Automatic real-time analysis and interpretation of arterial blood gas sample for Point-of-care testing: Clinical validation

Sancho Rodríguez-Villar; Paloma Poza-Hernández; Sascha Freigang; Idoia Zubizarreta-Ormazabal; Daniel Paz-Martín; Etienne Holl; Osvaldo Ceferino Pérez-Pardo; María Sherezade Tovar-Doncel; Sonja Maria Wissa; Bonifacio Cimadevilla-Calvo; Guillermo Tejón-Pérez; Ismael Moreno-Fernández; Alejandro Escario-Méndez; Juan Arévalo-Serrano; Antonio Valentín; Bruno Manuel Do-Vale; Helen Marie Fletcher; Jesús Medardo Lorenzo- Fernández

doi:10.1371/journal.pone.0248264

Peer Review History

Original SubmissionOctober 29, 2020
4 Dec 2020 Decision Letter - Tai-Heng Chen, Editor PONE-D-20-32648 Automatic real-time analysis and interpretation of arterial blood gas for Point-of-Care testing: clinical validation PLOS ONE Dear Dr. Rodriguez-Villar, 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. 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. 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, Tai-Heng Chen, M.D. Academic Editor PLOS ONE Journal requirements: When submitting your revision, we need you to address these additional requirements. 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 at https://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 2. 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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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 Reviewer #2: 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 Reviewer #2: No ****** 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: Based on the results, the arterial blood gas algorithm (ABG-a) is practical for acute and critical care. Only one questions are needed for explanation and one suggestion are recommended. Question: Please explain the relatively low sensitivity in respiratory acidosis (61.1%), metabolic acidosis (75.8%), and metabolic alkalosis (72.2%). Suggestion: The data (median & IQR) from enrolled samples in Table 7 & 8 seem so normal. The reports of minimum and maximum levels of tests may be demonstrated, as a kind of description of the severity and variability of tested samples. Some errors need to correct. Table 4: Acute renal failure or acute on chronic renal failure � acute kidney injury or acute on chronic kidney disease Table 8: 4,1 --> 4.1 Line 352: 83,4%--> 83.4% Reviewer #2: In this manuscript, authors compare the results of an automated acid-base disturbance algorithm to the opinions of experienced physicians. Acid base disorders are complicated, integrating many clinical observations, diagnosis, and recent treatment history into a mechanism underlying physiological perturbations. Thus the clinical relevance of an algorithmic solution is established. As this manuscript is not describing the algorithm, but only its agreement with clinicians, there are some points that I think would add tremendous value to the work. Chief among them is a calculation of the interpretability of the algorithm. In machine learning, there are several tools that allow a user to test how a classification changes, among them ICE (individual continuous expectation) and partial dependence plots. These tools let you assess how a small change in one measurement would affect the algorithmic diagnosis. Other uncertainty quantification methods may be used instead, but some measure of interpretability may be useful. Additionally, reporting the global accuracy in this type of work is misleading. The dataset is unbalanced (many more negative cases that positive cases, for at least some of the choices of acid base disorder. Without knowledge of the actual numbers of diagnoses (how many negative, how many metabolic acidosis, etc) it is impossible to interpret global accuracy, and its difficult to assess the importance of poor performance on some disease states. I would request that the authors include the number of patients with each disorder; this would be part of the PLOS requirement that "all data be made available". Additionally, reporting a beta-weighted F-score may give a more interpretable level of global accuracy, with beta chosen to reflect the relative cost between a false negative and a false positive. There are some parts of the manuscript where English usage and idiom take away from the results being presented. Manuscript would be improved with editing. ****** 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 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.] 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.0248264.r001
Revision 1
18 Dec 2020 Author Response 12/12/20 REBUTTAL LETTER Dear Academic Editor and Reviewers, RE: PONE-D-20-32648 Automatic real-time analysis and interpretation of arterial blood gas for Point-of-Care testing: clinical validation Thank you for reviewing and providing feedback to the paper. We will try to answer all your comments in a rigorous fashion by order. Reviewer #1: Based on the results, the arterial blood gas algorithm (ABG-a) is practical for acute and critical care. Only one question are needed for explanation and one suggestion are recommended. Question: Please explain the relatively low sensitivity in respiratory acidosis (61.1%), metabolic acidosis (75.8%), and metabolic alkalosis (72.2%). From the eight acid-base disorders, only three of them have a sensitivity of less than 80%. In the diagnosis of acid-base disorders, there is really no diagnostic test considered as reference “Gold standard” except for an expert opinion. Firstly, it is very remarkable that only this relatively low sensitivity occurs with those acid-base disorders classified as “single” and not “complex” acid-base disorders. In our opinion based on the observations during the study, we can appreciate that the software is able to run calculations on extremely mild deranged values from the arterial blood gases, and therefore can obtain more refined conclusions than that of the clinicians. Also, the ABG-a follows the rules of certain values cutting points. The clinicians however only consider the presence of “complex” acid-base disturbances when the results are very obviously deranged. This approach from the clinicians maybe explained by many reasons, not least of all limited time for analysing every single ABG result in such a rigorous and complex manner. The diagnostic judgment of experienced clinicians has been taken as a reference test, which without denying its validity, can change from one clinician to another. Further studies in this regard would be necessary, after which it would be possible to consider our algorithm as a reference test. Secondly, those diagnosis made by the ABG-a as “complex” still include the primary diagnosis of “respiratory acidosis”, “metabolic acidosis” and “metabolic alkalosis”. Not only keeping the safety standards but also improving the diagnosis. We know that in the human physiology, the presence of disturbances are complex and frequently not simple, making the ABG-a of great value in order to help with a more refined diagnosis. Suggestion: The data (median & IQR) from enrolled samples in Table 7 & 8 seem so normal. The reports of minimum and maximum levels of tests may be demonstrated, as a kind of description of the severity and variability of tested samples. We could understand that the suggestion relates to utilising means and standard deviations as opposed to medians and interquartile ranges because this form still present in some publications, but asking for the maximum and minimum values to describe and represent a quantitative variable is in our opinion inappropriate. The current trend is to describe quantitative values with median and interquartile range because they do not require compliance with normality; they are very robust, represent the data well and are not affected by the presence of extreme values. On the contrary, if they were described with the range and the minimum and maximum values, the representativeness of the data would be violated since those minimum and maximum values are usually atypical and remote values. Some errors need to correct: Table 4: Acute renal failure or acute on chronic renal failure � acute kidney injury or acute on chronic kidney disease Table 8: 4,1 --> 4.1 Line 352: 83,4%--> 83.4% We agree and these errors have been corrected on the manuscript. Reviewer #2: Additionally, reporting the global accuracy in this type of work is misleading. The dataset is unbalanced (many more negative cases than positive cases, for at least some of the choices of acid base disorder. Without knowledge of the actual numbers of diagnoses (how many negative, how many metabolic acidosis, etc) it is impossible to interpret global accuracy, and it is difficult to assess the importance of poor performance on some disease states. I would request that the authors include the number of patients with each disorder; this would be part of the PLOS requirement that "all data be made available". Additionally, reporting a beta-weighted F-score may give a more interpretable level of global accuracy, with beta chosen to reflect the relative cost between a false negative and a false positive. We agree that reporting global accuracy can be misleading and that reporting the frequency of each of the acid-base disorders helps with interpretation of the data. Table 10 has been modified to include a column with the number of cases of each of the acid-base disorders. It is observed that since there are fewer positive than negative cases, the sensitivity values are lower than those of specificity and the 95% CIs are wider in sensitivity and narrower in specificity. By reporting the global accuracy together with the sensitivity and specificity as well as the frequency of each disorder, as reflected in the modified table 10, there is less misunderstanding. The beta-weighted F-score could have been used as suggested, although it has the drawbacks that it ignores true negatives in its calculation and assigns equal importance to precision and recall. In our work we have chosen the analysis of reliability with the kappa index and accuracy with sensitivity, specificity and, together with them, and not in isolation, the global accuracy. 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. We are agreed as authors to be published our article peer review history Best regards Dr Sancho Rodriguez-Villar Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0248264.r002
