Dear Dr. Waltari,

Thank you very much for submitting your manuscript "AIRRscape: an interactive tool for exploring B-cell receptor repertoires and antibody responses" for consideration at PLOS Computational Biology.

As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the 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.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

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Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Gur Yaari

Guest Editor

PLOS Computational Biology

Rob De Boer

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: Provided as an attachment

Reviewer #2: See attachment.

Reviewer #3: Review is uploaded as an attachment.

Reviewer #4: This manuscript describes AIRRscape, an R Shiny application that can be run in the browser, and that allows for the comparison of antibody sequences based on V and J gene, and CDR3 length. It visualizes these antibody characteristics in the form of heatmaps and can examine the convergence of clonotypes by constructing phylogenetic-like trees. The three use cases illustrate potential applications of the tool. The source code is publicly available on GitHub. With the major comments addressed, especially concerning how it compares to other similar tools, I think AIRRscape could be a useful contribution to the field, particularly for researchers with less programming experience.

Major comments:

- Please provide an overview table of what new or improved functionality AIRRscape provides compared to other existing tools for antibody analyses, such as VDJtools https://doi.org/10.1371/journal.pcbi.1004503, immunarch http://doi.org/10.5281/zenodo.3367200, PASA https://doi.org/10.1371/journal.pcbi.1008607.

- Please update Figure 1 to show an overview of all types of AIRR analyses that are possible in AIRRscape.

- How are motifs defined and how are they discovered (e.g., line 64)? In line 203, the authors mention “healthy control motifs” – what does this mean? Please include the definitions and explanations of motifs in the manuscript.

- In multiple places throughout the manuscript, the authors mention the increasing size of the antibody repertoires and how AIRRscape can help. For example, the author summary (line 27) states: “With AIRRscape, we enable large-scale immune repertoire visualization and analysis...”. How scalable is it? Please quantify scalability.

Minor comments:

- R and R studio versions are missing, along with dependencies. It would be nice to have all that resolved automatically if possible or to have a list of required packages and tools with versions. With this resolved, AIRRscape worked well locally for me.

- The authors mention “processed flat files” multiple times (e.g., line 142): what does flat refer to in this context?

- In line 172, it says that users may choose to construct the topology via either neighbor-joining or parsimony tree building methods. Is this performed using some package or is it a native AIRRscape implementation?

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1: No

Reviewer #2: Yes: Krishna M. Roskin

Reviewer #3: No

Reviewer #4: No

Figure Files:

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Attachments

Attachment

Submitted filename: airrscape review.docx

Attachment

Submitted filename: AIRRscape.docx

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Submitted filename: 2022-AIRRscape- an interactive tool for exploring B-cell receptor repertoires and antibody responses.docx

Dear Dr. Waltari,

We are pleased to inform you that your manuscript 'AIRRscape: an interactive tool for exploring B-cell receptor repertoires and antibody responses' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests. Also, please address the minor commnets raised by reviewer #4 (see below).

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology. 

Best regards,

Gur Yaari

Guest Editor

PLOS Computational Biology

Rob De Boer

Section Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The points raised in my review have been addressed. Improvements to the scripts and provision of a web-based facility significantly improve usability for the average user.

Reviewer #3: None. Authors have responded to all comments.

Reviewer #4: The authors have successfully addressed the comments I had.

Some very minor points:

- Updating the added Table 1 to emphasize the main advantages of AIRRscape might make it clearer to readers why they should use AIRRscape and not some of the other tools listed, for a specific analysis, e.g., easier to use, visualization options.

- While this information is now available in README under the Tips heading, having a very short description or table title for the two tables in the AIRRscape tab might make it more user-friendly.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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 #3: No

Reviewer #4: No