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The excess lung cancer risk from smoking declines with time quit, but the shape of the decline has never been precisely modelled, or meta-analyzed. From a database of studies of at least 100 cases, we extracted 106 blocks of RRs (from 85 studies) comparing current smokers, former smokers (by time quit) and never smokers. Corresponding pseudo-numbers of cases and controls (or at-risk) formed the data for fitting the negative exponential model. We estimated the half-life (H, time in years when the excess risk becomes half that for a continuing smoker) for each block, investigated model fit, and studied heterogeneity in H. We also conducted sensitivity analyses allowing for reverse causation, either ignoring short-term quitters (S1) or considering them smokers (S2). Model fit was poor ignoring reverse causation, but much improved for both sensitivity analyses. Estimates of H were similar for all three analyses. For the best-fitting analysis (S1), H was 9.93 (95% CI 9.31–10.60), but varied by sex (females 7.92, males 10.71), and age (

ObjectivesThe study aimed to review the epidemiological evidence relating environmental tobacco smoke exposure to stroke in never smokers.MethodsThe study is similar to our review in 2006, with searches extended to March 2016.ResultsTwelve further studies were identified. A total of 28 studies varied considerably in design, exposure indices used, and disease definition. Based on 39 sex-specific estimates and the exposure index current spousal exposure (or nearest equivalent), the meta-analysis gave an overall fixed-effect relative risk estimate of 1.23 (95% confidence interval: 1.16-1.31), with significant (P

Our objective was to provide a comprehensive review of the epidemiologic evidence relating stroke to exposure to environmental tobacco smoke (passive smoking) in lifelong nonsmokers. In all, 7 prospective, 6 case-control, and 3 cross-sectional studies were identified that provided relevant information. The 16 studies varied considerably in design, exposure indices used, and disease definition. Based on 24 sex-specific relative risk estimates, and using current spousal exposure (or nearest equivalent) as the exposure index, meta-analysis gave an overall estimate of 1.25 (95% confidence interval 1.16-1.36), with no significant heterogeneity. There was no significant heterogeneity by sex, year of publication, fatality, or disease end point. There was some indication that relative risks were less elevated in prospective studies and in US or European studies. No elevation was seen for subarachnoid hemorrhage. The estimate was similar using ever rather than current exposure, or total rather than spousal exposure. Adjustment for risk factors other than age had no material effect on the estimate. Eight studies provided dose-response estimates, the combined relative risk for the highest level of exposure being 1.56 (95% confidence interval 1.34-1.82). Many studies have evident weaknesses, and recall bias and particularly publication bias are major concerns. Currently, the association is only suggestive of a possible causal relationship. A clearer picture could be obtained using data from existing very large prospective studies that have already provided risk estimates for passive smoking and heart disease, and by conducting large, well-designed studies of incident stroke.

We examine in detail arguments put forward to support the claim that exposure to environmental tobacco smoke (ETS) increases the risk of lung cancer in non-smokers. Hackshaw et al. [Br Med J 1997;315:980-988] have esti mated that the risk increases by 23% (95% Cl 14-32%) per 10 cigarettes/day smoked by the husband. The esti mated increase essentially disappears if proper adjust ment is made for smoking misclassification bias, if cor rection is made for the joint effects of confounding by fruit, vegetables, dietary fat and education, if errors in published data in one study are corrected, and if results from all pertinent studies are included (and not just those which report risk by level of smoking by the husband). Taking account of all these factors and using un- weighted estimates of the association between ETS ex posure and the confounding variables (as one very large study reported results discrepant from those for numer ous smaller studies), the risk increase per 10 cigarettes/ day was found to be 2% (95% Cl -3 to +7.5%), based on data from 47 ETS/lung cancer studies. Using weighted estimates, the risk increase was 5.5% (95% Cl 0 to +11 %). Restricting attention to the 36 studies that had adjusted for age, the increase was reduced further to -2% (95% Cl -6 to+3%) using un-weighted estimates, or to + 1 % (95% Cl -4 to +6%) using weighted estimates. These estimates are not materially affected by bias due to the reference group (non-smokers married to non-smokers) having some ETS exposure from other sources. Other sources of potential upward and downward bias, not formally taken account of in the analysis, are discussed. Based on extrapolation from the known lung cancer risk in smok ers, Hackshaw et al. [Br Med J 1997;315:980-988] esti mate that environmental tobacco smoke exposure would be expected to increase the risk of lung cancer in non-smokers by 19%. Using more appropriate assump tions (for the relative exposure to smoke constituents of passive and active smokers, for the lung cancer risk in those who have ever smoked and for the dose-response model) leads to a much lower estimate of about 0.5%. Even this estimate is open to question as a threshold might exist for the effects of tobacco smoke constituents on lung cancer risk. Whether or not a true risk exists, it is clear that this is not demonstrated by the overall evi dence. The true increase in risk per 10 cigarettes/day smoked by the husband is very unlikely to be as large as 23%. It might be as much as 5%, but it could well be 1 % or less, or even zero.