5 Feb 2021 Decision Letter - Tai-Heng Chen, Editor PONE-D-20-32648R1 Automatic real-time analysis and interpretation of arterial blood gas for Point-of-Care testing: clinical validation PLOS ONE Dear Dr. Rodriguez-Villar, 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. Please submit your revised manuscript by Mar 22 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, Tai-Heng Chen, M.D. Academic Editor PLOS ONE 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 #3: 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: Partly Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: I Don't Know ****** 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 #3: No ****** 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 #3: 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: (No Response) Reviewer #3: I think this paper is very interesting and well written. But, I have only one serious concern. According to Tables 7 and 8, both median and IQR are in the normal range. What are the values of the raw data that is the basis of this analysis? The author should show raw blood gas data as shown in PLOS Data policy. ****** 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 #3: 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.0248264.r003
Revision 2
9 Feb 2021 Author Response 06/02/21 REBUTTAL LETTER Dear Academic Editor and Reviewers, RE: PONE-D-20-32648 Automatic real-time analysis and interpretation of arterial blood gas for Point-of-Care testing: clinical validation Thank you for reviewing and providing feedback to the paper. We will try to answer all your comments in a rigorous fashion by order. 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: (No Response) Reviewer #3: I think this paper is very interesting and well written. But, I have only one serious concern. According to Tables 7 and 8, both median and IQR are in the normal range. What are the values of the raw data that is the basis of this analysis? The author should show raw blood gas data as shown in PLOS Data policy. Anonymous raw blood gas data showed as per PLOS Data policy. Please, see attached . Best regards Dr Sancho Rodriguez-Villar Attachments Attachment Submitted filename: Response to Reviewers 09_02_21.docx https://doi.org/10.1371/journal.pone.0248264.r004
17 Feb 2021 Decision Letter - Tai-Heng Chen, Editor PONE-D-20-32648R2 Automatic real-time analysis and interpretation of arterial blood gas for Point-of-Care testing: clinical validation PLOS ONE Dear Dr. Rodriguez-Villar, 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. Please submit your revised manuscript by Apr 03 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, Tai-Heng Chen, M.D. Academic Editor PLOS ONE 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 #3: 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: 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 #3: 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 #3: 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 #3: My concerns have been resolved. But, I don't know if the raw blood gas data does not have to be attached to the Manuscript. Leave it to the editor's judgment. ****** 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 #3: 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.0248264.r005
Revision 3
21 Feb 2021 Author Response Dear Editor, We are delighted that the Reviewer found our work to be of interest and value. We are grateful to him/her for taking time to comment on our manuscript and address each of the queries on a point-by-point basis. We think that the amended manuscript is improved and do very much hope that it is now considered acceptable for publication. Our answers to the comment from Reviewer #3: follow below. Reviewer #3: My concerns have been resolved. But I don't know if the raw blood gas data does not have to be attached to the Manuscript. Leave it to the editor's judgment. Answer: From us there is no problem to add the raw arterial blood gas data. As authors we give consent and we leave that decision to the Editor-in -Chief. Many thanks for your time. Dr. Sancho Rodríguez-Villar Honorary Senior Clinical Lecturer Department of Basic and Clinical Neuroscience. Institute of Psychiatry, Psychology & Neuroscience (IoPPN) Academic Neuroscience Centre, London SE5 8AF, UK T: 0207 848 0293 Attachments Attachment Submitted filename: Response to Reviewers 09_02_21.docx https://doi.org/10.1371/journal.pone.0248264.r006
24 Feb 2021 Decision Letter - Tai-Heng Chen, Editor Automatic real-time analysis and interpretation of arterial blood gas for Point-of-Care testing: clinical validation PONE-D-20-32648R3 Dear Dr. Rodriguez-Villar, 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, Tai-Heng Chen, M.D. Academic Editor PLOS ONE 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 #3: 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: 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 #3: 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 #3: 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 #3: My concerns have been resolved. But I don't know if the raw blood gas data does not have to be attached to the Manuscript. Leave it to the editor's judgment. ****** 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 #3: No https://doi.org/10.1371/journal.pone.0248264.r007
Formally Accepted
25 Feb 2021 Acceptance Letter - Tai-Heng Chen, Editor PONE-D-20-32648R3 Automatic real-time analysis and interpretation of arterial blood gas sample for Point-of-Care testing: clinical validation Dear Dr. Rodriguez-Villar: 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. Tai-Heng Chen Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0248264.r008

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