PONE-D-19-18906

Persistent frequent emergency department users with chronic ambulatory care sensitive conditions: a population-based cohort study

PLOS ONE

Dear Mr Chiu,

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 methodology of this study presents several shortcomings and there are relevant points in the manuscript that need further clarification:

1. The criteria for inclusion and exclusion of patients are questionable. Please, reconsider it according to the comments of the reviewers.
2. Besides, I have serious doubts about the use of ACSCs in this study. The authors selected patients with “at least one ED visit during the inclusion period, i.e. between the 1st of January 2012 and the 31st of December 2012, and diagnosed with an ACSC “. It would seem logical to assume that all the ED visits were categorized into ACSC and non-ACSC; afterward, the patients with an ACSC visit would have been followed for a three year period. However, I am not sure that this was the case. There is not any mention in the manuscript of the diagnoses or reasons for visiting the ED, but antecedents of chronic diseases instead. The concept of ACSCs is referred to conditions for which the adequate use of primary care services could avoid admissions or ED visits. Consequently, it is not appropriate to regard as ACSC the visits due to other reasons in patients whose chronic pathologies are adequately controlled in primary care or elsewhere.
3. In the statistical analyses it is not clear the reason for splitting the sample into training and validation ones.
4. Also, the comparison of the results of only two groups (“persistent & frequent” vs. “frequent but not persistent”) seems insufficient. A better option will be to include also a third group of “no frequent users” .
5. Follow all the valuable comments of the reviewers.

We would appreciate receiving your revised manuscript by Sep 21 2019 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.

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Juan F. Orueta, MD, PhD

Academic Editor

PLOS ONE

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Alain Vanasse has received grants for unrelated research from AstraZeneca Canada Inc. The authors declare no other competing interests.

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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: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

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: No

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: Thank you for the opportunity to read this manuscript, which concerns itself with a) estimating the prevalence of persistent frequent ED use, 2) identifying factors associated with this use and 3) comparing characteristics of frequent and non-frequent users. While I have offered comments to strengthen the paper should these authors resubmit to PLOS-One or elsewhere, I am not sure that it can make a contribution to this literature for reasons I detail in my comments. Ultimately, the fact that the study is described as a population based cohort study but the outcome variable was operationalized for only a subset of cases (and the fact that this is not clear in the manuscript) detract from the paper and preclude me from being able to recommend it for publication.

I offer comments by section.

Introduction

My initial comments were relative to the number of and appropriateness of the references in the introduction section. I would like to have seen more references (and potentially more explication) for the first set of assertions in the paper (e.g. the entire first paragraph). For example, even the second sentence (“Definition of frequent users varies depending on the context, though the most common definitions include having more than three or four visits during a 12-month period”) only includes one citation, the pertinence of which is not immediately appreciable. The premises in this paragraph form the bulk of their argument and feel insufficiently motivated (referenced) and under also under-nuanced. Is this true for cancer patients, patients with cancer related pain, the frail elderly, etc.? I am, in general, against language that suggests that patients “over-use” emergency care, when the situations of these patients’ lives is often such that it does represent the best care option for them at the time they choose it. Similarly, what is meant by ‘vulnerable’ patients on line 60? More detail and nuanced description of patterns of emergency care use are needed overall in the introduction. Although they have cited Billings (2013), it feels as through they have missed the subtleties of this piece.

As an other example, the exclusion from the cohort of patients who had died within 3 years of their index visit strengthened my opinion that the intro section could do a better job with the nuances of what constitutes ‘frequent and persistent use’ as in some cases (terminally ill patients) there may well be another definitions. I had also initially commented that looking deeper into this literature would also provide guidance for these investigators about whether it is in fact true that “no study exploring persistent frequent use with ACSC has been published.”

However – as I read further in the manuscript and identified the issue of ‘outcome cases’ vs ‘reference cases’, and realized that the analyses in the paper are actually relative to ‘persistent and frequent users’ vs ‘frequent users’, I felt that the intro should also be revised in light of this focus. The reader assumes that the study is about ‘high users’ vs ‘non high users’ when in in fact is it about ‘persistent high users’ vs ‘episodic high users’. The literature review provided does little to shed light on hypothesis that may relate to ‘those with frequent use’ vs ‘those with persistent frequent use’. In fact, it is a bit misleading to imply that this is a ‘population based cohort study’ when in fact less than 10% of the sample is utilized for the primary analytic aim of the study.

Materials & Methods Section

Consistent with my comment above – I felt that the method section should make it clearer early on what cases comprise the actual analytic sample in this study. The reader does not know until Table 3. Figure 1 should be similarly revised to reflect this.

Other comments:

Is the RAMQ datasource actually exhaustive? i.e. is it literally all adult patients in the province? Please detail, for American readers this is going to be a difficult concept to grasp. Does it contain all the variables used, or is it matched with (an)other data source? It wasn’t entirely clear to me if the RAMQ and the RAMQ administrative data are the same. If not, was it possible to match all cases in the cohort across the databases used? Cases lost (if any) during this process should be detailed in Fig. 1.

As cases were excluded for rural residential status with no/low metropolitan influence (but cases with rural status with high metropolitan influence were included), this variable should be more clearly defined.

The splitting of the testing and validation samples should be described in more detail, this is a somewhat unusual technique and deserves further explication. What is the rationale for this approach over others? Does it have any implications if there are temporal dependencies in the data?

Most importantly, and weaved throughout all my comments: In the section ‘Outcome and Dependent variables’, it should be made clearer that the binary outcome was ‘persistent & frequent users’ compared with the reference category ‘frequent but not persistent’. I was somewhat surprised when I reached the results section to see that this was the case. It is natural, given the language used and overall framing of this study, for the reader to assume that the reference category in analyses is going to be ‘non frequent (non persistent) user’ (e.g. the rest of the sample). This should also be addressed in figure 1, as the reader cannot tell (easily) from either the text or the figure what N was actually used in analyses (one does not see it until Table 3). It is difficult to tell if everyone who was not in the ‘persistent’ category were by default included in the other category? There must certainly have been cases for whom the index visit was the only visit? Is it fair to categorize them as ‘frequent but not persistent’? This is quite confusing until one reaches Table 3.

I was going to comment on the applicability of logistic regression with such a low frequency of cases on the outcome compared to the reference category, until I realized what was going on with the reference category (there is in fact a reasonable distribution of cases to controls in the analytic sample). Unless I am misunderstanding, these analyses really only include the approximately 13,000 cases categorized as either ‘persistent frequent’ or ‘frequent but not persistent’. This has to be made clearer throughout the manuscript. The rationale for not using the other (more obvious) reference category should be presented and as I said above, the introduction section should be made consistent with this approach.

However, the paper still requires more detail on the backward selection technique used – did it result in only sex and age category as control variables, as is implied? This is confusing as Table 2 presents the odds ratios for many predictors in the multivariable model.

Results

As the sample was split for training and validation it should be clarified in the Tables what sample(s) were used for which analyses. It is not stated what the N’s are that resulted from this process (size of each subsample), and as I highlight below, it remains somewhat unclear throughout the rest of the paper when the split samples were used, and what size the split samples were with respect to the total, frequent users, and persistent users. The fact that this study rests on approx. 13,000 cases is fine, but it should not be represented in the paper as being based on the full sample.

Reviewer #2: The manuscript by Chiu YM et al. analyze in an adult population characterized by an ambulatory care sensitive conditions (ACSC) the prevalence of and the factors eventually associated to the condition of persistent frequent users in the Emergency Department. The manuscript is clearly written, data are well collected and the conclusions are well supported by novel and interesting results.

My main methodological concern is related to some criteria used for the selection of the experimental sample. In particular previous studies (see in particular PLOS ONE |2016 Dec 14;11(12):e0165939. doi: 10.1371/journal.pone.0165939. eCollection 2016.) have shown that older patients present clinical and social characteristics related to the definition of “elderly frail frequent users”. This data do not seem to be confirmed in the present study. Is it possible that the exclusion of patients affected by dementia and of patients died in the three years following their index may have caused a bias in the interpretation of data considering that dementia is strictly correlated with the old age? The authors need to discuss this issue.

Furthermore the authors state that previous use of ED turned out to be the most important factor for all methods in encouraging the transition from occasional to persistent frequent users. My question is why does this happen? Which are the mechanisms linking the previous ED use to the transition in persistent frequent user?

Can the authors provide some data about the hospital admission of the occasional and persistent frequent user? It is not clear to the reviewer the data “Previous hospitalization” in Tab. 3, please clarify this issue and eventually discuss these data.

Page 15, line 235: What do the authors mean for “...heavier ED history.” ?

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Reviewer #1: No

Reviewer #2: No

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PONE-D-19-18906R1

Persistent frequent emergency department users with chronic ambulatory care sensitive conditions: a population-based cohort study

PLOS ONE

Dear Dr Chiu,

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. Although the revised manuscript has improved, there are several important concerns that remain inadequately addressed.Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process:

- Most of the mentions of ACSC found in the title, text and tables are misleading. Almost universally, ACSC are referred to preventable hospitalizations or ED visits potentially avoidable. The population of this study are all the patients with any of a group of chronic diseases that visited ER. Such diseases could be considered as ACSC if they would have been the reason for such visits. Consequently, in order to avoid confusion for the readers, the term ACSC should be replaced by “chronic conditions” or other similar.

- As reviewer 2 points out, I do not find a sufficient reason to exclude the patients with dementia. It seems plausible that such patients presented different health care needs to others subjects, but the same reason can be argued in relation to other diseases (for example HBP compared to asthma, COPD, or CHF) or age-groups.

- The authors should also follow the recommendations of reviewer 1 about the statistical model, inclusion of measures of model fit, and presentation of the results.

We would appreciate receiving your revised manuscript by Dec 30 2019 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,

Juan F. Orueta, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments:

Besides, there are some minor errors in the draft. The description of the process to exclude patients presented in text (page 7) does not follow the same order as the one in figure 1; it seems to be a typo in the number and percentage of patients due to death. Also, in discussion (page 16, line 261) it is stated that “deprivation indices were not significant in our analyses”, in contradiction to the results of the study.

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: (No Response)

Reviewer #2: (No Response)

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

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

Reviewer #1: Yes

Reviewer #2: Partly

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

Reviewer #1: No

Reviewer #2: Yes

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

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

Reviewer #1: No

Reviewer #2: No

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

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

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

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

Reviewer #1: I think the paper is improved with the changes. The purpose is clearer and the samples included in the analyses are also clearer. However, I continue to have some questions about the statistical approach and statistical conclusions, and the reporting of the results as well.

There is still an issue in these logistic regressions concerning the rarity of the outcome for the group ‘Persistent frequent users’, which comprise only 1/10 of 1% of the sample. As these models are inferential models intended to produce generalizable inferences about relationships between predictive factors and membership in a rare utilization group I think the models need more attention. Especially given the number of predictive variables (and their levels) considered in these models. (As an example, I wonder how many cases there are in the multidimensional cross-tabs of ‘age >-85 and ‘ has ACSC diabetes’, given all the other predictors. One might assume that this multidimensional cell size is quite small.) I think that in order for the results from these models to be credible some additional sensitivity analyses are warranted. I recommend considering Firths’ penalized logistic regression (Puhr R, Heinze G, Nold M, Lusa L, Geroldinger A. Firth‘s logistic regression with rare events – accurate effect estimates and predictions? Statistics in Medicine 2017.).

Additionally I strongly recommend the variable and model screening processes be reported as well as some measures of model fit, at a minimum an R2 measure, and possibly also ROC/AUC or information criteria measures for model fit and precision in order to allow readers to gauge for themselves how these models fit, and potentially how incrementally important the identified predictors are relative to a baseline model.

Reporting issues:

the statistical analysis section states that the first result is ‘prevalence of persistent frequent ED use’, however Table 1 does not contain that result (rather it reports ‘frequent users’). Is this a typo in the table?

Pg 11, line 207-208 should specify if the results presented in Table 2 represent the results of 2 separate models comparing 1) occasional frequent users to the entire sample and 2) comparing Persistent frequent users to the entire sample (vs comparing these two groups to each other) because it is still confusing. Additionally, the N’s should be reported in this table.

What are the cells in Table 2 that contain a ‘-‘? Were those coefficients not estimable?

Reviewer #2: The revised version of manuscript by Chiu YM et al. responded only partially to our concerns and also to the important concerns of other reviewers and to the Journal Requirements. In particular I continue to be convinced that not consider older people with chronic diseases such as dementia who, in my opinion, often could be considered as ambulatory care sensitive, may cause a bias in the full interpretation of the problem.

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Reviewer #1: No

Reviewer #2: No

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

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Persistent frequent emergency department users with chronic conditions: a population-based cohort study

PONE-D-19-18906R2

Dear Dr. Chiu,

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.

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With kind regards,

Juan F. Orueta, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: All comments have been addressed

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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: (No Response)

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Reviewer #1: Yes: Marianna LaNoue