A debate has been smoldering over the meaning of obesity in reducing the world burden of stroke. Like so many debates in medicine, it begins with disagreements about the interpretation of evidence, the meaning of statistical test results, and the role of bias. In one camp, are those who see that obesity is associated with increased risk for stroke and say that it as an important target for primary and secondary prevention. In the other, are those who agree that obesity increases stroke but say

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... hat it is more effective to treat the consequence of obesity that are responsible for stroke risk (ie, hypertension and dyslipidemia) than obesity itself. What everyone can agree on is that obesity is epidemic. In the United States, the prevalence of obesity (ie, body mass index [BMI] >30 kg/m 2 ) increases with age from 17% for children aged <20 years to 32% to 33% among adults 20 to 39 years, and 36% to 42% for adults ≥40 years. 1,2 In adults, the evidence that obesity is associated with increased risk for ischemic stroke is consistent and compelling. 3 In fact, risk for ischemic stroke increases almost linearly starting at a BMI of ≈20 and adults with a BMI of >30 kg/m 2 have about a 70% increased risk for ischemic stroke compared with patients with a BMI <25 kg/m 2 . 4, 5 In this issue of Stroke, Mitchell et al 6 raise further concern about obesity by showing an association with increased stroke risk in a study composed exclusively of young adults. Mitchell et al 6 studied men and women aged 15 to 49 years who participated in 3 separate case-control studies. A total of 1201 case subjects with ischemic stroke were identified from 59 hospitals in the Maryland/Washington, DC, area. A total of 1154 control subjects were identified by random-digit dialing and frequency matched to case subjects for age (within 10 years), region of residence, and ethnicity. 7,8 Despite the young age of the case subjects, 42% had hypertension, 17% had diabetes mellitus, and 40% were obese. In an analysis adjusted for age, sex, race, and smoking, obesity was associated with a 65% increased risk for ischemic stroke (odds ratio, 1.65; 95% confidence interval, 1.33-2.04), but the association was substantially attenuated by further adjustment for hypertension, and diabetes mellitus (odds ratio, 1.21; 95% confidence interval, 0.96-1.51). This finding of Mitchell et al 6 on hypertension and diabetes mellitus is consistent with research among older populations. In fact, there is broad agreement that these factors partially mediate the observed association between obesity and risk for vascular disease. Other mediators include vascular inflammation, insulin resistance, and dyslipidemia. Herein lies the controversy on the interpretation of obesity research. In statistical terms, a mediator is something that is on the causal pathway between an independent variable and a dependent variable. For example, obesity causes the hypertension (the mediator) that causes the stroke. Adjustment for a mediator will always attenuate a measure of association, but whether it affects the importance of the unadjusted finding is a matter of interpretation. In the case of obesity among young adults, some will highlight the unadjusted findings of Mitchell et al 6 to say we should treat the obesity to prevent the mediators which result in stroke. Others will say, treat the mediators and leave the obesity alone. If we had better therapy for obesity, there would probably be no controversy and we would all agree that treating obesity is the best first option. A justification for this approach is that the adjusted odds ratio of Mitchell et al 6 was still 1.21 overall (95% confidence interval, 0.96-1.51) and 1.34 in men (95% confidence interval, 0.96-1.88). This elevated odds ratio suggests that residual risk may remain and that that even optimal prescription of risk-reducing therapy (eg, hypertension therapy) would still leave many young obese patients exposed to untreated risk. This is particularly true because the only practical risk-reducing therapy for mediators of vascular disease in obesity is hypertension therapy. Research has not firmly established that tight control of diabetes mellitus reduces risk for vascular disease; there are no specific therapies recommended for treating the inflammation of obesity, and many young patients are not currently considered candidates for lipid-lowering therapy. Another argument in favor of treating obesity in young adults (and not just the mediators) is that young adults carry the burden of obesity for more years than older patients and, therefore, may realize a larger lifetime benefit from weight reduction. Treatment of obesity, furthermore, would have benefits beyond stroke reduction, including a possible reduction in risk for vascular cognitive impairment and dementia through mechanisms that include modulation of inflammation, hypertension, hyperglycemia, dyslipidemia, and insulin resistance. 9 How reliable are the findings by Mitchell et al? 6 Case-control studies achieve reliability by enrolling unbiased samples of cases and controls from the underlying population and accurately classifying clinical characteristics, including exposure status. Mitchell et al 6 accepted case subject referrals 7 and did not report their enrolled fraction, thus raising the possibility