How much does it cost to measure immunity? A costing analysis of a measles and rubella serosurvey in southern Zambia

Andrea C. Carcelen; Kyla Hayford; William J. Moss; Christopher Book; Philip E. Thuma; Francis D. Mwansa; Bryan Patenaude

doi:10.1371/journal.pone.0240734

Peer Review History

Original SubmissionApril 22, 2020
25 Jun 2020 Decision Letter - Ka Chun Chong, Editor PONE-D-20-11421 How much does it cost to measure immunity? A costing analysis of a measles and rubella serosurvey in southern Zambia PLOS ONE Dear Dr. Carcelen, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ACADEMIC EDITOR: Please address the comments from the reviewers. Please submit your revised manuscript by Aug 09 2020 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. 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Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests Additional Editor Comments (if provided): [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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: No Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No 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 giving me the opportunity to review this interesting paper. I think the topic is relevant and based on sound data. However, I have several concerns regarding the presentation. Abstract: Background: the reason why serosurveys are valuable is not clearly stated. Methods are more detailed than required Results: Please see my comment to Results, line 214 to 223. Introduction: The introduction is hard to read as it seems to be a collection of single one-sentence statements that lack context. Thus, the reason why the study was performed remains somewhat unclear. The aim of the study should be described better. To me, the phrase “cost integrated vaccine-preventable disease surveillance that includes calculating serosurvey” is not understandable. Methods: Line 105 to 106: “Clusters were defined as administrative boundaries known as Supervisory Enumeration Area” – what does that mean? Line 112-115: Meaning unclear. Line 133 to 137: Meaning unclear. Line 155-57: Surprisingly high amount of Man-power to collect specimens, 3 working days à five persons to collect 41 specimens. Please explain why teams contain five persons. Line 174.175: Why were community health care workers invited to accompany the working team, thus enhancing the costs? Results: Lien 214 to 223: I don’t understand the presentation of the percentages. In total 220 % are presented. How are they broken down? Line 237 to 239: I do not see the relevance of this information. Line 240 to 242: Incomplete sentence. Line 242-243: Discussion of results Line 244 to 250: Very detailed information, but unclear relevance. Sensitivity analysis: I do not understand how the sensitivity analysis was performed. Discussion: No overview of the main results Relevance of the study: It is not discussed how measuring seronegativity contributes to public health, or how the costs for a serosurvey relate to cost of other measurements to enhance public health, like vaccination campaigns or nutrition supplements. Line 326 to 327: Incomplete& grammatically wrong sentence. Line 330: not included into the pdf Line 334 to 337: Unclear why this is a weakness Acknowledgement: One of the co-authors is acknowledged for his contribution. Figures: The figures are of insufficient quality in the pdf-file provided. Reviewer #2: Thanks for the manuscript and it read very well. Please see the following comments for further improvement of the manuscript. 1. Line 244 to 248 should be in methods section for better clarity including the age range for serology survey. 2. Line 251 to 256 would be clear if the author presents as a table in result section. 3. The authors stated in the method section that 12 children were selected from each cluster. But in line 293 to 295 stated the fact about women of child bearing age which do not seem to be in this survey. Please clarify this fact. 4. It would be more informative if author could provide the administration of vaccination coverage in the survey area to argue with needs to conduct serology survey. 5. Figures in the manuscript is not clear and suggest to provide higher resolution figure. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0240734.r001
Revision 1
23 Aug 2020 Author Response Thank you kindly for the thorough review of the manuscript. We have reviewed the comments and provided responses below in blue. Additionally, we have updated the manuscript, and noted where in the manuscript the changes are reflected. Line numbers are based on unmarked version. 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 This has been updated. 2. 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. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. 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. The minimal anonymized data set necessary to replicate our study findings has been uploaded as supporting files. 