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PONE-D-20-28251

Magnitude of asymptomatic COVID-19 cases throughout the course of infection: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Muluneh Alene Addis,

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 Dec 12 2020 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:

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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.

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We look forward to receiving your revised manuscript.

Kind regards,

Kin On Kwok, Ph.D

Academic Editor

PLOS ONE

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When submitting your revision, we need you to address these additional requirements.

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2. Please confirm that you have included all items recommended in the PRISMA checklist including the full electronic search strategy used to identify studies with all search terms and limits for at least one database. Please attach a Supplemental file of the results of the individual components of the quality assessment, not just the overall score, for each study included. See https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1000100#pmed-1000100-t003 for guidance. Thank you.

3. Please ensure that you refer to Figure 2 in your text as, if accepted, production will need this reference to link the reader to the figure.

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Additional Editor Comments (if provided):

This article aims to assess the magnitude of asymptomatic and pre-symptomatic COVID-19 cases which is essential and currently relevant for COVID-19 pandemic. Search terms may need to be refined to include as many as articles in the initial search. Will the authors consider to have pooled estimate stratified by age, setting such as hospital or community and study period to enrich the content. Also the exclusion criteria was not explicit mentioned. In terms of the language, authors are suggested to have substantial edit to arrive at the publishable quality.

[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: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: 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: No

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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: Background

- Severe Acute Respiratory Syndrome Corn babirusa 2, instead of Sever respiratory syndrome Coronavirus 2

- This systematic review and meta-analysis aims to determine the pooled magnitude of asymptomatic COVID-19 cases throughout the course of infection? What about total cases, pre-symptomatic cases? The course of infection or the course of outbreak?

Method

- Additional search terms: cases, incidence, proportion, incubation period, serial interval

- Systematic review does not only include observational studies

- Study setting: worldwide? At hospital? At community?

- Population: All age group? Please provide age range.

- Publication status: I would not include unpublished articles

- Exclusion criteria: Not clear. Please explain.

- Outcome variable and data extraction: Please provide more details on the “predestined data extraction form”. The 1st section: How to assess the methodological quality of each study? The 2nd section: How to evaluate the comparability of the study group? The 3rd section: How to assess the outcome and statistical analysis?

Results

- What about incubation period and serial interval?

- please explain how to perform sensitivity analysis

Reviewer #2: Assessing the magnitude of asymptomatic and pre-symptomatic COVID-19 cases is important and currently relevant for COVID-19 pandemic over social and economic impacts.

Authors have here taken up a systematic review and meta-analysis on asymptomatic and pre-symptomatic and claimed symptom-based screening might fail to identify all potential SARS-CoV-2 infections. Finally, authors suggested to scale-up mass testing and targeting high risk populations to tackle the pandemic.

I anticipate that authors will be further address the suggested issue, mentioned below to improve the manuscript and its understanding to a broad readership.

1. Page-3: “Up to date, there are more than 22 million total cases with 780,000 deaths, worldwide (3).”, “Up to date” is not a right phrase to use here. Provide specific date of extracting data instead. Also, suggest to revise it as the study reporting the digits from long back in July, 2020.

2. Page-3: “Studies vary depending on the number of study participants recruited, the type of design employed and the country in which the study conducted.”, The sentence is not clear enough. What is the meaning of “the number of study participants recruited”? Need to revise the sentence for clarity. Further authors used the terms “Studies vary”, but not clearly mentioned in what context.

3. Page-3: Continuation of point 2 above, author need to present the research potential and motivation of the such review study in this paragraph before mentioning the objectives. Though author has mentioned the combining the exiting finding might strengthen the evidence.

4. Page-4: “In addition, we searched from the reference lists of the included studies to identify any other studies that may have been missed by our search strategy.”, I fell such statement is redundant as it’s a part of the review when reviewers need to assess the main text along with the title and abstract.

5. Page-4: “Our search was performed between the 1st of June and the 15th of July, 2020.”, the review time window is much backdated. Possibly suggest to update the time window to catch more data.

6. Page-4: “Inclusion criteria”, the term ‘Design’ is not really referring the design of the reviewed studies, instead it’s the outcome variable for which the review is subject to. It preferably better of mentioning “Estimates/ Estimates reported” instead of “Design”? Else clarify.

7. Page-4: “Exclusion criteria” need to mention clearly. Current form is not conveying what author wanted to mention. Need more detailed criteria.

8. Page-4: “Two experienced authors (MA and LY) extracted all essential data from the included studies using a predesigned data extraction form.”, hope these two review author did the search independently. If yes, please mention it else no need to mention specifically in the text. Independent search one if the tools to ensure the reproducibility of the results.

9. Page-5: “In addition, 10 articles were removed due to not extractable result and the outcome of interest not reported.”, This 10 studies were excluded after assessing the related “Text” of the articles. Need to be clearly mention it, as mentioned similarly for “titles and abstracts”.

10. Page-6: Table 1, “Study period” is not mentioned clearly for some of the studies. Need to clearly have a note for this in the table. Wonder, is it due to the missing information in the text.

11. Page-7: Author presented the magnitudes of ‘asymptomatic’ COVID-19 cases, wonder if it is included the ‘pre-symptomatic’ cases as well. Need clarification. Accordingly, the title of the manuscript should be revised.

12. Page-9: “We also compared the proportion of asymptomatic SARS-CoV-2 infections with previously emerged coronavirus pandemics.”, I wonder whether the MERS was a Pandemic? Otherwise, better to be specific by using ‘pandemics/epidemics’ or just simply ‘outbreaks”.

13. Page-9-10: “The result of this study suggest that contact and symptom based screening might fail to identify all potential SARS-CoV-2 infections.”, Author clamed this without any discussion in the main text on it. I would prefer to illustrate this in the discussion section first with the results and then suggest in the conclusion. Conclusion should be related to the results, otherwise take-home massage will be weaker to the readers.

14. Page-9-10: “Scale-up mass testing, which targeting high risk populations is recommended to tackle the pandemic. Continuation of the above points, ‘mass testing’ and ‘testing of the target high risk group’ are two different things. Prefer to revise or rearrange the sentence here.

15. Many of the references were in preprint now published should be updated.

16. The references are not according to the PloS One specification (“Vancouver” style). Need to be updated.

17. Finally, I would suggest to the authors to give some effort in the presentation and language of the manuscript to avoid the redundancy of text and improve the language for general readers.

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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: 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.

PONE-D-20-28251R1

Magnitude of asymptomatic COVID-19 cases throughout the course of infection: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Addis,

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.

As suggested by the reviewer number 2, the authors are recommended to improve the language for general readers.

Please submit your revised manuscript by Mar 08 2021 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Kin On Kwok, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

[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: All comments have been addressed

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: Yes

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: 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 #1: Yes

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 #1: Yes

Reviewer #2: No

**********

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: (No Response)

Reviewer #2: Authors tried to revise the manuscript but unable to improve the manuscript adequately. I further suggest authors to make the text precise and continuous for readers’ interest. In fact, authors missed/ avoided some of the comments/suggestions to address, here I strongly suggest to take up these seriously and revise the text extensively. I added those in further comments below as “Comments/Suggestions on Response #xx in R1”.

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Reviewer#2

Comments/suggestions#1: Page-3: “Up to date, there are more than 22 million total cases with 780,000 deaths, worldwide.”, “Up to date” is not a right phrase to use here. Provide specific date of extracting data instead. Also, suggest to revise it as the study reporting the digits from long back in July, 2020.

Response #1: Dear reviewer, we thank you for your constructive comments and suggestions. The comments are very important to improve the manuscript. In the revised version of the manuscript, we provided the specific date with the current level COVID-19 cases and deaths.

Comments/Suggestions on Response #1 in R1: Response and revision acceptable.

Comments/suggestions#2: Page-3: “Studies vary depending on the number of study participants recruited, the type of design employed and the country in which the study conducted.” The sentence is not clear enough. What is the meaning of “the number of study participants recruited”? Need to revise the sentence for clarity. Further authors used the terms “Studies vary”, but not clearly mentioned in what context.

Response#2: Thank you. Yes, we learnt that the sentence needs revision, and we already revised it in the revised version of the manuscript. In other word “the number of study participants recruited” means the sample size for a particular study. In addition, we describe in detail that in what context study varies.

Comments/Suggestions on Response #2 in R1: Still text needs to be revised. Please simplify as “Studies vary depending on the number of participants recruited, the type of design employed and the country in which the study conducted.”

Comments/suggestions#3: Page-3: Continuation of point 2 above, author need to present the research potential and motivation of such review study in this paragraph before mentioning the objectives. Though author has mentioned the combining the exiting finding might strengthen the evidence. Response#3 Thank you. We try to explain further the potential and motivation of this study, in the revised form of the manuscript.

Comments/Suggestions on Response #3 in R1: I was expecting more on motivations here. Specially to indicate why authors took up this study.

Comments/suggestions#4: Page-4: “In addition, we searched from the reference lists of the included studies to identify any other studies that may have been missed by our search strategy.”, I fell such statement is redundant as it’s a part of the review when reviewers need to assess the main text along with the title and abstract.

Response#4: Thank you. We considered to revise it.

Comments/Suggestions on Response #4 in R1: What are the revision here? It was just a suggestion. If you want to keep the sentence, no problem, still make sense. But could not understand what revision has been made in this context as claimed by author in revised version?

Comments/suggestions#5: Page-4: “Our search was performed between the 1st of June and the 15th of July, 2020.” the review time window is much backdated. Possibly suggest to update the time window to catch more data.

Response#5: Thank you. We already updated the searching time.

Comments/Suggestions on Response #5 in R1: Response and revision acceptable.

Comments/suggestions#6: Page-4: “Inclusion criteria”, the term ‘Design’ is not really referring the design of the reviewed studies, instead it’s the outcome variable for which the review is subject to. It preferably better of mentioning “Estimates/ Estimates reported” instead of “Design”? Else clarify.

Response#6: Based on the suggestion given, we mentioned “Estimates reported” instead of “Design”.

Comments/Suggestions on Response #6 in R1: Response and revision acceptable.

Comments/suggestions#7: Page-4: “Exclusion criteria” need to mention clearly. Current form is not conveying what author wanted to mention. Need more detailed criteria.

Response#7: In the revised version of the manuscript, we provided clearly the exclusion criteria of this study.

Comments/Suggestions on Response #7 in R1: Still not clear. Authors should not use the subjective term ‘fully’ here. What did the authors mean by ‘fully’?

Comments/suggestions#8: Page-4: “Two experienced authors (MA and LY) extracted all essential data from the included studies using a predesigned data extraction form.” hope these two review author did the search independently. If yes, please mention it else no need to mention specifically in the text. Independent search one if the tools to ensure the reproducibility of the results.

Response#8: Thank you, we removed the name of the authors upon your suggestion.

Comments/Suggestions on Response #8 in R1: Not sure, whether I was able to convey the issue to the authors by the comment? Removing the authors’ names were not the suggestion. Here I wanted to know whether two authors had performed the data extraction from the studies included independently or not? Generally, in systematic review and metanalysis the two (or more) authors performed such data extraction independently to ensure the reproducibility. Further, how did the authors settled the mismatches? should be clearly mentioned in the text.

Comments/suggestions#9: Page-5: “In addition, 10 articles were removed due to not extractable result and the outcome of interest not reported.” This 10 studies were excluded after assessing the related “Text” of the articles. Need to be clearly mention it, as mentioned similarly for “titles and abstracts”. Response#9: In the revised manuscript, we explicitly mention the reason for excluding studies.

Comments/Suggestions on Response #6 in R1: Response and revision acceptable.

Comments/suggestions#10: Page-6: Table 1, “Study period” is not mentioned clearly for some of the studies. Need to clearly have a note for this in the table. Wonder, is it due to the missing information in the text.

Response#10: Thank you. Some original studies did not explicitly provided the study period (data collection period).

Comments/Suggestions on Response #10 in R1: Please mention these as a footnote. Indicate with notation ‘*’ in the table text and explain it in the table footnote.

Comments/suggestions#11: Page-7: Author presented the magnitudes of ‘asymptomatic’ COVID-19 cases, wonder if it is included the ‘pre-symptomatic’ cases as well. Need clarification. Accordingly, the title of the manuscript should be revised.

Response#11: Thank you. The outcome of interest (objective) of this study was to estimate the pooled magnitudes of asymptomatic COVID-19 cases throughout the course infection. We will come on that with another article.

Comments/Suggestions on Response #11 in R1: Response and revision acceptable.

Comments/suggestions#12: Page-9: “We also compared the proportion of asymptomatic SARS-CoV-2 infections with previously emerged coronavirus pandemics.” I wonder whether the MERS was a Pandemic. Otherwise, better to be specific by using ‘pandemics/epidemics’ or just simply ‘outbreaks”.

Response#12: Thank you. We restated it.

Comments/Suggestions on Response #12 in R1: Response and revision acceptable.

Comments/suggestions#13 Page-9-10: “The result of this study suggest that contact and symptom based screening might fail to identify all potential SARS-CoV-2 infections.” Author clamed this without any discussion in the main text on it. I would prefer to illustrate this in the discussion section first with the results and then suggest in the conclusion. Conclusion should be related to the results, otherwise take-home massage will be weaker to the readers.

Response#13: Thank you. We already revised it.

Comments/Suggestions on Response #13 in R1: Actually authors has removed the sentence. Response and revision acceptable.

Comments/suggestions#14: Page-9-10: “Scale-up mass testing, which targeting high risk populations is recommended to tackle the pandemic. Continuation of the above points, ‘mass testing’ and ‘testing of the target high risk group’ are two different things. Prefer to revise or rearrange the sentence here. Response#14: Thank you. We already revised it.

Comments/Suggestions on Response #14 in R1: Response and revision acceptable.

Comments/suggestions#15: Many of the references were in preprint now published should be updated. 16. The references are not according to the PloS One specification (“Vancouver” style). Need to be updated.

Response#15: Thank you. We already updated the references according to the PLOS ONE requirement.

Comments/Suggestions on Response #15 in R1: Response and revision acceptable.

Comments/suggestions#16: Finally, I would suggest to the authors to give some effort in the presentation and language of the manuscript to avoid the redundancy of text and improve the language for general readers.

Response#16: Thank you dear reviewer. We try to write the manuscript in acceptable quality of English language.

Comments/Suggestions on Response #16 in R1: Still the text need several improvement in English language, specially in terms of preciseness.

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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: Sheikh Taslim Ali

[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.

Magnitude of asymptomatic COVID-19 cases throughout the course of infection: a systematic review and meta-analysis

PONE-D-20-28251R2

Dear Dr. Addis,

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,

Kin On Kwok, Ph.D

Academic Editor

PLOS ONE