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PONE-D-19-24166

National U.S. Time-trends in Opioid Use Disorder Hospitalizations and Associated Healthcare Utilization and Mortality

PLOS ONE

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PLOS ONE

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Additional Editor Comments (if provided):

I have read this manuscript with great interest. I advise you to take note of the very detailed comments of both reviewers and respond accordingly. I look forward to your revised manuscript.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Yes

Reviewer #2: 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: The authors used 781,000+ hospital records from a National Institutional sample of hospitalizations for the period 1998 through 2016 to calculate rates of hospitalization by age race and gender for Opioid overdose Hospitalizations and in hospital mortality noting that the rates increase from 59.8 per 100,00 to 190 per 100,000 over the 18 years period.

They indicate that on a national basis this is one of the first and only papers to chronicle this information which makes it unique. They examined healthcare utilization outcomes over time. Can they move this forward by examining some of the regional differences in west, midwest, Northeast and south regions , are these all the same with regard to white and black and by age?

A geospatial map of rates or table would be helpful showing black , white Hospitalization rates as well as a regional difference map as opposed to a multivariate logistic regression which is interesting but does not show important nuances in time , person and place.

Much can be learned in the details of this study, Older white male rates of mortality and hospitalization have been detailed previously so presenting some of the details would prove to be important.

A few questions, they indicate older white opioid hospitalizations fared worse that black and younger admits. Please comment on the reasons for this , specifically what were the causes of death among older white admits ; was this just an age phenomenon or was there something specific to region or urban /rural.

Please show stratification by average days of hospitalization by age and gender and race.

OUD and old age can be linked to end stage cancer diagnoses, please provide the information of end of life related causes of death versus others.

How much of the co morbidity was opioid and drug related, aka, Hepatitis C, HIV and myocardial endocarditis and valvular disease?

ALso the logistic regressions should be given more detail with tables shown. What was the median length of stay hospitalization for those under 55 and over 55?

This data set has the ability to show important ground breaking information .

Reviewer #2: The authors conducted an observational study form National Inpatient Sample, and showed an increase in OUD hospitalizations and associated inpatient mortality. Age, sex, race, and Deyo-Charlson comorbidity index are independent factors of healthcare utilization and mortality related to index OUD hospitalization.

Is there any data to support these independent factors associated with healthcare utilization and mortality related to OUD hospitalization?

Some comorbidity indices have been developed to measure and weigh the overall burden of comorbidities, for example, Charlson comorbidity index(CCI), Deyo CCI, Romano CCI. Is there any special reason for choosing Deyo CCI in this article.

Minor point: Table 4: The form after “Rural” is empty. Should it be “Ref”?

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Reviewer #1: No

Reviewer #2: No

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National U.S. Time-trends in Opioid Use Disorder Hospitalizations and Associated Healthcare Utilization and Mortality

PONE-D-19-24166R1

Dear Dr. Singh,

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,

Sandra C. Buttigieg, MD PhD FFPH MSc MBA MMCFD

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

Reviewer #2: 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

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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

Reviewer #2: Yes

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

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

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

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

Reviewer #1: I have reviewed the revised version and believe the authors have satisfactorily addressed the comments of the reviewers. My only remaining concern is that when considering hospitalization data in a life table way, one would usually remove those individuals who have a primary secondary diagnosis of cancer as often an opioid overuse/abuse

may be due to end stage cancer and pain relief which is considered acceptable in most settings, In other studies this is acknowledged and those individuals are removed prior to the analysis and/or are enumerated in the preliminary methods portion of the paper, I did not see this and so will leave it up to the editors to determine if they wish the authors to further comment on this adjustment.

Reviewer #2: The author's responce is complete, espeically in the part of first reviewer. I think expanded discussion and additional result will make this article meaningful.

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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.

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

Reviewer #1: No

Reviewer #2: Yes: Hsien-Yuan, Chang