The Return of Genetic Research Results in the Context of an International Colon Cancer Family Registry

Thesis (Ph.D.)--University of Washington, 2015-12The overall aim of this dissertation study was to describe the experience of the Colon Cancer Family Registry (C-CFR) with return of results (ROR) from genetic research and to document site-specific ROR outcomes. The C-CFR is comprised of six registry sites: the University of Hawaii, Honolulu, HI (HI); the Mayo Clinic, Rochester, MN (MA); the Fred Hutchinson Cancer Research Center, Seattle, WA (SE); the University of Southern California, Consortium, Los Angeles, CA (USC); the Cancer Care Ontario, Canada (ON); and the University of Melbourne, Melbourne, Australia (AU). Registry site-specific experiences with ROR and ROR-related outcomes were explored using a mixed-methods study design. For Specific Aim 1, qualitative interviews with 14 registry investigators and staff from the six C-CFR sites demonstrated the complexity of ROR protocol development and implementation in practice. Thematic analysis from the interviews identified three main factors underlying site-specific ROR protocol and implementation differences: 1) the training and prior experience of C-CFR staff, 2) access to a robust public health infrastructure, and 3) the influence of local regulatory norms and/or informed consent. For Specific Aim 2, multivariable logistic regression model analysis of the association between acceptance of Lynch Syndrome (LS) genetic research results and participant demographic characteristics had identified the participant’s age, marital status, and race/ethnicity as significantly associated with the likelihood of LS genetic research result acceptance. Overall, the proportion of participants accepting LS genetic research results among the SE, HI, MA and AU C-CFR sites was 63% (481/763). For Specific Aim 3, a sequential mixed-methods investigation of Seattle C-CFR participants approached for LS-related ROR explored post-disclosure result clinical validation and sharing of results with family members and health care providers. Twenty-six of 34 SE C-CFR participants (76.5%) who accepted non-CLIA genetic research results completed a survey 12 months post disclosure. Of these, 4 (15.4%) reported having clinically verified their non-CLIA genetic research results, 22 (84.6%) reported having shared the results with family members, and 15 (57.7%) participants shared with their health care providers. Follow-up qualitative interviews with a subset of these participants found that acting on the recommendation of the research team and informing future clinical care were the main reasons given for pursuing clinical verification. Participants who did not verify their results cited lack of insurance coverage and limited perceived personal and/or clinical benefits as relevant reasons to their decision. From the experience of a multi-site international research cancer registry, results from this dissertation study provide valuable insights into the complexity of ROR protocol development and implementation, as well as the potential impact of genetic research result return on participants and their families. As such, these study findings should help guide future policy development regarding the return of individual results from genetic research in related settings

Enhanced retinal responses in Huntington\u27s disease patients.

BACKGROUND: Huntington\u27s disease (HD) is a fatal progressive neurodegenerative disease characterized by chorea, cognitive impairment and psychiatric symptoms. Retinal examination of HD patients as well as in HD animal models have shown evidence of retinal dysfunction. However, a detailed retinal study employing clinically available measurement tools has not been reported to date in HD. OBJECTIVE: The goal of this study was to assess retinal responses measured by electroretinogram (ERG) between HD patients and controls and evaluate any correlation between ERG measurements and stage of disease. METHODS: Eighteen patients and 10 controls with inclusion criteria of ages 18-70 years (average age HD subjects: 52.1 yrs and control subjects: 51.9 yrs) were recruited for the study. Subjects with previous history of retinal or ophthalmologic disease were excluded. Retinal function was examined by full-field ERG in both eyes of each subject. Amplitudes and latencies to increasing flash intensities in both light- and dark-adaptation were measured in all subjects. Statistical analyses employed generalized estimating equations, which account for repeated measures per subject. RESULTS: We analyzed the b-wave amplitudes of ERG response in all flash intensities and with 30 Hz flicker stimulation. We found statistically significant increased amplitudes in HD patients compared to controls at light-adapted (photopic) 24.2 and 60.9 cd.sec/m2 intensities, dark-adapted (scotopic, red flash) 0.22 cd.sec/m2 intensity, and a trend toward significance at light-adapted 30 Hz flicker. Furthermore, we found a significant increase in light-adapted ERG response from female compared to male HD patients, but no significant difference between gender amongst controls. We also noted a positive association between number of CAG repeats and ERG response at the smallest light adapted intensity (3.1 cd.sec/m2). CONCLUSIONS: ERG studies revealed significantly altered retinal responses at multiple flash intensities in subjects with an HD expansion allele compared to controls. Significant differences were observed with either light-adapted tests or the dark-adapted red flash which suggests that the enhanced responses in HD patients is specific to the cone photoreceptor pathway

A Report on Ten Asia Pacific Countries on Current Status and Future Directions of the Genetic Counseling Profession: The Establishment of the Professional Society of Genetic Counselors in Asia

The Professional Society of Genetic Counselors in Asia (PSGCA) was recently established as a special interest group of the Asia Pacific Society of Human Genetics. Fostering partnerships across the globe, the PSGCA’s vision is to be the lead organization that advances and mainstreams the genetic counseling profession in Asia and ensures individuals have access to genetic counseling services. Its mission is to promote quality genetic counseling services in the region by enhancing practice and curricular standards, research and continuing education. The PSGCA was formally launched during the Genetic Counseling Pre-Conference Workshop held at the 11th Asia-Pacific Conference on Human Genetics in Hanoi, Viet Nam, September 16, 2015. The pre-conference workshop provided an opportunity for medical geneticists and genetic counselors from across 10 Asia Pacific countries to learn about the varied genetic counseling practices and strategies for genetic counseling training. This paper provides an overview of the current status and challenges in these countries, and proposed course of unified actions for the future of the genetic counseling profession

Ensuring best practice in genomics education and evaluation: reporting item standards for education and its evaluation in genomics (RISE2 Genomics)

Purpose: Widespread, quality genomics education for health professionals is required to create a competent genomic workforce. A lack of standards for reporting genomics education and evaluation limits the evidence base for replication and comparison. We therefore undertook a consensus process to develop a recommended minimum set of information to support consistent reporting of design, development, delivery, and evaluation of genomics education interventions. Methods: Draft standards were derived from literature (25 items from 21 publications). Thirty-six international experts were purposively recruited for three rounds of a modified Delphi process to reach consensus on relevance, clarity, comprehensiveness, utility, and design. Results: The final standards include 18 items relating to development and delivery of genomics education interventions, 12 relating to evaluation, and 1 on stakeholder engagement. Conclusion: These Reporting Item Standards for Education and its Evaluation in Genomics (RISE2 Genomics) are intended to be widely applicable across settings and health professions. Their use by those involved in reporting genomics education interventions and evaluation, as well as adoption by journals and policy makers as the expected standard, will support greater transparency, consistency, and comprehensiveness of reporting. Consequently, the genomics education evidence base will be more robust, enabling high-quality education and evaluation across diverse settings

Ensuring best practice in genomics education and evaluation: reporting item standards for education and its evaluation in genomics (RISE2 Genomics).

PURPOSE: Widespread, quality genomics education for health professionals is required to create a competent genomic workforce. A lack of standards for reporting genomics education and evaluation limits the evidence base for replication and comparison. We therefore undertook a consensus process to develop a recommended minimum set of information to support consistent reporting of design, development, delivery, and evaluation of genomics education interventions. METHODS: Draft standards were derived from literature (25 items from 21 publications). Thirty-six international experts were purposively recruited for three rounds of a modified Delphi process to reach consensus on relevance, clarity, comprehensiveness, utility, and design. RESULTS: The final standards include 18 items relating to development and delivery of genomics education interventions, 12 relating to evaluation, and 1 on stakeholder engagement. CONCLUSION: These Reporting Item Standards for Education and its Evaluation in Genomics (RISE2 Genomics) are intended to be widely applicable across settings and health professions. Their use by those involved in reporting genomics education interventions and evaluation, as well as adoption by journals and policy makers as the expected standard, will support greater transparency, consistency, and comprehensiveness of reporting. Consequently, the genomics education evidence base will be more robust, enabling high-quality education and evaluation across diverse settings

Mutation spectrum in the large GTPase dynamin 2, and genotype–phenotype correlation in autosomal dominant centronuclear myopathy

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 ( DNM2 ), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM‐related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice‐site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue‐specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. Hum Mutat 33:949–959, 2012. © 2012 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92087/1/22067_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/92087/2/humu_22067_sm_SuppInfo.pd