Clinical phenotypes of chronic cough categorised by cluster analysis

Jiyeon Kang; Woo Jung Seo; Jieun Kang; So Hee Park; Hyung Koo Kang; Hye Kyeong Park; Sung-Soon Lee; Ji-Yong Moon; Deog Kyeom Kim; Seung Hun Jang; Jin Woo Kim; Minseok Seo; Hyeon-Kyoung Koo

doi:10.1371/journal.pone.0283352

Peer Review History

Original SubmissionSeptember 8, 2022
26 Dec 2022 Decision Letter - Bharat Bhushan Sharma, Editor PONE-D-22-25031Clinical Phenotypes of Chronic Cough Categorised by Cluster AnalysisPLOS ONE Dear Dr. Koo, 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. ACADEMIC EDITOR: Further clarification is necessary regarding individual components of cough clusters and why it is important to divide cough into the clusters identified by the authors in the manuscript. Do you think that your findings challenge current thinking about cough as a clinical symptom? The evidence presented must be strong enough to prove your case. Try to cite all the relevant work that would contradict your thinking and address it appropriately. Please submit your revised manuscript by Feb 09 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, Bharat Bhushan Sharma, M.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. 3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. 4. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. 5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Additional Editor Comments: The manuscript has been reviewed by a set of reviewers. Further clarification is necessary regarding individual components of cough clusters and why it is important to divide cough into the clusters identified by the authors in the manuscript. Do you think that your findings challenge current thinking about cough as a clinical symptom? The evidence presented must be strong enough to prove your case. Try to cite all the relevant work that would contradict your thinking and address it appropriately. [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 Reviewer #3: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: 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 Reviewer #3: 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 Reviewer #3: 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: Following up you arguments was a little challenging it would be better that you clear delineate the cough assessment and clustering. From table 1 female predominate all groups but this is not reflected in the text. There is some attempt to link clustering with etiology but other than Asthma/CVA and GERD its not claear if other clustering predicted cause. This is a good start as the world is moving to ML and AI Reviewer #2: This manuscript by Kang et al. focused on the clinical phenotypes of chronic cough. Authors evaluated the characteristics and severity of chronic cough using the COugh Assessment Test (COAT) and the Korean version of the Leicester Cough Questionnaire (K-LCQ) and categorized patients with chronic cough into 4 clusters using the cluster analysis. As authors mentioned, etiology of cough and underlying diseases in patients with chronic cough are various. Therefore, the concept of this study to clarify the characteristics of these patients is valuable and results seem agreeable. Although this manuscript seems written well, authors may want to consider several issues as follows. Major comments 1) It is difficult to understand why the etiology of chronic cough was diagnosed only 4 diseases such as upper airway cough syndrome (UACS), asthma/cough variant asthma (CVA), eosinophilic bronchitis (EB), and gastroesophageal reflux disease (GERD). How did authors deal with other respiratory diseases such as interstitial pneumonia, COPD, and lung cancer? Were these diseases included in UACS? Otherwise, authors should clarify what diseases are included in UACS. 2) In relation to above, although only GERD was listed as an extra pulmonary cause of chronic cough, how did authors categorize other diseases such as chronic sinusitis and congestive heart failure. 3) It is unknown whether this clustering was associated with any outcome in patients with chronic cough from this study. Minor comments 1) Number of patients seems relatively small to identify clusters. 2) In Table 1, “current smoker” is duplicated and is not a diagnosis. In addition, what does “idiopathic” mean? Is this same as “unknown cause”? 3) In Table 1, If so, its number may be 19 as described in the main text. Furthermore, according to the Supplementary Figure S2B, number of multiple cause should be 20. Please make sure all numbers carefully again. 4) In Table 1, for what dis asterisk indicate statistical significance? Comparison should be performed among 4 clusters. Reviewer #3: In the manuscript, the authors tried to categorise the phenotypes of chronic cough by cluster analy based on the characteristics and severity of cough assessed by the COugh Assessment Test (COAT) and the Korean version of the Leicester Cough Questionnaire. They found chronic cough could be divided into four cluster pehenotypes: 1) elderly with mild cough, 2) middle-aged with less severe cough, 3) relatively male-predominant youth with severe cough, and 4) female-predominant elderly with severe cough. All clusters had distinct demographic and symptomatic characteristics and underlying causes. They concluded four distinct phenotypes of chronic cough reflected the significant differences in the aetiologies and provided a stratified medical approach for individualising diagnostic and therapeutic strategies. It is an interesting research. However, there are several isssus to be addressed. Major comments 1.Four cough phenotypes were clustered based on the simple characteristics and simple tools of cough evaluation tool, and may reflect some feature of common etiologies underlying chronic cough. However, the common causes of chronic cough can be easily identified and management following the current approach for chronic cough. Do we really need these cluster phenotypes since their identification seems to have no potential ability to improve the diagonosis and treatment of these common etiologies? 2.In the cohort of the patients with chronic cough, there were 19 (6.3%) patients whose cause was not identified and 20 participants (7.8%) who had multiple causes for their cough. What about their distribution in four cluster phenotypes? I think it may help to seek specific therapy if the phenotypes of these chronic refractory cough can be identified by the cluster analysis because their management is difficult and challenging. . The minor comments 1.Cluster 1 had a mild cough and older age with GERD as a main underlying etiology. Please explain why GERD-associated cough coughed mildly. 2.It is a surprise that age was negatively correlated with the COAT scores for questions 1-5 and the total COAT. ****** 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: Dr Evans Amukoye 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. Attachments Attachment Submitted filename: Clinical Phenotypes of Chronic Cough Categorised by Cluster Analysis.docx https://doi.org/10.1371/journal.pone.0283352.r001
Revision 1
24 Jan 2023 Author Response Additional Editor Comments: The manuscript has been reviewed by a set of reviewers. Further clarification is necessary regarding individual components of cough clusters and why it is important to divide cough into the clusters identified by the authors in the manuscript. Do you think that your findings challenge current thinking about cough as a clinical symptom? The evidence presented must be strong enough to prove your case. Try to cite all the relevant work that would contradict your thinking and address it appropriately. Answer: Thank you for your comment. Cough is the most prevalent symptom of numerous diseases, including pulmonary and extra-pulmonary diseases. In addition, cough-related symptoms are highly variable, making it quite difficult to determine the underlying cause. Furthermore, guidelines for chronic cough evaluation require a variety of specialized equipment that is impractical for many primary care centers with limited resources, thereby increasing the difficulty for physicians. Due to these challenges, some guidelines also recommend empirical treatment for potential causes first, followed by re-evaluation of treatment response as an alternative strategy. Therefore, identifying the subtypes of these heterogeneous phenotypes of chronic cough is crucial for better understanding of the pathophysiology and treatment of disease. So far, the majority of research on chronic cough had primarily focused on epidemiology and diagnostic flow. Few studies had described phenotypes and compared differences according to etiology. The aim of our study was to identify specific subtypes using cluster analysis in order to assist physicians in diagnosing the cause of chronic cough based on the phenotypes of heterogeneous patients. Reviewers' comments: 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: Following up you arguments was a little challenging it would be better that you clear delineate the cough assessment and clustering. From table 1 female predominate all groups but this is not reflected in the text. There is some attempt to link clustering with etiology but other than Asthma/CVA and GERD its not clear if other clustering predicted cause. This is a good start as the world is moving to ML and AI Answer: Thank you very much for your comments. As you pointed, proportion of females in all clusters was greater than fifty percent, which is usual pattern for chronic cough population. We added the following sentences to the Result section to clarify the predominance of females. (Page 9, line 141) Among them, 94 (36.9%) men and 161 (63.1%) women were included, with a male-to-female ratio of 1:1.71. (Page 12, line 205) Cluster 3 represented 31.8% (81/255) of the participants and comprised the youngest population. Although less than 50%, the proportion of men (46.9%) was the highest, and the total COAT scores and the scores for each COAT question were the highest. Furthermore, as you pointed, we were unable to identify the specific predominance other than asthma/CVA and GERD. To clarify the facts, we added the following limitation to Discussion section: (Page 16, Line 296) Lastly, distinct differences of UACS or EB in each cluster were not observed, and additional methods to specify these differences are required. Reviewer #2: This manuscript by Kang et al. focused on the clinical phenotypes of chronic cough. Authors evaluated the characteristics and severity of chronic cough using the COugh Assessment Test (COAT) and the Korean version of the Leicester Cough Questionnaire (K-LCQ) and categorized patients with chronic cough into 4 clusters using the cluster analysis. As authors mentioned, etiology of cough and underlying diseases in patients with chronic cough are various. Therefore, the concept of this study to clarify the characteristics of these patients is valuable and results seem agreeable. Although this manuscript seems written well, authors may want to consider several issues as follows. Major comments 1) It is difficult to understand why the etiology of chronic cough was diagnosed only 4 diseases such as upper airway cough syndrome (UACS), asthma/cough variant asthma (CVA), eosinophilic bronchitis (EB), and gastroesophageal reflux disease (GERD). How did authors deal with other respiratory diseases such as interstitial pneumonia, COPD, and lung cancer? Were these diseases included in UACS? Otherwise, authors should clarify what diseases are included in UACS. Answer: Thank you for your insightful comment. Previous reports have highlighted UACS, asthma including CVA, EB, and GERD as the primary causes of chronic cough in non-smokers with normal chest radiographs. We added the following sentence to the Introduction section: (Page 4, Line 62) The most common causes of chronic cough are known as upper airway cough syndrome (UACS), cough variant asthma (CVA), eosinophilic bronchitis (EB), and gastroesophageal reflux disease (GERD) [3-6]. We also included patients without structural lung disease in chest X-ray or CT, following the previous definition. We appreciate for allowing us to clarify the inclusion criteria. Inclusion criteria in the Method section were specified as follows: (Page 6, Line 88) The cause of chronic cough was assessed following the Korean cough guideline [18] by pulmonary specialists in each hospital, excluding those for patients with suspected abnormalities on plain chest radiography/computed tomography or with chronic respiratory disease, such as overt asthma, COPD, bronchiectasis, tuberculosis-destroyed lung, and lung cancer. 2) In relation to above, although only GERD was listed as an extra pulmonary cause of chronic cough, how did authors categorize other diseases such as chronic sinusitis and congestive heart failure. Answer: Thank you for your points. Chronic sinusitis was categorized as upper airway cough syndrome, while structural diseases with abnormal chest X-ray including heart failure were excluded. Additionally, only patients with chronic cough as the primary reason for hospital visit were enrolled; those with other diseases who primarily complained of other symptoms, such as dyspnea, but cough as a secondary symptom were not enrolled. We clarified the inclusion criteria in the Method section as above mentioned. (Page 6, Line 88) The cause of chronic cough was assessed following the Korean cough guideline [18] by pulmonary specialists in each hospital, excluding those for patients with suspected abnormalities on plain chest radiography/computed tomography or with chronic respiratory disease, such as overt asthma, COPD, bronchiectasis, tuberculosis-destroyed lung, and lung cancer. 3) It is unknown whether this clustering was associated with any outcome in patients with chronic cough from this study. Answer: Thank you for your comments. As you pointed, we did not collect prognostic data, and the lack of longitudinal data, such as treatment success, recurrence, or even death, is one of our study’s significant limitations. This limitation was outlined in the Discussion section. We modified this sentence further to specify the outcomes as follows: (Page 16, Line 294) Since we did not gather prognostic data, such as treatment success or recurrence, longitudinal studies using clustering methods are required to evaluate the implications of clusters. Minor comments 1) Number of patients seems relatively small to identify clusters. Answer: Thank you for your points. That is correct. We added that limitation to the Discussion section as follows: (Page 16, Line 288) The number of patients included for clustering was relatively small, which might have diminished the significance between clusters. 2) In Table 1, “current smoker” is duplicated and is not a diagnosis. In addition, what does “idiopathic” mean? Is this same as “unknown cause”? Answer: Thank you very much for allowing us the opportunity to correct our error. The duplicated smoking variable was eliminated from Table 1. According to the ACCP guideline (Unexplained (idiopathic) cough: ACCP evidence-based clinical practice guidelines. Chest 2006 Jan;129(1 Suppl):220S-221S), idiopathic or unexplained cough was defined as a cough with no etiology identified after evaluation, also known as an unknown cause. To specify the cause, we changed the term ‘idiopathic’ to ‘idiopathic cough’ in Table 1. 3) In Table 1, If so, its number may be 19 as described in the main text. Furthermore, according to the Supplementary Figure S2B, number of multiple cause should be 20. Please make sure all numbers carefully again. Answer: Thank you very much for thorough review and suggestions. We sincerely appreciate the opportunity to correct our error. As you pointed, the exact number of patients with multiple causes is 20 and those with idiopathic cough is 16. Changes are made to the numbers in the Result section and Table 1. (Page 9, Line 148) In 16 (6.3%) patients, the cause could not be identified and a total of 20 participants (7.8%) had multiple causes for their cough (S2B Fig). 4) In Table 1, for what dis asterisk indicate statistical significance? Comparison should be performed among 4 clusters. Answer: We greatly appreciate your comment. All comparisons were re-evaluated using cluster 1 as the reference. Reviewer #3: In the manuscript, the authors tried to categorise the phenotypes of chronic cough by cluster analy based on the characteristics and severity of cough assessed by the COugh Assessment Test (COAT) and the Korean version of the Leicester Cough Questionnaire. They found chronic cough could be divided into four cluster phenotypes: 1) elderly with mild cough, 2) middle-aged with less severe cough, 3) relatively male-predominant youth with severe cough, and 4) female-predominant elderly with severe cough. All clusters had distinct demographic and symptomatic characteristics and underlying causes. They concluded four distinct phenotypes of chronic cough reflected the significant differences in the aetiologies and provided a stratified medical approach for individualising diagnostic and therapeutic strategies. It is an interesting research. However, there are several issues to be addressed. Major comments 1.Four cough phenotypes were clustered based on the simple characteristics and simple tools of cough evaluation tool, and may reflect some feature of common etiologies underlying chronic cough. However, the common causes of chronic cough can be easily identified and management following the current approach for chronic cough. Do we really need these cluster phenotypes since their identification seems to have no potential ability to improve the diagnosis and treatment of these common etiologies? Answer: Thank you for your comments. In guideline, algorithm for chronic cough evaluation includes chest radiography, PNS view, spirometry with bronchodilator reversibility test, bronchoprovocation test, induced sputum analysis, FENO, gastro-endoscopy, and for the specific diagnosis, chest CT, PNS CT, bronchoscopy, and echocardiography are additionally required. However, these tests require a variety of specialized laboratory equipment and space, which is not feasible for many primary care centers due to limited resources. Because of these challenges, some guidelines also recommend empirical treatment for potential causes first and subsequent re-evaluating treatment response as an alternative strategy. Therefore, clustering the phenotype would be advantageous for many primary care centers that treat numerous patients with chronic cough. We added the following sentence to the Introduction section: (Page 4, Line 64) However, the associated symptoms of chronic cough vary widely, and determining the aetiology of chronic cough is a difficult process as it can develop for various reasons [7-11]. Guidelines for the evaluation of chronic cough include a variety of specialized equipment, which is not feasible for many primary care centres due to limited resources [3-6]. 2.In the cohort of the patients with chronic cough, there were 19 (6.3%) patients whose cause was not identified and 20 participants (7.8%) who had multiple causes for their cough. What about their distribution in four cluster phenotypes? I think it may help to seek specific therapy if the phenotypes of these chronic refractory cough can be identified by the cluster analysis because their management is difficult and challenging. Answer: Thank you for your insightful comment. Unfortunately, there were no significant differences in the distribution of these patients between clusters. The numbers and percentages are detailed in Table 1. The minor comments 1.Cluster 1 had a mild cough and older age with GERD as a main underlying etiology. Please explain why GERD-associated cough coughed mildly. Answer: Thank you very much for your comment. We were unable to find the reference because trials comparing cough severity in each etiology had not been conducted. One of our potential hypotheses is that typical GERD-related coughs tend to be periodic, such as coughing at night time or after meal, so that the overall mean cough severity may be less severe than in other diseases with persistent respiratory tract inflammation. We added following explanation to the Discussion section: (Page 14, Line 260) Moreover, patients with GERD reported less severe cough. One of our hypotheses is that typical GERD-related coughs tend to be periodic, such as coughing at night or after meal, so that the overall mean cough severity may be less severe than in diseases with persistent inflammation of respiratory tract. 