PONE-D-24-23017Predicting long-term functional anti-VEGF treatment outcomes in a real-world settingPLOS ONE

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Reviewers' comments:

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Comments to the Author

1. 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 #1: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: No

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3. 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 #1: Yes

Reviewer #2: No

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4. 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 #1: Yes

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: ・The authors described that MA after one year was the strongest predictor. But what caused MA at 1 year? They should rather evaluate the factors which cause MA at 1 year. Also, discuss it in the discussion section.

・Are there patients who received cataract surgery during the follow up? This could influence on the result.

・In conclusion, they described that the number not reaching treatment intervals of >10 weeks may be a robust biomarker for early treatment response and drying potential of anti-VEGF. However, previous studies showed that drying in the induction phase influences on final visual acuity. I feel this result is a little bit controversial. You should discuss it more.

Reviewer #2: The authors have carefully analyzed long-term visual prognostic factors using a large retrospective cohort, revealing that macular atrophy at one year post-treatment initiation holds significant explanatory power for long-term visual prognosis. While many clinical trials on nAMD focus on factors related to exudative control, focusing on atrophy is clinically important, and the results presented using real-world data are both useful and intriguing for clinicians involved in nAMD treatment.

The manuscript is presented in an intelligible fashion. However, authors need to address issues presented below:

• The criteria used by the authors to select covariates for the multivariate linear regression model are ambiguous. The authors have stated in the Methods section, "In cases with several options for the same variable (CRT, IRF and SRF as well as MA), the timepoint with the most explanatory potential (R2) was chosen." However, it remains unclear how the authors would proceed if the relationship of R2 values varied across different dependent variables (VA at each timepoint).

• The authors state, "To exclude a selection bias, we furthermore assessed the subsample of eyes that had been followed over minimally 5 years after diagnosis under intravitreal anti-VEGF therapy (n = 262), undertaking the same analyses, which revealed almost identical results (data not shown)." However, these results should be presented in the Supplementary material.

• In Results, the authors say, “Interval extension to more than 10 weeks was predictive of short-term, but not long-term VA (up to 3 years). We therefore decided not to include this covariate in our model.” However, CRT after loading was also not a significant predictor for VA up to year 3. Even if CRT after loading is a well-known factor, why is there a need to exclude “Interval extension to more than 10 weeks” from the multivariate model just for that reason?

• In Conclusions, “The number of eyes not reaching treatment intervals of ≥10 weeks may be a more robust biomarker for early treatment response and drying potential of anti-VEGF drugs.” This statement seems inconsistent with the previous content. A discussion on why it can be called a robust biomarker is necessary.

• The main finding presented by the authors (MA at 1 year predicting long-term visual acuity) should be discussed in relation to the natural history of AMD or the impacts of treatment. In the Discussion, the authors state, “This might be explained by the fact that MA regularly escapes detection at baseline because of overlay phenomena.” Do the authors believe that MA exists from the baseline? This should be considered since MA after the loading phase showed less predictive power for long-term visual acuity (Table 2). The state of RPE and the outer retina is generally clear after the loading phase. It is a well-known fact that MA appears after nAMD treatment and its causal relationship with anti-VEGF therapy is suspected（Macular Atrophy in Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial Comparing Ranibizumab and Aflibercept (RIVAL Study) - PubMed (nih.gov)）. How did eyes with MA compare to those without in terms of the number of injections and control of exudation?

• It is mentioned that patients were treated with T & E, but more specific protocols should be provided. How often were the dosing intervals extended? Also, how was the reduction in intervals handled when exudation recurred?

• To ensure that readers fully understand the advantages of this work on real-world data, more detailed descriptions of patient outcomes are necessary. It is mentioned in the results that 39.5% of patients were lost to follow-up. Were the remaining 60.5% continuously treated with T&E for five years? Were there any cases where the treatment method was switched to pro re nata? Were cases with atypical outcomes like macular hemorrhage or RPE tear during follow-up included in the analysis? Were there any cases that received other treatments like PDT?

• The breakdown of nAMD subtypes included in the study should be also mentioned. Eyes that exhibited macular atrophy at one year might be those with a higher risk of atrophy, such as RAP.

• In Results, the authors say, "this model reached an unprecedented effect size," which should be kept to objective expression. Whether the effect size is "unprecedented" can only be understood by the reader if other reports on long-term visual prognosis prediction models are specifically mentioned, demonstrating the model's higher explanatory power.

• In Results, “Covariates with a significant predictive value over at least 2 timepoints were integrated in the model.” For better readability, it should be stated as: “Covariates with a significant predictive value over at least 2 timepoints were integrated into a multivariate model in the second step.”

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Reviewer #1: No

Reviewer #2: No

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Predicting long-term functional anti-VEGF treatment outcomes in neovascular AMD in a real-world setting

PONE-D-24-23017R1

Dear Dr. Garweg,

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.

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Kind regards,

Tatsuya Inoue

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors addressed all the comments.

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

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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

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

Reviewer #2: Yes

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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

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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

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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: (No Response)

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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: Yes: Shuichiro Aoki

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