Bayesian polygenic risk estimation approach to nuclear families with discordant sib-pairs for myelomeningocele

Adolfo Aguayo-Gómez; Leonora Luna-Muñoz; Yevgeniya Svyryd; Luis Ángel Muñoz-Téllez; Osvaldo M. Mutchinick

doi:10.1371/journal.pone.0316378

Peer Review History

Original SubmissionMay 3, 2024
17 Sep 2024 Decision Letter - Yun Li, Editor PONE-D-24-17409Bayesian Polygenic Risk Estimation Approach to Nuclear Families with Discordant Sib-Pairs for MyelomeningocelePLOS ONE Dear Dr. Mutchinick, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Nov 01 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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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: Partly Reviewer #2: Yes Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: 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 Reviewer #3: 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 Reviewer #3: 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 paper, the authors have adopted a Bayesian approach to estimate polygenic risk and identify the significant genes related to neural tube disorders (NTDs). While the topic of the paper is significant, the paper should be better constructed and include more details about the tests, mechanisms used, assumptions, modeling techniques etc. For example: 1. Section 2.3.3: Bayesian Analysis: Bayesian is an estimation approach which allows one to incorporate prior knowledge about model parameters. It performs estimation through posterior sampling. However, it still needs a particular model to work on. The stats section in the paper lacks proper description of the exact model that was used, the model parameters, what prior were assumed in the Bayesian analysis and how posterior sampling was done. 2. Line 134: “The analysis were conducted by categorizing gene variants into missense and non-missense..." - How was this categorization done? 3. “Independent effects are assumed when combining the effects of multiple variants" - can the authors discuss the practicality of this assumption and what happens when it is violated. 4. Bayesian Analysis Results: Can the authors provide some measures of model diagnostics and time complexity? General comment: The authors should include more details and be specific about the analysis performed for completion Reviewer #2: The manuscript described a scientifically plausible protocol in qualifying polygenic risk among the target population. The statistical analysis is performed in accordance with the aim of the study. Yes. Yes. Reviewer #3: The manuscript presents a study that identifies a polygenic risk profile for Myelomeningocele in Mexican families, highlighting significant genetic associations and the impact of folic acid fortification on disease risk. The study employed a family-based analysis using the transmission disequilibrium test and Bayesian methods to examine 656 single nucleotide polymorphisms across 395 genes in 203 Mexican nuclear families with discordant siblings. The findings reveal that 150 genetic risk variants were identified in 10 genes, with TDT analysis highlighting significant statistical differences in allele transmission for ten variants. Further, Bayesian analysis shows a significant reduction in risk probabilities after the folic acid fortification. This work advances our genetic understanding of MMC and could enhance prevention and screening strategies for MMC and other congenital malformations. ****** 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 Reviewer #3: 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/. 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Revision 1
23 Oct 2024 Author Response October 21, 2024 Rebuttal letter Dear Editor-in-Chief, Dear Academic Editor and Reviewers, We sincerely appreciate all reviewers' insightful feedback, which allowed us to significantly improve the clarity and depth of our manuscript, "Bayesian Polygenic Risk Estimation Approach to Nuclear Families with Discordant Sib-pairs for Myelomeningocele." In this rebuttal letter, we have carefully addressed all the reviewers' comments and made the corresponding revisions to the manuscript. Specifically, we have clarified the Bayesian framework used, expanded the methodological details, and provided further discussion on the assumptions and computational aspects of the analysis. We hope the revised manuscript answers the reviewers' comments and suggestions. Sincerely yours, Osvaldo M. Mutchinick, MD, PhD Professor of Medical Genetics Chief, Department of Genetics National Institute of Medical Sciences and Nutrition Salvador Zubirán Vasco de Quiroga 15, Col. Belisario Domínguez, Tlalpan 14080, Mexico City, Mexico Phone: (5255) 5487-0900, Ext. 2514/2515 Direct Phone: (5255) 5655-6138 E-mail: osvaldo@unam.mx Response to Journal Requirements We have carefully reviewed the journal's additional requirements and have addressed each of them as follows: PLOS ONE Style Requirements We have ensured that the revised manuscript meets PLOS ONE's style requirements. Data Availability Statement We confirm that our submission includes all the raw data required to replicate our study's results. These data are included within the manuscript and its "supporting Information files" to ensure full reproducibility. Should the reviewers or editors require additional data, we agree to provide them upon request. Ethics Statement. We have included a complete ethics statement in the 'Methods' section of the revised manuscript. This statement specifies the name of the Institutional Review Board (IRB) or Ethics Committee that approved the study, the written consent procedures, and any relevant waivers obtained. We hope these revisions meet the journal's requirements, and we remain available for any further clarifications. Response to reviewers Reviewer #1: Observation 1. Section 2.3.3: Bayesian Analysis: Bayesian is an estimation approach which allows one to incorporate prior knowledge about model parameters. It performs estimation through posterior sampling. However, it still needs a particular model to work on. The stats section in the paper lacks proper description of the exact model that was used, the model parameters, what prior were assumed in the Bayesian analysis and how posterior sampling was done. Response: We have removed the section numbering from the document. The "Bayesian analysis" section, previously identified as 2.3.3, starts on line 126 of the revised manuscript. We would like to clarify that our approach employs Bayesian principles to estimate the probability of neural tube defects (NTDs) based on allele transmission frequencies. However, it does not involve a formal Bayesian regression model or posterior sampling. Instead, we use a Bayesian probabilistic framework to adjust for known MMC prevalence, which acts as our prior and calculates posterior probabilities of disease given exposure to specific genetic variants. Our model framework is based on Bayes' Theorem, where the prior probability is the population prevalence of MMC, and the likelihood is based on the observed allele frequencies in both MMC-affected and non-affected sibs. Specifically, the posterior probability of disease given exposure to a genetic variant is estimated using the following formula: P("MMC" │"Exposed to TDT transmitted Variant i" )=(f_"MMC-sibs" ^((i) )×P("MMC" ))/(f_"MMC-sibs" ^((i) )×P("MMC" )+f_"Non-affected-sibs" ^((i) )×(1-P("MMC" )) ) Where: - f_"MMC-sibs" ^((i) ): Is the frequency of the TDT-transmitted allele in MMC-affected sibs. - f_"Non-affected-sibs" ^((i) ) : Is the frequency of the TDT transmitted allele in Non-affected sibs. - P("MMC" ) ∶ Is the prevalence of MMC. Observation 2. Line 134: "The analysis were conducted by categorizing gene variants into missense and non-missense..." - How was this categorization done? Response: We classified variants into two main categories: missense variants and non-missense variants. Missense variants are nucleotide changes that lead to amino acid substitutions, potentially altering protein function. Non-missense variants include synonymous variants, which do not change the amino acid sequence, and intronic variants, which occur in non-coding regions but may affect gene expression regulation. We used the Ensembl Variant Effect Predictor (VEP) for variant annotation. VEP provided comprehensive predictions on the functional impact of each variant, which we used for categorization. When multiple variants were identified within the same gene, we selected the variant with the highest predicted functional impact or most significantly associated with MMC. More detailed descriptions of the categorization process are provided in the supplementary file. Observation 3. "Independent effects are assumed when combining the effects of multiple variants" - can the authors discuss the practicality of this assumption and what happens when it is violated. Response: The assumption of independent effects simplifies the calculation of polygenic risk by allowing us to combine the effects of multiple variants multiplicatively, as follows: P("MMC" │"Exposed to variants i,j,…" )=(∏_k▒f_"MMC-sibs" ^((k) ) ×P("MMC" ))/(∏_k▒f_"MMC-sibs" ^((k) ) ×P("MMC" )+∏_k▒f_("Non-affected-sibs" )^((k) ) ×(1-P("MMC" )) ) This assumption holds when the variants are located in different genes or pathways and do not interact biologically. The above is reasonable for variants that are unlinked and functionally independent. However, when variants are in linkage disequilibrium or are part of the same biological pathway, this assumption may be violated, leading to biased estimates. In such cases, interactions between variants could amplify or suppress the individual effects, which our method does not capture. To mitigate this issue, we selected one variant per gene to minimize potential linkage effects and reduce multicollinearity, thus limiting the risk of confounding due to interactions between linked variants. We recognize that this approach may miss some gene-gene interactions and discuss this limitation. Observation 4. Bayesian Analysis Results: Can the authors provide some measures of model diagnostics and time complexity? Response: Traditional convergence diagnostics are not applicable since we did not employ a formal Bayesian regression model with posterior sampling. Our approach involves direct calculation of posterior probabilities rather than iterative sampling. However, we can discuss the computational complexity of the analysis. The complexity is driven by the combinatorial nature of calculating probabilities for multiple variants. Given (n) variants, the number of combinations we need to evaluate is (2^n-1). For each combination, we compute the posterior probabilities. Time complexity grows exponentially with the number of variants, but we limit the number of variants per analysis for practical purposes to maintain computational feasibility. We also employed progressive computation in our Shiny application to provide real-time feedback on the calculations, improving user experience. General comment: The authors should include more details and be specific about the analysis performed for completion. Response: We appreciate the feedback and revised the manuscript to include more details about the analysis, especially about the categorization and selection of variants, the probabilistic framework used for Bayesian analysis, and the assumptions of independence. Additionally, we will provide more specific information about the computational aspects of our methodology, including the limitations of the independent effects assumption and the steps we took to mitigate its potential violations. We hope that our responses clarify and address all comments, and we are open to further enriching our manuscript based on any additional suggestions. Reviewer #2 and Reviewer #3: The authors sincerely appreciate positive comments on the study. We also thank all the reviewers for their time and thoughtful review of our manuscript. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0316378.r002
26 Nov 2024 Decision Letter - Yun Li, Editor PONE-D-24-17409R1Bayesian Polygenic Risk Estimation Approach to Nuclear Families with Discordant Sib-Pairs for MyelomeningocelePLOS ONE Dear Dr. Mutchinick, 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 a few remaining minor points raised during the review process. Please submit your revised manuscript by Jan 10 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. 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Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed Reviewer #3: 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 Reviewer #3: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: (No Response) ****** 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 Reviewer #3: (No Response) ****** 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 Reviewer #3: (No Response) ****** 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 answered all questions and made necessary recommended modifications in the paper. Thank you for addressing the comments. Reviewer #2: This revision addressed most previous comments, and the research was presented in a clear and informative manner. Some figures and tables, however, need to be adjusted in size for better readability (e.g. Line 163-164, the last column of Table 1 showing HGVSp extends out of the page; line 223, figure 1 is not there). Other issues mostly involve small grammar mistakes (e.g. Line 173, a period punctuation mark is missing) and long sentences that are generally acceptable. Reviewer #3: (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: No Reviewer #2: No Reviewer #3: 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. 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Revision 2
28 Nov 2024 Author Response November 28, 2024 Rebuttal letter Dear Dr. Yun Li, Academic Editor Plos One We sincerely appreciate the insightful feedback provided by all reviewers and regret the minor issues raised during the review process. We hope that we have fulfilled the journal's requirements through this carefully corrected revision of our manuscript, 'Bayesian Polygenic Risk Estimation Approach to Nuclear Families with Discordant Sib-pairs for Myelomeningocele'. Sincerely yours, Osvaldo M. Mutchinick, MD, PhD Professor of Medical Genetics Chief, Department of Genetics National Institute of Medical Sciences and Nutrition Salvador Zubirán Vasco de Quiroga 15, Col. Belisario Domínguez, Tlalpan 14080, Mexico City, Mexico Phone: (5255) 5487-0900, Ext. 2514/2515 Direct Phone: (5255) 5655-6138 E-mail: osvaldo@unam.mx Response to Journal Requirements We have carefully reviewed the journal's additional requirements and have addressed each of them as follows: 1. Completeness and correctness of the reference list: - We realized that references number 4 and 40 were duplicates. Reference 40 (Lines 416-418) was eliminated, and the annotation of the other references was corrected in the text (lines 246, 266, 273, and 299) and the final list of references (lines 419, 421, 425, 429, and 432). - Reference 5 (lines 315-318) was corrected to meet the journal's guidelines. - Reference 35 (lines 401-403): the DOI was added, and the hyperlink to the article was eliminated. 2. Revision of the cited articles: - We reviewed all cited articles by searching in the Retraction Watch Database [1], CrossRef [2], Google Scholar [3], PubMed [4], and directly on the websites of the journals where the articles were published. None of the 44 references appeared retracted. [1]. Retraction Watch. Retraction Watch Database [Internet]. New York: The Center for Scientific Integrity; c2024 [cited 2024 Nov 26]. Available from: https://retractionwatch.com/the-retraction-watch-database/ [2]. CrossRef. CrossRef Metadata Search [Internet]. Lynnfield: CrossRef; c2024 [cited 2024 Nov 26]. Available from: https://search.crossref.org/ [3] Google Scholar. Google Scholar [Internet]. Mountain View: Google; c2024 [cited 2024 Nov 26]. Available from: https://scholar.google.com/ [4] National Center for Biotechnology Information (NCBI). PubMed [Internet]. Bethesda: U.S. National Library of Medicine; c2024 [cited 2024 Nov 26]. Available from: https://pubmed.ncbi.nlm.nih.gov/ Response to reviewers Reviewer #2: Comment 6. "This revision addressed most previous comments, and the research was presented in a clear and informative manner. Some figures and tables, however, need to be adjusted in size for better readability (e.g. Line 163-164, the last column of Table 1 showing HGVSp extends out of the page; line 223, figure 1 is not there). Other issues mostly involve small grammar mistakes (e.g. Line 173, a period punctuation mark is missing) and long sentences that are generally acceptable." Response: - Regarding Table 1, we retained its original size as it was necessary to ensure clarity and readability, modifying the paper sheet size. - Regarding Figure 1, the figure was not placed in the main manuscript, as stipulated in the journal's guidelines (https://journals.plos.org/plosone/s/submission-guidelines#loc-references): "Do not include figures in the main manuscript file. Each figure must be prepared and submitted as an individual file. … Figure captions are inserted immediately after the first paragraph in which the figure is cited. Figure files are uploaded separately..." - To ensure compliance, we checked the figure using the PACE tool (https://pacev2.apexcovantage.com/). The adjustments were as follows: the image file was flattened, dimensions were adjusted to 7.49 in W x 4.69 in H, and the TIF file was converted to a valid TIF format. Following these changes, we uploaded a new figure file. - We have thoroughly reviewed the manuscript for grammatical errors and addressed several issues, including: � Line 81: The word "off" was deleted � Line 173: Final punctuation corrected. � Line 181: Extra space removed before the number "0.001". � Lines 118, 186, 195, 198, 212, 227, 244, 266, 433: "TDTDS" changed to "TDT-DS" for better clarity. � S1 File and S2 Table: "TDTDS" changed to "TDT-DS" � Lines 211, 238-241, 250-252, 258, 267, 268, 271, 273, 274: Gene names formatted in italics. � Line 233: Space added after the word "model." � Line 255: "increased" changed to "increase." � Line 281: "pre" changed to "pre-." � Line 296: "ad hoc" formatted in italics. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0316378.r004
11 Dec 2024 Decision Letter - Yun Li, Editor Bayesian Polygenic Risk Estimation Approach to Nuclear Families with Discordant Sib-Pairs for Myelomeningocele PONE-D-24-17409R2 Dear Dr. Mutchinick, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Yun Li Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0316378.r005
Formally Accepted
17 Dec 2024 Acceptance Letter - Yun Li, Editor PONE-D-24-17409R2 PLOS ONE Dear Dr. Mutchinick, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Yun Li Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0316378.r006

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