PNTD-D-25-00509

Socioeconomic risk markers of dengue mortality in the 100 Million Brazilian Cohort (2007-2018): A nationwide registry-based cohort study

PLOS Neglected Tropical Diseases

Dear Dr. Cardim,

Thank you for submitting your manuscript to PLOS Neglected Tropical Diseases. After careful consideration, we feel that it has merit but does not fully meet PLOS Neglected Tropical Diseases'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 within 60 days, August 10, 2025. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosntds@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pntd/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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If you would like to make changes to your financial disclosure, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Md. Kamrujjaman, Ph.D

Academic Editor

PLOS Neglected Tropical Diseases

Qu Cheng

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

Comments to the Authors:

Please note that one of the reviews is uploaded as an attachment.

Journal Requirements:

1) Please ensure that the CRediT author contributions listed for every co-author are completed accurately and in full.

At this stage, the following Authors/Authors require contributions: Luciana Lobato Cardim, Maria da Glória Teixeira, Maria da Conceição N. Costa, Wema Meranda Mitka, Camila Silveira Silva Teixeira, Andreia C. Santos, Gervasio Santos, André Portela Fernandes de Souza, Liam Smeeth, Mauricio L. Barreto, Elizabeth B. Brickley, Enny S. Paixão, and Julia M. Pescarini. Please ensure that the full contributions of each author are acknowledged in the "Add/Edit/Remove Authors" section of our submission form.

The list of CRediT author contributions may be found here: https://journals.plos.org/plosntds/s/authorship#loc-author-contributions

2) We have noticed that you have uploaded Supporting Information files, but you have not included a list of legends. Please add a full list of legends for your Supporting Information files after the references list.

3) We note that you have indicated that there are restrictions to data sharing for this study. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see https://journals.plos.org/plosntds/s/data-availability#loc-unacceptable-data-access-restrictions.

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We will update your Data Availability statement on your behalf to reflect the information you provide.

Reviewers' Comments:

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: This is a study of great social relevance, with detailed and clearly explained methodology, as well as a consistent discussion.

Reviewer #3: (No Response)

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: The results are consistent and presented appropriately, I only suggest reviewing table 2.

Review the race/ethnicity variable number “1.021” in Table 2, as well as the employment variable number “1.106”

Reviewer #3: (No Response)

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #2: It presented results relevant to public health, consistent with the objectives and method used. The limitations are important, however, they do not compromise the result.

Reviewer #3: (No Response)

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: The hierarchical analysis made it possible to identify how the different levels interacted, affecting the health of the most vulnerable individuals. In this regard, we saw in the results that black and Asian individuals are more likely to die from dengue fever. In the discussion, this finding was attributed to structural racism and social conditions that affect black or mixed-brown people. And as for the Asian group, would it also be due to conditions similar to those of the other groups? Why did you choose not to associate the black group with the mixed-brown group?

Reviewer #3: (No Response)

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Using socioeconomic data from the 100 Million Brazilian Cohort linked to compulsory notification records for dengue and death certificates, this cohort study investigates the socioeconomic factors associated with death following dengue cases in Brazil. Results suggest that people within the lowest socioeconomic position experience increased risks of dengue-specific and all-cause deaths during the 15 days following dengue symptom onset. The findings emphasize the profound significance of rational allocation of healthcare resources in reducing the disease burden of dengue. However, I still have the following concerns:

Introduction. Please ensure all epidemiological data are properly referenced and verifiable, such as ‘In 2024, more than 14 million dengue cases and over 10,000 dengue-related deaths were reported globally.’

Methods. Please describe in detail the exclusion criteria for this study population and whether non-endemic areas, short-term residence, and immunized persons were considered.

Methods. The study outcome included all-cause deaths that occurred within 15 days of the onset of dengue symptoms, whether this included accidents. How the authors considered these causes of death.

Results. Since the authors viewed race/ethnicity as a distal factor in dengue mortality, affecting access to education, housing, and health care, which in turn is associated with dengue. This seems to be a framework for mediation analysis, and I'm curious about the results of the mediation analysis.

Results. Sensitivity analysis, such as multiple interpolation, is recommended to improve the reliability of the results.

Discussion. Elevated mortality risks for Black, Asian, and mixed-race individuals align with structural inequities, but the absence of adjustment for comorbidities (e.g., diabetes, hypertension) weakens causal interpretations. The authors acknowledge this limitation but should discuss its potential impact on OR estimates.

Discussion. It is recommended that the authors provide further discussion on the elevated case fatality rates within 15 days of dengue symptom onset for people who are retired or living on pensions. The authors mention that even after adjusting for age, the mortality rate is higher among those who are retired or living on pensions. This may have suggested that the effect of being retired or living on a pension is independent of aging. I think this is a novel phenomenon.

Discussion. The direction of the effect of place of residence when only laboratory-confirmed dengue cases are included contradicts the main analysis and requires further discussion.

Discussion. Please propose specific measures for equitable access to health care and health improvement, and state who is responsible for them. Family doctors or the CDC?

Inconsistent formatting (e.g., “OR=1.58” vs. “OR = 1.58”) should be unified.

Reviewer #2: The manuscript is clear and presents the results in a simple and direct way, facilitating understanding.

Reviewer #3: (No Response)

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Reviewer #1: Yes: Yongfu Yu, School of Public Health, Fudan University, China

Reviewer #2: No

Reviewer #3: 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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Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Attachments

Attachment

Submitted filename: Reviewer_Report_PNTD-D-25-00509_Updated_june.docx

PNTD-D-25-00509R1

Socioeconomic markers of dengue mortality in the 100 Million Brazilian Cohort (2007-2018): A nationwide registry-based cohort study

PLOS Neglected Tropical Diseases

Dear Dr. Cardim,

Thank you for submitting your manuscript to PLOS Neglected Tropical Diseases. After careful consideration, we feel that it has merit but does not fully meet PLOS Neglected Tropical Diseases'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 within 30 days Oct 25 2025. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosntds@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pntd/ 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 editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to any formatting updates and technical items listed in the 'Journal Requirements' section below.

* 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, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Md. Kamrujjaman, Ph.D

Academic Editor

PLOS Neglected Tropical Diseases

Qu Cheng

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

Additional Editor Comments:

Reviewer #1:

Reviewer #3:

Reviewer #4:

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Reviewers' comments:

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: The study objectives are clearly stated with a testable hypothesis. The design, population, and sample size are appropriate, and the statistical analyses adequately support the conclusions. Ethical and regulatory requirements appear to have been met.

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: The study adequately addresses all the points raised. The analysis presented aligns with the proposed analysis plan. The results are clearly and comprehensively presented, and the tables are of sufficient quality to ensure clarity and facilitate understanding. There are only two minor comments that the authors may consider as suggestions.

1. Page 11/line 246: In the Results section, in the sentence “…using only the SIM records, dengue and dengue haemorrhagic fever were attributed as an underlying cause of death…”, the authors refer to the older classification of dengue cases. I recommend explicitly noting that, although dengue notifications now follow the revised clinical classification, deaths in the Mortality Information System (SIM) are still coded using the older ICD-10 categories (A90 and A91), which do not distinguish cases with warning signs from severe dengue. This clarification would help readers understand that analyses based on SIM data reflect the older classification system.

2. Page 15/line 289/290: Looking at the table 3, the variables living in rural areas as well as self-identifying as Asian does not seems to be statistically significant.

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: The conclusions of the manuscript are well supported by the data presented. The limitations of the analysis are clearly described, and the authors provide a thoughtful discussion of how these findings contribute to advancing our understanding of the socioeconomic factors associated with dengue mortality. The public health relevance of the results is appropriately addressed. Overall, the manuscript is well-structured and informative. There are three suggestions that the authors may consider when making adjustments:

1. Page 19/line 365: The authors draw attention to a purportedly increased all-cause mortality among individuals self-identified as Asian. It would be important to reference additional studies that have reported similar findings. Although this result appears atypical, it is borderline in terms of statistical significance (with the confidence interval very close to one) and, when weighed against the relevance of the other findings, does not seem to warrant particular emphasis. In this regard, it may be more relevant to highlight the higher all-causes mortality among individuals identifying as Brown (Pardo) compared to those identifying as White, given that Brown/mixed-race individuals constitute the largest group within the Brazilian population.

2. Page 21/Line 406: In this section, the authors state that it was not possible to determine the number of infections per individual, nor which episode was the most severe. This statement is not entirely clear. Would it not be possible to identify, at least within the study period, those cases with other reported episodes of dengue (notified as probable dengue cases) in the SINAN database?

3. The authors used CadÚnico data to classify cases according to social, economic, and household characteristics. This group is already highly vulnerable from a socioeconomic perspective. This suggests that, if the entire Brazilian population and its wide inequalities in living conditions were considered, differences in lethality would likely be much more pronounced. It would be appropriate for the authors to include a comment on this effect in their discussion.

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: (No Response)

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The author has addressed most of the concerns. I think the current version of the manuscript is suitable for publication.

Reviewer #3: (No Response)

Reviewer #4: This article makes an important contribution to the discussion of socioeconomic factors associated with dengue mortality, through a novel analysis of a specific Brazilian population benefiting from income transfer programs. The methods employed are appropriate for addressing the research questions.

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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 #3: No

Reviewer #4: Yes: Gerusa Gibson

[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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Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Attachments

Attachment

Submitted filename: Reviewer_Report_Accept.docx

Dear Dr Cardim,

We are pleased to inform you that your manuscript 'Socioeconomic markers of dengue mortality in the 100 Million Brazilian Cohort (2007-2018): A nationwide registry-based cohort study' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Md. Kamrujjaman, Ph.D

Academic Editor

PLOS Neglected Tropical Diseases

Qu Cheng

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

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