Evaluation of health-related quality of life and the related factors in a group of Chinese patients with interstitial lung diseases

Xue-Yan Yuan; Hui Zhang; Li-Ru Huang; Fan Zhang; Xiao-Wen Sheng; Ai Cui

doi:10.1371/journal.pone.0236346

Peer Review History

Original SubmissionJanuary 11, 2020
2 Mar 2020 Decision Letter - Paola Faverio, Editor PONE-D-20-00941 Evaluation of health-related quality of life and the related factors in a group of Chinese patients with interstitial lung diseases PLOS ONE Dear Dr. Ai Cui, 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. Thank you for your submission to PLOS ONE. Both the reviewers highlighted the originality of the data and the importance of the topic. However some fundamental methodological pitfalls need to be addressed. In particular, the heterogeneity of the population analysed. Given the high number of diagnoses, with different clinical characteristics and prognosis, that can be included in the family of interstitial lung diseases, I suggest to restrict the study to the main diagnoses. Furthermore, the statistical analysis need a complete revision by an expert statistician. We would appreciate receiving your revised manuscript by April 14th, 2020. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols 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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Paola Faverio 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 http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly 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: General comments 1. The researchers have collected an impressive amount of data, but the study lacks both structure and focus. The analytical approach is questionable and there are methodological limitations, in particular with respect to the study population. The manuscript contains large amounts of information, but adds little new knowledge. It is not easily accessible to the reader. 2. My main concern is the heterogeneous patient population. The material comprises a mix of diagnoses including idiopathic interstitial pneumonias (IIP), hypersensitivity pneumonitis (HP), CTD-ILD and sarcoidosis - all well-defined diseases with disease-specific clinical characteristics and disease-specific prognosis. To analyze such a variety of diseases under the same ILD-umbrella is not meaningful. 3. The study lacks an appropriate purpose. The aim is to “investigate HRQL in patients with ILD and identify factors influencing HRQL among these patients”. To what end? What do the researchers want to find out? What is the hypothesis? ILD is a common denominator for various diseases with different courses, different responses to therapy and different prognosis. To assess HRQL in a mixed ILD-population is not useful. I would advise the research group to focus on disease-specific HRQL. Based on the number of patients in the various disease-groups, it may be an idea to confine the study to the two largest groups - IIP (69.5%) and CTD-ILD (15%) - and compare HRQL in those two diseases. 4. The study lacks generalizability. The results of the study may be relevant to the Chinese medical community, but they cannot be generalized to other parts of the world. The study was carried out in 2017/18. At that time, anti-fibrotic treatment was commonly prescribed to patients with IPF in North-America, Europe, Australia and Japan. In the present study, only 5 patients received such drugs (table 1) while “other drugs” were used by 74% – presumably drugs that are not generally prescribed outside of China. Since drugs will affect symptoms, course of disease, side-effects and prognosis, they will also invariably affect measures of HRQL. This adds to the difficulties in interpreting and generalizing the results of the study. Specific comments Introduction. Lines 53-64, 65-67 and 67-68. Three statements that all need references. Methods. 1. The prospective cohort was followed up though “face-to-face or telephone interviews”. How could “physiological indicators” (like PFTs) be registered by telephone? What was the procedure for follow-up with respect to the questionnaires? (lines 84-87) 2. ILDs have insidious onset. How was “date of ILD-diagnosis” defined? (line 96) 3. Equipment, guidelines and ref.values for PFTs should be specified. (lines 98-100) 4. Were the two radiologists blinded to clinical information? (line 101) 5. The minimum clinically important differences in scores should be given for each of the questionnaires. Statistics 1. Predictors cannot be identified in a cross-sectional study (lines 152-154) 2. The model seems overloaded (table 3) 3. Multiple correlations are probably not the method of choice for analyzing between-group changes in the prospective study (lines 157-160). 4. An expert statistician should be consulted with respect to analytical approach. Results 1. In general, I suggest dropping the use of two decimal places (text and tables). It indicates a precision level that is not real. Example: duration of symptoms 19.89 +27.34 months (line 168 + tab1). 2. Tab 2. All variables have large SDs, simply reflecting the fact that wide ranges will always be found in very heterogeneous study populations. To what end is such information useful? 3. In the longitudinal study, relatively large proportions of patients had improvements in both symptoms (dyspnea, cough) and PFTs, and also in HRQ scores. Patients with ILD tend to deteriorate or remain stable over time, not improve. Presumably the unexpected findings reflect that in a mixed study population - including patients with a broad variety of diagnoses/diseases - some will respond to therapy/drugs while others will not. (lines 246-257). Reviewer #2: The original research article by Yuan and co-authors assessed longitudinally the quality of life of 200 ILD patients at baseline, and at 6- and 12-month follow up correlating the changes in HRQoL with the changes in pulmonary function tests. The authors found that HRQoL deteriorates during the follow up of ILD patients and seems to be associated with determinants such as dyspnea, cough, and depression. Overall the manuscript is well written and comprehensive; therefore I suggest only minor revisions. 1. Abstract – Introduction – Lines 16-18. The sentence “There are limited therapeutic options and strong side effects, which eventually lead to respiratory failure and affect the quality of life of patients” seems to suggest that the treatment-related side effects cause respiratory failure. 2. Abstract – Results – Line 27. Correct “The mean age was 60.7 years old, …” with “The mean age was 60.7 years, …”. 3. Introduction – Lines 65-68. I suggest quoting the few available studies dealing with HRQoL in ILD patients. 4. Results – Line 164. I suggest using the same number of decimals for the median age and its standard deviation, as it has been done in the whole manuscript for continuous variables. 5. Results – Table 1. Correct “Ethmic group” with “Ethnic group”. 6. Results – Lines 251-252. Does the sentence “Similarly, 42.4% of patients’ FVC% predicted and 48.8% of patients’ DLco% predict were improved or stable” refer to the 12-month follow up? If so, it should be specified in the text. 7. Results – Lines 263-264. “The associations between longitudinal changes 263 in HRQoL and clinical characteristics is shown in Table 4”. I suggest indicating in the text which clinical characteristics were tested in this analysis. 8. Results – Line 284. Change “the emergence of the first symptom” with “the onset of the first symptom”. 9. Discussion. This paper is an example of the raising interest in the patient-reported outcome measures (PROs) in IPF and ILDs in general. However, the minimal clinically significant difference of the PROs used in this paper (mMRC, LCQ, HADS, SGRQ and SF-36 questionnaire) is currently unknown. This should be mentioned among the limitations of this paper. ****** 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 to be viewed.] 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 us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0236346.r001
Revision 1
10 Apr 2020 Author Response Dear Prof. Paola Faverio, Thank you for your kind letter. We revised the manuscript in accordance with your and the reviewers’ comments and advices, and carefully proof-read the manuscript to correct spelling, expression and statistical analytical approach errors. Here below is our description on revision according to your and the reviewers’ comments and advices. Thank you for your submission to PLOS ONE. Both the reviewers highlighted the originality of the data and the importance of the topic. However some fundamental methodological pitfalls need to be addressed. In particular, the heterogeneity of the population analysed. Given the high number of diagnoses, with different clinical characteristics and prognosis, that can be included in the family of interstitial lung diseases, I suggest to restrict the study to the main diagnoses. Furthermore, the statistical analysis need a complete revision by an expert statistician. We appreciate all the comments and suggestions from the editors and reviewers, these will be great of help to improve our present work. We appreciate the suggestion and totally agreed with your opinion about the heterogeneity of the population. We restrict the population in our study to idiopathic interstitial pneumonias (IIP) and CTD-ILD, and then we reanalyzed the data. We also appreciate your reminding about the statistical analysis. We specifically consulted the expert statistician and improved the defects in our study. Reviewer #1: General comments 1. The researchers have collected an impressive amount of data, but the study lacks both structure and focus. The analytical approach is questionable and there are methodological limitations, in particular with respect to the study population. The manuscript contains large amounts of information, but adds little new knowledge. It is not easily accessible to the reader. Response: Thank you for the comments. We agreed with the reviewer’s opinion on the defects in data processing and statistical analysis. The data of the study were from patients with ILDs in china, and there is a large space for study on the quality of life in these patients in china. In present study, We adjusted the study population to focus on patients with IIP and CTD-ILD, and we revised the writing of the manuscript to make it easier for the reader to access the important information (Line 236-243, Line 282-294, Line 444-452, Table 1, Table 2 ). 2. My main concern is the heterogeneous patient population. The material comprises a mix of diagnoses including idiopathic interstitial pneumonias (IIP), hypersensitivity pneumonitis (HP), CTD-ILD and sarcoidosis - all well-defined diseases with disease-specific clinical characteristics and disease-specific prognosis. To analyze such a variety of diseases under the same ILD-umbrella is not meaningful. Response: Thank you for the comments. At first, we look forward to exploring a universal predictive model for ILDs, so we collected all patients clinically diagnosed with ILDs and followed them up for 12 months. Since ILD belongs to a group of diseases and the heterogeneity is very significant, it is obviously inappropriate. We think your views on the heterogeneous patient population are very reasonable and Based on your suggestion, we have eliminated HP, sarcoidosis and other types of ILD, and re-analyzed the data (Line 236-521, Table 1, Table 2, Figure 1, Figure 3 ). 3. The study lacks an appropriate purpose. The aim is to “investigate HRQL in patients with ILD and identify factors influencing HRQL among these patients”. To what end? What do the researchers want to find out? What is the hypothesis? ILD is a common denominator for various diseases with different courses, different responses to therapy and different prognosis. To assess HRQL in a mixed ILD-population is not useful. I would advise the research group to focus on disease-specific HRQL. Based on the number of patients in the various disease-groups, it may be an idea to confine the study to the two largest groups - IIP (69.5%) and CTD-ILD (15%) - and compare HRQL in those two diseases. Response: Thanks for your comments and suggestions on our study. We agreed with the opinion on the aim of the study, and we focused on IIP and CTD-ILD according to your suggestion. We re-analyzed sociodemographic, disease-related characteristics in both ILD subtypes and compared HRQL in them. 4. The study lacks generalizability. The results of the study may be relevant to the Chinese medical community, but they cannot be generalized to other parts of the world. The study was carried out in 2017/18. At that time, anti-fibrotic treatment was commonly prescribed to patients with IPF in North-America, Europe, Australia and Japan. In the present study, only 5 patients received such drugs (table 1) while “other drugs” were used by 74% – presumably drugs that are not generally prescribed outside of China. Since drugs will affect symptoms, course of disease, side-effects and prognosis, they will also invariably affect measures of HRQL. This adds to the difficulties in interpreting and generalizing the results of the study. Response: We appreciate your comment on the generalizability of the research. We are sorry that our way of expression may has interfered with you. In our study, “others” included “no intervention”, “antioxidants” and “traditional Chinese medicine”, which “no intervention” was used in 113 patients (56.2%). We refined the presentation of data to separate “no intervention” from “others” (table 1). Meanwhile, anti-fibrotic treatment is not commonly prescribed to patients with IPF due to the price problem, and anti-fibrotic treatment is only applicable to patients with IPF, not all patients with ILDs. Theses factors finally leads to the low application of anti-fibrotic treatment in present study. We agreed with your opinion that drugs may be the confounding factor affecting HRQL in ILDs. In present study, we focused on the impact of disease severity on quality of life. Although drugs may have an impact on quality of life, it is mainly a change in the severity of the diseases after treatment. We analyzed the effect of drugs factor on HRQL with ILD by linear regression analysis (table 3), but we are sorry that the statistical analysis cannot fully explain the real-world problems. Specific comments Introduction. Lines 53-64, 65-67 and 67-68. Three statements that all need references. Response: We appreciate for your advice, several publications have been added in corresponding statements of the article (Line 67-68, Curr Opin Pulm Med. 2013; 19: 474–479, Sarcoidosis Vasc Diffuse Lung Dis. 2016; 33: 341–348, Respirology. 2014; 19: 1019–1924; Line 69-72, Am J Respir Crit Care Med. 2007; 176: 636–643; Line 74-75, Respir Res. 2019; 20: 59–72, Respirology. 2017; 22: 950–956, Respir Res. 2020; 21: 36–47; Line 79-80, Respirology. 2014; 19: 1019–1924, Respiration. 2007; 74: 401–405; Line 81-84, Respir Med. 2017; 127: 1–6, Respirology. 2018, Chest. 2014; 145: 1333–1338, J Bras Pneumol. 2010; 36: 562–570). Methods. 1. The prospective cohort was followed up though “face-to-face or telephone interviews”. How could “physiological indicators” (like PFTs) be registered by telephone? What was the procedure for follow-up with respect to the questionnaires? (lines 84-87) Response: Thank you for your comments, it is indeed our unclear expression in previous manuscript. During the follow-up, some patients did not complete the questionnaires for personal reasons after pulmonary function test in our hospital. We registered the questionnaires by telephone within one week after the completion of the pulmonary function test. We corrected the inaccurate expression (Line 103-107). 2. ILDs have insidious onset. How was “date of ILD-diagnosis” defined? (line 96) Response: Thank you for the remind. “Date of ILD-diagnosis” was defined as the time from symptom onset to the diagnosis of ILD in our hospital. We are sorry for the ambiguous expression and modified “Date of ILD-diagnosis” to “disease duration” (Line 116). 3. Equipment, guidelines and ref.values for PFTs should be specified. (lines 98-100) Response: Thank you for your advice, we added relevant information in the manuscript (Line 123-128). 4. Were the two radiologists blinded to clinical information? (line 101) Response: Yes, we are sorry for our negligence of this information and added it into the manuscript (Line 129-131). 5. The minimum clinically important differences in scores should be given for each of the questionnaires. Response: Thank you for the remind, the minimum clinically important differences of PROs using in our manuscript is currently unknow. We mentioned this fact among the limitations of this paper (Line 778-786). Statistics 1. Predictors cannot be identified in a cross-sectional study (lines 152-154) Response: Thank you for the remind, we modified the presentation of this part (Line 195-196). 2. The model seems overloaded (table 3) Response: We appreciate for your advice, and we simplified the model and described the results of univariate and multivariate linear regression analysis separately (table 3, table 4). 3. Multiple correlations are probably not the method of choice for analyzing between-group changes in the prospective study (lines 157-160). Response: Thank you for the remind, we changed the statistical method from multiple correlations to linear regression analysis and we further assessed HRQoL using one-way analysis of variance (ANOVA) followed by pairwise comparisons according to the Least-Significant-Difference method (Line 213-218). 4. An expert statistician should be consulted with respect to analytical approach. Response: Thank you for your advice, we consulted the expert statistician and corrected the deficiencies (Line 191-195, Line 213-218). In addition, we re-analyzed the data (Table 1, Table 2, Table 5, S1 Table). Results 1. In general, I suggest dropping the use of two decimal places (text and tables). It indicates a precision level that is not real. Example: duration of symptoms 19.89 +27.34 months (line 168 + tab1). Response: Thank you for your suggestion, we totally agreed that two decimal places indicates a precision level that is not real. We changed the use of two decimal places to one decimal place in all text and tables. 2. Tab 2. All variables have large SDs, simply reflecting the fact that wide ranges will always be found in very heterogeneous study populations. To what end is such information useful? Response: We agreed that variables that have large SDs reflect the very heterogeneous populations in our study. So, we limited the study population to IIP and CTD-ILD patients and re-analyzed the data. The results for the two group was added. 3. In the longitudinal study, relatively large proportions of patients had improvements in both symptoms (dyspnea, cough) and PFTs, and also in HRQ scores. Patients with ILD tend to deteriorate or remain stable over time, not improve. Presumably the unexpected findings reflect that in a mixed study population - including patients with a broad variety of diagnoses/diseases - some will respond to therapy/drugs while others will not. (lines 246-257). Response: Thank you for your comments. We agreed that the heterogeneous study populations in our study led to the unexpected findings, so we excluded Sarcoidosis, HP and other ILD subtypes in our analysis. After reanalyzing the data, we found that symptoms including dyspnea and cough deteriorated or remained stable or in most patients at follow-up (S1 table). At 6-month and 12-month follow-up, patients with IIP had a stable quality of life compared with baseline in HRQoL measured by SF-36 PCS, SGRQ total domains. However, the HRQOL in patients with CTD-ILD had a valuable improvement at 6-month and 12-month follow-up. The reason for the fact is likely to be the therapy or drugs. We are sorry for our negligence in this factor at follow-up and we explained this in the discussion (Line 792-793). Reviewer #2: The original research article by Yuan and co-authors assessed longitudinally the quality of life of 200 ILD patients at baseline, and at 6- and 12-month follow up correlating the changes in HRQoL with the changes in pulmonary function tests. The authors found that HRQoL deteriorates during the follow up of ILD patients and seems to be associated with determinants such as dyspnea, cough, and depression. Overall the manuscript is well written and comprehensive; therefore I suggest only minor revisions. 1. Abstract – Introduction – Lines 16-18. The sentence “There are limited therapeutic options and strong side effects, which eventually lead to respiratory failure and affect the quality of life of patients” seems to suggest that the treatment-related side effects cause respiratory failure. Response: Thank you for the remind, it is indeed our mistake in the expression. The sentence (Line 16-19) was modified. 2. Abstract – Results – Line 27. Correct “The mean age was 60.7 years old, …” with “The mean age was 60.7 years, …”. Response: Thank you for pointing out the error, we have corrected it. 3. Introduction – Lines 65-68. I suggest quoting the few available studies dealing with HRQoL in ILD patients. Response: Thank you for your advice, several available studies have been added in corresponding statements of the manuscript (Line 81-84, Respir Med. 2017; 127: 1–6, Respirology. 2018. https://doi.org/10.1111/ resp. 13293, Chest. 2014; 145: 1333–1338, J Bras Pneumol. 2010; 36: 562–570) 4. Results – Line 164. I suggest using the same number of decimals for the median age and its standard deviation, as it has been done in the whole manuscript for continuous variables. Response: Thank you for your advice, we have unified all the median±SD to one number of decimals in the whole manuscript. 5. Results – Table 1. Correct “Ethmic group” with “Ethnic group”. Response: Thank you for pointing out the error, we have corrected it. 6. Results – Lines 251-252. Does the sentence “Similarly, 42.4% of patients’ FVC% predicted and 48.8% of patients’ DLco% predict were improved or stable” refer to the 12-month follow up? If so, it should be specified in the text. Response: Yes, thank you for your suggestion. We have made additional explanations in the text (Line 427-429). 7. Results – Lines 263-264. “The associations between longitudinal changes in HRQoL and clinical characteristics is shown in Table 4”. I suggest indicating in the text which clinical characteristics were tested in this analysis. Response: We appreciate for your advice, and specific clinical characteristics including FVC% predicted, DLco% predicted, mMRC and LCQ total score have been described in the manuscript (Line 498-500). 8. Results – Line 284. Change “the emergence of the first symptom” with “the onset of the first symptom”. Response: Thank you for your advice, we have corrected it. 9. Discussion. This paper is an example of the raising interest in the patient-reported outcome measures (PROs) in IPF and ILDs in general. However, the minimal clinically significant difference of the PROs used in this paper (mMRC, LCQ, HADS, SGRQ and SF-36 questionnaire) is currently unknown. This should be mentioned among the limitations of this paper. Response: Thank you for your advice, we have elaborated this limitation in the discussion of the manuscript (Line 778-786). We acknowledge the editors’ and reviewers’ comments and suggestions very much, which are valuable in improving the quality of our manuscript. Thank you again for the guidance and help. Sincerely yours, Xue-Yan Yuan, Ai Cui 2020-04-07 Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0236346.r002
27 May 2020 Decision Letter - Paola Faverio, Editor PONE-D-20-00941R1 Evaluation of health-related quality of life and the related factors in a group of Chinese patients with interstitial lung diseases PLOS ONE Dear Dr. Ai Cui, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The quality of the research article have much improved after the revisions made. I agree with the minor revisions proposed by Reviewer 3. I also suggest the authors to have the abstract of the manuscript, particularly the sentences changed during the review, rechecked by an English translator. Please submit your revised manuscript by June 20th, 2020. 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, Paola Faverio 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 #2: 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 #2: Yes Reviewer #3: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes 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 #2: Yes 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 #2: Yes Reviewer #3: Yes ****** 6. Review Comments to the Author Reviewer #2: (No Response) Reviewer #3: Xue-yan Yuan and collaborators wrote a research article trying to clarify the role of health-related quality of life factors in a cohort of Chinese patients affected by ILD. This topic has been widely discussed in literature, however it is still a subject of interest. Some minor revisions need to be made. Methods Line 80. In this section I suggest you to add which ILDs you include in your cohort (lately in the section Results you state you have considered only ILD patients with a diagnosis of CTD-ILD or IIP). Results Line 180 since idiopathic interstitial pneumonias include different entities as well as CTD-ILD (Am J Respir Crit Care Med. 2013 Sep 15;188(6):733-48) I suggest you to specify the composition of your cohort. This could help better understand your results since in both groups are included entities with different evolution and prognosis. Moreover it could help understanding why antifibrotic drug were administered in only 2.9% of the IPP group (were IPF patients the minority of this group?) Line 238. “ILD subtype (IIP vs CTD-ILD) was associated with most dimensions of the SGRQ and the SF-36 PCS” I suggest you to deepen this statement. Are there significant differences in the results of this questionnaires in IPP patients compared to CTD-ILD? In section Results the comparison between IPP and CTD-ILD is clear only in the first and second paragraphs (patient characteristics and HRQoL) while in the other paragraphs (factors influencing HRQoL assessed at the time of enrollment; relationship between the change in HRQoL and changes 274 in clinical characteristics and clinical characteristics and HRQoL of patients who died during follow-up) the comparison is absent. In these last paragraphs you consider “ILD subtypes” as a factor influencing or not HRQoL while I think it could be of interest analyze not only the whole cohort but also if there are differences between the two groups in terms of HRQoL. Moreover, a better focus on differences between the two groups should be highlighted in the section Discussion and in the section Conclusion. ****** 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 #2: No Reviewer #3: Yes: Anna Stainer [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. 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Revision 2
14 Jun 2020 Author Response Dear Prof. Paola Faverio, Thank you for your kind letter. We have revised our manuscript after reading the comments and suggestions provided by you and the reviewers. The following is what we have modified in response to your and the reviewers’ comments and advice. I agree with the minor revisions proposed by Reviewer 3. I also suggest the authors to have the abstract of the manuscript, particularly the sentences changed during the review, rechecked by an English translator. We appreciate all your and the reviewers’ comments and advice. According to your suggestion, we employed an English-language editing service, Academic English Editors (AJE) to polish our wording of the changed sentences and abstract, and the revised parts were marked in the red in the “Revised Manuscript with Track Changes”. We also elaborated on the diagnosis of the included patients in this study. Responds to the reviewer’s comments: Reviewer #3: Xue-yan Yuan and collaborators wrote a research article trying to clarify the role of health-related quality of life factors in a cohort of Chinese patients affected by ILD. This topic has been widely discussed in literature, however it is still a subject of interest. Some minor revisions need to be made. Methods 1. Line 80. In this section I suggest you to add which ILDs you include in your cohort (lately in the section Results you state you have considered only ILD patients with a diagnosis of CTD-ILD or IIP). Response: Thank you for the comment and suggestion. The specific ILDs subtypes have been described in the manuscript (Line 84, Line 89, and Line 91: “Patients aged ≤85 years who were diagnosed with ILDs including IIP and CTD-ILD at the Department of Respiratory and Critical Medicine of Capital Medical University”, “The diagnosis of IIP or CTD-ILD”). Results 1. Line 180 since idiopathic interstitial pneumonias include different entities as well as CTD-ILD (Am J Respir Crit Care Med. 2013 Sep 15;188(6):733-48) I suggest you to specify the composition of your cohort. This could help better understand your results since in both groups are included entities with different evolution and prognosis. Moreover it could help understanding why antifibrotic drug were administered in only 2.9% of the IPP group (were IPF patients the minority of this group?) Response: Thank you for the remind. According to your suggestion, we have revised our manuscript and the specific composition of our included patients has been increased in the manuscript (Line 200-204: “139 were diagnosed with IIP (101 idiopathic non-specific interstitial pneumonia (NSIP) cases, 18 unclassifiable IIP cases, 11 respiratory-bronchiolitis-ILD cases, 7 IPF cases, and 2 others), and 30 were diagnosed with CTD-ILD (12 Sjögren’s syndrome (SS) cases, 6 undifferentiated CTD cases, 4 polymyositis/dermatomyositis (PM/DM) cases, 3 scleroderma (SSc) cases, 2 rheumatoid arthritis (RA) cases, and 3 others) (S1 Table)”). 2. Line 238. “ILD subtype (IIP vs CTD-ILD) was associated with most dimensions of the SGRQ and the SF-36 PCS” I suggest you to deepen this statement. Are there significant differences in the results of this questionnaires in IIP patients compared to CTD-ILD? Response: Yes, patients with IIP had significantly better quality of life than patients with CTD-ILD in terms of SF-36 PCS, SGRQ activity, SGRQ impact, and SGRQ total domains in our study which were showed in Table 2. We appreciate your suggestion, and we have further elaborated the relevant information in the manuscript (Line 262-267: “As shown in Table 3, HRQoL was found to be significantly affected by multiple factors. ILD subtype was negatively associated with the SF-36 PCS and positively associated with most dimensions of the SGRQ in the univariate liner regression analyses. As previously mentioned, patients with CTD-ILD had a lower quality of life as measured by the SF-36 PCS and SGRQ activity, impact, and total domains when compared with patients with IIP”). 3. In section Results the comparison between IIP and CTD-ILD is clear only in the first and second paragraphs (patient characteristics and HRQoL) while in the other paragraphs (factors influencing HRQoL assessed at the time of enrollment; relationship between the change in HRQoL and changes in clinical characteristics and clinical characteristics and HRQoL of patients who died during follow-up) the comparison is absent. In these last paragraphs you consider “ILD subtypes” as a factor influencing or not HRQoL while I think it could be of interest analyze not only the whole cohort but also if there are differences between the two groups in terms of HRQoL. Response: Thanks for your comments and suggestions. In this study, we mainly focused on the quality of life of all patients with ILDs and their influencing factors. Meanwhile, ILD subtypes were weakly associated with SF-36 PCS. So, we did not analyze the influencing factors in HRQoL of IIP and CTD-ILD patients, respectively. We compared the quality of life of IIP and CTD-ILD patients, and found HRQoL of patients with IIP was better than that of patients with CTD-ILD. 4. Moreover, a better focus on differences between the two groups should be highlighted in the section Discussion and in the section Conclusion. Response: We appreciate for your advice and agree with the opinion. We had an in-depth discussion of the differences between the two groups. (Line 376-378, Line 402-409, Line 415, Line 419-424, Line 504-506) Finally, we acknowledge the editor’ and reviewers’ comments and suggestions very much, which are valuable in improving the quality of our manuscript. Thank you again for the guidance and help. Sincerely yours, Xue-Yan Yuan, Ai Cui 2020-06-14 Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0236346.r004
7 Jul 2020 Decision Letter - Paola Faverio, Editor Evaluation of health-related quality of life and the related factors in a group of Chinese patients with interstitial lung diseases PONE-D-20-00941R2 Dear Dr. Ai Cui, 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, Paola Faverio Academic Editor PLOS ONE Additional Editor Comments (optional): The issues reasonably raised by the reviewers have been addressed. 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: Xue-yan Yuan and collaborators wrote a research article trying to clarify the role of health-related quality of life factors in a cohort of Chinese patients affected by ILD. This topic has been widely discussed in literature, however it is still a subject of interest. All requested corrections were made by the Authors. No further revisions are required ****** 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: Yes:** Anna Stainer https://doi.org/10.1371/journal.pone.0236346.r005
Formally Accepted
17 Jul 2020 Acceptance Letter - Paola Faverio, Editor PONE-D-20-00941R2 Evaluation of health-related quality of life and the related factors in a group of Chinese patients with interstitial lung diseases Dear Dr. Cui: 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. Paola Faverio Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0236346.r006

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