The added value of right ventricular function normalized for afterload to improve risk stratification of patients with pulmonary arterial hypertension

Marco Vicenzi; Sergio Caravita; Irene Rota; Rosa Casella; Gael Deboeck; Lorenzo Beretta; Andrea Lombi; Jean-Luc Vachiery

doi:10.1371/journal.pone.0265059

Peer Review History

Original SubmissionJuly 13, 2021
20 Aug 2021 Decision Letter - James West, Editor PONE-D-21-22876 The added value of right ventricular function normalized for afterload to improve risk stratification of patients with pulmonary arterial hypertension PLOS ONE Dear Dr. Vicenzi, 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. Both reviewers had areas where they thought clarification was needed, and potentially inclusion of additional data which you're likely to already have in hand. Please submit your revised manuscript by Oct 04 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. 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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: 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: 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: Title : The added value of right ventricular function normalized for afterload to improve risk stratification of patients with pulmonary arterial hypertension Authors : Vicenzi M et al. Comments In the introduction and in abstract, the authors have repeatedly stated that the current risk stratification scores do not include echo cardiographic parameters. I don’t think this statement is totally correct. I agree that the echo/ imaging parameters have not been included as much we want them to be, but REVEAL has pericardial effusion and ESC/ERS has RA area in them. Thus, I would suggest changing the introduction to state something like only limited imaging parameters have been included which do not reflect the comprehensive view of the RV function. Methods: The study includes patients from over 15 years. There is no mention of how these patients were included, selected or all patients with IPAH or HPAH. Consecutive patients with regular follow up? How did they account for patients who were lost to follow up or whose outcome data was not available? “All non-invasive tests were performed within 14 days, without changes in treatments or patients’ conditions” this statement need clarity, 14 days of what? 14 days of stable therapy? That’s generally a very short period to consider stability on therapy Also methods section, describes the methods of each testing ie echo, RHC, walk test etc but it doesn’t describe study design. For example, how these patients were selected? If a patient had multiple serial echo’s and walk test or CPET studies, how did the authors decide which echo to review or which walk test to include or CPET. Or they included all patients with all of their testings? “To control for any residual learning effect, the second of two tests performed on at least 2 separate days was used for the present study.” Above statement need clarification. Since it’s a retrospective study, these tests are standard of care, so how did they have walk tests done at two different days? My understanding is, as a part of routine follow ups patients generally perform one walk test. Results: RHC and CPET data are not directly relevant to the central focus of the study. So I would suggest to put in as supplementary data Results are not flowing well. It is very confusing in the way its currently written. I understand the message but the presentation is very confusing. Again, there is no mention that these echo and all other parameters are baseline? Ie diagnostic or the follow ups How did the authors come up with the cut of 3.74 for TAPSE/TRV ratio? In the French analysis, without echo, the authors are saying 15 with 4/3 low risk criteria vs 2/1/0 low risk had no difference in outcomes ? explain this. AUC of the TAPSE/TRV is very low—so without the risk score if someone uses it as stand alone parameter, it doesn’t have much predictive value. Is it possible for the authors to combine the TAPSE/TRV ratio with the average compera score and compare it with COMPERA score alone to predict outcome Discussion is nicely written. Reviewer #2: The article is very good and I am sure that many people will read and use it. Abstract: Usually, the audience should find out your most important findings by reading the abstract, while you have generalized in the this part and have not mentioned any number or cut point. By inserting this part, the summary of the article will be more complete and better. In addition, your abstract is not structured. Introduction: If you find it appropriate, explain a little more about the study of COMPERA and the French PNH and its classifications, so that the audience does not have to refer to other data articles to understand the content from the beginning. Discussion: In the section on discussing the characteristics of people according to the TAPSE / sPAP ratio, although what you are looking for is understandable, but like the data in Table 4, you did not provide a separate table for this ratio and Cutpoint 0.24, and did not explain. which it is appropriate to give a similar tabular data or give an explanation in this regard. ****** 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:** Sandeep Sahay 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.0265059.r001
Revision 1
6 Nov 2021 Author Response We would thank the reviewers for their thoughtful comments that helped us to revise and hopefully improve our work. Please find below a point-by-point answers and the respective changes in the manuscript. Reviewer #1: - In the introduction and in abstract, the authors have repeatedly stated that the current risk stratification scores do not include echo cardiographic parameters. I don’t think this statement is totally correct. I agree that the echo/ imaging parameters have not been included as much we want them to be, but REVEAL has pericardial effusion and ESC/ERS has RA area in them. Thus, I would suggest changing the introduction to state something like only limited imaging parameters have been included which do not reflect the comprehensive view of the RV function. A: We thank the reviewer for this comment. We agree that echocardiography is took in account in REVEAL and in ESC/ERS risk stratification. However, echocardiography is not included in the simplified risk algorithms proposed by COMPERA or the French network. This has been clarified in the text. - Methods: The study includes patients from over 15 years. There is no mention of how these patients were included, selected or all patients with IPAH or HPAH. Consecutive patients with regular follow up? How did they account for patients who were lost to follow up or whose outcome data was not available? A: Thank you for this important comment. Our center has used echocardiography and biomarkers since the beginning. We have now detailed the selection of patients. - “All non-invasive tests were performed within 14 days, without changes in treatments or patients’ conditions” this statement need clarity, 14 days of what? 14 days of stable therapy? That’s generally a very short period to consider stability on therapy A: This point is now simplified and clarified. All non-invasive tests were executed up to 14 days after changes of medical therapy. We therefore believe this is unlikely to affect our results. - Also methods section, describes the methods of each testing ie echo, RHC, walk test etc but it doesn’t describe study design. For example, how these patients were selected? If a patient had multiple serial echo’s and walk test or CPET studies, how did the authors decide which echo to review or which walk test to include or CPET. Or they included all patients with all of their testings? A: Thank you for this comment. The text is now updated, and the patients’ selection is detailed. - “To control for any residual learning effect, the second of two tests performed on at least 2 separate days was used for the present study.” Above statement need clarification. Since it’s a retrospective study, these tests are standard of care, so how did they have walk tests done at two different days? My understanding is, as a part of routine follow ups patients generally perform one walk test. A: We thank the reviewer for this important comment. As stated in a previous response, our center has adopted the standards of clinical trials since the late 90’S. Therefore, all patients underwent a first learning/training test and a second one that was used for the present study. This approach is known to limiting the risk of possible bias. We have clarified the text. - Results: RHC and CPET data are not directly relevant to the central focus of the study. So I would suggest to put in as supplementary data A: Thanks for this suggestion. We have built S1 Table. - Results are not flowing well. It is very confusing in the way its currently written. I understand the message but the presentation is very confusing. Again, there is no mention that these echo and all other parameters are baseline? Ie diagnostic or the follow ups How did the authors come up with the cut of 3.74 for TAPSE/TRV ratio? A: We thank the reviewer for this comment. Optimal cut-point was calculated via Contal and O’Quingley’s analysis. We have now specified in the text. - In the French analysis, without echo, the authors are saying 15 with 4/3 low risk criteria vs 2/1/0 low risk had no difference in outcomes ? explain this. A: Thanks for this comment. The FPHN strategy was able to separate patients with 4/3 low criteria from those with 2/1/0 low criteria. As now reported in the text we detailed the results and we specified that no significant difference was found among the two groups with 4 or 3 low criteria and among the three groups with 2, 1 or 0 criteria. - AUC of the TAPSE/TRV is very low—so without the risk score if someone uses it as stand alone parameter, it doesn’t have much predictive value. A: Thank you for this important comment. We performed ROC analysis in order to compare TAPSE, TAPSE/TRV and TAPSE/sPAP as marker of contractility, the former, and surrogate of RV-PA coupling, the last two. We agree that AUCs were absolutely low for TAPSE/TRV and TAPSE/sPAP, however relatively to TAPSE they were bigger and obtained a significant p value. In our analysis TAPSE/TRV or TAPSE/sPAP have not been considered as prognostic marker standing alone, but added as “second-step analysis” to COMPERA and FPHN strategies. On the other hand, we did not suggest to use TAPSE/TRV or TAPSE/sPAP alone, and moreover they may be included in a multiparameter approach. - Is it possible for the authors to combine the TAPSE/TRV ratio with the average compera score and compare it with COMPERA score alone to predict outcome. A: We thank the reviewer for this suggestion. We performed the analysis as here reported. However, TAPSE/TRV was not able to further separate patient at high-risk (high-high vs high-low, blue line vs green line. Chi2 1.628, log rank 0.202). We did not apply the TAPSE/TRV stratification to group at low-risk because of the absence of events (n=4, survival 100%). Discussion is nicely written. We would like to thank the reviewer for her/his appreciation of our manuscript. Reviewer #2: The article is very good and I am sure that many people will read and use it. - Abstract: Usually, the audience should find out your most important findings by reading the abstract, while you have generalized in the this part and have not mentioned any number or cut point. By inserting this part, the summary of the article will be more complete and better. In addition, your abstract is not structured. A: We would like to thank the reviewer for her/his kind words. We have written abstract and structured as requested. - Introduction: If you find it appropriate, explain a little more about the study of COMPERA and the French PNH and its classifications, so that the audience does not have to refer to other data articles to understand the content from the beginning. A: The text is now updated: COMPERA and FPHN registries are now better described. - Discussion: In the section on discussing the characteristics of people according to the TAPSE / sPAP ratio, although what you are looking for is understandable, but like the data in Table 4, you did not provide a separate table for this ratio and Cutpoint 0.24, and did not explain. which it is appropriate to give a similar tabular data or give an explanation in this regard. A: Thank you for this comment. We built the Table 4 and we discussed the differences among the two subgroups in order to point out that functional capacity assessed via exercise cardiopulmonary testing and not NYHA FC is associated to RV-PA coupling and provides a more sensible and comprehensive approach. We added S1 Table built according to the TAPSE/sPAP ratio as suggested. We would like to thank the reviewer for his appreciation of our manuscript. Attachments Attachment Submitted filename: Response_to_reviewer_R1.docx https://doi.org/10.1371/journal.pone.0265059.r002
27 Dec 2021 Decision Letter - James West, Editor PONE-D-21-22876R1The added value of right ventricular function normalized for afterload to improve risk stratification of patients with pulmonary arterial hypertensionPLOS ONE Dear Dr. Vicenzi, 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. There are slight additional details requested. Please submit your revised manuscript by Feb 10 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, James West, PhD Academic Editor PLOS ONE [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) Reviewer #2: 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 Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 Reviewer #2: 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 Reviewer #2: 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: Thank you addressing my comments. I think your team has answered most of the concerns but your response to reviewer file doesn't reflect that well. I would like you to send responses, citing page number and the line number where you have provided the response. it appears to be missing from response to reviewer file. additionally, how did you define events in this analysis? I think I missed it in earlier version to ask this. For example, see below. Through out the manuscript you are referring to events, what do you mean by these events, are they mean death/transplant or they mean clinical worsening as defined as ....? or PAH related hospitalization or its composite of all of these. its important to define these well Patients at intermediate-risk were not significantly separated from those at low-risk (log-rank test p=0.258, Chi2=1.278), while showed a significant reduction of events if compared with those at high-risk (log-rank test p=0.003, Chi2=8.969). In the above statement, what are the events? How did they define it? I don’t see any mention in the methods section. Additionally, is it possible for the authors to combine the risk score from COMPERA/French scoring to combine with the echo parameters and come up with the ROC/AUC as recently published by Sahay S et al E-REVEALlite 2.0 in predicting disease progression in PAH. published in pulmonary circulation. https://onlinelibrary.wiley.com/doi/abs/10.1002/pul2.12026 Lastly, I think it will be nice to get the finalized paper reviewed by someone who is non-physician English speaker to read through for any grammatical errors and to correct syntax of many statements. Reviewer #2: Thanks to the respected authors, I think all the points have been accepted and applied. The article is well organized and now has a complete and understandable form. Also, the right conclusions are obtained and well supported by data are and suitable for publication. ****** 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 #2: Yes:** Hamidreza Javadi. Associated professor of cardiology. Cardiology department. Faculty of medicine. Qazvin university of medical sciences. Qazvin. IRAN. [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.0265059.r003
Revision 2
7 Feb 2022 Author Response We would thank the reviewers for their constructive comments. We believe it substantially helped us improving our work, and we would like to apologise for delivering a revision that did not reflect the requested changes. Please find below the point by point responses we wish to provide to the reviewer in R1, with the page/line reference for each answer Reviewer #1: Thank you addressing my comments. I think your team has answered most of the concerns but your response to reviewer file doesn’t reflect that well. I would like you to send responses, citing page number and the line number where you have provided the response. It appears to be missing from response to reviewer file. -- We thank the reviewer for his comment. We are sorry for delivering a revised manuscript that did not reflect the requested changes. Please find below the point-by-point responses we wish to provide to the reviewer in R1, with the page/line reference for each answer. Additionally, how did you define events in this analysis? I think I missed it in earlier version to ask this. For example, see below. Through out the manuscript you are referring to events, what do you mean by these events, are they mean death/transplant or they mean clinical worsening as defined as ....? or PAH related hospitalization or its composite of all of these. Its important to define these well. Patients at intermediate-risk were not significantly separated from those at low-risk (log-rank test p=0.258, Chi2=1.278), while showed a significant reduction of events if compared with those at high-risk (log-rank test p=0.003, Chi2=8.969). In the above statement, what are the events? How did they define it? I don’t see any mention in the methods section. -- Thank you for stressing this important point. As reported in the text (see section “Materials and Method – design of the study), we considered as event exclusively death and lung transplantation. The patients that were lost at follow-up were not included in analysis (page 6 line 12-14). Additionally, is it possible for the authors to combine the risk score from COMPERA/French scoring to combine with the echo parameters and come up with the ROC/AUC as recently published by Sahay S et al E-REVEALlite 2.0 in predicting disease progression in PAH. published in pulmonary circulation. -- We thank the reviewer for this suggestion and we do acknowledge the very elegant work of Sahay et al, now added the reference. We however feel that it may be inappropriate to multiply the risk assessment tools as they appear to provide consistent answers. We would therefore prefer keeping our message as simple as possible, if this is agreeable to the reviewer Lastly, I think it will be nice to get the finalized paper reviewed by someone who is non-physician English speaker to read through for any grammatical errors and to correct syntax of many statements. -- Thank you for your comment. The manuscript was proof-edited by a native English speaker. Reviewer #2: Thanks to the respected authors, I think all the points have been accepted and applied. The article is well organized and now has a complete and understandable form. Also, the right conclusions are obtained and well supported by data are and suitable for publication. -- We thank the reviewer for his very positive comment. 4th October 2021 – Responses to Reviewer #1: - In the introduction and in abstract, the authors have repeatedly stated that the current risk stratification scores do not include echo cardiographic parameters. I don’t think this statement is totally correct. I agree that the echo/ imaging parameters have not been included as much we want them to be, but REVEAL has pericardial effusion and ESC/ERS has RA area in them. Thus, I would suggest changing the introduction to state something like only limited imaging parameters have been included which do not reflect the comprehensive view of the RV function. We thank the reviewer for this comment. We agree that echocardiography is took in account in REVEAL and in ESC/ERS risk stratification. However, echocardiography is not included in the simplified risk algorithms proposed by COMPERA or the French network. This has been clarified in the text (see page 4, line 25 in final R2 version) - Methods: The study includes patients from over 15 years. There is no mention of how these patients were included, selected or all patients with IPAH or HPAH. Consecutive patients with regular follow up? How did they account for patients who were lost to follow up or whose outcome data was not available? Thank you for this important comment. Our center has used echocardiography and biomarkers since the beginning. We have now detailed the selection of patients (see page 6, from line 6 to line 12 in final R2 version) - “All non-invasive tests were performed within 14 days, without changes in treatments or patients’ conditions” this statement need clarity, 14 days of what? 14 days of stable therapy? That’s generally a very short period to consider stability on therapy This point is now simplified and clarified. All non-invasive tests were executed up to 14 days after changes of medical therapy. We therefore believe this is unlikely to affect our results. - Also methods section, describes the methods of each testing ie echo, RHC, walk test etc but it doesn’t describe study design. For example, how these patients were selected? If a patient had multiple serial echo’s and walk test or CPET studies, how did the authors decide which echo to review or which walk test to include or CPET. Or they included all patients with all of their testings? Thank you for this comment. The text is now updated, and the patients’ selection is detailed (see page 6, lines 11 and 12) - “To control for any residual learning effect, the second of two tests performed on at least 2 separate days was used for the present study.” Above statement need clarification. Since it’s a retrospective study, these tests are standard of care, so how did they have walk tests done at two different days? My understanding is, as a part of routine follow ups patients generally perform one walk test. We thank the reviewer for this important comment. As stated in a previous response, our center has adopted the standards of clinical trials since the late 90’S. Therefore, all patients underwent a first learning/training test and a second one that was used for the present study. This approach is known to limiting the risk of possible bias. We have clarified the text (see page 7, lines 5 and 6) - Results: RHC and CPET data are not directly relevant to the central focus of the study. So I would suggest to put in as supplementary data Thanks for this suggestion. We have built S1 Table. - Results are not flowing well. It is very confusing in the way its currently written. I understand the message but the presentation is very confusing. Again, there is no mention that these echo and all other parameters are baseline? Ie diagnostic or the follow ups How did the authors come up with the cut of 3.74 for TAPSE/TRV ratio? We thank the reviewer for this comment. Optimal cut-point was calculated via Contal and O’Quingley’s analysis (see page 8 lines 16 and 17 in final R2 version). We have now specified in the text. - In the French analysis, without echo, the authors are saying 15 with 4/3 low risk criteria vs 2/1/0 low risk had no difference in outcomes ? explain this. Thanks for this comment. The FPHN strategy was able to separate patients with 4/3 low criteria from those with 2/1/0 low criteria. As now reported in the text we detailed the results and we specified that no significant difference was found among the two groups with 4 or 3 low criteria and among the three groups with 2, 1 or 0 criteria (see page 13, from line 3 to 7) - AUC of the TAPSE/TRV is very low—so without the risk score if someone uses it as stand alone parameter, it doesn’t have much predictive value. Thank you for this important comment. We performed ROC analysis in order to compare TAPSE, TAPSE/TRV and TAPSE/sPAP as marker of contractility, the former, and surrogate of RV-PA coupling, the last two. We agree that AUCs were absolutely low for TAPSE/TRV and TAPSE/sPAP, however relatively to TAPSE they were bigger and obtained a significant p value. In our analysis TAPSE/TRV or TAPSE/sPAP have not been considered as prognostic marker standing alone, but added as “second-step analysis” to COMPERA and FPHN strategies. On the other hand, we did not suggest to use TAPSE/TRV or TAPSE/sPAP alone, and moreover they may be included in a multiparameter approach. - Is it possible for the authors to combine the TAPSE/TRV ratio with the average compera score and compare it with COMPERA score alone to predict outcome. We thank the reviewer for this suggestion. We performed the analysis as here reported. However, TAPSE/TRV was not able to further separate patient at high-risk (high-high vs high-low, blue line vs green line. Chi2 1.628, log rank 0.202). We did not apply the TAPSE/TRV stratification to group at low-risk because of the absence of events (n=4, survival 100%). Discussion is nicely written. We would like to thank the reviewer for her/his appreciation of our manuscript. 4th October 2021 – Response to Reviewer #2: The article is very good and I am sure that many people will read and use it. - Abstract: Usually, the audience should find out your most important findings by reading the abstract, while you have generalized in the this part and have not mentioned any number or cut point. By inserting this part, the summary of the article will be more complete and better. In addition, your abstract is not structured. We would like to thank the reviewer for her/his kind words. We have written abstract and structured as requested. - Introduction: If you find it appropriate, explain a little more about the study of COMPERA and the French PNH and its classifications, so that the audience does not have to refer to other data articles to understand the content from the beginning. The text is now updated: COMPERA and FPHN registries are now better described. - Discussion: In the section on discussing the characteristics of people according to the TAPSE / sPAP ratio, although what you are looking for is understandable, but like the data in Table 4, you did not provide a separate table for this ratio and Cutpoint 0.24, and did not explain. which it is appropriate to give a similar tabular data or give an explanation in this regard. Thank you for this comment. We built the Table 4 and we discussed the differences among the two subgroups in order to point out that functional capacity assessed via exercise cardiopulmonary testing and not NYHA FC is associated to RV-PA coupling and provides a more sensible and comprehensive approach. We added S1 Table built according to the TAPSE/sPAP ratio as suggested. Attachments Attachment Submitted filename: R2_Response_to_Reviewers_def.docx https://doi.org/10.1371/journal.pone.0265059.r004
23 Feb 2022 Decision Letter - Lucio Careddu, Editor The added value of right ventricular function normalized for afterload to improve risk stratification of patients with pulmonary arterial hypertension PONE-D-21-22876R2 Dear Dr. Vicenzi, 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. This final version includes all the changes suggested by the reviewers; the text has improved in the various points suggested and enriched the subject matter. 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. 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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 #2: 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 Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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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 ****** 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: Excellent job by the authors in addressing comments! Congratulations. I do not have any further comments Reviewer #2: Thank you for your good article. The applied changes have made your article better, smoother and more understandable. I suggest you complete the title of Table 3 as well. Univariate and multivariate regression analysis of echocardiographic parameters. ****** 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 #2: Yes:** Hamidreza Javadi.MD. Cardiologist. Qazvin University of medical sciences. Qazvin. Iran. https://doi.org/10.1371/journal.pone.0265059.r005
Formally Accepted
25 Apr 2022 Acceptance Letter - Lucio Careddu, Editor PONE-D-21-22876R2 The added value of right ventricular function normalized for afterload to improve risk stratification of patients with pulmonary arterial hypertension Dear Dr. Vicenzi: 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. Lucio Careddu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0265059.r006

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