Establishment of an early diagnosis model of colon cancerous bowel obstruction based on 1H NMR

Jie Zeng; Jin Peng; Hua Jiang; Pengchi Deng; Kexun Li; Daolin Long; Kai Wang

doi:10.1371/journal.pone.0266730

Peer Review History

Original SubmissionAugust 4, 2021
24 Nov 2021 Decision Letter - Oscar Millet, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-21-25026 Establishment of an early diagnosis model of colon cancerous bowel obstruction based on 1HNMR PLOS ONE Dear Dr. Peng, 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. The paper was considered interesting by the reviewer, but a number of issues must be addressed before we can further consider the work. Please submit your revised manuscript by Jan 06 2022 11:59PM. 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In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. [Note: HTML markup is below. Please do not edit.] 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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 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: No ****** 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 ****** 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: In this manuscript 1H NMR coupled with machine learning is used to build a model for the differential diagnosis of acute colon cancerous bowel obstruction (CBO) vs. adhesive bowel obstruction (ABO) in serum. Although the entire spectrum is proposed to function as “biomarker”, then the authors concentrate the discussion on six metabolites. It would be important to know what would be the prediction accuracy, sensitivity and specificity of a model based on these metabolites rather than on the whole binned spectrum, to evaluate the contribution of the other molecules. The NMR analysis was limited to the acquisition of CPMG spectra, thus excluding all lipoproteins components, which would help defining metabolic alterations. It is a common practice in 1H NMR metabolomics to use at least NOESY and CPMG experiments. The serum handling procedure are largely divergent with respect to ISO standards (ISO 23118:2021 Molecular in vitro diagnostic examinations — Specifications for pre-examination processes in metabolomics in urine, venous blood serum and plasma), which could in principle affect the outcome of the downstream metabolomics analysis. Possibly the adopted procedure does not influence the comparison between the two groups of patients enrolled in the same study, but it might affect the general applicability of the model. It would be also important to know what has been administered to the patients in the time interval between admission and blood collection (e.g. Ringer acetate solutions or contrast agents for imaging, and not just “drugs” affect the NMR metabolic profiles, Metabolomics 2015;11(6):1769-1778.). Formal aspects: Missing information: the data availability statement does not describe where the data can be found Spelling: Throughout the text: 1H NMR Page 10, … 5 seconds Page 12 (Discussion), … between the two groups ****** 6. 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 [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.] 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0266730.r001
Revision 1
23 Dec 2021 Author Response Response to academic editor： We really appreciate you for your carefulness and conscientiousness. Your suggestions are really valuable and helpful for revising and improving our paper. According to your suggestions, we have made the following revisions on this manuscript: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found athttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf. Response：Thank you for your detailed comments. We have revised the manuscript according to the PLOSOne guideline thoroughly, which are highlighted in red in the revised manuscript. 2. Please ensure that you include a title page within your main document. We do appreciate that you have a title page document uploaded as a separate file, however, as per our author guidelines (http://journals.plos.org/plosone/s/submission-guidelines#loc-title-page) we do require this to be part of the manuscript file itself and not uploaded separately. Could you therefore please include the title page into the beginning of your manuscript file itself, listing all authors and affiliations. Response：Thank you very much for your advice. The title page have been added into the beginning which are highlighted in red in the revised manuscript. (page 1, lines5-12) 3. We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. A copy of your manuscript showing your changes by either highlighting them or using track changes (uploaded as a supporting information file) A clean copy of the edited manuscript (uploaded as the new manuscript file). Response：Thank you for your detailed comments. We have thoroughly copyedited the manuscript for language usage, spelling, and grammar. The amendments are highlighted in red in the revised manuscript.( page 1, lines1,30,38; page3, line42; page5, lines16,18-20; page 6, lines9,12,25-26; page 7, lines11-12; page 9, lines6-7.) 4. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. Response：Thank you for your detailed comments. The correct grant numbers is 2018YSKY0017-9( Basic scientific research business expenses of Science ＆ Technology Department of Sichuan Province) , which is also corrected in the ‘Funding Information’ section. 5. Thank you for stating the following in the Acknowledgments Section of your manuscript:“The present study was supported by Basic scientific research business expenses of public welfare scientific research institutes of Sichuan Province, China (grant no. 30504010428).” We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “No, The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript”. Please include your amended statements within your cover letter; we will change the online submission form on your behalf. Response：Thank you for your positive comments. We have removed funding-related text from the manuscript. The study was supported by Basic scientific research business expenses of Science ＆ Technology Department of Sichuan Province (grant no.2018YSKY0017-9), and the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Kexun Li and Daolin Long who were studying for a master's degree got ￥12,000 as Labor wage from this foundation, respectively. Mean while, the other authors of this manuscript got no salary from the funder. 