ProSPective evaluation of the dIagnostic accuracy of siNe spiN non-contrast flatdEtectoR CT (FDCT) for the detection of intracranial hemorrhage in stroke patients - Protocol of a non-inferiority comparison to multi detector CT

Marios Psychogios; Alex Brehm; Nitin Goyal; Grégoire Boulouis; Jan-Karl Burkhardt; Shakeel A. Chowdhry; Donald Frei; Jan Gralla; Johannes Kaesmacher; Ryan T. Kellogg; Christopher P. Kellner; Demetrius K. Lopes; Eytan Raz; Daniel Strbian; Laura Mannismäki; Alejandro Tomasello; Ioannis Tsogkas; Alexander von Hessling; Grzegorz M. Karwacki; Raphael Guzman; Nikki Rommers; David S. Liebeskind; Adam S. Arthur; on behalf of the SPINNERS investigators

doi:10.1371/journal.pone.0330608

Peer Review History

Original SubmissionMarch 12, 2025
9 Jun 2025 Decision Letter - Stephan Meckel, Editor Dear Dr. Brehm, 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. 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. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Stephan Meckel, MD, 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. Please include a complete copy of PLOS’ questionnaire on inclusivity in global research in your revised manuscript. Our policy for research in this area aims to improve transparency in the reporting of research performed outside of researchers’ own country or community. The policy applies to researchers who have travelled to a different country to conduct research, research with Indigenous populations or their lands, and research on cultural artefacts. The questionnaire can also be requested at the journal’s discretion for any other submissions, even if these conditions are not met. Please find more information on the policy and a link to download a blank copy of the questionnaire here: https://journals.plos.org/plosone/s/best-practices-in-research-reporting. Please upload a completed version of your questionnaire as Supporting Information when you resubmit your manuscript. 3. Thank you for stating the following financial disclosure: “Grant (to University Hospital Basel, MP) from Siemens Healthineers AG for conducting the trial as an investigator initiated trial. Experts nominated by and employees of Siemens Healthineers AG were consulted during the protocol development, but the Global PI (MP) and the US PI (AA) had the final decision to all suggestions. Siemens Healthineers AG will have no influence on data acquisition, data management, data analyses or scientific interpretation and publication of the results.” 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. 4. Thank you for stating the following in the Competing Interests section: “Grant from Siemens Healthineers AG for conducting the trial as an investigator initiated trial.” Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. 5. One of the noted authors is a group or consortium “SPINNERS investigators”. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. 6. 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 . 7. We note that the original protocol file you uploaded contains a confidentiality notice indicating that the protocol may not be shared publicly or be published. Please note, however, that the PLOS Editorial Policy requires that the original protocol be published alongside your manuscript in the event of acceptance. Please note that should your paper be accepted, all content including the protocol will be published under the Creative Commons Attribution (CC BY) 4.0 license, which means that it will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. Therefore, we ask that you please seek permission from the study sponsor or body imposing the restriction on sharing this document to publish this protocol under CC BY 4.0 if your work is accepted. We kindly ask that you upload a formal statement signed by an institutional representative clarifying whether you will be able to comply with this policy. Additionally, please upload a clean copy of the protocol with the confidentiality notice (and any copyrighted institutional logos or signatures) removed. 8. We note that the original protocol that you have uploaded as a Supporting Information file contains an institutional logo. As this logo is likely copyrighted, we ask that you please remove it from this file and upload an updated version upon resubmission. Additional Editor Comments: Please address both reviewer's comments in your revision thoroughly, in particular address the uncertainty regarding sample size calculations as well as the statistical model for primary endpoint analysis! [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??> Reviewer #1: Partly Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: No ****** Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. Reviewer #1: This is an interesting study with a well formulated statistical design and analysis plan with very clear statistical objectives in that the primary Objective is to evaluate if non-contrast syngo DynaCT Sine Spin imaging is non-inferior for the detection of intracranial hemorrhages compared to non-contrast MDCT imaging. It will be deemed non-inferior if the lower bound of the 95%-CI of the sensitivity is above 95% and the lower bound of the 95%-CI of the specificity is above 95% for the detection of intracranial hemorrhages (predefined non-inferiority margin). This is a very routine and clear goal for this endeavor. There are several clarifications needed. The sample size explanation on page 60 of the protocol is complex It is not quite clear that this simulation of scenario of possible outcomes of number of difficult cases, number of readers at 6, and the drop-out rate at 5% yields a total of 252 patients. Also considering the secondary objective, is it possible that the variation , if any , of the Fleiss kappa impact the study? What careful planning noted by the authors will be involved to minimize the number of missing data? Specifically detail the planned primary analysis for the FAS. Will it involve assessment of the primary endpoint (intracranial hemorrhage), using only a generalized linear random-effects model with a logit link used, with ‘reader’ and ‘patient’ as random effects and difficult cases weighted at 2%? The 95% CIs for sensitivity and specificity will be derived from the fixed effect intercept using Wald’s method. How will the model be validated as appropriate? Also how will the result be validated (sensitivity and robustness) if an imputed data set is not planned? The data management, quality assurance and data security are sufficiently detailed and well planned. As an informational query, is there any possibility that the readers may have outcomes that need to be reconciled for a final assessment? If so, what will be the strategy? Reviewer #2: The paper answers a research question if the proposed approach However, there are still some comments to the authors that need further refinement. 1. In the introduction part, authors may give the full name of SPINNERS if this is an abbreviated name. Otherwise, the authors may provide a reference. 2. In lines 118-120, the authors should clearly introduce how many buckets are used. And specify the number of participants in each bucket using individual bullets. Authors may consider the term 'groups' instead of 'buckets' 3. Authors should provide a detailed explanation to describe the flow chart for the study design. 4. The author should explain the population before data filtering to provide an overall picture of your study cohort to readers. 5. The authors may provide a clinical characteristic table to demonstrate the study population. 6. The authors might consider a thorough proofread to polish grammar. ****** 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.0330608.r001
Revision 1
23 Jun 2025 Author Response Dear Dr. Meckel, First, we want to express our gratitude for your and the reviewer’s evaluation of the manuscript. Important points were raised, which improve the quality of the manuscript. We have updated the trial status on page 10 line 261 – 262 to reflect the status. Please find attached a point-by-point reply to the points raised: Journal Requirements: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Thank you for raising this important point, we have adapted the manuscript and file naming accordingly. 2. Please include a complete copy of PLOS’ questionnaire on inclusivity in global research in your revised manuscript. Our policy for research in this area aims to improve transparency in the reporting of research performed outside of researchers’ own country or community. The policy applies to researchers who have travelled to a different country to conduct research, research with Indigenous populations or their lands, and research on cultural artefacts. The questionnaire can also be requested at the journal’s discretion for any other submissions, even if these conditions are not met. Please find more information on the policy and a link to download a blank copy of the questionnaire here: https://journals.plos.org/plosone/s/best-practices-in-research-reporting. Please upload a completed version of your questionnaire as Supporting Information when you resubmit your manuscript. Thank you very much to pointing us to this important questionnaire. We have filled out the questionnaire and uploaded it with the revision. 3. Thank you for stating the following financial disclosure: “Grant (to University Hospital Basel, MP) from Siemens Healthineers AG for conducting the trial as an investigator-initiated trial. Experts nominated by and employees of Siemens Healthineers AG were consulted during the protocol development, but the Global PI (MP) and the US PI (AA) had the final decision to all suggestions. Siemens Healthineers AG will have no influence on data acquisition, data management, data analyses or scientific interpretation and publication of the results.” 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. Thank you for bringing this up. In our opinion the financial disclosure statement correctly reflects the role of the funder in the trial. Employees of the funder (Siemens Healthineers AG) and experts nominated by the funder were consulted during the protocol development stage, however all decision were made by the Global PI (MP) and the US PI (AA). However, for clarity we would slightly reformulate the statement: “A grant from Siemens Healthineers AG was given to the University Hospital Basel (Sponsor Investigator Marios Psychogios) for conducting the trial as an investigator-initiated trial. Durin the planning phase of the trial experts nominated by and employees of Siemens Healthineers AG were consulted, but the Global PI (Marios Psychogios) and the US PI (Adam Arthur) had the final decision to all suggestions. Siemens Healthineers AG had no role in the collection, monitoring, analysis, and interpretation of the data or scientific interpretation and publication of the results. This does not alter our adherence to PLOS ONE policies on sharing data and materials.” We sincerely hope this addresses the concerns raised. 4. Thank you for stating the following in the Competing Interests section: “Grant from Siemens Healthineers AG for conducting the trial as an investigator initiated trial.” Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. Thank you for bringing this up. We confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials. We have included this in the updated statement (see answer under point 3). 5. One of the noted authors is a group or consortium “SPINNERS investigators”. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. We have added this under acknowledgments. Thank you for bringing this up. 6. 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 have included the captions and updated them accordingly. 7. We note that the original protocol file you uploaded contains a confidentiality notice indicating that the protocol may not be shared publicly or be published. Please note, however, that the PLOS Editorial Policy requires that the original protocol be published alongside your manuscript in the event of acceptance. Please note that should your paper be accepted, all content including the protocol will be published under the Creative Commons Attribution (CC BY) 4.0 license, which means that it will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. Therefore, we ask that you please seek permission from the study sponsor or body imposing the restriction on sharing this document to publish this protocol under CC BY 4.0 if your work is accepted. We kindly ask that you upload a formal statement signed by an institutional representative clarifying whether you will be able to comply with this policy. Additionally, please upload a clean copy of the protocol with the confidentiality notice (and any copyrighted institutional logos or signatures) removed. We have uploaded a clean version of the protocol with the confidentiality note crossed out and a letter confirming publication under CC BY 4.0 is permitted given the manuscript is accepted for publication. 8. We note that the original protocol that you have uploaded as a Supporting Information file contains an institutional logo. As this logo is likely copyrighted, we ask that you please remove it from this file and upload an updated version upon resubmission. We have removed the logo in the new version. Reviewer #1: Reviewer #1: This is an interesting study with a well formulated statistical design and analysis plan with very clear statistical objectives in that the primary Objective is to evaluate if non-contrast syngo DynaCT Sine Spin imaging is non-inferior for the detection of intracranial hemorrhages compared to non-contrast MDCT imaging. It will be deemed non-inferior if the lower bound of the 95%-CI of the sensitivity is above 95% and the lower bound of the 95%-CI of the specificity is above 95% for the detection of intracranial hemorrhages (predefined non-inferiority margin). This is a very routine and clear goal for this endeavor. There are several clarifications needed. Thank you for kind summary of the study, please see below answers to the points raised. The sample size explanation on page 60 of the protocol is complex It is not quite clear that this simulation of scenario of possible outcomes of number of difficult cases, number of readers at 6, and the drop-out rate at 5% yields a total of 252 patients. Also considering the secondary objective, is it possible that the variation , if any , of the Fleiss kappa impact the study? We apologize for the unclarity to the reviewer. Indeed, the simulation scenario with 6 independent readers, 14 difficult cases (with a sensitivity of 70%) and an assumed sensitivity of 99% and specificity of 98% yielded a total sample size of 252 patients including drop out based on 999 simulated experiments. We have now clarified those assumptions in the respective section of the paper. The distribution of the number of positive and negative hemorrhagic patients, as well as the number of difficult cases are predefined, and patients are recruited according to the bins. Therefore, the variability of sample sizes is fixed. In the simulations, we assumed a moderate positive correlation among readers to reflect similar experience levels. This introduces a baseline level of agreement above chance, which does elevate Fleiss’ kappa values somewhat. However, it is important to note that Fleiss’ kappa is not determined by correlation alone. It is primarily influenced by the overall pattern of agreement across readers and the distribution of category ratings. Given the expected high performance (i.e., near-perfect sensitivity and specificity), disagreement is mostly concentrated in the small subset of “difficult” cases. Consistent ratings in these cases have a disproportionately large influence on the kappa statistic. Our setup allows us to estimate Fleiss’ kappa under plausible clinical conditions without biasing the results through over- or underestimation of inter-reader agreement. Furthermore, the assumed correlation also impacts the statistical power of the study. A very high correlation reduces the effective independence of the readers, lowering variability and thereby decreasing the power to detect differences in agreement. Conversely, assuming no correlation would overestimate power and risk underpowering the study in practice. We selected six readers to strike a balance between sufficient replication per patient (to enable robust estimation of sensitivity, specificity, and kappa) and avoiding excessive redundancy due to correlation. Our simulations