PONE-D-21-13763

A logistic regression model based on inpatient health records to predict drug-induced liver injury caused by ramipril – an angiotensin-converting enzyme inhibitor

PLOS ONE

Dear Dr. Nguyen,

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.

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Edford Sinkala

Academic Editor

PLOS ONE

Additional Editor Comments:

There is need to include limitations in this study. Discussion section has a lot of numbers that are supposed to be confined to the result section. Please discuss the results in the discussion section

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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: Partly

Reviewer #2: Yes

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

Reviewer #1: No

Reviewer #2: Yes

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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: No

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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: Reviewer comments

i. In line 25 in the abstract there is an error

ii. In line 40, there is a statement that “age has been associated with a higher risk of Drug Induced Liver Injury” but it is not clear the direction of association.

iii.

iv. In line 41, the authors have indicated that “female sex appear to be more susceptible to DILI compared to man” Authors should consider using a more appropriate adjective “male”

v. In line 44, the authors indicated the National Institutes of Health maintains a searchable database of drug but there is no indication where this institute is. This should be made clear.

vi. The authors assessed the risk factors of DILI during ramipril and establish a logistic regression model to estimate the DILI of inpatients using ramipril in Vietnamese people. How the authors did insured that all the participants in this study were Vietnamese since they were using retrospective hospital records? What was the definition of someone to be Vietnamese in this study?

vii. The authors have indicated that the used data for the year 2018 to 2020. What was the justification for using data between this periods? What was the defined follow-up time in this study since it is a retrospective cohort study?

viii. In this study there is no indication when it was conducted.

ix. In line 73, authors have indicated that this study was reviewed and approved by the Hai Phong International Hospital Institutional Review Board, Vietnam but there is no reference to provide evidence.

x. In line 74, there is a statement that this study was conducted in accordance with the Declaration of Helsinki and the International Conference on the Harmonization of the Technical Requirements for the Registration of Pharmaceuticals for Human Use - Good Clinical Practice guidelines. This deserves to be referenced.

xi. Even if this data was obtained from some database, include epidemiological questionnaire that was also used to gather sociodemographic and clinical data for this study. Please explain thoroughly how the questionnaire was designed, implemented, filled, and checked for accuracy and completeness.

xii. In line 78, what ACEB compounds?

xiii. In line 82, there is an indication that ALT and ALP had upper normal limit. What were these limits?

xiv. Authors need to indicate the duration of exposure to ramipril and dosage as well as those on ACEIs.

xv. Since this study used clinical assessment as part of DILI diagnosis and it is possible that different physicians with different clinical experience could have led to similar patients classified differently or different patients classified in the same group resulting in misclassification. How did authors dealt with this issue?

xvi. Specifically, what clinical parameters were used for DILI diagnosis by clinicians?

xvii. It is important for authors to report the other drugs patients were on apart from ramipril since this not a randomized clinical trial. Further, dosages and duration of treatment for ramipril and ACEIs that were used should be reported.

xviii. In line 100, the authors have indicated that they collected data on height, weight and BMI. BMI can be important in explain DILI but this variable and others has not be reported anywhere in the results section. What could be the possible explanation for this omission?

xix. In line 101 one of the variable collected was history but it is not clear. History about what?

xx. In line 106 authors have indicated that they mapped the variables collected by the MHR to 32 discrete variables and they have referred to Figure 2 which is not detailed. It is not clear what these 32 variables were?

xxi. In line 111, R statistical software should include manufacturer, name and country should be added in the manuscript.

xxii. Line 111, authors used forward variable selection method when constructing logistic regression model. What was the justification for choosing this method as oppose to other methods? Further, in forward selection inclusion of a new variable may make an existing variable in the model non-significant. How did the authors dealt with this drawback? If so how?

xxiii. In 128, the use of abbreviation H0 should first be written in full before using it even if it is a well- known abbreviation.

xxiv. Line 138, indicates that ethical approval was obtained from the ethics subcommittees of the Hai Phong International Hospital. Authors need to provide evidence by including the reference number.

xxv. In this study, authors have claimed that rimipril caused DILI. It is important to recognize that causality cannot be established definitively through a retrospective cohort study which is an observation study; however, such studies are powerful tool that can provide important evidence to suggest causality, as well as information regarding the strength of an association between ramipril and DILI. What authors have reported is an association between ramipril and DILI.

xxvi. It is important for authors to give a biological plausibility to establish the observed relationship and identify a scientifically valid mechanism by which the ramipril can associated with DILI.

xxvii. Surprisingly, authors have not included limitations in this study and the findings of this study could be distorted by many factors not limited to biases, misclassification and measurement error, confounding and effect modification (also called “interaction”).

xxviii. In line 147, under the results for table 1, the footnotes are not complete.

xxix. In line 151, authors have reported that “average age of 64.2, and the majority were men (57%)”. Authors should explain the central measure of tendency used with units and why? Further, the reported percentage should be accompanied by an absolute number.

xxx. In line 154, there is a statement that “on the day of admission, the ALT test results of the ramipril group averaged 31.8 74.6 (UI 155 / L)” This should be made clearer to the readership. This applies to a number of sections where such results have been reported.

xxxi. In a number of sections such lines 158 and 159, authors have not indicated the reported central measure of tendency. This should be made clear.

xxxii. In table 2, authors have reported (n±SD) suggesting number and standard deviation for age and length of hospital stay. This is not appropriate. Standard deviation should be reported with appropriate measure of central tendency. This applies to the other tables in the results section.

xxxiii. What statistical tests were performed to obtain the p-values for different variables in table 2 and other tables in the results?

xxxiv. Although there are some footnotes under table 2, there are some still missing. This applies to table 3a.

xxxv. What were the comorbidity in the study?

xxxvi. The authors used multivariate logistic regression model. Was this really multivariate logistic regression or multivariable regression?

xxxvii. In the discussion the authors keep repeating the estimate (odds ratio) and p-value. This is repetition of results. Authors should just discuss!

xxxviii. In line 245, there is a statement that “on the day of DILI, the ALT and ALP levels in our patient were elevated by 8.2” Which particular patient is being referred to and why?

xxxix. Authors should make it clear whether which method of analysis they used. Either intention to treat analogue or per protocol analysis and why?

xl. Authors have recommended that clinicians should be aware of age and liver disease before prescribing ramipril to avoid the risk of DILI in patients. This is surprising since age showed no difference between DILI and ACEIs groups as well as liver disease at 97.5% CI. What was the rational for this recommendation?

Reviewer #2: A well written paper on an important subject. The following corrections should be made.

Line 65, the word first is out of place, one expects it to be followed by a second action, which is not done in this sentence.

Line 72-26 - Subjects

This sentence belongs to the ethics section, not where it is currently.

Line 154-156 - the ± sign is missing from the numbers in the text and needs to be corrected.

Analysis

Sex and duration/how long someone has been on treatment, although found to be important factors in other studies, have not been included in the model or discussed at all. This needs to be explained.

Discussion

A discussion of factors associated with DILI from Ramipril (from the modeling) needs to be placed within the context of findings from similar studies in the literature. This has not been done. Are your findings novel, similar or different from those found by similar studies?

Limitations

Authors need to discuss the limitations of their findings. Why should we believe these findings?

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Reviewer #1: Yes: Dr Patrick Kaonga, University of Zambia, School of Public Health, Department of Epidemiology and Biostatistics

Reviewer #2: No

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PONE-D-21-13763R1A logistic regression model based on inpatient health records to predict drug-induced liver injury caused by ramipril – an angiotensin-converting enzyme inhibitorPLOS ONE

Dear Dr. Nguyen,

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. PLOS ONE's publication criteria require that the data presented in PLOS ONE manuscripts must support the conclusions drawn (http://journals.plos.org/plosone/s/criteria-for-publication#loc-4). We have some concerns about the conclusions in the manuscript. This is a retrospective observational study. However, here there are claims related to causation, e.g. "Our study demonstrated that using ramipril increases the risk of DILI" and "We found that taking ramipril increased the 2.68-fold risk of DILI (OR=2.68, p<0.001) compared to other ACEIs". Please revise your manuscript to address any instances of claims that are not supported by your results, e.g lines 251-252, lines 259-260 and lines 266-268 and also address the limitations of your study.

Please submit your revised manuscript by Jun 20 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.

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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,

Miquel Vall-llosera Camps

Senior Editor

PLOS ONE

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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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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: 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: All comments that were raised in the previous version of the manuscript have been addressed. In my opinion the manuscript is ready to be published in PLOS ONE.

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Reviewer #1: Yes: Patrick Kaonga - Post-doc, PhD, MPH

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PONE-D-21-13763R2A logistic regression model based on inpatient health records to predict drug-induced liver injury caused by ramipril – an angiotensin-converting enzyme inhibitorPLOS ONE

Dear Dr. Nguyen,

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 Jul 07 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.

