Effects of the killer immunoglobulin–like receptor (KIR) polymorphisms on HIV acquisition: A meta-analysis

Suwit Chaisri; Noel Pabalan; Sompong Tabunhan; Phuntila Tharabenjasin; Nipaporn Sankuntaw; Chanvit Leelayuwat

doi:10.1371/journal.pone.0225151

Peer Review History

Original SubmissionJune 26, 2019
26 Jun 2019 Author Response Attachments Attachment Submitted filename: Responses to editorial comments 26 June 2019.docx https://doi.org/10.1371/journal.pone.0225151.r001
7 Aug 2019 Decision Letter - Srinivas Mummidi, Editor PONE-D-19-15826 Effects of the killer immunoglobulin–like receptor (KIR) polymorphisms on HIV acquisition: a meta-analysis PLOS ONE Dear Dr. Pabalan, Thank you for submitting your manuscript to PLOS ONE. Both reviewers felt that the study was well designed and executed. There are some minor concerns that were expressed which could be easily addressed. We would appreciate receiving your revised manuscript by 10/1/2019. 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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Thank you for stating in your Funding Statement: [SC was supported by Thailand Research Fund and the Commission on Higher Education under the Grant for New Researcher (No.MRG 6180172)]. * Please provide an amended statement that declares all the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. * Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf. [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: 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: The authors have done a terrific job at reviewing the relevant literature on the role of KIR polymorphisms in HIV acquisition, and, more importantly, at extracting the data and meta-data from these studies to perform a meta-analysis. The meta-analysis was satisfactorily performed. Scoring and ranking studies according to the CB scale lends credence to the meta-analysis to the extent that it establishes the quality of the "input" studies. A major finding of the study is that the 2DL3 polymorphism is significantly protective against HIV acquisition even after Bonferroni correction. This was established only after outlier removal where outlier studies were identified by heterogeneity analysis and removed accordingly. The subsequent post-outlier treatment analysis yielded a strong inference that 2DL3 is indeed protective against HIV acquisition. There are two very minor suggestions that may strengthen the paper a little bit: 1) Clarification and interpretation of the significant interaction result between Caucasians and Africans. What does this mean even simply at an epidemiological level? 2) The Benjamini-Hochberg false discovery rate (BH FDR) is often a desirable alternative to the more rigorous Bonferroni correction in that it represents a nice balance between guarding against false discoveries and making true discoveries, as opposed to simply guarding against false discoveries in a relatively more conservative manner (as in the Bonferroni correction). This is not necessary for the authors to implement but its implementation may yield more results surviving multiple correction if the BH FDR is used. Reviewer #2: This is an interesting meta-analysis for effects of genetic variants on HIV acquisition. The paper was well written and methods were rigorously used and described. A minor comment regarding the Galbraith plot. Was it based on an specific protective size of effect? Please define in the text if you did so. It is advisable to the authors include the size of effect plot (arc) on Figure 3. Define Zwoliska in the same figure legend. This unique point was responsible for the 45% heterogeneity between studies. There was not mention on the discussion regarding the advantage or disadvantages of using sensitivity approach versus eliminating the outlier. Table 4 should clarify if the numbers in brackets are those affecting the results? (i.e.: Modifying the ORs in extreme results?). Can you clarify their significance? ****** 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. 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Revision 1
31 Aug 2019 Author Response Reviewer #1: The authors have done a terrific job at reviewing the relevant literature on the role of KIR polymorphisms in HIV acquisition, and, more importantly, at extracting the data and meta-data from these studies to perform a meta-analysis. The meta-analysis was satisfactorily performed. Scoring and ranking studies according to the CB scale lends credence to the meta-analysis to the extent that it establishes the quality of the "input" studies. A major finding of the study is that the 2DL3 polymorphism is significantly protective against HIV acquisition even after Bonferroni correction. This was established only after outlier removal where outlier studies were identified by heterogeneity analysis and removed accordingly. The subsequent post-outlier treatment analysis yielded a strong inference that 2DL3 is indeed protective against HIV acquisition. There are two very minor suggestions that may strengthen the paper a little bit: COMMENT: 1) Clarification and interpretation of the significant interaction result between Caucasians and Africans. What does this mean even simply at an epidemiological level? RESPONSE: We clarify and interpret the significant interaction result between Caucasians and Africans. Prevalence of HIV in Africa is higher compared to that in North America and Europe (Caucasians) [1]. This epidemiological finding suggests less risk for Caucasians and higher risk for Africans which agrees with our 2DL3 result that protects Caucasians (OR, 0.19) from risk of HIV acquisition. LINES 306-308 Extent of the significant Caucasian effect is thus placed in context when compared with its non-significant African counterpart. COMMENT: 2) The Benjamini-Hochberg false discovery rate (BH FDR) is often a desirable alternative to the more rigorous Bonferroni correction in that it represents a nice balance between guarding against false discoveries and making true discoveries, as opposed to simply guarding against false discoveries in a relatively more conservative manner (as in the Bonferroni correction). This is not necessary for the authors to implement but its implementation may yield more results surviving multiple correction if the BH FDR is used. RESPONSE: We sincerely thank the reviewer for the insight provided about correcting for multiple comparisons. We did implement BH-FDR and obtained 11 significant P-values against the two with the Bonferroni correction. Then we found that explaining the 11 significant outcomes did not readily converge with the epidemiology and physiology literature. From the BH-FDR approach, this made the explanations messy which muddled the principal message of our study. Thus, we found that applying the Bonferroni correction, conservative as it is, readily lent more credence to our main message with better support from the literature. The Table at the end of this document puts the BH-FDR results in column Reviewer #2: This is an interesting meta-analysis for effects of genetic variants on HIV acquisition. The paper was well written and methods were rigorously used and described. COMMENT: A minor comment regarding the Galbraith plot. Was it based on an specific protective size of effect? RESPONSE: We thank the reviewer for this question. The Galbraith plot is mainly used to find source(s) of heterogeneity in meta-analysis. Thus, it would identify which component study/studies are outliers. In calculating the values along the Y-axis (log OR / SE), we indeed use the range of effect sizes (which maybe from protective to increased risk) from all the included studies in order to derive the log values. Rather than the specific protective size of effect as basis, it is the consequence of outlier analysis, which the Galbraith plot is the main instrument in identifying the outlier(s). COMMENT: Please define in the text if you did so. It is advisable to the authors include the size of effect plot (arc) on Figure 3. RESPONSE: The reason we use the log OR /SE is to derive positive and negative confidence limits for the Galbraith plot along the y-axis. Unfortunately, size of effect plot (arc) did not allow the above when we attempted to do so. COMMENT: Define Zwoliska in the same figure legend. This unique point was responsible for the 45% heterogeneity between studies. RESPONSE: In the legend of figure 3 (below) we define the role of the outlying study, Zwolinska et al in terms of the heterogeneity in the Caucasian forest plot of the 3DS1S1 genotype comparison. LINES 621-625 Figure 3: Galbraith plot analysis to detect the source of heterogeneity among Caucasian studies; the study above the +2 confidence limit is the outlier, Zwolinska et al [44]; whose presence in the PRO forest plot (Figure 2) accounts for 50% of the heterogeneity. Removal of this study [44] from the PSO forest plot (Figure 4) reduced the heterogeneity to 5%. OR: odds ratio; SE: standard error. COMMENT: There was not mention on the discussion regarding the advantage or disadvantages of using sensitivity approach versus eliminating the outlier. RESPONSE: We thank the reviewer for this comment. We explain the pros and cons of using sensitivity analysis in the Discussion. Mainly, pooled ORs need to be tested for their stability. We address the question: will any study-specific OR be responsible for the instability of the pooled OR? This is tested simply by omitting one study at a time then recalculating the pooled OR without that study. LINES 356-363 The advantage or disadvantages of using sensitivity approach versus eliminating the outlier is contextualized in terms of the following: Sensitivity treatment evaluates robustness of the pooled ORs while outlier elimination addresses heterogeneity. Favorable outcome of sensitivity analysis is robustness, where no study contributed to instability of the results. On the other hand, favorable outcomes of outlier treatment involve both heterogeneity and significance. In our study, heterogeneity was either reduced or eliminated; significance was intensified. These effects from outlier treatment and those from sensitivity analysis, contribute to strengthening the evidence that we present. COMMENT: Table 4 should clarify if the numbers in brackets are those affecting the results? (i.e.: Modifying the ORs in extreme results?). Can you clarify their significance? RESPONSE: The bracketed numbers in the sensitivity analysis Table 4 are simply indications of the references that rendered non-robustness to the comparisons. Removing a study that results in a change of the pooled OR from significant (P < 0.05) to non-significant (P > 0.05) indicates non-robustness (instability) of the comparisons. The significance of the number brackets (Table 4) is a measure of stability/instability of the pooled results. LINES 336-337 PRO: pre–outlier; PSO: post-outlier; the value in brackets indicate the references articles that contributed to instability of associations. References 1. Maartens G, Celum C, Lewin SR (2014) HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet 384: 258-271. Attachments Attachment Submitted filename: Responses to reviewer_31_AUG_2019.docx* https://doi.org/10.1371/journal.pone.0225151.r003
30 Oct 2019 Decision Letter - Srinivas Mummidi, Editor Effects of the killer immunoglobulin–like receptor (KIR) polymorphisms on HIV acquisition: a meta-analysis PONE-D-19-15826R1 Dear Dr. Pabalan, 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. 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With kind regards, Srinivas Mummidi, D.V.M., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 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: Yes 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: The authors have satisfactorily addressed my comments. The authors are to be congratulated for a fine manuscript worthy of publication in the journal. Reviewer #2: The authors made the suggested changes in the manuscript. The paper is well designed and the statistics well performed. The sections of the paper accomplish the PRISMA requirements. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No https://doi.org/10.1371/journal.pone.0225151.r004
Formally Accepted
8 Nov 2019 Acceptance Letter - Srinivas Mummidi, Editor PONE-D-19-15826R1 Effects of the killer immunoglobulin–like receptor (KIR) polymorphisms on HIV acquisition: a meta-analysis Dear Dr. Pabalan: 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 Dr. Srinivas Mummidi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0225151.r005

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