Effect size estimates from umbrella designs: Handling patients with a positive test result for multiple biomarkers using random or pragmatic subtrial allocation

Miriam Kesselmeier; Norbert Benda; André Scherag

doi:10.1371/journal.pone.0237441

Peer Review History

Original SubmissionDecember 20, 2019
20 Dec 2019 Author Response Attachments Attachment Submitted filename: Kesselmeier_et_al_Response_to_Reviewer_to_PONE-D-18-36382R1.pdf https://doi.org/10.1371/journal.pone.0237441.r001
17 Jun 2020 Decision Letter - Khaled Khatab, Editor PONE-D-19-35136 Effect size estimates from umbrella designs: handling patients with a positive test result for multiple biomarkers using random or pragmatic subtrial allocation PLOS ONE Dear Dr Kesselmeier, 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 add a subsection that describes "what this study added to the current knowledge." Further comparisons with relevant studies still need to be included in the discussion section. Please add clear and separate subsections that describe "strength and the limitations of this study" The authors discussed the limitations of the study (which still needs to be placed in a separate subsection); however, the future work plan was not mentioned and how the authors plan to overcome the limitations of this study in the future work. Please submit your revised manuscript by 2^nd August, 2020. 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'. 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We will update your Data Availability statement on your behalf to reflect the information you provide. [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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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: Following from the previous three reviewers of this manuscript, I can confirm that the authors have significantly revised the manuscript in accordance with the concerns raised by the previous reviewers. The authors have demonstrated their originality, ingenuity and expertise in the presentation of the main idea of the papers. The statistical methods applied are appropriately applied and are relevant to the objectives of the study with detailed supporting information included. However, the areas I feel the authors should review are minor. For example; In Line 46, I suggest the following sentence: "The aim of this study is three-fold" be reworded as: "The objectives of this study are in three-fold (or are fundamentally three)"..... In line 70, the parameter (or coefficient), ϕ (phi) should rather be referenced "correlation measure" and not dependency measure as used by the authors. Though figures A1 and A2 like other figures were referenced in the manuscript, I expected the authors to give brief discussion on the figures, in terms of the information they want the readers to derive and how do such details support to their results. Finally, I suggest that the authors check to see they explain what each parameters used in the equations uniquely represent to enhance the comprehension and flow of their lay audience. ****** 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 [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. 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Revision 1
13 Jul 2020 Author Response Point-by-point response to the editor’s and reviewer’s comments Academic editor Please add a subsection that describes "what this study added to the current knowledge." RESPONSE: Thank you for this comment. We included this paragraph in the Discussion as fourth paragraph after our summary of our investigation (first three paragraphs). Further comparisons with relevant studies still need to be included in the discussion section. RESPONSE: We repeated our literature search to identify the current evidence and extended the discussion where necessary. The newly introduced literature is highlighted in red (in the text body, not in the references) in the manuscript version with tracked changes. Please add clear and separate subsections that describe "strength and the limitations of this study" RESPONSE: We included the subsection heading “Strength and limitations of this study” and additional headings for an easier navigation within the discussion. The authors discussed the limitations of the study (which still needs to be placed in a separate subsection); however, the future work plan was not mentioned and how the authors plan to overcome the limitations of this study in the future work. RESPONSE: We agree that the future work is not directly described. We contrasted the limitations with the strengths and discussed the impact of the limitations on the conclusions from our investigation. Our research was just the first step to quantify the possible impact of an umbrella design on clinical trial results. This point need further investigation, which we now state in the revised version of the manuscript as suggested by the reviewer. As we did not want to leave the reader without any idea of a possible solution, we applied weighted linear regression as an obvious solution. However, it is unclear to which extent this approach can be used in practice. Consequently, there is more work to be done for a solid advice. We originally did not include this statement, as we wanted to avoid those typical last sentences stating that further work is needed. Nevertheless, we added such a sentence in the revised version of the manuscript, but would leave it to the editor whether to include it or not. Reviewer #1 Following from the previous three reviewers of this manuscript, I can confirm that the authors have significantly revised the manuscript in accordance with the concerns raised by the previous reviewers. The authors have demonstrated their originality, ingenuity and expertise in the presentation of the main idea of the papers. The statistical methods applied are appropriately applied and are relevant to the objectives of the study with detailed supporting information included. RESPONSE: We thank the reviewer for his thorough review and the helpful suggestions. We provide a point-by-point response below. Please note that we had to adapt the referencing to the sections, as there is no section numbering allowed. However, the areas I feel the authors should review are minor. For example; In Line 46, I suggest the following sentence: "The aim of this study is three-fold" be reworded as: "The objectives of this study are in three-fold (or are fundamentally three)"..... RESPONSE: Done. Thank you. We rephrased the sentence. In line 70, the parameter (or coefficient), ϕ (phi) should rather be referenced "correlation measure" and not dependency measure as used by the authors. RESPONSE: We slightly modified the wording and write throughout the manuscript “correlation (dependency) measure” to emphasise that we use the correlation for the definition of the dependency between the biomarkers. Otherwise, it might be confusing as we talk about (in)dependent biomarkers throughout the manuscript. Though figures A1 and A2 like other figures were referenced in the manuscript, I expected the authors to give brief discussion on the figures, in terms of the information they want the readers to derive and how do such details support to their results. RESPONSE: The results presented in Fig S1 and S2 are, as stated in the manuscript, in line with the results from the analytical deductions as well as the simulation study. If we extend the presentation in the results, the description would be similar to those in the previous sections. As we want to avoid reporting similar results several times for the ease of reading, we originally decided to show the results for completeness but comment only very briefly on it. The real data application supports the previous results. The content of the supplemental figures is for the readers a proof of principle for the real data application. In the revised version of the manuscript, we tried to write it more clearly by inclusion of the word “already”. Finally, I suggest that the authors check to see they explain what each parameters used in the equations uniquely represent to enhance the comprehension and flow of their lay audience. RESPONSE: Thank you for this comment. We rephrased parts of the deductions in the S2 Note to (hopefully) clarify and facilitate reading. Furthermore, we added missing + for the test result indicators in the definition of phi. Attachments Attachment Submitted filename: Response_to_Reviewer_PONE_D_19_35136_R1.pdf https://doi.org/10.1371/journal.pone.0237441.r003
28 Jul 2020 Decision Letter - Khaled Khatab, Editor Effect size estimates from umbrella designs: handling patients with a positive test result for multiple biomarkers using random or pragmatic subtrial allocation PONE-D-19-35136R1 Dear Dr Kesselmeier, 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, Professor Khaled Khatab, PhD. Academic Editor PLOS ONE Reviewers' comments: https://doi.org/10.1371/journal.pone.0237441.r004
Formally Accepted
3 Aug 2020 Acceptance Letter - Khaled Khatab, Editor PONE-D-19-35136R1 Effect size estimates from umbrella designs: handling patients with a positive test result for multiple biomarkers using random or pragmatic subtrial allocation Dear Dr. Kesselmeier: 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 Professor Khaled Khatab Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0237441.r005

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