PONE-D-22-09612Healthcare resource use and associated costs of hospitalized COVID-19 patients in Spain: a retrospective analysis from the first to the third pandemic wave. EPICOV study.PLOS ONE

Dear Dr. Drago,

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Academic Editor

PLOS ONE

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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: Yes

Reviewer #2: Partly

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

Reviewer #1: No

Reviewer #2: No

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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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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

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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: Thank you for the opportunity to review this manuscript on healthcare utilization and cost of COVID-19. While the information on cost of COVID-19 care is important, I believe it is important that it includes adjusted measures of association, in order to answer the questions asked in the paper.

Page 5, line 97: Please give some insight into how representative these hospitals are of the whole Spain population. What % of total hospitals do they amount to? Are patient or hospital characteristics different? For example, are private hospitals characterized by better standards of care, compared to public ones? It is important in understanding who is represented in this study.

Page 5, line 107: Suggest making this sentence more concise and list the specific date ranges here right away, supported by citations. It does not seem that holiday information (eg Christmas) adds much important information to this.

Page 6, line 114: Please provide more information on how the anonymized data were collected. What was the response rate? Are all patients with COVID-19 in these hospitals included?

Page 7, line 134: Were patients exclusively admitted through the ED? If so please specify in the text.

Page 7: Was information available on underlying medical conditions?

Page 8: Were any statistical models used? It seems that GLM models with Gamma distribution accounting for specific patient and/or hospital characteristics are needed to compare the costs by these characteristics. All models should be adjusted for age, sex, race/ethnicity, underlying medical conditions (if available) With unadjusted measures of association, it is hard to say whether some of these subpopulations or waves are actually different or whether the difference is driven by other characteristics. For example, the statement in the Conclusions section states that age and ICU admission were the most important drivers of the cost; but it is not possible to assess that without adjusting for all these factors in one model.

Page 8: Means in this skewed distribution are very much affected by the tail length and outliers; suggest using median costs, in addition to mean costs.

Page 18: The “increase” of LOS and costs with age represents unadjusted means (is that correct?). Suggest using GLM models with age group as the covariate of interest (adjusted for other important controls) to estimate whether this difference was indeed meaningful and significant.

Methods: Suggest plotting the cost distribution for full sample and/or certain subsets – so that we can understand the skewness and min/max costs.

Methods: Please consider a supplemental analysis that would censor the costs above 99th percentile. It is possible that means may not be so different after removing those super-utilizers with extremely high costs.

Methods and Results: While mean costs are interesting, it would also be interesting to understand the specific contributions of all patient characteristics to cost in terms of percent. For example, as age increases, what is the increase in costs in percent? This gives us some understanding of the magnitude of this difference (2% or 50%), rather than just dollar terms.

Figures: Please add footnotes describing what is shown in each figure (whether these are adjusted or unadjusted cost means). Each figure must stand alone and be interpretable without looking at the Methods.

Reviewer #2: Major issues:

(1) There is already a paper which present costs related to cost of COVID cases. The authors cited it https://healtheconomicsreview.biomedcentral.com/articles/10.1186/s13561-021-00340-0

Then what is the added value of the current paper?

(2) In my view it is not ok to mix cost and mortality. Your paper deals mainly with cost and there are a lot of information that you can present about costs. I recommend to make a different paper in mortality/survival, etc.

(3) The paper has rather a descriptive manner, rather a case-study. If the sample is random, I suggest to make an inference of COVID cost’s

(4) Related to (1),(3) . Probably is more important to see what combination of factors/covariates drive to higher costs? This can be an added value of the paper. In this sense, I suggest to use for example regression modelling.

(5) You present some results about sensitivity, but in the methods the sensitivity analysis is described too vague. It is DeterministicSA or ProbabilitySA, I guess is DSA.

(6) You deal with samples in each wave, why you do not test if the difference is statistically significant? Between waves and or between groups of patients.

(7) We know that LOS and age are determinants for higher costs, but it is something else a characteristic of COVID hospitalized cases? If you want to add a value to your study, why not a comparison with severe classic Pneumonia cases? If the cost are not significantly higher, than….

(8) In the sense of (7) I suggest to search for a combination of factors such as , age-group+ group of comorbidities.

(9) Can we see a distribution of patients by cost? I believe is a long tail distribution, then the mean cost may be not relevant….Eg. you sum 3patients*2000 +1patients *10000 and you have a mean of 4000. The range of cost is not enough relevant.

(10) Maybe a synthetic 8 figure/diagram is useful to understand the patient path-way. Eg diagnosed at family medicine-� covid ward-� ICU, or Non-diagnosed----emergency---ICU.

(11) For the hospital costs we have a DRG cost? Then, the structure of patients per hospital is the same in each wave? I think we have a hospital or regional effect cost when DRG is computed. Please clarify!

Minor issues

(1) Reference [27] has a broken link

(2) If you decide to keep mortality in the analysis then , in the methodology some description, formula or something else should appear about mortality. Then if then, maybe you should take into account

(3) I don’t know if it so important to use so many age-groups . The difference are small. Using so many age-groups you reduce sub-sample size. Why not children? (<18), Then 18-29, 30-49, 50-69, 70+, or something similar.

(4) Secondary diagnosis at hospital admission, n/N (%) please use other notation, Usually n= the sample size and N is the population size.

(5) Secondary diagnosis at hospital admission, n/N (%). I don’t understand the shares. In my view we should see how many COVID patients have an I10 or E11 as secondary diagnostic. Now I think it is a share of how many I10 are in the secondary diagnostics divided by patients*nr_of secondary diagnostics ?!. Please clarify!

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Reviewer #1: No

Reviewer #2: No

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PONE-D-22-09612R1Healthcare resource use and associated costs of hospitalized COVID-19 patients in Spain: a retrospective analysis from the first to the third pandemic wave. EPICOV study.PLOS ONE

Dear Dr. Drago,

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 Jan 05 2023 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,

Martial L Ndeffo Mbah, Ph.D

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:

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: (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 #1: Partly

Reviewer #2: No

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

Reviewer #1: No

Reviewer #2: No

**********

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: No

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 #1: Yes

Reviewer #2: Yes

**********

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: I appreciate the authors’ responses to my comments. While most of my comments and questions have been resolved, I have two that have not been fully resolved. My focus is especially on the adjusted measures of association; although authors have provided them, I feel that the table/figure needs to be included in the manuscript and explained in more detail as well.

R1, Comment 1: I feel that my comment about the representativeness was only partially addressed. Could the authors add in the text the total number of hospitals in Spain that were open during the pandemic, as well as the % that the 17 hospitals included in the study represent? I appreciate the added limitation, but quantifying the representativeness would be helpful here.

R1, Comment 6: I appreciate that the authors addressed my comment by using adjusted GLM models and providing adjusted measures of association in the text. I have some more comments on the modeling, however.

. More comments below:

- Estimates need to include confidence intervals.

- Why aren’t all estimates shown in the table in the authors’ responses? I see only age and LOS as predictors of cost among non-ICU patients and wave (but only third wave vs first wave), sex, and LOS as a predict among ICU patients. I would suggest that all coefficients are presented.

- Even more important than coefficients, predicted costs from the GLM models can be used in the place of unadjusted mean costs in the figures. Their 95% Cis can show whether the costs in the three waves were truly different.

- Are these estimates currently included in the main figures? If estimates are not included in the main results, I would suggest replacing one of the figures with the adjusted predicted costs (and 95% CI) in each wave. That can be easily done by using the “margins” Stata post-estimation command to get predicted costs. This would help us see if the costs were truly different by wave after controlling for other covariates.

- To estimate differences by wave for each characteristic (Figure 3A), authors may want to include both wave categorical variable and its interaction with those characteristics (eg wave (1,2,3), age (<12, 12-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, 80), and wave*age). They can then use the Stata “margins” post-estimation command to predict the cost in each wave and at each level of covariate included in the interaction.

Reviewer #2: I appreciate the work of authors but there are some issue which in my view do not match.

The major thing is that the title, the abstract and the conclusions suggest that achieved results characterize the cost/patient for entire population of COVID-19 patient in Spain. The sample selection and thus the methods and the results do not support this hypothesis. In my view there two options (1) if the authors try to extend the costs results for a typical ICU/non-ICU patient from Spain, then they need a representative sample; (2) if the authors cannot achieve a representative sample, I recommand to underline the fact, that this is work is just a case-study, and everywhere in the paper should be clearly specified that "in our/current sample"/ "in our/current case", the results are. The phrases which induce the extension of results should be avoided in my view. Indeed in the limitations paragraph the authors try to explain differences between the current sample and the population, but the arguments are not solid. My worries are related to the thing that costs may be overestimated in particular hospitals compared with anothers. There is no proof that error are compensating each-other.

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Reviewer #1: No

Reviewer #2: No

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Healthcare resource use and associated costs in a cohort of hospitalized COVID-19 patients in Spain: a retrospective analysis from the first to the third pandemic wave. EPICOV study.

PONE-D-22-09612R2

Dear Dr. Drago,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Martial L Ndeffo Mbah, Ph.D

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: (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: No

**********

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

Reviewer #2: No

**********

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

**********

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: (No Response)

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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: Furthermore, this sample of hospitals represented 2.2% of

489 Spanish hospitals [41]. In that respect, the study population might not accurately represent

490 the population attended in the Spanish healthcare system. Nonetheless

Therefore, we suggest that

507 the costs obtained are an approximation of the actual costscosts were considered

508 representative of the Spanish public healthcare system.

If you assume that your patients sample might not accurately represent the entire population of patients, then in my view there are not enough suport information to conclude that estimated cost are a bad or a good representation of the real costs. I really appreciate your efforts but I cannot accept the conclusion without a strong evidence report.

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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 #2: No

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