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. 2020 Aug 21;15(8):e0238072. doi: 10.1371/journal.pone.0238072

Sensitivity and specificity of high-resolution wide field fundus imaging for detecting neovascular age-related macular degeneration

Maiko Maruyama-Inoue 1,*,#, Yoko Kitajima 2,#, Shaheeda Mohamed 3,#, Tatsuya Inoue 1,#, Shimpei Sato 2,#, Arisa Ito 1,#, Shin Yamane 1,#, Kazuaki Kadonosono 1,#
Editor: Demetrios G Vavvas4
PMCID: PMC7442256  PMID: 32822418

Abstract

Purpose

Early detection and treatment are important management strategies for neovascular age-related macular degeneration (AMD). The purpose of this study was to determine the sensitivity and specificity in detecting neovascular AMD using two wide-field imaging systems: ClarusTM (CLARUS 500™, Carl Zeiss Meditec AG, Jena, Germany) and Optos®(Optos California®, Optos PLC, Dunfermline, United Kingdom), compared to conventional digital fundus photographs.

Methods

We retrospectively analyzed 109 eyes of 73 consecutive patients with neovascular AMD, who underwent standard examination and multimodal imaging, including fundus photography, and optical coherence tomography (OCT). Unmasked graders utilized slit-lamp biomicroscopy and OCT to diagnose neovascular AMD. Masked graders evaluated ClarusTM, Optos®, and digital fundus photograph methods to determine the presence of choroidal neovascularization associated with AMD. Sensitivity and specificity analyses were performed using combined fundoscopy and OCT as the reference standard.

Results

Ninety eyes were diagnosed with neovascular AMD and the remaining 19 eyes were normal based on the reference standard. Of these, neovascular AMD was detected using ClarusTM in 94.4% (85/90). The sensitivities of Optos® and digital fundus photographs were 81.1% (73/90) and 87.8% (79/90), respectively. The specificities using ClarusTM, Optos®, and digital fundus photographs were 89.5% (17/19), 94.7% (18/19), and 89.5% (17/19), respectively.

Conclusion

ClarusTM, with its ability to image high-resolution wide field fundus, was considered superior for diagnosing neovascular AMD with high sensitivity and specificity. It may be a useful screening tool for early detection of neovascular AMD, facilitating prompt referral and treatment.

Introduction

Age-related macular degeneration (AMD) is the leading cause of severe irreversible vision loss in older adults in the United States and other developed countries [1, 2]. Recently, anti-vascular endothelial growth factor (VEGF) agents have demonstrated efficacy in improving visual acuity outcomes in patients with neovascular AMD [3, 4]. However, larger lesion size and worse visual acuity at baseline were associated with a poorer visual outcome [5]. Therefore, early detection and treatment initiation at onset of neovascular AMD results in better therapeutic outcomes [6]. In this regard, there are several fundus imaging systems available for screening. ClarusTM (CLARUS 500TM, Carl Zeiss Meditec AG, Jena, Germany) is a newly designed scanning laser ophthalmoscope that can obtain 133-degree field of the retina in a single image without mydriasis. Also incorporated into this system are features of partially confocal optics and true color imaging using red, green, and blue laser ophthalmoscopy scans. The high-resolution of 7.3 microns and high image quality that avoids eyelash and eyelid artifacts enables diagnosis of a variety of lesions in the retina.

Optos® (Optos California®, Optos PLC, Dunfermline, United Kingdom) also consists of an ultra-wide field (UWF) image that can obtain 200-degree field of the retina in a single image without mydriasis. However, the Optos® fundus image is slightly different from a real color image because it combines monochromatic red and green scanning laser ophthalmoscopy scans. Optos® has been useful for detecting a variety of retinal lesions such as retinal tears, retinal detachment, and diabetic retinopathy (DR) or peripheral macular lesions [7–9]. However, eyelash artifacts with Optos® may prevent clear imaging of the inferior periphery [8].

Digital fundus photograph (TRC-50DX, Topcon, Tokyo, Japan), a mydriatic high-resolution fundus photography with retinal images of 35 or 50-degree field, is frequently used for detecting macular lesions [10, 11] However, this method is easily influenced by artifacts such as cataract and small pupils [12].

The purpose of this study was to evaluate the accuracy of ClarusTM, Optos®, and digital fundus photographs for detecting neovascular AMD. The sensitivity and specificity of these techniques were determined by comparing to the reference standard, which included fundoscopy combined with optical coherence tomography (OCT) data.

Patients and methods

Study design

Between June and July 2019, Japanese patients diagnosed with neovascular AMD who were seen in the Department of Ophthalmology at the Yokohama City University Medical Center formed the study population. The medical records of 73 (146 eyes) consecutive patients were extracted for this retrospective analysis. The study was conducted according to the principles of the Declaration of Helsinki, and informed consent was obtained from all eligible patients. This study was approved by the Ethics Committee of the Yokohama City University Medical Center.

Data collection

All patients underwent ophthalmologic examination, including slit-lamp biomicroscopy, spectral-domain OCT (SD-OCT) imaging (Heidelberg Spectralis HRA + OCT; Heidelberg Engineering, Germany), and color fundus photography using ClarusTM, Optos®, and digital fundus photographs. Images obtained by ClarusTM were taken in a single-shot of 133-degree field or auto-montaged image of 200-degree field with mydriasis. Images obtained by Optos® and the digital fundus photographs were from a single-shot with mydriasis. Images of 50-degree field of macula in each imaging device were used for evaluation by masked graders.

Unmasked evaluation of neovascular AMD

The patients were examined by two unmasked graders (MM and YK). The findings obtained from slit-lamp biomicroscopy and SD-OCT imaging in the macula were reviewed by the unmasked graders. We included their fellow eyes with neovascular AMD and normal fundus. However, eyes that showed age-related maculopathy (ARM) were excluded. Normal fundus was defined as none or minimal macular changes of age-related disease. Lesions in ARM can be early with drusen and/or mild retinal pigment epithelium abnormalities or late with features of geographic atrophy [13]. Neovascular AMD was defined as “present” if there were any characteristic signs of choroidal neovascularization (CNV) on medical examination. Both active and inactive CNV in the diagnosis of neovascular AMD were included in this study.

Of the 73 patients, 17 patients had bilateral neovascular AMD, 37 fellow eyes showed ARM, and the remaining 19 fellow eyes were graded as normal by the unmasked graders. Therefore, the fundus images of a consecutive series of 109 eyes of 73 patients (both treatment naïve and treated eyes) with neovascular AMD were retrospectively reviewed by the masked graders.

Masked evaluation of sensitivity and specificity of retinal imaging

Two retina specialists (SS and AI) who were blinded to the purpose and results of the study evaluated images from the three modalities used in this study—ClarusTM, Optos®, and digital fundus photographs, without any additional patient information. Grading for neovascular AMD was performed in a binary manner (1 = present, 0 = absent). The graders were allowed to adjust magnification and evaluated 50-degree field of macula. Retinal images thus obtained were evaluated two times after an interval of one week. When the evaluation was inconsistent, a third masked reader (TI) made the final arbitration. By using the first obtained data from the masked graders, sensitivity and specificity of the three retinal imaging devices for diagnosing neovascular AMD were determined by comparison against a reference, the analysis using combined slit-lamp biomicroscopy and SD-OCT information by unmasked graders. Figs 1 and 2 show example images of neovascular AMD and normal eyes, respectively.

Fig 1. Fundus photographs of an eye with neovascular AMD obtained using the three imaging systems.

Fig 1

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(A) ClarusTM; (B) Optos®; (C) Digital fundus photograph.

Fig 2. Fundus photographs of a normal eye obtained using the three imaging systems.

Fig 2

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(A) ClarusTM; (B) Optos®; (C) Digital fundus photograph.

Statistical analysis

The two graders’ inter-observer and intra-observer agreements were assessed using the kappa statistic. Inter-observer agreements were assessed by using the first obtained data from the masked graders. Intra-observer agreements were assessed by using the data obtained two times after an interval of one week. Kappa statistic was defined as follows: greater than 0.81 represents “excellent” agreement; 0.61–0.80 represents “good” agreement; 0.41–0.60 represents “moderate” agreement and less than 0.40 represents “poor” agreement [14]. The sensitivity and specificity of the fundus imaging systems were compared using McNemar test. Proportion of phakic eyes in true positives/negatives or false positives/negatives was compared using Fisher’s exact test. Statistical analysis was performed using Ekuseru-Toukei 2012 (Social Survey Research Information, Tokyo, Japan). A P value <0.05 was considered statistically significant.

Results

Patient characteristics and unmasked evaluation of neovascular AMD

Demographic and clinical characteristics of patients with AMD are shown in Table 1. Of the 109 eyes, 90 (82.6%) exhibited neovascular AMD and the remaining 19 eyes (17.4%) were marked normal. Mean patient age was 77.5 ± 8.4 years (median, 78 years; range, 57–97 years). Of the 73 patients, 52 were men and 21 were women. Among the 109 eye, 73 eyes were phakic and 36 eyes were pseudophakic. Mean logMAR best corrected visual acuity was 0.423 (20/53 Snellen equivalent) in the affected eyes and −0.043 (20/18 Snellen equivalent) in the fellow normal eyes.

Table 1. Clinical characteristics of the patients with neovascular AMD.

Number of patients 73
Number of eyes 109
Age, mean ± SD, year 77.5 ± 8.4
Sex(Male/Female) 52/21
Lens status(Phakic/Pseudophakic) 73/36
Baseline logMAR visual acuity, mean ± SD
    Eyes with neovascular AMD 0.423 ± 0.496 (Snellen equivalent 20/53)
    Eyes with normal -0.043 ± 0.062 (Snellen equivalent 20/18)
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AMD = age-related macular degeneration; SD = standard deviation; logMAR = logarithm of the minimum angle of resolution.

Inter- and intra- grader agreement for diagnosing AMD

Inter-observer agreement showed a good kappa value (± standard error) of 0.640 ± 0.083 (P < 0.001) for ClarusTM, moderate kappa of 0.595 ± 0.075 (P < 0.001) for Optos®, and 0.543 ± 0.080 (P < 0.001) for the digital fundus photographs (Table 2).

Table 2. Inter-observer agreement for detecting CNV in three imaging modalities.

Grader 1 Grader 2 Agreement (%) Kappa value P value
+ -
ClarusTM + 74 13 86.2 0.640 P < 0.001
- 2 20
Optos® + 64 20 81.7 0.595 P < 0.001
- 0 25
Digital fundus photograph + 68 21 80.7 0.543 P < 0.001
- 0 20
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Intra-observer agreement showed an excellent kappa of 0.882 ± 0.058 (P < 0.001) for ClarusTM, 0.810 ± 0.069 (P < 0.001) for Optos®, and 0.878 ± 0.060 (P < 0.001) for the digital fundus photographs for grader 1 (SS, Table 3). Intra-observer agreement showed an excellent kappa of 0.863 ± 0.054 (P < 0.001) for ClarusTM, good kappa of 0.743 ± 0.065 (P < 0.001) for Optos®, and 0.795 ± 0.061 (P < 0.001) for the digital fundus photographs for grader 2 (AI, Table 4).

Table 3. Intra-observer agreement for detecting CNV in three imaging modalities (grader 1).

First data Second data Agreement (%) Kappa value P value
+ -
ClarusTM + 86 1 96.3 0.882 P < 0.001
- 3 19
Optos® + 82 2 93.6 0.810 P < 0.001
- 5 20
Digital fundus photograph + 87 2 96.3 0.878 P < 0.001
- 2 18
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Table 4. Intra-observer agreement for detecting CNV in three imaging modalities (grader 2).

