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ARTICLES: J. H. Veldink, S. Kalmijn, G. J. Groeneveld, M. J. Titulaer, J. H.J. Wokke, and L. H. van den Berg Physical activity and the association with sporadic ALS Neurology 2005; 64: 241-245 [Abstract] [Full text] [PDF]

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Physical activity and the association with sporadic ALS

Alberto Ascherio   (16 April 2005)

Reply to Ascherio

Jan H. Veldink, Sandra Kalmijn, Leonard H. van den Berg   (16 April 2005)

Physical activity and the association with sporadic ALS 16 April 2005
Alberto Ascherio, Harvard School of Public Health Depat. of Nutrition, HSPH, 665 Huntington Ave, Boston, MA 02115 Send Correspondence to journal: Re: Physical activity and the association with sporadic ALS aascheri{at}hsph.harvard.edu Alberto Ascherio	Veldink et al [1] reported a strong association between leisure time physical activity and earlier age at ALS onset and propose that this may reflect a possible adverse effect of physical activity. However, this association was based on analyses conducted among ALS cases only, and is thus potentially confounded by age (or, more specifically, birth cohort). For example, it could be explained if younger individuals in the source population were more physically active than older individuals, as could be expected from secular trends in leisure time physical activity. It would be interesting to see results appropriately adjusted for age. A simple and direct way to do this would be to report: 1) the odds ratio (OR) for physical activity stratified by age; and 2) the results of a test for interaction between age and physical activity. The latter could be done by adding to the multivariate logistic regression model (with disease status as the dependent variable), an interaction term between physical activity (below or above the median), and age (continuous). Although the reporting of the relation between exposures of interest and age at onset in clinical series is common, it is potentially misleading and should be discouraged. References 1. Veldink et al. Physical activity and the association with sporadic ALS. Neurology, 2005; 64:241-5.
Reply to Ascherio 16 April 2005
Jan H. Veldink, UMCU Heidelberglaan 100 3584 CX Utrecht, The Netherlands, Sandra Kalmijn, Leonard H. van den Berg Send Correspondence to journal: Re: Reply to Ascherio j.h.veldink{at}neuro.azu.nl Jan H. Veldink, et al.	We agree with Dr. Ascherio that an uncontrolled analysis of exposures of interest and age at onset in patients with ALS might be misleading. In our original manuscript, we did perform our analysis of physical activity during leisure time in both patients and controls to correct for secular trends. As we stated, we also performed the multivariate Cox regression analysis in controls with the filling out of the questionnaires as the event. This showed that neither physical activity measure was related to age at event in controls (p = 0.56 and p = 0.87), thus excluding a birth cohort effect, and suggesting a disease-related effect. It has been shown that both sporadic and familial ALS are heterogeneous disorders that show a large clinical variability. The identification of modifiable factors that determine outcome in ALS may contribute to new treatment strategies. We encourage investigating exposures of interest with age at onset with proper correction for birth cohort effects (especially with duration of disease) and with proper correction for known prognostic factors. However, we agree that extensive subgroup analysis in relatively small studies can lead to the finding of spurious relationships that need confirmation in independent studies. We therefore limited the number of exploratory subgroup analyses in our manuscript. Nevertheless, the subgroup analyses proposed by Dr. Ascherio are of interest to further determine the nature of the possible association between physical activity and age at onset in ALS. Our finding of a patient-specific association between level of physical activity during leisure time and age at event can be explained by: (1) a chance finding, since our review suggests that physical activity does not seem to be an important risk factor at all for ALS, (although subgroup analyses were not investigated previously); (2) susceptibility for ALS is determined by other genetic and environmental factors, and physical activity accelerates the onset of disease. This would be reflected by an increased odds ratio (OR) in a young cohort and a decreased odds ratio in an elder cohort, with a non-significant OR around 1 in the cohort as a whole; or (3) high level of physical activity is a risk factor for early onset ALS specifically. This would be reflected by an increased OR in a young cohort, and a non-significant OR around 1 in an elder cohort. As proposed, we determined the OR stratified by age, and we determined the OR of the interaction variable in the logistic regression model (Table). For comparison, our original results are located in the left column. The highest quartile of late leisure time activity now shows a significantly increased OR in the young cohort, and a non-significantly lower OR in the elder cohort. The highest quartile of early activity was similar in both age groups, however low level activity seemed rarer in younger patients. To determine whether these results suggest that high level physical activity during leisure time is associated with early onset in susceptible persons, or is associated with early-onset-ALS specifically, a large, preferably multi-center study, is needed. We want to emphasize that these analyses are only exploratory. Table