PROJECT SUMMARY / ABSTRACT Dr. Tracy E. Madsen is an Assistant Professor in the Department of Emergency Medicine at Rhode Island Hospital and the Alpert Medical School of Brown University. In the proposed research project, Dr. Madsen will investigate differences in ischemic stroke risk between women and men and will investigate potential reasons for sex differences in stroke risk including the influence of sex hormones and sex hormone binding globulin (SHBG) on biologic mechanisms leading to vascular disease. Dr. Madsen's Career Development Award has the potential to lead to a greater understanding of sex differences in ischemic stroke risk as well as more knowledge of how sex hormones and SHBG affect stroke risk in women and men. These findings could lead to novel ways to predict stroke risk and prevent stroke in a more personalized, sex-specific manner and to the use of primary and secondary prevention strategies for vascular disease in ED patients. In the first phase, Dr. Madsen will conduct secondary analyses of two national datasets (Greater Cincinnati/ Northern Kentucky Stroke Study and Reasons for Geographic and Racial Differences in Stroke) to investigate sex differences in stroke incidence over time and sex differences in the severity of stroke risk factors. In the second aim, Dr. Madsen will use existing stroke cohorts (Women's Health Initiative (WHI) and the Framingham Heart Study (FHS)) to study the potential sex-specific association between SHBG and ischemic stroke. This will include the investigation of the relationship between SHBG and other markers of vascular risk including insulin resistance, inflammation, and lipid metabolism. Finally, in the third aim, she will develop a sex-specific stroke risk score that includes factors related to reproductive history as well as sex hormone biomarkers and conduct a pilot validation study. Dr. Madsen has assembled an interdisciplinary team of committed, well-qualified co-mentors and collaborators: Dr. Simin Liu, primary mentor with expertise in the study of SHBG, sex steroids, and molecular mechanisms leading to vascular disease risk, Dr. Jo-Ann Manson, mentor with expertise in reproductive endocrinology, Dr. Karen Furie, with expertise in stroke prevention in women and clinical trials in stroke prevention, Dr. Dawn Kleindorfer, a nationally known stroke epidemiologist with expertise in sex differences in stroke, and Dr. Virginia Howard, another stroke epidemiologist but with expertise in the use of longitudinal data from stroke cohorts to study sex differences in stroke epidemiology. Collaborators include Dr. Sudha Seshadri, MD, a senior investigator of the Framingham Study and Dr. Jane Khoury, PhD, statistician on the project. Dr. Madsen will be completing her proposed research activities in the Department of Emergency Medicine affiliated with Rhode Island Hospital, a comprehensive stroke center, the Alpert Medical School of Brown University, and the Brown University School of Public Health.

PROJECT NARRATIVE Despite a decline in stroke incidence over time, stroke remains a leading cause of death and disability among women and men. We lack a clear understanding of differences between women and men in stroke risk or in the contribution of sex hormones, sex hormone binding globulin (SHBG), and reproductive history to stroke risk. This project seeks to advance our knowledge of sex differences in the risk of ischemic stroke, of the role of SHBG and estradiol in stroke risk, and of the relationship between SHBG and markers of vascular disease including insulin resistance, inflammation, and lipid metabolism. We will use our data to develop a sex-specific stroke risk score, and the results of our research could lead to novel approaches to risk stratification for ischemic stroke among both women and men as well as to innovative prevention strategies.