PONE-D-21-26611SARS-CoV-2 seroprevalence among patients with severe mental illness: a cross-sectional studyPLOS ONE

Dear Dr. Sass,

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 all the points raised below during the review process.

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Academic Editor

PLOS ONE

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“This study was funded by Mental Health Services, the Capital Region of Denmark.”

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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

Reviewer #4: Yes

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

Reviewer #1: No

Reviewer #2: I Don't Know

Reviewer #3: Yes

Reviewer #4: 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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #4: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript entitled ‘The SARS- CoV-2 seroprevalence among patients with severe mental illness: a cross-sectional study’ with the aim to determine whether a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder is associated with an increased risk of COVID-19.

This is quite an interesting study but the manuscript can be further improved.

Abstract

Page 3 Line 47, the comma to indicate 95% CIs could be omitted e.g 95% CI, 0.79-2.20 can be presented as 95% CI 0.79-2.20 or 95% CI: 0.79-2.20.

Page 3 Line 49, comparison of gender to be highlighted.

Methods

The type of SMI included in the study to be clearly stated.

Statistical analyses

Line 121, the word respectively to be added after tests.

Line 121, unpaired t-tests and Pearson’s chi-square tests to be written as unpaired t-test and Pearson’s chi-square test. Likewise with Line 154-155, 161-162.

Line 124, the sentence ‘to adjust for gender and age, we calculated RRs for gender and age groups’ requires revision. The word adjust not clear.

Line 129, the word adjust to be replaced with another word. Likewise with Line 187.

Results

Table 1, the empty column to be removed.

Line 143-144, the sentence requires revision.

Line 151, the title for Table 1 is too short.

Table 1, decimal point for p value to be standardized. N to be used for overall sample size (Total). No.(%) to be replaced with n(%).

Line 166-175, Line 181-189, data/results to be presented in table form. The analysis whether crude or adjusted to be clearly stated. Multivariable statistical test could be explored.

The cited reference to be spaced out from the previous word throughout the manuscript e.g. COVID-19(14,16,21). [ ] to be used instead of ( ).

List of references to conform with PLoS ONE format.

Reviewer #2: Line 99 and Figure 2 – While Blood donors were used as a comparison, is there an estimate of the average population rate of COVID positivity in Denmark in February 2021? And if so, is this different? Blood donors may not be representative of the general population and this should be addressed in the text. The authors should discuss more why the patients in this study had a lower than population rate of positivity but, as noted in the Discussion, probably a higher rate of hospitalization due to COVID-19.

In general the results suggest that mental health patients are significantly less likely to have contracted COVID-19 is a surprising finding and contrary to most other studies. Clearly the study is limited by the patients who chose to be screened and may have not agreed to screening because they knew they had had COVID-19. This complicates the interpretation of the results unless there is another reason for the difference. Enhanced discussion is needed

Reviewer #3: The manuscript is well written and studies an underserved population (severe mentally ill). The focus on COVID in this population is highly timely. Investigation of such a population is challenging for many reasons and the authors have done an excellent job describing their approach and success.

A major strength of the study is reliance on serology for estimates of prevalence, which is not subject to many bias and other potential confounding factors related to medical care, patient perception, isolation, and testing of the mentally ill.

The study findings of a low prevalence of COVID (~4%) in the mentally ill population is remarkable and worth recognition. The factors that contribute to the low prevalence are important to recognize. This reviewer feels the low prevalence rate alone should be a major focus, rather than comparison to another group.

The major weakness of the study is the attempt to compare their study population to a reference group. While of interest, the rate of blood bank donors is a poor comparison group. The rate of similarly institutionalized individuals would make a much better comparison group, of which, admittedly there are few. One suggestion might be prisoners.

Another analytic approach might be to compare the mentally ill patients to multiple other groups that may have been published, such as local COVID rates in Denmark among citizens, or specialized groups (health care workers). The limitation of the comparison group is redundantly addressed in the discussion and the limitations sections.

Reviewer #4: This study is original as it examines the association between severe mental disorders and risk of COVID-19. The author uses a cross-sectional study on psychiatric centers with blood donors as control. The study is of interest even if the results are not significant.

I have some questions for this manuscript including the following (organized by manuscript section).

Methods - Statistical analysis

Due to the small number of expected subjects (<5) in some categories, and the highly unbalanced marginal sums of the actual data set, Pearson’s chi-square test cannot be applied. It is better to use Fisher’s exact test.

Results

All seroprevalences in the text are crude prevalences and not corrected prevalences as suggested by Rogan et al. 1978 and indicated in the method paragraph. So give the corrected prevalences even if there are not significantly different from the crude prevalence. Do the same in the abstract.

I don’t find the same prevalences than authors for male and female:

Crude prevalence = 4.69% for female (32/683) instead of 5.27% in the text

Corrected prevalence= 4.97% for female (0.0469+1-1)/(0.945+1-1) according to Rogan et al. 1978)),

Crude prevalence = 4.70% for male (27/575) instead of 4.00% in the text

Corrected prevalence= 4.97% for male

Even if there are no cases of SARS-COV-2 antibodies among patients with schizoaffective disorder, it is possible to calculate the 95% CI.

For mental health diagnosis, it will be better to calculate prevalence for each diagnosis separately, and relative risk as compared to schizophrenia which is the largest group, and not as compared to remaining included patients with SMI which include people with different prevalences.

For the different districts of Copenhagen, I would separate central part and Amager from the other districts which have higher corrected prevalences of respectively 6.67 and 6.78 while others have corrected prevalences of 2.74.

Even if it seems evident, gives the reference in the sentence 174-175 about age. It could be another group than ≥ 30 years.

RR between participants and blood donors is 0.41 instead of 0.40 with approximation (0.405).

Table 1: there is an extra empty column. Thank you to delete it. I will be interested to have age by group and not as a continued variable, the mean age being included in the text.

Discussion

The paragraph lines 218- must be just after lines 211.

I will be interesting to know if there are some difference in the literature according severe mental health diagnosis and to discuss it and not only according sex differences.

It would also be interesting to discuss the difference between neighbourhoods. Is it differences in socio-economic level, in population characteristics?

Problems at the end of line 259 for reference 20.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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PONE-D-21-26611R1SARS-CoV-2 seroprevalence among patients with severe mental illness: a cross-sectional studyPLOS ONE

Dear Dr. Sass,

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 last remaining points raised below during the review process.

Please submit your revised manuscript by Feb 26 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Ray Borrow, Ph.D., FRCPath

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: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: (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: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

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 #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The word adjusted could still be used as alternative to the word corrected.

For Table 1 & 2, chi-squares test where applicable could still be utilized provided the assumptions of the statistical test are fulfilled/met. Please check the assumptions and also recheck the p values. If Fisher's Exact test is used, one sided or two sided p value to be stated.

Reviewer #2: Revisions were adequate Revisions were adequate Revisions were adequate Revisions were adequate Revisions were adequate

Reviewer #3: (No Response)

Reviewer #4: I thank the authors for their responses to comments. Nevertheless, I have some other comments.

Introduction

If you want to use the acronym SMI, it is best to associate it with severe mental illness as in the abstract. Otherwise use SMD for severe mental disorders.

Methods - Statistical analysis

Due to the small number of expected subjects (<5) in some categories, and the highly unbalanced marginal

sums of the actual data set, Pearson’s chi-square test cannot be applied. It is better to use Fisher’s exact test.

Author response: Fisher’s exact test could not be made with too many groups or observations.

Reviewer comment : The extension of Fisher's exact test to the case where the two variables have any finite number of modalities, but greater than two, was first performed by G. H. Freeman and J.H. Halton in 1951. This test is sometimes referred as the Freeman-Halton or Fisher-Freeman-Halton test. So it is possible to calculate Fisher’s exact test with more than 2 modalities in one variable.

It is written in Table 1 that Ficher’s exact test was used. I think this is not the case for Diagnosis according the author response.

Results

It is possible to have standardized decimal point in p value.

0.35 Could be witten 0.350.

There is a confusion in the article between total population (for me the 7310 subjects) and the study population (for me the 1258 subjects

Table 1: change the Table title by « Baseline characteristics of study population according to SARS-Cov-2 serology

Table 2: change the Table title by « Baseline characteristics of total population by study participation

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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: No

Reviewer #3: No

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.

SARS-CoV-2 seroprevalence among patients with severe mental illness: a cross-sectional study

PONE-D-21-26611R2

Dear Dr. Sass,

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

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

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Kind regards,

Ray Borrow, Ph.D., FRCPath

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: