PONE-D-22-06716Risks for death after admission to pedaitric intensive care (PICU) - a comparison with the general populationPLOS ONE

Dear Dr. Hannegård Hamrin,

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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: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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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: No

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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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: The authors have utilised a large population based dataset to compare mortality in PICU patients in PICU or after discharge and have compared this, suing relative measure, to the general population of children. Given that children are admitted to PICU with life-threatening medical or surgical condition it is unsurprising that their SMR is markedly higher that the general population. I am also unclear how valuable using relative measures of risk alone are in this situation - in fact could cause great concern amongst parents. I think further re-analyses and clarification of the importance of these findings i.e "so what' are important before this paper is suitable for publication.

Major concerns

1. please present absolute risks as well as relative risks throughout the manuscript

2. please clearly articulate the 'so what' of these analyses

3. Is the diagnostic group based on reason for admission to PICU or underlying health conditions? Most children admitted to PICU have underlying complex medical condition so understanding this groups is very important when thinking through the implications of this study.

4. I would ask that the authors present the data for within PICU and after PICU discharge mortality see this paper https://adc.bmj.com/content/103/6/540. Understanding the risk after discharge is really important in terms of needs for palliative care services and parental expectations

5. What about children with multiple diagnoses, they often have higher risk of mortality?

6. I am unclear how the hierarchical nature of these data have been accounted for in these analyses - ie. children with multiple admissions?

7. Please present the numbers of children where life-sustaining treatment was withdrawn within ICU

8. all these comments relate to being able to identify (prospectively) which children may be at higher risk of death- doing this retrospectively once they have had more than one PICU admission is not necessarily that useful

Minor points

1. two decimal places are adequate in tables

2. this sentence is incorrect "Subsequent mortality during the first year

176 after PICU discharge was 46.0% (n=204)" and should be corrected

Reviewer #2: Thank you for the opportunity to review this paper, which compared the mortality of PICU-admitted children to those of the matched general Swedish population.

The comparison was further stratified into various categories: age, risk factor (via PIM2), and diagnosis. Importantly, splitting patients according to whether they had only a single PICU admission or multiple ones was appropriate because the authors’ premise about multiple PICU admissions serving as a proxy for chronic illness/conditions is a sound one.

Main comment:

My biggest issue is the lack of granularity in the data provided in the submission. Having the raw numbers of what went into the SMR calculations would be helpful; at the very least – the observed deaths of the PICU patients at the follow-up times, in the binned categories, etc). Would it be possible to provide this as Supplementary Material? The SMRs shown in Figures 3-5 can only be eye-balled and cannot be reproduced from the data provided in the submission. This is why I answered “No” to Question 3 (regarding data underlying findings in the manuscript).

These questions/comments are to help clarify details of computations and Figures:

a) Figure 2: Assuming that the study year was 2020, the number of total patients (needed in the denominator) after year 4 is steadily decreasing – e.g. all admissions (years 2008-2016) are eligible for Time<4 years, but only those admitted in 2008 are available at Time=12 years (after admission). It might be helpful to annotate in the Figure (or provide in a supplementary table) the number of patients at each time point (years after admission) that the survival rate is being plotted.

b) Figure 3 and lines 169-171 either show or mention SMR at “PICU admission” – this may be a misunderstanding on my part, but how do you get a non-zero SMR (i.e. non-zero observed deaths) at time of admission? For this, are you counting the deaths that occurred in the PICU at some later time than admission?

c) On page 14, line 191 states “All PDR groups were within the 95% CI limits of SMR …” – this is for repeated admissions; however in Figure 4B, the SMRs for 2 PDR groups (10-25%, 25-50%) look just a little outside the limits.

Other (minor) comments:

i) Full title in the submission (not manuscript) – “pedaitric” should be “pediatric”

ii) Lines 227-228 (Discussion section) – Figure 2 (the survival rate) is a stronger support for this statement than the 1-year SMR.

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Reviewer #1: Yes: Professor Lorna Fraser

Reviewer #2: No

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PONE-D-22-06716R1Risks for death after admission to pediatric intensive care (PICU) - a comparison with the general populationPLOS ONE

Dear Dr. Hannegård Hamrin,

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.

The reviewer ask for some additional clarifications regarding Figure 3. Could you please revise the manuscript to address these concerns?

Please submit your revised manuscript by Aug 26 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'.
• 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,

Thomas Tischer

Staff Editor

PLOS ONE

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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: (No Response)

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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

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

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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

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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

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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: Thank you for providing the supplementary material. The responses, along with the additional tables in the supplements, addressed most of my previous concerns.

I have a remaining comment/question regarding Figure 3. In my previous review, I had asked about the non-zero SMR at year=0 (time of PICU admission). The response did not really clear up my original question.

In Figure 3, there is a certain "binning" taking place for the number of years on the horizontal axis, i.e. data are plotted only for discrete years 0, 1, 2, 3, 4, and 5 after PICU admission. When you plot the SMR for say year=0, are you counting the observed deaths up to, but strictly less than, 1 year from PICU admission? Likewise, does the SMR for year=1 reflect observed deaths that occurred at least 1 year, but strictly less than 2 years, after PICU admission?

This revised statement -- "The SMRs, during the total follow-up time for the entire PICU patient population with single and repeated admissions was 35.2% ... and 108.0 ...." (lines 176-179, page 14) -- where the stated numbers correspond to the year=0 point on the horizontal axis, still does not track with my understanding of what Figure 3 is supposed to be showing. How does "total follow-up time" track with year=0?

Figure 3, especially the number corresponding to year=0 for repeated admissions, is referenced in the Discussion section, so please make sure to explain clearly/thoroughly what year=0 (after PICU admission) really mean.

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Reviewer #2: No

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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.

Risks for death after admission to pediatric intensive care (PICU) - a comparison with the general population

PONE-D-22-06716R2

Dear Dr. Hannegård Hamrin,

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.

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Kind regards,

Robert Jeenchen Chen, MD, MPH

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

Reviewer #3: All comments have been addressed

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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

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

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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

Reviewer #3: Yes

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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

Reviewer #3: Yes

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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: Thank you for making the clarification about Figure 3.

Reviewer #3: No additional comments from me as I think my previous comments were already addressed in the previous version.

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Reviewer #2: No

Reviewer #3: No

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