PONE-D-21-23252

Regional and demographic variations of Carotid artery Intima and Media Thickness (CIMT): A systemic review and meta-analysis.

PLOS ONE

Dear Dr. Abeysuriya,

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Reviewers' comments:

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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: Partly

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

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

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Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: 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: In this manuscript Abeysuriya et al. present a meta-analysis on systematic search regional and demographic variations of carotid artery intima and media thickness. In a first step, the authors screened PubMed, Oxford Medicine Online, EBSCO, Taylor & Francis, Oxford University Press and Embase databases (with a supplementary search in Web of Science and Google Scholar) for eligible on carotrid artery intima and media thickness published between January 1980 January up to December 2020. Subsequently, meta-analyses were done using random-effects models.

Of 2847 potential articles, 46 eligible articles were included in the review contributing data for 49 381 individuals. The authors report a significant difference in the mean CIMT between regions, with countries in the African, American and European regions had a higher pooled mean CIMT compared to those in the Southeast Asian, Western Pacific and Eastern Mediterranean regions. Males appeared to have a higher pooled mean CIMT than females in the non-CHD group. The CHD group had a significantly higher mean CIMT than the non-CHD group. Age and region were significant predictors of CIMT among the non-CHD group.

This manuscript presents interesting data, however, several questions remain:

Major comments:

1. Section “Method and analysis”, paragraph “Study selection“: According to this paragraph, titles and abstracts of the search results were screened against pre-specified criteria by two independent reviewers for study selection. Please add a description of the pre-specified criteria for study selection to the text.

2. Section “Method and analysis”, paragraph “Study quality”: The quality of selected studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. It is important to assess the quality of reports in a consistent manner with other studies. The CONSORT statement and the STROBE statement represent 2 of the most widely accepted and used guidelines for accurate reporting and transparency. Therefore, it is recommended to additionally assess the quality of reports in reference to the CONSORT statement and the STROBE statement prior to including them in the analysis.

3. Section “Method and analysis”, paragraph “Steps of Meta-analyses”: The meta-analyses were performed using random-effects models. Which model was used? Was the model based on inverse variance-weighted average method or weighted sum of z-scores?

4. Section “Method and analysis”, paragraph “Steps of Meta-analyses”: Due to the comparison of highly heterogeneous populations in different WHO regions with very divers individual risk profiles, there is a high chance of confounding. With regard to the extracted CIMT estimates, how did the model of the authors account for the risk of residual confounding? Were the estimates extracted from the primary studies confounder-adjusted or unadjusted data? The extraction process should be clarified. In addition, comparisons of adjusted and crude estimates allow insights into the importance of confounding. To reliably detect independent regional differences as well as potential influencing variables, the random-effects model should be adjusted for all known risk factors for cardiovascular disease, if possible from the data set.

5. Section “Method and analysis”, paragraph “Assessment of heterogeneity of studies”: In addition to the QUADAS-2 criteria, the Newcastle-Ottawa Scale should be applied to minimize risk of bias.

6. Section “Results”: What was the percentage of included subjects from grey literature and from published literature? What proportion of the total number of included patients is derived from each of the databases as a source? These numbers should be added to the results section as well as to the flow diagram in “Figure 1”.

7. Section “Discussion”: The discussion is mainly descriptive with an extended presentation of the results of the meta-analysis and its underlying primary studies. A reflection of possible underlying factors and differential population characteristics of the respective WHO regions would contribute to strengthen the discussion. Furthermore, general text flow and readability of the discussion should be significantly improved.

Minor comments:

1. Section “Abstract”: The search strategy is not clearly described in the abstract. Therefore, adding a summarized description of the search strategy is recommended.

2. Section “Method and analysis”, paragraph “Search strategy”: The search strategy for PubMed should be specified in the text section of the search strategy paragraph. The separate box displaying the paragraph should be removed from the main manuscript.

3. Section “Method and analysis”, paragraph “:Data extraction”: For articles based on the same population, the authors state that the ‘more comprehensive one’ was selected. Please add a precised description of the data extraction criteria.

4. Section “Results”, “Table 3” and “Table 4”: “Table 3” and “Table 4” show mean CIMT values of different carotid segments by WHO region among patients with and without CHD. To provide a more focused illustration of the results, the content of “Table 3” and “Table 4” should be summarized in a single table.

5. Section “Results”: The text flow in the sections results is partially very tough. Therefore, it should be revised to ensure a more fluid presentation of the results.

Reviewer #2: Comments to the authors:

The authors present a systematic review and meta-analysis of differences of carotid intima media thickness (CIMT) in various regions around the globe, based on the WHO definition of regions. Analysis and pooling data of 49 381 patients showed a difference in CIMT between African, American and European population versus Southeast Asian, Western Pacific and Eastern Mediterranean. The authors found significant regional differences of mean CIMT between CHD and non-CHD groups. The authors conclude that CIMT varies according to region, age and sex among the non-CHD group and that there are significant regional differences of mean CIMT between CHD and non-CHD groups. The authors also state that there is a need to develop country-specific CIMT cutoff values to screen at-risk populations for CHD. The following points arose to the reviewers eyes when reading the manuscript:

Major comments:

- Regarding the conclusion, that there is a need to establish country specific CIMT cutoff values, I find it difficult to state this in light of the presented data. For my understanding in this study, differences between countries have not been investigated (since the results are based on WHO regions). As the authors also state in the discussion, there are many factors that affect CIMT, and there are known regional differences in the prevalence of those risk factors (e.g. BMI, hypertension, diabetes). Since reference values are based on studies on a healthy population, it would be interesting to look at geographical differences in comparing healthy cohorts. Is there a possibility to address this? Otherwise I would recommend to rewrite this part of the conclusion.