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,

Jorge Enrique Machado-Alba, M.D; Ph.D

Academic Editor

PLOS ONE

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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 #3: (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 #3: No

**********

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

Reviewer #3: 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 #3: No

**********

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 #3: No

**********

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 #3: This study is about establishing approaches to predict the ramipril induced liver injury. Authors selected 1686 inpatients to generate 3 models predicting DILI by using logistic regression. But the processing of building risk estimation models is not clear, what are the criteria to keep those variables in model 1, 2, 3, respectively. Authors stated they used 2-fold cross-validation technique to evaluate the predictive performance, but the validation evaluation results with a1 and a2 were not presented. When doing the performance measurement by using ROC curve, authors did not provide the risk scores and corresponding cutoff points of each model. Based on the ROC curves, three models have perfect performances of predicting IDLI, but it was too good to be true because all three models can nearly predict every DILI case with very small part of false positive. If this paper just only wanted to identify the risk factors for ramipril induced liver injure prevention, the odd ratio (OR) of multiple regression is enough for drawing reliable conclusions.

Furthermore, Table 2 is not necessary because it is not relevant to the study purposes. Instead, characteristics of included patients (1686) should be presented in results part.

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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 #3: Yes: Yong Zhang

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Attachments

Attachment

Submitted filename: PONE-D-21-13763_R2_reviewer05282022.docx

PONE-D-21-13763R3

A logistic regression model based on inpatient health records to predict drug-induced liver injury caused by ramipril – an angiotensin-converting enzyme inhibitor

PLOS ONE

Dear author,

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 Jul 15 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,

Jorge Enrique Machado-Alba, M.D; Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Dear authors

We send you the comments of the evaluators of your manuscript so that you can carry out the corrections.

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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 #3: (No Response)

**********

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 #3: No

**********

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

Reviewer #3: 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 #3: No

**********

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 #3: No

**********

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 #3: The revised paper added more details and solved some of my concerns. But still I have little confidence about the reliability of those three models, because they are too good to be true (I can’t believe it!). Authors, based on their models, created 3 new indexes. We can call these indexes as risk score and authors this time provided the optimal cutoff points of those 3 risk scores for predicting of DILI. By using these risk scores, we then could perfectly predict the DILI. It is out of common sense because the components of those risk scores have weak or not strong impacts on DILI with margin positive OR values (in table 4). Therefore, in order to justify the performance of those models, author should double check their analysis and provide the details of those 3 risk scores in their studying population.

**********

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 #3: Yes: Yong Zhang

[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.

PONE-D-21-13763R4

A logistic regression model based on inpatient health records to predict drug-induced liver injury caused by ramipril – an angiotensin-converting enzyme inhibitor

PLOS ONE

Dear Dr. Phuong Thu Nguyen, MD, PhD,

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.

We await your responses to complete the process with your manuscript.

Please submit your revised manuscript on August 13, 2022. 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,

Jorge Enrique Machado-Alba, M.D; Ph.D

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.

[Note: HTML markup is below. Please do not edit.]

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 #3: 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 #3: Yes

********** 

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

Reviewer #3: 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 #3: No

********** 

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 #3: 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 #3: New version of the paper is much more reasonable. In methods part, there is a content of model evaluation with 2-fold cross-validation (page 7), but the evaluation results were absent. I believe readers like me may have some interests about the results of model evaluation.

********** 

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 #3: Yes: Yong Zhang

**********

[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.

PONE-D-21-13763R5

A logistic regression model based on inpatient health records to predict drug-induced liver injury caused by ramipril – an angiotensin-converting enzyme inhibitor

PLOS ONE

Dear Dr. Nguyen,

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 Aug 26 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.

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,

Jorge Enrique Machado-Alba, M.D; Ph.D

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.

[Note: HTML markup is below. Please do not edit.]

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 #3: (No Response)

********** 

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 #3: Partly

********** 

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

Reviewer #3: 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 #3: No

********** 

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 #3: 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 #3: Authors responded me with some R software codes, but not really addressed my concerns.

In this study, whole dataset was divided into two subsets to do cross-validation. Each subset will generate an optimal model with logistical regression method. Therefore, there should be two models for validation by the other subset. Then, by comparing MSE (mean squared error), Then the best model will be decided (validated). Last time, I asked for author to present the validation results. Authors responded that table 5 and figure 4 were the validation results. But I think those are results of performance evaluation.

Usually, we use one dataset or subset to generate one model, i.e. one regression equation. But the 3 datasets or subsets for each 3 model were not clearly given in this paper. Therefore, methods about the 3 models should be described with more specific details.

Besides, in page 7 line 127, about model development, “differences among groups were analyzed…”, What does the group in this sentence refer to? and results about groups differences were also not provided.

********** 

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 #3: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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.

A logistic regression model based on inpatient health records to predict drug-induced liver injury caused by ramipril – an angiotensin-converting enzyme inhibitor

PONE-D-21-13763R6

Dear Dr. Phuong Thu Nguyen,

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,

Jorge Enrique Machado-Alba, M.D; Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear authors

Congratulations, your work has been accepted for publication.

Jorge Machado

Academic Editor