PONE-D-21-20756

Lipoprotein(a) as a risk factor for cardiovascular disease in a South Indian population: A case control study

PLOS ONE

Dear Dr. JAIDEEP CHANAYIL 

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PLOS ONE

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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

Reviewer #1: No

Reviewer #2: No

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

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: PONE-D-21-20756

General comments:

1. This is a good study question and I would encourage the authors to make the presentation better.

2. I believe that South Asians is better than Asian Indians. Most of the global studies use data from South Asia and not India alone.

3. The basic limitation in the study is use of mean levels of lipoprotein(a). Lp(a) typically has a skewed distribution and I would recommend that the authors use median values with 25-75 interquartile intervals (IQR) or data presentation. Similarly intergroup comparisons should be performed with non-parametric statistics (Kruskall-Wallis or other tests). An expert opinion from a statistician should be obtained. In the current form the data are not understandable, SD’s are more than the mean values. I am skeptical for use of other parametric tests in the statistics.

4. The article is too lengthy. Especially the introduction and discussion sections.

Specific comments:

Abstract:

5. The Background statement is lengthy. Please make it a one liner.

6. Please describe the method of identifying controls here.

7. All the results could change after the change in statistical methodology highlighted in point no. 3 above.

Introduction:

8. Please describe the evolution of Lp(a) as a risk factor especially focusing on Emerging Risk Factors Collaboration, Danish studies and Mendelian Randomization studies. To be identified it is essential that the factor follows all the Bradford-Hill criteria.

9. Remove the redundant and duplicate statements from this section. Paragraphs 1, 3, 4, 5, 6, and 7 could be deleted/shortened. Previous studies should be could be referenced and details could be discussed in Discussion. No need to provide details of Lp(a) structure.

10. I agree that this is a large study. However, this is not the largest study, INTERHEART study Lp(a) data have been published with more cases/controls than the present one.

11. The literature review is incomplete.

12. Objectives are not defined at all.

Methods:

13. Ethics clearance should be in the first paragraph.

14. Too many abbreviations make for a tough reading. The language needs major improvement so as to improve understanding.

15. I would not include individuals with less than 50% obstructive lesions as controls. These are the persons in whom acute coronary events happen, especially in the young and should be included in CAD group.

16. Most of the guidelines, including latest European and North American, recommend a cut-off of >50 mg/dl and high Lp(a). This cut off should be used. >30mg/dl could be a secondary cut-off.

17. Statistical analyses need major revision. Highlighted in point no. 3 supra. Why adjust for age, when age is the defining characteristics and age-stratified analyses have ben done?

Results:

18. Please describe the characteristics of non-CAD patients.

19. In Table 1, there are too many data. Anyway, this should be revised after exclusion of controls with any evidence of CAD on coronary angio.

20. Dyslipidemia is a wrong word. Please specify the hyperlipidemias as, LDL >=130, non-HDL >=160, and TG >=150. Similarly low HDL should be better defined according to international guidelines. Arbitrary cut-offs are not recommended.

21. Alcohol intake Y/N is also wrong. Please specify the alcohol intake cut-off used in international studies.

22. Age-stratified data on Table 2 should be reduced or combined in Table 1.

23. Presentation of statistical analyses are not understandable at all. The problem with the currently available statistical packages is that they produce too many outputs which are not relevant to the study question. Please take guidance from an expert to create more useful statistics.

24. Figure 1 should be a bar graph and not a line graph.

25. Discussion:

26. The first paragraph should report principal conclusions of the study.

27. Too much space has been taken up by pathophysiology of Lp(a). This must be deleted.

28. Review of Indian studies is incomplete. Also include some studies from other South Asian countries.

29. The current guidelines recommend measurement of Lp(a) in every individual, at least once in lifetime. In Indian context it could be more than once, given the varies of laboratory variations.

30. Limitations should be more specific. This is not a prospective study, sample size is small (although larger than most Indian studies), control population could be better selected as age-matching is uneven (more young patients than controls), etc.

31. Too much repetition.

32. The length of the Discussion section should be less.

Reviewer #2: Manuscript Number: PONE-D-21-20756

Lipoprotein(a) as a risk factor for cardiovascular disease in a South Indian population: A case control study

PLOS ONE

Thank you for the opportunity to review this manuscript. The manuscript identified lipoprotein(a) as a risk factor (predictor?) for CVD, particularly those aged below 50 years. Overall, the manuscript is good in its concept and will be of interest to those involved in CVD prevention and management. However, I have major issues in the novelty of the study, methodological issues and results that need to be addressed critically. Specific comments and questions are provided below.

General

1. The present manuscript reported on a topic that has been studied previously in India as well as other parts of the world. Many studies, both predictive and causal, have already been published on this topic and found somewhat similar results, indicating LP (a) is an independent risk factor of CAD. On paragraph 6 of the background, several studies have been mentioned from India, which showed more or less consistent results. However, with the abundance of such studies, the motivation to conduct this study is not well justified. What makes this study different from the others in terms of study population, methodology, approach, or context other than a bit larger sample? The authors need to explain why their study was necessary, and what it adds to common knowledge.

2. It is essential to clearly state whether this is a ‘prediction’ study that identifies predictors of CAD or ‘causal’ which needs controlling for confounding and adjustment for selection biases. Based on the description from the introduction and method section, the aim of this study looks more of causal, i.e., means to identify the role of LP (a) as a risk for CAD. However, in the analysis and result section, the authors described the ROC curve, which is completely prediction (discriminatory potential) of LP(a) for CAD, means…confounding is not an issue (Grobbee and Hoes 2014). Moreover, in paragraph 4 of the discussion, the authors emphasize LP(a) to be considered to reclassify patients, which is completely prediction in nature. Thus, the authors should explicitly describe whether the aim is prediction or causal and descriptions should be consistent throughout the manuscript. In addition, if the aim is causal, there are several biochemical parameters (lipid profile) that need to be controlled to claim that LP(a) is an independent risk factor of CAD.

Title

3. The title refers to cardiovascular diseases, which includes several categories, which is not limited to coronary artery diseases (CAD). However, the study is specifically for CAD. There are several risk factors which are limited to specific CVD types. If the outcome is CVD, controls are also CVD patients other than CAD. Thus, I would suggest limiting the title specific to CAD, which is the focus of this study.

Background

4. Introduction, paragraph 4: the first two descriptions do not have references.

5. The role of paragraph 7 of the background is not clear or not well placed in the background.

Methods

6. How the number of cases and control (the ratio) was determined? It is an unbalanced case to control ratio.

7. Controls were supraventricular tachycardia (SVT), atrial fibrillation, atypical chest pain with a normal coronary angiogram. First, these cardiac conditions might be related to the main exposure of interest, i.e. LP(a). This may underestimate the association between LP(a) and CAD. The study would have benefited from multiple control groups. Would it have been better to compare the cases with healthy counterparts in addition to these cases?

8. Ethics statement: It is not clear how this study is exempted from ethical review. It is acceptable that consent might not be required as it is a hospital record. However, it doesn’t necessarily mean ethical review is not required.

Analysis

9. In the analysis section, the authors described that Lp(a) is not normally distributed. However, in the result section of the abstract and the main document, LP(a) is described using mean (SD). This is evidenced by table 4 of the result section, which indicates huge variation in mean and median. The authors described that they used log-transformation. Nevertheless, throughout the manuscript, raw values of LP(a) are reported. Thus, the authors should revise the analysis and results accordingly.

10. Receiver operating characteristic curve (ROC) analysis was used to obtain the predictive accuracy of Lp(a) by disease status. What is the importance of ROC…if the study aim is causal.

11. LP(a) is continuous variable and treated as continuous in one occasion and as categorical in another place. It is better to make it consistent based on the prior hypothesis.

12. Table 1 and 2: ‘lipoprotein’, which specific type of lipoprotein?

13. It is puzzling that the main exposure of interest (Lipoprotein) is not included in the multivariable analysis for ‘all ages’.

Results

14. The authors described that “We found that Lp(a) was able to prediction accuracy of Lp(a) was 57% as compared to 62% for diabetes and 70% for tobacco use (Table 5). The ROC curve drawn with these variables in the model gives a predictive probability of about 80%”. This indicates that the predictive capacity of LP(a) is very low…only 7% over just tossing a coin. It would be better to see the added value of LP(a) apart from other predictors including, tobacco, diabetes, BP, BMI, etc.…

Discussion

15. Last paragraph of the discussion section: “Given that Lp(a) values are stable from the first decade of life and considering that Lp(a) values are genetically determined, Lp(a) should be considered for risk stratification in families with premature CAD and or with high Lp(a) levels in the family”. Based on this description, the aim of this study is prognostication in its nature, i.e. to evaluate the prognostic performance of LP(a) in predicting CAD. If so, the AUC is only 57%, which is very low, a bit higher than chance. If the aim is not to see the causal role of LP(a) so as to guide preventive interventions, I would suggest restructuring the whole manuscript as a prognostic research. The theoretical design and approach to statistical analysis is different for causal and prediction research.

