PONE-D-24-13634Association between demographic, clinical characteristics and severe complications by SARS-CoV-2 infection in a community-based healthcare network in ChilePLOS ONE

Dear Dr. Leniz,

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 review and address the comments from the reviewers, in particular the methodological aspects expressed by reviewer 2. Also, please update the references to reflect better what is already know in the topic and what your study is adding. ==============================

Please submit your revised manuscript by Jul 04 2024 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,

Juan Pablo Gutierrez

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. In the online submission form, you indicated that your data is available only on request from a third party. Please note that your Data Availability Statement is currently missing [the name of the third party contact or institution / contact details for the third party, such as an email address or a link to where data requests can be made]. Please update your statement with the missing information.

3. 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 delete it from any other section.

4. 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.

Additional Editor Comments:

1. Improve the background by updating the literature review, in particular for papers addressing the same or similar topic in Latin-america. Systematic reviews and meta-analysis have been published on the topic

2. Explain the reasons for an invalid RUN o lack of data of enrollment

3. Provide further details on the data source; why you coded the conditions? Those are not register directly there?

4. It is not clear the procedure for comorbidities, in particular what this means: Therefore, we included in the model those comorbidities with a good level of identification based on their prevalence in the sample

5. Please clarify in lines 202 & 203: those individuals were newly enrolled on that period? Are the total number of individuals enrolled? How this is a sample if you are including all?

6. In table 1 will be useful to add a column for those that tested positive

[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: Partly

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: The authors present a study aimed to evaluate the association between demographic and clinical characteristics with severe complications by SARS-CoV-2 infection, using a retrospective population-based cohort from Chile (n=44,674).

The article is well written but, in my opinion, it requires significant changes. My specifics comments are below.

Major Comments

I consider that the document lack of a clearly defined study population and study outcomes.

Given that authors aimed to evaluate complications by SARS-CoV-2 infection, it is not entirely clear why no-COVID-19 subjects were also analyzed. Additionally, considering that Ancora Network population is not representative of Chilean population, it is not evident why did the authors decided to analyze these specific inhabitants. Moreover, the terms "any hospital admission", "hospital admissions due to a COVID-19", "ICU admission" and "ICU admission due to COVID-19" are mentioned along the manuscript, making it hard to follow.

In this sense, it is important that authors bring context regarding the selection of the study population and decide to select or not only COVID-19 subjects. In the case that they decided to analyze no-COVID-19 persons, it is necessary to include an outcome regarding SARS-CoV-2 infection and develop a subgroup analysis considering this outcome.

It is also needed that authors define and homologate the study outcomes along the manuscript.

Given that the findings of this study are previously reported, in my opinion the novelty of the research objective was not entirely clear.

Minor Comments

-Introduction:

As mentioned before please include a brief explanation of the population origin. A map with location of the three primary healthcare centers and the districts may be helpful. To bring context to readers, the introduction may also include information regarding healthcare insurance, FONASA, Ancora Network and COVID-19 epidemiological surveillance in Chile.

-Materials and Methods:

Please describe the calculation of follow up time and the definition of COVID-infection (it was only by PCR? Clinical definition? Antigen Rapid test was not used for epidemiological surveillance?). As above-mentioned and similar whti COVID-19 death, definitions of main outcomes including hospitalization and UTI may be only restricted to COVID-19 related. A combination of the three outcomes may be also considered. Other variables that may be helpful may be obesity, chronic kidney disease, wave of infection, mechanical ventilation, and cause of encounters with a physician or a nurse. The subgroup analysis may be sustained in background and objectives.

-Results and Discussion:

A flowchart showing the selection steps may be included as principal figure.

Please present results regarding follow-up time.

Figure 1: please also add a curve showing the COVID-19 cases.

Table 1 and S5 table: please include totals in the first row and present statistical test comparing groups.

Table 2: add the variable "number of COVID-19 infections ".

Please correct the term "prevalence" in Line 176.

Include as limitation of the study the lack of information regarding clinical conditions control such as of diabetes and hypertension.

-Subsidiary aspects

Specify the A (lowest income), B ,C , and D (highest income) categories for FONASA variable in all tables

Reviewer #2: Interesting study

In the summary it says: "Among the 44,674 people, 460 (1.03%) had a hospital admission, 217(0.49%) had an ICU admission and 533(1.19%) died due to COVID-19," which does not apply completely with the results. I suggest writing it as it is in the results... 217 of them were also admitted to the ICU (xxx%). "In addition, the death toll must be changed from 533, which corresponds to the total cohort, to 89, which are those who died due to COVID-19."

In the summary it says: "Hypertension and diabetes pre-existing conditions … " I would eliminate "pre-existing conditions" because it is obvious that they are pre-existing.

The expression "any hospital admission" is also not clear; "hospital admission" would be better.

Also, in the summary it says: "from higher-income", it should say "from higher-income countries".

Among the authors' workplaces appears: "(6) (School of Computing and Information Systems, University of Melbourne)", however none of the authors have that membership.

It would be useful to have a table comparing the risk factors of all COVID patients with those who die from COVID, not just the entire cohort as shown in table 1.

In Sociodemographic factors it says: "People 70 years or older had 1.51 times (HR 1.51; 95% CI 1.42 to 1.62) and 38% 240 (HR 1.38; 95% CI 1.24 to 1.53) higher risk ..". I think it is better to keep the same numerical expression format, this is 1.51 times, without mixing it with percentages.

It says: "People 70 years or older had 1.86 times (HR 1.86; 95% CI 1.68 to 2.06) higher risk of dying due to a COVID-19 … than those aged 54 years or younger." However, the basis of comparison according to table 2 is with ages between 18 to 34.

I

t says: "Compared with male sex, females were 0.96, 0.94 and 0.68 times less likely .. l", the confidence intervals are missing.

The title of table number 2 says: "Hazard Ratio of the risk for any hospital admission or an ICU admission due to …… ." "COVID deaths" must be included

In Clinical factors it says: "The number of frequently dispatched drugs was associated with a higher risk of hospital and ICU admissions … " Must include numbers.

**********

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: Yes: Rodrigo Gil

**********

[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.

PONE-D-24-13634R1Association between demographic, clinical characteristics and severe complications by SARS-CoV-2 infection in a community-based healthcare network in ChilePLOS ONE

Dear Dr. Leniz,

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 address the comments made by reviewer 1 

==============================

Please submit your revised manuscript by Nov 08 2024 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,

Juan Pablo Gutierrez

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.

[Note: HTML markup is below. Please do not edit.]

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 #1: (No Response)

Reviewer #2: All comments have been addressed

**********

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 #1: Partly

Reviewer #2: (No Response)

**********

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

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

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 #1: Yes

Reviewer #2: (No Response)

**********

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 #1: Yes

Reviewer #2: (No Response)

**********

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 #1: The authors had made changes improving considerably their manuscript. However, we still have the following suggestions:

-Please add information regarding COVID-19 epidemiological surveillance in Chile. Given that only PCR information was analyzed, it is important to clarify why Antigen Rapid Test data was not considered. COVID-19 epidemiological surveillance in Chile was only based on PCR? Was Antigen Rapid Test data not available for analysis? If the last case is true, this lack of availability may be pointed as a very important limitation of the report.

- The last paragraph in the introduction section benefits from a general aim that encompasses all the analysis and subgroups analysis carried out. This aim may be split into specific objectives.

- The methodology section requires an explanation regarding calculation of follow up time.

- Table 2: please revise the title which started as "Fig 4". Is the "n=42,588" correct? It is different from "n=44,674" on table 1. If the model is considering COVID-19 and non-COVID-19 cases, why is not possible to calculate HR for COVID-19 infection as outcome?

- The lack of availability of other variables such as obesity, chronic kidney disease, wave of infection, mechanical ventilation may be included into the study limitations.

-Specify the A (lowest income), B, C , and D (highest income) categories for FONASA variable in all supplementary tables and figures (S1_Table.docx, S4_Fig.docx, S5_Table.docx, S7_Table.docx).

Reviewer #2: (No Response)

**********

7. 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: Yes: RODRIGO GIL DIB

**********

[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.

Association between demographic, clinical characteristics and severe complications by SARS-CoV-2 infection in a community-based healthcare network in Chile

PONE-D-24-13634R2

Dear Dr. Leniz,

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,

Juan Pablo Gutierrez

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: