Data used
All data considered were for males and for the period 1980-2009. Effects on mortality were restricted to those aged 30-79 years.
Annual data by five year age groups on population size for Sweden, and in the case of Approach 2 for other European countries, came from the United Nations website [10].
Annual data by five year age groups for Sweden and other European countries on deaths from lung cancer, COPD, IHD and stroke (“the four diseases”), all SRDs, all non-smoking-related diseases (NSRD), and all causes combined came from the WHO database [11]. The definition of SRDs was based on that defined by Tachfouti et al [12] with minor modifications, as described in detail in Supplementary File 1.
Published data were used to estimate prevalence for Sweden for nine groups of tobacco use, representing each combination of the 3 x 3 matrix smoker (never/former/current) x snus user (never/former/current), separately for 20 age groups (15, 16, 17, 18, 19, 20, 21-24, 25-29, 30-34 … 80-84 and 85+). Details of the source publications and the methods used to estimate the prevalences are given in Supplementary File 2.
Other data used were specific to particular approaches and the sources are described below.
Approach 1
In males in 1980-2009 in European countries other than Sweden tobacco users were nearly all cigarette smokers. Approach 1 estimates the effect of snus use in Swedish males based on a comparison of their mortality rates with those seen in combined male data from other European countries with an overall prevalence of current tobacco use similar to that in Sweden. Comparisons were made annually from 1980 to 2009 of mortality from the four diseases for the combined age group 30-79 years with age-standardization to the European standard population (ESP 1976) [13].
For Sweden the overall prevalence of current tobacco use in each year for each age group was estimated by combining all those estimated prevalences for the nine tobacco use groups described above which involved current smoking and/or current snus use.
Annual data on the prevalence of current smoking for European countries was extracted from the Global Burden of Disease Study 2015 [14], although data for countries with an average population size less than 500,000, with sales of tobacco products other than manufactured cigarettes or snus greater than 35%, or with markedly incomplete mortality data were not considered. Countries were considered similar to Sweden if the average annual absolute difference between their prevalence and that in Sweden for 1980-2009 was less than 4%.
For each five year age group, annual mortality rates (per 100,000) for each of the four diseases and countries were then calculated by dividing estimates of the numbers of deaths by estimates of the population size [10] and multiplying by 100,000. Weights calculated from the ESP 1976 [13] for each five year age-group then provided the age-standardized mortality rates. For each disease, year and country, these were divided by the corresponding value for Sweden to give the disease specific mortality rate ratios (normalized to Swedish data).
For each disease, year and country, the number of deaths in Sweden occurring at age 30-79 years was then multiplied by the corresponding rate ratio to obtain the hypothetical number of deaths that would have occurred with the mortality rate of the comparison country. The mean of these hypothetical numbers of deaths was then compared with the historical number of deaths in Sweden.
As mortality in Sweden may be lower than that in other countries for reasons other than tobacco use, adjusted hypothetical numbers of deaths were also calculated. The method was as described in the previous paragraph except that the year- and country-specific rate ratios used to multiply deaths in Sweden for each of the four diseases were each divided by the corresponding rate ratio calculated for deaths from all NSRD.
The differences between the hypothetical numbers (adjusted or unadjusted) of deaths in Sweden and the historical numbers are indicators of the increase in deaths that would have occurred in Sweden had snus not been on the market.
Approach 2
As for Approach 1, Approach 2 estimates a hypothetical mortality rate for Swedish males assuming that snus was not available and that those who had used snus smoked instead. Approach 2 compares the historical numbers of deaths in males aged 20-79 years from a specified disease that occurred in Sweden in a defined year (A) with the hypothetical number if snus users had smoked cigarettes instead (B), the difference (B-A) being an estimate of the increase in deaths that would have occurred if snus had not been available.
The estimation required annual age-specific data for Swedish males on tobacco use prevalence for the nine categories as described earlier, population size [10] and numbers of deaths for the diseases of interest [11]. It also required estimates of relative risks of the four diseases for current and former smokers. These estimates, shown in Table 1, came from published meta-analyses [3, 15, 16]. Table 1 also includes estimates of relative risks for current snus use, again taken from a published meta-analysis [8]. As can be seen the relative risks for current snus use were all non-significant and close to 1, so it was decided to estimate mortality assuming that disease risk depends only on smoking.
Table 1. Relative risks of tobacco related disease in Swedish males
|
Age range
|
Relative Risk (95% CI)
Current smoker
|
Relative Risk (95% CI)
Former smoker
|
Relative Risk (95% CI)
Current snus
|
Lung Cancer
|
Any
|
8.68 (7.14-10.54)
|
2.62 (2.01-3.42)
|
0.80 (0.60-1.06)
|
COPD
|
Any
|
3.31 (2.80-3.92)
|
1.99 (1.76-2.25)
|
0.80 (0.40-1.60)
|
IHD
|
to 54
55 to 64
65 to 74
75 to 79
Any
|
3.38 (2.92-3.91)
2.32 (2.05-2.62)
1.70 (1.56-1.86)
1.27 (1.21-1.33)
|
1.36 (1.21-1.53)
1.38 (1.22-1.55)
1.25 (1.16-1.34)
1.16 (1.08-1.25)
|
1.01 (0.91-1.12)
|
Stroke
|
to 54
55 to 64
65 to 74
75 to 79
Any
|
2.48 (1.94-3.17)
2.13 (1.93-2.34) 1.39 (1.23-1.58) 1.06 (0.96-1.17)
|
1.10 (0.90-1.34)
1.17 (1.01-1.36)
1.15 (1.04-1.26)
1.00 (0.89-1.12)
|
1.04 (0.92-1.17)
|
Table 1 presents relative risks for lung cancer, COPD, IHD and stroke for current and former smokers compared to never smokers and for current snus users relative to never users. Estimates for IHD and stroke for smoking are given by age, but other relative risks are assumed to be independent of age. The estimates for smoking come from published meta-analyses for lung cancer [15], for COPD [16], and for IHD and stroke [3]. The estimates for snus use come from another published meta-analysis [8].
If one subdivides the population into nine groups, one can compare risk in the alternative situations, as summarized in Table 2. Note that death rates in the historical situation (A) and hypothetical situation (B) are identical in six of the nine groups, differing only for groups 4, 7 and 8.
Table 2. Estimating death rates in Approach 2
|
Historical tobacco habits
|
Death rate in situation
|
|
Group
|
Smoking
|
Snus use
|
A
|
B
|
Difference
|
|
|
|
|
|
|
1
|
Never
|
Never
|
N
|
N
|
None
|
2
|
Never
|
Former
|
N
|
F
|
Higher in B
|
3
|
Never
|
Current
|
N
|
C
|
Higher in B
|
4
|
Former
|
Never
|
F
|
F
|
None
|
5
|
Former
|
Former
|
F
|
F
|
None
|
6
|
Former
|
Current
|
F
|
C
|
Higher in B
|
7
|
Current
|
Never
|
C
|
C
|
None
|
8
|
Current
|
Former
|
C
|
C
|
None
|
9
|
Current
|
Current
|
C
|
C
|
None
|
For the nine tobacco use groups, Table 2 shows the death rates that would apply in situation A, which concerns the historical number of deaths in males from a specified disease that did occur in Sweden in a defined year, and in situation B, which concerns the hypothetical number that would have occurred in that year if snus users had smoked cigarettes instead. N is the death rate in never smokers, F is that in former smokers and C is that in current smokers.
The estimation, which was carried out separately for different five year age groups, with the results then combined over age group, requires estimates for each year of the population size in each group, N, and of the total number of deaths from the disease of interest, D.
Given the proportions in the nine groups, (Pi, i = 1 ….. 9) and the relative risk of disease for former smokers and current smokers compared to never smokers, RF and RC we first estimated the death rate in never smokers, U, from the formula
U = D / [N (P1 + P2 + P3 + RF (P4 + P5 + P6) + RC (P7 + P8 + P9)]
The number of deaths in each group in situation A was then obtained by multiplying N*U*Pi by 1 for groups 1 to 3, RF for groups 4 to 6 and by RC for groups 7 to 9. The number of deaths in each group in situation B is the same as that in situation A in six groups (1, 4, 5, 7, 8, 9) but is multiplied by RF for group 2, RC for group 3 and RC/RF for Group 6.
Approach 3
The methodology of the PHIM, which was designed to assess the population-level health impact of marketing a SFTP, has already been summarized in the background section and is described in more detail elsewhere [2, 3]. The application of the PHIM used in Approach 3 involves comparison of mortality from the four main SRDs in the historical scenario (SNUS) in which snus is present and the hypothetical scenario (NO-SNUS) in which it is not. In each scenario tobacco transition probabilities (TTPs) determine the rate at which individuals change tobacco groups. Based on the tobacco use histories built up, the relative risks of each disease are then estimated for each individual, and are used to determine the number of deaths attributable to tobacco. The difference between the estimated numbers of deaths for the two scenarios (NO-SNUS minus SNUS) then provides the increase in mortality if snus had not been available.
In Approach 3, simulated samples of 100,000 males start in 1980 with a distribution of smoking habits consistent with the prevalence in Swedish males in that year.
In the SNUS scenario individuals start in five groups – never tobacco (representing the combination of groups 1 + 2 of the original nine groups shown in Table 2), current cigarettes only (7 + 8), current snus only (3), current dual use (9) and former tobacco (4 + 5 + 6). This was based on two assumptions. One was that there was no increase in risk associated with former use of snus, consistent with epidemiological evidence that exclusive snus use is associated with little or no increase in the incidence of the smoking attributable diseases studied [8, 9]. This suggests that any risk of former snus use can be ignored, so indicating that groups 1 + 2, 4 + 5 and 7 + 8 could each be combined as having equivalent risk. Evidence that current snus users who formerly smoked (“switchers”) have risks very similar to those of never users who quit smoking (“quitters”) [17] also justified the decision to count those originally in group 6 as having equivalent risk to the other former cigarette smoking groups 4 and 5.
In the NO-SNUS scenario, individuals start in three groups again based on the original nine groups – never cigarettes (1), former cigarettes (2 + 4 + 5) and current cigarettes (3 + 6 + 7 + 8 + 9). Thus, this scenario included as former smokers all those who had used either or both products but did not currently use them, and as current smokers all those who were current users of either or both product. Never smokers included only those who had never used either product. Effectively it was assumed that cigarette smoking totally replaced snus use.
During each year of the 30 year follow-up period (1980-2009), individuals can switch groups according to defined TTPs. In the SNUS scenario there are 15 TTPs, three relating to initiation, three relating to quitting, three relating to re-initiation and six relating to switching. Thus, for example, individuals may initiate or re-initiate to each of the three current use groups, or may quit from each of them. In the NO-SNUS scenario there are three TTPs, representing initiation, quitting and re-initiation. The values of the TTPs used, which are age dependent, are given in Supplementary File 3 which also provides further details of the methodology. Note that the TTPs for initiation and re-initiation in the NO-SNUS scenario are the same as the three TTPs in the SNUS scenario, while the TTPs for quitting in NO-SNUS are the same as the three identical TTPs for quitting in SNUS.
Comparison is between mortality in the two scenarios over the 30 year follow-up period. Note that any individual reaching age 80 drops out of the population, so by the end of follow-up smoking prevalence refers to those aged 40–79. The model requires the disease- and age-specific estimates of the relative risk associated with continued smoking, and also requires estimates of the quitting half-life, the time after quitting when the increase in relative risk associated with smoking has halved. These estimates, derived from published meta-analyses, are provided in our earlier paper [3], which clarifies the sources used.
The model also requires estimates of the “relative exposure” (RE) corresponding to the current tobacco use pattern. This takes the value 0 for an individual not using tobacco (a never or former user), 1 for a current cigarette smoker, f for a current SNUS user (the f-factor), and g for a dual user (the g-factor), a dual user being an individual whose tobacco use pattern consists of a substantial use of both cigarettes and snus. The results shown in Table 1 suggest that the f-factor is close to zero and the g-factor is close to 1. In Approach 2 and in the main analysis using Approach 3, we assume that f = 0 and g = 1. In Approach 3 we also conduct sensitivity analyses, with g = 1.0 and f = 0.1 or 0.2, with f = 0.0 and g = 0.9, 0.8 or 0.5, and with f = 0.1 and g = 0.9 or 1.1.
For each of the four major SRDs and for each five-year age group and each year of follow-up the PHIM estimates the mean relative risk for each of the two scenarios. The number of deaths occurring in the SNUS scenario is the number that actually occurred, while the number occurring in the NO-SNUS scenario can be obtained by multiplying this number by the ratio of the mean relative risks in the NO-SNUS and SNUS scenarios. The difference between these two numbers of deaths is then the required increase in deaths for that disease, age group and year.
The estimated increases in deaths for each disease so far described take no account of the reduced population size that would have existed in the hypothetical scenario. For the main analysis, with f = 0.0 and g = 1.0, we also present survival-adjusted estimates, using methodology previously described [2].
Years of life lost
For each disease and each year of follow-up, separately for the historical and hypothetical scenario, Approaches 2 and 3 both generate estimates of the number of deaths occurring in each year of follow-up for each of the five year age groups from 30-34 to 75-79. These estimates were also converted to numbers of years of life lost before age 80, taking the midpoints of the age groups as 32.5, 37.5, .. 77.5. Thus, those dying at age 30-34 would lose 80 – 32.5 = 47.5 years, for example.