Duke Institute for Genome science and Policy

Durham, NC, United States

Duke Institute for Genome science and Policy

Durham, NC, United States
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Beskow L.M.,Duke Institute for Genome science and Policy | Check D.K.,Duke University | Ammarell N.,Duke University
AJOB Empirical Bioethics | Year: 2014

Background: Certificates of Confidentiality are intended to facilitate participation in critical public health research by protecting against forced disclosure of identifying data in legal proceedings, but little is known about the effect of Certificate descriptions in consent forms. Methods: To gain preliminary insights, we conducted qualitative interviews with 50 HIV-positive individuals in Durham, NC, to explore their subjective understanding of Certificate descriptions and whether their reactions differed based on receiving a standard versus simplified description. Results: Most interviewees were neither reassured nor alarmed by Certificate information, and most said it would not influence their willingness to participate or to provide truthful information. However, compared with those receiving the simplified description, more who read the standard description said it raised new concerns, that their likelihood of participating would be lower, and that they might be less forthcoming. Most interviewees said they found the Certificate description clear, but standard-group participants often found particular words and phrases confusing, while simplified-group participants more often questioned the information's substance. Conclusions: Valid informed consent requires comprehension and voluntariness. Our findings highlight the importance of developing consent descriptions of Certificates and other confidentiality protections that are simple and accurate. These qualitative results provide rich detail to inform a larger, quantitative study that would permit further rigorous comparisons. © Taylor & Francis Group, LLC.

Moaddeb J.,Duke Institute for Genome science and Policy | Haga S.B.,Duke University
Therapeutic Advances in Drug Safety | Year: 2013

Over the last decade, the number of clinical pharmacogenetic tests has steadily increased as understanding of the role of genes in drug response has grown. However, uptake of these tests has been slow, due in large part to the lack of robust evidence demonstrating clinical utility. We review the evidence behind four pharmacogenetic tests and discuss the barriers and facilitators to uptake: (1) warfarin (drug safety and efficacy); (2) clopidogrel (drug efficacy); (3) codeine (drug safety and efficacy); and (4) abacavir (drug safety). Future efforts should be directed toward addressing these issues and considering additional approaches to generating evidence basis to support clinical use of pharmacogenetic tests. © The Author(s), 2013.

Beskow L.M.,Duke Institute for Genome science and Policy | Burke W.,University of Washington | Fullerton S.M.,University of Washington | Sharp R.R.,Cleveland Clinic | Sharp R.R.,Case Western Reserve University
Genetics in Medicine | Year: 2012

Although issues involved in offering individual results to participants in genomic research have received considerable attention, communication of aggregate results has been the subject of relatively little ethical analysis. Offering participants aggregate results is typically assumed to be a good thing, and studies have found that a significant majority of biobank research participants, when asked about their interest in aggregate results, say that access to such information would be important. Even so, return of aggregate results remains a relatively uncommon practice. In this article, we explore the opportunities involved in communicating aggregate results to participants in genomic research, including affirming the value of research participation, informing participants about research being conducted based on broad consent for future unspecified research, educating participants and the public about the research process, and building trust in the research enterprise. We also explore some of the challenges, including the complex intersection between individual and aggregate results, as well as practical hurdles. We conclude by offering our preliminary recommendations concerning the provision of aggregate results and an agenda for much-needed future research. ©American College of Medical Genetics and Genomics.

