Testing for mutations in the BRCA1 and BRCA2 breast-ovarian cancer susceptibility genes has been performed in over 70,000 individuals. Like other sequence-based tests, the results can reveal a normal sequence, a clearly deleterious mutation or a sequence variant of uncertain significance (VUS), in which it is not known whether the VUS confers an increased cancer risk. VUS results are confusing and occur in approximately 12% of tests. Their adequate interpretation requires a basic understanding of genetic principles, the laboratory methods utilized and pedigree analysis.

This is a competing renewal to continue our investigations of the use of molecular cytogenetic testing by array copy number analysis in prenatal diagnostic testing. We have completed a prospective blinded comparison of copy number analysis (aCNA) with standard conventional karyotyping in 4400 unselected prenatal diagnostic tests. Our work demonstrates that aCNA identifies all pathologic findings seen by karyotyping and provides significant incremental information in 2% of all patients tested.

Despite significant efforts, African Americans continue to experience excess rates of morbidity and mortality from all forms of cancer relative to individuals from other ethnic and racial groups. Research is now being conducted to the molecular basis of cancer through genetic-based studies and to translate this information into strategies for cancer detection, prevention, and treatment. African American reluctance to participate in cancer genetics research will significantly limit efforts to apply these approaches to address racial disparities in cancer outcomes.

Myocardial infarction (Ml) and peripheral arterial disease (PAD) pose an enormous public health burden and there is an urgent need to develop new strategies for their prevention and treatment. Both are manifestations of atherosclerotic vascular disease yet differ in risk factor profiles and clinical presentation. A major aim of this proposal is to identify novel genetic determinants of atherosclerotic vascular disease.

Two major issues have garnered significant attention leading to the development of a range of policies regarding data disclosure and data-sharing in biomedical research. While the disclosure of data is relevant to all types of biomedical research, it has garnered particular attention with respect to genetics and genomics research due to some of the unique aspects of the data and the high public profile of the field.

This project would address several questions concerning parental rights and responsibilities in forming families and the morality of using genetic technology to prevent or create children with impairments: 1) Are genetic impairments subject to greater concern than other alleged sources of harm to future children? If so, is that greater concern justified? 2) Do public attitudes, practices, and policies toward reproductive conduct take account of whether that conduct affects the identity of the future child? Should they?

The long-term objective of this Pathway to Independence Award (K99/ROO) is to train to become an independent researcher in bioethics with a strong interdisciplinary foundation in genetics and epidemiology. My research plan is to characterize ethical and social issues in genetic studies of complex traits and evaluate how and whether they differ from those in genetic studies of Mendelian traits. This research will enable current and future complex disease researchers and policy makers to understand and address these issues proactively.

How do ordinary Americans make sense of genetic research? How might they decide whether or not to participate in such research? The proposed study aims to address these questions, in a two-year panel study unfolding in three broad phases:
-an initial, general-population baseline survey of relevant knowledge, attitudes and opinions;

Advances stemming from the Human Genome Project have prompted concerns about the general public's readiness to utilize this information to make informed health decisions. As a strategy to increase genetic literacy among the general public, tools are now available to enable individuals to record their family health history. However, little is known about whether the public is able to access the tools, understand how to use them, and apply the information by taking health protective actions, which can compromise the potential effectiveness of the tools.

Most, if not all, human diseases have one or more genetic factors that contribute to cause, likelihood of occurrence, severity, and response to existing or experimental treatments. There is a general perception that the ability to define a person's genetic makeup will lead to better health, improved treatments and a better understanding of risks to other family members. However, many genetic technologies increase uncertainty and confusion in the minds of patients, relatives, doctors, health insurers and others.