Hackshaw et al. estimated that adjustment for bias due to misclassification of smoking habits reduces the ob served relative risk of lung cancer in non-smoking wom en associated with smoking by the husband from 1.24 to 1.18. This bias estimate is little affected by using an alter native method for misclassification adjustment or by using updated data from 47 studies rather than data from the 37 studies used by Hackshaw et al. The bias is increased if strong evidence of much higher misclassifi cation rates in Asian women is taken into account and could then explain about half the observed association. Misclassification correction has not previously been at tempted for dose-response data. We describe a suggest ed approach and apply it to data relating risk to amount smoked by the husband. As shown in paper II of this series the unadjusted increase in risk per 10 cigarettes/ day smoked by the husband is 10% (95% Cl 5 to 15%), reducing to either 6% (95% Cl 1 to 11 %) or 9% (95% Cl 5 to 14%) after adjustment for confounding by fruit, vege table and fat consumption and education using respec tively unweighted or weighted means to combine evi dence on the ETS/confounder association from different studies. Further adjustment for plausible levels of mis classification similarly reduced these two estimates to, respectively, 2% (95% Cl -3 to 8%) or 5.5% (95% Cl 0 to 11 %). Difficulties in applying misclassification bias cor rections are discussed. Other sources of bias will be con sidered in later papers in this series.

A higher concentration of high density lipoprotein cholesterol (HDL-C) in ex-smokers than smokers has consistently been observed. Better evidence of quitting effects comes from within-subject changes. We extend an earlier meta-analysis to quantify the reduction, and investigate variation by time quit and other factors. We conducted Medline and Cochrane searches for studies measuring HDL-C in subjects while still smoking and later having quit. Using unweighted and inverse-variance weighted regression analysis, we related changes (in mmol/l) to intra-measurement period, and estimated time quit, and to study type, location and start year, age, sex, product smoked, validation of quitting, baseline HDL-C, baseline and change in weight/BMI, and any study constraints on diet or exercise. Forty-five studies were identified (17 Europe, 16 North America, 11 Asia, 1 Australia). Thirteen were observational, giving changes over at least 12 months, with most involving >1000 subjects. Others were smoking cessation trials, 12 randomized and 20 non-randomized. These were often small (18 of

Background National smoking-specific lung cancer mortality rates are unavailable, and studies presenting estimates are limited, particularly by histology. This hinders interpretation. We attempted to rectify this by deriving estimates indirectly, combining data from national rates and epidemiological studies. Methods We estimated study-specific absolute mortality rates and variances by histology and smoking habit (never/ever/current/former) based on relative risk estimates derived from studies published in the 20th century, coupled with WHO mortality data for age 70–74 for the relevant country and period. Studies with populations grossly unrepresentative nationally were excluded. 70–74 was chosen based on analyses of large cohort studies presenting rates by smoking and age. Variations by sex, period and region were assessed by meta-analysis and meta-regression. Results 148 studies provided estimates (Europe 59, America 54, China 22, other Asia 13), 54 providing estimates by histology (squamous cell carcinoma, adenocarcinoma). For all smoking habits and lung cancer types, mortality rates were higher in males, the excess less evident for never smokers. Never smoker rates were clearly highest in China, and showed some increasing time trend, particularly for adenocarcinoma. Ever smoker rates were higher in parts of Europe and America than in China, with the time trend very clear, especially for adenocarcinoma. Variations by time trend and continent were clear for current smokers (rates being higher in Europe and America than Asia), but less clear for former smokers. Models involving continent and trend explained much variability, but non-linearity was sometimes seen (with rates lower in 1991–99 than 1981–90), and there was regional variation within continent (with rates in Europe often high in UK and low in Scandinavia, and higher in North than South America). Conclusions The indirect method may be questioned, because of variations in definition of smoking and lung cancer type in the epidemiological database, changes over time in diagnosis of lung cancer types, lack of national representativeness of some studies, and regional variation in smoking misclassification. However, the results seem consistent with the literature, and provide additional information on variability by time and region, including evidence of a rise in never smoker adenocarcinoma rates relative to squamous cell carcinoma rates.

Background Smoking is a known cause of the outcomes COPD, chronic bronchitis (CB) and emphysema, but no previous systematic review exists. We summarize evidence for various smoking indices. Methods Based on MEDLINE searches and other sources we obtained papers published to 2006 describing epidemiological studies relating incidence or prevalence of these outcomes to smoking. Studies in children or adolescents, or in populations at high respiratory disease risk or with co-existing diseases were excluded. Study-specific data were extracted on design, exposures and outcomes considered, and confounder adjustment. For each outcome RRs/ORs and 95% CIs were extracted for ever, current and ex smoking and various dose response indices, and meta-analyses and meta-regressions conducted to determine how relationships were modified by various study and RR characteristics. Results Of 218 studies identified, 133 provide data for COPD, 101 for CB and 28 for emphysema. RR estimates are markedly heterogeneous. Based on random-effects meta-analyses of most-adjusted RR/ORs, estimates are elevated for ever smoking (COPD 2.89, CI 2.63-3.17, n = 129 RRs; CB 2.69, 2.50-2.90, n = 114; emphysema 4.51, 3.38-6.02, n = 28), current smoking (COPD 3.51, 3.08-3.99; CB 3.41, 3.13-3.72; emphysema 4.87, 2.83-8.41) and ex smoking (COPD 2.35, 2.11-2.63; CB 1.63, 1.50-1.78; emphysema 3.52, 2.51-4.94). For COPD, RRs are higher for males, for studies conducted in North America, for cigarette smoking rather than any product smoking, and where the unexposed base is never smoking any product, and are markedly lower when asthma is included in the COPD definition. Variations by sex, continent, smoking product and unexposed group are in the same direction for CB, but less clearly demonstrated. For all outcomes RRs are higher when based on mortality, and for COPD are markedly lower when based on lung function. For all outcomes, risk increases with amount smoked and pack-years. Limited data show risk decreases with increasing starting age for COPD and CB and with increasing quitting duration for COPD. No clear relationship is seen with duration of smoking. Conclusions The results confirm and quantify the causal relationships with smoking.

One possible contributor to the reported rise in the ratio of adenocarcinoma to squamous cell carcinoma of the lung may be differences in the pattern of decline in risk following quitting for the two lung cancer types. Earlier, using data from 85 studies comparing overall lung cancer risks in current smokers, quitters (by time quit) and never smokers, we fitted the negative exponential model, deriving an estimate of 9.93years for the half-life – the time when the excess risk for quitters compared to never smokers becomes half that for continuing smokers. Here we applied the same techniques to data from 16 studies providing RRs specific for lung cancer type. From the 13 studies where the half-life was estimable for each type, we derived estimates of 11.68 (95% CI 10.22–13.34) for squamous cell carcinoma and 14.45 (11.92–17.52) for adenocarcinoma. The ratio of the half-lives was estimated as 1.32 (95% CI 1.20–1.46, p

Background Smoking is a known lung cancer cause, but no detailed quantitative systematic review exists. We summarize evidence for various indices. Methods Papers published before 2000 describing epidemiological studies involving 100+ lung cancer cases were obtained from Medline and other sources. Studies were classified as principal, or subsidiary where cases overlapped with principal studies. Data were extracted on design, exposures, histological types and confounder adjustment. RRs/ORs and 95% CIs were extracted for ever, current and ex smoking of cigarettes, pipes and cigars and indices of cigarette type and dose–response. Meta-analyses and meta-regressions investigated how relationships varied by study and RR characteristics, mainly for outcomes exactly or closely equivalent to all lung cancer, squamous cell carcinoma (“squamous”) and adenocarcinoma (“adeno”). Results 287 studies (20 subsidiary) were identified. Although RR estimates were markedly heterogeneous, the meta-analyses demonstrated a relationship of smoking with lung cancer risk, clearly seen for ever smoking (random-effects RR 5.50, CI 5.07-5.96) current smoking (8.43, 7.63-9.31), ex smoking (4.30, 3.93-4.71) and pipe/cigar only smoking (2.92, 2.38-3.57). It was stronger for squamous (current smoking RR 16.91, 13.14-21.76) than adeno (4.21, 3.32-5.34), and evident in both sexes (RRs somewhat higher in males), all continents (RRs highest for North America and lowest for Asia, particularly China), and both study types (RRs higher for prospective studies). Relationships were somewhat stronger in later starting and larger studies. RR estimates were similar in cigarette only and mixed smokers, and similar in smokers of pipes/cigars only, pipes only and cigars only. Exceptionally no increase in adeno risk was seen for pipe/cigar only smokers (0.93, 0.62-1.40). RRs were unrelated to mentholation, and higher for non-filter and handrolled cigarettes. RRs increased with amount smoked, duration, earlier starting age, tar level and fraction smoked and decreased with time quit. Relationships were strongest for small and squamous cell, intermediate for large cell and weakest for adenocarcinoma. Covariate-adjustment little affected RR estimates. Conclusions The association of lung cancer with smoking is strong, evident for all lung cancer types, dose-related and insensitive to covariate-adjustment. This emphasises the causal nature of the relationship. Our results quantify the relationships more precisely than previously.