Defining an intermediate category of tuberculin skin test: A mixture model analysis of two high-risk populations from Kampala, Uganda

Henok G. Woldu; Sarah Zalwango; Leonardo Martinez; María Eugenia Castellanos; Robert Kakaire; Juliet N. Sekandi; Noah Kiwanuka; Christopher C. Whalen

doi:10.1371/journal.pone.0245328

Peer Review History

Original SubmissionJuly 21, 2020
1 Sep 2020 Decision Letter - Francesco Di Gennaro, Editor PONE-D-20-22617 DEFINING AN INDETERMINATE TUBERCULIN SKIN TEST: A MIXTURE MODEL ANALYSIS OF TWO HIGH-RISK POPULATIONS FROM KAMPALA, UGANDA PLOS ONE Dear Dr.ssa Castellanos, 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 20 September. 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. 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Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. 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. Additional Editor Comments (if provided): Dear Authors, follow reviewer indication to improve your article [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: No ****** 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: In this study entiled: Defining an indeterminate tuberculin skin test: a mixture model analysis of two high-risk populations from Kampala, Uganda This is a well-intended initiative to address a major problem affecting the African population. 1The study, context is in keeping with other literature on the topic. Latent TB remains a pool for active TB disease and treatment of latent TB would be a better elimination strategy. 2 Indeed the readily available TST is not well interpreted because of cross reaction of the BCG vaccine and non tuberculosis bacteria. Consequently the identification of the true latent infected individuals may sometimes be missed out. The other tests like IGRA for latent TB diagnosis is not validated endemic areas. Therefore the most popular test may remain TST. 3 The authors therefore set out to map out the epidemiological distribution of TST in two study populations of urban Kampala using mixture model method and to define criteria for diagnosis of the TST test. 4 The selected study populations were appropriate, Kawempe division one of the crowding areas of Kampala yet crowding is among the well known risk factors for mtb transmission. 5 Sample size and study duration for both studies were adequate to generate sufficient data for the analysis. 6 The mixture model method used was appropriate since they were dealing with interactable variables and data was from two different populations. The Lubaga division included controls in their study. The Kawempe study however did not include controls. 7Hartigans’ dip test of unimodality to asses distribution was unimodal or multimodal was appropriate . 8 The Finite mixture normal model was for heterogeneity was appropriate. 9 presentations of data available is appropriate with tables and figures supporting it 10The authors were able to determine an intermediate reading they referred to as indeterminate. Reviewer’s comments In view of the above observations, the this study, Defining an indeterminate tuberculin skin test: a mixture model analysis of two high-risk populations from Kampala, Uganda I am only concerned about the Kawempe study that did not have a control group. Are these findings generalized to other populations at risk of disease? On the whole I find this study appropriate for publication Reviewer #2: This manuscript clearly defines a new category of clinical relevance in the application of the highly pervasive tuberculin skin test for tuberculosis in resource poor settings. This new category introduces greater rigor and robustness in the algorithm for decision making in regard to committing a borderline subject to tuberculosis treatment or not by proposing a follow up step for those in this category. General Comments 1. Your work is technically sound and received the rigour it deserves, by clearly describing the subject recruitment procedure. You, however, mention completely nothing about the appropriateness of your sample size with reference to the characteristics of the study population. A simple map to illustrate the relative locations of Lubaga and Kawempe within Kampala City would provide some spatial clarity to your audience. I suggest that you consider providing these pieces of information for benefit of the audience. 2. The data underlying the findings have not been made available. Was it not possible to deprecate the identities of the study subjects and achieve anonymity? Specific Comments Title After reading your manuscript a couple of times, I suggest it should read as: "Defining an Intermediate Category of Tuberculin Skin Test: A Mixture Model Analysis of Two High-Risk Populations From Kampala, Uganda" Abstract line #27 please note that Kampala does not have districts within, the administrative units of Lubaga and Kawempe are officially referred to as "divisions". Introduction line #78 Please consider a brief explanation of what the Mixture Model Analysis involves. line #79 consider explaining the concept of criterion based methods. Alternatively, consider clearly acknowledging the authorities of these two concepts in lines #78 and #79. Materials and Methods line #123 please find and appropriately acknowledge the Ministry of Health Guidelines on HIV. line #150 EM appears for the first time as an abbreviation. Consider writing this in full at first mention with the abbreviation in brackets. line #152 consider revising to read as "......"mixdist"(33) in the R programming language (R Core Team)". Discussion line #290 consider deleting ".......the other....". these appear redundant and do not add clarity to your point here. line #346 what is the rationale for this period? This is certainly not deduced from your data and analysis. line #364 please provide the authorities referred to here as "......others" ****** 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:** ESTER LILIAN ACEN Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: ester,s review comments.docx https://doi.org/10.1371/journal.pone.0245328.r001
Revision 1
