Trajectory of the arterial-alveolar oxygen gradient in COPD for a decade

Kazuma Nagata; Susumu Sato; Kiyoshi Uemasu; Naoya Tanabe; Atsuyasu Sato; Shigeo Muro; Toyohiro Hirai

doi:10.1371/journal.pone.0318377

Peer Review History

Original SubmissionMay 17, 2024
27 Dec 2024 Decision Letter - Alonso Soto, Editor PONE-D-24-19081Trajectory of the Arterial-Alveolar Oxygen Gradient in COPD for a decadePLOS ONE Dear Dr. Sato, 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 Feb 10 2025 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, Alonso Soto, PhD 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. Thank you for stating the following financial disclosure: “This work was supported by JSPS KAKENHI Grant Numbers 19K08624, 16K09536, 25461156, 21590964, 16390234, JP22K11391 and JP22H04411. This research was also supported by grants from the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group of the Ministry of Health, Labour and Welfare of Japan (JPMH20FC1027, JPMH23FC1031).” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. Thank you for stating the following in the Competing Interests section: “S.S. reports a grant from Nippon Boehringer Ingelheim Co. and grants from Philips-Respironics, Fukuda Denshi, Fukuda Lifetec Keiji, and ResMed that did not pertain to the submitted work. K.N. reports a honoraria for lectures at Teijin Healthcare unrelated to the submitted work. S.M. reports a grant from ROHTO Pharmaceutical unrelated to submitted work.” Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. 4. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Before we proceed with your manuscript, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. Please update your Data Availability statement in the submission form accordingly. Additional Editor Comments: SUMMARY Abbreviations should be mentioned in full the first time they are cited (COPD, LTOT) Background:please change the phrase "CRF is a vital pathophysiology in patients with COPD... MEASUREMENTS: How LTOT need was assessed? TABLES use only 3 decimals for p values. RESULTS Line 188 A-aDO2 refers to baseline values? Delta A-aDO2 represents the change after 1 year? Please explain it [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 Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No 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: 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 Reviewer #2: 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: Congratulations to the Authors: Overall, the manuscript adheres well to the STROBE checklist. It provides a comprehensive examination of the arterial-alveolar oxygen gradient (A-aDO2) trajectory in COPD patients, with an emphasis on its potential as a prognostic marker for chronic respiratory failure. The manuscript could improve by adding details about sample size calculations, bias mitigation strategies, and a clearer acknowledgment of funding sources. However, it successfully addresses most aspects of the STROBE checklist, making it a well-structured and methodologically sound observational study. Congratulations on an important contribution to the field. Major Observations: 1. Sample Size (STROBE Item 10): The manuscript does not provide any sample size calculation or justification for how the sample size was determined. This is critical for validating the statistical power of the study and ensuring that the sample size is sufficient to detect significant differences in outcomes. The absence of this analysis raises concerns about the reliability of the results and their generalizability. 2. Bias (STROBE Item 9): Although potential biases, such as missing data at later follow-up points, are briefly mentioned in the discussion, the methods section lacks a thorough explanation of how these biases were addressed. Specifically, the manuscript should provide more detail on how missing data were handled and what steps were taken to minimize selection bias in the patient cohort. 3. Study Design and Timeline Clarity (STROBE Items 5 and 6a): The description of the study design could benefit from greater clarity regarding the timing of follow-up assessments. While it is mentioned that arterial blood gas (ABG) analysis was performed annually, a more detailed explanation of the exact timing of assessments and how they align with patient visits, exacerbations, or disease progression would improve the understanding of the study's longitudinal design. Reviewer #2: explain more in discussion what it `s the impact to the country where they develop the research. the topic is interesting , an introduction apropiate . acceptable methodology and statistics. table of results presented according to international standards ****** 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: Yes: Johan Azañero-Haro 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.0318377.r001
Revision 1
2 Jan 2025 Author Response Response to the Editor SUMMARY Abbreviations should be mentioned in full the first time they are cited (COPD, LTOT) Thank you for your comment. Response: We have revised this as suggested. Background: please change the phrase "CRF is a vital pathophysiology in patients with COPD… Response: Following your suggestion, we revised the relevant sentence as follows: "Chronic respiratory failure (CRF) is a critical complication in patients with chronic obstructive pulmonary disease (COPD) and is characterized by an increase in the arterial-alveolar oxygen gradient (A-aDO2)." MEASUREMENTS: How LTOT need was assessed? Response: Thank you for pointing this out. The attending physician determined the need for long-term oxygen therapy (LTOT) based on the patient's clinical condition. This decision was primarily guided by the presence of progressive resting hypoxemia, defined as an arterial oxygen tension (PaO₂)≤55 Torr or a percutaneous oxygen saturation (SpO₂)≤88%. We have included this information in the revised manuscript to clarify the assessment process. TABLES use only 3 decimals for p values. Response: We have revised this as suggested. RESULTS Line 188 A-aDO2 refers to baseline values? Delta A-aDO2 represents the change after 1 year? Please explain it Response: Thank you for your comment. To clarify, we have revised the text to define explicitly A-aDO₂ and ΔA-aDO₂. The updated text now reads: "In the multivariate model, which included factors believed to be predictors of CRF development in COPD patients (e.g., KCO, FEV1, age, body mass index (BMI), and smoking index), both baseline A-aDO₂ and ΔA-aDO₂ (change over the first year) were found to be significantly associated with CRF development." Response to the Reviewer #1 Congratulations to the Authors: Overall, the manuscript adheres well to the STROBE checklist. It provides a comprehensive examination of the arterial-alveolar oxygen gradient (A-aDO2) trajectory in COPD patients, with an emphasis on its potential as a prognostic marker for chronic respiratory failure. The manuscript could improve by adding details about sample size calculations, bias mitigation strategies, and a clearer acknowledgment of funding sources. However, it successfully addresses most aspects of the STROBE checklist, making it a well-structured and methodologically sound observational study. Congratulations on an important contribution to the field. Major Observations: 1. Sample Size (STROBE Item 10): The manuscript does not provide any sample size calculation or justification for how the sample size was determined. This is critical for validating the statistical power of the study and ensuring that the sample size is sufficient to detect significant differences in outcomes. The absence of this analysis raises concerns about the reliability of the results and their generalizability. Response: Thank you for highlighting this point. Although a formal sample size calculation was not performed before the study due to its retrospective nature, we conducted a post-hoc sample size analysis using the observed data from the present study. Using the observed means and standard deviations (CRF group: 3.76 ± 5.24 Torr/year; non-CRF group: 0.42 ± 6.65 Torr/year), we calculated the required sample size to detect a significant difference with α=0.05 and β=0.2. The analysis indicated that approximately 51 subjects per group (a total of 101 subjects) would be needed to achieve sufficient statistical power. Since our study included 157 subjects, we consider the sample size adequate to detect significant differences. We have added this explanation to the manuscript. Bias (STROBE Item 9): Although potential biases, such as missing data at later follow-up points, are briefly mentioned in the discussion, the methods section lacks a thorough explanation of how these biases were addressed. Specifically, the manuscript should provide more detail on how missing data were handled and what steps were taken to minimize selection bias in the patient cohort. Response: Thank you for your comment. We included only completers in the non-CRF group to address potential biases related to missing data. We performed the analyses restricted to patients with at least three evaluations during the stable phase (5-10 years) and the deterioration phase (0-5 years). These analyses, detailed in Table S2, showed consistent results with our primary findings, supporting the robustness of our conclusions. We have incorporated this information into the Limitation section to provide transparency about how missing data were managed. Study Design and Timeline Clarity (STROBE Items 5 and 6a): The description of the study design could benefit from greater clarity regarding the timing of follow-up assessments. While it is mentioned that arterial blood gas (ABG) analysis was performed annually, a more detailed explanation of the exact timing of assessments and how they align with patient visits, exacerbations, or disease progression would improve the understanding of the study's longitudinal design. Response: Thank you for your valuable comment. To clarify the timing of follow-up assessments, we have revised the Measurements section to provide more detailed information. Specifically, we now explain that ABG analyses were scheduled annually, with the first follow-up conducted one year after baseline. Subsequent assessments were aligned with stable phases, defined as at least four weeks after recovery from any exacerbation, to minimize variability due to acute changes. These revisions improve the clarity of the study design and timeline. Response to the Reviewer #2 explain more in discussion what it’s the impact to the country where they develop the research. the topic is interesting, an introduction appropriate. acceptable methodology and statistics. table of results presented according to international standards Response: Thank you for your insightful comment. To address this, we have added a statement in the Limitation section to emphasize the relevance of our findings to Japan. Specifically, we noted that the Japanese Respiratory Society (JRS) guidelines currently lack specific recommendations regarding the timing of ABG measurements or the clinical significance of A-aDO₂. Our findings highlight the potential importance of establishing such recommendations to improve the prediction and management of CRF progression in Japan. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0318377.r002
15 Jan 2025 Decision Letter - Alonso Soto, Editor Trajectory of the Arterial-Alveolar Oxygen Gradient in COPD for a decade PONE-D-24-19081R1 Dear Dr. Sato, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Alonso Soto, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0318377.r003
Formally Accepted
20 Jan 2025 Acceptance Letter - Alonso Soto, Editor PONE-D-24-19081R1 PLOS ONE Dear Dr. Sato, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Alonso Soto Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0318377.r004

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 .