !


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conditions tend to be asymptomatic in the early stages and yet present with devastating visual impairments in later stages. This, along with the fact that there are effective treatments for some stages of these diseases, has led to the screening and early detection of these conditions to become a very important topic, receiving intense public health focus. Despite American Ophthalmology Association’s recommendation for annual ophthalmic screening for diabetic patients and annual or biennial ophthalmic screening for all individuals 65 years or older, it estimated that in the United States alone there are 3.07 million individuals who are unaware of their diabetic retinopathy and 6.05 million people who are unaware of their agerelated macular degeneration.44 To be able to reduce the number of undiagnosed individuals, great discussion and attention has been given to methods other than the conventional face-to-face strategies for mass screening and early detection of these diseases. These alternative methods, in addition to be being accurate and reliable, must also be cost-effective, simple to operate, easily accessible throughout the world, and patient friendly. The emergence of telemedicine has led to the design of many pilot and feasibility studies that have evaluated the role telemedical technologies play in screening and diagnosing many medical diseases, including those within the field of ophthalmology. The reason why telemedicine can have an important role in screening and detecting diabetic retinopathy and age-related macular degeneration is that both of these conditions can be diagnosed visually via varying imaging techniques. However, the goldstandard for acquiring ophthalmic images in detecting and grading both diabetic retinopathy and age-related macular degeneration is stereoscopic film-based fundus photography.20,62 Acquiring these film-based images is time-consuming, expensive, requires skilled ophthalmic photographers, creates difficult storage and transfer problems between facilities, and is generally unsuitable for incorporation into telemedical systems. The advancement in technology that led to the development of digital imaging techniques of the posterior segment of the eye has made teleophthalmology a potentially feasible strategy in detecting and diagnosing diabetic retinopathy and age-related macular degeneration. However, for a telemedical approach to be deemed successful, it must first prove to be at least comparable to the current gold standards in place for evaluating the same parameters in terms of accuracy, reliability, cost-effectiveness, and patient satisfaction. As a result, a number of studies have evaluated these factors comparing telemedical approaches with the conventional diagnostic and screening methods. With respect to the feasibility of using telemedicine for screening and diagnosing diabetic retinopathy, the present paper reviewed studies that have compared


12 K. Vaziri et al. telemedical digital imaging with the gold standard 30 , seven standard-field, stereoscopic 35-mm color film slides of the ocular fundus. Direct comparison of these studies is difficult as different studies varied in the number of fields, field degrees, mydriatic status. and the capacity of the image photographer and graders. Despite these differences, these studies showed high specificity for telemedical digital imaging in detecting different diabetic retinopathy severity levels. Specificities varied across studies and appeared to be lower for severe NDPR. These studies showed a good to excellent agreement between digital imaging and film images in detecting different diabetic retinopathy severity levels. One of the concerns with using digital imaging in grading severity of diabetic retinopathy has been the proportion of images with poor quality that were not gradable. The studies reviewed in this paper had ungradable digital images ranging from 0% to 14.9%, which can still be considered very acceptable. especially since the patients with ungradable digital images would have been referred for an in-office retina examination using conventional techniques, so they would not have been deprived of eye care. The poor quality of these images was mostly attributed to media opacity and poor pupillary dilation, which might partly explain the observation that the two studies with highest ungradable proportion of digital images utilized non-mydriatic digital cameras. By contrast, the three validity studies with the lowest proportion of ungradable telemedical digital images also used mydriatic digital cameras (Table 1). There was no obvious association, however, between the proportion of ungradable digital images and the skill level of the photographer. As can be seen in Table 5, while in most reviewed studies the proportion of ungradable digital images was higher than that of ETDRS seven-field filmbased fundus photographs, with the exception of studies by Silva et al.27 and Lin et al.,33 the proportion of ungradable photographs is not very different between the two imaging techniques. While neither of the two aforementioned studies offered any explanations for the discrepancy observed between the ungradable proportions of digital imaging and standard film photography, it might be relevant to note that in Lin and colleagues’ study,23 an ophthalmic photographer acquired all the film-based fundus photographs, while only a research associate (a non-photographer) acquired all the digital fundus images. Schiffman et al.29 reported the highest proportion of ungradable digital images and also highest proportion of ungradable standard seven-field film photographs among the studies that were reviewed and they reported an almost perfect agreement in the gradability of eyes between their DigiScope (teleretinal fundus camera) with the ETDRS film-based fundus photography, indicating

that the issues with imaging were not unique to telemedical digital imaging. The non-mydriatic Optos ultra-widefield retinal digital imaging (Optos, PLC, Scotland, U.K) using scanning laser ophthalmoscope is a novel imaging device which was utilized by Kernt et al.33 and Silva and co-workers27 in teleretinal validity studies. These scanning laser imaging systems allow a greater area of the retina to be photographed without the need of dilatation, which is more convenient for the patients and also shown to be less affected by media opacity.63 As such, this technology has the potential to be used for telemedical population-based screening of diabetic retinopathy; however, more studies are required to assess the validity of this expensive strategy. In addition to favorable agreements between telemedical digital imaging and the gold standard in detecting different diabetic retinopathy severity levels and diabetic retinopathy-related lesions, the review of cost-analysis studies showed that a telemedical approach for screening and detecting diabetic retinopathy is also cost-effective and adds to patient adherence by cutting down on travel time and costs incurred by the patients. Our review also showed that the convenience of telemedical strategies has been reflected in high patient satisfaction and increased adherence to annual screenings. It is also important to mention that most diabetic care is given in primary care offices. Therefore, since telemedical digital imaging approaches in screening for diabetic retinopathy have been shown to be feasible, many studies have assessed telemedical diabetic retinopathy screening in primary care physicians offices and have done so with favorable results.60,64–67 The role of telemedicine in AMD has been a much smaller one than that in diabetic retinopathy. One reason could be that, up until a decade ago, there were no appropriate treatment modalities for this condition. After landmark studies showing the importance of antioxidants and minerals in slowing or stopping the progression of non-exudative AMD and the role, first, of photodynamic therapy and, later, intravitreal anti-VEGF injections in controlling or even reversing the effects of exudative AMD, much more attention has been given to the early detection of this disease. As a result, similar with diabetic retinopathy, the role of telemedical digital imaging in detecting AMD has recently begun to be evaluated. While the study by Lim and colleagues46 showed low sensitivity and specificity for digital imaging in detection of AMD, other studies reviewed in our paper had positive results. Similar to telemedicine studies in diabetic retinopathy, digital image quality was affected by media opacity in the AMD telemedicine studies. There were no cost analysis or patient satisfaction studies evaluating telemedical approaches in detecting age-related macular degeneration. Seminars in Ophthalmology


Telemedicine for Macular Degeneration and Diabetic Retinopathy Optical Coherence Tomography (OCT) has revolutionized the management of neovascular AMD and high-risk dry AMD. This rapid, non-invasive, and quick diagnostic outpatient test can be performed on patients with miotic pupils, especially since the area of interest (i.e., the macula) resides directly in the central visual axis posteriorly. This diagnostic test is easy to administer and simple for patients to undergo. Amazingly, we were unable to find a single study evaluating the validity of OCT imaging utilized telemedicine for the evaluation of patients with (1) no AMD, (2) some AMD, or (3) advanced AMD (dry AMD with central geographic atrophy or patients with any neovascular AMD). In conclusion, telemedical approaches show promising results for screening and detecting diabetic retinopathy and AMD. As the role of telemedicine is in its infancy with respect to age-related macular degeneration, a greater number of studies would be needed to further assess the feasibility, validity, and cost-effectiveness of this emerging technology in detecting AMD, especially when utilizing advanced OCT devices. Also, as most of the telemedical studies tend to have ‘‘store-and-forward’’ type of study designs, future studies could evaluate the feasibility of ‘‘real-time’’ teleophthalmology in detecting diabetic retinopathy and age-related macular degeneration.

DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Funding: Supported by NIH Center Core Grant P30EY014801, Research to Prevent Blindness Unrestricted Grant, Departmentof Defense (DODGrant#W81XWH-09-1-0675).

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