The preventative effects of statin on lung cancer development in patients with idiopathic pulmonary fibrosis using the National Health Insurance Service Database in Korea

Yoo Jung Lee; Nayoon Kang; Junghyun Nam; Eung Gu Lee; Jiwon Ryoo; Soon Seog Kwon; Yong Hyun Kim; Hye Seon Kang

doi:10.1371/journal.pone.0299484

Peer Review History

Original SubmissionSeptember 7, 2023
2 Nov 2023 Decision Letter - Tsai-Ching Hsu, Editor PONE-D-23-28368The preventative effects of statin on lung cancer development in patients with idiopathic pulmonary fibrosis using the National Health Insurance Service Database in KoreaPLOS ONE Dear Dr. Kang, 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 Dec 17 2023 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, Tsai-Ching Hsu, Ph.D. Academic Editor PLOS ONE Journal Requirements: 1. When submitting your revision, we need you to address these additional requirements. 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. Did you know that depositing data in a repository is associated with up to a 25% citation advantage (https://doi.org/10.1371/journal.pone.0230416)? If you’ve not already done so, consider depositing your raw data in a repository to ensure your work is read, appreciated and cited by the largest possible audience. You’ll also earn an Accessible Data icon on your published paper if you deposit your data in any participating repository (https://plos.org/open-science/open-data/#accessible-data). 3. Thank you for stating in your Funding Statement: This work was supported by the Institute of Clinical Medicine Research of Bucheon St. Mary’s Hospital, Research Fund, 2020 (BCMC20BD07). Please provide an amended statement that declares all the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf. 4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. Additional Editor Comments: Please revise your manuscript according to the referees’ comments and ensure the revised manuscript with all changes clearly highlighted. [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: No ****** 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: No 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: The authors present an epidemiological study with a satisfying sample of patients regarding the impact of statin use in IPF survival. However, there are methodological issues that may have affected research results. Particularly, as the authors do not include lung function parameters and the use of antifibrotics in their registry, important aspects that is known to affect survival in IPF studies limit the significance of their results. Major comments: 1. You do not include important clinical parameters in IPF patients of both groups, including FVC, DLCO and 6MWT that could have impacted the survival. Lung function would allow us to assess the severity of both groups. I think that this is a serious limitation in the study. 2. The fact that the exercise was significantly different between the statin and the non statin groups could be related to the severity of patients. In case of severe pulmonary fibrosis in which patients need oxygen may have less exercise that other milder cases. 3. The are diverse clinical characteristics that differ between the 2 groups. Why you do not include all these variables in the multivariate analysis. 4. Did you include age in the multivariate analysis? 5. How could diabetes have affected OS in IPF? Maybe there is a confounding here? 6. Another important limitation is the fact that you have not taken into consideration antifibrotics that affect progression and mortality. So, this may have also affect OS threatening your internal validity. 7. Another limitation, is that you have included patients based on ICD-10, here there might be also misclassification and information bias. It should be also stated in the limitations paragraph. Minor comments: 1. Please correct in Table 2, 1st row, 3rd column the word ‘statin’. Reviewer #2: This study shows the clinical impact of statin administration on the development of lung cancer and overall survival in patients with IPF using the NHIS database. However, the following comments are need to be modified. Major> 1. Please provide the "Patients flow chart" as figure 1 including inclusion criteria and exclusion criteria. 2. Did you conduct multivariate analysis in Table 3? The variable 'statin compliance' applies only to the 'statin user' group, so does that mean the non-user group was excluded from the analysis? 3. You previously suggested that statins have a preventive effect on lung cancer development in IPF patients. However, this effect was not found in the current paper. What do you think about this? (https://doi.org/10.1016/j.chest.2022.08.1445) Minor> 1. Please provide the disease name for the injury code as supplementary material. (M05.1, M05.2,78 M05.3, M05.8, M05.9, M06.0, M06.8, M06.9, M30.1, M31.3, M31.7, M32, M33, M34, M35.0, 79 M35.1, D86, J84.0, J60~J70.9. J84 etc.) 2. Please provide a more detailed definition of “statin use”. 3. Please provide definitions of “Drinking amount at a time” and “Physical activity intensity” in the text. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: Review PLOS 2023.docx https://doi.org/10.1371/journal.pone.0299484.r001
Revision 1
29 Dec 2023 Author Response Dear Editor-in-Chief, We would like to thank you and the reviewers of the PLOS ONE for taking the time to review our article. It is truly honorable to receive the letter of revision to enrich the work of research we have performed. We would like to appreciate for the time and efforts by the editors to this paper. We have made some corrections and clarifications in the manuscript after going over the reviewers’ comments. The changes are summarized below: Reviewer #1: The authors present an epidemiological study with a satisfying sample of patients regarding the impact of statin use in IPF survival. However, there are methodological issues that may have affected research results. Particularly, as the authors do not include lung function parameters and the use of antifibrotics in their registry, important aspects that is known to affect survival in IPF studies limit the significance of their results. Major comments: 1. You do not include important clinical parameters in IPF patients of both groups, including FVC, DLCO and 6MWT that could have impacted the survival. Lung function would allow us to assess the severity of both groups. I think that this is a serious limitation in the study. Answer: We agree with reviewer’s opinion. As the reviewer told, functional volume capacity (FVC), diffusing capacity for carbon monoxide (DLCO) and six-minute walk test (6MWT) are very important factors to impact on the survival of IPF patients. However, NHIS dataset does not include serial pulmonary function tests and 6MWT of every patient, therefore it was hardly possible to be gathering and analyze each of FVC and forced expiratory volume in one second (FEV1) of selected 9182 patients. We further described detailed sentences in discussion section, line 342-345. 2. The fact that the exercise was significantly different between the statin and the non-statin groups could be related to the severity of patients. In case of severe pulmonary fibrosis in which patients need oxygen may have less exercise than other milder cases. Answer: Thank you for your comments. We also agree with reviewer’s comments. The the phrase of ‘physical activity’ and the ‘exercise’ as a noun were used interchangeably in Korean languege, so we made correction from the word of ‘exercise’ in the manuscript into ‘physical activity’ at table 1, table 3 and table 4, and highlighted the corrections in manuscript at line 35, 208-209, 224-225, 294, 305 and 308 because it was more appropriate. Physical activity frequency were different between statin and non-statin user group, and lower frequency of physical activity was noted at statin user group. As the reviewer pointed, we could not consider the severity of IPF based on pulmonary function test, 6MWT and oxygen use, because NHIS dataset does not collect these varibles, and we added detailed sentences in limitation, line 342-345. However, considering the possibility of correlation between the physical activity frequency and other clinical factors associated with IPF patients, we performed cox proportional hazard regression analysis including physical activity frequency as confounding factors. As a result, physical activity frequency was independently associated with reduced hazard in mortality of IPF patients, but not associated with lung cancer development. 3. There are diverse clinical characteristics that differ between the 2 groups. Why you do not include all these variables in the multivariate analysis. Answer: Thank you for your comments. We additionally included all variables for multivariate analysis (age at diagnosis of IPF, sex, BMI, total cholesterol, blood pressure, smoking history, drinking frequency, drinking amount, physical activity frequency, comorbidities) which are different between two groups (Table 3). 4. Did you include age in the multivariate analysis? Answer: Thank you for your comments. We included ages at first diagnosis of IPF in multivariate analysis (Table 3 and Table 4). 5. How could diabetes have affected OS in IPF? Maybe there is a confounding here? Answer: We agree with your reviewer’s opinion. In our study, diabetes mellitus (DM) was associated with reduced hazard ratio of OS in IPF patients. As we explained at discussion section, these findings would be associated to DM medications. Metformin is known to be involved in anti-fibrotic physiology and has inhibitory effect in myofibroblasts differentiations. Also, another popularly used GLP-1 receptor agonist was found to have anti-pulmonary fibrosis effects in animal models. In our study, we did not conduct an investigation on various types of diabetic drugs, so it was not possible to confirm whether mortality was reduced by DM or diabetic drugs. So, further investigation was needed to confirm these findings. 6. Another important limitation is the fact that you have not taken into consideration antifibrotics that affect progression and mortality. So, this may have also affected OS threatening your internal validity. Answer: We fully agree with reviewer’s comments. We collected IPF patients between 2002 and 2018. The official date of release of pirfenidone was July 2011(https://www.shionogi.com/content/dam/shionogi/global/news/pdf/2011/e_110712.pdf). However, pirfenidone has been reimbursed since 2015, and nintedanib is still not reimbursed in Korea. The definite limitation of our study is that the history of two antifibrotic drugs were not included in the analysis because the timing of domestic use of drugs and imbursements were different. We added detailed sentences in line 341-342. 7. Another limitation, is that you have included patients based on ICD-10, here there might be also misclassification and information bias. It should be also stated in the limitations paragraph. Answer: Thank you for your comments. We added detailed sentences at limitation section, line 331-333. Minor comments: 1. Please correct in Table 2, 1st row, 3rd column the word ‘statin’. Answer: Thank you for your comments. We corrected the word at table 2. Reviewer #2: This study shows the clinical impact of statin administration on the development of lung cancer and overall survival in patients with IPF using the NHIS database. However, the following comments are need to be modified. Major> 1. Please provide the "Patients flow chart" as figure 1 including inclusion criteria and exclusion criteria. Response: We fully agree with reviewer’s comments. We summarized briefly inclusion and exclusion criteria at material and method sections. There was an issue on processing the number of patients we selected and excluded in the flowchart because the period of use of health insurance data has expired, it is currently difficult to accurately determine the number of patients who meet the exclusion criteria. Instead, in order to clarify to understand out study, we added to adjunctive information in the manuscript about the study design and the population in the section of method. (line 76-86) 2. Did you conduct multivariate analysis in Table 3? The variable 'statin compliance' applies only to the 'statin user' group, so does that mean the non-user group was excluded from the analysis? Answer: The results shown on Table 3 by Cox proportional hazard analysis were performed under multivariate analysis. We agree with reviewer’s opinion, so variable ‘statin compliance’ was excluded from our multivariate analysis. (Table 3) 3. You previously suggested that statins have a preventive effect on lung cancer development in IPF patients. However, this effect was not found in the current paper. What do you think about this? (https://doi.org/10.1016/j.chest.2022.08.1445) Answer: Thank you for your review our other study. Previous study was conducted using our clinical ware house on the same topic as this study, and showed the same conclusions as current study using NHIS data. In previous study, taking statin reduced hazard ratio for lung cancer development and was associated with longer overall survival in IPF patients. One of the results that we would like to emphasize on this study was the higher compliance with statin use had better risk reducing effect on lung cancer development by delaying its onset of time during the lifetime of the IPF patients. To confirm the preventative effect of regular statin use in lung cancer development, prospective study design should be followed to overcome the data-based results we performed. Minor> 1. Please provide the disease name for the injury code as supplementary material. (M05.1, M05.2,78 M05.3, M05.8, M05.9, M06.0, M06.8, M06.9, M30.1, M31.3, M31.7, M32, M33, M34, M35.0, 79 M35.1, D86, J84.0, J60~J70.9. J84 etc.) Answer: Thank you so much for your comments. We made the list of disease for each codes and attached under the file named ‘S1_Codes list of interstitial lung diseases.docx’ and described on line 649. 2. Please provide a more detailed definition of “statin use”. Answer: We’re grateful for your comments. The detailed description of “statin use” are added on the section of method in line 100-106 and revised its limitation in line 335-338. 3. Please provide definitions of “Drinking amount at a time” and “Physical activity intensity” in the text. Answer: Thank you for the comments. The definitions of “Drinking amount at a time” was described in line 111-123. The definitions of “Physical activity intensity” were exhibited at line 125-134. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0299484.r002
1 Feb 2024 Decision Letter - Tsai-Ching Hsu, Editor PONE-D-23-28368R1The preventative effects of statin on lung cancer development in patients with idiopathic pulmonary fibrosis using the National Health Insurance Service Database in KoreaPLOS ONE Dear Dr. Kang, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Mar 17 2024 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, Tsai-Ching Hsu, Ph.D. Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [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 #2: All comments have been addressed Reviewer #3: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: Yes Reviewer #3: Yes ****** 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 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 #2: (No Response) Reviewer #3: erratum: 1.line 223: and older age at diagnosis advice shifting " and " to "though " and it will make readers understand more easily 2.line 287 were invetigated by Would you mind to get rid of the word "by " here? 3.Figure 1-A/1-B: Would you mind to write ipf into IPF in capital letters? 4.line -41 Would you mind to change the words"lipid-lowering " into "cholesterol production" it would be more correct , because that when statin blocks active site of lipid-lowering ezyme, how it will make lipid getting down possible by blocking its function 5.line 166: maybe you miss the symbol of "% " behind the number 18.7 6.suggestion on your discussion: Is it still the same results as well as the DM , a reduced mortality(OS) factor, in non-statin user group after your meta-analysis? You may consider to support and strengthen your point of view if it still has significant P value in non-statin use group processing meta-analysis ****** 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: 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.0299484.r003
Revision 2
8 Feb 2024 Author Response Dear Editor-in-Chief, We would like to thank you and the reviewers of the PLOS ONE for taking the time to review our article. It is truly honorable to receive the letter of revision to enrich the work of research we have performed. We would like to appreciate for the time and efforts by the editors to this paper. We have made some corrections, answers, and clarifications in the manuscript after going over the reviewers’ comments. The changes are summarized below: Reviewer #1: The authors present an epidemiological study with a satisfying sample of patients regarding the impact of statin use in IPF survival. However, there are methodological issues that may have affected research results. Particularly, as the authors do not include lung function parameters and the use of antifibrotics in their registry, important aspects that is known to affect survival in IPF studies limit the significance of their results. Major comments: 1. You do not include important clinical parameters in IPF patients of both groups, including FVC, DLCO and 6MWT that could have impacted the survival. Lung function would allow us to assess the severity of both groups. I think that this is a serious limitation in the study. Answer: We agree with reviewer’s opinion. As the reviewer told, functional volume capacity (FVC), diffusing capacity for carbon monoxide (DLCO) and six-minute walk test (6MWT) are very important factors to impact on the survival of IPF patients. However, NHIS dataset does not include serial pulmonary function tests and 6MWT of every patient, therefore it was hardly possible to be gathering and analyze each of FVC and forced expiratory volume in one second (FEV1) of selected 9182 patients. We further described detailed sentences in discussion section, line 342-345. 2. The fact that the exercise was significantly different between the statin and the non-statin groups could be related to the severity of patients. In case of severe pulmonary fibrosis in which patients need oxygen may have less exercise than other milder cases. Answer: Thank you for your comments. We also agree with reviewer’s comments. The the phrase of ‘physical activity’ and the ‘exercise’ as a noun were used interchangeably in Korean languege, so we made correction from the word of ‘exercise’ in the manuscript into ‘physical activity’ at table 1, table 3 and table 4, and highlighted the corrections in manuscript at line 35, 208-209, 224-225, 294, 305 and 308 because it was more appropriate. Physical activity frequency were different between statin and non-statin user group, and lower frequency of physical activity was noted at statin user group. As the reviewer pointed, we could not consider the severity of IPF based on pulmonary function test, 6MWT and oxygen use, because NHIS dataset does not collect these varibles, and we added detailed sentences in limitation, line 342-345. However, considering the possibility of correlation between the physical activity frequency and other clinical factors associated with IPF patients, we performed cox proportional hazard regression analysis including physical activity frequency as confounding factors. As a result, physical activity frequency was independently associated with reduced hazard in mortality of IPF patients, but not associated with lung cancer development. 3. There are diverse clinical characteristics that differ between the 2 groups. Why you do not include all these variables in the multivariate analysis. Answer: Thank you for your comments. We additionally included all variables for multivariate analysis (age at diagnosis of IPF, sex, BMI, total cholesterol, blood pressure, smoking history, drinking frequency, drinking amount, physical activity frequency, comorbidities) which are different between two groups (Table 3). 4. Did you include age in the multivariate analysis? Answer: Thank you for your comments. We included ages at first diagnosis of IPF in multivariate analysis (Table 3 and Table 4). 5. How could diabetes have affected OS in IPF? Maybe there is a confounding here? Answer: We agree with reviewer’s opinion. In our study, diabetes mellitus (DM) was associated with reduced hazard ratio of OS in IPF patients. As we explained at discussion section, these findings would be associated to DM medications. Metformin is known to be involved in anti-fibrotic physiology and has inhibitory effect in myofibroblasts differentiations. Also, another popularly used GLP-1 receptor agonist was found to have anti-pulmonary fibrosis effects in animal models. In our study, we did not conduct an investigation on various types of diabetic drugs, so it was not possible to confirm whether mortality was reduced by DM or diabetic drugs. So, further investigation was needed to confirm these findings. 6. Another important limitation is the fact that you have not taken into consideration antifibrotics that affect progression and mortality. So, this may have also affected OS threatening your internal validity. Answer: We fully agree with reviewer’s comments. We collected IPF patients between 2002 and 2018. The official date of release of pirfenidone was July 2011(https://www.shionogi.com/content/dam/shionogi/global/news/pdf/2011/e_110712.pdf). However, pirfenidone has been reimbursed since 2015, and nintedanib is still not reimbursed in Korea. The definite limitation of our study is that the history of two antifibrotic drugs were not included in the analysis because the timing of domestic use of drugs and imbursements were different. We added detailed sentences in line 341-342. 7. Another limitation, is that you have included patients based on ICD-10, here there might be also misclassification and information bias. It should be also stated in the limitations paragraph. Answer: Thank you for your comments. We added detailed sentences at limitation section, line 331-333. Minor comments: 1. Please correct in Table 2, 1st row, 3rd column the word ‘statin’. Answer: Thank you for your comments. We corrected the word at table 2. Reviewer #2: This study shows the clinical impact of statin administration on the development of lung cancer and overall survival in patients with IPF using the NHIS database. However, the following comments are need to be modified. Major> 1. Please provide the "Patients flow chart" as figure 1 including inclusion criteria and exclusion criteria. Response: We fully agree with reviewer’s comments. We summarized briefly inclusion and exclusion criteria at material and method sections. There was an issue on processing the number of patients we selected and excluded in the flowchart because the period of use of health insurance data has expired, it is currently difficult to accurately determine the number of patients who meet the exclusion criteria. Instead, in order to clarify to understand out study, we added to adjunctive information in the manuscript about the study design and the population in the section of method. (line 76-86) 2. Did you conduct multivariate analysis in Table 3? The variable 'statin compliance' applies only to the 'statin user' group, so does that mean the non-user group was excluded from the analysis? Answer: The results shown on Table 3 by Cox proportional hazard analysis were performed under multivariate analysis. We agree with reviewer’s opinion, so variable ‘statin compliance’ was excluded from our multivariate analysis. (Table 3) 3. You previously suggested that statins have a preventive effect on lung cancer development in IPF patients. However, this effect was not found in the current paper. What do you think about this? (https://doi.org/10.1016/j.chest.2022.08.1445) Answer: Thank you for your review to our other study. Previous study was conducted using our clinical warehouse on the same topic as this study, and showed the same conclusions as current study using NHIS data. In previous study, taking statin reduced hazard ratio for lung cancer development and was associated with longer overall survival in IPF patients. One of the results that we would like to emphasize on this study was the higher compliance with statin use had better risk reducing effect on lung cancer development by delaying its onset of time during the lifetime of the IPF patients. To confirm the preventative effect of regular statin use in lung cancer development, prospective study design should be followed to overcome the data-based results we performed. Minor> 1. Please provide the disease name for the injury code as supplementary material. (M05.1, M05.2,78 M05.3, M05.8, M05.9, M06.0, M06.8, M06.9, M30.1, M31.3, M31.7, M32, M33, M34, M35.0, 79 M35.1, D86, J84.0, J60~J70.9. J84 etc.) Answer: Thank you so much for your comments. We made the list of disease for each codes and attached under the file named ‘S1_Codes list of interstitial lung diseases.docx’ and described on line 649. 2. Please provide a more detailed definition of “statin use”. Answer: We’re grateful for your comments. The detailed description of “statin use” are added on the section of method in line 100-106 and revised the limitations of our study in the third section, specifically in lines 335-338. 3. Please provide definitions of “Drinking amount at a time” and “Physical activity intensity” in the text. Answer: Thank you for the comments. The definitions of “Drinking amount at a time” was described in line 111-123. The definitions of “Physical activity intensity” were exhibited at line 125-134. Reviewer #3: 1. ~ 5. Erratum: Answer: The errata suggested from No.1 to 5 were mostly made corrections on the manuscript and highlighted; No.1 was in line 223, No.2 was in line 287, No.4 was in line 41, and No.5 was in line 166. Lastly, in response to the erratum No.3, the lowercase letters “ipf” have been corrected to capital letters in the description of Figure 1-A and 1-B and uploaded. Thank you for your comments. 6. Is it still the same results as well as the DM, a reduced mortality (OS) factor in non-statin user group after your meta-analysis? You may consider to support and strengthen your point of view if it still has significant P value in non-statin use group processing meta-analysis. Answer: Thank you for the suggestion. In our study, DM was identified as one of the risk-reducing factors for overall survival (OS) in IPF patients, encompassing both statin users and non-users, with a reduction of nearly 22%. According to the multivariate Cox regression analysis, we proposed that the influencing factor may be attributed to glucose-lowering drugs, such as metformin, exhibiting potent anti-fibrotic effects. Further investigation is necessary to ascertain the prescription rates, types, and effects of diabetes medications on IPF mortality in both statin and non-statin users in the future. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0299484.r004
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Formally Accepted
26 Feb 2024 Acceptance Letter - Tsai-Ching Hsu, Editor PONE-D-23-28368R2 PLOS ONE Dear Dr. Kang, 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. Tsai-Ching Hsu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0299484.r006

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