confirmed that under the assumed parameters, this design yields adequate power to meet our primary study objective. What careful planning noted by the authors will be involved to minimize the number of missing data? Specifically detail the planned primary analysis for the FAS. Will it involve assessment of the primary endpoint (intracranial hemorrhage), using only a generalized linear random-effects model with a logit link used, with ‘reader’ and ‘patient’ as random effects and difficult cases weighted at 2%? The 95% CIs for sensitivity and specificity will be derived from the fixed effect intercept using Wald’s method. How will the model be validated as appropriate? Also how will the result be validated (sensitivity and robustness) if an imputed data set is not planned? We thank the reviewer for raising these points regarding the primary analysis. Minimizing the number of missing data: This study takes place in an emergency setting, and it includes two scans that should be taken within 4 hours of one another. There is no follow-up visit and no foreseeable scenario in which a patient might be lost to follow-up. All scans are rated by an independent core-lab after recruitment has been completed and the primary analysis only includes the readings of the scans. Therefore, no missing data are expected. There are two intercurrent events defined which would lead to missing data: • Indeterminate scans: this is avoided as much as possible through thorough training of the participating study centers, and a lead-in phase consisting of the first five cases from each site. However, indeterminate scans may still occur due to operating failures (e.g., clear artefacts due to objects in the field of view, wrong positioning of the head) or technical failure due to missing calibration of the scanner. In accordance with the protocol, those cases are identified by the independent core-lab and those patients are excluded from analysis. Excluded cases are replaced to ensure adequate power. • Intracranial hemorrhage between the two scans: this is a rare, but possible intercurrent event. The consequence of this intercurrent event is a correct reading of no hemorrhage as the ground truth, and a hemorrhage identified on the FDCT scans which is also correct. The possibility of a hemorrhage between the two scans is investigated in case of a discrepancy in the ground truth and at least 5 out of 6 readers of the independent core-lab. In this case, a second independent core-lab evaluates all images and if there is a possibility of an intracranial hemorrhage that occurred between the two scans, the patient is excluded from analysis. This approach avoids biasing of false positives. Since the scans are rated by an independent core-lab and given the exclusion of patients with intercurrent events, we do not expect missing data in the primary analysis. All analysis is based on FAS with all patients without intercurrent events as described above. Primary analysis We estimate sensitivity and specificity of non-contrast FDCT for the detection of intracranial hemorrhage using generalized mixed‑effects model (GLMM) with a logit link function and binomial distribution. The model is fit once in patients with and once in patients without hemorrhage, as defined by the ground truth. The model’s estimated marginal probability in patients with hemorrhage represents sensitivity, while the estimated marginal probability in patients without hemorrhage represents specificity. Models are fit with the glmer() function from the R package lme4. We use the “nloptwrap” optimizer to improve convergence in near‑separation situations that we expect due to the assumed very high sensitivity and specificity. Difficult cases are weighted with 2% (i.e., the difficult cases contribute only 2% of the model’s effective information, and the normal cases contribute the remaining 98%). Specific weights are calculated by dividing the mass of difficult cases (n*0.02) by the total number of difficult cases. In the same way, we calculate the weight for the normal cases, using 98% as a contribution. From the fixed effect intercept of sensitivity and specificity, the 95% confidence interval (CI) is calculated applying the method of Wald. Although profile‑likelihood or bootstrap CIs can be used, near‑boundary estimates (sensitivities/specificities close to 100%) can lead to non‑finite profile intervals or numerical instabilities. The Wald CI on the log‑odds scale is guaranteed to yield finite, interpretable intervals on the probability scale. We test whether the lower bounds of the 95% CI of both the sensitivity and the specificity are both higher than the pre-specified margin of 95%. Non‑inferiority (i.e. performance above the threshold) is declared if the lower bound of the two‑sided 95% CI for both sensitivity and specificity exceeds 0.95. This corresponds to a one‑sided alpha = 0.025. Since sensitivity and specificity are treated as co-primary endpoints, testing both at the same alpha level does not reduce power or require correction. Validation of the model of the primary analysis To ensure the model is appropriate and well-specified, we will undertake the following steps: • Model assumption check: we will verify model convergence and examine fit diagnostics such as residuals and random effect distribution, and influential observations. We will also inspect the estimated variances for the random effect to ensure meaningful contributions and no overfitting. • Sensitivity analysis: We do not expect missing data for the primary analysis, but we might exclude patients. We will compare the baseline characteristics of the excluded patients with the included patients to understand the potential bias. We will also assess the robustness of the non-inferiority conclusions with other link funct https://doi.org/10.1371/journal.pone.0330608.r002
