LAUSR

Background: Identifying mechanisms of neurodegenerative disease causation has for long seemed to be beyond the pale of traditional epidemiological tools. Elucidating a plausible mechanism for initiation of amyotrophic lateral sclerosis (ALS) has appeared particularly elusive (1). The impression, that environmental risk factors for ALS were not providing consistent direction, meant there was no sturdy epidemiologically-based "handle" to grasp when trying to envisage a biological mechanism for triggering sporadic ALS (2). There have been challenges with interpreting the data. At times, generic concerns over potential limitations of traditional epidemiological studies have appeared to overshadow the findings in circumstances where these limitations had been overcome largely. At other times, studies with different degrees of methodological limitations have been lumped together, thereby obscuring the results of the studies with less limitations. On occasion, methodological limitations have been downplayed or ignored entirely.Emergence of Mendelian Randomization (MR) methods has offered the promise of overcoming some of the potential limitations of epidemiological studies that used traditional methods. MR methods apply concepts developed in the field of economics to infer causality in the presence of unmeasured confounding (3). The principal idea is: 1) a genetic pattern is identified that predicts a suspected risk factor - a laboratory value in patients' blood, or a particular behavior; 2) that pattern is sought in patients and controls; 3) excess presence of the pattern in patients suggests that the risk factor plays a causal role in producing the disease.However, application of MR methods requires that several underlying assumptions, specific to these methods, have been satisfied (3). Moreover, epidemiological analyses using MR methods need to adhere to core epidemiological and statistical principles. Finally, findings from MR studies need to be interpreted critically, with close attention to the context from which they arise, and with utilization of internal and external comparators (4,5).This presentation will discuss the assumptions that need to be met to apply MR methods in general and how they relate to studies in patients with ALS, drawing on recently published reports.