PONE-D-21-39689Axial light loss of monocytes as a readily available prognostic biomarker in patients with suspected infection at the emergency departmentPLOS ONE

Dear Dr. de Hond,

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.

 This is an interesting paper that offers promising preliminary results in an important subject area. In addition to the reviewer comments, please consider the following in your revisions:-can you explain what "semi-automated" data collection is? how much was done by computer vs hand and whas there any manual checking of data pulled automatically?-please include a detailed explanation of missing data-please describe the multiple imputation process in more detail-please include details about model calibration-the discussion is well-written overall and makes some very good points. however, i think that the tone is a bit too conclusive in that this is a single retrospective study from a single center. In addition, automated variable selection techniques are notorious for creating over-fit models--while i think this is a reasonable first step, i do not think these data can be considered definitive. furthermore,  prospective validation is definitely needed before this should be used in routine clinical practice. i would recommend that the discussion be modified slightly to reflect this fact.

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Academic Editor

PLOS ONE

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: PONE-D-21-39689

It is a little unclear whether or not all the patients in the study timeframe were included if they were >=18 and had a suspected infection or whether or not it required an abnormal SIRS or qSOFA score.

This was a post-hoc analysis of a prospectively collected database and blood samples. The cv-ALL contributed to improving the performance of know disease severity scores. That said the baseline characteristics of the survivors vs. non-survivors were not balanced. The OR of qSOFA and MEWS was much more robust for the selected outcomes that cv-ALL alone.

Was lactate included in the analysis? cv-ALL is independent of overall WBC? It would suggest yes – given that they are both in the final model, however one would think there is significant interaction b/w these variables.

What is the rationale for a higher CCI being less likely to be admitted to the MCU/ICU – is it related to ICU-restrictions of these patients?

I would have liked to see some basic data concerning process measures such as time to antibiotics which is strongly correlated with outcome in the sicker sepsis/septic shock patients.

This is an interesting response to the MDW theme and offers an alternative that may be more accessible and affordable to institutions interested in pursing such options.

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Reviewer #1: No

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PONE-D-21-39689R1Axial light loss of monocytes as a readily available prognostic biomarker in patients with suspected infection at the emergency departmentPLOS ONE

Dear Dr. de Hond,

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.

Thank you for taking the time to revise the manuscript--I think that it is substantially improved. My remaining concern relates to non-reporting of model calibration in the current iteration of the paper (NB: HL test is a goodness of fit measure rather than one of calibration). To me, regardless of how (or even if) one intends prediction models to be used, calibration is an important data point to include--calibration and discrimination (eg, AUC) go hand-in-hand. This is also the recommendation from TRIPOD guidelines (https://www.equator-network.org/reporting-guidelines/tripod-statement/). Please see the reference below for a more detail description of why I (and others) feel calibration is of great import. https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1466-7 I would also note that sub-optimal model calibration, in and of itself, would in no way preclude publication. if this were the case, it would be an important limitation to address/discuss. i think that this study has value to add to the medical literature and that it is important that results be reported fully and transparently so that researchers who take up this subject matter have as much information as possible when planning and executing further studies.

Please submit your revised manuscript by Jul 23 2022 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'.
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• 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,

Robert Ehrman, MD, MS

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.

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Reviewers' comments:

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Axial light loss of monocytes as a readily available prognostic biomarker in patients with suspected infection at the emergency department

PONE-D-21-39689R2

Dear Dr. de Hond,

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.

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Kind regards,

Robert Ehrman, MD, MS

Academic Editor

PLOS ONE

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