Peppercorn J.,Duke University | Hamilton E.,Duke University | Marcom P.K.,Duke University | Beskow L.,Duke Institute for Genome science and Policy | Lyman G.H.,Duke University
Cancer | Year: 2013

BACKGROUND This study evaluated self-reported knowledge, practice, and attitudes toward commercially available cytochrome P450 2D6 (CYP2D6) pharmacogenomic testing for patients on tamoxifen for breast cancer (CYPT) among US oncologists while evidence for the use of the test was evolving. METHODS A self-administered survey of medical oncology breast cancer specialists at National Comprehensive Cancer Network (NCCNO) centers and a random sample of community-based oncologists (CBOs) was undertaken. The survey evaluated knowledge and use of the CYP2D6 test and response to hypothetical test results. RESULTS In total, 201 of 459 (44%) oncologists responded. At a time when CYPT remained experimental, 31% of oncologists reported use of CYPT and 56% reported willingness to order CYPT outside of a clinical trial if requested by a patient. Compared to oncologists specializing in breast cancer, oncologists in community-based practice were more likely to use CYPT routinely (21% versus 11%, P <.06), to order CYPT on patient request (66% versus 44%, P <.001), and to change management for premenopausal women with intermediate metabolism (34% CBO versus 8% NCCN, P <.001). Oncologists cited data from randomized trials and professional guidelines as most influential when considering use of a genetic test. CONCLUSIONS Prior to definitive evidence, a minority of oncologists reported using the CYP2D6 test routinely, and many indicated willingness to change management of patients based on test results. There is a need to educate clinicians and the public regarding the uncertain benefits of commercially available genetic tests in clinical practice when evidence from ongoing trials is still emerging. Cancer 2013;119:3703-3709. © 2013 American Cancer Society.

Chan M.Y.,National University of Singapore | Lin M.,Duke Translational Medicine Institute | Lucas J.,Applied Genomics | Moseley A.,Duke Institute for Genome science and Policy | And 7 more authors.
Thrombosis and Haemostasis | Year: 2012

Plasma proteins mediate thrombogenesis, inflammation, endocardial injury and structural remodelling in atrial fibrillation (AF). We hypothesised that anti-coagulation with rivaroxaban, a direct factor Xa inhibitor, would differentially modulate biologically-relevant plasma proteins, compared with warfarin, a multi-coagulation protein antagonist. We performed unbiased liquid chromatography/tandem mass spectroscopy and candidate multiplexed protein immunoassays among Japanese subjects with non-valvular chronic AF who were randomly assigned to treatment with 24 weeks of rivaroxaban (n=93) or warfarin (n=94). Nine metaproteins, including fibulin-1 (p=0.0033), vitronectin (p=0.0010), haemoglobin α (p=0.0012), apolipoproteins C-II (p=0.0017) and H (p=0.0023), complement C5 precursor (p=0.0026), coagulation factor XIIIA (p=0.0026) and XIIIB (p=0.0032) subunits, and 10 candidate proteins, including thrombomodulin (p=0.0004), intercellular adhesion molecule-3 (p=0.0064), interleukin-8 (p=0.0007) and matrix metalloproteinase-3 (p=0.0003), were differentially expressed among patients with and without known clinical risk factors for stroke and bleeding in AF. Compared with warfarin, rivaroxaban treatment was associated with a greater increase in thrombomodulin (Δ 0.1 vs. 0.3 pg/ml, p=0.0026) and a trend towards a reduction in matrix metalloproteinase- 9 (Δ 2.2 vs. -4.9 pg/ml, p=0.0757) over 24 weeks. Only modest correlations were observed between protein levels and prothrombin time, factor Xa activity and prothrombinase-induced clotting time. Plasma proteomics can identify distinct functional patterns of protein expression that report on known stroke and bleeding risk phenotypes in an ethnically-homogeneous AF population. The greater upregulation of thrombomodulin among patients randomised to rivaroxaban represents a proof-of-principle that pharmacoproteomics can be employed to discern novel effects of factor Xa inhibition beyond standard pharmacodynamic measures. © Schattauer 2012.

Orlando L.A.,Duke University | Wu R.R.,Duke University | Himmel T.,Duke Institute for Genome science and Policy | Powell K.P.,Cone Health | And 3 more authors.
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2014

The Genomic Medicine Model aims to facilitate patient engagement, patient/provider education of genomics/personalized medicine, and uptake of risk-stratified evidence-based prevention guidelines using MeTree, a patient-facing family health history (FHH) collection and clinical decision support (CDS) program. Here we report the number of increased risk (above population-level risk) patients identified for breast/ovarian cancer, colon cancer, hereditary syndrome risk, and thrombosis; the prevalence of FHH elements triggering increased-risk status; and the resources needed to manage their risk. Study design: hybrid implementation-effectiveness study of adults with upcoming well-visits in 2 primary care practices in Greensboro, NC. Participants: 1,184, mean age=58.8, female=58% (N=694), non-white=20% (N=215). Increased Risk: 44% (N=523). Recommendations: genetic counseling=26% (N=308), breast MRI=0.8% (N=10), breast chemoprophylaxis=5% (N=58), early/frequent colonoscopies=19% (N=221), ovarian cancer screening referral=1% (N=14), thrombosis testing/counseling=2.4% (N=71). FHH elements: 8 FHH elements lead to 37.3% of the increased risk categorizations (by frequency): first-degree-relative (FDR) with polyps age ≥60 (7.1%, N=85), three relatives with Lynch-related cancers (5.4%, N=65), FDR with polyps age <60 (5.1%, N=61), three relatives on same side of family with same cancer (4.9%, N=59), Gail score ≥1.66% (4.9%, N=58), two relatives with breast cancer (one ≤age 50) (4.1%, N=49), one relative with breast cancer ≤age 40 (4.1%, N=48), FDR with colon cancer age ≥60 (1.7%, N=20). MeTree identifies a high percentage of individuals in the general primary care population needing non-routine risk management/prevention for the selected conditions. Implementing risk-stratification in primary care will likely increase demand for related-resources, particularly colon screening and GC. Understanding the prevalence of FHH elements helps predict resource needs and may aid in guideline development. © 2014 Wiley Periodicals, Inc.

Yang N.,Duke University | Ginsburg G.S.,Duke Institute for Genome science and Policy | Ginsburg G.S.,Duke University | Simmons L.A.,Duke University
Obesity Reviews | Year: 2013

The prevalence of obesity in America has reached epidemic proportions, and obesity among women is particularly concerning. Severe obesity (body mass index ≥35kgm-2) is more prevalent in women than men. Further, women have sex-specific risk factors that must be considered when developing preventive and therapeutic interventions. This review presents personalized medicine as a dynamic approach to obesity prevention, management and treatment for women. First, we review obesity as a complex health issue, with contributing sex-specific, demographic, psychosocial, behavioural, environmental, epigenetic and genetic/genomic risk factors. Second, we present personalized medicine as a rapidly advancing field of health care that seeks to quantify these complex risk factors to develop more targeted and effective strategies that can improve disease management and/or better minimize an individual's likelihood of developing obesity. Third, we discuss how personalized medicine can be applied in a clinical setting with current and emerging tools, including health risk assessments, personalized health plans, and strategies for increasing patient engagement. Finally, we discuss the need for additional research, training and policy that can enhance the practice of personalized medicine in women's obesity, including further advancements in the '-omics' sciences, physician training in personalized medicine, and additional development and standardization of innovative targeted therapies and clinical tools. © 2012 International Association for the Study of Obesity.

Iwabuchi M.,Duke University | Sheng H.,Duke University | Thompson J.,Duke Institute for Genome Science and Policy | Wang L.,Duke University | And 5 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2014

Ubiquitylation is a posttranslational protein modification that modulates various cellular processes of key significance, including protein degradation and DNA damage repair. In animals subjected to transient cerebral ischemia, ubiquitin-conjugated proteins accumulate in Triton-insoluble aggregates. Although this process is widely considered to modulate the fate of postischemic neurons, few attempts have been made to characterize the ubiquitin-modified proteome in these aggregates. We performed proteomics analyses to identify ubiquitylated proteins in postischemic aggregates. Mice were subjected to 10 minutes of forebrain ischemia and 4 hours of reperfusion. The hippocampi were dissected, aggregates were isolated, and trypsin-digested after spiking with GG-BSA as internal standard. K-ε-GG-containing peptides were immunoprecipitated and analyzed by label-free quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. We identified 1,664 peptides to 520 proteins containing at least one K-ε-GG. Sixty-six proteins were highly ubiquitylated, with 10 or more K-ε-GG peptides. Based on selection criteria of greater than fivefold increase and P<0.001, 763 peptides to 272 proteins were highly enriched in postischemic aggregates. These included proteins involved in important neuronal functions and signaling pathways that are impaired after ischemia. Results of this study could serve as an important platform to uncover the mechanisms linking insoluble ubiquitin aggregates to the functions of postischemic neurons. © 2014 ISCBFM All rights reserved.

Yang W.,Multidisciplinary Neuroprotection Laboratories | Thompson J.W.,Duke Institute for Genome Science and Policy | Wang Z.,Multidisciplinary Neuroprotection Laboratories | Wang Z.,Zhengzhou University | And 5 more authors.
Journal of Proteome Research | Year: 2012

Transient cerebral ischemia dramatically activates small ubiquitin-like modifier (SUMO2/3) conjugation. In cells exposed to 6 h of transient oxygen/glucose deprivation (OGD), a model of ischemia, SUMOylation increases profoundly between 0 and 30 min following re-oxygenation. To elucidate the effect of transient OGD on SUMO conjugation of target proteins, we exposed neuroblastoma B35 cells expressing HA-SUMO3 to transient OGD and used stable isotope labeling with amino acids in cell culture (SILAC) to quantify OGD-induced changes in levels of specific SUMOylated proteins. Lysates from control and OGD-treated cells were mixed equally, and HA-tagged proteins were immunoprecipitated and analyzed by 1D-SDS-PAGE-LC-MS/MS. We identified 188 putative SUMO3-conjugated proteins, including numerous transcription factors and coregulators, and PIAS2 and PIAS4 SUMO ligases, of which 22 were increased or decreased more than ±2-fold. In addition to SUMO3, the levels of protein-conjugated SUMO1 and SUMO2, as well as ubiquitin, were all increased. Importantly, protein ubiquitination induced by OGD was completely blocked by gene silencing of SUMO2/3. Collectively, these results suggest several mechanisms for OGD-modulated SUMOylation, point to a number of signaling pathways that may be targets of SUMO-based signaling and recovery from ischemic stress, and demonstrate a tightly controlled crosstalk between the SUMO and ubiquitin conjugation pathways. © 2011 American Chemical Society.

Orlando L.A.,Duke Institute for Genome science and Policy | Henrich V.C.,University of North Carolina at Greensboro | Hauser E.R.,Duke University | Hauser E.R.,Epidemiological Research and Information Center | And 2 more authors.
Personalized Medicine | Year: 2013

As an essential tool for risk stratification, family health history (FHH) is a central component of personalized medicine; yet, despite its widespread acceptance among professional societies and its established place in the medical interview, its widespread adoption is hindered by three major barriers: quality of FHH collection, risk stratification capabilities and interpretation of risk stratification for clinical care. To overcome these barriers and bring FHH to the forefront of the personalized medicine effort, we developed the genomic medicine model (GMM) for primary care. The GMM, founded upon the principles of the Health Belief Model, Adult Learning Theory and the implementation sciences, shifts responsibility for FHH onto the patient, uses information technology (MeTree©) for risk stratification and interpretation, and provides education across multiple levels for each stakeholder, freeing up the clinical encounter for discussion around personalized preventive healthcare plans. The GMM has been implemented and optimized as part of an implementation-effectiveness hybrid pilot study for breast/ovarian cancer, colon cancer and thrombosis, and risk for hereditary cancer syndromes in two primary care clinics in NC, USA. This paper describes the conceptual development of the model and key findings relevant for broader uptake and sustainability in the primary care community. © 2013 Future Medicine Ltd.

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