PONE-D-23-01793COVID-19 in Pakistan: A national analysis of five pandemic wavesPLOS ONE

Dear Dr. Khan,

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 address the reviewers' comments, especially their major concerns. In particular, your statement that seems to imply that vaccinations led to higher mortality needs to be changed. The risk of confounding bias in such study types needs to be highlighted which may have led to spurious findings which can occur even after adjustment due to residual confounding. ==============================

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Kind regards,

Huzaifa Ahmad Cheema

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

Reviewer #4: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

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 is a nation-wide review of the first five waves of COVID-19 in Pakistan. Although much has been written about COVID-19, nation-wide data from an under-resourced setting are lacking, thus this manuscript is a valuable additional to the medical literature. It offers a fairly comprehensive review of the epidemiology of these waves in Pakistan, covering a number of important and interesting variables. The manuscript is well written, completed an appropriate analysis, and is well-cited. Although I rarely make this determination in reviewing manuscripts for the first time, I believe it is ready to accept for publication as it currently stands. My congratulations to the authors on their excellent work.

Reviewer #2: This is an interesting manuscript on a timely subject, which brings valuable information and evidence on the COVID-19 pandemic.

The main observation concerns the objectives of this analysis: they should be clearly and unambiguously stated. The conclusions should state whether (and how) they were met.

Major observations:

(1) Page 6, line 128: the manuscript comprises statistical analysis and inferences.

(2) Page 5 and page 7 -- lists of themes and independent variables in the regression model, respectively: the presumed connection between the two lists needs to be revised and clarified; if there is no connection, the lists should nevertheless be revised for more clarity and meaningfulness (namely, remove all ambiguity).

(3) Page 8, line 162: Statistical(!) tests were performed to insure that the required assumptions for the regression model were met.

When revising, please also consider the following:

(A) Page 5, line 93: double-check the reference to Table 1.

(B) Page 6, Model specification: the model itself should be independent of the statistical package employed to analyze the data; I would kindly suggest specifying the statistical package at the end of the section.

(C) Page 6, line 132 (equation): t must be detailed/explained; equation should also have a number.

(D) Pages 13-14, Table 3: the outcome/dependent variable(s) must be clearly stated, together with the number of data records; a landscape layout should be considered, as well. I also recommend having a more informative caption: the explicit/unambiguous connection with the regression model.

Additional comments:

(a) Page 3 – Introduction: the citations and references' numbering is incorrect; please revise.

(b) Table S1 – length of hospital stay: the terms "hospital admissions" and "new hospital admissions" are confusing. "Hospital admissions" seems to refer to the number of hospitalized patients at a given time. Please revise the definition and remove any ambiguity.

(c) Page 3, line 51: please revise the SARS-CoV-2 strains, namely the Alpha strain notation) and also revise the tables that include the notation.

(d) Page 8, Table 3: the connection with the regression model's predictors should be explicit (for example by adding an additional column).

(e) Pages 9-12, Table 2: the table is very long and confusing due to the lack of horizontal lines. Authors might consider splitting into meaningful separate tables with landscape layout.

(f) Authors should use a consistent notation of the pandemic waves throughout the manuscript (for example, choose one of "wave 3" or "third wave").

(g) Please double-check all specifications of confidence intervals throughout the manuscript (an example of faulty notation is on page 13, line 225).

Reviewer #3: Well scientific written manuscript. Need to address following few questions

1. describe little bit about specific criteria in abstract method

2. The rationale and justification for this article must be incorporated

3. Please mention impact of study

4. Provincial specific cultural and social, religious, education status, social mobalization, public compliance, administrative, infrastructural (etc) factors must be considered for NPI. Did these factors may have played a role as confounder.

Reviewer #4: The article under review provides a comprehensive overview of the key parameters associated with five waves of COVID-19 in Pakistan. The paper presents pertinent information and employs statistical methodology. While the manuscript is well-structured overall, I have a few points of feedback to share.

1. Regarding the statement in the summary, "A one percent increase in vaccinations increased daily new COVID-19 deaths by 0.10% (95% CI: 0.01, 0.20)," it is essential to clarify the source of this data, since it is not clear in the text or in the tables. The current phrasing might inadvertently imply a causal relationship between vaccination and an increase in daily deaths. It is crucial to revise this sentence to avoid the misunderstanding that vaccination directly led to higher mortality. Although the data allows for different interpretations, a clear causal link cannot be established solely from these numbers.

2. Consider incorporating a comparative analysis between the official death data examined in your study and the excess mortality data. This comparison is pertinent since the cumulative death count over the five waves appears to be considerably lower than the excess mortality figures reported in early 2022 (https://doi.org/10.1016/S0140-6736(21)02796-3). Additionally, the insights provided in this article could benefit from a cross-reference to related research, as indicated by this source: https://doi.org/10.1038/s41586-022-05522-2.

3. Enhance the clarity of the visual representation by marking the initiation and conclusion of each wave within the figure 1. To provide a more comprehensive perspective, it would be valuable to disaggregate the data by gender, including both cases and fatalities. Furthermore, it could be beneficial to highlight the time points at which vaccination initiatives were introduced.

4. Concerning Table 3, the significance of the asterisk accompanying all values of LOG (Daily New COVID-19 Cases) – 21-day delay) requires clarification. Please elucidate the purpose of these asterisks to aid the reader's understanding of the presented data.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Ehsan Ahmed Larik

Reviewer #4: No

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Attachments

Attachment

Submitted filename: PONE-D-23-01793_reviewer.pdf

COVID-19 in Pakistan: A national analysis of five pandemic waves

PONE-D-23-01793R1

Dear Dr. Khan,

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,

Huzaifa Ahmad Cheema

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have satisfactorily addressed the revisions.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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 #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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 #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 #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 #2: The Authors have carefully addressed all the issues raised by the reviewers and the manuscript has been substantially improved. It will certainly convey the intended comprehensive analysis and will also bring a valuable insight into the COVID-19 related mortality in Pakistan, a country from the South Asian region for which there is still little evidence regarding the pandemic.

I would kindly make two recommendations to further improve the quality:

(a) a professional scientific proofreading would help addressing the few language issues still present in the manuscript;

(b) to improve the readability of Table 2 (page 10), Authors might consider either adding % when numbers in parentheses are percentages (rather than standard deviation values) or expressing the statistics related to the numerical variables as mean(i.e., average) +/- standard deviation.

Reviewer #3: All comments have been addressed. A much better revised article submitted. No specific advise. The article is clear, correct, and unambiguous.

Reviewer #4: The authors have implemented the majority of the suggested revisions provided by the reviewers. The manuscript has improved clarity.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: Yes: Dr. Ehsan Ahmed Larik

Reviewer #4: No

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