![Figure][1] Earlier this year, after 12 years, 7.5 million forms, and 1 million clinic visits, the Women's Health Initiative (WHI), a major 15-year research program of the U.S. National Institutes of Health (NIH), announced its research findings about women and chronic diseases. It indicated that certain interventions to treat cardiovascular disease, cancer, and osteoporosis were not as beneficial as thought. Conventional wisdom appeared to have been stood on its head, provoking strong reactions among scientists and the public: disbelief, disagreement, discouragement, and a fair measure of dissention and disharmony. Upon reflection, the results are reasonable, but we learned some lessons about how to clarify the broad application of findings as complex as those of the WHI. Now, in preparing to further delve into this rich resource of participant data, the WHI can make the most of an unprecedented opportunity to understand the mechanisms by which disorders in women develop, how they can be prevented, and how interventions can confer benefits or risks. Launched in 1991, the WHI reflected increasing attention to women's health and a strong demand for reliable information to guide their health care decisions. It is the first broad-scale examination of the major causes of disability and death among postmenopausal women, recruiting more than 161,000 volunteers in the United States between 50 and 79 years of age. Clinical trials tested three interventions: hormone therapy to prevent coronary heart disease and osteoporotic fractures, a reduced-fat diet to prevent breast and colorectal cancers and coronary heart disease, and calcium and vitamin D supplementation to prevent fractures and colorectal cancer. ![Figure][1] CREDIT: GETTY IMAGES The hormone trials were prematurely halted when an unfavorable risk/benefit profile indicated that estrogen-based therapies increased the risk of coronary heart disease, stroke, and breast cancer. The other trials failed to definitively establish the merits of their interventions. On the positive side, certain subgroups derived a benefit regarding breast cancer and bone health. The conclusion was that there may be a role for low-fat diets or calcium and vitamin D supplementation in preventing some chronic diseases. Should we be surprised by the WHI results? I think not. The study identified strategies that had been correlated with beneficial outcomes among selected cohorts of women and then tested the efficacy of these strategies in a huge group of volunteers representing a range of ages, backgrounds, and experiences. This was all quite reasonable and entirely concordant with NIH's public health mission, but it was probably naive to expect results that would be broadly applicable to such a diverse group. On the contrary, it makes sense to expect that the interventions may be beneficial (or harmful) only among woman with particular genetic, biological, and/or environmental characteristics. It is precisely this issue that will be the focus of the next chapter of the WHI. We have solicited proposals to mine the WHI data to identify genes and biological markers that might explain the pathways of disease development as well as the effects of treatment on disease outcomes. For example, genetic polymorphisms in a particular blood coagulant (factor V Leiden) increase the risk for venous thrombosis; hormone therapy also increases the thrombotic risk in some women. We are eager to understand the level of thrombotic risk for women with a genetic susceptibility to thrombosis when exposed to environmental and treatment factors, such as hormone therapy. These research findings would have direct implications for treatment options. It is important that the first chapter of the WHI study emphasized examining the biological differences between women and men. But I believe there is equal or even greater merit in examining individual biological variability—how women differ from one another—to understand why a given woman may fall ill and how we can best make her well. This knowledge is an essential prerequisite to the development of prevention and treatments that are tailored to the unique personal characteristics and health needs of each woman. Our investment in the WHI will yield untold rewards to women worldwide if we succeed, and this is exciting news for all women. [1]: pending:yes