DALIA- a comprehensive resource of Disease Alleles in Arab population

Aastha Vatsyayan; Parul Sharma; Shrey Gupta; Sumiti Sandhu; Seetha Lakshmi Venu; Vandana Sharma; Bouabid Badaoui; Kaidi Azedine; Serti Youssef; Anna Rajab; Alaaeldin Fayez; Seema Madinur; Anop Ranawat; Kavita Pandhare; Srinivasan Ramachandran; Sridhar Sivasubbu; Vinod Scaria

doi:10.1371/journal.pone.0244567

Peer Review History

Original SubmissionAugust 27, 2020
8 Oct 2020 Decision Letter - Obul Reddy Bandapalli, Editor PONE-D-20-26943 DALIA- a Comprehensive Resource of Disease Alleles in Arab Population PLOS ONE Dear Dr. Scaria, 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. One of the reviewers raised concerns on the way the population is described and the rationale for this study is not clear. Please make those points clear and also the other points raised by the reviewers. Also explain your reasons for the interpretation that large family size results in genetic disorders. Not clear why that would be the case, and what is the evidence that family sizes are large among Arabs providing supporting references also for the source of information on the population size. Please submit your revised manuscript by Nov 22 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'. 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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: No Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know 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 seeks to describe how a comprehensive database for genetic information on Arab populations was formed, and it's characteristics. The rationale for data base need is strong: heavy burden of genetic disorders in the region underscores the need for genome data analyses. However, the purpose of the paper is not clear. The authors need to state with more clarity what the paper aims to do, and why that aim is important for advancing the field. Other details are elaborated below. 1. There is no source of information in terms of the basic statement that there are twenty-three Arab States with a total population of around 420 million individuals and roughly encompassing 5% of the world population. What are the 23 countries? How is Arab defined? 2. The authors seem to conflate Arab with Middle Eastern. Need to distinguish Arab from Middle Eastern. 3. The authors state that large family size results in genetic disorders. Not clear why that would be the case, and what is the evidence that family sizes are large among Arabs? 4. Supporting information is difficult to make sense of. What does it support and how does that information advance the aims of the paper? Reviewer #2: DALIA- a Comprehensive Resource of Disease Alleles in Arab Population by Aastha Vatsyayan et al has compiled and made the resource important for genetic analysis of Arab population. It is quite an impressive work done. The features in the database have been incorporated thoughtfully. ****** 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/. 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Revision 1
25 Nov 2020 Author Response Response to Reviewers RESPONSE TO REVIEWER 1 Reviewer #1: This paper seeks to describe how a comprehensive database for genetic information on Arab populations was formed, and it's characteristics. The rationale for data base need is strong: heavy burden of genetic disorders in the region underscores the need for genome data analyses. However, the purpose of the paper is not clear. The authors need to state with more clarity what the paper aims to do, and why that aim is important for advancing the field. Other details are elaborated below. ANS: We thank the reviewers for the prompt review and suggestions. The aim of creating the data collection is to provide a ready reference to genetic variants reported from Arab populations. This is relevant as a significant number of genetic variants with clinical implications are not readily curated and available in global databases like ClinVar, which necessitates the creation of focussed and local databases relevant to the populations. The database as its name suggests, encompasses genetic variants reported from the 23 Arab countries. 1. There is no source of information in terms of the basic statement that there are twenty-three Arab States with a total population of around 420 million individuals and roughly encompassing 5% of the world population. What are the 23 countries? How is Arab defined? ANS: We thank the reviewer for asking for the clarifications. The 23 Arab countries are defined as per the Arab League [1]. We have now updated the manuscript with more details as well as relevant citations. The Arab League is an alliance of Arab countries that aims to foster cooperation in economics, communication, culture, nationality, social welfare, and health and military affairs among its 22 members, namely: Algeria, Bahrain, the Comoros Islands, Djibouti, Egypt, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Mauritania, Oman, Palestine, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, the United Arab Emirates, and Yemen [1–4]. Israel, though not a part of this alliance, has a portion of population that comprises Arabs [5,6], however the exact reported total figures vary. These 23 countries are represented in the DALIA database. Though estimates vary, the Arab League has a population of about 427.87 million people, and is home to about 5.6% of the world population [7,8]. All 22 countries form a part of the Arabic speaking world, as does the Arabic population in Israel. 2. The authors seem to conflate Arab with Middle Eastern. Need to distinguish Arab from Middle Eastern. ANS: We apologise for any confusion regarding this. The data encompasses genetic variants reported in Arab populations. The Allele frequency estimates use the Middle Eastern datasets, as no population scale data for the Arab populations exist in public domain. We have now clarified this in the revised manuscript. 3. The authors state that large family size results in genetic disorders. Not clear why that would be the case, and what is the evidence that family sizes are large among Arabs? ANS: We apologise for the confusion. We have now removed the statement in the revised manuscript and added references wherever appropriate to clarify the statements. 4. Supporting information is difficult to make sense of. What does it support and how does that information advance the aims of the paper? ANS: While the manuscript provides a detailed overview of the DALIA database, The supporting information provides the detailed metrics for the Allele frequencies as well as FST calculations, for the interest of clinicians and genetic epidemiologists with a ready dataset and reference. An example of such use would be the analysis of allele frequencies as shown in our paper, in which we compared the variant allele frequencies in Qatar and GME with those in global populations reported in 1000 Genomes and ExAC databases. We obtained 142 statistically significant variants (Fisher’s Exact Test, p-value < 0.01) as a result of this analysis (S1 Fig), 94 of which (Fig 3) were selected for ease of study after applying Bonferroni correction. All significant variants represent potential targets that could be pathogenic for specific populations, and thus make ideal targets for screening in those populations, and consequently for genetic counselling. As evidence, we performed the ACMG annotation of 4 G6PD variants, two of which were found to have evidence to qualify being annotated as pathogenic or likely pathogenic. Further, iHS and Fst are two widely used tests to determine positive selection, which can help map changing allele frequencies at population scale. In our work, we found 10 genes that had extreme iHS scores, indicating selection. Each of then 10 plots (Fig 4, S2-S10 Figs) also depicts all known variants along the length of the gene, along with its exon structure. These genes could be linked with diseases of interest - e.g., MEFV is linked to Familial Mediterranean Fever, ABCA4 to Stargardt macular dystrophy [9] and CLDN deafness (OMIM 605608), and would help researchers visualize whether a variant in a positively selected gene is selected, and also lies in the coding region, and what its scores are. RESPONSE TO REVIEWER 2 Reviewer #2: DALIA- a Comprehensive Resource of Disease Alleles in Arab Population by Aastha Vatsyayan et al has compiled and made the resource important for genetic analysis of Arab population. It is quite an impressive work done. The features in the database have been incorporated thoughtfully. ANS: We thank the reviewer. References 1. The state of health in the Arab world, 1990–2010: an analysis of the burden of diseases, injuries, and risk factors. Lancet. 2014;383: 309–320. 2. The Arab League. [cited 21 Nov 2020]. Available: https://www.cfr.org/backgrounder/arab-league 3. Geography of the Modern Middle East and North Africa. [cited 21 Nov 2020]. Available: http://www.middleeastpdx.org/resources/original/geography-of-the-modern-middle-east-and-north-africa/ 4. Khachfe HH, Refaat MM. Bibliometric analysis of Cardiovascular Disease Research Activity in the Arab World. International Cardiovascular Forum Journal. 2019. doi:10.17987/icfj.v15i0.554 5. Danial-Farran N, Brownstein Z, Gulsuner S, Tammer L, Khayat M, Aleme O, et al. Genetics of hearing loss in the Arab population of Northern Israel. Eur J Hum Genet. 2018;26: 1840–1847. 6. Brunstein Klomek A, Nakash O, Goldberger N, Haklai Z, Geraisy N, Yatzkar U, et al. Completed suicide and suicide attempts in the Arab population in Israel. Soc Psychiatry Psychiatr Epidemiol. 2016;51: 869–876. 7. Arab Countries 2020. [cited 21 Oct 2020]. Available: https://worldpopulationreview.com/country-rankings/arab-countries 8. Member states of the Arab League. [cited 21 Nov 2020]. Available: https://www.worlddata.info/alliances/arab-league.php 9. Piccardi M, Fadda A, Martelli F, Marangoni D, Magli A, Minnella AM, et al. Antioxidant Saffron and Central Retinal Function in ABCA4-Related Stargardt Macular Dystrophy. Nutrients. 2019;11. doi:10.3390/nu11102461 Attachments Attachment Submitted filename: Response_to_Reviewers_DALIA.docx https://doi.org/10.1371/journal.pone.0244567.r002
14 Dec 2020 Decision Letter - Obul Reddy Bandapalli, Editor DALIA- A Comprehensive Resource of Disease Alleles in Arab Population PONE-D-20-26943R1 Dear Dr. Scaria, 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, Obul Reddy Bandapalli, MSc, PhD 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 #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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #2: The authors have answered the reviewers concern. No additional comments. Also the data related to database has been included ****** 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 #2: No https://doi.org/10.1371/journal.pone.0244567.r003
Formally Accepted
4 Jan 2021 Acceptance Letter - Obul Reddy Bandapalli, Editor PONE-D-20-26943R1 DALIA- a Comprehensive Resource of Disease Alleles in Arab Population Dear Dr. Scaria: 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. Obul Reddy Bandapalli Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0244567.r004

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