Objective Many studies find that excess weight is associated with better

Objective Many studies find that excess weight is associated with better survival among individuals with cardiovascular disease (CVD). interval (CI) 0.78 However when the reference category was limited to the always normal weight the paradox disappeared (HR=1.16; 95% IRL-2500 CI 0.95 When analysis was additionally confined to never-smokers mortality risks were significantly higher in the overweight/obese group (HR=1.51; 95% CI 1.07 p=0.021). Conclusions The findings provide support for the hypothesis that lower mortality among individuals with CVD who are overweight/obese is IRL-2500 a product IRL-2500 of biases involving reverse causation and confounding by smoking. associated failure to properly control one would typically produce an overestimate of the impact of the other (30). In this case no “paradox” is observed but rather an exaggeration of the impact of a variable already suspected of influencing the outcome. Such exaggerations often help to confirm a hypothesis. As a result they may not receive the scrutiny that they deserve. Exaggerations are common in observational studies because IRL-2500 so many risk factors are positively associated. A paradox occurs on the other hand when results are contrary to expectations. Such a result is more likely when risk factors are correlated and when the confounding variable is omitted or poorly measured. Future studies of the obesity paradox should recognize the great threat to unbiased estimation posed by the negative correlation between smoking and obesity. Another likely explanation for widespread findings of an obesity paradox is Alpl that the reference group in analyses of BMI and mortality-the normal-weight group-are often a mix of low-risk stable weight individuals and high-risk individuals who have lost weight (21). In the present analysis we showed that in individuals with cardiovascular disease a majority of individuals in the normal-weight category at the time of survey were formerly overweight or obese. These individuals have much higher mortality than those who were consistently normal weight throughout life suggesting that their presence in the normal-weight category is often related to illness. Illness itself is not expected to change the value of other exposures that predict death from cardiovascular disease such as hypertension or high fasting plasma glucose. But it often produces weight loss an association that biases analyses of the mortality consequences of obesity unless proper caution is taken. This study has several limitations. First we relied on recalled maximum weight which may be subject to measurement error. Measurement error could inflate or reduce the estimated mortality risks depending on the direction of the misreporting; however the threat posed is likely to be small as we have adopted a simple binary measure of weight status for the analysis in this paper. Second to construct maximum lifetime BMI we combined recalled weight with measured height at survey. Height loss between max and survey could lead to max BMI being overestimated for some individuals. This may lead to underestimating of the mortality IRL-2500 risks associated with obesity. This study did not directly investigate biologic mechanisms that may reduce mortality among individuals with obesity who have developed CVD so we cannot conclude that any such mechanism is invalid. We can however conclude that large statistical biases may arise in the analysis of associations between obesity and mortality among those with CVD. We have shown that adjusting for these biases leads to eliminating the obesity paradox altogether. The main sources of bias result from reverse causation and confounding by smoking. Such biases are present in many studies of the mortality risks of obesity but they are exaggerated when attention is confined to those in a disease state such as cardiovascular disease. ? Answers to Study Importance IRL-2500 Questions Among individuals with cardiovascular disease a common finding is that individuals with overweight/obesity have better survival than normal-weight individuals. This finding is often attributed to potential biological advantages of excess fat stores during periods of illness. This study provides support for the hypothesis that the obesity paradox in cardiovascular disease is a product of reverse causal bias and confounding by smoking. Acknowledgments This work was supported.