Minor issues

• In general, the manuscript doesn’t have page and line numbers, which make the review process difficult to refer to specific descriptions.

• Be consistent in the use of decimal points

References

Grobbee, D. E. and A. W. Hoes (2014). Clinical epidemiology: principles, methods, and applications for clinical research, Jones & Bartlett Publishers.

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Reviewer #1: No

Reviewer #2: Yes: Hamid Yimam Hassen

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Attachment

Submitted filename: Comment_HYH.docx

PONE-D-21-20756R1Lipoprotein(a) as a risk factor for coronary artery disease in a South Asian population: A case control studyPLOS ONE

Dear Dr. JAIDEEP CHANAYIL MENON,

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.

Both reviewers still have some important methodological concerns that I advise that you address and return the manuscript for consideration.

Please submit your revised manuscript by Mar 12 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
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• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Geofrey Musinguzi, MPH, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

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

Reviewer #1: No

Reviewer #2: No

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: Thanks for submitting a revised version of this article. The manuscript is now much better, but some deficiencies remain.

1. The authors have log transformed the Lp(a) values and then performed the quantitative analyses. This is also an appropriate method, although I believe that using non-parametric comparisons such as median test for 2 group and Kruskal-Wallis test for multiple group comparisons are better methods. This should be discussed in the limitation sections of the article.

2. The interquartile ranges are typically presented as median (25-75 interquartile range, IQR), e.g. 55 (40-70). Nowhere the authors have presented data in this format. Moreover, the authors have reported mean levels of Lp(a) without any measurement of dispersion in the abstract, text and tables. All these should be revised.

3. The discussion section is still too long and instea dof discussing the findings of the article and comparing these with previous Indian and international studies, the authors focus on implications of the findings. Please modify.

4. Studies on Lp(a) from India are listed below. There are many such studies and should be referenced.

Table: Summary of case-control studies regarding importance of Lp(a) in CAD in India

First Author Year Journal Cases Lp(a) (n) Controls Lp(a) (n) Comment

Vashisht S 1992 Indian Heart J. 44(4):223-6 Lp(a)+++ (760)** Lp(a)+ (167)** Clinical CAD

Gupta R 1996 Int J Cardiol. 57(3):265-70 26.8+22.1 (77) 15.1+14.6 (24) Angiographic study

Mohan V 1998 Diabetes Care. 21(11):1819-23 24.6 (100)* 15.1 (100), 19.4 (100)* Diabetic CAD

Singh S 1999 J Assoc Phys Ind. 47(12):1157-60 (222) (67) Post MI

Gupta R 2000 Indian Heart J. 52(4):407-10 11.9+2.8 (48)# 6.7+3.4 (23)# Recent CAD <60y

Gambhir JK 2000 Indian Heart J. 52(4):511-5 35.0+32.4 (50) 20.3+17.0 (50) Young CAD <40y

Govindraju V 2003 J Ind Med Assoc. 101(8):458-60 32.2+1.4 (300) 30.0+2.6 (200) Stable CAD

Rajasekhar D 2004 Ind J Clin Biochem. 19(2):53-9 24.8+19.0 (151) 16.0+17.5 (49) Stable CAD

Wadhwa A 2013 J Assoc Phys Ind. 61(6):384-6 38.7+26.2 (40) 26.2+20.5 (40) Young MI <45y

Yusuf J 2014 Indian Heart J. 66(3):272-9 30.3 (450)* 20.0 (150)*

Bansal SK 2015 J Clin Diagn Res. 9(11):BC07-11 43.2+10.2 (30) 17.6+3.2 (30) Stable CAD <60y

Ramesh G 2018 Interv Med Appl Sci. 10(2):65-9 33.8+23.7 (51) 19.7+10.4 (51) Young MI <45y

Gupta MD 2018 Ind Heart J. 70(S3):S146-56 37.3+4.1 (125) 27.3+3.4 (103) Young MI <35y

Hanif S 2019 Pak J Med Sci. 35(6):1718-23 47.0+45.5 (90) 29.7+23.1 (90) Young MI <45y

*median value; #geometric mean; CAD coronary artery disease; MI myocardial infarction; **immunofluorescence technique

Reviewer #2: Manuscript Number: PONE-D-21-20756R1

Lipoprotein(a) as a risk factor for coronary artery disease in a South Asian population: A case control study

PLOS ONE

Thank you again for the opportunity to review this manuscript. However, I still have major issues that need to be addressed critically. Specific comments and questions are provided below.

1. The authors claim that it is a prediction study not causal or risk factor analysis. However, the title still reads as “…as a risk factor….”. The theoretical design, the approach to data analysis and interpretation of the study varies significantly for prediction and causal research. The description in the abstract and the whole body of the manuscript still reads as ‘…risk factor..’. In prediction, individual ORs do not have interpretive value. Prediction is not necessarily risk factor identification.

2. I still suggest authors consider evaluating the added value of LP(a) in predicting CAD along with other predictors such as tobacco, DM, etc.…. Whether statistically significant or not, AUC of 60% has minimal clinical importance. It is better to develop a multivariable prediction model with and without LP(a) and assess the added value.

3. Although LP(a) is not normally distributed, using mean with SD is not justified enough.

4. Whether significant or not on the univariable analysis, the main predictor of interest (LP (a)) should be included in the multivariable analysis.

5. I commend the authors for uploading the data used to produce this manuscript. It helps for open science. Looking in to the supporting information (Data), there are lots of missing values. However, there is no description on the missing data. Did the authors check for the missingness pattern? How did they manage it?

6. In addition, the outcome variable and predictors are not clearly labeled in the data. I suggest authors make it more clear and transparent.

• In spite of the comment in round 1 to add for line numbers, the manuscript still doesn’t have page and line numbers, which make the review process difficult to refer to specific descriptions. As far as I understand, the author guideline requests to put line numbers to ease the review process.

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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

Reviewer #2: Yes: Hamid Y. Hassen

[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.

Attachments

Attachment

Submitted filename: Table 7.docx

PONE-D-21-20756R2Association of lipoprotein(a) with coronary artery disease in a South Asian population: A case control studyPLOS ONE

Dear Dr. Menon,

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 Apr 22 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Geofrey Musinguzi, MPH, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. The Tables are very lengthy and provide unnecessary information.

2. I would suggest that in each row, in Tables 1 and 2, the authors only retain the Yes (risk factor, positive findings) row and delete the No row. This would make the Tables less cluttered and easier to comprehend.

Reviewer #2: Manuscript Number: PONE-D-21-20756R2

Association of lipoprotein(a) with coronary artery disease in a South Asian population: A case control study

PLOS ONE

Thank you once more. The authors addressed most of my concerns. However, I still have issues that need to be addressed. Specific comments and questions are provided below.

1.The authors’ focus shifted from a kind of prediction research to “Association of lipoprotein(a) with coronary artery disease”. Thus, the study approach, statistical analysis and interpretation of results would also change. There are descriptions in the manuscript that seem for prediction type of research. Here are some of the descriptions in the manuscript that confused risk factor identification research to prediction…

•First sentence of the discussion section still reads as “The study results suggest that Lp(a) has a modest predictive accuracy for CAD especially in subjects ≤50 years of age.”

•The first sentence of summary (page 13, line 13-14) also phrased as “In summary our study suggests that Lp(a) is an important predictor for CAD especially in the age group < 50 years.”

•The conclusion section of the abstract.

•Abstract line 13

•Analysis section, page 7 line 3 to 8. This description of analysis is still on prediction.

•Result page 10, lines 5 to 9: these descriptions are for prediction type of research.

•Even the justification of this study (last paragraph of the introduction) is prediction and risk stratification, which are the purpose of prediction research.

•Many more….

These sentences lead to an impression that the study is predictive. Better to revise it.

2.Result: page 8 line 5 to 6: “In cases, 39.3% had higher levels of Lp(a) as compared to 19% in controls and this was statistically significant (p=0.053)”. You set your significance level p<0.05 in the analysis. But here, P=0.053 is considered as significant. Revise the numerical inconsistency.

3.There are some grammar and spelling issues that need to be addressed to improve readability.

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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

Reviewer #2: No

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Association of lipoprotein(a) with coronary artery disease in a South Asian population: A case control study

PONE-D-21-20756R3

Dear Dr.Ravindran,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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,

Geofrey Musinguzi, MPH, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 comments.

Thanks for submitting the revised version. All the comments have been incorporated in the manuscript.

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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