Detecting drought regulators using stochastic inference in Bayesian networks

Aditya Lahiri; Lin Zhou; Ping He; Aniruddha Datta

doi:10.1371/journal.pone.0255486

Peer Review History

Original SubmissionMay 24, 2021
17 Jun 2021 Decision Letter - Steven M. Abel, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-21-16503 Detecting Drought Regulators using Stochastic Inference in Bayesian Networks PLOS ONE Dear Dr. Lahiri, 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. The reviewers have highlighted a few relatively minor points that should help to clarify aspects of the paper. Once addressed, the paper will be acceptable for publication in PLOS ONE. Please submit your revised manuscript by Aug 01 2021 11:59PM. 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Abel, Ph.D. Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. 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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. 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 [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: 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: This paper presents and interesting framework to study drought responses in the context of gene regulatory networks. The authors did a good job discussing the caveats relevant for interpreting their results. Regarding question 4 - the writing is overall fine but I have concerns about the explanation of some analyses. Lines 353-359 are a difficult to follow description of the analysis of expression data: The authors describe their raw data vaguely as “eQTL data points” but do not define what this means in precise terms. It was necessary to read the paper from which the authors obtained their expression data and manually read through their R scripts to understand the analyses. For example, the authors could state that they analyzed expression data of the genes of interest under drought conditions in 104 recombinant inbred lines. Reviewer #2: This study used prior information on four drought reporter genes and their regulators in Arabidopsis, and applied Bayesian inference technique to study the effect of perturbation to regulators on the reporter genes. The study draws inference on the activity of network nodes using experimental data, and the algorithm that simulates node intervention is well described. The study also provides experimental verification of the model, and some of it could be validated experimentally. Overall, the study seems to derive a potential mechanism underlying the known drought regulatory network, rather than finding new regulators of drought. As such, I see this as a the only limitation of the study, as the nodes in the BN model are already well characterized in Arabidopsis but do not easily translate to major crops. It would be nice to state this in the discussion. What was the rationale behind using eQTL data for LPD estimations? Could RNA-seq data be used? Minor: Line 10: California is duplicated. Please rephrase. Line 191: …., the local marginal probability distribution is given by θICE1? Will the cpt of ice not dependent on all its parent nodes? Line: 468: “...that activating MYC2 or inhibiting ATAF1 468 was the best strategy to regulate the drought-responsive reporter genes”. Explain why it is the best? ****** 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: Yes:** Chirag Gupta [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
15 Jul 2021 Author Response July 14, 2021 Dear Reviewers, We would like to thank you for taking the time and effort to review our manuscript and code. We sincerely appreciate all the constructive feedback and suggestions you have provided towards improving our manuscript. We have first addressed the comments of Reveiwer#1 and then Reviewer#2. The responses to Reviewer comments are made in a point-by-point fashion below. Reviewer comments and PLOS ONE requirements are presented in italics. The changes listed below have been incorporated and highlighted in our revised manuscript. All the Authors have reviewed and approved these changes. Response to Reviewer #1 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 Author Response: We thank the Reviewer for their evaluation. 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Author Response: We thank the Reviewer for their evaluation. 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 Author Response: We thank the Reviewer for their evaluation. 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 Author Response: We have made the changes listed below (section and line wise) to improve the language, presentation, and clarity of our manuscript. Abstract: Line 2: Removed comma from the second sentence after the word “drought”. Introduction: Line 5: Added comma after the word “deficit”. Line 14: Added comma after the word “China”. Line 27: Replaced the word “which” with “that”. Line 28-30: Restructured the sentence to make it easier to read. Line 35: Changed wording to “plant breeding methods”. Plant Defense Mechanism: Line 58-59: Added comma after the words “nitrogen” and “acid”. Line 68: Added comma after the words “drought” and “avoidance”. Line 74: Added comma after the word “instead”. Drought Signaling Networks: Line 87: Remove comma after the word “pathways”. Line 92-95: Restructured sentence to improve the explanation of abscisic acid. Line 101-103: Restructured sentence to clarify the role of abscisic and jasmonic acid in drought regulation. Line 111: Added comma after the word “factor”. Line 116: Added comma after the word “here”, changed the word “independent” to “independently”. Line 125: Removed comma after the word “2017”. Line 130: Added comma after the word “Arabidopsis”. Line 137: Added comma after the word “RD29A”. Line 145-146: Improved the sentence structure to clarify the role of MYB2 and MYC2 in the regulation of ERD1. Bayesian Network Model: Line 179: Added comma after the word “protein” Line 181-182: Rephrased the sentence to better explain the binary nature of the nodes in the BN. Line 191-194: Rephrased the sentences to better explain the workflow of BNs from LPD estimation to inference. Parameter Estimation in Bayesian Networks: Line 200-201: Clarified reference to prior sections and added comma after the word “defined”. Line 218-220: Restructured the sentence to clarify the drawback involving prior distribution in BN. Sampling based Inference in Bayesian Networks: Line 262-264: Added a comma after the word “section”. Removed comma after the word “model”. Changed “to determine” to “in determining”. Line 266: Removed comma after the word “time” and added comma after word “1” Line 273-278: Rephrased these lines to clarify the concept of multiply connected networks and the limitation of exact inference. Line 281: Deleted the word “would” after the word “BN”. Line 319: Added comma after the word “variables” Line 325: Added comma after the word “regulated” Results: Line 371: Removed comma after the word “GSE42408” Line 376: Removed comma after the word “ERD1” Line 379: Added comma after the word “analysis” Line 387: Deleted the word “In” before the word “Figs 5” Line 389: Added commas after the words “Fig 6” and “Fig 5”. Line 391: Added comma after the word “scores”. Line 392: Added comma after the word “inhibition” Line 392-395: Restructured the sentences better to explain the results of single node intervention analysis. Line 398: Removed comma after the word “analysis” Line 406-407: Reworded the sentence to include more specific detail on the cited study. Line 411: Removed comma after the word “genes”. Line 413: Added comma after the word “inhibition”. Additional Changes: References to figures in the manuscript have been changed Fig.