PONE-D-19-21999

Validating the Chinese geriatric trigger tool and analyzing adverse drug event associated risk factors in elderly Chinese patients: A retrospective review

PLOS ONE

Dear Mr Xu,

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.

All 3 reviewers independently concluded there were major revisions required. The reviewers have provided detailed instructions which we invite you to address. There are concerns around structure, language and, most importantly, statistics. We would appreciate receiving your revised manuscript by Mar 16 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Katie MacLure, PhD, MSc (dist)., BSc (1st)

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"The authors would like to thank all the researchers for their participation in the study.

The authors also would like to thank the Cadre Health Care Committee of Sichuan (2018-103), which approved the planning, execution and analysis as proposed in the grant application.

Funding: The Cadre Health Care Committee of Sichuan supported this study."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

4. Please amend your manuscript to include your abstract after the title page.

5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: Partly

**********

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

Reviewer #1: I Don't Know

Reviewer #2: No

Reviewer #3: N/A

**********

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

Reviewer #3: No

**********

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: No

Reviewer #2: Yes

Reviewer #3: No

**********

5. Review Comments to the Author

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

Reviewer #1: Abstract:

The abstract is well-organised with the necessary information. Comments:

-Avoid using terms such as elderly by adopting term such as older adults

Methods: Describe how 1800 patients were selected

Conclusion: Why a shorter upgraded version ?

-Language use such as The aim of the study..

To attempt to shorten the list

Was calculated to use to select ..

Led to detect

METHODS

Sample size: Cite the calculation method: The sample size 67 was expanded to 600 cases per year.

Please explain what is subheading “Study Source” means

Please explain how this is possible: A sample of 25 cases was randomly selected from 74 eligible patients per half a month, for a total of 1800 cases

Unclear statement: There was 84 one “other ADEs” category, which comprised ADEs not related to one of the triggers listed above).

I understood the tool has been described in this article by the same authors: Hu Q, Qin Z, Zhan M, Wu B, Chen Z, Xu T. Development of a trigger tool for the detection of adverse drug events in Chinese geriatric inpatients using the Delphi method. Int J Clin Pharm 2019; 28. doi: 10.1007/s11096-019- 304 00871-x

-Is the sample used in this study considered as part of the presented data in the published article?

Conclusion: Try to avoid over-generalisation:

To our knowledge, this was the first study which included such a large sample to validate the Chinese 236 geriatric trigger tool and investigate ADEs in elderly Chinese elderly patients.

Conflict of interest in term of promoting the hospital unnecessarily: This hospital has been ranked second for 10 consecutive years in the composite index ranking of Chinese hospitals.

Reviewer #2: The authors have validated previously-developed prediction model for adverse drug events (ADEs). The model was upgraded by reducing the predictors (the triggers of ADEs). Higher positive predictive value was the goal of this study. I have several concerns before it can be considered for publication.

Major issues:

1. Line 55~67: Please be straightforward in ‘Study Design and Setting’. The commonly-expected information are the study design, name of hospital, country, and period of data extraction. The period information is still unavailable. No need to explain sample size estimation in this study that was already conducted, except for those subset of comparison that has no significant difference.

2. Line 123~124: Why did the authors choose significance level P<0.1, instead of P<0.05?

3. Line 81~83, 99~100; Table 1, 3~5: Please make a single table showing the trigger, unadjusted odds ratio (OR) with 95% confidence interval (CI) and P-value, adjusted odds ratio (aOR) with the same attributes, and positive predictive value (PPV) of each trigger. The OR is taken from a univariate logistic regression for each trigger while the aOR is taken from multivariate logistic regression including each trigger with variables of patient characteristics. There were a lot of significant differences in patient characteristics between patients with and without ADEs, while those were not variables of interest. These may affect association between each trigger and the outcome. Since this study aim to reduce the triggers from the original tools, only triggers with significant aOR should be included for the final model. Then both original and upgraded trigger tools should be fitted using the same configuration of multivariate logistic regression. The patient characteristics should be forced into the models either those using original or upgraded triggers. No predictor selection should be applied for the model using original triggers. This feature/predictor selection method may or may not be applied to the model using upgraded triggers. However, it is suggested to use the selection method if the authors want to reduce the triggers even more. It is also suggested to compare selection method (forward vs. backward vs. stepwise) since stepwise selection do not always give the best prediction model compared to other selection method. In the end, the PPV using all triggers can be calculated from the predicted outcomes of the models using either original or upgraded triggers. Meanwhile, the PPV should be calculated from univariate logistic regression including one trigger and patient characteristics without any selection method.

 

Minor issues:

Typos, grammatical errors, potentially-misleading statistical report, inadequate arguments in discussion, etc. are found in the manuscript. Please correct those. For example:

All lines: Please put superscripted citation after the punctuation (if available).

In line 69: Do you mean ‘Data Source’?

In line 70~71: … who had had a hospital stay of more than 24hours … (double ‘had’; miss the space in ’24hours’)

In line 74: The number of cases is a part of results. Please do not mention it in Methods.

In line 84: … of the triggers listed above) --> there is no pair of the parentheses?

Line 117: Do we really need to mention the widely-used Microsoft Excel 2016? What was the critical contribution of this software for hypothesis testing?

In line 137: … and respiratory systems 29-31, results which are similar … --> … and respiratory systems,29-31 which are similar …

In line 241: … underwent surgery.. (double punctuation marks)

Reviewer #3: In this manuscript, the authors aimed to evaluate the performance of the Chinese geriatric trigger tool to detect adverse drug events (ADEs) and identify the ADE-risk factors in elderly Chinese patients. The study is interesting, however, a number of issues should be addressed before its publication.

Major issues:

1. In table 1, the authors did chi-square test to evaluate the inter-group difference for categorical variables (Table 1). Can the author explain why the age grouping at 74 and 90? In addition, since the number of people over 90 is small, it might be better to merge 74-90 and 90- into one group. Otherwise, the calculated test value might be biased.

2. The authors used the stepwise logistic regression to find the risk factors for ADEs and used variance inflation factors (VIFs) to identify collinearity and remove the variables with VIF > 4. According to the author's description "stepwise logistic regression was performed for variables associated with diagnoses at a significance level of p < 0.1", there should be 13 variables (7 categorical variables and 6 continuous variables) in the initial model. It would be better to represent the process of stepwise logistic regression in the Appendix and tell the readers which variables were removed due to collinearity.

3. The results described in lines 139-143 were inconsistent with Table 3.

4. The explanation of triggers in lines 79-84, lines 159-164, and tables 4 & 5 were confusing. According to tables 4 & 5, there were 14 laboratory indices, and 7 plasma concentrations, which were different from lines 82-83. It was not clear how the authors separate 42 triggers into Table 4 and Table 5, as well as what the definition of positive was.

Minor issues:

1. There were some errors in table 1, for example,

# of patients with ADEs and # of patients without ADEs;

total number for ICU (Yes vs No) and patients without ADEs for ICU (Yes vs No.)

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Validating the Chinese geriatric trigger tool and analyzing adverse drug event associated risk factors in elderly Chinese patients: A retrospective review

PONE-D-19-21999R1

Dear Dr. Xu,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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.

With kind regards,

Katie MacLure, PhD, MSc (dist)., BSc (1st)

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 #2: All comments have been addressed

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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

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 #2: Yes

Reviewer #3: 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 #2: Yes

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 #2: Although the authors did not answered all my major or minor questions point-by-point, I managed to find the revised parts by myself.

Reviewer #3: All comments have been addressed in the revised manuscript.

One suggestion: It is better to separate the organ/system items in Table 3, or they might get mixed up.

**********

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 #2: No

Reviewer #3: No