12 Oct 2020 Author Response RESPONSE TO EDITOR AND REVIEWERS (We also uploaded an attached file with this same information) PONE-D-20-22617 DEFINING AN INDETERMINATE TUBERCULIN SKIN TEST: A MIXTURE MODEL ANALYSIS OF TWO HIGH-RISK POPULATIONS FROM KAMPALA, UGANDA PLOS ONE Response: We appreciate the careful review and thoughtful comments of our manuscript. In our revision, we have made every effort to clarify the concerns raised by you and the reviewers and to respond accordingly. Please note that the line numbers we provided correspond to the revised clean version of the manuscript. 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 R/We have revised those requirements and made changes to meet PLOS ONE’s style requirements. 2. Please address the following: a) Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information. In addition, please provide further details concerning the development of this tool. R/We have included as Supporting File 1 the standard questionnaire we used in the study for the collection of the main participant’s characteristics (English and Luganda version). We have added this information in the manuscript (lines 96-98). b) Please ensure you have thoroughly discussed any potential limitations of this study within the Discussion section, including the potential introduction of biases during data collection. R/ We now have included measures we took to reduce recall bias during the data collection (lines 122-124). Moreover, from line 329 to line 331, we have discussed the potential limitations of our study, including biases regarding our study population. c) Please describe the reasons for any missing data, if known. R/ All subjects included in our analysis had the tuberculin skin test (TST) result which was main outcome of interest. For some subjects, there is missing covariate information. The dataset for this analysis, which was finalized in 2017, had missing values of education, marital status, HIV status, and BCG vaccine status. Information collected through self-report may result from the refusal of the study participant to answer the question. HIV testing was not indicated on all study participants, so was obtained using a standard protocol. As for BCG vaccination, we collected this variable in overlapping ways. We examined each person for a BCG scar and verified the presence of scar with vaccination card where available. Most participants younger than 20 years had a vaccination card. For adults, we relied on verbal confirmation that they had received a BCG vaccination when younger. We have updated the footnote of Table 1 to explain that for the 285 subjects with missing BCG result; 85 of these 285 answered that they did not know whether they had received the vaccine or not. To evaluate the effect of this missing information, we performed a sensitivity analysis and found that those with and without BCG information did not differ as regards to age, sex, and TST values (lines 185-187). 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 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 identifying or sensitive patient information) 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. Data Availability: Data cannot be made publicly available due to ethical restrictions. The IRB approval for this study restricts the sharing of individual-level data. An anonymized dataset is available upon request form researchers who meet the criteria for access to confidential information. Data requests may be sent to the Human Subjects Office Director at University of Georgia, Kim Fowler (phone contact: 706-542-5318, and email contact: irb@uga.edu). In particular, we welcome researchers willing to create a strong data-sharing partnership and collaboration with the Ugandan researchers who generated the data. ________________________________________ 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: In this study entitled: Defining an indeterminate tuberculin skin test: a mixture model analysis of two high-risk populations from Kampala, Uganda This is a well-intended initiative to address a major problem affecting the African population. 1The study, context is in keeping with other literature on the topic. Latent TB remains a pool for active TB disease and treatment of latent TB would be a better elimination strategy. 2 Indeed the readily available TST is not well interpreted because of cross reaction of the BCG vaccine and non tuberculosis bacteria. Consequently the identification of the true latent infected individuals may sometimes be missed out. The other tests like IGRA for latent TB diagnosis is not validated endemic areas. Therefore the most popular test may remain TST. 3 The authors therefore set out to map out the epidemiological distribution of TST in two study populations of urban Kampala using mixture model method and to define criteria for diagnosis of the TST test. 4 The selected study populations were appropriate, Kawempe division one of the crowding areas of Kampala yet crowding is among the well known risk factors for mtb transmission. 5 Sample size and study duration for both studies were adequate to generate sufficient data for the analysis. 6 The mixture model method used was appropriate since they were dealing with interactable variables and data was from two different populations. The Lubaga division included controls in their study. The Kawempe study however did not include controls. 7Hartigans’ dip test of unimodality to asses distribution was unimodal or multimodal was appropriate . 8 The Finite mixture normal model was for heterogeneity was appropriate. 9 presentations of data available is appropriate with tables and figures supporting it 10The authors were able to determine an intermediate reading they referred to as indeterminate. Reviewer’s comments In view of the above observations, this study, Defining an indeterminate tuberculin skin test: a mixture model analysis of two high-risk populations from Kampala, Uganda R/We thank and appreciate the favorable review to our manuscript. I am only concerned about the Kawempe study that did not have a control group. R/We agreed and have included as limitation of the study that we do not have control group for the Kawempe study (lines 329-331). Are these findings generalized to other populations at risk of disease? R/We included the following paragraph as our closing paragraph (lines 387-392): “We do not presume to suggest that there are fixed or standard criteria that define latent tuberculosis infection across populations. As has been pointed out by others, population characteristics and the goals of testing affect the choice of cutoff values. We do propose, however, that the process of TST surveys within populations at risk, followed by a mixture model analysis, is an evidence-based approach that can define meaningful criteria for latent infection in a given population.” On the whole I find