COVID-19-Related Age Profiles for SARS-CoV-2 Variants in England and Wales and States of the USA (2020 to 2022): Impact on All-Cause Mortality
Round 1
Reviewer 1 Report (Previous Reviewer 2)
This article studies the effect of SARS-CoV-2 infection on all cause of mortality as a function for example of age, gender and covid variants.
The analysis is based on the data provided by the Office for National Statistics (ONS) for England and Wales. The studies of mortality versus age are also performed on data from different American states provided by the US Center for disease Control.
However, we find the analysis inadequate to support the authors’ conclusions.
The analysis is based on the death rates recorded in the pre-Covid year 2019 compared to the death rates during the Covid. The description of the methodology used to extract the excess of deaths from an assumed average baseline is not clear. A crucial point of the analysis is to define precisely the pre-Covid baseline for mortality, but the method used by the authors is questionable since they exploit only the year 2019, rather than to extend it to a larger period (>5 years) in order to better evaluate fluctuations. Moreover the authors apply some corrections to the data which are not supported by any scientific evidence, making impossible to judge the reliability of the results.
All the plots reported in the paper are missing error bars and nowhere is discussed the statistical significance of the results. It’s impossible to draw conclusions from the reported data in the absence of any quantitative statistical analysis
For the above-mentioned reasons, I don’t consider the paper eligible for publication in this journal.
The English language is approximate and in some cases makes it difficult for the reader to understand the text
Author Response
Dear Reviewer,
Many thanks for your valued time and input into this manuscript.
Can we firstly note that there appears to be a bizarre software glitch between the MDPI template and Microsoft word which occurs when the document is opened on different computers. Random Chinese characters will sometimes appear in the Figures, the text will sometimes be altered, punctuation can go missing and spaces between words can dissapear. This is not the first time we have encountered such problems. Some of the annoying features noted appear to fall into this category and simply were not present in the submitted draft.
Your specific points. All changes in red text.
The base year. The years 2011 to 2019 were used to establish the 2019 base year. The description of the method has been changed to ensure that this is clear to all readers. Statistical issue are covered in depth in the Supplementary material S4 and also in S2.
The section covering the limitations of the study has been expanded.
English language has been edited as requested.
The absence of 95% confidence intervals. This is already a very data-rich paper and it was our opinion when submitting the paper that adding 95% confidence intervals would only add considerable distracting clutter to the figures. May we note that the other two reviewers did not request 95% CIs. Hence, we request that the Figures remain as they are. As mentioned there is ample statistical analysis in S2 and S4.
Corrections not supported by scientific evidence. It would be helpful if you could specifically define why certain corrections are not supported by scientific evidence.
Reviewer 2 Report (Previous Reviewer 3)
Manuscript ID : idr-2399682
Title: Age profiles for SARS-CoV-2 variants in England and Wales and states of the USA (2020 to 2022): impact on all-cause mortality.
Authors: Rodney P Jones * , Andrey Ponomarenko
Jones and Ponomarenko present their analysis on the effects of age and sex upon all-cause mortality during 2020 and 2021 in England and Wales. This manuscript presents that “each SARS-CoV-2 variant has an intrinsic year of age profile relating to death, which is then modified by population characteristics such as the gender, proportion of persons at each age with high occupational, clinical, or genetic risk”.
Overall, this is an interesting manuscript, and the research and interpretation are adequate. The manuscript provides valuable information regarding the observed age profile related to death for the SARS-C0V-2 variants in England and Wales.
However, the Reviewer found a few issues in the manuscript and would like to see them addressed by the Authors before this manuscript is ready to be considered for publication.
Specific comments and suggestions:
INTRODUCTION
Line 51 to 52: “Influenza and SARS-CoV-2 are both examples of the class of RNA viruses showing 51 high mutation rates [8-12].” Please, delete this sentence or move elsewhere (sounds out of place).
Line 55 to 58: “Research in the USA suggests that COVID–19 deaths may have started in early January 2020 [15]”. Please, delete one of these repeated sentences.
RESULTS
Line 517: “Puerto Rico (which in more recent times has become a US state).”. Factual correction. Puerto Rico is not a state of the United States of America, it is a territory and has been so since 1898 when it was ceded by Spain to the United States at the end of the Spanish-American War. Statehood has not been granted. Please make the appropriate correction.
Line 560 to 561: “DiscussionThese results confirm the profiles for age, gender and variant seen in the 560 USA in Figure 6. “ Please fix sentence. Remove the word “Discussion”.
DISCUSSION
Line 729 to 731: “Hence previous (usually in childhood – called a birth cohort) exposure to one clade will generally invoke a response to the first clade when exposed to an antigenically different one.”. Please, revise this sentence, the use of “hence” makes the sentence sound incomplete. Please verify this paragraph for clarity and conciseness.
Line 732: “cause the ‘wrong’ antigen is produced.” Did you mean “antibody”?
Line 734: “been trained and the time taken in the training process can be avoided resulting in a much”. Please, eliminate for conciseness.
Line 762 to 768: Please revise these paragraphs for clarity and conciseness.
Line 859 to 894: Please, delete these sentences which are repeated from elsewhere in the text.
PLEASE DISCUSS THOROUGHLY THE LIMITATIONS OF THE STUDY.
REFERENCES
Revise numbering of references both in this section and text. Verify numbers are concordant with the text.
This manuscript was not properly revised before submitting and in certain parts looks more like a draft. Please, delete repeated parts and loose sentences and revise for typos, misplaced numbers and headings. Also, revise for conciseness and clarity.
Author Response
Dear Reviewer,
Many thanks for your valued time and input into this manuscript.
Can we firstly note that there appears to be a bizarre software glitch between the MDPI template and Microsoft word which occurs when the document is opened on different computers. Random Chinese characters will sometimes appear in the Figures, the text will sometimes be altered, punctuation can go missing and spaces between words can dissapear. This is not the first time we have encountered such problems. We have checked and the issues do not arise with ordinary word documents, only when the content is added into the template. Some of the annoying features noted appear to fall into this category and simply were not present in the submitted draft.
Your specific points.
Line 51-52. Moved to end of previous paragraph with additional explanation.
Line 55-58. Cannot find a repeated sentence. Is it still there?
Line 517. To explain, in January 2011 data for Puerto Rico suddenly appeared in the CDC monthly deaths for US states tabulation. We innocently/ignorantly assumed that Puerto Rico had become a US state. This has been corrected.
Line 560-561. Word 'Discussion' was not in the submitted manuscript. Is it still there?
Line 729-731. Word 'Hence' changed to 'The' for clarity.
Line 732. Word 'antigen' has been changed to 'antibody'.
Line 734. Wording changed
Lines 762-768. Changed as requested
Lines 859-894. Words 'As noted earlier' added for clarity.
Limitations section. Has been revised and expanded as requested.
Please note that while we believe that bthe reference numbering is correct, the reference numbering is further checked during the MDPI editing process.
Grammar, etc. The document has been checked.
Once again, many thanks.
Reviewer 3 Report (Previous Reviewer 5)
Line 56- Check the punctuation. There are some unnecessary symbols.
Line 360- Check the sentence. It sounds unclear.
Line 560- Chech this sentence. It starts. very unclear: "DiscussionThese results confirm the profiles for age, gender and variant seen in the 560 USA in Figure 6."
Lines 870- 891- The shift is different. Check it.
Line 891. This sentence is unfinished. "Puberty and excess female deaths remains an ."
Limitations of the study should be discussed in different paragraph and more detailed as well.
Please provide an English editing certificate. You can use MDPI English editing service. This will improve the quality of the manuscript.
Please provide an English editing certificate. You can use MDPI English editing service. This will improve the quality of the manuscript.
Author Response
Dear Reviewer,
Many thanks for your valued time and input into this manuscript.
Can we firstly note that there appears to be a bizarre software glitch between the MDPI template and Microsoft word which occurs when the document is opened on different computers. Random Chinese characters will sometimes appear in the Figures, the text will sometimes be altered, punctuation can go missing and spaces between words can dissapear. This is not the first time we have encountered such problems. Some of the annoying features noted appear to fall into this category and simply were not present in the submitted draft - at least viewed at our end.
Your specific points.
Line 56: Punctuation ammended
Line 360: Sentence changed for clarity.
Line 560. Discussion and 560 were not in the submitted manuscript. Are they still there?
Lines 870-891. Shift has be checked.
Line 891. Cannot find the unfinished sentence. Is it still there?
Limitations of the study have been revised and expanded as requested.
Punctuation, etc of the manuscript have been edited.
Round 2
Reviewer 2 Report (Previous Reviewer 3)
Manuscript ID: idr-2399682
Title: Title: COVID-related age profiles for SARS-CoV-2 variants in England and Wales and states of the USA (2020 to 2022): impact on all-cause mortality
Authors: Rodney P Jones *, Andrey Ponomarenko
Jones and Ponomarenko present their analysis on the effects of age and sex upon all-cause mortality during 2020 and 2021 in England and Wales. This manuscript presents that for England unvaccinated individuals have an age profile for death for each variant and that vaccination alters the shape of the age profile dependent on age, sex, and virus variant.
The Reviewer thanks the Authors for thoroughly responding to our comments and critiques. The Reviewer finds that these have been addressed satisfactorily and therefore finds the present manuscript to be considered for possible publication.
Minor editing of English language may be required.
Author Response
Thank you for your time and input and decision that the paper progress to publication.
Reviewer 3 Report (Previous Reviewer 5)
Dear authors,
the manuscript must be revised.
I have seen many spelling and grammar mistakes. The English language and style must be edited.
For example: Line 9 "we use a 9-year time series and alternative methods to a"- This sentence is not grammatically written and it does not sound well.
You did not answered to my previous remarks.
The manuscript needs English language editing. I have seen many spelling and grammar mistakes.
Author Response
Dear authors,
the manuscript must be revised.
I have seen many spelling and grammar mistakes. The English language and style must be edited.
The document has been through Microsoft spell check and grammar check. As you will be aware the English language is highly nuanced and different people can say the same thing in multiple ways. Having published over 300 papers this is the first time anyone has suggested that English language and style must be edited.
As an academic editor for several journals, I tend to make allowance for different authors to express themselves using alternative writing styles.
For example: Line 9 "we use a 9-year time series and alternative methods to a"- This sentence is not grammatically written and it does not sound well.
Yes, this line had been troubling me. Line 9 has been altered to an easier to understand sentence.
You did not answered to my previous remarks.
We did address your technical remarks and also proofread the manuscript.
There appears to be an obscure bug on my computer (RPJ) which seems to allow persons using different computers to see different versions of the editing history. Hopefully any residual issues will be picked up during the final proofing stage.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
Peer review regarding "Roles for age, gender, vaccination history and SARS-CoV-2 variants in all-cause mortality: unexpected outcomes in a complex system"
I have read this article with great interest. The authors aimed to evaluate the effect of age, gender, COVID-19 vaccination, and SARS-CoV-2 variant on all-cause mortality during COVID-19 period using multi-national level single-year-of-age data. The purpose of the study was presented in the abstract and the title of the article corresponded to its most content.
While the authors have made good work for this research, there are several serious concerns.
1. Introduction: The authors provide a comprehensive landscape of literature related to the topic. However, there are several paragraphs that might not be relevant to the research questions and contents in the main text. For example, Line 53–61, the authors mentioned on how influenza and other vaccines affect all-cause mortality which is not relevant to most parts of the study. This might dilute the more important information and main message the authors want to deliver to readers. Please consider making the introduction part more concise and relevant.
2. Introduction: Last paragraph of the introduction (Line 104–114) explains how the authors use a who-when-where framework to interpret the unusual outcomes of COVID–19 vaccination. This might raise a major concern of selective reporting bias for readers as this infers that the authors might select analytical and interpretation methods post-hoc.
3. Methods: While there are extensive efforts to specify the data and population, there is a lack of statistical analysis methodology explained in the methods. Without pre-specified statistical analysis methods, the readers might be concerned about the validity and reproducibility of the results.
4. Methods: Some parts of the method secticontain introduction, rationales, opinions, and results which should reported elsewhere. For example, section 2.2 has elaborated rationale why the authors had to estimate the SYOA population in 2021, opinions on the estimation and methods, and followed by results.
5. Methods: Line 128: The authors mentioned performing methods described in section 2.2 on 2011–2020 while also mentioned that estimation based on 2020 population data and 2021 deaths yield good estimates. This might confuse the readers on which model the authors use and also why the authors end up performing this method between 2011–2020 under the light that only missing data was for 2021.
6. Results: There are several results based on the analyses that were not mentioned in the Methods. For example, section 3.1 explored the effect of MAUP, the World War 2 baby boom, and the distribution of death which did not mention in Methods. Another example is Figure 3 where the authors deploy third-order polynomial to create the trend line which was not mentioned before. The authors should explicitly state the methods on how they analyzed data for the results section.
7. Results: Some figures have overlapping plots and text which are difficult to read and understand. For example, Figure 2.
8. Results: Some figures contain non-English language which might not be understandable for all readers. For example, Figure 10.
9. Discussion: The discussion is unnecessarily long. The authors might consider making it more concise.
10. Conclusion: The conclusion is one-page long and needs to be shortened.
Reviewer 2 Report
This article tries to describe the effect of vaccination against the SARS-CoV-2 disease as a function of age, gender, vaccination history, with a rather detailed accompanying bibliography.
The analysis is based on the data provided by the Office for National Statistics (ONS) for England and Wales with the goal to evaluate the vaccination effectiveness against SARS-CoV-2 as a function of many different variables like the variants of the virus, the age, the gender etc..
However, we find the analysis inadequate to support the authors’ conclusions.
Most of the information in the paper comes from a subtraction of the death rates recorded in the pre-Covid years to the death rates during the Covid. The procedure is delineated in Section 2.3, but no quantitative information or plots are provided to support the final results. Some features of the death rate trends are just evaluated by “visual inspection” (beginning of page 4) which certainly is not a robust statistical method to extract features from scientific data. The methodology used in Section 2.3 is not expected to provide accurate predictions, as often discussed in the literature (see for instance Henry et al., Sci Rep 12, 1077 (2022)). The authors do not seem aware of these issues and do not discuss the limitations of this procedure in the article.
All the plots reported in the paper are missing error bars and nowhere is discussed the statistical significance of the presumed excesses or deficits of death rates. It’s impossible to draw conclusions from the reported data in the absence of any quantitative statistical analysis of the data.
The very long Section 4 “Discussion” is not based on the reported data but it's rather a discussion of the results reported in other studies in bibliography.
For the above-mentioned reasons, I don’t consider the paper eligible for publication in this journal.
Reviewer 3 Report
Manuscript ID: idr-2063589
Title: Roles for age, gender, vaccination history and COVID–19 variants in all-cause mortality: unexpected outcomes in a complex system
Authors: Rodney P Jones, Andrey Ponomarenko
Jones and Ponomarenko present their analysis on the adverse outcomes due to non-specific effects of the COVID vaccine measured by evaluating the change in all-cause mortality (ACM). The ACM rate at monthly intervals and the SYOA data from January 2021 to May 2022 from England and Wales was obtained from the Office for National Statistics. In this study, the Authors question the ability of COVID vaccine to reduce ACM for all groups and that in the necessity to develop and implement the vaccines adverse events may have been overlooked. The study confirms vaccination of the elderly population was successful however, poor ACM outcomes were observed for persons under 40 years. The Authors recommend long term surveillance of all-cause disease outcomes after COVID–19 vaccination and reconsidering vaccination for children and healthy people under 40 years due to higher risks than possible benefit from the vaccine.
Overall, this is an interesting manuscript, and the research and interpretation are adequate. The manuscript provides valuable information regarding the observed adverse outcomes due to non-specific effects of the COVID vaccine noting an increase in all-cause deaths for children and people under 40 years.
However, the Reviewer found a few issues in the manuscript and would like to see them addressed by the Authors before this manuscript is ready for publication.
Specific comments and suggestions:
A. RESULTS
LINE 284: Please remove extra “that”.
LINE 285: “above which the gap (dashed line)”. Please check, there is no dashed line in Figure 6.
LINE 323: “Hence if we were to take the 1000 all-cause deaths per 100 000 person years as the vaccine cutoff point for healthy individuals” . Is this an arbitrarily chosen number to fit? Because then, if 500 were to be taken as cutoff point, then vaccination would be indicated for all individuals over 18 years. Please explain the reason for selecting this cutoff point.
LINE 327-328: “In the seemingly politically driven rush to vaccinate the entire adult population, the very low likelihood of death in unvaccinated younger adults was completely overlooked.”. Certainly, the Authors are entitled to their opinion to ascribe political intentions on a vaccination campaign intended to prevent death due to COVID-19. However, this being a scientific manuscript and not an editorial, it would be best to tone down and maintain a factual tone “there was a rush”. Whether or not there were political reasons or agendas, just let your results speak in favor of your point of view.
LINE 375-376: “Persons who received only the first dose of the vaccine at greater than 21 days ago experience higher mortality than the unvaccinated in more than 70% of months.” This statement may be based on the numbers, but the higher mortality observed cannot be attributed purely to the vaccine. There are other factors which may be involved. What about behavior? Those individuals with one dose may have felt already protected and therefore engaged in behaviors that exposed them to infection while the unvaccinated may have kept in lockdown. What about the factor of treatment or clinical management that was available at the time? It is more complicated than just numbers!
LINE 452: “that some of the alarmingly poor outcomes”. Please keep the tone objective and removed from your own emotions or judgement (it is not an opinion piece). This can be changed to something more on the lines of “the exceedingly poor outcome” or “remarkably poor outcome”, etc.
B. DISCUSSION
LINE 760: “(vsiRNAs) in immunized plants”. Why are plants relevant in the context of this manuscript? Please provide an explanation for this.
LINE 819: “which could arise from racial differences in the frequency of risk genes”. Please, change “from racial differences” to “from population differences in the frequency of risk genes” or “from geographical differences in the frequency of risk genes”. Race is not a biological attribute but a social construct.
Thank you kindly
Reviewer 4 Report
Mentioning the nationality of delta variant is unnecessary and I think it needs to be avoided.
Reviewer 5 Report
Dear authors,the topic of your work is current and interesting.
However, I have noticed some paragraphs which need to be corrected:
1. The font is different at page 1 and page 2. Please check the "Instructions for Authors" of the journal.
2. Please describe better Figure 1. in the text.
3. Page 15, line 544- missing punctuation.
4. The conclusion could be improved.
For example this sentence does not sound good: "There is no such thing as ‘perfect’ protection only a balance between the risks and 1359 rewards, which this study demonstrates are far more complex than has been appreciated."
Something more, do not include references in the conclusion.