2. It is a surprise that age was negatively correlated with the COAT scores for questions 1-5 and the total COAT. Answer: Thank you very much for your comment. We added following sentences to explain the potential mechanism. (Page 13, Line 228) An increase in age was negatively correlated with the total COAT score in the overall sample; however, there was no such correlation within each cluster. Decrease of subjective perception of cough severity with increasing age suggests the possible influence of age on generation or perception of cough. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0283352.r002
2 Mar 2023 Decision Letter - Bharat Bhushan Sharma, Editor PONE-D-22-25031R1Clinical phenotypes of chronic cough categorised by cluster analysisPLOS ONE Dear Dr. Koo, 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. ============================== ACADEMIC EDITOR: Please proofread your paper thoroughly and correct spelling, punctuation, grammar, and formatting errors. Because all references will be linked electronically as much as possible to the papers they cite, proper formatting of references is crucial. For more information, please refer to submission guidelines of the journal. ============================== Please submit your revised manuscript by Apr 16 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, Bharat Bhushan Sharma, M.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. Additional Editor Comments: Please proofread your paper thoroughly and correct spelling, punctuation, grammar, and formatting errors. Because all references will be linked electronically as much as possible to the papers they cite, proper formatting of references is crucial. For more information, please refer to submission guidelines of the journal. [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: All comments have been addressed 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 #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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 #1: Yes 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 #1: Yes 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 #1: This is a good start In using data (AI) to predict causes of chronic cough. I note no clustering in certain groups that leaves a lacuna, but as we get more data we may find out if we may/may not cluster all possible groups. I accept your responses Reviewer #2: This revised manuscript by Kang et al. focused on the clinical phenotypes of chronic cough. Authors evaluated the characteristics and severity of chronic cough using the COugh Assessment Test (COAT) and the Korean version of the Leicester Cough Questionnaire (K-LCQ) and categorized patients with chronic cough into 4 clusters using the cluster analysis. Authors revised the manuscript appropriately according to the reviewers’ comments. It appeared better. I do not have further comment to be resolved. Reviewer #3: After revision, the quality of manuscript has greatly been improved. I have no further comments for the revised manuscript that need to be addressed. ****** 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: 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.0283352.r003
Revision 2
3 Mar 2023 Author Response Thank you very much for allowing us the opportunity to correct our errors. We corrected spelling, punctuation, grammar, and reference formatting errors all through the manuscript. Both tracked and clean versions of the manuscript are provided. Again, we appreciate all the invaluable comments that improved the overall quality of our manuscript. Attachments Attachment Submitted filename: Response to reviewer_R2.docx https://doi.org/10.1371/journal.pone.0283352.r004
7 Mar 2023 Decision Letter - Bharat Bhushan Sharma, Editor Clinical phenotypes of chronic cough categorised by cluster analysis PONE-D-22-25031R2 Dear Dr. Koo, 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, Bharat Bhushan Sharma, M.D. Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0283352.r005
Formally Accepted
9 Mar 2023 Acceptance Letter - Bharat Bhushan Sharma, Editor PONE-D-22-25031R2 Clinical phenotypes of chronic cough categorised by cluster analysis Dear Dr. Koo: 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 Professor Bharat Bhushan Sharma Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0283352.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .