The influence of age, gender and pharmacogenetic profiles on the perspective on medicines in the German EMPAR study

Veronica Atemnkeng Ntam; Tatjana Huebner; Michael Steffens; Christoph Roethlein; Britta Haenisch; Julia Stingl; Roland Linder; Catharina Scholl

doi:10.1371/journal.pone.0311267

Peer Review History

Original SubmissionMarch 7, 2024
23 Jun 2024 Decision Letter - Hoh Boon-Peng, Editor PONE-D-24-09164The influence of age, gender and pharmacogenetic profiles on the beliefs about medicines in the German EMPAR studyPLOS ONE Dear Dr. Huebner, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== ACADEMIC EDITOR: Overall, the reviewers are pleased with the work submitted. A slight concern pertaining the research question, being the link of Pgx markers and belives towards medicine is vague and should be clarified further, focusing more on the impact of having pgx tests and their outlook on medicine afterwards would be more helpful. ============================== Please submit your revised manuscript by Aug 07 2024 11:59PM. 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Kind regards, Hoh Boon-Peng, PhD Academic Editor PLOS ONE Journal requirements: 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 2. Thank you for stating the following financial disclosure: “This EMPAR study was funded by the Innovation Fund of the Federal Joint Committee in Germany (Gemeinsamer Bundesausschuss). Grant number: 01VSF16047.” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." 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Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process. 4. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. 5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 6. Please review your reference list to ensure that it is complete and correct. 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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: Dear Authors, Congratulations on your study. some of my comment are as follows: 1. In the title, the word outlook or perspective would better represent views and beliefs. 2. How far back does the retropective data collected? 3. EMPAR questionnaire: Would be great to have a simple explanation on the questionnaire, such as how many questions for each block. for the gene testing block, is one question enough to understand the participants' prespective? 4. Figure 3: I find the box plot contains less information than the suppl. table 4. I prefer the table to be in the main manuscript. 5. From the ICD-10 Y57.9! database, does any of the subjects benefited from genotyping? what were their score for gene testing compared to the rest of the population? 6. Figure 6 carry very little information on its own. is there correlating data from their ICD code, for example, does the ICD code relate to the variant(s)? does genetic testing solve their ICD code issue? Reviewer #2: This manuscript provides valuable insights into the factors influencing beliefs about medications. All the analyses were well conducted. Following are some minor comments: 1. There should be an explanation of “BMQ” when it is first mentioned in the main context (line 35). I suggest a thorough proofreading. 2. Did the authors considered genetic variations on other genes besides the 4 genes mentioned in the manuscript? 3. There might be additional interesting findings by analyzing a) the association between education levels and patients' beliefs and b) the interaction between different variables. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0311267.r001
Revision 1
30 Aug 2024 Author Response Dear reviewers, dear editor, Thank you very much for your comments, suggestions and questions to improve the quality of the manuscript of our research article! Please find our answers and descriptions of implemented changes below. Journal requirements: 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 Thank you very much, we checked the requirements and adjusted the manuscript accordingly! 2. Thank you for stating the following financial disclosure: “This EMPAR study was funded by the Innovation Fund of the Federal Joint Committee in Germany (Gemeinsamer Bundesausschuss). Grant number: 01VSF16047.” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. We included the suggested statement "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." according to the instructions. Further amendments were not necessary. 3. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process. Thank you very much, we prepared the data table S2 Table1 that will be available in the supporting information. We furthermore changed the Email address of the corresponding author, as the old address will soon not be valid. 4. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. We performed changes to the manuscript according to the instructions. 5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. We performed changes to the manuscript according to the instructions. 6. 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. We revised the manuscript according to the instructions. Reviewers' comments: Reviewer's Responses to Questions Reviewer #1: Dear Authors, Congratulations on your study. some of my comment are as follows: 1. In the title, the word outlook or perspective would better represent views and beliefs. Thank you very much! We changed the wording accordingly. The new title of the manuscript is “The influence of age, gender and pharmacogenetic profiles on the perspective on medicines in the German EMPAR study” 2. How far back does the retrospective data collected? Data of a range of 3-4 years was collected for each participant. Data of one year prior to initial prescription of the drugs of interest or the Y57.9! diagnosis, the year of an initial prescription or the Y57.9! diagnosis if it was detected in 2013-2018 and data of one to two subsequent years (for recruited participants in 2018 only data of one subsequent year was available) was provided by the involved health insurance company. Thus, the earliest data was available from 2012 and the latest time at which data was retrieved was 2019. We included the information in the methods section in line 132-135 of the revised version. 3. EMPAR questionnaire: Would be great to have a simple explanation on the questionnaire, such as how many questions for each block. for the gene testing block, is one question enough to understand the participants' prespective? We adjusted the explanation of the questionnaire in the methods section in line 155-157 of the revised version to improve the information on the number of questions in each block. The gene testing question was not part of a validated questionnaire block such as the Harm, Benefit, Overuse and Perceived Sensitivity to Medicines blocks of the validated BMQ questionnaire. The one question item on gene testing is not sufficient for a validation and thorough assessment of the participants’ perspectives on gene testing. We included it to receive an impression of the participants’ attitude towards the use of preemptive testing in routine care. However, for an appropriate evaluation a different study design and an appropriate, validated question block is necessary as here participants explicitly gave their consent to participate in gene testing. These limitations were addressed in the discussion in line 462-471. 4. Figure 3: I find the box plot contains less information than the suppl. table 4. I prefer the table to be in the main manuscript. Thank you very much! The table is indeed more informative. We removed the box plot and exchanged it with the table. The manuscript and the supplementary material were adjusted accordingly. 5. From the ICD-10 Y57.9! database, does any of the subjects benefited from genotyping? what were their score for gene testing compared to the rest of the population? The occurrence and frequency of the ICD-10 Y57.9! diagnosis is currently evaluated in terms of a correlation with specific prescriptions and gene variants or phenotypes. The results will be published elsewhere. The score for gene testing in the ICD-10 Y57.9! collective did not differ significantly compared to the other collectives of the EMPAR population. 6. Figure 6 carry very little information on its own. is there correlating data from their ICD code, for example, does the ICD code relate to the variant(s)? does genetic testing solve their ICD code issue? Figure 6. only shows how the number or accumulation of actionable variants correlates with the evaluated questionnaire scores. Further evaluations in terms of specific ICD 10 codes, medications and relevant actionable variants or phenotypes are currently in progress and will be published elsewhere. Reviewer #2: This manuscript provides valuable insights into the factors influencing beliefs about medications. All the analyses were well conducted. Following are some minor comments: 1. There should be an explanation of “BMQ” when it is first mentioned in the main context (line 35). I suggest a thorough proofreading. an explanation of “BMQ” when it is first mentioned in the main context (line 35) We performed a thorough proofreading and checked all abbreviations as suggested. An explanation of “BMQ” was added in line 34 in the revised version when it is first mentioned in the main context. An explanation of “EMPAR” was added in line 27-29, of “ICD” in line 41, of “CYP” in line 193, of “SLCO1B1”in line 195, of “VKORC1” in line 196 of the revised version when it is first mentioned in the main context. No further unexplained abbreviations at first mentioning were detected. 2. Did the authors considered genetic variations on other genes besides the 4 genes mentioned in the manuscript? In this manuscript we only focused on the genes and gene variants with the highest evidence (PharmGKB Clinical Annotation Levels of Evidence 1A or 1B) to be actionable with regard to the medication of main study interest (cholesterol lowering drugs and anticoagulants/ antiplatelet agents). Further evaluations including comedications and other relevant genes/gene variants covered by the iPLEX® PGx 74 and the VeriDose® CYP2D6 CNV panel are in progress and will be published elsewhere. 3. There might be additional interesting findings by analyzing a) the association between education levels and patients' beliefs and b) the interaction between different variables. Thank you very much! The evaluation of the suggested issues is indeed interesting. The patients' beliefs with regard to education levels were assessed; however, as mainly no information on the education level was available and predominantly high education levels were reported in the study population, the results were inconclusive and therefore not included in the manuscript. We included the information on the education level in the discussion section in line 457-460 of the revised version. The interaction between different variables is currently assessed in terms of specific prescriptions, pharmacogenes and ICD-10 codes and will be published elsewhere. Thank you for your consideration! With best regards, Dr. Tatjana Hübner Attachments Attachment Submitted filename: Response to Reviewers.pdf https://doi.org/10.1371/journal.pone.0311267.r002
17 Sep 2024 Decision Letter - Hoh Boon-Peng, Editor The influence of age, gender and pharmacogenetic profiles on the perspective on medicines in the German EMPAR study PONE-D-24-09164R1 Dear Dr. Huebner, 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, Hoh Boon-Peng, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0311267.r003
Formally Accepted
30 Sep 2024 Acceptance Letter - Hoh Boon-Peng, Editor PONE-D-24-09164R1 PLOS ONE Dear Dr. Huebner, 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 Professor Dr Hoh Boon-Peng Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0311267.r004

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