Smoking and the risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis Alvaro Alonso, 1,2 Giancarlo Logroscino, 3 Miguel A Herna ´n 4,5 ABSTRACT Background Epidemiologic studies have provided inconsistent results on the association of cigarette smoking with the incidence of amyotrophic lateral sclerosis (ALS). To summarise published evidence and explore sources of heterogeneity, we conducted a systematic review and meta-analysis of studies that evaluated this association. Methods Published studies evaluating the association of smoking with incidence of ALS were searched in bibliographic databases, with relevant information collected from each article. A random effects approach was used to pool the relative rate (RR) estimates from different studies. Between study heterogeneity was explored with a meta-regression approach. Results 18 publications reported associations between smoking and ALS risk in 15 case control studies and five cohort studies. The pooled RR (95% CI) of ALS was 1.28 (0.97 to 1.68) for current versus never smokers and 1.12 (0.98 to 1.27) for ever versus never smokers. The study specifics RRs were heterogeneous (p<0.01). The proportion of women in the study population explained 46% of between study variability. The estimated RR (95% CI) of ALS for ever versus never smokers was 0.86 (0.71 to 1.03) in men and 1.66 (1.31 to 2.10) in women. Interpretation This meta-analysis does not support an overall strong association of smoking with ALS risk but suggests that smoking might be associated with a higher risk of ALS in women. INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease of unknown aetiology. 1 Cigarette smoking has been proposed as a potential causative factor for ALS but published epidemio- logic studies have provided inconsistent results. Methodological differences and heterogeneity in studied populations could account in part for these disparities. 2 We conducted a systematic review and meta- analysis of published studies to estimate more precisely the association between smoking and incidence of ALS, and to identify sources of heterogeneity across studies. METHODS Search strategy We performed a systematic search of published studies in Medline (1950eApril 2009), EMBASE (1980eApril 2009) and ISI Web of Science (1975eApril 2009) using the terms ‘(ALS OR amyotrophic lateral sclerosis OR motor neuron disease) AND (smok*OR tobacco OR cigar*)’. We considered studies published in any language. Bibliographic references in the publications meeting inclusion criteria (see below) were reviewed to identify additional relevant papers. Selection criteria Studies meeting the following criteria were included in the review: (1) case control or cohort design; (2) information on smoking status referred to the period prior to diagnosis of ALS; (3) outcome defined as a medical diagnosis of ALS or presence of ALS in a death certificate; and (4) reporting of measures of association between smoking and ALS, or enough information to compute the association, or the corresponding author providing the neces- sary information on request. No specific exclusion criteria were applied. Data extraction From each identified eligible publication, the following information was abstracted: study design (case control, cohort), location, number of partici- pants, period of recruitment, type of cases and controls (for case control studies), average follow- up (for cohort studies), method of case ascertain- ment, diagnostic criteria, response rate, mean age and range, proportion of men in the study sample, adjustment variables, as well as the main results (ORs or rate ratios of ALS in current smokers vs never smokers, in ever smokers vs never smokers and results by gender if available). In cases where the original publication did not provide enough information to estimate associations between smoking and ALS, the corresponding author was contacted. 3e5 Statistical analysis In case control studies with density sampling of controls, the OR estimates the rate ratio in the source population while in case control studies not using density sampling the OR is a good approxi- mation to the rate ratio when incidence of disease is low, as in the case of ALS. 6 Therefore, in this article we use the term rate ratio (RR) for association measures from both cohort and case control studies. Heterogeneity of study specific RR estimates was evaluated by computing the Q and I 2 statistics. 7 I 2 is a measure of heterogeneity recommended by the Cochrane collaboration, ranging between 0% (no heterogeneity) to 100%. 7 Because of the evidence of heterogeneity, we did not adopt a fixed effects approach to pool the study specific estimates. Rather, we used the DerSimonian and Laird random effects method. 8 To assess sources of heterogeneity we regressed the log RR on study specific characteristics < Additional data, tables and figures are published online only. To view these files please visit the journal online (http:// jnnp.bmj.com). 1 Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA 2 Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Pamplona, Spain 3 Department of Neurological Sciences, University of Bari, Bari, Italy 4 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA 5 Harvard-MIT Division of Health Sciences, Boston, Massachusetts, USA Correspondence to Dr A Alonso, Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 S, Suite 300, MN 55416, USA; aalogut@alumni.unav.es Received 7 April 2009 Revised 22 June 2009 Accepted 6 July 2009 Published Online First 16 July 2010 J Neurol Neurosurg Psychiatry 2010;81:1249e1252. doi:10.1136/jnnp.2009.180232 1249 Short report on May 5, 2021 by guest. 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