A two-tiered latent class and spatial analytical approach to identify clusters of neonatal mortality among very low birth weight infants: A population-based cohort study

Daniela Testoni Costa-Nobre; Adriana Sanudo; Kelsy Nema Areco; Ana Sílvia Scavacini Marinonio; Milton Harumi Miyoshi; Tulio Konstantyner; Carina Nunes Vieira e Oliveira; Rita de Cassia Xavier Balda; Mandira Daripa Kawakami; Paulo Bandiera-Paiva; Rosa Maria Viera Freitas; Mônica La Porte Teixeira; Bernadette Cunha Waldvogel; Maria Fernanda de Almeida; Ruth Guinsburg; Carlos Roberto Veiga Kiffer

doi:10.1371/journal.pone.0343004

Peer Review History

Original SubmissionSeptember 11, 2025
10 Dec 2025 Decision Letter - Ricardo Gurgel, Editor Dear Dr. Costa-Nobre, Please submit your revised manuscript by Jan 24 2026 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. 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'. 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If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. 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. 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 If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references.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. [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? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ******** Reviewer #1: The submitted study aims to identify and analyze patterns of neonatal deaths among very low birth weight newborns in the state of São Paulo, Brazil. It is a robust investigation that examined more than 100,000 live births and over 40,000 neonatal deaths over a 16-year period. Relevant patterns were identified using a concise methodology and a rigorous statistical analysis, employing two statistical approaches that are appropriate to the research topic and objectives. As expected within the Brazilian context, regional disparities and persistent problems were observed, which require attention and targeted efforts toward addressing preventable factors, as highlighted by the authors. This is a topic of utmost importance that should be brought to academic discussion. Reviewer #2: commend the authors on a well-written and thoughtfully structured manuscript. The study employs a sophisticated methodology and presents findings with significant utility for public health and the field of perinatology. During my review, I identified several areas with potential for enhancement, which I outline below. 1. Adherence to the STROBE Statement To ensure comprehensive reporting and identification of best practices, I recommend the authors explicitly confirm that all items of the STROBE checklist have been addressed. Item 4 (Title and Abstract): The manuscript's title should clearly state the study design. While the use of Latent Class Analysis implies an observational design, the specific type (which I understand to be a retrospective cohort study) should be explicitly stated in the title, or if not possible, the abstract. This is a key requirement for immediate reader comprehension. Other Items: Certain other STROBE criteria appear to be only partially met. These include a more detailed description of the sampling method and a clearer explanation of how potential biases were mitigated in the methodology. 2. Formulation of the Conclusion The conclusion, both in the abstract and the main text, should provide a direct and concise answer to the study's primary objective. While the results section presents the data, the conclusion must synthesize these findings to explicitly state how they address the aim of analyzing mortality patterns using the two methodologies. A summary of the distinct patterns identified for each methodology should be clearly articulated in the concluding remarks. 3. Application of the RECORD Checklist Given that this study utilizes large, routinely collected health databases, the application of the RECORD checklist (Benchmark et al., 2015) is highly recommended. This checklist is an extension of STROBE specifically for such datasets. * Key items to address include providing a flow diagram illustrating the patient selection and data linkage process (which could be included as a supplement). * Furthermore, a detailed description of the data cleaning and preparation procedures is essential. This should cover the handling of missing data, inconsistencies, and coding errors, including the percentage of missing data and the methods used for its treatment (e.g., imputation, exclusion). 4. Application of the RECORD-PE Checklist Finally, due to the perinatal focus of the research, I strongly suggest applying the RECORD-PE checklist (Perinatal Extension, Hermanussen et al., 2021). This extension is tailored for observational studies involving maternal, fetal, and newborn data. Reviewer #3: PLOS ONE Review This study is well designed and methodologically robust, employing probabilistic Latent Class Analysis (LCA) to uncover unobserved subgroups of neonatal deaths that share similar combinations of characteristics. This approach adds considerable depth beyond the deterministic ICD-10 classification by revealing latent diagnostic patterns underlying the recorded causes of death. I included some suggestions for better clarification and strengthening of the paper. Title: I would suggest adjusting the phrasing as: “A two-tiered latent class and spatial analytical approach to identify clusters of early and late neonatal mortality among very low birth weight infants”. Abstract Objective: Line 27: …patterns of neonatal deaths among very low birth weight… maintain consistency between title (early/late mortality) and the abstract (general neonatal mortality) Introduction Line 58 spatial-temporal- better to replace with: spatio-temporal Line 152: 34% were <28 weeks... refine as: “… 34% were born before 28 weeks of gestation.” To clarify the reference to gestational age. Methods The authors may need more detailed justification why the four diagnostic groups were selected (infection, intrapartum event, malformation, respiratory) as they are broad and include overlapping ICD codes. Results The paper would benefit from clearly identifying which classes are the main drivers of overall spatial disparities in neonatal mortality across the state. The results are reported by class, but the implications for how these patterns translate into health system gaps remain somewhat implicit. Strengthening the link between (1) each class’s spatial clustering, (2) the likely underlying service-delivery challenges, and (3) the most relevant targeted interventions would enhance the translational value and clarity of the findings. Discussion The Discussion could better detail how referral bias may over- or under-estimate clustering. Linking between each latent class and actionable strategies could be articulated more clearly. Providing class-specific examples (e.g., infection prevention bundles vs. improvements in delivery-room care) would strengthen policy relevance. Conclusion Given the paper’s title, the conclusion should more explicitly highlight what the study reveals about early vs late neonatal deaths across latent classes, based on the survival curves. ******** 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: MARCOS ALVES PAVIONE 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.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. Attachments Attachment Submitted filename: REVISION - PLOS ONE .pdf https://doi.org/10.1371/journal.pone.0343004.r001
Revision 1
27 Jan 2026 Author Response Dear Dr. Gurgel, Dear Academic Editor and Reviewers, We would like to thank you and the reviewers for the careful evaluation of our manuscript contributing to the overall quality of our work. We are grateful for the positive assessment of the scientific merit, methodological rigor, and relevance of the study. Below, we provide a detailed, point-by-point response to all comments raised by the Academic Editor and the reviewers. All changes have been incorporated into the revised manuscript and are highlighted in the tracked-changes version. Page and line numbers refer to the revised manuscript. Responses to Journal and Editorial Requirements 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Response: We have revised the manuscript to fully comply with PLOS ONE formatting and style guidelines. File naming, structure, headings, tables, and figures were checked and adjusted according to the official PLOS ONE templates. 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. Discrepancies were identified between the Funding Information, Financial Disclosure, and text within the manuscript. Response: We appreciate the editor’s careful review of the funding information. We have taken the following actions: • All funding-related text has been removed from the manuscript body and Acknowledgments section, in accordance with PLOS ONE policy. • The Funding Statement has been corrected and standardized. • The Financial Disclosure has been clarified to explicitly state the role of the funders. 3. Thank you for stating the following financial disclosure: [The author(s) received no specific funding for this work.]. At this time, please address the following queries: a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution. b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” c) If any authors received a salary from any of your funders, please state which authors and which funders. d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. We have taken the following actions: • All funding-related text has been removed from the manuscript body and Acknowledgments section, in accordance with PLOS ONE policy. • The Funding Statement has been corrected and standardized. • The Financial Disclosure has been clarified to explicitly state the role of the funders. Funding was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Project #2017/03748-7. The funding agency did not interfere with or participate in the study design, data analysis, interpretation of the results, or the writing and revision of the manuscript. The authors received no other specific funding for this work. Use of the data was possible due to agreements between Fundação SEADE and Universidade Federal de São Paulo (#23089.004297/2008-11; #23089.000057/2014-95; #23089.120254/2019-34). The authors have declared that no competing interests exist. 4. Thank you for stating the following in your manuscript: [Fundação de Amparo à Pesquisa de São Paulo - FAPESP, Project # 2017/03748-7. The funding agency did not interfere or participate in the design of the study, data analysis, interpretation of the results, writing or revising of the manuscript.] We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: [The author(s) received no specific funding for this work.] Please include your amended statements within your cover letter; we will change the online submission form on your behalf. We have adjusted as mentioned above: Funding was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Project #2017/03748-7. The funding agency did not interfere with or participate in the study design, data analysis, interpretation of the results, or the writing and revision of the manuscript. The authors received no other specific funding for this work. Use of the data was possible due to agreements between Fundação SEADE and Universidade Federal de São Paulo (#23089.004297/2008-11; #23089.000057/2014-95; #23089.120254/2019-34). The authors have declared that no competing interests exist. 