Uncovering bridging diseases in complex multimorbidity pathways: A network science approach

Javier Alvarez-Galvez; Javier Arroyo

doi:10.1371/journal.pone.0323208

Peer Review History

Original SubmissionNovember 8, 2024
8 Nov 2024 Author Response https://doi.org/10.1371/journal.pone.0323208.r001
14 Jan 2025 Decision Letter - Kate E Dibble, Editor PONE-D-24-50745Uncovering Bridging Diseases in Complex Multimorbidity Pathways: A Network Science ApproachPLOS ONE Dear Dr. Alvarez-Galvez, 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 Feb 28 2025 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. 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If your ethics statement is written in any section besides the Methods, please delete it from any other section. 6. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 1 in your text; if accepted, production will need this reference to link the reader to the Table. Additional Editor Comments: Good morning, We recommended a major revision for this manuscript as there are a number of outstanding areas for improvement. Please see the reviewer comments for more suggestions/edits. If you have any questions, please let me know. Dr. Dibble [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? 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: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The manuscript provides valuable insights into multimorbidity patterns using network science methods, and the data appears to support the conclusions. However, I have a few suggestions: Abstract: I suggest revising the introduction of the abstract to provide a clearer context and set the stage for the study’s objectives. The abstract currently jumps into the methodology without giving enough background on the significance of the study. A more comprehensive introduction will help the reader better understand the relevance of the research. Consider adding a sentence or two discussing multimorbidity profiles to provide context and highlight the study’s importance. Presentation and Clarity: The manuscript is detailed but could benefit from minor rephrasing for clarity. A quick review for grammatical errors is recommended. Gender-Specific Health Inequalities: The study's focus on gender differences is important. Expanding on how the findings can inform practical healthcare strategies for both sexes would be valuable. Future Directions: A suggestion for future studies is a longitudinal approach to understand disease trajectories and their role in multimorbidity progression. Reviewer #2: Review report Title: “Uncovering Bridging Diseases in Complex Multimorbidity Pathways: A Network Science Approach” Dear Editor, thank you for the opportunity to review this manuscript. The papers characterized patterns of multimorbidity and identified the bridging 20 diseases that facilitate the formation of complex multimorbidity patterns using network sciences. The paper addresses important public health aspects to understand complex multimorbidity patterns. The paper also readable. However, addressing the following points may benefit the manuscript. General comments • There are some clarity issues than need to be adressed. e.g., “...so the absence connections implies that there are no relationships or that they are too weak to be significant (line 140)”, “There indicators were binary and …(line 115) etc. • Same issues are there, particularly in method sections. • There are also long sentences that don’t allow to breath. e.g., line 122 to 1226 Methods • Could you provide for using an estimation error of ±2.5 units when a 5% error margin is more commonly applied? • After determining a minimum sample size of 2,200, why didn’t you apply your selection criteria (e.g., participants with two or more chronic conditions)? • The calculation of the response rate is unclear. You planned to interview a minimum of 2,200 individuals, but ended up with 1,592 respondents with multimorbidity. What was the size included in your analysis ? or How does this translate to a response rate of only 13.3% (line 90)? Could you please described adequacy of your sample size, because of such analysis requires a bit largers sample size to reach cetrain conclusion ? • The description of sample size, inclusion and exclusion criteria, and data collection procedures would benefit from being placed under separate subheadings rather than being mixed into the Study Design section. • While you described how sparsity is achieved through the networking process, could you elaborate on how conditional independence assumptions were met? This is particularly important for chronic conditions that frequently co-occur (e.g., depression and anxiety), as their relationships may obscure the effects of other conditions. • Could you provide more detail on how relationships among diseases or conditions are represented in the graph? For instance, how do you effectively capture associations and describe the parameterization process? • In the final section of your Data Analysis (line 184), it would be helpful to describe the logistic regression approach in greater detail, especially since it may differ from approaches applied to other types of data. Results • For better clarity, the results could be organized into subheadings, such as prevalence estimates from the mixed graphical models for men and women, centrality analyses results, and findings from the logistic regression. ****** 6. 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 #2: Yes: Yitagesu Habtu ******** [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.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0323208.r002
Revision 1
21 Feb 2025 Author Response Response to reviewer #1: 1. Abstract: Comment (C): The introduction of the abstract should provide a clearer context and set the stage for the study’s objectives. Response (R): We have revised the abstract to include a brief introduction on multimorbidity profiles and their significance in health research. This provides a better context before presenting the methodology and findings. 2. Presentation and Clarity: C: Minor rephrasing for clarity and grammatical errors should be addressed. R: We conducted a thorough proofreading of the manuscript, and we also have included subsections structure for better readability and clarity. 3. Gender-Specific Health Inequalities: C: Expand on how findings can inform practical healthcare strategies for both sexes. R: We have elaborated in the discussion section on how our findings can be used to inform gender-specific healthcare interventions. 4. Future Directions: C: Consider suggesting a longitudinal approach to understand disease trajectories in multimorbidity progression. R: We have added a section in the discussion suggesting future research directions, emphasizing the need for longitudinal studies to track multimorbidity evolution over time. Response to reviewer #2: 1. Clarity Issues: C: Some sentences need rewording for clarity. R: As recommended, we revised sentences throughout the manuscript to improve clarity and conciseness. 2. Methods: C: Justify the use of an estimation error of ±2.5 units when a 5% margin is more common. R: Thanks for this observation. We have provided an explanation in the methods section for choosing ±2.5 units, emphasizing the need for higher precision in estimating multimorbidity patterns. C: Explain why selection criteria were not applied after determining a minimum sample size of 2,200. R: We clarified that the full sample was initially considered (to have a representative sample of people in this area, including also 50+ people without multimorbidity), and selection criteria were applied subsequently to focus exclusively on individuals with multimorbidity. C: Clarify the calculation of response rate. R: We have included a more detailed explanation of how the response rate was calculated, addressing the difference between the total surveyed individuals and those included in the final analysis. C: Improve the organization of sample size, inclusion/exclusion criteria, and data collection procedures. R: These components have been reorganized under a separate subheading to enhance the readability and logical flow of sample size calculation and selection criteria. C: Elaborate on how conditional independence assumptions were met. R: Thanks for this observation. We have explained in the methods section that “our implementation of mixed graphical models (MGM) incorporates LASSO regularization to enforce sparsity, thereby ensuring that only the strongest partial correlations remain in the network structure. This approach improves interpretability by reducing false associations and capturing the most meaningful disease relationships […] in terms of conditional independence, MGMs use the structure of a Markov random field to represent conditional relationships between variables. Formally, the model ensures that a variable is conditionally independent of the rest of the variables given its neighborhood in the network.” Thus, our methodology not only ensures a more accurate representation of multimorbidity structures but also strengthens the validity of inferred relationships by addressing the issues of indirect associations and multicollinearity, which are common limitations in traditional regression-based approaches. C: Provide more details on how disease relationships are represented in the graph. R: We expanded the methods section to describe the parameterization process and how disease associations were captured using the mixed graphical model (MGM). C: Describe the logistic regression approach in greater detail. R: We added a more comprehensive description of our logistic regression approach. 3. Results: C: Organize results into subheadings for better clarity. R: We restructured the results section with subheadings: (a) Disease prevalence Estimates, (b) Detecting multimorbidity patterns, (c) Identifying bridging diseases, and (d) Association between bridging diseases and multimorbidity patterns, making it easier for readers to navigate the results. Subsections have also been incorporated into methods and discussion sections. We sincerely appreciate the valuable feedback provided by the reviewers. These revisions have strengthened our manuscript, making it more precise, structured, and impactful. We hope the changes address all concerns and look forward to your further feedback. Best regards, The Co-authors Attachments Attachment Submitted filename: Response to reviewers_v2.docx https://doi.org/10.1371/journal.pone.0323208.r003
3 Apr 2025 Decision Letter - Kate E Dibble, Editor Uncovering Bridging Diseases in Complex Multimorbidity Pathways: A Network Science Approach PONE-D-24-50745R1 Dear Dr. Alvarez-Galvez, 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. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Kate E Dibble, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0323208.r004
Formally Accepted
Acceptance Letter - Kate E Dibble, Editor PONE-D-24-50745R1 PLOS ONE Dear Dr. Alvarez-Galvez, 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. 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 Dr. Kate E Dibble Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0323208.r005

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