J. Michael Gaziano

To examine interactions among the angiotensin converting enzyme (ACE) insertion/deletion, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, and tissue plasminogen activator (t-PA) insertion/deletion gene polymorphisms on risk of myocardial infarction using data from 343 matched case-control pairs from the Physicians Health Study. We examined the data using both conditional logistic regression and the multifactor dimensionality reduction (MDR) method. One advantage of the MDR method is that it provides an internal prediction error for validation. We summarize our use of this internal prediction error for model validation. The overall results for the two methods were consistent, with both suggesting an interaction between the ACE I/D and PAI-1 4G/5G polymorphisms. However, using ten-fold cross validation, the 46% prediction error for the final MDR model was not significantly lower than that expected by chance. The significant interaction initially observed does not validate and may represent a type I error. As data-driven analytic methods continue to be developed and used to examine complex genetic interactions, it will become increasingly important to stress model validation in order to ensure that significant effects represent true relationships rather than chance findings.

During the last century, cardiovascular disease (CVD) has burgeoned from a relatively minor disease worldwide to a leading cause of morbidity and mortality. By 2020 it is projected that CVD will surpass infectious disease as the world's leading cause of death and disability. Some of this increase in the relative importance of CVD is due to improved public health measures and medical care leading to longer life spans and reduced mortality from other causes. However, a substantial portion of the increasing global impact of CVD is attributable to economic, social, and cultural changes that have led to increases in risk factors for CVD. These changes are most pronounced in the countries comprising the developing world. Because the majority of the world's population lives in the developing world, the increasing rate of CVD in these countries is the driving force behind the continuing dramatic worldwide increase in CVD. In order to blunt the impact of the global explosion in CVD, it will be crucial to attempt to understand and reduce the global increase in CVD risk factors. In this review, the authors describe the changes responsible for the global epidemic of CVD, with particular attention to the contributions of established risk factors and their impact on the growth of CVD among the world's various economic sectors. The authors outline the major challenges facing countries in different economic sectors, and discuss ways to address these challenges with the goal of reducing the global burden of CVD. (Prev Cardiol.

Nonnarcotic analgesics are among the most widely used medications and are used at least weekly by one quarter of US adults.^1-3 High acute doses of analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), have been implicated as causes of acute renal failure,^4-7 which is most commonly seen among patients with impaired renal function. It has also been suggested that prolonged use of various analgesics may cause progressive renal damage ultimately leading to chronic kidney failure. The earliest study linking chronic analgesic use and chronic renal dysfunction was reported almost 50 years ago.⁸ In the ensuing half century, numerous case reports, several case-control studies, and 2 small cohort studies have raised the possibility of an association between use of various analgesics and chronic renal disease.

To examine whether cholesterol lowering with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statin drugs) reduces the risks of stroke and total mortality. We conducted a computerized literature search from 1985 through 1995 to identify all published trials testing statin drugs. The Cholesterol and Recurrent Events (CARE) data were added after the report was published in October 1996. Our search was limited to English-language articles and included published overviews containing relevant individual trials. Criteria for inclusion of randomized trials in the overview were (1) statin drugs alone used to reduce lipid levels rather than multifactorial interventions including another type of cholesterol-lowering drug and (2) inclusion of data on deaths and/or strokes. Data were extracted by 2 researchers, and only minor discrepancies, which were easily resolved by discussion, occurred. Principal investigators of the trials and their funding agencies were also contacted to secure any relevant data not included in the published reports. A total of 16 individual trials including approximately 29 000 subjects treated and followed up an average of 3.3 years were included in the overview. The average reductions in total and low-density lipoprotein cholesterol achieved were large-22% and 30%, respectively. A total of 454 strokes (fatal plus nonfatal) and 1175 deaths occurred. Those assigned to statin drugs experienced significant reductions in risks of stroke of 29% (95% confidence interval [CI], 14%-41%) as well as total mortality of 22% (95% CI, 12%-31%), which was attributable to a significant reduction in cardiovascular disease (CVD) deaths of 28% (95% CI, 16%-37%). There was no evidence of any increased risk in non-CVD mortality (relative risk [RR], 0.93; 95% CI, 0.75-1.14). There was also no significant increase in risk of cancer (RR, 1.03; 95% CI, 0.90-1.17). This overview of all published randomized trials of statin drugs demonstrates large reductions in cholesterol and clear evidence of benefit on stroke and total mortality. There was, as expected, a large and significant decrease in CVD mortality, but there was no significant evidence for any increases in either non-CVD deaths or cancer incidence.

Advances in diagnosis and treatment of cancer, as well as increased understanding of the mechanisms of the disease, have provided and will certainly continue to provide enormous benefit to affected individuals. At the same time, interventions that may prevent common cancers from developing in healthy people could, at least in theory, afford even greater benefits to society as a whole. The hypothesis that antioxidant vitamins might reduce cancer risk is based on a large body of both basic and human epidemiologic research. A large number of case-control and cohort studies provide remarkably consistent data suggesting that consumption of foods rich in antioxidant vitamins reduce risks of developing epithelial cancers. These data raise the question of a possible role of antioxidants, such as vitamins C and E, and beta carotene, in the primary prevention of cancer as well ar cardiovascular disease but do not provide a definitive answer. Despite the lack of clear benefit, there has been a rapid increase in the consumption of supplements of these micronutrients. Limited randomized trial data on the role of supplemental antioxidants are available. A number of randomized trials are currently underway designed to test the hypothesis that antioxidants prevent chronic diseases and to evaluate the long term safety of the widespread practice of supplementation. Well designed and well conducted large-scale randomized trials are necessary to provide a definitive positive or negative result on which public policy can be based, or a null result that is truly informative and that can then safely permit the rechanneling of already limited resources to other areas of research.