6. Thank you for stating the following in your Competing Interests section: “NO authors have competing interests” Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state ""The authors have declared that no competing interests exist."", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. Response：Thank you for your detailed comments. The authors have declared that no competing interests exist, which are highlighted in red in the revised manuscript. (page 9, lines 29-30) 7. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. Response： The full ethics statement has been included in the ‘Methods’ section of the manuscript file, which is highlighted in red in the revised manuscript.( page 2, lines 19) Response to reviewer #1: We really appreciate you for your carefulness and conscientiousness. Your suggestions are really meaningful and useful for revising and improving this paper. According to your suggestions, we have made the following revisions on this manuscript: 1. In this manuscript 1H NMR coupled with machine learning is used to build a model for the differential diagnosis of acute colon cancerous bowel obstruction (CBO) vs. adhesive bowel obstruction (ABO) in serum. Although the entire spectrum is proposed to function as “biomarker”, then the authors concentrate the discussion on six metabolites. It would be important to know what would be the prediction accuracy, sensitivity and specificity of a model based on these metabolites rather than on the whole binned spectrum, to evaluate the contribution of the other molecules. Response：We appreciate the reviewers' feedback. Regarding the accuracy, sensitivity, and specificity of the model composed of six metabolites in comparison to the entire classification spectrum for predicting CBO, we searched the HMDB for 1470 possible metabolites after obtaining 35 segments of chemical shifts with VIP values greater than 1 via PCA and PLS-DA analysis of the spectral matrix, of which 388 possible endogenous metabolites were detected in blood. According to the Jaccard value, the top 30 metabolites were selected. By comparing standard spectra with HMDB (1H NMR Spectrum [1D, 600 MHz, D2O, anticipated]), it was shown that 15 metabolites had the lowest peaks at chemical shifts that overlapped with the above 35 segments. Mnova software was used to determine the peak intensities of these 15 shifts separately, and a t-test revealed that the peak intensities of six shifts were substantially different. Six chemical shifts correspond to six metabolites, and the integrals of the lowest peak intensity are notably different S2 Table. We have revised the article in light of the reviewers' comments. (page 5, lines 2-28) 2. The NMR analysis was limited to the acquisition of CPMG spectra, thus excluding all lipoproteins components, which would help defining metabolic alterations. It is a common practice in 1H NMR metabolomics to use at least NOESY and CPMG experiments. Response：We appreciate your kind words. Due to financial and time constraints, we have only completed the 1H NMR test at this stage. We will use GC-MS or LC-MS for the mass spectrometry test verification of the above substances in the next stage. We have also revised the article in light of the reviewers' comments. (page 8, line 41) 3. The serum handling procedure are largely divergent with respect to ISO standards (ISO 23118:2021 Molecular in vitro diagnostic examinations — Specifications for pre-examination processes in metabolomics in urine, venous blood serum and plasma), which could in principle affect the outcome of the downstream metabolomics analysis. Possibly the adopted procedure does not influence the comparison between the two groups of patients enrolled in the same study, but it might affect the general applicability of the model. Response： Regarding the specimen handling process, we made an error expression: Because of the particularity of emergency patients (more admitted at night), our plan was to draw whole blood from the peripheral veins of all participants within 2 hours after admission, and used vacuum blood collection tubes to collect 3ml of whole blood for each participant (vacuum tube with blue cap without addition, 10.25mm×64mm, batch number 363095, American BD company), immediately put it in a refrigerator at -20℃, and centrifuge at 3000r/min for 15min within 48h, and took the supernatant , Transferred to EP tube, -80 ℃ refrigerator for refrigeration. But the actual operation was to draw 3ml of whole blood from the peripheral vein within 2 hours after admission into the tubes (Blue cap with sodium citrate, 10.25mm×64mm, batch number 363095, US BD company), centrifuged inside at 16000r/min for 15min in 30 minutes, took the supernatant, transferred to EP tube, and refrigerate at -80℃. After the specimens were collected, they were transferred to the laboratory to thaw at room temperature and transferred to a 5mm Wilmad NMR tube for on-board testing and analysis. Although the thawing temperature is different from that specified in ISO 23118:2021 and requires extended time detection, we believe that, while the serum handling procedures are different, the differences determined by the method based on the overall molecular magnetic resonance hydrogen spectroscopy profile are similar. That is, our method, PLS-DA, PCA, relies heavily on linear transformations to identify the components with the highest variation among the different grouped samples, and so is mostly unaffected by the aforementioned criteria. We have also revised the article in light of the reviewers' comments. (page 3, lines 22-29, 32-33; ) 4. It would be also important to know what has been administered to the patients in the time interval between admission and blood collection (e.g. Ringer acetate solutions or contrast agents for imaging, and not just “drugs” affect the NMR metabolic profiles Response：Thank you very much for your advice. Within 48 hours, none of our patients had medical procedures (e.g., oral or intravenous administration, gastrointestinal decompression, enemas), with the exception of fasting and water fasting for >24 hours, which we included in our exclusion criteria. No patient received imaging examination using contrast agents, and no patient got intravenous or oral rehydration prior to specimen collection. We have already revised the article in light of the reviewers' comments. (page 2, lines 38,44; page 3, lines 1-3 ) 5. Formal aspects: Missing information: the data availability statement does not describe where the data can be found. Response：Thank you for your constructive comments. In accordance with the principles of medical ethics, the raw data of the desensitized papers can be downloaded at https://github.com/dcpengjin/metabolomics_data.git 6. Spelling: Throughout the text: 1H NMR Page 10, … 5 seconds Page 12 (Discussion), … between the two groups. Response： We appreciate the reviewers' helpful and constructive suggestions for grammar and spelling changes. All errors mentioned above have been corrected. We have already revised the article in light of the reviewers' comments. (page 1, lines 2,15; page 3, lines 41-42; page 6, lines 9,12,26) Attachments Attachment Submitted filename: Response to reviewer.docx https://doi.org/10.1371/journal.pone.0266730.r002
28 Feb 2022 Decision Letter - Oscar Millet, Editor PONE-D-21-25026R1Establishment of an early diagnosis model of colon cancerous bowel obstruction based on 1HNMRPLOS ONE Dear Dr. Peng, 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. Specifically, there are still a couple of points raised by the reviewer that require to be amended. Please submit your revised manuscript by Apr 14 2022 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Oscar Millet Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [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 #1: (No Response) ******** 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: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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: I believe the previous comments 1 and 2 have been misunderstood. 1. The question was very simple: what is the difference in prediction accuracy, sensitivity and specificity if the authors use the entire binned spectrum? This procedure does not require any assignment (for details see for example https://doi.org/10.1016/j.trac.2018.10.036). I invite the authors to test this approach. 2. I was suggesting to use 1H NMR NOESY spectra to derive information on the lipoprotein components (see Bruker IVDR tool; https://doi.org/10.1021/acs.analchem.8b02412), not to perform MS analyses. ****** 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 [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.] 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0266730.r003
Revision 2
19 Mar 2022 Author Response Response to academic editor： Your suggestions are really valuable and helpful for revising and improving our paper. According to your suggestions, we have made the following revisions on this manuscript: 1. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Response：Thank you for your detailed comments. We have reviewed our reference list thoroughly to ensure that it is complete and correct. we did not find any records about being retracted of these papers that we cited in the manuscript. In this revision, we cited another three papers.The amendments are highlighted in red in the revised manuscript.( lines195,216,339,424-427,498-500.) Response to reviewer #1: Your suggestions are really meaningful and useful for revising and improving this paper. According to your suggestions, we have made the following revisions on this manuscript: 1. The question was very simple: what is the difference in prediction accuracy, sensitivity and specificity if the authors use the entire binned spectrum? This procedure does not require any assignment (for details see for example https://doi.org/10.1016/j.trac.2018.10.036). I invite the authors to test this approach. Response： The papers you recommended are very valuable to us. We performed ROC analysis on the 6 metabolites which have significant differences between the two groups and the full-spectrum prediction model. According to the AUC value, the prediction accuracy of the full-spectrum model was higher. For the verified source code see: https://github.com/dcpengjin/metabolomics_data.git. We also have revised the article in light of the reviewers' comments. (lines 192-195) 2. I was suggesting to use 1H NMR NOESY spectra to derive information on the lipoprotein components (see Bruker IVDR tool; https://doi.org/10.1021/acs.analchem.8b02412), not to perform MS analyses. Response：Thank you very much for your professional advice and reminders. Our original purpose was to observe small molecules through a relatively faster 1H-NMR test. Due to the economic and time constraints, this study did not carry out NOESY test, so it was flawed in identifying lipoproteins, and the analysis of macromolecular proteins will be further discussed in future experiments. We have also revised the article in light of the reviewers' comments. (line 337-341) Attachments Attachment Submitted filename: Response to reviewer.docx https://doi.org/10.1371/journal.pone.0266730.r004
28 Mar 2022 Decision Letter - Oscar Millet, Editor Establishment of an early diagnosis model of colon cancerous bowel obstruction based on 1HNMR PONE-D-21-25026R2 Dear Dr. Peng, 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, Oscar Millet Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0266730.r005
Formally Accepted
6 Apr 2022 Acceptance Letter - Oscar Millet, Editor PONE-D-21-25026R2 Establishment of an early diagnosis model of colon cancerous bowel obstruction based on 1H NMR Dear Dr. Peng: 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. Oscar Millet Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0266730.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .