Doctor of Philosophy

dissertationThe purpose of this research was to describe calculated risk, risk perceptions of future breast cancer, and accuracy of risk perceptions of relatives (sisters or daughters) of women who have breast cancer and received genetic counseling regarding indeterminate negative BRCA1/2 test results. A secondary purpose was to evaluate breast cancer screening recommendations from relative's primary care providers (PCPs) and recent screening participation. We assessed the type and amount of information about genetic counseling/testing that was shared among family members and with PCPs. Latent variable modeling was used to assess the influence of perceived amount of shared information on the accuracy of relative's own risk perceptions about breast cancer. Using a cross-sectional design, surveys and telephone interviews were conducted with 85 female relatives. Most estimated their risk to be higher than calculated estimates, yet calculated risk demonstrated that most were at average-risk (operationalized as 20% lifetime risk by Claus or BRCAPRO), warranting annual breast magnetic resonance imaging (MRI) screening according to national guidelines; none of these women received recommendations for MRI screening. Regarding sharing of information, nearly 20% of relatives reported that nothing was iv shared with them about their family member's genetic counseling; most (76.5%) did not discuss their family member's genetic testing or test results with their PCP. Further, relatives were generally unaware of the existence of a genetic counseling summary letter provided as part of standardized genetic counseling. Those who perceived more information was shared with them about their relative's genetic counseling had more accurate perceptions of their own risk for breast cancer (correlation = 0.748 (p=0.000) than women who perceived less information was shared (correlation = 0.346 (p=0.05). Our findings underscore the need for effective strategies that facilitate sharing of genetic counseling information with relatives and PCPs

Genome sequencing and carrier testing: decisions on categorization and whether to disclose results of carrier testing

We are investigating the use of genome sequencing for preconception carrier testing. Genome sequencing could identify one or more of thousands of X-linked or autosomal recessive conditions that could be disclosed during preconception or prenatal counseling. Therefore, a framework that helps both clinicians and patients understand the possible range of findings is needed to respect patient preferences by ensuring that information about only the desired types of genetic conditions are provided to a given patient

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Breast Cancer Risk Assessment: Calculating Lifetime Risk Using the Tyrer-Cuzick Model

AbstractOne size does not fit all for breast cancer screening. Early detection and prevention are most effective for those most at risk. Several United States organizations recommend offering annual screening breast magnetic resonance imaging in addition to mammography for women with > 20% lifetime risk for breast cancer using models that take extensive family history into account. The purpose of this article is to help nurse practitioners make critical decisions about breast cancer screening and referrals to genetic services for women based on their lifetime risk for breast cancer. This article reviews several software-based risk assessment models and provides instructions for using the Tyrer-Cuzick model

Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene

<p>Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values</p>