Study and population characteristics
We found 6,619 studies (6,510 papers from the initial searches, plus 109 papers from supplemental searches). We identified 21 papers for inclusion in the study (Appendix 2); comprising 14 unique longitudinal cohort studies (Appendices 4 ‒ 8). The data in the primary studies were collected between 2013 and 2016 and the longitudinal follow-up period ranged from 4 months to 2.5 years. Only one study had two follow-up time points . Fifteen primary papers were completed using North American data [33-47] and six primary papers were based on European data [48-53]. The included studies had a range of research questions related to e-cigarette use; 17 asked about ever use of e-cigarettes [33, 36-40, 42, 44-53], and 4 asked about e-cigarette use in the past 30 days [35, 40, 43, 44]. No study provided information on e-cigarette type, generation or liquid. All papers measured tobacco cigarette smoking during follow-up as an outcome variable: 18 papers investigated ever use of tobacco cigarettes between baseline and follow-up [33, 35, 37-52], and 4 asked about past 30-day use of tobacco cigarettes [39, 40, 42, 44]. All publications which conducted regression analysis included potential confounding variables as covariates in their regression model, ranging from the inclusion of 3 variables to the inclusion of 17. Based on previous research, we grouped the covariates into three groups: demographic (e.g. ethnicity, family affluence), interpersonal (e.g. number of friends/family members that smoke) or intrapersonal (e.g. such impulsivity, sensation seeking, rebellion) . One paper  only included variables from one domain, while eight papers [35, 38, 43, 46, 47, 50, 51, 53] included variables from two domains, and ten papers [33, 34, 39, 40, 42, 44, 45, 48, 49, 52] included variables from all three domains. The age of the included population was between 13 and 19 years at baseline.
Overall, using the NHLBI quality assessment tool , we judged four studies to be high-quality[39, 44, 47, 52] as they had a representative and clearly defined sample with a participation rate of more than 50%, a loss to follow-up rate of 20% or less, and a sample size justification or variance calculation for the main outcomes (Appendix 3). The remaining studies in the meta-analysis were moderate quality and tended to have higher loss to follow up or lower participation rates.
In order to ascertain whether a meta-analysis was appropriate and which studies should be included, a feasibility analysis was conducted, taking outcome, exposure, unit of measurement, and length of time to follow-up into account as they employed the same method of analysis (Appendix 9). Based on these criteria, nine studies with 16,808 participants were considered eligible for meta-analysis of ever using e-cigarette at baseline and smoked tobacco cigarettes at any time during the follow-up period (Figure 1), while three studies of past-30-day e-cigarette use at baseline and smoked tobacco cigarettes at any time during the follow-up period were eligible.
Ever e-cigarette use at baseline and subsequent cigarette smoking at follow-up
Our ever e-cigarette-use meta-analysis was based on the primary study adjusted odds ratios and calculated a combined 4.06 (95%CI: 3.00-5.48, I2 68%) times higher odds of initiating smoking tobacco cigarettes for those who had ever used e-cigarettes at baseline, although this combined odds ratio was reduced slightly to 3.71 times (95%CI: 2.83-4. 86, I2 35%) when only the four high-quality studies [39, 44, 47, 52] were included in a sensitivity analysis(Appendix 10).
A further sensitivity analysis was conducted on the six studies [33, 39, 44, 48, 49, 52] which controlled for the three domains of covariates – that is, demographic, interpersonal, and intrapersonal factors. The results of this analysis (OR: 3.82; 95% CI: 2.66–5.48; I2 69%) were similar to the results for the high-quality studies assessment, but the level of heterogeneity remained moderate to high (Appendix 10).
Three subgroup analysis were completed (Appendix 10). The first considered studies which collected data pre-2014 [33, 39, 47] in comparison with those which collected their initial data from 2014 onwards [38, 44, 48, 49, 51, 52], due to the increase in e-cigarette use that was observed around this time . The combined OR for studies which collected data from 2014 onwards increased substantially (pre-2014 AOR: 2.81, 95%CI: 2.45–3.72 I2 78%); compared to 2014 onwards (5.16, 95%CI: 3.69–7.21 I2 38%). However, the confidence intervals overlap indicating that they are not statistically significantly different.
The second subgroup analysis considered the length of time to follow-up, as studies included in the analyses had follow-up periods which ranged from 4 months to 2 years. However, as only two studies had follow-up periods of less than 1 year [49, 51] including one study which had a very small sample size, the meta-analysis for this subgroup did not provide meaningful results.
Finally, given the importance of the context of these studies (including social norms, regulatory environment, etc.), we conducted a subgroup analysis of the European studies as compared with the studies from the USA. The combined OR was higher in the European studies (OR: 6.22, 95%CI: 3.73–10.38 I2 54%) [48, 49, 51, 52] as compared with the USA studies (OR: 3.18, 95%CI: 2.26–4.47 I2 65%) [33, 38, 39, 44, 47]. However, the confidence intervals overlap indicating that they are not statistically significantly different.
Past-30-day e-cigarette use at baseline and subsequent cigarette smoking at follow-up
Four studies examined the impact of past-30-day e-cigarette use at baseline and subsequent cigarette smoking at follow-up [35, 40, 43, 44]. A meta-analysis was conducted using the primary studies adjusted odds ratios (Appendix 10). The analysis included 30,018 participants from three of the four studies measuring past-30-day e-cigarette use at baseline, and found a significant positive association between past-30-day e-cigarette use at baseline and subsequent cigarette smoking initiation at follow-up (OR: 2.14; 95% CI: 1.75–2.62; I2 0%) (Figure 2) [35, 40, 44]. One of the four studies was excluded following feasibility analysis.
Level and certainty of evidence
We assigned a level of evidence of 3 using British Medical Journal guidelines , as this is a systematic review of cohort studies, some of which had high loss to follow-up and/or very small sample sizes. However, with respect to certainty of evidence , we have moderate confidence that the true effect is probably close to the estimated effect for initiating smoking at follow-up for those who had ever used e-cigarettes at baseline.