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PONE-D-21-11112

Pre-hospital delay and its associated factors in Acute Myocardial Infarction in a developing country

PLOS ONE

Dear Dr. Chowdhury,

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.

Although all reviewers and editors found that this manuscript has merit and addresses a significant clinical problem, the reviewers raise some important issues. These comments include data presentation and statistical analysis (reviewer #1 and #2), discussion to be improved (reviewer #1 and #2), insufficient data on patients’ background, confounders, and quantitative hours of delay (reviewer #2), and sex differences (reviewer#2). In addition, among 333 patients, the number of patients who visited NICVD or ICHRI should be provided separately.

Please submit your revised manuscript by Jun 26 2021 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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We look forward to receiving your revised manuscript.

Kind regards,

Michinari Nakamura, MD

Academic Editor

PLOS ONE

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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: Partly

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

Reviewer #1: Yes

Reviewer #2: No

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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

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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

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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: OVERALL SUMMARY

This study presents conclusions for a cross sectional study conduct in a low-income country examining pre-hospital delays for patients seen for cardiovascular disease outcomes adjusting for potential confounders. The work is insightful and thought provoking. See below for comments from my review.

INTRODUCTION

The authors do not discussion findings from previous studies examining pre-hospital delay for cardiovascular outcomes.

Paragraphs 2 and 3 can be combined as they are talking about the same thought. After shortening the combined paragraph more can be added which presents results from actual scientific studies as opposed to just medial guidelines.

The introduction is not sufficient as it stands. The authors need to use past studies to make a case for the issue they are studying and point out the gaps in previous research that their research addresses.

METHODS

The authors need to define mid to lower socio-economic class populations. What income level is this? Can be different depending on country. This first paragraph on study location can be shortened. Its adequate to talk about the medical facility, its resources, and the population being studied. It would also be good to add where geographically these facilities are located and what is the median income/ other economic variables associated with the region. Have other studies also categorized this area as underserved? Should include a citation if so.

Bolding and quotations marks are not needed ** See author formatting guidelines.

Images should be included at the end of the text and follow journal formatting guidelines. ** See author guidelines.

RESULTS

Results from the 95% confidence interval should be presented in text with odds ratios in place of the p-values. P-values can be presented in the table alongside the 95% CI and OR estimates. However, it is more appropriate to present confidence intervals when discussing the odd ratios.

DISCUSSION

How do the demographics for your study compare with the demographics living in the study area? For example, a majority of patients in this study were 51-70 years of age (no doubt due to the condition of interest). It would be interesting to know if the area served by the medical facility is located in a generally older population setting.

The discussion was well thought out and included comparison to other studies.

Reviewer #2: Pre-hospital delay and its associated factors in Acute Myocardial Infarction in a developing country

This paper complements existing literature on AMI care in LMICs. The main logistic regression analysis could be strengthened with a stronger theory-based rationale for the variables used. The authors seem to choose the variables for the model empirically, rather than from a theory of what is most important. They describe the findings after the fact — e.g., reasons for diabetes associated with more likelihood of >12 hour delay because diabetes is associated with low-symptom AMI — but they should test these ideas within the data that they have. These additional analyses don’t need their own tables, but they can be reported within the text.

The analysis should as much as possible derive from which factors are most influential for policy and practice, such as identifying which populations to be targeted.

The hours of delay as a quantity is also important due to effect of each increment of delay on outcomes: e.g., authors say each 30 minute delay before PCI associated with greater 1-year mortality. dichotomizing the hours of delay and doing logistic regression loses information, and understanding quantitative hours is also important. In addition to the logistic regression, hours of delay is a count variable, and it could be modeled with an over dispersed Poisson or negative binomial regression.

The authors very clearly justify the 12 hour dichotomized variable. This dichotomized variable isn’t a rare event, so logistic regression give odds ratios that are much larger than the relative risks. A model such as Poisson with robust standard errors or negative binomial for this binary variable would give prevalence ratios, which can be interpreted as relative risks, and will be smaller than the odds ratios.

Women have different presentations of AMI, different social roles, and table 3 indicates that the median time to presentation is 21 hours. That’s astounding. Consider separating analysis into men and women, to see whether the associations differ.

The authors describe this study as cross-sectional. However, the authors followed the patients by medical records in addition to the survey, so it would be reasonable to describe this as a retrospective cohort study. The investigators’ design is actually a very usual retrospective cohort study.

The power is well-justified for a bivariate analysis. However, the authors do a multivariate regression analysis. The paper would be stronger with some type of sample size justification. Consider Gelman and Carlin’s Type S and Type M errors, at least to estimate probability that the estimates are in wrong direction.

Sentences shouldn’t begin with a number.

Table 1 includes prior PCI and CABG, but this section seems like it should have also prior AMI as complementary information. — presumably this information was recorded and excluded as oversight?

The authors group smoking/tobacco into just one variable. Mode of ingesting tobacco may be important to report separately (e.g., bidi), and also betel/areca nut, if these were asked on survey.

Table 2 gives just a few numbers and would be much more clear as a data display because clearly there’s a long tail on this distribution on time to arrive to hospital, and it’s very right-skewed. The information could be displayed in 4 histograms, for instance.

Tables should start on their own page and not run to the next.

Table 3 has a typo: under total column, percent of women is listed as 62.4%.

Age as dichotomized variable loses so much information. 3-5 groups may be more reasonable for age so the authors have a chance to detect an age effect.

The p-value in table 3 is strictly to test the dichotomized version of the variable. However, a test of the quantitative variable would also be useful. It doesn’t need its own column: test the medians using Wilcoxon and use asterix or bold to indicate significance. I suspect 4 hour median difference by hypertension status is significant.

The authors find in table 3 that in general people with risk factors take longer to get to the hospital: people with hypertension, diabetes, family history, and smokers. Why is this? Is this association due to socioeconomic status? Age? The authors can evaluate this question with their data.

The authors put a lot of variables into their logistic regression model that have multicollinearity, such as education and income. Putting many variables into a model and seeing what is significant doesn’t actually find out what is most important. The limited sample size makes this difficult, but some variables are so important that they could be stratified on. For instance, typical vs atypical symptoms, which is the largest effect. The variables associated with longer time for the atypical symptoms may differ from the variables important for people with typical symptoms. Distance from hospital is also very important. Other variables may be more appropriate to include as numbers, such as distance from hospital and income and years of education.

The regression has diagnosis as a predictor of delay, but diagnosis happened after the delay (after going to the hospital, that is) rather than before, so it’s not logical to put it into the regression. If there is a variable that is associated with the NSTEMI vs STEMI diagnosis that is apparent prior to going to the hospital, that would be more reasonable. In discussion authors mention less severe symptoms and say they can’t test. However, the symptom related variables collected in the survey may be associated with these.

The implications of this research for policy and practice should be thought about before choosing variables. For instance, if the question is which populations should be targeted for messaging about AMI symptoms, then the variables should correspond to demographic variables and also include interaction terms: e.g., between income and gender because low-income women may have longer delays than low-income men and than women overall.

“Diabetes Mellitus is not only a major risk factor of coronary artery disease, it also results in silent MI (25) and more atypical symptoms, all of which could contribute to delays in recognizing symptoms, and hence delays in presentation.” — this is interesting, and it’s a hypothesis that could be tested with the symptom data that was collected.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-11112R1Pre-hospital delay and its associated factors in Acute Myocardial Infarction in a developing countryPLOS ONE

Dear Dr. Chowdhury,

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.

The reviewers commented favorably on your manuscript, but had some worthwhile suggestions. The authors should address the remaining issues. I am pleased to accept your manuscript, based on your revising it.

Please submit your revised manuscript by Oct 28 2021 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.

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,

Michinari Nakamura, MD

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

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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

**********

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

Reviewer #1: No

**********

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

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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

**********

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: Authors made an excellent attempt at making all reviewer suggestions. Still a few minor things remain which affect overall interpretation and reading of the manuscript.

1) P values need to be removed from OR estimate sin the abstract and the results/discussion. You can leave them in the regression table, but it is most appropriate to interpret OR along with 95% CI's.

** You will notice for example that one of your variables was significant at the 0.03 level but the interval included 1, meaning although statistically significant it could not be as influential as others which did not include 1 in the interval.

2) Did you logistic regression include two outcomes? If not, then the regression that was conducted was a multivariable logistic regression, not a multivariate. Univariate logistic regression is a fine model selection to builds a final model, but realize that including all variables in a model may change the associations observed in univariate models. SOI in this way a forward or backward variable selection process maybe more appropriate than using univariate logistic regression to identify influential variables.

** The wording for multivariate needs changed. The other comment doesn't need included in the manuscript, other than to point out in the discussion that there are potential confounders not included in bivariate models.

3) Although the authors include a paragraph which mentions previous studies, they do not present specific findings from these in the introduction. This change is needed to enhance the readers experience and understanding for the current state of myocardial infarction in that country.

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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

[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.

Pre-hospital delay and its associated factors in Acute Myocardial Infarction in a developing country

PONE-D-21-11112R2

Dear Dr. Chowdhury,

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.

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Kind regards,

Michinari Nakamura, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: