Development of a risk score for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis

Kefyalew Addis Alene; Kerri Viney; Darren J. Gray; Emma S. McBryde; Zuhui Xu; Archie C. A. Clements

doi:10.1371/journal.pone.0227100

Peer Review History

Original SubmissionSeptember 13, 2019
5 Nov 2019 Decision Letter - HASNAIN SEYED EHTESHAM, Editor PONE-D-19-25758 Development of a risk score for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis PLOS ONE Dear Dr. Alene, 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. We would appreciate receiving your revised manuscript by Dec 20 2019 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. 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In your ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, 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. Additional Editor Comments: This manuscript has been reviewed by 2 reviewers. Both reviewers feel that this manuscript should be accepted. I have also gone through this manuscript and also the comments of both the reviewers. I recommend this manuscript for a minor revision. [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: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Reviewer #: It is good research article about risk score development for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis (MDR-TB) using routinely collected data from two large countries that have a high MDR-TB burden and are geographically, economically and epidemiologically distinct. Further, this is the first published report on the development of a simple scoring system to predict poor treatment outcomes (death, lost to follow up or treatment failure) in patients with MDR-TB. The authors introduced the statistical method and analysis of the poor outcomes among patients with multidrug-resistant tuberculosis, which is helpful to better understand the current methods about detection and treatment failure in patients with MDR-TB. This developed risk score can be useful to identify and estimate the absolute risk of poor treatment outcome in patients with MDR-TB. Thus, I suggest acceptance of this article, as this study and risk score can be helpful for the clinicians to provide a better medical care and financial and psychosocial support to patients undergoing MDR-TB treatment. Reviewer #2: Authors of the manuscript entitled "Development of a risk score for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis" have attempted to develop a statistical model aimed at deciphering risk scores for poor treatment outcomes among patients with multidrug resistance TB. Though similar studies based on risk scores for prediction of poor treatment outcome in the case of drug susceptible TB, dengue, coronary heart diseases, pulmonary embolism etc. have been previously reported but not in the case of MDR-TB. This manuscript can be accepted with following minor revisions that may add further value to the work. 1>A detailed study flow chart may be included for clarity. 2>Lines 164-170: Authors preferred use of smear conversion rates over culture conversion rates for risk score prediction. Sensitivity of smear conversions analyses may not be one of the good variable for risk score predictions thus leading to a moderate AUROC of 0.69 that is much less than the 0.9 and might compromise the applicability of the risk scores for prediction of poor treatment outcomes. Thus it may be prudent to include clinical factors with high sensitivity and specificity for prediction of risk scores and thus an improved AUROC. 3>Authors have merged data from patient cohorts of two geographically distinct countries with high MDR-TB burden. Though it would have been of high significance if they had carried out risk score based predictions on individual cohorts using statistically significant numbers. 4> This study may be a good attempt toward carrying out risk score based predictions of poor treatment outcome in the case of MDR-TB patients and may thus help clinicians in decision making in the case of MDR-TB patients. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: Reviewer Comments.pdf https://doi.org/10.1371/journal.pone.0227100.r001
Revision 1
27 Nov 2019 Author Response Response to editor and reviewers’ comment Ref.: PONE-D-19-25758 Title: Development of a risk score for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis Journal: PLOS ONE Authors: Kefyalew Addis Alene, Kerri Viney, Darren J Gray, Emma S McBryde, Zuhui Xu, Archie CA Clements Dear Editor Prof Hasnain Seyed Ehtesham Subject: Submission of revised paper mentioned above Thank you for the opportunity to revise our manuscript. We appreciate the thoughtful review and constructive suggestions. We have carefully reviewed the comments and have revised the manuscript accordingly. Following this letter are the editor and reviewer comments with our point-by-point responses for each specific comment raised by the reviewers in green font, including how and where the text was modified. The change made in the manuscript is shown in a separate track change document and uploaded to the system with the revised version of the manuscript. We hope the revised version is now suitable for publication and look forward to hearing from you in due course. Yours sincerely, Kefyalew Addis Alene Corresponding Author Response to editor’s comment 1. When submitting your revision, we need you to address these additional requirements. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Response: We followed the PLOS ONE style templates when submitting the revised version of the manuscript. 2. In your ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, 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. Response: We have now mentioned that “Ethics approval was obtained from the Australian National University Human Research Ethics Committee (protocol number 2016/218) and from the Institutional Review Board of the University of Gondar. Permission was granted to access the secondary data from Tuberculosis Control Institute of Hunan Province, and this was documented in a letter. All data were fully anonymized before we accessed them, and the study was conducted in collaboration with researchers from Gondar University and Hunan Chest Hospital.” Additional Editor Comments 3. This manuscript has been reviewed by 2 reviewers. Both reviewers feel that this manuscript should be accepted. I have also gone through this manuscript and also the comments of both the reviewers. I recommend this manuscript for a minor revision. Response: We greatly appreciate the editor for giving us a chance to revise our manuscript. We have carefully reviewed the comments and have revised the manuscript accordingly. Response to reviewers’ comment Reviewer #1: It is good research article about risk score development for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis (MDR-TB) using routinely collected data from two large countries that have a high MDR-TB burden and are geographically, economically and epidemiologically distinct. Further, this is the first published report on the development of a simple scoring system to predict poor treatment outcomes (death, lost to follow up or treatment failure) in patients with MDR-TB. The authors introduced the statistical method and analysis of the poor outcomes among patients with multidrug-resistant tuberculosis, which is helpful to better understand the current methods about detection and treatment failure in patients with MDR-TB. This developed risk score can be useful to identify and estimate the absolute risk of poor treatment outcome in patients with MDR-TB. Thus, I suggest acceptance of this article, as this study and risk score can be helpful for the clinicians to provide a better medical care and financial and psychosocial support to patients undergoing MDR-TB treatment. Response: We greatly appreciate the thoughtful comments of the reviewer. Reviewer #2: Authors of the manuscript entitled "Development of a risk score for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis" have attempted to develop a statistical model aimed at deciphering risk scores for poor treatment outcomes among patients with multidrug resistance TB. Though similar studies based on risk scores for prediction of poor treatment outcome in the case of drug susceptible TB, dengue, coronary heart diseases, pulmonary embolism etc. have been previously reported but not in the case of MDR-TB. This manuscript can be accepted with following minor revisions that may add further value to the work. 1. A detailed study flow chart may be included for clarity. Response: We now include the following flow chart in the revised version of the manuscript for clarity 721 patients with drug resistant TB in two hospitals 120 not bacteriologically confirmed 601 bacteriologically confirmed patients 22 did not start MDR-TB treatment 579 MDR-TB patients who started treatment 9 treatment outcomes were not recorded 570 MDR-TB patients with recorded treatment outcomes Figure 1: Flowchart of eligible participants for our study on the development of a risk score for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis, and reasons for exclusion. 2. Lines 164-170: Authors preferred use of smear conversion rates over culture conversion rates for risk score prediction. Sensitivity of smear conversions analyses may not be one of the good variable for risk score predictions thus leading to a moderate AUROC of 0.69 that is much less than the 0.9 and might compromise the applicability of the risk scores for prediction of poor treatment outcomes. Thus it may be prudent to include clinical factors with high sensitivity and specificity for prediction of risk scores and thus an improved AUROC. Response: When we checked for the presence of multi-collinearity, a high degree of collinearity was observed between smear and culture conversion status. Thus, we selected smear conversion for the final model to avoid the observed multi-collinearity. We selected smear conversion because it is less expensive, widely available, and more convenient than culture conversion to predict the treatment outcomes of patients at peripheral and lower-resource settings. However, we run two different models that contain culture conversion and smear conversion a sensitivity analysis, and we found similar AUROC results. 3. Authors have merged data from patient cohorts of two geographically distinct countries with high MDR-TB burden. Though it would have been of high significance if they had carried out risk score-based predictions on individual cohorts using statistically significant numbers. Response: As we have mentioned in the limitation section of the manuscript, it would be more meaningful if we could calculate the risk score using data from one of the study hospitals and validate this score using the data obtained from the other hospital. However, since we had very few data from University of Gondar Hospital, it was impractical to do this. Thus, we preferred to merge the data and randomly divide it into derivation and validation groups. Therefore, our score system requires external validation using larger datasets and using prospective data in other settings or countries. 4. This study may be a good attempt toward carrying out risk score-based predictions of poor treatment outcome in the case of MDR-TB patients and may thus help clinicians in decision making in the case of MDR-TB patients. Response: We appreciate the thoughtful comments of the reviewer. Attachments Attachment Submitted filename: Response to Reviewers_.docx https://doi.org/10.1371/journal.pone.0227100.r002
13 Dec 2019 Decision Letter - HASNAIN SEYED EHTESHAM, Editor Development of a risk score for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis PONE-D-19-25758R1 Dear Dr. Alene, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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. With kind regards, HASNAIN SEYED EHTESHAM Academic Editor PLOS ONE Additional Editor Comments (optional): I have gone through the revised manuscript and also the Authors response to reviewers comment. The authors have satisfactorily addressed all the comments made by the reviewers and have revised the manuscript accordingly. I recommend this manuscript for publication. Reviewers' comments: https://doi.org/10.1371/journal.pone.0227100.r003
Formally Accepted
20 Dec 2019 Acceptance Letter - HASNAIN SEYED EHTESHAM, Editor PONE-D-19-25758R1 Development of a risk score for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis Dear Dr. Alene: I am 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 notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Prof HASNAIN SEYED EHTESHAM Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0227100.r004

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