O group is a protective factor for COVID19 in Basque population

Maider Muñoz-Culla; Andres Roncancio-Clavijo; Bruno Martínez; Miriam Gorostidi-Aicua; Luis Piñeiro; Arkaitz Azkune; Ainhoa Alberro; Jorge Monge-Ruiz; Tamara Castillo-Trivino; Alvaro Prada; David Otaegui

doi:10.1371/journal.pone.0249494

Peer Review History

Original SubmissionNovember 16, 2020
4 Dec 2020 Decision Letter - Raffaele Serra, Editor PONE-D-20-36036 O Group is a protective factor for COVID19 in Basque population PLOS ONE Dear Dr. Otaegui, 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 article is interesting but it needs some extra work before it can be accepted. Please submit your revised manuscript by Jan 18 2021 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. 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To comply with PLOS ONE submission guidelines, in your Methods section, please provide additional information regarding your statistical analyses and ensure you have included (1) the name and version of any software package used, alongside any relevant references, (2) the technical details or procedures required to reproduce the analysis . For more information on PLOS ONE's expectations for statistical reporting, please see https://journals.plos.org/plosone/s/submission-guidelines.#loc-statistical-reporting. 4.Thank you for stating in your Funding Statement: [This project has been partially supported by Instituto de Salud Carlos III (COV20/00314).]. Please provide an amended statement that declares all the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf. Additional Editor Comments (if provided): The article is potentially interesting but some concerns need to be addressed. [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: Yes ******** 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: Yes ****** 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 study, the authors compare the distributions of blood group types in (apparently) symptomatic COVID19 patients diagnosed in Gipuzkoa (Basque country, Spain) with the distributions of blood group types found in the general population, as inferred from a local Basque blood bank. They conclude that O blood group is protective, whereas A blood group is a risk factor. This study joins a handful of others, from various parts of the world, confirming an influence of blood group on vulnerability to COVID19 infection. I have a few suggestions for the authors to consider: 1. In the abstract, I would suggest moving what is currently the second sentence (the call for replication of the work in different regions of the world) to the end of the abstract text, after the main results have been presented. I would also encourage the authors to give, in the abstract, some quantification of the degree of protection conferred by group O blood (e.g, the odds ratio). 2. The authors state that all patients had tested positive for SARS-CoV-2 infection at Donostia University Hospital “according to the actual guidelines.” Could they please describe briefly those guidelines? Were these patients symptomatic, asymptomatic, or a mix of the two? Later, in the results, it appears that all the COVID patients had some level of clinical symptoms, but it would be good to clarify that asymptomatic individuals were excluded from the study, if that is indeed the case. 3. The results section states “According with the literature, in our data group A is more frequent in COVID19 patients (48.3% . . . )”; the authors need to be explicit that they are comparing this with the frequency of group A in the general Basque population. 4. I think the authors could add value to their paper by testing whether blood groups A, B, and AB differ from each other in terms of susceptibility to COVID infection. The authors emphasize group A, but it seems like group B might be still more susceptible, and AB perhaps the most susceptible. 5. The authors state that “No difference has been found in ABO group distribution with severity”, but the readers cannot evaluate this claim, because the data are not shown. I would encourage the authors to include the data broken down into severity categories, along with some formal statistical analysis of disease severity effects. This could be done in an on-line electronic supplement if the authors don’t wish to include it in the main text of the manuscript. 6. The manuscript needs a final light editing to correct numerous small problems with English grammar. (I would have called some of these out, but my copy of the manuscript does not have line numbers.) ****** 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.0249494.r001
Revision 1
26 Jan 2021 Author Response POINT-BY-POINT RESPONSE TO THE REVIEWERS Reviewer #1 In this study, the authors compare the distributions of blood group types in (apparently) symptomatic COVID19 patients diagnosed in Gipuzkoa (Basque country, Spain) with the distributions of blood group types found in the general population, as inferred from a local Basque blood bank. They conclude that O blood group is protective, whereas A blood group is a risk factor. This study joins a handful of others, from various parts of the world, confirming an influence of blood group on vulnerability to COVID19 infection. I have a few suggestions for the authors to consider: 1. In the abstract, I would suggest moving what is currently the second sentence (the call for replication of the work in different regions of the world) to the end of the abstract text, after the main results have been presented. I would also encourage the authors to give, in the abstract, some quantification of the degree of protection conferred by group O blood (e.g, the odds ratio). We thank to the reviewer for this comment. As suggested we change the abstract and add the required information. 2. The authors state that all patients had tested positive for SARS-CoV-2 infection at Donostia University Hospital “according to the actual guidelines.” Could they please describe briefly those guidelines? Were these patients symptomatic, asymptomatic, or a mix of the two? Later, in the results, it appears that all the COVID patients had some level of clinical symptoms, but it would be good to clarify that asymptomatic individuals were excluded from the study, if that is indeed the case. Thanks for the comment. We added this information to the method section of the manuscript to clarify that all the COVID19 patients included in the study were symptomatic and how the positivity for the virus was tested. Approved SARS_CoV-2 qPCR test has been performed for all the samples at Microbiology department in the Donostia University Hospital. The moment in which all data for this study were retrieved, was a moment in the pandemic in which all the patients that came to the Hospital were Symptomatic. 3. The results section states “According with the literature, in our data group A is more frequent in COVID19 patients (48.3% . . . )”; the authors need to be explicit that they are comparing this with the frequency of group A in the general Basque population. Thanks for notice it. We have added this to the manuscript and have rewritten the sentence to avoid any misunderstanding. 4. I think the authors could add value to their paper by testing whether blood groups A, B, and AB differ from each other in terms of susceptibility to COVID infection. The authors emphasize group A, but it seems like group B might be still more susceptible, and AB perhaps the most susceptible. We change our results section adding tests for each group. 5. The authors state that “No difference has been found in ABO group distribution with severity”, but the readers cannot evaluate this claim, because the data are not shown. I would encourage the authors to include the data broken down into severity categories, along with some formal statistical analysis of disease severity effects. This could be done in an on-line electronic supplement if the authors don’t wish to include it in the main text of the manuscript. We add in Table 1 a distribution of the ABO groups with severity. 6. The manuscript needs a final light editing to correct numerous small problems with English grammar. (I would have called some of these out, but my copy of the manuscript does not have line numbers.) Thanks to the reviewer for the comment. We have reviewed the manuscript and polish the language, so we hope that now the English grammar is correct. Attachments Attachment Submitted filename: reponse to the reviewers_ABOgroups_MMC.docx https://doi.org/10.1371/journal.pone.0249494.r002
9 Feb 2021 Decision Letter - Raffaele Serra, Editor PONE-D-20-36036R1 O Group is a protective factor for COVID19 in Basque population PLOS ONE Dear Dr. Otaegui, 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 manuscript was improved but it needs further revision as suggested by the reviewer. Please submit your revised manuscript by Mar 26 2021 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, Prof. Raffaele Serra, M.D., Ph.D Academic Editor PLOS ONE Additional Editor Comments (if provided): While the manuscript was improved it needs further reworking. [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: No ****** 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 reviewed this manuscript previously, so my current reading emphasized looking for changes since the first draft. The reviewers successfully implemented many changes, and I think this revision is improved. I do think, however, that given that the new analyses shown in Table 1 now show that blood types B and AB are even greater risk factors than blood type A, the rest of the discussion in the manuscript (which emphasizes effects of blood group A and ignores B and AB) seems now incomplete and not quite appropriate. I would encourage the authors to modify the discussion to reflect their results: O is protective, and A and especially B are risk factors. The authors also mention in passing that there seems to be a higher risk of infection for men. If they wish to make this point, I think they should support it with some sort of quantitative statistical test. Given that men and women may have different exposures to infection or different likelihoods of seeking medical care when sick, I don’t know how strong the evidence in Table 1 really is with regards to effects of sex. I’d encourage the authors to make a decision to either (1) choose to introduce the question of differential vulnerability to infection, and then formally test it, or (2) omit the issue altogether, and instead focus only on blood group. (Option 2 might be the best, but it’s really up to the authors.) The manuscript still does not have line numbers, making it very difficult for me to suggest fixes to small grammatical errors. The paper still needs a final editing to correct numerous small problems. ****** 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.0249494.r003
Revision 2
2 Mar 2021 Author Response POINT-BY-POINT RESPONSE TO THE REVIEWER Reviewer #1 Reviewer #1: I reviewed this manuscript previously, so my current reading emphasized looking for changes since the first draft. The reviewers successfully implemented many changes, and I think this revision is improved. We want to thanks the reviewer by her/his help to improve our manuscript. I do think, however, that given that the new analyses shown in Table 1 now show that blood types B and AB are even greater risk factors than blood type A, the rest of the discussion in the manuscript (which emphasizes effects of blood group A and ignores B and AB) seems now incomplete and not quite appropriate. I would encourage the authors to modify the discussion to reflect their results: O is protective, and A and especially B are risk factors. We agree with the reviewer that blood type B and even AB seems to be risk factor, however me try to focus our discussion in A and O group that are the two more represented in our patient’s population. Blood type B is only present in 36 patients and AB in 16 and that why we focus in the other 2 blood groups. We change our discussion to include the observation about B and AB group. The authors also mention in passing that there seems to be a higher risk of infection for men. If they wish to make this point, I think they should support it with some sort of quantitative statistical test. Given that men and women may have different exposures to infection or different likelihoods of seeking medical care when sick, I don’t know how strong the evidence in Table 1 really is with regards to effects of sex. I’d encourage the authors to make a decision to either (1) choose to introduce the question of differential vulnerability to infection, and then formally test it, or (2) omit the issue altogether, and instead focus only on blood group. (Option 2 might be the best, but it’s really up to the authors.) Thanks to the reviewer for this comment. We thought that could be interesting for the readers to have the data by gender but we are totally agree with the reviewer that with our experimental design we cannot say that men shows a higher infection and may be the data can reflect the effect of other issues. Therefore, to focus in the point that we think is more interesting, we rewrite the paragraph and the Table 1 to show just the data from patients vs controls. The manuscript still does not have line numbers, making it very difficult for me to suggest fixes to small grammatical errors. The paper still needs a final editing to correct numerous small problems. The manuscript has been reviewed by different persons to correct the grammatical problems and do it more readable. Line numbers had been included. https://doi.org/10.1371/journal.pone.0249494.r004
19 Mar 2021 Decision Letter - Raffaele Serra, Editor O Group is a protective factor for COVID19 in Basque population PONE-D-20-36036R2 Dear Dr. Otaegui, 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, Prof. Raffaele Serra, M.D., Ph.D Academic Editor PLOS ONE Additional Editor Comments (optional): amended manuscript is acceptable 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 ******** 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 ****** 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 think the revision is very successful in providing a more balanced discussion of the risk associated with A, B, and AB blood groups. ****** 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 https://doi.org/10.1371/journal.pone.0249494.r005
Formally Accepted
29 Mar 2021 Acceptance Letter - Raffaele Serra, Editor PONE-D-20-36036R2 O Group is a protective factor for COVID19 in Basque population Dear Dr. Otaegui: 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 Prof. Raffaele Serra Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0249494.r006

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