PONE-D-19-21700

TPMS technology to infer biomarkers of macular degeneration prognosis in in silico simulated prototype-patients under the study of heart failure treatment with sacubitril and valsartan

PLOS ONE

Dear Prof. Oliva,

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.

Additionally to the reviewers comments, I would like to ask the authors to more clearly highlight the theoretical nature of their work that addresses mainly the theoretical possibility of the method but not necessarily clinical effects. This is particularly true in view of the absence of evidence that the side effect investigated is relevant in patients. The authors should interpret their findings with these thoughts in mind. Finally, the authors should give some more insight in how they think the method should be used for future research and how this may influence both research and clinical practice.

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We look forward to receiving your revised manuscript.

Kind regards,

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

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Thank you for stating the following in the Competing Interests section:"I have read the journal's policy and the authors of this manuscript have the following competing interests: Baldo Oliva, currently serves on the editorial board as academic editor of PLOS ONE."

We note that one or more of the authors are employed by a commercial company: "Anaxomics Biotech SL, Barcelona"

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Reviewers' comments:

Reviewer's Responses to Questions

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: Yes

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

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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: Yes

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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 applied the Therapeutic Performance Mapping System (TPMS) technology to the prediction of macular degeneration (MD) in patients receiving sacubitril valsartan. They report that "a lower response in term of heart failure treatment is more associated to macular degeneration development" and propose "a set of 30 potential biomarkers... to identify mechanisms (or patients) more prone to suffering macular degeneration when presenting good heart failure response".

The primary targets of this paper are data scientists or information engineers. As a clinical cardiologist, I refrain from judging the technical aspects of the study. I just make a comment about the study design and the plausibility of results.

The Authors present MD as "a common/recurrent adverse effect" of therapy with sacubitril valsartan, which does not seem to be the case. Indeed, 5 years after the publication of the PARADIGM HF study, 3 years after the latest ESC guidelines and 2 years after the update to ACC/AHA guidelines, a dedicated literature search does not give any results except for some outdated concerns of a greater risk of Alzheimer's disease (AD) and MD based on conceptual considerations. See for example doi 10.1038/nrcardio.2016.200: "Additionally, inhibition of neprilysin metabolism of amyloid-β peptides might have an effect on Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy". Nonetheless, the increased risk of AD has not been confirmed by dedicated studies. Therefore, the Authors propose a sophisticated approach inevitably burdened by a lot of assumptions and simplifications to solve a problem (i.e., how to predict MD) that does not seem to exist.

Reviewer #2: Jorba et al., used the Therapeutic Performance Mapping System (TPMS) approach to look for biomarkers which can predict MD in HF patients treated with sacubitril/valsartan. The potential for in-silico clinical trials is clearly shown by this system biology approach. There is a strong methodological base to test the hypothesis on. Although it is based on a string of assumptions inherent to the methodology, which make the eventual translation difficult. At some points the manuscript seems a bit tedious, and some analyses seem to be redundant.

Major

- The approach depends heavily on assumptions and definitions. For example, the HPN is created based on proteins related to the disease (heart failure in this case) from BED. It is difficult to retrieve these proteins used as input, however this input of proteins determines strongly all the other analyses. HF is an extreme heterogeneous disease which has many etiologies and a diverse scale on pathomechanisms. For example: is the input from BED mainly based on ischemic HF, or HF due to abnormal loading conditions?

- Is tissue-specificity taking into account? Restrictions of the HPN are based on gene expression datasets. However, many proteins/genes involved in the pathogenesis of HF are tissue-specific to the heart. Eventually there is a link in the lowHF and highMD group pointing towards fibrinolysis, how should I interpret these results in the light of tissue specificity?

- In line with previous point, in the end a list of biomarkers is proposed, the best-classifier proteins can be used as biomarker. Although no suggestions are made how these should reach clinical implementation. Should these markers be measured in blood, or are they only measurable as RNA in cardiac biopsies?

- How are the MD effectors determined? Are they also retrieved from BED? The HPN is build upon the BED input from HF. How complete is this one for MD?

- It’s difficult to interpret the TSignal values (supplemental figure 1). Low and high is defined as first and fourth quartile. How do the 2nd and 3th quartile fit in supplementary figure 1. How is the distinguishment among the four quartiles, or is there an overlapping spectrum from first to fourth quartile?

- It is a bit confusing that certain aspects seem to intertwine. To me, the most interesting part is the analysis regarding high versus low MD in the lowHF group. However, before this analysis there is a lot of emphasis on the low versus high HF group, which is also interesting, but seems not be the purpose of this manuscript and the further analysis.

- In addition, it is not clear why the last analysis using GUILDify is performed. Also in the conclusion it is stated that 30 biomarkers are proposed (out of the previous analysis). But thereafter, 10 out of the 30 are proposed to be involved in the comorbidity between HF and MD. What does this mean? The multiple analyses seem to introduce more confusion than clarity at this point.

Minor

- Try to focus the introduction immediately towards HF instead of cardiovascular diseases in general.

- Figure 1 (especially a) is difficult to read. I can’t read the text in this figure.

- In figure 2, how can there be BCP in the upper right corner? What does a differential non-best classifier protein exactly mean?

- What does a differential non-BCP imply?

- Are there more proteins which are differential best-classifier proteins which did not reach significance? Ie Opposite effect in low versus high, although not p<0.01.

- Input for the GO enriched function LHF+HHF- has only 6 proteins as input, this seems a very low input for a GO enrichment analysis.

- The approach with the Hausdorff and Euclidean distances seems a bit redundant as the MDS plot better shows how it ‘actually’ works. Visually, the graph is a bit unattractive, as there is much overlap between the groups, indicating that there is no clear clustering. Maybe the graph has to be split into a high and low HF plot, to better show how the MD groups cluster within the HF groups.

- The part that describes how biomarkers are selected is to confusing (352-370), try to describe it more compact and to the point.

- Line 416-17 “In Fig 2, the differencial best-classifier proteins with higher score can be identified by a larger area”. It is not clear what is meant with this sentence?

- Line 462-64 “We found that… to MD”. This sentence does not make sense and is not in line with the rest of the manuscript.

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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PONE-D-19-21700R1

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

PLOS ONE

Dear Prof. Oliva,

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.

==============================

ACADEMIC EDITOR:

Both reviewers were satisfied with the reply and the changes made. However, you did not address my comment, which has been as follows:

Additionally to the reviewers comments, I would like to ask the authors to more clearly highlight the theoretical nature of their work that addresses mainly the theoretical possibility of the method but not necessarily clinical effects. This is particularly true in view of the absence of evidence that the side effect investigated is relevant in patients. The authors should interpret their findings with these thoughts in mind. Finally, the authors should give some more insight in how they think the method should be used for future research and how this may influence both research and clinical practice.

Some of the changes made partly address this but not completely. I would like to ask you to address these points specifically and adjust the manuscript accordingly.

==============================

We would appreciate receiving your revised manuscript by Feb 27 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

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

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

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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 #1: All comments have been addressed

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 #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

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 #1: Yes

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 #1: Yes

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 #1: The Authors have modified their paper to address the issues raised by the Reviewers. I have no further comments.

Reviewer #2: Thank you for the elaborate reponse to my questions. I feel that all my comments have been addressed accordingly.

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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 #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

PONE-D-19-21700R2

Dear Dr. Oliva,

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

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With kind regards,

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE