Investigating the added value of biomarkers compared with self-reported smoking in predicting future e-cigarette use: Evidence from a longitudinal UK cohort study

Jasmine N. Khouja; Marcus R. Munafò; Caroline L. Relton; Amy E. Taylor; Suzanne H. Gage; Rebecca C. Richmond

doi:10.1371/journal.pone.0235629

Peer Review History

Original SubmissionMarch 2, 2020
23 Apr 2020 Decision Letter - Antonio Palazón-Bru, Editor PONE-D-20-06112 Investigating the added value of biomarkers compared with self-reported smoking in predicting future e-cigarette use: Evidence from a longitudinal UK cohort study PLOS ONE Dear Miss Khouja, 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 would appreciate receiving your revised manuscript by Jun 07 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, Antonio Palazón-Bru, PhD Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 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 https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 1. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. [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: Yes Reviewer #2: Yes Reviewer #3: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 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: Yes ****** 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 Reviewer #3: Yes ****** 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: In this article by Khouja et al, the authors used data from a cohort of young adults (ALPSAC) who were assessed for tobacco exposure using cotinine at age 15 and e-cigarette use using self-report at age 22. The authors found that cotinine levels were associated with higher risk of ever e-cigarette use, which was attenuated after adjustment for cigarette smoking patterns. Those who were labeled as “experimenters” and late-onset regular smokers had increased odds of ever using e-cigarettes at age 22. This study is important in that it demonstrates that there may be a temporal relationship between early cigarette use in adolescent and subsequent e-cigarette use in early adulthood. This reviewer suspects that the results are likely still confounded given the marked attenuation in measures of association after subsequent adjustment for cigarette use patterns. However no prior study had such granular data about tobacco exposure patterns at multiple points in time to correlate traditional cigarette use with future e-cigarette use. The authors are to be commended for this effort though this reviewer considers these results to be hypothesis generating given possible residual confounding and the use of multiple time points in this study. This certainly justifies the need for future studies with more frequent and timely assessment longitudinal changes in cigarette and e-cigarette use. While the long-term safety of e-cigarettes remains unclear, one cannot conclusively label e-cigarettes as being “safer” than cigarettes in the absence of long-term data. Of particular interest is pulmonary and cardiovascular complications associated with e-cigarette use. There may also be psychosocial comorbidities associated with e-cigarette use, There is therefore a concern that warrants the identification of risk factors associated with e-cigarette use. The authors also found discrepancies between objectively measured cigarette use (cotinine) and subjective measured use (self-report) whereby more than half of participants with cotinine levels indicative of active cigarette use indicated that they were current daily smokers. These results are certainly important and point to the limitations of self-reported data with regards to tobacco use be it cigarettes or e-cigarettes. The authors of the present study showed a higher risk of e-cigarette use with prior cigarette use. Do the authors also have follow up data at age 22 to determine the association between e-cigarette and cigarette use? Did the authors also examine the association between cigarette and subsequent current e-cigarette use (rather than ever)? These data would be interesting to see. Along similar lines, is there data on vaping patterns among current e-cigarette users? Reviewer #2: Dear authors, I have reviewed your manuscript and I only have two minor suggestions 1.L.256: the table S3 is very inclusive and informative, therefore it would be helpful for the reader if it was included in the results section in the main body of the manuscript (not as a supplementary material) . 2. L.381-387: please describe your study's limitations clearly as so, under a Limitations subtitle. Reviewer #3: The main claim of the paper is that biomarkers such as cotinine are more accurate than self-reported smoking in predicting future e-cigarette use. In my opinion the best way for the authors to assess that would be by performing a comparison between the smoking status in the age of 16 based on cotinine levels and the smoking status in the age of 16 based on self-report using chi-square in the population of e-cigarette vapers in the age of 22. In the 1st paragraph of the “Introduction” of their paper the authors state that: “Evidence suggests that e-cigarettes are considerably less harmful than smoking …........ frequent e-cigarette use among tobacco-naïve young people is rare”. Existing evidence are conflicting as far as: 1) The harmfullness of e-cigarette compared to tobacco cigarette, 2) The effectiveness of e-cigarette in aiding smoking cessation, and 3) The frequency of e-cigarette use among tobacco-naïve young people. Thus, in my opinion, based on the existing evidence, the authors should have had a neutral attitude concerning e-cigarette role on those aspects rather than a possitive one. In the 2nd paragraph of the “Discussion” of their paper the authors state that: “Furthermore, this evidence does not support the theory …... the relationship is more complex”. In my opinion such a conclusion cannot be supported by the results of this research. Such a conclusion could only come of by a research that would investigate the long-term smoking status of young people who started vaping without being tobacco cigarette smokers. Thus, in my opinion, this sentence should be drawn out of this paper. In the 6th paragraph of the “Discussion” of their paper (lines 346 – 355) the authors report that “early onset regular smoking was not clearly associated with later e-cigarette use but experimentation and late onset regular smoking was”. This was a finding in a period in which e-cigarette was not widely available. Nowadays, when e-cigarette is widely available, it is possible that a proportion of “late onset regular smokers” and/or “experimenters” might start vaping instead of smoking and turn to smoking or dual use later. In my opinion this should be discussed in that paragraph. ****** 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: Yes: Mahmoud Al Rifai 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. https://doi.org/10.1371/journal.pone.0235629.r001
Revision 1
10 Jun 2020 Author Response Dear Dr. Palazón-Bru, We would like to thank the reviewers for their time and efforts reviewing our manuscript. We have addressed their comments and provided details of edits made to the manuscript in light of the suggestions made. Reviewer #1 1. This study is important in that it demonstrates that there may be a temporal relationship between early cigarette use in adolescent and subsequent e-cigarette use in early adulthood. This reviewer suspects that the results are likely still confounded given the marked attenuation in measures of association after subsequent adjustment for cigarette use patterns. However, no prior study had such granular data about tobacco exposure patterns at multiple points in time to correlate traditional cigarette use with future e-cigarette use. The authors are to be commended for this effort though this reviewer considers these results to be hypothesis generating given possible residual confounding and the use of multiple time points in this study. This certainly justifies the need for future studies with more frequent and timely assessment longitudinal changes in cigarette and e-cigarette use. While the long-term safety of e-cigarettes remains unclear, one cannot conclusively label e-cigarettes as being “safer” than cigarettes in the absence of long-term data. Of particular interest is pulmonary and cardiovascular complications associated with e-cigarette use. There may also be psychosocial comorbidities associated with e-cigarette use. There is therefore a concern that warrants the identification of risk factors associated with e-cigarette use. The authors also found discrepancies between objectively measured cigarette use (cotinine) and subjective measured use (self-report) whereby more than half of participants with cotinine levels indicative of active cigarette use indicated that they were current daily smokers. These results are certainly important and point to the limitations of self-reported data with regards to tobacco use be it cigarettes or e-cigarettes. RESPONSE: We thank the reviewer for their positive comments about the importance and novelty of the study. We agree that these findings can be viewed as exploratory and hypothesis-generating, with the need for more research to investigate temporal relationships between smoking and e-cigarette use. However, we would like to emphasise the value of the longitudinal approach taken in our study, with the ability to rule out reverse causality. We also agree that discrepancies between cotinine and self-report identified in this analysis are of interest, particularly among those who report not smoking but who have cotinine levels consistent with being an active smoker (with the caveat of the differences in time of assessment). We appreciate the concern regarding the statements made around the safety of e-cigarettes, and have made the description more neutral since health risks have not been evaluated in this study. Page 4, line 49: “Evidence suggests that e-cigarettes could be considerably less harmful than smoking [3] and that they can be effective in aiding smoking cessation [4]. Furthermore, frequent e-cigarette use among tobacco-naïve young people appears to be rare [5]. However, concerns have been raised about the use of e-cigarettes by non-smokers and given the potential harms of e-cigarette use (e.g., adverse pulmonary [6] and cardiovascular [7] effects), further investigation of the potential risk factors for e-cigarette use is warranted.” 2. The authors of the present study showed a higher risk of e-cigarette use with prior cigarette use. Do the authors also have follow up data at age 22 to determine the association between e-cigarette and cigarette use? RESPONSE: In table 1, we show that ever e-cigarette users are more likely to have ever smoked than never users by 22 years (95% and 48% respectively; p<.001) and ever users were more likely to currently smoke than never users at 22 years (62% and 14% respectively; p<.001). We also provide the data at 16 years (Table 1) for comparison. Unadjusted odds ratios can be calculated with the data provided, but the main aim of the study was to assess cotinine levels in relation to future e-cigarette use. As described in our discussion, cotinine assessment at age 22 would not be able to distinguish cigarette from e-cigarette use, which was of importance to our study. 3. Did the authors also examine the association between cigarette and subsequent current e-cigarette use (rather than ever)? These data would be interesting to see. Along similar lines, is there data on vaping patterns among current e-cigarette users? RESPONSE: There are too few current e-cigarette users in ALSPAC (n = 111) who also have cotinine measures at 15 (n = 41) and also have data for all covariates (n= 28) to conduct any meaningful analyses on current e-cigarette users at 22 years. Limited data on patterns of use were collected at 22 years meaning we are unable to assess patterns of use. Reviewer #2 4. L.256: the table S3 is very inclusive and informative, therefore it would be helpful for the reader if it was included in the results section in the main body of the manuscript (not as a supplementary material). RESPONSE: We thank the reviewer for their suggestions, we have moved Table S3 to the main body of the manuscript (now Table 3). 5. L.381-387: please describe your study's limitations clearly as so, under a Limitations subtitle. RESPONSE: We have added a limitations subtitle (page 22, line 413). Reviewer #3 6. The main claim of the paper is that biomarkers such as cotinine are more accurate than self-reported smoking in predicting future e-cigarette use. In my opinion the best way for the authors to assess that would be by performing a comparison between the smoking status in the age of 16 based on cotinine levels and the smoking status in the age of 16 based on self-report using chi-square in the population of e-cigarette vapers in the age of 22. RESPONSE: We thank the reviewer for their comments and agree that a comparison between the prediction of self-report versus cotinine would be useful so we have added the following (page 14, line 283): “Furthermore, e-cigarette use at 22 years was more strongly associated with cotinine levels indicating active smoking (OR adjusted for age and sex = 10.47, 95% CI 4.88 to 22.46, p < .001), than with self-reported active daily/weekly smoking at 15 years (OR adjusted for age and sex = 7.77, 95% CI 5.09 to 11.85, p < .001), albeit with overlapping confidence intervals (Table 5).” 7. In the 1st paragraph of the “Introduction” of their paper the authors state that: “Evidence suggests that e-cigarettes are considerably less harmful than smoking …........ frequent e-cigarette use among tobacco-naïve young people is rare”. Existing evidence are conflicting as far as: 1) The harmfulness of e-cigarette compared to tobacco cigarette, 2) The effectiveness of e-cigarette in aiding smoking cessation, and 3) The frequency of e-cigarette use among tobacco-naïve young people. Thus, in my opinion, based on the existing evidence, the authors should have had a neutral attitude concerning e-cigarette role on those aspects rather than a positive one. RESPONSE: In line with the reviewer’s advice and the advice of Reviewer 1, we have amended this paragraph (see first response to Reviewer 1). 8. In the 2nd paragraph of the “Discussion” of their paper the authors state that: “Furthermore, this evidence does not support the theory …... the relationship is more complex”. In my opinion such a conclusion cannot be supported by the results of this research. Such a conclusion could only come of by a research that would investigate the long-term smoking status of young people who started vaping without being tobacco cigarette smokers. Thus, in my opinion, this sentence should be drawn out of this paper. RESPONSE: As suggested, we have removed this sentence from the manuscript. 9. In the 6th paragraph of the “Discussion” of their paper (lines 346 – 355) the authors report that “early onset regular smoking was not clearly associated with later e-cigarette use but experimentation and late onset regular smoking was”. This was a finding in a period in which e-cigarette was not widely available. Nowadays, when e-cigarette is widely available, it is possible that a proportion of “late onset regular smokers” and/or “experimenters” might start vaping instead of smoking and turn to smoking or dual use later. In my opinion this should be discussed in that paragraph. RESPONSE: This is an interesting hypothesis, but we feel this would be too speculative to include based on our results. However, on page 22 (line 408) we have re-emphasised that finding those who smoke infrequently or started smoking later in life are more likely to try e-cigarettes compared with early onset smokers “highlights a difference between certain groups of the population in likelihood to engage in e-cigarette use.” Attachments Attachment Submitted filename: 200603_Response PLOS ONE.docx https://doi.org/10.1371/journal.pone.0235629.r002
19 Jun 2020 Decision Letter - Antonio Palazón-Bru, Editor Investigating the added value of biomarkers compared with self-reported smoking in predicting future e-cigarette use: Evidence from a longitudinal UK cohort study PONE-D-20-06112R1 Dear Dr. Khouja, 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, Antonio Palazón-Bru, 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 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 #1: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 #1: 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 #1: 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 #1: The authors have satisfactorily answered my inquiries. I do not have additional comments and I think the paper is now suitable for publication. Reviewer #3: (No Response) ****** 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 #1: Yes: Mahmoud Al Rifai Reviewer #3: No https://doi.org/10.1371/journal.pone.0235629.r003
Formally Accepted
26 Jun 2020 Acceptance Letter - Antonio Palazón-Bru, Editor PONE-D-20-06112R1 Investigating the added value of biomarkers compared with self-reported smoking in predicting future e-cigarette use: Evidence from a longitudinal UK cohort study Dear Dr. Khouja: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Antonio Palazón-Bru Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0235629.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .