PONE-D-20-20071

Opioid use as a potential contributing factor to the rise of pancreatic cancer; an analysis of state and national level databases from the United States

PLOS ONE

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Academic Editor

PLOS ONE

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Reviewers' comments:

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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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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: The authors present results of a study using state and national level databases to assess the association between opioid use and pancreatic cancer. Using mixed effects models and state level data across 16 years of observation, authors find that opioid death rates are associated with incident pancreatic cancer rates 4 years later as well as change over time in the incident pancreatic cancer rates. They conclude that opioid use may account for some of the increase in pancreatic cancer. The manuscript will be strengthened if the authors consider the following points.

1. Authors are using estimated values from a variety of sources (and include 95% confidence intervals in the supplemental tables). Did the authors use the uncertainty in these values in any way in their analyses? At least some mention of this as a limitation would be good.

2. Were the assumptions of normality met for the outcomes evaluated with the mixed effects regression model? I am wondering about the opioid death rates in particular.

3. In the results, authors interpret the multivariate model results and in particular mention that obesity rate was not associated with the rate of pancreatic cancer. However, there is an interaction in the model (between obesity rate and opioid death rate), which makes the interpretation of the main effect not as straight forward. Authors should clarify their interpretation. Also, it is not clear from the table whether this interaction was an interaction with time. The coefficient in the text differs slightly than that in the table, so that should be corrected. The sentence in the text reporting that interaction and the sentence following it likely should be combined (as the last sentence is an incomplete sentence).

4. The authors used lagged risk factors to predict the rates of pancreatic cancer. Did authors consider assessing how change in opioid death rates were associated with change in pancreatic cancer rates?

5. Do the authors have any comments about the limitations of ecologic analyses in the context of their question?

Minor points:

1. In the abstract, the authors give the result of how the opioid death rate predicted incident pancreatic cancer. Authors might want to clarify here that they are predicting incident pancreatic cancer 4 years later. Also, in the next line, authors talk about the significant effect on the estimated annual change. The earlier sentence refers to the initial level of a state's opioid death rate, but they appear to use the time-varying 4-year lagged variable, so the effect on change over time is not restricted to just the initial level.

2. Under Data collection: "This data was" should be "These data were" and authors refer to Tables 1-5, but I think they mean Supplemental Tables 1-5. ("this data" also appears in the Discussion section and should "these data").

3. Figure 1: Panels C and D use the same colors, but they have different meanings. Since authors likely want readers to visually compare the two graphs to see the changes in opioid death rates, authors should consider having the same rate categories and colors (where applicable) and then have additional categories/colors to more easily see the differences.

Reviewer #2: the highlighted text should be edited and rewrite. also potential ecologic fallacy is one of the limitations of the current study that should be addressed in the discussion. figures in the text had not good resolution.

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Reviewer #1: No

Reviewer #2: No

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Submitted filename: PONE-D-20-20071_reviewer (1).pdf

Opioid use as a potential risk factor for pancreatic cancer in the United States; an analysis of state and national level databases

PONE-D-20-20071R1

Dear Dr. Bishehsari,

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.

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Kind regards,

Ram K. Raghavan

Academic Editor

PLOS ONE

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