# to Fig # to meet the style requirements of PLOS ONE. Line 157: Capitalized the alphabet “M” in the section heading “Materials and Methods”. Line 195: Capitalized the initial alphabets of the words “estimation” and “networks” in the section heading “Parameter Estimation in Bayesian Networks”. Line 261: Capitalized the initial alphabets of the words “inference” and “networks” in the section heading “Sampling Based Inference in Bayesian Networks”. Line 349-350: Fixed the position of Table 1. 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 Comment #1: This paper presents and interesting framework to study drought responses in the context of gene regulatory networks. The authors did a good job discussing the caveats relevant for interpreting their results. Regarding question 4 - the writing is overall fine but I have concerns about the explanation of some analyses. Author Response: We thank the Reviewer for their kind words. We have made the following changes to improve the explanation of various analysis in our paper. Lines 28-30: Restructured the sentence to make it easier to read and better introduce the notion of the internal drought defensive mechanism of plants. Line 92-95: Restructured sentence to improve the explanation of abscisic acid. Line 101-103: Restructured sentence to clarify the role of abscisic and jasmonic acid in drought regulation. Line 145-146: Improved the sentence structure to clarify the role of MYB2 and MYC2 in the regulation of ERD1. Line 181-182: Rephrased the sentence to better explain the binary nature of the nodes in the BN. Line 191-194: Rephrased the sentences to better explain the workflow of BNs from LPD estimation to inference. Line 218-220: Restructured the sentence to clarify the drawback involving prior distribution in BN. Line 273-278: Rephrased these lines to clarify the concept of multiply connected networks and the limitation of exact inference. Line 392-395: Restructured the sentences better to explain the results of the single node intervention analysis. Line 406-407: Reworded the sentence to include more specific detail on the cited study. Reviewer #1 Comment #2: Lines 353-359 are difficult to follow description of the analysis of expression data: The authors describe their raw data vaguely as “eQTL data points” but do not define what this means in precise terms. It was necessary to read the paper from which the authors obtained their expression data and manually read through their R scripts to understand the analyses. For example, the authors could state that they analyzed expression data of the genes of interest under drought conditions in 104 recombinant inbred lines. Author Response: We appreciate the Reviewer for raising this concern and for their helpful suggestions. We have incorporated these suggestions in Lines 351-357. Additionally, we have added the rationale behind choosing this dataset. Response to Reviewer #2 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 #2: Yes Author Response: We thank the Reviewer for their evaluation. 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes Author Response: We thank the Reviewer for their evaluation. 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 #2: Yes Author Response: We thank the Reviewer for their evaluation. 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 #2: Yes Author Response: We thank the Reviewer for their evaluation. 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 #2 Comment #1: This study used prior information on four drought reporter genes and their regulators in Arabidopsis, and applied Bayesian inference technique to study the effect of perturbation to regulators on the reporter genes. The study draws inference on the activity of network nodes using experimental data, and the algorithm that simulates node intervention is well described. The study also provides experimental verification of the model, and some of it could be validated experimentally. Overall, the study seems to derive a potential mechanism underlying the known drought regulatory network, rather than finding new regulators of drought. As such, I see this as a the only limitation of the study, as the nodes in the BN model are already well characterized in Arabidopsis but do not easily translate to major crops. It would be nice to state this in the discussion. Author Response: We thank the Reviewer for their insightful comments. We have incorporated the requested changes in the discussion section in Lines 457-459. Reviewer #2 Comment #2: What was the rationale behind using eQTL data for LPD estimations? Could RNA-seq data be used? Author Response: We thank the Reviewer for raising this question. We have explained the rationale of using eQTL data and other details pertaining to this specific dataset in Lines 351-358. Yes, we can use RNA-seq data as well for the estimations of LPDs. Reviewer #2 Comment #3: Minor: Line 10: California is duplicated. Please rephrase. Author Response: We thank the Reviewer for notifying us about this typographical error, we have remedied this error in Line 10-11. Reviewer #2 Comment #4: Line 191: …., the local marginal probability distribution is given by θICE1? Will the cpt of ice not dependent on all its parent nodes? Author Response: We thank the Reviewer for notifying this error. Indeed, the CPT on a node is dependent on all its parent nodes, and ICE1 is dependent on HOS1 and SIZ1. The corrections are incorporated in Lines 188-190. Reviewer #2 Comment #5: Line: 468: “...that activating MYC2 or inhibiting ATAF1 468 was the best strategy to regulate the drought-responsive reporter genes”. Explain why it is the best? Author Response: We thank the Reviewer for raising this concern. We have provided the explanation in Lines 473-477. Attachments Attachment Submitted filename: Response to Reviewers.pdf https://doi.org/10.1371/journal.pone.0255486.r002
19 Jul 2021 Decision Letter - Steven M. Abel, Editor Detecting Drought Regulators using Stochastic Inference in Bayesian Networks PONE-D-21-16503R1 Dear Dr. Lahiri, 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, Steven M. Abel, Ph.D. Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0255486.r003
Formally Accepted
6 Aug 2021 Acceptance Letter - Steven M. Abel, Editor PONE-D-21-16503R1 Detecting Drought Regulators using Stochastic Inference in Bayesian Networks Dear Dr. Lahiri: 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. Steven M. Abel Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0255486.r004

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