- Ethnical aspects: It is known that in regards to cardio- and cerebrovascular disease the ethnical background plays a detrimental role. The presented study seems to calculate the values of patients from countries, but irrespective of their ethnicity. Is there also a possibility to analyze the impact of the ethnical background?

- Geographical aspects: There is also a different burden of cardiovascular and cerebrovascular diseases within one WHO region, e.g. Northern Europe versus southern Europe. Some regions also seem to be underrepresented. Authors tried to apply statistical methods relativize this fact and they also comment this in the study limitations section, that WHO classification is also partly based on political aspects as well. Would it not be clinically more reasonable to compare trials of comparable quality using a classification that is only based on geographical aspects (even taking into account not to cover the whole globe)?

- Time span: Authors have reviewed and compared data on CIMT in the time span from 1980 to 2020. Within 40 years, the spatial resolution of ultrasound systems has revolutionized and is still becoming more precise, and therefore the measurements of vessels and their segments are not entirely comparable. Furthermore, there are significant differences in measuring the CIMT manually and automatically. Further factors that have changed over the decades are methodical quality of trials, the quality of trial performance, and the presence of trial audits are not respected in the study and are very likely to influence the outcome. Would it be possible to analyze only studies with a similar technological standard? This would improve the value of this study, since it would minimize bias due to technical and methodical differences.

- The statistical methods seem to be sufficient.

- Search strategy seems to be representative according to selected keywords, but the heterogeneity of population and patients with co-morbidity is not reflected.

Minor Comments:

Line 59: word „diseases“ is missing.

Line 64: The sentence starting with “The current COVID-19 pandemic…” is not relevant to the presented review and I would suggest to delete it.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-23252R1Regional and demographic variations of Carotid artery Intima and Media Thickness (CIMT): A systemic review and meta-analysis.PLOS ONE

Dear Dr. Abeysuriya,

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 Jun 02 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,

Andreas Zirlik, MD

Academic Editor

PLOS ONE

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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: (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

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

Reviewer #1: Yes

Reviewer #2: 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 #1: (No Response)

Reviewer #2: 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: Yes

Reviewer #2: 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: Overall the authors were responsive to the previous comments of these reviewers and the manuscript improved subsequently. Crucial aspects were appropriately addressed by the authors’ reply. However in the eyes of this reviewer, some points remain to be clarified:

Major comments?

1. Section “Discussion”: How do the authors interpret the value of these findings? Because of the descriptive background of this analysis and the different adjustment for different risk factors regarding the included studies, it is indeed difficult to demonstrate an incremental value of the participant’s geographical region/country. Therefore, as already indicated by reviewer 2, the topic should be considered very cautiously in the discussion. Statements on causal relationships and incremental value of the variable region for risk prediction should therefore be avoided. Adapt more defensive wording regarding this relationship.

Minor comments:

1. Section “Results”, Table 1: “Summary of studies used in systematic review and meta-analysis, reporting demography: As requested, the authors added further information on the adjustment of the studies included in the analyses. However, the mention of "factors adjusted for" and "adjusted predictors of CIMT" seems repetitive. Therefore, the column "Adjusted predictors of CIMT" should be removed since all relevant information is already listed in the column "Factors adjusted for."

2. Section “Method and analysis”: Grammar and spelling of the newly added text parts should be revised.

3. Section “Results”: Since the included studies and corresponding details are already listed in Table 1, there is no need to cite the respective studies again separately in the results section.

Reviewer #2: Most of the concerns mentioned in the first review of the manuscript were addressed. Nonetheless there are still minor comments regarding the rewritten conclusion of the authors:

The conclusion, that region or country specific CIMT values are important when developing risk assessment tools to screen at-risk population of CHD is not supported by the data presented, since in this study only differences in CIMT between WHO regions were examined and not their impact to a certain CV risk and significant confounding is possible. CIMT in fact may be important in the risk assessment, but the presented data do not fully validate the role of CIMT differences between WHO regions regarding CV risk. Furthermore, in my opinion the conclusion that CHD is a predictor for CIMT is clinically not sound. As for my understanding, the presented data show a clear association between CHD and CIMT and not necessarily that the presence of CHD predicts CIMT values.

Therefore, I would recommend to precise the conclusion according to the presented data which may help to improve the quality of the manuscript.

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

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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.]

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Regional and demographic variations of Carotid artery Intima and Media Thickness (CIMT): A systemic review and meta-analysis.

PONE-D-21-23252R2

Dear Dr. Abeysuriya,

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.

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Kind regards,

Andreas Zirlik, MD

Academic Editor

PLOS ONE

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Reviewers' comments: