Association between different atherogenic and insulin resistance indices and infertility in polycystic ovary syndrome patients

Kasra Jafari; Nazanin Azmi-Naei; Nooshan Tajik; Ashraf Moini; Amene Abiri

doi:10.1371/journal.pone.0343783

Peer Review History

Original SubmissionOctober 16, 2025
19 Dec 2025 Decision Letter - Ricardo Cobucci, Editor -->PONE-D-25-55841-->-->Association between different atherogenic and insulin resistance indices and infertility in polycystic ovary syndrome patients-->-->PLOS One Dear Dr. Abiri, 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. Dear authors, as you can see, the reviewers have requested substantial revisions to your manuscript. We are certainly willing to reconsider a revised submission, but please know that this is not preliminary acceptance of your paper. When returning your revised manuscript, please be sure to include a point-by-point summary of the suggestions of the reviewers that specifies how and where in the text you have addressed the suggestions. 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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: Yes ******** -->2. Has the statistical analysis been performed appropriately and rigorously? --> Reviewer #1: Yes Reviewer #2: Yes ****** -->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: No 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: No ****** -->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: This cross-sectional study examines the association between five metabolic indices (TyG, TyG-BMI, AIP, TG-HDL, METS-IR) and infertility in 669 Iranian women with PCOS. The authors report that all indices were significantly higher in infertile women, with AIP showing the strongest association (adjusted OR = 9.065). However, ROC analysis revealed modest predictive performance (AUCs 0.598–0.625), suggesting limited standalone clinical utility. The study addresses a relevant clinical question and is methodologically sound in many respects. However, several issues must be addressed: 1. TyG-BMI formula in the Methods --> it should be TyGxBMI not TgXBMI. 2. Specify how “unsuccessful conception” was documented and whether other causes of infertility were considered. 3. Given the modest AUCs, emphasize that these indices are not yet suitable for standalone clinical prediction. 4. Expand limitations: Address potential unmeasured confounders (e.g., diet, physical activity, detailed infertility workup). 5. Consider adding a sensitivity analysis: Excluding women with very high TG-HDL ratios (>2.5) where the association became non-significant. Figure 1: 1. Clarity of Red Dashed Line: The caption should explicitly state that the red dashed line represents OR = 1 (no association). 2. Threshold Annotation: Adding a vertical dotted line at TG-HDL ≈ 2.5 with a brief note (e.g., “threshold”) would help readers quickly interpret the inflection point. Figure 2: 1. The legend lists “TG_HDL” and “TyG_HDL.” However“TyG_HDL” is not described in the text. 2. Some lines are very close together (AIP, TG-HDL). Consider using dashed/dotted styles or clearer color differentiation. 3. It would be helpful to add AUC values in the legend (e.g., “AIP (AUC = 0.625)”) for immediate comparison. 4. “BMI” is included in the ROC but not discussed in the predictive performance results. Either explain its inclusion or remove it to avoid distraction. Reviewer #2: PONE-D-25-55841 I am writing to express my opininion on Association between different atherogenic and insulin resistance indices and infertility in polycystic ovary syndrome patients which submitted in plos one journal. This study suffred from lack of novelity, its not sutible for publication untill major revision. Authors failed to picture the rationality of this study? What is main novelity? Previous study answer this question how you fill the gap? How many women you excluded due to the exclusion criteria? How were the techniues of assessments , kits, methodes… How was diagnostic criteria of PCOS? What is definition of infertility? It was better to have a control group for comparison. Please discuss about any pollsible bias of study. What is clinical implication of study? Editor advised to check the usig of AI. ****** -->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: 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. https://doi.org/10.1371/journal.pone.0343783.r001
Revision 1
31 Jan 2026 Author Response Dear Dr. Ricardo Ney Oliveira Cobucci, We sincerely appreciate the time and effort you and the reviewer have dedicated to evaluating our manuscript, "Association between different atherogenic and insulin resistance indices and infertility in polycystic ovary syndrome patients" (Manuscript ID: PONE-D-25-55841). We are grateful for the constructive feedback, which has helped us improve the quality of our work, and accept our sincerest apologies for the late response, since, because of the total internet shutdown in Iran, we were not able to communicate. We have carefully addressed all the comments and suggestions provided by the reviewer. Below, we provide a point-by-point response to each remark, detailing the revisions made in the revised manuscript. All changes have been highlighted in the revised version for easy reference in yellow. Reviewer #1 We are truly grateful for your kind and encouraging words. Your positive feedback means a great deal to our team and reinforces our commitment to further research in this area. Thank you for taking the time to review our work so thoughtfully. Comment 1: "TyG-BMI formula in the Methods --> it should be TyGxBMI not TgxBMI.” Response 1: We corrected this typo. Comment 2: "Specify how “unsuccessful conception” was documented and whether other causes of infertility were considered.” Response 2: Infertility status was determined based on documentation in medical records and defined as failure to achieve pregnancy after at least 12 months of regular unprotected intercourse, as recorded during routine clinical assessments by treating gynecologists. Classification was therefore not based solely on self-report. Male factor infertility was explicitly excluded. Other female causes of infertility unrelated to PCOS were considered when information was available in medical records; however, infertility was classified as all-cause infertility within a PCOS population. We have clarified this point in the Measurements and Tools section (lines 110-117) and acknowledged the potential for residual misclassification in the Limitations section (lines 343-344). Comment 3: "Given the modest AUCs, emphasize that these indices are not yet suitable for standalone clinical prediction.” Response 3: We agree with the reviewer and thank them for this valuable suggestion. We have revised the Results (lines 243-246), Discussion (lines 258-262), and Conclusion (lines 359-361) sections to explicitly state that these indices are not suitable as standalone tools for infertility prediction in women with PCOS and should be interpreted as adjunctive metabolic markers rather than independent screening instruments. Comment 4: "Expand limitations: Address potential unmeasured confounders (e.g., diet, physical activity, detailed infertility workup).” Response 4: We have expanded the Strengths and Limitations section (lines 344-348) to explicitly acknowledge the potential influence of unmeasured confounders (as you asked for diet, physical activity, and detailed infertility workup) and their possible role in the residual confounding. Comment 5: "Consider adding a sensitivity analysis: Excluding women with very high TG-HDL ratios (>2.5) where the association became non-significant.” Response 5: We thank the reviewer for this insightful suggestion. To address potential non-linearity and the influence of extreme values, we modeled the association between the TG–HDL ratio and infertility using restricted cubic spline analysis, which provides a flexible and statistically appropriate assessment without imposing arbitrary cut points. The spline analysis demonstrated a significant overall and non-linear association, with loss of statistical significance at higher TG–HDL values. Importantly, as illustrated in the spline plot (barcode plot on the X axis of Fig. 1), the number of observations decreases substantially at TG–HDL ratios above approximately 2.5, which may partly explain the widening confidence intervals and loss of statistical significance in this range, rather than a true absence of association. Given that non-linearity has already been formally evaluated and that post hoc exclusion based on a threshold may introduce selection bias, we chose not to perform an additional sensitivity analysis at this stage. However, if the reviewer or editor considers such an analysis essential, we would be pleased to perform it and report the results in a subsequent round of revisions or as supplementary material. Comments on Figure 1: Comment 1: Clarity of Red Dashed Line: The caption should explicitly state that the red dashed line represents OR = 1 (no association). Response 1: We have revised the caption of Figure 1 accordingly (lines 230-233). Comment 2: Threshold Annotation: Adding a vertical dotted line at TG-HDL ≈ 2.5 with a brief note (e.g., “threshold”) would help readers quickly interpret the inflection point. Response 2: We have revised Figure 1 accordingly. Comments on Figure 2: Comment 1: “The legend lists “TG_HDL” and “TyG_HDL.” However“TyG_HDL” is not described in the text.” Response 1: We have removed the TyG-HDL from Figure 2. Comment 2: “Some lines are very close together (AIP, TG-HDL). Consider using dashed/dotted styles or clearer color differentiation.” Response 2: We have made necessary edits and replaced Fig 2 with a new plot. Comment 3: “It would be helpful to add AUC values in the legend (e.g., “AIP (AUC = 0.625)”) for immediate comparison.” Response 3: We have added the AUC values in the new plot. Comment 4: “BMI” is included in the ROC but not discussed in the predictive performance results. Either explain its inclusion or remove it to avoid distraction.” Response 4: We have removed the BMI from the new plot. Reviewer #2 Thank you for taking the time to review our work. We’re grateful for your guidance throughout the review process. Comment 1: “Authors failed to picture the rationality of this study? What is main novelity? Previous study answer this question how you fill the gap?” Response 1: The novelty of our study lies in the comprehensive, PCOS-specific evaluation of multiple metabolic indices, including the first assessment of AIP in relation to infertility, along with non-linear modeling and ROC analysis to assess clinical relevance. While we mentioned these in the last paragraph of our Introduction section, we have revised the text (lines 79-89) to more explicitly highlight these gaps and to clarify the novelty of our study. Comment 2: “How many women you excluded due to the exclusion criteria?” Response 4: We have clarified the number of participants excluded (n=335) based on the predefined exclusion criteria in the Study Design and Participants section (lines 160-161). Comment 3: “How were the techniues of assessments , kits, methodes…” Response 4: We have revised the Measurements and Tools section to provide additional details on the assessment techniques and methods (lines 103-109). Comment 4: “How was diagnostic criteria of PCOS?” Response 4: We have clarified the diagnostic criteria of PCOS in the Measurements and Tools section (lines 118-122). Comment 5: “What is definition of infertility?” Response 5: We have clarified the definition of infertility in the Measurements and Tools section (lines 110-117). Comment 6: “It was better to have a control group for comparison.” Response 6: The primary objective of this study was to examine the association between metabolic indices and infertility within a population of women with PCOS, rather than to compare women with and without PCOS. Accordingly, we used an internal comparison between infertile (cases) and fertile (control) women with PCOS to minimize confounding related to the diagnosis of PCOS itself and to better characterize metabolic heterogeneity within this high-risk group. While inclusion of a non-PCOS control group may be informative for other research questions, it was beyond the scope of the present study. Comment 7: “Please discuss about any pollsible bias of study.” Response 7: We have expanded the Strengths and Limitations section to explicitly discuss potential sources of bias(including selection bias related to the tertiary-care setting, residual confounding from unmeasured lifestyle and reproductive factors, etc.) (lines 344-351). Comment 8: “What is clinical implication of study?” Response 8: We have added a Clinical Implications subsection to the Discussion to clarify the potential relevance of our findings (lines 318-327). Comment 9: “Editor advised to check the usig of AI.” Response 9: We confirm that no artificial intelligence tools were used for data collection, statistical analysis, result generation, or scientific interpretation in this study. Any language editing, where applicable, was limited to improving grammar and clarity, and all content was reviewed and approved by the authors. Sincerely, Dr. Amene Abiri Attachments Attachment Submitted filename: response 2026-01-07.pdf https://doi.org/10.1371/journal.pone.0343783.r002
11 Feb 2026 Decision Letter - Ricardo Cobucci, Editor Association between different atherogenic and insulin resistance indices and infertility in polycystic ovary syndrome patients PONE-D-25-55841R1 Dear Dr. Abiri, 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 Ney Oliveira Cobucci, Ph.D Academic Editor PLOS One Additional Editor Comments (optional): Congratulations. 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 ******** -->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 ****** -->3. Has the statistical analysis been performed appropriately and rigorously? --> Reviewer #1: Yes ****** -->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: Yes ****** -->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 ****** -->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: (No Response) ****** -->7. 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 ******** https://doi.org/10.1371/journal.pone.0343783.r003
Formally Accepted
Acceptance Letter - Ricardo Cobucci, Editor PONE-D-25-55841R1 PLOS One Dear Dr. Abiri, 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 Ney Oliveira Cobucci Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0343783.r004

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