Prognostic model of in-hospital ischemic stroke mortality based on an electronic health record cohort in Indonesia

Nizar Yamanie; Yuli Felistia; Nugroho Harry Susanto; Aly Lamuri; Amal Chalik Sjaaf; Muhammad Miftahussurur; Anwar Santoso

doi:10.1371/journal.pone.0305100

Peer Review History

Original SubmissionFebruary 22, 2023
5 Jul 2023 Decision Letter - Yee Gary Ang, Editor PONE-D-23-03260Prognostic Model of In-hospital Ischemic Stroke Mortality Based on an Electronic Health Record Cohort in IndonesiaPLOS ONE Dear Dr. Santoso, 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 Aug 19 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. 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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. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed: 1) Tian, X., Liu, J., Yu, C., Hou, Y., Zhan, C., Lin, Q., ... & Wang, J. (2021). Long-term trends in stroke management and burden among low-income women in a rural area from China (1992–2019): a prospective population-based study. Frontiers in Neurology, 1895. 2) Fonarow GC, Saver JL, Smith EE, Broderick JP, Kleindorfer DO, Sacco RL, Pan W, Olson DM, Hernandez AF, Peterson ED, Schwamm LH. Relationship of national institutes of health stroke scale to 30-day mortality in medicare beneficiaries with acute ischemic stroke. J Am Heart Assoc. 2012 Feb;1(1):42-50. doi: 10.1161/JAHA.111.000034. 3) Sun GW, Shook TL, Kay GL. Inappropriate use of bivariable analysis to screen risk factors for use in multivariable analysis. J Clin Epidemiol. 1996 Aug;49(8):907-16. doi: 10.1016/0895-4356(96)00025-x. PMID: 8699212. In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed. 3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. 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Please ensure that you refer to Figures 1 and 2 in your text as, if accepted, production will need this reference to link the reader to the figure. Additional Editor Comments: This is an interesting study and I invite the authors to submit a revised version addressing the concerns of the 2 reviewers. [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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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: 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: thank you for the review chance. I would like to recommend the inclusion of thrombophilia types [e.g. protein C, protein S, antithrombin deficiency ..etc] as well as inclusion of other prognostic scales " e.g. THRIVE and Orpington scales...etc" as the Asian population has higher incidence of small-vessel ischemic stroke and stroke occurrence in younger ages as compared to Caucasian population, partly due to thrombophilia etiologies. Reviewer #2: In this manuscript entitled 'Prognostic Model of In-hospital Ischemic Stroke Mortality Based on an Electronic Health Record Cohort in Indonesia' the authors investigate the predictors of in-hospital mortality in patients with ischemic stroke (IS). The study is based on the IS medical records from the National Brain Centre Hospital, Jakarta, Indonesia with a total of 3278 patients with IS. The authors worked on an interesting topic regarding public health meassage and local regional South-east Asia countries but, in my opinion, there are some methodological issues and suggestions to consider. - there is a discrepancy between the period in which the study was conducted (one would imagine operationally) and the period of observation and date collection, respectively October 2021 to February 2022 versus years 2019-2020 (without specifying exact beginning and end). The authors should better explain this difference and possibly consider the possibility, if any, of extending the observation period. It would also be useful for the date collection to have a precise observation period (not only year but also month and/or day). - As far as the outcome under analysis is concerned, it is presumable that the cases were identified using the ICD definition. This should be made explicit. - It is unclear whether the mortality assessment was only carried out intra-hospital. Did the observation continue for some time outside the hospital as well? - The time-to-event analysis should be enriched with a competitive risk analysis as discharge represents an event that can drastically change the patients' medical history. Therefore not only simple COX but also cumulative incidence function curves and the Fine and Gray model (Resche-Rigon M et al. Crit Care. 2006 Feb;10(1):R5). - The authors claim to have removed all records with missing data. Before simple removal it would be appropriate to investigate the significance of this missingness using appropriate analyses (pattern analysis, missing per patient, missing per item, missing by outcome). It is evident that, for example, a reduction in the number of subjects leads to a change in the incidence of outcomes (from 4.69% mortality to 3.48%), so it is assumed that in the 7.9% of missing data there is a different percentage of subjects with an unfavourable outcome. Could this have introduced a bias into the analysis? - The authors state that they selected the variables using a stepwise regression, forward or backward? Furthermore, they mention the use of other classification models compared with appropriate metrics. Both models and metrics should be listed and in a hypothetical supplementary material, the results of these comparisons should be presented to see if the type of algorithm may have influenced the final selection of variables. - Table 1 should also present the overall data and not only the comparison between subjects with and without an event. - Was the GCS used as a continuous variable or category? Shouldn't it be a continuous score? - The figure presented represents the survival plot as estimated from the Cox's regression model. The time-to-event variable should be described a priori without any modelling. The overall kaplan meier, median follow-up, median survival and confidence interval should be presented. This would help readers to better understand the type of patients and the time frame studied. ****** 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: Mohamed Mostafa Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0305100.r001
Revision 1
18 Aug 2023 Author Response Response to Reviewers Reviewer #1: thank you for the review chance. I would like to recommend the inclusion of thrombophilia types [e.g. protein C, protein S, antithrombin deficiency ..etc] as well as inclusion of other prognostic scales " e.g. THRIVE and Orpington scales...etc" as the Asian population has higher incidence of small-vessel ischemic stroke and stroke occurrence in younger ages as compared to Caucasian population, partly due to thrombophilia etiologies. We thank the reviewer for this important comment and agree that the suggested prognostic scales and thrombophilia types are important for Asian population. Sadly, we do not have the necessary information. Hence, we did not include nor mention any of those data in our manuscript. Reviewer #2: In this manuscript entitled 'Prognostic Model of In-hospital Ischemic Stroke Mortality Based on an Electronic Health Record Cohort in Indonesia' the authors investigate the predictors of in-hospital mortality in patients with ischemic stroke (IS). The study is based on the IS medical records from the National Brain Centre Hospital, Jakarta, Indonesia with a total of 3278 patients with IS. The authors worked on an interesting topic regarding public health meassage and local regional South-east Asia countries but, in my opinion, there are some methodological issues and suggestions to consider. - there is a discrepancy between the period in which the study was conducted (one would imagine operationally) and the period of observation and date collection, respectively October 2021 to February 2022 versus years 2019-2020 (without specifying exact beginning and end). The authors should better explain this difference and possibly consider the possibility, if any, of extending the observation period. It would also be useful for the date collection to have a precise observation period (not only year but also month and/or day). We acknowledge that the statement of operational study duration and data collection duration led to confusion. To avoid this problem, we removed the line about operational study duration in paragraph 1 of methods section. We apologize for the wrong data collection period written in paragraph 4 of methods section, we changed the data collection years in the line and added the specific start and end date of data collection duration. Old line: “Data for a period of one year were collected from 2019 to 2020.” New line: “Data for a period of one year was collected from 1 January to 31 December 2020.” - As far as the outcome under analysis is concerned, it is presumable that the cases were identified using the ICD definition. This should be made explicit. We realize that we did not write it clearly that the diagnosed cases were recorded in medical record along with their ICD definition. We revised the following line in the first paragraph of methods section: Old line: “The study population included hospitalised IS patients according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) definition.” New line: “The study population included hospitalised IS patients according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) definition along with the ICD-10 code I63 for acute ischemic stroke.” - It is unclear whether the mortality assessment was only carried out intra-hospital. Did the observation continue for some time outside the hospital as well? Our apologies for not stated it in the methods section that we only assessed mortality during hospitalization. We added the necessary information in the first line of Clinical outcomes of methods section. Old line: “The clinical outcomes were all-cause and stroke-related mortality rates.” New line: “The clinical outcomes were all-cause and stroke-related mortality rates during hospitalization.” - The time-to-event analysis should be enriched with a competitive risk analysis as discharge represents an event that can drastically change the patients' medical history. Therefore not only simple COX but also cumulative incidence function curves and the Fine and Gray model (Resche-Rigon M et al. Crit Care. 2006 Feb;10(1):R5). We thank the reviewer for raising the issue about competing risk. We added the cumulative incidence function curves and the comparison of Cox regression results against Fine and Gray models in the results section. - The authors claim to have removed all records with missing data. Before simple removal it would be appropriate to investigate the significance of this missingness using appropriate analyses (pattern analysis, missing per patient, missing per item, missing by outcome). It is evident that, for example, a reduction in the number of subjects leads to a change in the incidence of outcomes (from 4.69% mortality to 3.48%), so it is assumed that in the 7.9% of missing data there is a different percentage of subjects with an unfavourable outcome. Could this have introduced a bias into the analysis? Indeed, we took into account the possibility of bias being introduced in this analysis. We thoroughly explored the missingness to assess the mechanism, i.e. MCAR/MAR/MNAR. It’s understandably challenging to differentiate MAR/MNAR through statistical analysis procedure; and it is more practical to determine whether the missing values occurred due to MCAR/non-MCAR, which could be MAR/MNAR. For clinical research, complete-case analysis in datasets with MAR entries still produces valid results (read more: https://doi.org/10.1016/j.jclinepi.2022.08.016). In another review of published RCTs, the majority of published studies still used complete case-analysis by discarding entries with null values (read more: https://doi.org/10.1186/1471-2288-14-118). Meanwhile, another review also suggested excluding observation in case of missingness in primary predictors for studies with cross-sectional design (read more: https://doi.org/10.1016/j.pmrj.2015.07.011). As such, we concluded that using a complete-case analysis is still arguably sound and justified. We attached our exploration on missingness in our supplementary materials, page 2-12. - The authors state that they selected the variables using a stepwise regression, forward or backward? Furthermore, they mention the use of other classification models compared with appropriate metrics. Both models and metrics should be listed and in a hypothetical supplementary material, the results of these comparisons should be presented to see if the type of algorithm may have influenced the final selection of variables. We agree that more detail about the analysis should be added as supplementary. We attached the supplementary about the detail of our analysis along with our revised manuscript. We used a bidirectional stepwise regression, a combination of forward and backward selection. We added this information in the first paragraph of Statistical analysis. Old line: “To aid the exploratory procedure, significant variables reported in previous studies are included in stepwise regression models.” New line: “To aid the exploratory procedure, significant variables reported in previous studies are included in stepwise regression models using a combination of forward and backward selection.” - Table 1 should also present the overall data and not only the comparison between subjects with and without an event. We added a column in Table 1 that showed the baseline characteristic for the overall patients in our manuscript. - Was the GCS used as a continuous variable or category? Shouldn't it be a continuous score? We understand that the GCS should be a continuous variable however the clinicians only assessed eye and movement scores of GCS as continuous measurement while the verbal as either coherence or incoherence. Thus, we decided to include GCS in the analysis separately for eye, movement, and verbal assessment. - The figure presented represents the survival plot as estimated from the Cox's regression model. The time-to-event variable should be described a priori without any modelling. The overall kaplan meier, median follow-up, median survival and confidence interval should be presented. This would help readers to better understand the type of patients and the time frame studied. Thank you for the suggestion, we have added the descriptive statistics in our supplementary file from page 22 to 29. Attachments Attachment Submitted filename: Response to Reviewers Rebuttle Paper 1 B-2_final.docx https://doi.org/10.1371/journal.pone.0305100.r002
16 Oct 2023 Decision Letter - Yee Gary Ang, Editor PONE-D-23-03260R1Prognostic Model of In-hospital Ischemic Stroke Mortality Based on an Electronic Health Record Cohort in IndonesiaPLOS ONE Dear Dr. Santoso, 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 Nov 30 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, Yee Gary Ang, MBBS MPH Academic Editor PLOS ONE Additional Editor Comments: The original reviewers were not available to review the paper so we had asked 2 more reviewers. Please kindly address their concerns before resubmitting. [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 #3: (No Response) Reviewer #4: (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 #3: Partly Reviewer #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: I Don't Know Reviewer #4: 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 Reviewer #4: 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: No Reviewer #4: 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: The authors present a retrospective observational study used IS medical records from a single (teriary, high volume) center in Indonesia, with predictors of in-hospital mortality in patients with IS. I would suggest the authors to consider the following suggestions: - having the manuscript checked by a native english speaker for errors regarding grammar, synthax etc. - having a more focused and structured discussion section Reviewer #4: The author explore in their paper Prognostic Model of In-hospital Ischemic Stroke Mortality Based on an Electronic Health Record Cohort in Indonesia. The research is intriguing however i have some concern about the possibile confounding variabels Major Criticism Do the authors explore in deep all cause of mortality? Indeed Ischemic Stroke has several complications, including infections? indeed mortality after ischemic stroke other than metabolic or cardiac causes has other factors as infection well known since a decades: "Post-stroke infection: A systematic review and meta-analysis 10.1186/1471-2377-11-110" particularly pneumonia " Int J Stroke. 2019 Feb;14(2):125-136. doi: 10.1177/1747493018806196" Therefore please specify if you can have access or not to ICD classification on Clicical dismission records Further it would be usefull also estimate how many patients had previous hosptial access Minor Criticism improve material and methods better clarifing the data extraction emthofd and model on ICD evaluation, for istance you shoudl eport waht kind of code you explored and why you selected those Improve tables in terms of better details about previous hospital access and cause of mortality ****** 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: No Reviewer #4: 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.0305100.r003
Revision 2
14 Dec 2023 Author Response Response to Reviewers Reviewer #3: The authors present a retrospective observational study used IS medical records from a single (tertiary, high volume) center in Indonesia, with predictors of in-hospital mortality in patients with IS. I would suggest the authors to consider the following suggestions: - having the manuscript checked by a native English speaker for errors regarding grammar, synthax etc. - having a more focused and structured discussion section. We thanked reviewer for the comment. We revised discussion section to make the structure better and more focused. Further, we asked professional proofreader to proofread our manuscript after we addressed comments from all reviewers. Reviewer #4: Major Criticism Do the authors explore in deep all cause of mortality? Indeed, Ischemic Stroke has several complications, including infections? indeed mortality after ischemic stroke other than metabolic or cardiac causes has other factors as infection well known since a decade: "Post-stroke infection: A systematic review and meta-analysis 10.1186/1471-2377-11-110" particularly pneumonia " Int J Stroke. 2019 Feb;14(2):125-136. doi: 10.1177/1747493018806196" Therefore please specify if you can have access or not to ICD classification on Clinical dismission records Further it would be useful also estimate how many patients had previous hospital access. Minor Criticism improve material and methods better clarifying the data extraction method and model on ICD evaluation, for instance you should report what kind of code you explored and why you selected those. Improve tables in terms of better details about previous hospital access and cause of mortality. We appreciated the reviewer’s inputs to improve our manuscripts. We went back to our medical record to get the related data, however due to time constraint we could only get aggregate data. It was also very hard for us to get specific ICD 10 for cause of death because clinical autopsy is not compulsory procedure in Indonesia. 499 (14%) patients were referred from other hospital and the prominent cause of death was cardiac arrest, followed by pneumonia, and sepsis. We decided to add these data in the first paragraph of results section, not in table 1 because we only have aggregate data. The following lines were added the first paragraph of results section: Around 14% of the patients (499 out of 3,561) were referred from other previous hospitals. The top three causes of death were cardiac arrest, pneumonia, and sepsis. Attachments Attachment Submitted filename: Response to Reviewers Rebuttal Paper 1 B 2023-11-27.docx https://doi.org/10.1371/journal.pone.0305100.r004
20 Feb 2024 Decision Letter - Yee Gary Ang, Editor PONE-D-23-03260R2Prognostic Model of In-hospital Ischemic Stroke Mortality Based on an Electronic Health Record Cohort in IndonesiaPLOS ONE Dear Dr. Santoso, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== There were mixed reviews between 4 reviewers. Please kindly read through the comments carefullly and address them before submitting again. ============================== Please submit your revised manuscript by Apr 05 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, Yee Gary Ang, MBBS MPH Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #3: (No Response) Reviewer #5: All comments have been addressed Reviewer #6: All comments have been addressed Reviewer #7: (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 #3: Partly Reviewer #5: Yes Reviewer #6: Yes Reviewer #7: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: I Don't Know Reviewer #5: Yes Reviewer #6: Yes Reviewer #7: No ****** 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 Reviewer #5: Yes Reviewer #6: Yes Reviewer #7: No ****** 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: No Reviewer #5: Yes Reviewer #6: No Reviewer #7: 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: The most important limitation of this study, besides the lack of generalizability, is the completeness of the data. This results in omitting important prognostic factors such as glycemia, history of diabetes and occurence of infection. Although pneumonia and sepsis were in the top 3 causes of mortality, presence of infection was not included in the model. Reviewer #5: (No Response) Reviewer #6: The authors raise a very important socio-economic public health problem stroke. However, the prediction model nowadays are computed using machine learning methods this can not render the merit for the publication of this study given lack of this kind of studies in LMICs. The English language must be improved!! Reviewer #7: Thank you for your hard work conducting the research. The study findings provide valuable insights into predictors of in-hospital mortality among IS patients in Indonesia. Here are a few comments: 1. Subject Selection Process The process of selecting subjects should be presented more clearly than the variable extraction process to reduce selection bias. Exclusion criteria should be defined and the reasons for exclusion should be explained. It should also be clearly indicated how many subjects were excluded in the process. Based on the information provided in the text alone, it is difficult to determine which group was ultimately included in the analysis. Especially, since there were quite a few subjects without blood glucose data, it is unclear whether they were all excluded from the analysis. If the target group is not transparently defined, the results are difficult to trust as they may reflect analysis of a heterogeneous population. 2. Adjustment for Comorbidities Adjustment for comorbidities is necessary using a comorbidity index. If obtaining variables for the comorbidity index is difficult, it is necessary to investigate and mention the major comorbidities. Adjustment should be made based on the number of comorbidities, or alternatively, adjustment should be made for major comorbidities. Especially, since the data was collected during the Covid-19 pandemic, Covid-19-related deaths could have had a significant impact, so this should be taken into consideration. 3. Co-variants Definition There is no accurate definition for heart disease, renal disease, uncontrolled diabetes, uncontrolled hypertension, etc. 4. Sex as Predictors for Mortality If sex becomes an important factor, additional analysis should be conducted by dividing by gender to determine if there are differences in factors related to post-stroke mortality according to sex. 5. Figure 2 Needs Modification It seems that Figure 2 needs to be revised. Is the x-axis in Figure 2(A) correct? Is it "year" or "length of stay"? Although it is not an observation for 50 years, the graph indicates that it has been tracked for 50 years. The intended message in Figure 2(B) is not well understood. It's not clear what is being explained in the survival analysis. It would be helpful if the rationale for showing the survival curve in the manuscript is well explained. 6. Other Comments 1) The lack of explanations for tables and figures in the text makes it difficult to match them with the content and lowers comprehensibility. 2) It is necessary to mention the possibility of more intensive drug therapy for patients with severe conditions who had low blood triglyceride levels, low-density lipoprotein (LDL) levels, and total cholesterol. 3) It should be noted that the analyzed data represent only one year and may not reflect long-term trends, and that the data collected from the hospital may be limited in terms of external environmental factors or additional factors affecting patients. ****** 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: No Reviewer #5: No Reviewer #6: Yes: Amanuel Sisay Endeshaw Reviewer #7: 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.0305100.r005
Revision 3
28 Apr 2024 Author Response Response to reviewers: 1. Subject Selection Process The process of selecting subjects should be presented more clearly than the variable extraction process to reduce selection bias. Exclusion criteria should be defined and the reasons for exclusion should be explained. It should also be clearly indicated how many subjects were excluded in the process. Based on the information provided in the text alone, it is difficult to determine which group was ultimately included in the analysis. Especially, since there were quite a few subjects without blood glucose data, it is unclear whether they were all excluded from the analysis. If the target group is not transparently defined, the results are difficult to trust as they may reflect analysis of a heterogeneous population. We thank the reviewer for highlighting the problem in understanding the patient’s selection process for our analysis. We replaced figure 1 with STROBE flowchart to make it easier to understand how we came to the final number of 3,278 patients for the analysis. 2. Adjustment for Comorbidities Adjustment for comorbidities is necessary using a comorbidity index. If obtaining variables for the comorbidity index is difficult, it is necessary to investigate and mention the major comorbidities. Adjustment should be made based on the number of comorbidities, or alternatively, adjustment should be made for major comorbidities. Especially, since the data was collected during the Covid-19 pandemic, Covid-19-related deaths could have had a significant impact, so this should be taken into consideration. We agree that comorbidities are important risk factors. We added pneumonia and sepsis into the analysis and revised the tables, results, and discussion to accommodate the new results. However, we could not add COVID-19 diagnosis as one of comorbidities into the analysis because only 13 patients were diagnosed with COVID-19 and none of them died. We added this into the limitation of our study. 3. Co-variants Definition There is no accurate definition for heart disease, renal disease, uncontrolled diabetes, uncontrolled hypertension, etc. We apologize that we did not write a clear definition for uncontrolled diabetes and uncontrolled hypertension. We added the definition for those 2 terms under the paragraphs (highlighted in yellow) for the definition of heart disease and renal disease. Additionally, diagnosis of cardiovascular disease and renal disease were determined using the International Classification of Diseases, 10th revision (ICD-10) as a standard operational procedure in our hospital, as presented in Methods section. 4. Sex as Predictors for Mortality If sex becomes an important factor, additional analysis should be conducted by dividing by gender to determine if there are differences in factors related to post-stroke mortality according to sex. Thanks indeed for your suggestion, and in addressing your valuable suggestion we already performed the Cox-regression model and Fine-gray model as well, to adjust the confounders. These were presented in Table-2 A and table-2B. 5. Figure 2 Needs Modification It seems that Figure 2 needs to be revised. Is the x-axis in Figure 2(A) correct? Is it "year" or "length of stay"? Although it is not an observation for 50 years, the graph indicates that it has been tracked for 50 years. The intended message in Figure 2(B) is not well understood. It's not clear what is being explained in the survival analysis. It would be helpful if the rationale for showing the survival curve in the manuscript is well explained. Once again, we thank the reviewer for pointing out the mistake in Figure 2A. The correct x-axis should be “length of stay”, not “year”. We replaced the figure with the correct one. We agree with the reviewer that the title for Figure 2B was not clear enough. We changed the title into: Figure 2B Estimated survival probability based on Cox’s regression model result in table 2B. 6. Other Comments 1) The lack of explanations for tables and figures in the text makes it difficult to match them with the content and lowers comprehensibility. 2) It is necessary to mention the possibility of more intensive drug therapy for patients with severe conditions who had low blood triglyceride levels, low-density lipoprotein (LDL) levels, and total cholesterol. 3) It should be noted that the analyzed data represent only one year and may not reflect long-term trends, and that the data collected from the hospital may be limited in terms of external environmental factors or additional factors affecting patients. Thanks indeed for your valuable suggestions • We already added the explanation within the text (Results section#) to improve comprehensibility as suggested. • The treatment strategy was applied in out hospital based on the clinical practice guidelines, particularly for treating dyslipidemia. • We added into limitation that our data could not be generalized to other populations for multiple reasons, including that it only represented 1 year period. Attachments Attachment Submitted filename: Response to Reviewer.docx https://doi.org/10.1371/journal.pone.0305100.r006
16 May 2024 Decision Letter - Yee Gary Ang, Editor PONE-D-23-03260R3Prognostic Model of In-hospital Ischemic Stroke Mortality Based on an Electronic Health Record Cohort in IndonesiaPLOS ONE Dear Dr. Santoso, 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 address the residual comments before resubmitting. />============================== Please submit your revised manuscript by Jun 30 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. 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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 #7: All comments have been addressed Reviewer #8: 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 #7: Partly Reviewer #8: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #7: I Don't Know Reviewer #8: 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 #7: No Reviewer #8: 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 #7: Yes Reviewer #8: 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 #7: Thank you for your hard work. It's not easy to determine which group each graph represents in Figure 2-A. It would be helpful to specify the names of the groups for the dotted and solid line graphs. Please label the X-axis in Figure 2-B. It is likely to be "length of day." Reviewer #8: The answers given to the questions asked in the previous evaluations and the requested corrections were adequately fulfilled. ****** 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 #7: No Reviewer #8: 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.0305100.r007
Revision 4
23 May 2024 Author Response Dear Reviewers, Thank you for your valuable feedback on our manuscript. We have carefully considered your comments and made the necessary revisions to improve the clarity and accuracy of our paper. Specifically, you mentioned the need for labeling the X-axis in Figure 2-B. We have addressed this concern and have now labeled the X-axis as "Length of Day." We also have revised label of predictors in Figure-2A. This label accurately reflects the data presented in the figure and ensures that the information is clear and interpretable for our readers. Additionally, we have incorporated some useful information and enhanced the clarity of the manuscript based on your suggestions. We appreciate your attention to detail and believe that these revisions enhance the overall quality of our manuscript. Please find the revised figure included in the updated manuscript. Thank you once again for your insightful suggestions. Sincerely, Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0305100.r008
24 May 2024 Decision Letter - Yee Gary Ang, Editor Prognostic Model of In-hospital Ischemic Stroke Mortality Based on an Electronic Health Record Cohort in Indonesia PONE-D-23-03260R4 Dear Dr. Santoso, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Yee Gary Ang, MBBS MPH Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0305100.r009
Formally Accepted
3 Jun 2024 Acceptance Letter - Yee Gary Ang, Editor PONE-D-23-03260R4 PLOS ONE Dear Dr. Santoso, 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. Yee Gary Ang Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0305100.r010

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