First data Second data Agreement(%) Kappa value P value
+ -
ClarusTM + 76 0 94.5 0.863 P < 0.001
- 6 27
Optos® + 64 0 88.1 0.743 P < 0.001
- 13 32
Digital fundus photograph + 68 0 90.8 0.795 P < 0.001
- 10 31
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Masked grading outcomes and analyses of accuracy

A diagnosis of neovascular AMD was confirmed using ClarusTM in 85 eyes, Optos® in 73 eyes, and digital fundus photographs in 79 eyes by the masked readers. On the other hand, a diagnosis of normal fundus was confirmed using ClarusTM in 17 eyes, Optos® in 18 eyes, and digital fundus photographs in 17 eyes. The sensitivities for the detection of neovascular AMD by ClarusTM, Optos®, and digital fundus photographs were 94.4% (85/90), 81.1% (73/90), and 87.8% (79/90), respectively, compared with the reference. The specificities were 89.5% (17/19), 94.7% (18/19), and 89.5% (17/19), respectively (Table 5). The sensitivity of the ClarusTM was significantly higher than Optos® (P = 0.010), but not significantly higher than digital fundus photographs (P = 0.211). The sensitivity of the digital fundus photographs was not also significantly higher than Optos® (P = 0.211). On the other hand, the specificity of the fundus imaging systems was not significantly different (all P > 0.05).

Table 5. Sensitivity and specificity for diagnosing neovascular AMD in three imaging modalities.

Unmasked graders Masked graders Sensitivity (%) Specificity (%)
+ -
ClarusTM + 85 5 94.4 89.5
- 2 17
Optos® + 73 17 81.1 94.7
- 1 18
Digital fundus photograph + 79 11 87.8 89.5
- 2 17
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Sub-analyses in phakic versus pseudophakic eyes

Of the 109 eyes, false positives or false negatives were recorded using ClarusTM in 7 eyes, Optos® in 18 eyes, and digital fundus photographs in 13 eyes. All 7 eyes which showed false positives/negatives using ClarusTM were phakic eyes. Of the 18 eyes which showed false positives/negatives using Optos®, 15 eyes were phakic and remaining 3 eyes were pseudophakic. Among the 13 eyes which had false positives/negatives using the digital fundus photographs, 10 eyes were phakic and remaining 3 eyes were pseudophakic. Proportion of phakic or pseudophakic in each imaging modalities is shown in Table 6. Although there were no significant differences in three imaging modalities, ClarusTM tended to have less proportion of phakic eyes which showed false positives/negatives. Also, true positives/negatives were recorded in all pseudophakic eyes using the ClarusTM (Table 6).

Table 6. Proportion of phakic/pseudophakic in three imaging modalities.

Phakic (%) Pseudophakic (%) P-value
ClarusTM True positives/negatives 66(60.6) 36(33.0) P = 0.093
False positives/negatives 7(6.4) 0(0)
Optos® True positives/negatives 58(53.2) 33(30.3) P = 0.169
False positives/negatives 15(13.8) 3(2.7)
Digital fundus photograph True positives/negatives 63(57.8) 33(30.3) P = 0.539
False positives/negatives 10(9.2) 3(2.7)
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Discussion

In this study, three types of retinal imaging systems, namely, ClarusTM, Optos®, and digital fundus photographs, were used to detect neovascular AMD. ClarusTM had the highest sensitivity (94.4%) for diagnosing neovascular AMD, compared to Optos® and digital fundus photographs. This is the first report that describes the usefulness of ClarusTM for detecting neovascular AMD.

It has been estimated that worldwide, 8.7% of the general population suffers from AMD, and there is an upward trend in the projected number of patients in the next two decades [15]. Recent developments in treatments include the use of inhibitors of VEGF for blocking CNV in patients with neovascular AMD [3, 4]. Therefore, early detection and diagnosis of neovascular AMD enables prompt treatment for the maximum benefit. The current standard for diagnosing neovascular AMD relies on fluorescein angiography and OCT [16, 17]. However, fundus camera has been extensively used and is still important for early detection and also for examining eyes with neovascular AMD [10] and evaluating lesions before and after treatment.

Recently, an UWF imaging has been widely used for screening or identification of retinal pathology [18]. For example, Optos UWF images improved detection of peripheral lesions in DR and enabled more accurate classification of the disease [19]. Hirano et al compared ClarusTM with Optos® in patients with DR and described that both systems were useful for assessing DR severity [20]. However, the comparison of wide-field imaging systems with conventional digital fundus camera for diagnosing macular lesions, especially neovascular AMD, remains unclear.

In this study, two retina specialists, who had ophthalmology residency for more than 5 years and retina-vitreous fellowship for more than 2 years, were selected as masked graders with similar abilities as unmasked graders. The intra- and inter-observer agreements for three retinal imaging systems were moderate or good, suggesting a high degree of repeatability and reproducibility.

We found that the sensitivity for detecting neovascular AMD using ClarusTM was 94.4%. In comparison, the sensitivities of Optos® and digital fundus photographs were 81.1% and 87.8%, respectively. The sensitivity of ClarusTM was significantly higher than Optos®. We speculated that lesions associated with neovascular AMD such as hemorrhage or fluid can be represented more clearly using true color imaging by red, green, and blue laser ophthalmology scans incorporated in ClarusTM. Furthermore, ClarusTM has a wide-field retinal camera with a 7-micron resolution that detects retinal lesions even in the macula. In addition to its partially confocal optics, because red scanning laser ophthalmoscopy penetrates deep into the choroid, ClarusTM may not be easily affected by cataracts (Fig 3). In fact, ClarusTM tended to have the least proportion of phakic eyes which showed false positives/negatives in three imaging devices. Optos® offers a combination of monochromatic red and green scanning laser ophthalmocsopy, which may prevent clear imaging of retinal lesions (Fig 4); eyelash artifact or vitreous opacity may also obscure the fundus photographs [8]. Also, the resolution of Optos® is 14 microns, which is lower than that of ClarusTM, affecting accurate imaging of the macula.

Fig 3. Fundus photographs of a normal eye obtained using the three imaging systems.

Fig 3

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(A) Clear imaging obtained by ClarusTM; (B) ClarusTM imaging with 50-degree field of macula. (C) Blurred imaging obtained by Optos®, particularly in the inferior area; (D) Imaging obtained by the digital fundus photograph is obscured due to cataract.

Fig 4. Fundus photographs of an eye with neovascular AMD which was diagnosed as normal, using Optos® and digital fundus photograph.

Fig 4

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(A) Imaging obtained by ClarusTM (B) OCT imaging shows inactive occult CNV. (C) ClarusTM imaging with 50-degree field of macula shows the area of retinal pigment epithelium (RPE) alteration in the macula (white arrowhead); two masked graders classified the image as neovascular AMD; (D) Optos® imaging shows unclear RPE alteration; one masked grader classified the image as neovascular AMD while the other grader and the third grader also diagnosed it as normal; (E) Digital fundus photograph shows obscure RPE alteration; one masked grader classified the image as neovascular AMD while the other grader and the third grader also diagnosed it as normal.

Although the sensitivity of Optos® tended to be lower than digital fundus photographs, there were no significant differences between the two modalities, which was consistent with a previous report that there was a good agreement between grading by digital fundus camera and Optos® in the macula [21].

On the other hand, although the sensitivity showed no significant differences between ClarusTM and digital fundus photographs, digital fundus photographs tended to have lower sensitivity than ClarusTM. Digital fundus photographs depict high-resolution images, however, media opacity such as cataract or small pupil deteriorates image quality (Fig 5) [12]. In this study, the proportion of phakic patients who showed false positives/negatives using digital fundus photographs tended to be higher than that of ClarusTM. High detection sensitivity achieved by ClarusTM suggests that it may be a useful tool for the clinical diagnosis of neovascular AMD, and potentially, the reduced need for slit-lamp examination in the future. For example, the ClarusTM can be potentially beneficial when realizing telemedicine systems, which could help to streamline the AMD referral process, reduce waiting times and reduce the overall burden of healthcare costs.

Fig 5. Fundus photographs of an eye with neovascular AMD, which was diagnosed as normal using Optos® and digital fundus photograph.

Fig 5

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(A) Imaging obtained by ClarusTM (C) OCT imaging shows active fibrovascular pigment epithelium detachment. (B) ClarusTM imaging with 50-degree field of macula shows a neovascular AMD lesion (white arrowhead); two masked graders classified the image as neovascular AMD; (D) Optos® imaging shows an unclear lesion that was classified as normal by two masked graders; (E) Digital fundus photograph shows unclear imaging due to cataract; two masked graders also classified the image as normal.

All three imaging systems evaluated in this study showed high specificity, with few false positives, indicating that these imaging modalities are likely to result only in necessary referrals.

In this study, the male ratio was much higher than that of female. In Japan, patients with neovascular AMD have a male predominance [22], which is converse to population-based studies in Caucasians [23, 24]. Although the reason for this is unclear, genetic differences between Japanese and Caucasians or the higher smoking rate in males in Japan may underlie such differences.

The limitations of this study are its retrospective nature and the small sample size. The results of this study need to be validated with further prospective studies involving more patients. Although ClarusTM and Optos® can be usually taken without mydriasis, in this study, all images were taken with mydriasis. Others have demonstrated that mydriatic image obtained using the Optos® system is better than non-mydriatic images for determining severity of DR [25]. Therefore, it will be important to investigate the reliability of ClarusTM to discern in the presence or absence of mydriasis. Because of the high risk for progression to AMD, early detection for ARM is also helpful to initiate treatment earlier. However, we excluded eyes with ARM in this study, and future investigations should consider the sensitivity and specificity of ClarusTM for detecting ARM.

Conclusion

ClarusTM, with its ability to image high-resolution wide field fundus, was considered superior for diagnosing neovascular AMD with high sensitivity and specificity. It may be a useful screening tool for early detection of neovascular AMD, facilitating prompt referral and treatment.

Data Availability

All relevant data are within the manuscript.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Demetrios G Vavvas

20 May 2020

PONE-D-20-09112

Sensitivity and Specificity of High-resolution Wide Field Fundus Imaging for Detecting Age-related Macular Degeneration

PLOS ONE

Dear Dr Maruyama-Inoue,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS ONE

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Reviewer #1: Partly

Reviewer #2: Yes

**********

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Reviewer #1: No

Reviewer #2: N/A

**********

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Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Major revisions required:

1. Clarus images were not taken using universal methodology (either single shot or montage images). Since the whole aim of this study is to compare agreement and sensitivity/specificity of two imaging devices, the imaging protocol for each device has to be universal for all eyes included.

2. Inter-observer agreement is rather low. (barely above 0.6 for clarus and below 0.6 for optos and digital fundus photos ) This essentially means that for the binary task of presence/absence of CNV, graders in this study disagreed in about half of the images. please see relevant literature on inter-observer agreement on CNV. I would suggest graders to go over the images again to attempt reaching agreement at an acceptable for scientific literature level.

3. lines 196-197: ‘moderate or good [agreement] suggesting a high degree of reproducibility and subjectivity’. Please see above comment. Also, ’Subjectivity’ does not seem a positive characteristic in a retinal imaging study.

4. Study population and inclusion criteria is unclear.

(a) Methods lines 146-147 say ‘In this study, unmasked graders evaluated 109 eyes of 73 patients with neovascular AMD’ then lines 149-150 ‘Of the 109 eyes, 90 (82.6%) exhibited neovascular AMD and remaining 19 eyes (17.4%) were marked normal’.

(b) Lines 152-153: were fellow eyes included in this study ? were all those fellow eyes normal while the contralateral eye had nAMD ?

5. The whole discussion has 1 reference (!) - and this is in the limitations part. The total number of 8 references for the whole manuscript is surprisingly low, especially for a retinal imaging study. There is a plethora of imaging articles that should be discussed herein for comparison with the authors results. In the current version there is a marked lack of an elaborate discussion.

Additional revisions required:

6. Lines 206-207: please add phakia status and relevant subgroup analysis in phakic vs pseudophakic eyes since this is discussed as a potential advantage of Clarus over Optos.

7.Title has to be revised since this study only investigated neovascular AMD (nAMD). similar changes have to be made in introduction of abstract and manuscript.

8. Abstract Conclusion : ‘improving therapeutic outcomes and maintenance of better visual acuity’ this is not supported by the study’s results. Similar changes needed in manuscripts conclusion line 264.

9. Abstract Conclusion: ’superior for examination of detailed macular lesions’ is not supported by study’s results. Extensive evaluation of a device in multiple aspects is needed before attempting to claim superiority and this study is limited in terms of methodology. also the authors did not evaluate multiple macular lesions herein.

Reviewer #2: Thank you for submitting your manuscript. While the purpose of this study is of great scientific interest, in my opinion many aspects of your manuscript need to be extensively improved.

Major remarks

The “Introduction” section (lines 56-79) could be significantly strengthened. While I am aware of your scientific work and your writing style, I would strongly suggest you expand this section, review the literature but also add relevant references. In many statements I believe that a reference is missing such as in line 59 but also the 2nd and the 3rd paragraphs have no references at all. I would strongly encourage you to at least site a website in order to support the content when needed. In addition, in the 2nd sentence (line 57) you will also need to clarify that you are actually talking about neovascular AMD. This should also be added in your “Purpose” section (Abstract, first sentence) but I would suggest you add it also in your title, the short title and in the “Discussion” (e.g. lines 88, 190). While these statements might be true, you should support those based on other publications and maybe add some epidemiological data as well. The same applies for line 59 regarding screening. In general, this weakness is found throughout your manuscript.

In regard to your “Data Collection”, you do not really talk about the actual numbers. It seems like most of your patients had bilateral neovascular AMD. This is an important point not only to highlight it in your Methods but also consider it during your analysis and interpretation of the results.

Please, add a citation for ARM (lines 85-97).

Line 107: When you say that “Data obtained from slit-lamp biomicroscopy and SD-OCT were reviewed by two unmasked graders” do you mean that the patient was examined by two ophthalmologists? What kind of data did you collect? Please, explain/describe those characteristics.

Line 149: You say that you tested 109 from 73 patients. Those 19 eyes that were marked normal are not actually “the remaining”. You need to explain whether you scanned in total both eyes of the 73 patients (n=146) and if yes, what happened to the remaining 18 eyes. Did all of these belong to the ARM group? Were they excluded for other reason (e.g scan quality)?

Please, expand your “Introduction” and “Discussion” sections and talk more about the strengths and the weaknesses of these three devices. Also, based on the current literature, make a comment on the use of this device in other retina diseases.

I would include the lens status of those patients not only in the demographic table but also consider it as a parameter in your statistical analysis. You mention that “Clarus may not be easily affected by cataracts” (lines 206-207). If so, it would be interesting to see the results of this analysis.

Please, consult a statistician. Explain why you chose to use McNemar’s test and not Cohen’s.

Also, it would be better to use tables in order to present the results of your analysis.

Minor remarks

Consider adding keywords. This can increase the number of people finding and reading your article.

You could make a comment on the male to female ratio of your cohort compared to other cohorts and studies.

Line 252: please, review the sentence. In general, the quality of your manuscript can be improved even more after a careful proofreading.

Thank you.

**********

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Reviewer #2: No

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PLoS One. 2020 Aug 21;15(8):e0238072. doi: 10.1371/journal.pone.0238072.r002

Author response to Decision Letter 0

4 Jun 2020

June 2nd, 2020

Demetrios G. Vavvas, MD, PhD.

Academic Editor

PLOS ONE

RE: PONE-D-20-09112, entitled "Sensitivity and Specificity of High-resolution Wide Field Fundus Imaging for Detecting Age-related Macular Degeneration"

Dear Dr. Demetrios G. Vavvas

Thank you very much for your kind reviewing our manuscript.

You will find the author’s comments for manuscript on this letter which was revised based on the reviewer’s comments.

We are looking forward to seeing your favorable comments in the future.

We greatly appreciate your editing work.

With Best regards,

Corresponding author;

Maiko Maruyama-Inoue, M.D.

Yokohama City University Medical Center

4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan.

E-mail: maicoo@urahp.yokohama-cu.ac.jp

Fax: +81 45 253 8490

Phone: +81 45 261 5656

Journal Requirements

1) When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: Thank you for your requirements. I ensured that this manuscript meets PLOS ONE’s style requirements.

Reviewer’s comments

Reviewer #1

1. Clarus images were not taken using universal methodology (either single shot or montage images). Since the whole aim of this study is to compare agreement and sensitivity/specificity of two imaging devices, the imaging protocol for each device has to be universal for all eyes included.

Response: We thank the reviewer for these comments. As you point out, it is important to be universal for this study. Although Clarus images were taken in a single-shot of 133-degree field or auto-montaged image of 200-degree field, we used 50-degree field of the macula when evaluating. Images taken by Optos and fundus photograph were also evaluated using 50-degree field. We added the sentence about it.

Page 6, line 106-107

Images of 50-degree field of macula in each imaging devices were used when these images are evaluated for the masked graders.

2. Inter-observer agreement is rather low. (barely above 0.6 for clarus and below 0.6 for optos and digital fundus photos ) This essentially means that for the binary task of presence/absence of CNV, graders in this study disagreed in about half of the images. please see relevant literature on inter-observer agreement on CNV. I would suggest graders to go over the images again to attempt reaching agreement at an acceptable for scientific literature level.

Response: Thank you for the comment. Kappa value is different from the proportion of agreement. Proportion of agreement in Clarus was 94/109 (86.2%, Kappa value was 0.640), in Optos was 89/109 (81.7%, Kappa value was 0.595), and in digital fundus photograph was 88/109 (80.7%, Kappa value was 0.543). We think these values are acceptable for scientific literature level. Our previous report, which compared FA with OCTA for detecting CNV, showed that inter-observer agreement was 0.454-0.686 (Inoue M et al, IOVS, 2016). It was almost the same as this study.

Table 2

I added the proportion of the agreement.

3. lines 196-197: ‘moderate or good [agreement] suggesting a high degree of reproducibility and subjectivity’. Please see above comment. Also, ’Subjectivity’ does not seem a positive characteristic in a retinal imaging study.

Response: We thank the reviewer for this suggestion. This is our mistake. We deleted the word ‘subjectivity’.

Page 15, line 236-238

The intra- and inter-observer agreements for three retinal imaging systems were moderate or good, suggesting a high degree of repeatability and reproducibility.

4. Study population and inclusion criteria is unclear.

(a) Methods lines 146-147 say ‘In this study, unmasked graders evaluated 109 eyes of 73 patients with neovascular AMD’ then lines 149-150 ‘Of the 109 eyes, 90 (82.6%) exhibited neovascular AMD and remaining 19 eyes (17.4%) were marked normal’.

(b) Lines 152-153: were fellow eyes included in this study ? were all those fellow eyes normal while the contralateral eye had nAMD ?

Reponse: Thank you for the comments. In Methods section, we described the inclusion criteria. We included the normal fellow eye but excluded eyes which had ARM. We added the sentence in the result section.

Page 7, line 112-116

We included their fellow eyes with neovascualr AMD and normal fundus. However, eyes that showed ARM were excluded. Normal fundus was defined as none or minimal macular changes of age-related disease. Lesions in ARM can be early with drusen and/or mild retinal pigment epithelium abnormalities or late with features of geographic atrophy.

Page 7, line 120-124

Of the 73 patients, 17 patients had bilateral neovascualr AMD, 37 fellow eyes showed age-related maculopathy (ARM), and remaining 19 fellow eyes were normal by the unmasked graders. Therefore, the fundus imaging of a consecutive series of 109 eyes of 73 patients (both treatment naïve and treated eyes) with neovascular AMD were retrospectively reviewed by the masked graders.

5. The whole discussion has 1 reference (!) - and this is in the limitations part. The total number of 8 references for the whole manuscript is surprisingly low, especially for a retinal imaging study. There is a plethora of imaging articles that should be discussed herein for comparison with the authors results. In the current version there is a marked lack of an elaborate discussion.

Response: We thank the reviewer for the comment. We added some paragraphs in the discussion section and finally listed 25 references.　

Additional revisions required:

6. Lines 206-207: please add phakia status and relevant subgroup analysis in phakic vs pseudophakic eyes since this is discussed as a potential advantage of Clarus over Optos.

Response: Thank you for the suggestion. I added subgroup analysis in phakic and pseudophakic eyes and discussed it.

Page 13, line 199-209 and table 6

Of the 109 eyes, false positives or false negatives were recorded using the ClarusTM in 7 eyes, the Optos® in 18 eyes, and the digital fundus photographs in 13 eyes. All 7 eyes which showed false positives/negatives using the ClarusTM were phakic eyes. Of the 18 eyes which showed false positives/negatives using the Optos®, 15 eyes were phakic and remaining 3 eyes were pseudophakic. Among the 13 eyes which had false positives/negatives using the digital fundus photographs, 10 eyes were phakic and remaining 3 eyes were pseudophakic. Proportion of phakic or pseudophakic in each imaging modalities is shown in Table 6. Although there were no significant differences in three imaging modalities, ClarusTM tended to have less proportion of phakic eyes which showed false positives/negatives. Also, true positives/negatives were recorded in all pseudophakic eyes using the ClarusTM (Table 6).

7.Title has to be revised since this study only investigated neovascular AMD (nAMD). similar changes have to be made in introduction of abstract and manuscript.

Response: Thank you for your comment. We changed the title and also some changes were made in the manuscript.

Title

Sensitivity and Specificity of High-resolution Wide Field Fundus Imaging for Detecting Neovascular Age-related Macular Degeneration

Short title

Accuracy of ClarusTM for Neovascular AMD

Page 5, line 83-84

The purpose of this study was to evaluate the accuracy of ClarusTM, Optos®, and digital fundus photographs for screening neovascular AMD.

8. Abstract Conclusion : ‘improving therapeutic outcomes and maintenance of better visual acuity’ this is not supported by the study’s results. Similar changes needed in manuscripts conclusion line 264.

Response: Thank you for your comment. We deleted the words ‘improving therapeutic outcomes and maintenance of better visual acuity’ in the abstract and manuscripts conclusion.

9. Abstract Conclusion: ’superior for examination of detailed macular lesions’ is not supported by study’s results. Extensive evaluation of a device in multiple aspects is needed before attempting to claim superiority and this study is limited in terms of methodology. also the authors did not evaluate multiple macular lesions herein.

Response: Thank you for your comment. We changed the words from ‘examination of detailed macular lesions’ to ‘diagnosing neovascular AMD’ in the abstract and manuscripts conclusion.

Page 3, line 39-40 and page 20, line 317-318

ClarusTM, possessing an ultra-wide field imaging system, was considered superior for diagnosing neovascular AMD with high sensitivity and specificity.

Reviewer #2

1. The “Introduction” section (lines 56-79) could be significantly strengthened. While I am aware of your scientific work and your writing style, I would strongly suggest you expand this section, review the literature but also add relevant references. In many statements I believe that a reference is missing such as in line 59 but also the 2nd and the 3rd paragraphs have no references at all. I would strongly encourage you to at least site a website in order to support the content when needed. In addition, in the 2nd sentence (line 57) you will also need to clarify that you are actually talking about neovascular AMD. This should also be added in your “Purpose” section (Abstract, first sentence) but I would suggest you add it also in your title, the short title and in the “Discussion” (e.g. lines 88, 190). While these statements might be true, you should support those based on other publications and maybe add some epidemiological data as well. The same applies for line 59 regarding screening. In general, this weakness is found throughout your manuscript.

Response: We thank the reviewer for this suggestion. We expanded the ‘Introduction’

section and added many references. In the 2nd sentence, ‘Purpose’ section, the short

title, and ‘Discussion’ section, I changed from ‘AMD’ to ‘neovascular AMD’. Finally, I

listed 25 references.

2. In regard to your “Data Collection”, you do not really talk about the actual numbers. It seems like most of your patients had bilateral neovascular AMD. This is an important point not only to highlight it in your Methods but also consider it during your analysis and interpretation of the results.

Please, add a citation for ARM (lines 85-97).

Response: I’m sorry for confusing you. I clarified the number of neovascualr AMD in the data collection section. Also, I added the citation for ARM.

Page 7, line 120-124

Of the 73 patients, 17 patients had bilateral neovascualr AMD, 37 fellow eyes showed age-related maculopathy (ARM), and remaining 19 fellow eyes were normal by the unmasked graders. Therefore, the fundus imaging of a consecutive series of 109 eyes of 73 patients (both treatment naïve and treated eyes) with neovascular AMD were retrospectively reviewed by the masked graders.

3. Line 107: When you say that “Data obtained from slit-lamp biomicroscopy and SD-OCT were reviewed by two unmasked graders” do you mean that the patient was examined by two ophthalmologists? What kind of data did you collect? Please, explain/describe those characteristics.

Response: Thank you for your comments. I described how to diagnose neovascualr AMD more clearly.

Page 7, line 110-112

The patients were examined by two unmasked graders (MM and YK). The findings obtained from slit-lamp biomicroscopy and SD-OCT imaging in the macula were reviewed by the unmasked graders.

4. Line 149: You say that you tested 109 from 73 patients. Those 19 eyes that were marked normal are not actually “the remaining”. You need to explain whether you scanned in total both eyes of the 73 patients (n=146) and if yes, what happened to the remaining 18 eyes. Did all of these belong to the ARM group? Were they excluded for other reason (e.g scan quality)?

Response: We thank the reviewer for the comment. 37 fellow eyes showed ARM, therefore, we excluded these eyes.

Page 7, line 120-124

Of the 73 patients, 17 patients had bilateral neovascualr AMD, 37 fellow eyes showed age-related maculopathy (ARM), and remaining 19 fellow eyes were normal by the unmasked graders. Therefore, the fundus imaging of a consecutive series of 109 eyes of 73 patients (both treatment naïve and treated eyes) with neovascular AMD were retrospectively reviewed by the masked graders.

5. Please, expand your “Introduction” and “Discussion” sections and talk more about the strengths and the weaknesses of these three devices. Also, based on the current literature, make a comment on the use of this device in other retina diseases.

Response: Thank you for your suggestion. I talked more about three devices. Also, I described the use of these devices in DR in the discussion section.

Line 227-234

Recently, an ultra-wide-field (UWF) imaging has been widely used for screening or identification of retinal pathology. [18] For example, Optos UWF images improved detection of peripheral lesions in DR and enabled to lead more accurate classification of the disease.[19] Regarding of ClarusTM, Hirano et al compared the ClarusTM with Optos® in patients with DR and described that both systems were useful for assessing DR severity.[20] However, the comparison of an UWF imaging with conventional digital fundus camera for diagnosing macular lesions, especially neovascular AMD, remained unclear.

Line 272-275

Although the sensitivity of Optos® tended to have lower than digital fundus photographs, there were no significant difference between the two modalities, which was consistent with the previous report that there was a good agreement between grading digital fundus camera and Optos® in the macula.[21]

6. I would include the lens status of those patients not only in the demographic table but also consider it as a parameter in your statistical analysis. You mention that “Clarus may not be easily affected by cataracts” (lines 206-207). If so, it would be interesting to see the results of this analysis.

Response: Thank you for the suggestion. I added subgroup analysis in phakic and pseudophakic eyes and discussed it.

Page 13, line 199-209 and table 6

Of the 109 eyes, false positives or false negatives were recorded using the ClarusTM in 7 eyes, the Optos® in 18 eyes, and the digital fundus photographs in 13 eyes. All 7 eyes which showed false positives/negatives using the ClarusTM were phakic eyes. Of the 18 eyes which showed false positives/negatives using the Optos®, 15 eyes were phakic and remaining 3 eyes were pseudophakic. Among the 13 eyes which had false positives/negatives using the digital fundus photographs, 10 eyes were phakic and remaining 3 eyes were pseudophakic. Proportion of phakic or pseudophakic in each imaging modalities is shown in Table 6. Although there were no significant differences in three imaging modalities, ClarusTM tended to have less proportion of phakic eyes which showed false positives/negatives. Also, true positives/negatives were recorded in all pseudophakic eyes using the ClarusTM (Table 6).

Page 16, line 248-250

In fact, ClarusTM tended to have the least proportion of phakic eyes which showed false positives/negatives in three imaging devices.

7. Please, consult a statistician. Explain why you chose to use McNemar’s test and not Cohen’s.

Response: Cohen's kappa coefficient is a statistic which measures inter-rater agreement for qualitative (categorical) items. On the other hand, McNemar's test assesses the dependence of categorical data that are matched or paired. In this case, we think McNemar’s test is appropriate way for comparing the ability to diagnose neovascualr AMD by using paired data.

8. Also, it would be better to use tables in order to present the results of your analysis.

Response: I appreciate your comment. I added table 2-6 to show the results.

Minor remarks

9. Consider adding keywords. This can increase the number of people finding and reading your article.

Response: Thank you for your comment. We added keywords.

10. You could make a comment on the male to female ratio of your cohort compared to other cohorts and studies.

Response: I appreciate your comment. I added the comment about male/female ratio.

Page 19, line 299-303

In this study, the male ratio was much higher than that of female. In Japan, patients with neovascular AMD is a male preponderance [22], which is converse to population-based studies in Caucasion.[23,24] Although the reason has not been clarified, genetic differences between Japanese and Caucasian patients or the higher smoking rate in male in Japanese people may underlie.

11. Line 252: please, review the sentence. In general, the quality of your manuscript can be improved even more after a careful proofreading.

Response: Thank you for your comment. We corrected the sentence.

Page 19, line 306-307

Although ClarusTM and Optos® can be usually taken without mydriasis, in this study, all images were taken with mydriasis.

Decision Letter 1

Demetrios G Vavvas

1 Jul 2020

PONE-D-20-09112R1

Sensitivity and Specificity of High-resolution Wide Field Fundus Imaging for Detecting Neovascular Age-related Macular Degeneration

PLOS ONE

Dear Dr. Maruyama-Inoue,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Thank you for submitting your revised manuscript. Since there is no professional editing step before acceptance please make some more grammatical syntax edits before the final acceptance.  

Line 236: please, add an explanation about the abilities of the graders. In addition, there are several typos, grammar and syntactic errors such as in lines: 59, 112, 120, 141, 143, 152, 154, 193, 195, 207, 222, 226, 273, 276, 279, 300, 302, 318, 319. Please, revise.

Please submit your revised manuscript by Aug 15 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Demetrios G. Vavvas

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Thank you for submitting your revised manuscript.

Please, find a few more comments and suggestions.

I would recommend instead of using the word “screening” to use “early detection” or “detecting” throughout your manuscript. In your conclusions, you could probably state whether this could be or not a promising screening tool.

Also, you could use the word “classified” instead of “judged” when referred to the graders.

Line 236: please, add a couple of abilities of the graders.

In addition, there are several typos, grammar and syntactic errors such as in lines: 59, 112, 120, 141, 143, 152, 154, 193, 195, 207, 222, 226, 273, 276, 279, 300, 302, 318, 319. Please, revise.

Thank you.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

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PLoS One. 2020 Aug 21;15(8):e0238072. doi: 10.1371/journal.pone.0238072.r004

Author response to Decision Letter 1

11 Jul 2020

July 11th, 2020

Demetrios G. Vavvas, MD, PhD.

Academic Editor

PLOS ONE

RE: PONE-D-20-09112, entitled "Sensitivity and Specificity of High-resolution Wide Field Fundus Imaging for Detecting Age-related Macular Degeneration"

Dear Dr. Demetrios G. Vavvas

Thank you very much for your kind reviewing our manuscript.

You will find the author’s comments for manuscript on this letter which was revised based on the reviewer’s comments.

We are looking forward to seeing your favorable comments in the future.

We greatly appreciate your editing work.

With Best regards,

Corresponding author;

Maiko Maruyama-Inoue, M.D.

Yokohama City University Medical Center

4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan.

E-mail: maicoo@urahp.yokohama-cu.ac.jp

Fax: +81 45 253 8490

Phone: +81 45 261 5656

Journal Requirements

1) Thank you for submitting your revised manuscript. Since there is no professional editing step before acceptance please make some more grammatical syntax edits before the final acceptance.

Response: Thank you for your requirements. I made grammatical syntax edits.

Reviewer’s comments

Reviewer #2

1. I would recommend instead of using the word “screening” to use “early detection” or “detecting” throughout your manuscript.

Response: We thank the reviewer for the suggestion. I changed the word ‘screening’ to ‘early detection’ or ‘detecting’.

Line 61, line74, line83, line224, line312

2. In your conclusions, you could probably state whether this could be or not a promising screening tool.

Response: Thank you for the comment. I added the sentence in conclusions.

line 42-43, line 319-321

It may be a useful screening tool for early detection of neovascular AMD, facilitating prompt referral and treatment.

3. Also, you could use the word “classified” instead of “judged” when referred to the graders.

Response: We thank the reviewer for the suggestion. I changed the word ‘judged’ to ‘classified’.

line 264, line 266, line 268, line 292, line 293, line 295

4. line 236: please, add a couple of abilities of the graders.

Response: Thank you for the comment. I described more detail about the graders.

Page 15, line 233-235,

In this study, two retina specialists, who had ophthalmology residency for more than 5 years and retina-vitreous fellowship for more than 2 years, were selected as masked graders with similar abilities as unmasked graders.

5. In addition, there are several typos, grammar and syntactic errors such as in lines: 59, 112, 120, 141, 143, 152, 154, 193, 195, 207, 222, 226, 273, 276, 279, 300, 302, 318, 319. Please, revise.

Response: Thank you for the comment. I revised several errors.

Decision Letter 2

Demetrios G Vavvas

10 Aug 2020

Sensitivity and Specificity of High-resolution Wide Field Fundus Imaging for Detecting Neovascular Age-related Macular Degeneration

PONE-D-20-09112R2

Dear Dr. Maruyama-Inoue,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Demetrios G. Vavvas

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Demetrios G Vavvas

12 Aug 2020

PONE-D-20-09112R2

Sensitivity and Specificity of High-resolution Wide Field Fundus Imaging for Detecting Neovascular Age-related Macular Degeneration

Dear Dr. Maruyama-Inoue:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Demetrios G. Vavvas

Academic Editor

PLOS ONE

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