this study appropriate for publication Reviewer #2: This manuscript clearly defines a new category of clinical relevance in the application of the highly pervasive tuberculin skin test for tuberculosis in resource poor settings. This new category introduces greater rigor and robustness in the algorithm for decision making in regard to committing a borderline subject to tuberculosis treatment or not by proposing a follow up step for those in this category. General Comments 1. Your work is technically sound and received the rigour it deserves, by clearly describing the subject recruitment procedure. You, however, mention completely nothing about the appropriateness of your sample size with reference to the characteristics of the study population. A simple map to illustrate the relative locations of Lubaga and Kawempe within Kampala City would provide some spatial clarity to your audience. I suggest that you consider providing these pieces of information for benefit of the audience. R/Thank you very much for your comments. We have included a paragraph describing the appropriateness of our sample size for this analysis (lines 173-177). Also, we have included a map (Figure 1) illustrating the relative locations of Lubaga and Kawempe Divisions. 2. The data underlying the findings have not been made available. Was it not possible to deprecate the identities of the study subjects and achieve anonymity? R/ Data cannot be made publicly available due to ethical restrictions. The IRB approval for this study restricts the sharing of individual-level data. An anonymized dataset is available upon request form researchers who meet the criteria for access to confidential information. Data requests may be sent to the Human Subjects Office Director at University of Georgia, Kim Fowler (phone contact: 706-542-5318, and email contact: irb@uga.edu). In particular, we welcome researchers willing to create a strong data-sharing partnership and collaboration with the Ugandan researchers who generated the data. Specific Comments Title After reading your manuscript a couple of times, I suggest it should read as: "Defining an Intermediate Category of Tuberculin Skin Test: A Mixture Model Analysis of Two High-Risk Populations From Kampala, Uganda" R/We appreciate the suggestion and we have modified our title (line 1 and line 2). Abstract line #27 please note that Kampala does not have districts within, the administrative units of Lubaga and Kawempe are officially referred to as "divisions". R/We agreed with this suggestion. We have changed the term in line 26. Introduction line #78 Please consider a brief explanation of what the Mixture Model Analysis involves. R/We have included a brief explanation of the mixture model analysis (lines 77-79) in the Introduction Section, added references and we have provided a detailed explanation in the Methods Section (lines 154 -164). line #79 consider explaining the concept of criterion based methods. Alternatively, consider clearly acknowledging the authorities of these two concepts in lines #78 and #79. R/We have expanded on the criterion for assigning latent infection using tuberculin skin test and we have provided appropriate references (lines 81-85). Materials and Methods line #123 please find and appropriately acknowledge the Ministry of Health Guidelines on HIV. R/We have renamed and made the proper reference the Guidelines for Prevention and Treatment of HIV in Uganda (lines 137-138, 140). line #150 EM appears for the first time as an abbreviation. Consider writing this in full at first mention with the abbreviation in brackets. R/We have followed the suggestion and mention the full name of the expectation-maximization ‘EM’ algorithm (lines 165-166). line #152 consider revising to read as "......"mixdist"(33) in the R programming language (R Core Team)". R/We have revised and changed as suggested (lines 167-168). Discussion line #290 consider deleting ".......the other....". these appear redundant and do not add clarity to your point here. R/We have revised and deleted this term as suggested (line 311). line #346 what is the rationale for this period? This is certainly not deduced from your data and analysis. R/We have expanded the rationale for this period, explaining that after 2-4 weeks, a second test will show a booster response or a regression toward the mean (lines 369-371). line #364 please provide the authorities referred to here as "......others" R/We have added the corresponding references (389-390). Attachments Attachment Submitted filename: Response_to_Reviewers.docx https://doi.org/10.1371/journal.pone.0245328.r002
29 Dec 2020 Decision Letter - Francesco Di Gennaro, Editor Defining an intermediate category of tuberculin skin test: A mixture model analysis of two high-risk populations from Kampala, Uganda PONE-D-20-22617R1 Dear Dr. Castellanos, 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, Francesco Di Gennaro Academic Editor PLOS ONE Additional Editor Comments (optional): dear authors congratulations 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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: 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 #1: 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: My concerns have been addressed accordingly We agreed and have included as limitation of the study that we do not have control group for the Kawempe study (lines 329-331). (lines 387-392): “We do not presume to suggest that there are fixed or standard criteria that define latent tuberculosis infection across populations. As has been pointed out by others, population characteristics and the goals of testing affect the choice of cutoff values. We do propose, however, that the process of TST surveys within populations at risk, followed by a mixture model analysis, is an evidence-based approach that can define meaningful criteria for latent infection in a given population. ****** 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: Yes:** ESTER LILIAN ACEN https://doi.org/10.1371/journal.pone.0245328.r003
Formally Accepted
13 Jan 2021 Acceptance Letter - Francesco Di Gennaro, Editor PONE-D-20-22617R1 Defining an intermediate category of tuberculin skin test: A mixture model analysis of two high-risk populations from Kampala, Uganda Dear Dr. Castellanos: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Francesco Di Gennaro Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0245328.r004

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