The Statement of Task charges the committee with conducting a “comprehensive and systematic assessment and review of the literature” on the health effects of e-cigarettes. The committee’s approach was informed by published guidelines for conducting systematic reviews as well as the approaches taken by prior National Academies committees (CRD, 2009; Higgins and Green, 2011; IOM, 2008, p. 45, 2011a, pp. 10–24, 2011b, 2016, pp. 8–10; NASEM, 2017; NRC, 2014; OHAT, 2015; Sena et al., 2014; Whiting et al., 2016). For its assessment on the health effects of e-cigarettes, the committee conducted structured reviews of the literature on the effects of e-cigarette exposure on any biological outcome (whether human, animal, or in vitro). Because assessment of the overall public health impact of e-cigarettes requires understanding the relationship between e-cigarettes and combustible tobacco cigarettes, the committee also undertook comprehensive literature reviews of the effects of e-cigarette use on combustible tobacco cigarette smoking initiation and cessation. The committee did not systematically review the health effects of known constituents and contaminants of e-cigarette devices or their refill solutions (e.g., nicotine, certain metals). Because many of these constituents have been widely studied in other settings, the committee draws on existing bodies of evidence to describe potential health effects of these constituent parts. This appendix describes the committee’s strategy for identifying and reviewing literature in detail.
The committee conducted a series of searches in six databases—PubMed, Scopus, Web of Science, PsycINFO (ProQuest), MEDLINE (Ovid), and Embase (Ovid)—between February 1, 2017, and August 31, 2017, to identify all literature on e-cigarettes. Due to e-pub ahead of print and online first articles, 2018 citations were captured. In addition, a few 2016 and 2017 studies may not have been captured due to lags and discrepancies in database indexing. The committee applied no limits on date, language, or country to any of its searches. The following sections describe the committee’s search strategies to identify literature on the health effects of e-cigarettes and on the e-cigarettes and smoking transitions.
Health Effects of E-Cigarettes
Because the committee is interested primarily in the effects of e-cigarettes as a whole product, rather than the effects of their individual constituent parts, the committee conducted a search to identify literature on human, animal, and in vitro exposure to e-cigarettes. Human epidemiological evidence provides the strongest evidence, but due to the lack of available human studies, the committee also chose to review animal and in vitro exposure to e-cigarettes from which they could draw informed inferences. The committee’s initial search included all literature pertaining to e-cigarette exposures and was conducted as a series of six searches between February 1, 2017, and February 6, 2017. The search was conducted in five databases—PubMed, Scopus, Web of Science, PsycINFO (ProQuest), and MEDLINE (Ovid). All literature on e-cigarettes used the following key words and phrases: e-cigarette, e-cigarettes, “electronic cigarette,” “electronic cigarettes,” “electronic nicotine delivery,” “electronic nicotine device,” vape, vaping, and e-liquid. (The committee excluded the term “e-liquid” from searches in Scopus and Web of Science, which are multidisciplinary databases, where the term “e-liquid” produced results related to geothermal energy.) Searches in PubMed and MEDLINE also used the Medical Subject Headings (MeSH) term “electronic cigarettes.” This initial series of searches identified 3,494 unique results. The complete search syntax can be found in Boxes B-1A through B-1F. Titles and abstracts for all references were reviewed using inclusion criteria developed through a preliminary title and abstract review process. The final inclusion criteria for human, animal, and in vitro studies are listed in Box B-2.
The committee conducted a special search to identify literature on e-cigarette use and dependence. The search was conducted between July 14, 2017, and August 31, 2017, in the same five databases as the initial search. In addition to the e-cigarette terms described above, the
committee added the following terms: dependence, withdrawal, craving, appeal, addition, “abuse liability,” “subjective effects, “smoking urge,” “urge to smoke,” “smoking desire,” and “desire to smoke.” In PubMed and MEDLINE, they also used the MeSH terms “tobacco use disorder,” “substance withdrawal syndrome,” and “craving.” The complete search syntax can be found in Box B-3. This initial search identified 957 unique results. Titles and abstracts were reviewed for all literature that included an assessment of dependence using a validated instrument.
E-Cigarettes and Transitions to and from Combustible Tobacco Cigarette Smoking
To identify literature on the effects of e-cigarette use on smoking transitions (initiation and cessation), the committee conducted a series of subsearches within its initial search to identify epidemiological and experimental data on these smoking transitions. To do so, the committee added terms to the original search to restrict results to smoking transition outcomes of interest. Additionally, because there are many recent, systematic reviews on the effects of e-cigarettes on smoking initiation and cessation but few original studies, the committee chose to assess first these review articles rather than duplicating these efforts. The committee then complemented the evidence identified through these reviews with new studies published after the search dates of the most recent literature reviews, and also met the most rigorous inclusion/exclusion criteria used in the existing, prior systematic reviews.
To identify literature on smoking initiation, the key terms “smoking initiation” and “initiation” were added to the e-cigarette terms described in the section above. This search included all literature published through May 4, 2017, in six databases—PubMed, Scopus, Web of Science, PsycINFO (ProQuest), MEDLINE (Ovid), and Embase (Ovid). The complete search syntax can be found in Box B-4. The committee applied no limits on date, language, or country, and the search yielded 138 unique studies.
The committee conducted two searches on smoking cessation, one limited to reviews, and one limited to original, peer-reviewed research. The search of systematic reviews published through March 1, 2017, was conducted in seven databases—PubMed, Scopus, Web of Science, PsycINFO (ProQuest), MEDLINE (Ovid), Embase (Ovid), and Cochrane (Ovid). The key terms “smoking cessation” and “cessation,” and the MeSH term “smoking cessation” were added to the e-cigarette terms described above. The committee applied no limits on date, language, or country. This search produced 209 unique results. The search of primary literature published through May 3, 2017, was conducted in six databases—PubMed, Scopus, Web of Science, PsycINFO, MEDLINE (Ovid),
and Embase (Ovid). The key terms “smoking cessation,” “cessation,” “quit,” and “abstinence” and the MeSH term “smoking cessation” were added to the e-cigarette terms from the original search, and the committee applied no limits on date, language, or country. The complete search syntax can be found in Boxes B-5 and B-6. This search yielded 1,759 unique results.
Finally, the committee conducted a search of literature on e-cigarette exposure and smoking reduction. For this search, the key terms “smoking reduction” and “harm reduction” were added to the e-cigarette terms described in the section above. This search included all literature published through May 4, 2017, in six databases—PubMed, Scopus, Web of Science, PsycINFO (ProQuest), MEDLINE (Ovid), and Embase (Ovid).
The complete search syntax can be found in Box B-7. The committee applied no limits on date, language, or country. This search yielded 455 unique results.
After the initial searches, the committee continued to collect literature through the end date of August 31, 2017. A total of 641 unique results were identified.
Each relevant study was reviewed and assessed by committee members. The committee began by identifying what questions the literature addresses and then assessed the extent to which each study was able to answer each question of interest. In their assessment, the committee considered study design, elements of study design, study results, and other potential sources of conflict of interest or bias. Where committee members co-authored studies to be assessed, committee members who
did not participate in the study independently reviewed the work, with particular attention to the study design, results, and the interpretation of the results (i.e., conclusions). This section briefly describes these study characteristics; strengths and weaknesses of individual studies are best understood in the context in which they are being used. Thus, considerations for optimal study design and special considerations for different outcomes are discussed in each relevant section in the report text.
In general, randomized controlled trials (RCTs) are the gold standard for assessing the effectiveness of an intervention compared with nothing or other interventions. For areas where experimental studies are feasible, but RCTs are not available, the committee considered next-best designs—controlled studies (without randomization). In some cases, RCTs are not feasible because they would be unethical, in which case longitudinal observational designs offer the next strongest evidence. These include prospective cohort studies and crossover trials. For all studies, the committee considered multiple elements pertinent for assessing the studies’ internal and external validity. These elements include the study sample, such as sampling methods, basic demographic information (age, gender, and race/ethnicity), as well as study setting. The committee also considered analytical methods, such as statistical tests used, and their appropriateness. Finally, the committee considered the study results (including adjusted and unadjusted results where available), including the outcomes assessed and how these outcomes were operationalized.
Special Considerations for Interventions
As described in Chapter 3, the e-cigarette product and how it is used shape e-cigarette aerosol composition, exposure, and thus health effects. Therefore, when assessing experimental studies, the committee considered the device and e-liquid used, the nicotine concentration, the device settings (e.g., power, temperature, resistance), as well as the puffing protocols used. The committee also considered the comparison or control conditions.
Special Considerations for Observational Studies
Confounding is a challenge inherent in observational studies. Con-founders are a third variable related to both an exposure and an outcome and not in the causal pathway. If confounders are distributed unequally across groups (e.g., e-cigarette users and non-users), they can statistically bias the association between the exposure and outcome (i.e., observed effect or study results). Thus, the committee considered confounders and other covariates controlled for in observational studies.
For longitudinal (or cohort) studies, the committee considered followup periods and time points assessed. Additionally, loss to follow-up is a challenge in these studies. Because those lost could be systematically different from those who remain in the study, this systematic difference could bias study results. This may be important for the generalizability of findings. Methods exist to account for loss to follow-up. The committee
therefore considered the treatment of the study sample lost to follow-up in longitudinal studies.
Potential bias in the studies based on sponsorship, particularly by industry, is a concern in the health effects literature on e-cigarettes given the tobacco industry’s history of manipulating evidence to support their interests. The committee recognizes that there is a range of non-scientific influences that affect the ways in which investigators design, conduct, analyze, and interpret their data, including but not limited to research sponsorship and source of employment. The committee focused its assessment of the evidence on the quality of the research and the results that were reported, but recognized that financial interests raise concerns to varying degrees with the credibility of the findings. For completeness, the committee documents, in a table available as an online supplement the source of research sponsorship or other external involvement, noting whether each study was funded by industry, government, other (university, foundation), or not stated. The committee also notes other industry involvement, such as if industry is a source of employment. The table can be downloaded at https://www.nap.edu/catalog/24952.
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