5. Thank you for stating the following in your Competing Interests section: [No authors have competing interests]. Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. We have completed the Competing Interests section in the online submission form as requested and included the information in the cover letter. The statement has been updated to read as follows: Funding was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Project #2017/03748-7. The funding agency did not interfere with or participate in the study design, data analysis, interpretation of the results, or the writing and revision of the manuscript. The authors received no other specific funding for this work. Use of the data was possible due to agreements between Fundação SEADE and Universidade Federal de São Paulo (#23089.004297/2008-11; #23089.000057/2014-95; #23089.120254/2019-34). The authors have declared that no competing interests exist. 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. We reviewed the reviewer comments: no specific previously published works were recommended for citation. 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. We carefully reviewed the reference list to ensure completeness and accuracy. No retracted articles were cited in the manuscript. In response to the RECORD checklist requirements, two additional references were included to support methodological and reporting aspects addressed in the revision. The inclusions are below: Ref 10 Waldvogel BC, Morais LCC, Perdigão ML, Teixeira MLP, Freitas RMV, Aranha VJ. Experiência da Fundação Seade com a aplicação da metodologia de vinculação determinística de bases de dados. Ensaio & Conjuntura. 2019;1:1-25 Ref 12 Areco KN, Konstantyner T, Bandiera-Paiva P, Balda RCX, Costa-Nobre DT, Sanudo A, et al. Operational Challenges in the Use of Structured Secondary Data for Health Research. Front Public Health. 2021 Jun 15;9:642163. doi: 10.3389/fpubh.2021.642163. Reviewer #1 The submitted study aims to identify and analyze patterns of neonatal deaths among very low birth weight newborns in the state of São Paulo, Brazil. It is a robust investigation that examined more than 100,000 live births and over 40,000 neonatal deaths over a 16-year period. Relevant patterns were identified using a concise methodology and a rigorous statistical analysis, employing two statistical approaches that are appropriate to the research topic and objectives. As expected within the Brazilian context, regional disparities and persistent problems were observed, which require attention and targeted efforts toward addressing preventable factors, as highlighted by the authors. This is a topic of utmost importance that should be brought to academic discussion. Response: We thank Reviewer #1 for the positive and thoughtful evaluation of our study. We appreciate the recognition of its methodological rigor, analytical approach, and public health relevance, particularly regarding neonatal mortality patterns and regional disparities. Reviewer #2 1. Adherence to the STROBE Statement. To ensure comprehensive reporting and identification of best practices, I recommend the authors explicitly confirm that all items of the STROBE checklist have been addressed. Item 4 (Title and Abstract): The manuscript's title should clearly state the study design. While the use of Latent Class Analysis implies an observational design, the specific type (which I understand to be a retrospective cohort study) should be explicitly stated in the title, or if not possible, the abstract. This is a key requirement for immediate reader comprehension. Other Items: Certain other STROBE criteria appear to be only partially met. These include a more detailed description of the sampling method and a clearer explanation of how potential biases were mitigated in the methodology. Response: To clearly identify the study design, and to include the suggestion of reviewer #3, we have revised the manuscript title from “Latent class and spatial analyses in a tiered approach for identifying cluster areas of early or late neonatal mortalities” to “A two-tiered class and spatial analytical approach to identify clusters of neonatal mortality among very low birth weight infants: a population-based cohort study.” In addition, we explicitly stated the study design in the abstract (Page 2, Line 58) by adding the terms retrospective and cohort (“This retrospective population-based cohort study…”), and in the Methods section (Page 4, Line 120) (“This was a retrospective population-based cohort study using data from deterministic linkage…”). We have reviewed the manuscript using the STROBE checklist to ensure comprehensive reporting of all recommended items. A completed STROBE checklist is now provided as supplementary material. 2. Formulation of the Conclusion The conclusion, both in the abstract and the main text, should provide a direct and concise answer to the study's primary objective. While the results section presents the data, the conclusion must synthesize these findings to explicitly state how they address the aim of analyzing mortality patterns using the two methodologies. A summary of the distinct patterns identified for each methodology should be clearly articulated in the concluding remarks. Response: We thank the reviewer for this valuable suggestion and agree that the conclusion should more directly and concisely address the study’s primary objective. In response, we rewrote the conclusions in both the abstract and the main text to explicitly synthesize the findings and clarify how the combined methodologies address the aim of analyzing neonatal mortality patterns. In the abstract (Page 2, Line 65), the conclusion was revised to state: “The combined use of LCA and spatial analysis identified distinct patterns of neonatal mortality. LCA differentiated clinically meaningful profiles with specific timing of death, while spatial analysis revealed municipal-level clustering and overlap of these patterns. These findings showed how neonatal mortality is shaped by both diagnostic profiles and territorial context, providing actionable evidence to guide targeted improvements in perinatal and neonatal care to reduce preventable deaths among VLBW infants.” In the main text (Page 16, Line 424), the conclusion was rewritten as follows: “In conclusion, by applying a two-tiered approach, this study highlights how the combination of methodological rigor and epidemiological insight can uncover diagnostic and geographic patterns in neonatal mortality. Latent class analysis identified distinct and clinically meaningful diagnostic patterns, differentiating deaths predominantly related to intrapartum events from those associated with infections, respiratory conditions, and congenital malformations, with clear differences in timing of death. Spatial analysis further demonstrated that these classes were unevenly distributed across municipalities, revealing geographic clustering and overlap of specific mortality patterns that reflect heterogeneity in health system performance.” We believe these revisions directly respond to the reviewer’s concern by clearly summarizing the distinct contributions of each methodology and explicitly linking the findings to the study’s primary objective. 3. Application of the RECORD Checklist Given that this study utilizes large, routinely collected health databases, the application of the RECORD checklist (Benchmark et al., 2015) is highly recommended. This checklist is an extension of STROBE specifically for such datasets. * Key items to address include providing a flow diagram illustrating the patient selection and data linkage process (which could be included as a supplement). * Furthermore, a detailed description of the data cleaning and preparation procedures is essential. This should cover the handling of missing data, inconsistencies, and coding errors, including the percentage of missing data and the methods used for its treatment (e.g., imputation, exclusion). Response: We have addressed this recommendation in full: The RECORD checklist has been completed and included as Supplementary Material. We change the manuscript to better adhere to the RECORD checklist RECORD 6.2: Any validation studies of the codes or algorithms used to select the population should be referenced. If validation was conducted for this study and not published elsewhere, detailed methods and results should be provided. Data preparation and validation were conducted through a complex and time-consuming process that has been previously published. For clarity, we have now added the sentence below along with the corresponding reference. (Ref 12) We added in Page 4 Line 126: “Procedures to ensure data adequacy, including data preparation and data validation prior to data use, were undertaken and have been previously published.” Areco KN, Konstantyner T, Bandiera-Paiva P, Balda RCX, Costa-Nobre DT, Sanudo A, et al. Operational Challenges in the Use of Structured Secondary Data for Health Research. Front Public Health. 2021 Jun 15;9:642163. doi: 10.3389/fpubh.2021.642163. RECORD 6.3: If the study involved linkage of databases, consider use of a flow diagram or other graphical display to demonstrate the data linkage process, including the number of individuals with linked data at each stage. The deterministic data linkage procedures used in this study have been previously described in detail. Accordingly, we referenced the original methodological source (Reference #10), which provides a comprehensive description of the linkage process. Waldvogel BC, Morais LCC, P Attachments Attachment Submitted filename: PONE-D-25-47659_Response_23jan26.docx https://doi.org/10.1371/journal.pone.0343004.r002
2 Feb 2026 Decision Letter - Ricardo Gurgel, Editor A two-tiered latent class and spatial analytical approach to identify clusters of neonatal mortality among very low birth weight infants: a population-based cohort study PONE-D-25-47659R1 Dear Dr. Costa-Nobre, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . 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, Ricardo Q. Gurgel, PhD Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0343004.r003
Formally Accepted
Acceptance Letter - Ricardo Gurgel, Editor PONE-D-25-47659R1 PLOS One Dear Dr. Costa-Nobre, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Professor Ricardo Q. Gurgel Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0343004.r004

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