9 Jul 2025 Decision Letter - Stephan Meckel, Editor Dear Dr. Brehm, 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 Aug 23 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. 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 applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Stephan Meckel, MD, PhD 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. Additional Editor Comments: Please address reviewer 2's additional comment. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. Reviewer #1: The queries have been addressed adequately. Please check for typos. For example , on the revision, page 10, line 251 'Durin' should be 'During'. Reviewer #2: Thanks for addressing the previous comments and questions. I also have some comments for the current version: 1. In ischemic and hemorrhagic stroke, the authors may provide the definition such as ICD-10 or some other source for disease diagnosis. ****** 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 https://doi.org/10.1371/journal.pone.0330608.r003
Revision 2
21 Jul 2025 Author Response Dear Dr. Meckel, First, we want to express our gratitude for your and the reviewer’s evaluation of the manuscript. Important points were raised, which improve the quality of the manuscript. We have updated the trial status on page 10 line 261 – 262 to reflect the status. Please find attached a point-by-point reply to the points raised: 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. We have reviewed the reference list and ensured its completeness. One reference was incorrect numbered; we have corrected this. In specific in this sentence reference 6 was included but 7 was the correct reference: “We estimate a sensitivity of 99% and a specificity of 98% of non-contrast Sine Spin FDCT imaging for the detection of intracranial hemorrhage as described for the predecessor generation in the literature. [7]” Reviewer #1: The queries have been addressed adequately. Please check for typos. For example , on the revision, page 10, line 251 'Durin' should be 'During'. Thank you very much for highlighting this typo. We worked with a native speaker through the manuscript to improve grammar and correct all typos. Reviewer #2: Thanks for addressing the previous comments and questions. I also have some comments for the current version: 1. In ischemic and hemorrhagic stroke, the authors may provide the definition such as ICD-10 or some other source for disease diagnosis. Thank you for your suggestion. In our study, the diagnosis of ischemic and hemorrhagic stroke is made in the acute setting, primarily in the emergency room. At this stage, clinical evaluation (such as an acute neurological deficit assessed using NIHSS or GCS) combined with imaging findings on multidetector CT (MDCT) forms the basis for diagnosis. Since these assessments occur before formal coding and discharge documentation, referencing an ICD-10 code is not appropriate in this context. Furthermore, our inclusion criteria focus on patients who present via a pre-hospital stroke alert and are received as suspected acute stroke cases. This approach ensures timely triage and intervention, which is critical in the acute management of stroke. We have also clarified this in the protocol paper and added under “Population” (Page 6 line 149 – 153) the following sentence: “The diagnosis of an ischemic or hemorrhagic stroke is made in the acute setting, primarily in the emergency room, prior to patient enrollment. At this stage, clinical evaluation—such as the assessment of acute NIHSS or the Glasgow Coma Scale (GCS) — combined with imaging findings from the MDCT forms the basis for diagnosis.” Thank you for considering the manuscript for publication, Marios Psychogios and Adam S Arthur Attachments Attachment Submitted filename: Rebuttal_Letter_170725.pdf https://doi.org/10.1371/journal.pone.0330608.r004
5 Aug 2025 Decision Letter - Stephan Meckel, Editor ProSPective evaluation of the dIagnostic accuracy of siNe spiN non-contrast flat-dEtectoR CT (FDCT) for the detection of intracranial hemorrhage in stroke patients - Protocol of a non-inferiority comparison to multi detector CT PONE-D-25-10196R2 Dear Dr. Brehm, 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, Stephan Meckel, MD, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? Reviewer #1: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??> Reviewer #1: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: No ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete??> The PLOS Data policy Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. Reviewer #1: XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX ****** 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 ******** https://doi.org/10.1371/journal.pone.0330608.r005
Formally Accepted
Acceptance Letter - Stephan Meckel, Editor PONE-D-25-10196R2 PLOS ONE Dear Dr. Brehm, 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 You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. 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 Prof. Dr. Stephan Meckel Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0330608.r006

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