PONE-D-20-17129

COVID-19: Spatial Analysis of Hospital Case-Fatality Rate in France

PLOS ONE

Dear Dr. Souris,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Adrish

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: Partly

Reviewer #2: Yes

Reviewer #3: Partly

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: 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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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

Reviewer #3: 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 manuscript entitled “COVID-19: Spatial Analysis of Hospital Case-Fatality Rate in France” by Souris and Gonzalez has studied the influence of the hospital care system on lethality in metropolitan France during the inception of the COVID-19 epidemic. The study concludes that the higher case fatality rates observed in France is linked to the level of morbidity in the district. The study has also suggested that the case-fatality rates (CFR) may be linked to the hospital care available in the district, i.e., higher congestion of the hospitals or lower accessibility of the hospital care leads to the higher CFR. The manuscript is well written, the introduction is quite informative and the data are well presented and may be interesting for readers from varying fields. However, there are few concerns may be clarified are given below:

1. The abstract does not fully explains the study and needs to mention more about the findings presented in the discussion and conclusion.

2. Higher hospitalization leads to higher CFR, this explains that it is directly related to the higher morbidity, however, to compare with the hospital care system authors need to present a data showing the number of hospital/ beds accessible (per 1000). As explained higher hospital stress means 3 or more per 1000 does not explain the availability or accessibility to hospital care. Table 3 shows the total hospitalized and CFR. Here authors may put a data comparing the hospital care accessibility.

3. Table 3 also should show the data of hospitalized and death (%) 11 and 44 regions. This will help the readers to have better clarity.

4. The higher CFR is among the age group 50 and above. Is the overall difference found between CFR whole and CFR without regions 11 and 44 is due to the presence of higher number of higher age group cases?

5. Table 4 shows that the CFR varies from 0.134 for districts with a low hospitalization rate (less than 0.5 per 1000) to 0.150 for districts with a high hospitalization rate (less than 4 per 1000). How the average for all the districts higher (0.152)? What is the meaning of districts number? What does “all” in the last line shows?

6. Figure 12 presents districts with different morbidity and the lethality. Can the authors compare the low morbidity high lethality vs. high morbidity high lethality districts? Is there any similarity/ differences related to hospitalization/ accessible to hospitals or the aging population in these districts? The CFR is high in the higher age groups. To justify that the CFR is higher in the districts having higher hospital stress or due to lack of hospital care, authors need to show and compare the CFR rates between different age groups. Is the CFR is higher due to the presence of higher %age of higher age groups?

Reviewer #2: Comments to the Author

The authors show the increase in the case-fatality rate in France during epidemic peaks related to the level of morbidity, but not from the care or treatment of patients during hospital stress due to epidemic peaks. Although this paper was well written, I have several comments. Sufficient improvements for those issues are needed for the acceptance to the PLoS One.

Major comments

1. I believe that morbidity and mortality of COVID-19 are strongly related to patient’s factors including incidence of diabetes, and cardiovascular disease. Please indicate the difference of these risk factor between France and other countries or regions in France, or if there is no data, please indicate as a limitation.

2．In our country, there are differences in the availability of infectious disease wards and the capacity to operate ECMO depending on the region. Please explain differences of these factors between France and other countries or regions in France, or if there is no data please explain in the discussions and limitations.

3. Criteria of severity of COVID-19 by admitting ICU or not depend on capacity of each facility, so I concern that it may be inappropriate as an indicator of the severity. I consider that there is no correlation between the severity rate and the case-fatality rate. I believe that endotracheal intubation is relatively good indicator of the severity of the disease. Is it possible to discuss the difference in the severity of cases according to this standard and the difference from other countries?

Reviewer #3: Souris et al present a very unique and interesting analysis of the spatial distribution of COVID-19 cases requiring hospitalization in France, specifically analyzing hospital case-fatality rate to try to understand regional/geographic variations in healthcare. They report significant variations in CFR across regions, and conclude that higher CFR observed by districts are largely related to the level of morbidity/infection rate, and therefore to a putative overwhelming of the local healthcare systems during the acute phases of the epidemic, rather than any deficiency or failure of the local healthcare. Moreover, they suggest the geographic differences are not due to population risk factors or reporting systems, which they purport are uniform across France. Interestingly, the CFR variation is small compared to much greater variation across countries reported in the literature, suggesting marked international inconsistency in case reporting and death ascertainment/coding. The manuscript is very thorough, well-illustrated through figures, with very strong statistical assumptions-based robust analysis, largely well-written, and an important contribution at a time such as this.

Major Comments:

1. Abstract. Final sentence / concluding idea “However, the magnitude of this increase of case-fatality rate represents less than 10 per cent of the average case-fatality rate” is incomplete and leaves the findings unexplained; I would expand and clarify.

2. Data analysis.

a. (Pg 17): “The observed gross hospital case-fatality rate calculated by district showed a mean of 0.153 with a standard deviation of 0.045 … Without the Ile-de-France and Grand-Est regions, the mean gross case-fatality rate per district is 0.149 with a standard deviation of 0.048 (figure 6).” Given minimal change in mean CFR and SD by excluding the hardest hit areas, I don’t understand why the authors persist in the analysis with / without these regions

b. (Pg 18): “The spatial distribution of standardized morbidity rate (hospitalized cases) shows a significant spatial autocorrelation (Moran index: 1.54, p-value < 10-6), and this is expected for an infectious disease.” I don’t understand “autocorrelation” – a parameter with itself, or a value in a region correlating with values around it?

c. (Pg 19): “There is a correlation between the standardized hospitalization rate and the standardized case-fatality rate (Bravais-Pearson index=0.40) (Figure 10), a correlation which increases (0.48) if we limit the calculation to districts whose SLR is significantly different from 1 (p-value < 0.05).” It is unclear which correlation result the p value refers to? Relatedly, p value should be provided in Fig 10 or its legend.

3. Figures/Tables. Some are poorly formatted, with small fonts, poorly explained terminology, and with some sloppiness (French labels from software that are not translated/explained)

a. Fig 1. Y-axis title “Effectifs” unexplained. Why are data in decimal format compared to % format in Table 1?

b. Fig 2. Y-axis titles illegible. X-axis title “Calendar” not clearfor a linear numerical scale.

c. Table 3. Each age group is assigned a % for the various parameters, but the totals are decimal (1.0) !

d. Fig 12. The legend terminology “1-5, H for 1-4” is completely unclear! The wording is clear but does not relate to “H”.

4. Discussion: Several concluding statements are unclear, and don’t seem to be supported by data specifically presented in the Results. Moreover, much new data/analysis/calculations seem to be presented in the Discussion, which is inappropriate.

a. Pg 22: “the average case-fatality rate for all districts being about 15% higher than the average rate calculated in the 20% of districts with the lowest hospitalization rates” makes little sense. Moreover, the following conclusion “It is therefore very likely that the increase in hospital tension over the period under consideration has increased the hospital case-fatality rate” does not follow logically from the preceding.

b. Pg 23: “The first profile accounts for 60% of the patients (59,878 over 99,970). The case-fatality average for this profile is significantly higher (0.187) as compared with the other districts case-fatality average (0.138). The profile displays a 33% excess mortality, corresponding to 2,716 deaths (11,003 observed vs. 8,287 expected with the CFR 0.138). This excess mortality, corresponding to 16 % of all deaths, is likely to be the result of increased lethality due to overloading…” presents much more data/analysis than in the Results. Similarly for the 2nd profile.

c. Pg 24: “WHO data from 219 countries (WHO 20) show a mean case-fatality rate of 0.041 (median 0.029, standard deviation 0.045) with values between 0.31 (Nicaragua) and 0.00 (for countries that did not report deaths, like Vietnam). A T-test shows that the French average is therefore very significantly higher than the world average (p-value < 10-6)”

d. Pg 25: “difference observed between the average case-fatality rate in France and the average of the rates reported for all countries by international organizations or information sites (WHO, Wordometer, etc.). These differences probably stem from the reporting of cases and deaths, which is uneven from one country to another, and not from the care or treatment of patients” appears to be an unsubstantiated conclusion. Because the variation if pandemic stress in some regions of France only explained 10% of the overall CFR variation, why does this exclude the possibility that differences in healthcare quality/access could explain differences across countries?

5. Conclusions. Given the changing population of France with north African and other immigration, could regional population differences not explain some differences in risk of severity of COVID and thus CFR variation? Moreover, regarding the variation in European countries, population and healthcare quality differences are much too easily dismissed: (Pg 10) “In Europe, the characteristics of populations (in terms of risk factor for COVID-19) and health systems are comparable …”

6. References. I am very surprised given the complex geographic and statistical analysis that the reference list is so abbreviated ! It might be helpful to the average reader to perhaps have a few more to support the methodologic approaches, analysis, basics of healthcare statistics, etc.

Minor comments

1. Terminology.

a. Pg 16: “a cartographic representation by cartogram” should be revised.

b. Pg 21: “intensity of reanimation” is unclear.

c. Pg 22: “Hospital tension”

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Prof Sanjay Mehta, MDCM FRCPC

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PONE-D-20-17129R1

COVID-19: Spatial Analysis of Hospital Case-Fatality Rate in France

PLOS ONE

Dear Dr. Souris,

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.

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

ACADEMIC EDITOR: Please see comments by the reviewers. I am requesting you to address these concerns before I can accept the study for publication.

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

Please submit your revised manuscript by due date. 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Adrish

Academic 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 #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

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: Yes

Reviewer #3: 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 #1: Yes

Reviewer #2: Yes

Reviewer #3: 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: The authors have satisfactorily answer all the queries raised during revision. The manuscript now may be considered for publication.

Reviewer #2: The authors show the increase in the case-fatality rate in France during epidemic peaks related to the level of morbidity during hospital stress due to epidemic peaks. Author had responded correctly to my queries.

Reviewer #3: I thank the authors for extensive revisions to the paper, including improving the figures, legends, tables and abstract. The paper reads better. There are however a few issues I raised which were too easily dismissed and perhaps my concern not clear.

Major Comments:

1. My previous comment: d. Pg 25: “difference observed between the average case-fatality rate in France and the average of the rates reported for all countries by international organizations or information sites (WHO, Wordometer, etc.). These differences probably stem from the reporting of cases and deaths, which is uneven from one country to another, and not from the care or treatment of patients” appears to be an unsubstantiated conclusion. Because the variation if pandemic stress in some regions of France only explained 10% of the overall CFR variation, why does this exclude the possibility thatdifferences in healthcare quality/access could explain differences across countries?

Answer: The healthcare system in France is renowned for being of good quality, in terms of equipment, medical staff, patient care and treatment. COVID-19 patient management protocols in France do not differ significantly from those used in other European countries (Germany, Spain, Italy, Greece, etc.). It is therefore unlikely that the huge differences in lethality are due to differences in management or quality of care. But our conclusion concerns the possible degradation of care during periods of hospital stress (epidemic pic, ward and medical worker overload): the results indicate that this observed degradation, even substantial, cannot explain the difference in case-fatality rate with other countries, some of which have themselves experienced periods of hospital stress (e.g. Italy, Spain, UK, Mexico, Brazil).

Unresolved concern: The crux of the paper is that “epidemic stress” leading to some degradation of care explains only a small proportion of the variation in CFR across French regions. However, the authors have not clearly discussed or speculated what is the major reason for this huge variation in lethality! Moreover, their statements of “good quality” of French care and similar patient management protocols across European countries ignores the reality of medical care at the frontline or on the ground, where much variation occurs based on local administrations, local facilities, as well as local populations. Their response is inadequate.

2. My previous comment: Conclusions. Given the changing population of France with north African and other immigration, could regional population differences not explain some differences in risk of severity of COVID and thus CFR variation? Moreover, regarding the variation in European countries, population and healthcare quality differences are much too easily dismissed: (Pg 10) “In Europe, the characteristics of populations (in terms of risk factor for COVID-19) and health systems are comparable …”.

Answer: Official data collection and statistics on ethnic origin of population are prevented in France.

Unresolved concern: This limitation should be recognized/stated in the manuscript, but is not an excuse for lack of scientific consideration by the authors of this important basis for some of the regional / country differences. This point should be considered/discussed even in the absence of any specific data being available.

Minor comments

1. My previous comment: Pg 16: “a cartographic representation by cartogram” should be revised.

Answer: “Cartogram” is the specific name of this king of map, in which some thematic variable is substituted for land area or distance.

Unresolved concern: I accept the term is correct, but the language is awkward/repetitious, “… cartographic representation by cartogram” !

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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 #1: No

Reviewer #2: Yes: Masaki Okamoto

Reviewer #3: Yes: Professor Sanjay Mehta, MDCM FRCPC

[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-20-17129R2

COVID-19: Spatial Analysis of Hospital Case-Fatality Rate in France

PLOS ONE

Dear Dr. Souris,

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.

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

ACADEMIC EDITOR: Please review the comments made by the reviewers and provide a point by point response in your revised manuscript. 

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

Please submit your revised manuscript by due date. 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Adrish

Academic Editor

PLOS ONE

[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 #3: All comments have been addressed

Reviewer #4: (No Response)

**********

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 #3: Yes

Reviewer #4: No

**********

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

Reviewer #3: I Don't Know

Reviewer #4: No

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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 #3: Yes

Reviewer #4: No

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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 #3: Yes

Reviewer #4: No

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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 #3: (No Response)

Reviewer #4: 1) The concrete results in the manuscript include spatial autocorrelation of certain variables, a positive correlation between hospitalization rate and case-fatality rate, and a “weak” negative correlation between hospitalization rate and severity rate. However, there is concrete data and rigorous analysis to support one point the authors tried to stress—non-comparability of case-fatality rates across countries. Therefore, statements on this point should at most be kept in Discussion and removed from Abstract (the 4th paragraph) and Introduction (the 4th paragraph).

2) The exact definition of age standardized case-fatality rate is still unclear. In the formula in page 4, are P[a] and T[a] district specific or not? If they are, there should be subscript i; if not, that means the expectation E is the same in all the district of the France, which is the so-called “average rate for France”? It is unclear whether the district observed case fatality rate was age adjusted or not? My understanding is yes according to the term “district’s SLR”; however, what’s the formula for it? As I pointed out, the only formula so far is not district specific.

3) The language is verbose and many contents are superfluous. I suggest shortening the manuscript, removing unnecessary parts, and making only succinct points. Take an example, the whole page 4 seems can be removed.

4) The last sentence of the second paragraph in Introduction—“…, unlike case-fatality rates, which are normally calculated independently of the number of infected persons”— it is confusing to me, how the case-fatality rate could be independent of the number of infected persons? Isn’t it the denominator?

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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.

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Reviewer #3: Yes: Professor Sanjay Mehta, MDCM FRCPC

Reviewer #4: 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.]

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PONE-D-20-17129R3

COVID-19: Spatial Analysis of Hospital Case-Fatality Rate in France

PLOS ONE

Dear Dr. Souris,

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.

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ACADEMIC EDITOR: Please see below the unaddressed concern raised by the reviewer. I am unable to accept your study until these concerns have been appropriately addressed.

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

Please submit your revised manuscript by due date. 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.

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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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Adrish

Academic Editor

PLOS ONE

[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 #4: 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 #4: Yes

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

Reviewer #4: Yes

**********

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 #4: 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 #4: 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 #4: 1) The authors currently put in the last sentence of Abstract “…, suggesting marked international inconsistency in case reporting and death ascertainment/coding”, which is exactly what I commented—it is an implication from the results, not the direct results. Note that it is a very strong statement. Therefore, please remove it from Abstract and leave it only in Discussion.

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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 #4: 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.

COVID-19: Spatial Analysis of Hospital Case-Fatality Rate in France

PONE-D-20-17129R4

Dear Dr. Souris,

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,

Muhammad Adrish

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

You have satisfactorily answered all queries made by the reviewers

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 #4: 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 #4: Yes

**********

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

Reviewer #4: Yes

**********

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 #4: 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 #4: 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 #4: My comments were all addressed, I have no further critique.

My comments were all addressed, I have no further critique.

**********

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 #4: No