3. Thank you for stating the following in the Competing Interests section: 'AC, KH, WM, and BP received financial support from the Bill & Melinda Gates Foundation. Other authors declare that they have no competing interests' Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests This is correct. It did not alter our adherence to PLOS ONE policies on sharing data and materials. We added this to the cover letter. Reviewer #1: Thank you for giving me the opportunity to review this interesting paper. I think the topic is relevant and based on sound data. However, I have several concerns regarding the presentation. Abstract: Background: the reason why serosurveys are valuable is not clearly stated. This has been added (line 21). Methods are more detailed than required Some of the details have been removed (lines 27-28). Results: Please see my comment to Results, line 214 to 223. This has been clarified (lines 34-39). Introduction: The introduction is hard to read as it seems to be a collection of single one-sentence statements that lack context. Thus, the reason why the study was performed remains somewhat unclear. The aim of the study should be described better. To me, the phrase “cost integrated vaccine-preventable disease surveillance that includes calculating serosurvey” is not understandable. The introduction has been reworked to be more cohesive. The aim of the study is more clearly described in the last paragraph, with the clarification on the phrase noted (lines 85-90). Methods: Line 105 to 106: “Clusters were defined as administrative boundaries known as Supervisory Enumeration Area” – what does that mean? An Enumeration Area (EA) is a small geographic unit below a ward in urban areas and village in rural areas, into which the whole country is divided for census purposes. A supervisor is responsible for accounting for all of the people within their assigned enumeration areas. We tried to clarify that it is a small geographic area. (lines 100-102) Line 112-115: Meaning unclear. This has been modified. The intent was to explain that a bottom-up approach was used to cost each item required for the serosurvey. We included costs that were incurred by the government healthcare system as they implemented the serosurvey but did not include participant costs. (lines 107-110) Line 133 to 137: Meaning unclear. The text has been updated to be clearer. The intent was to explain Figure 1 and how the phases and categories were developed. (lines 127-132) Line 155-57: Surprisingly high amount of Man-power to collect specimens, 3 working days à five persons to collect 41 specimens. Please explain why teams contain five persons. The teams consisted of 5 people-1 supervisor, 1 phlebotomist, and 3 data collectors (one who was a back-up phlebotomist). This is the actual number of people that went out to the field for the serosurvey. Because this serosurvey was nested within a vaccination coverage survey, the teams conducting the serosurvey were asked to work at the same pace as those doing only the vaccination coverage survey. Whereas teams doing only the vaccination coverage survey in other clusters only needed to interview mothers of 12 children; serosurvey teams had to both interview and collect blood from everyone in the household of those 12 children. The mean number of participants enrolled in each household was 4 (IQR: 3-6) [1]. This meant that additional staff were required to complete all of the work within the allotted 2 weeks in the field. If more time had been allowed, the teams could have been smaller. Line 174.175: Why were community health care workers invited to accompany the working team, thus enhancing the costs? Community health workers accompanied the teams for several reasons. They are familiar with the area and could guide the teams in interpreting the maps. And they could make appropriate introductions to community leaders so the community was more likely to participate in the study. [2] (Lines 167-171) Results: Lien 214 to 223: I don’t understand the presentation of the percentages. In total 220 % are presented. How are they broken down? The paragraph has been reorganized to better clarify. The percentages are presented in a couple of formats: by phase of serosurvey implementation (as broken down in Table 1) and by input category (as denoted in Figure 2). This corresponds with the rows and columns from Figure 1. Additionally, lines 214-217 explain the costs per category input for just adding the serosurvey to the already planned coverage survey (the different colors in Figure 2). (Lines 209-218) Line 237 to 239: I do not see the relevance of this information. Cost ratio information has been moved to supplemental material. Line 240 to 242: Incomplete sentence. This sentence has been split into two and moved to supplemental material. Line 242-243: Discussion of results Cost ratio information has been moved to supplemental material. Line 244 to 250: Very detailed information, but unclear relevance. This has been condensed to get across the main points more clearly. The relevance was intended to denote that by adding additional children in the serosurvey than were in the vaccination coverage survey, there was an additional cost. Similarly, we included adults in the serosurvey sample, which also had an additional cost. The implications of this are in the discussion section (lines 295-304), highlighting that an immunity gap in women of childbearing age was identified through this serosurvey because adults were included. Sensitivity analysis: I do not understand how the sensitivity analysis was performed. One-way sensitivity analyses were done to see how changing parameters for the serosurvey would have affected the cost. For example, decreasing the number of team members to 2 resulted in a $5,000 cost savings, whereas increasing the number of team members to 6 resulted in increased costs. This was similarly done for time spent in the field, training, planning, and laboratory testing. The footnote for Figure 3 indicates what the ranges for the sensitivity analyses were. (lines 252-258) Discussion: No overview of the main results An initial paragraph has been added to provide an overview and the value of serosurveys in guiding immunization programs (lines 261-269). Relevance of the study: It is not discussed how measuring seronegativity contributes to public health, or how the costs for a serosurvey relate to cost of other measurements to enhance public health, like vaccination campaigns or nutrition supplements. We agree this is a really important question, but unfortunately we were not able to address it in this study. We are working through our research to better understand the added value of targeted serosurveys and how they could be used to guide immunization programs. In future research we would do a cost-benefit or cost-utility analysis to be able to compare the costs of a serosurvey to those of alternative strategies. Alternative strategies could include approximate measurements of seropositivity using vaccination coverage and fever rash surveillance systems,. This could also compare a targeted serosurvey with mop-up immunization in areas found to have low seroprevalence to a blanket vaccination campaign (lines 325-329). Line 326 to 327: Incomplete& grammatically wrong sentence. Thank you for catching this. It has been updated. Line 330: not included into the pdf We are not sure what this is in reference to, but the minimal dataset has now been made available. Line 334 to 337: Unclear why this is a weakness It was not intended to be a weakness, but rather a limitation in terms of generalizability. In our study, we hired new personnel. If this were integrated as an ongoing activity that forms part of the existing surveillance system, it could be done by existing staff. This could result in lowered costs and would make it more sustainable in the long run, rather than hiring and training new personnel. (Lines 396-399) Acknowledgement: One of the co-authors is acknowledged for his contribution. This has been removed and updated (line 352). Figures: The figures are of insufficient quality in the pdf-file provided. These have been updated. Reviewer #2: Thanks for the manuscript and it read very well. Please see the following comments for further improvement of the manuscript. 1. Line 244 to 248 should be in methods section for better clarity including the age range for serology survey. This line is intended to be a reminder for the reader as to why we are saying “additional” children and what the cost was for adding adults. We have tried to make this clearer in the methods section. (lines 97-98) 2. Line 251 to 256 would be clear if the author presents as a table in result section. A table has been added to the results section (line 244-246). 3. The authors stated in the method section that 12 children were selected from each cluster. But in line 293 to 295 stated the fact about women of child bearing age which do not seem to be in this survey. Please clarify this fact. The post-coverage evaluation survey selected one child from 12 different households in each cluster. However, our nested serosurvey collected specimens from all household members regardless of age, not just the child. Therefore, we were able to calculate seroprevalence estimates for women of childbearing age. 4. It would be more informative if author could provide the administration of vaccination coverage in the survey area to argue with needs to conduct serology survey. Administrative vaccination coverage for the 2016 measles-rubella vaccination campaign was 89.9% (95% confidence interval (CI): 85.9, 92.8) for 9 month to 16 year olds. By comparison, the serosurvey prevalence was 96.1% (95% CI: 92.4, 98.1) for measles and 98.4% (95% CI: 95.9, 99.4) for rubella for the same age range. For measles, the higher seroprevalence was likely due to the fact that many children had already been vaccinated through the routine immunization program. For rubella, this is likely because they had already been previously exposed to circulating rubella virus, as this was the first introduction of rubella vaccine. This justification for conducting serological surveillance has been added to the discussion (lines 286-294) 5. Figures in the manuscript is not clear and suggest to provide higher resolution figure. These have been updated. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0240734.r002
14 Sep 2020 Decision Letter - Ka Chun Chong, Editor PONE-D-20-11421R1 How much does it cost to measure immunity? A costing analysis of a measles and rubella serosurvey in southern Zambia PLOS ONE Dear Dr. Carcelen, 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 Oct 29 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Ka Chun Chong 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 #1: (No Response) Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 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: No Reviewer #2: 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: Thank you for giving med the opportunity to re-revise this manuscript which I consider much improved. My only comment is that there are a few typos, especially in the Introduction ("cost" instead of "costs" etc.), and iterations throughout the paper. I would recommend a critical run-through or a professional proof-read. Reviewer #2: (No Response) ****** 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:** Corinna Vossius MD PhD 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.0240734.r003
Revision 2
25 Sep 2020 Author Response We have had several proof-readers go through and critically review the language. We found only a couple of typos but tried to update some of the language to prevent confusion between “cost” and “costs”. https://doi.org/10.1371/journal.pone.0240734.r004
2 Oct 2020 Decision Letter - Ka Chun Chong, Editor How much does it cost to measure immunity? A costing analysis of a measles and rubella serosurvey in southern Zambia PONE-D-20-11421R2 Dear Dr. Carcelen, 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, Ka Chun Chong Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0240734.r005
Formally Accepted
6 Oct 2020 Acceptance Letter - Ka Chun Chong, Editor PONE-D-20-11421R2 How much does it cost to measure immunity? A costing analysis of a measles and rubella serosurvey in southern Zambia Dear Dr. Carcelen: 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. Ka Chun Chong Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0240734.r006

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