The promise of “personalized medicine” guided by an understanding of each individual's genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant ...information. We describe the operational implementation of prospective genotyping linked to an advanced clinical decision‐support system to guide individualized health care in a large academic health center. This approach to personalized medicine entails engagement between patient and health‐care provider, identification of relevant genetic variations for implementation, assay reliability, point‐of‐care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most of whom were scheduled for cardiac catheterization, were genotyped on a multiplexed platform that included genotyping for CYP2C19 variants that modulate response to the widely used antiplatelet drug clopidogrel. These data are deposited into the electronic medical record (EMR), and point‐of‐care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.
Clinical Pharmacology & Therapeutics (2012); 92 1, 87–95. doi:10.1038/clpt.2011.371
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Expectations of results from genome sequencing by end users are influenced by perceptions of uncertainty. This study aimed to assess uncertainties about sequencing by developing, evaluating, and ...implementing a novel scale. The Perceptions of Uncertainties in Genome Sequencing (PUGS) scale comprised ten items to assess uncertainties within three domains: clinical, affective, and evaluative. Participants (n=535) from the ClinSeq® NIH sequencing study completed a baseline survey that included the PUGS; responses (mean = 3.4/5, SD=0.58) suggested modest perceptions of certainty. A confirmatory factor analysis identified factor loadings that led to elimination of two items. A revised eight‐item PUGS scale was used to test correlations with perceived ambiguity (r = −0.303, p < 0.001), attitudinal ambivalence (r = −0.111, p = 0.011), and ambiguity aversion (r = −0.093, p = 0.033). Results support nomological validity. A correlation with the MICRA uncertainty subscale was found among 175 cohort participants who had received results (r = −0.335, p < 0.001). Convergent and discriminant validity were also satisfied in a second sample of 208 parents from the HudsonAlpha CSER Project who completed the PUGS (mean = 3.4/5, SD = 0.72), and configural invariance was supported across the two datasets. As such, the PUGS is a promising scale for evaluating perceived uncertainties in genome sequencing, which can inform interventions to help patients form realistic expectations of these uncertainties.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while ...sequencing affected individuals reveals disease‐associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize the benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants that were not initially reported in 23 individuals, 6 described here, comprising a 16% increase in P/LP yield. We also downgraded 3 LP and 6 variants of uncertain significance (VUS) due to updated population frequency data. The likelihood of identifying a new P/LP variant increased over time, as ~22% of individuals who did not receive a P/LP variant at their original analysis subsequently did after 3 years. We show here that reanalysis and data sharing increase the diagnostic yield and accuracy of clinical sequencing.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The Vanderbilt DNA repository, BioVU, links DNA from leftover clinical blood samples to de‐identified electronic medical records (EMRs). After initiating adult sample collection, pediatric extension ...required consideration of ethical concerns specific to pediatrics and implementation of specialized DNA extraction methods. In the first year of pediatric sample collection, more than 11,000 samples from individuals younger than 18 years were included. We compared data from the pediatric BioVU cohort with those from the overall Vanderbilt University Medical Center pediatric population and found similar demographic characteristics; however, the BioVU cohort had higher rates of select diseases, medication exposures, and laboratory testing, demonstrating enriched representation of severe or chronic disease. The fact that the sample accumulation is not balanced may accelerate research in some cohorts while limiting the study of relatively benign conditions and the accrual of unaffected and unbiased control samples. BioVU represents a feasible model for pediatric DNA biobanking but involves both ethical and practical considerations specific to the pediatric population.
Clinical Pharmacology & Therapeutics (2013); 93 2, 204–211. doi:10.1038/clpt.2012.230
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Systems medicine is the name for an assemblage of scientific strategies and practices that include bioinformatics approaches to human biology (especially systems biology); "big data" statistical ...analysis; and medical informatics tools. Whereas personalized and precision medicine involve similar analytical methods applied to genomic and medical record data, systems medicine draws on these as well as other sources of data. Given this distinction, the clinical translation of systems medicine poses a number of important ethical and epistemological challenges for researchers working to generate systems medicine knowledge and clinicians working to apply it.
This article focuses on three key challenges: First, we will discuss the conflicts in decision-making that can arise when healthcare providers committed to principles of experimental medicine or evidence-based medicine encounter individualized recommendations derived from computer algorithms. We will explore in particular whether controlled experiments, such as comparative effectiveness trials, should mediate the translation of systems medicine, or if instead individualized findings generated through "big data" approaches can be applied directly in clinical decision-making. Second, we will examine the case of the Riyadh Intensive Care Program Mortality Prediction Algorithm, pejoratively referred to as the "death computer," to demonstrate the ethical challenges that can arise when big-data-driven scoring systems are applied in clinical contexts. We argue that the uncritical use of predictive clinical algorithms, including those envisioned for systems medicine, challenge basic understandings of the doctor-patient relationship. Third, we will build on the recent discourse on secondary findings in genomics and imaging to draw attention to the important implications of secondary findings derived from the joint analysis of data from diverse sources, including data recorded by patients in an attempt to realize their "quantified self." This paper examines possible ethical challenges that are likely to be raised as systems medicine to be translated into clinical medicine. These include the epistemological challenges for clinical decision-making, the use of scoring systems optimized by big data techniques and the risk that incidental and secondary findings will significantly increase. While some ethical implications remain still hypothetical we should use the opportunity to prospectively identify challenges to avoid making foreseeable mistakes when systems medicine inevitably arrives in routine care.
As genomic sequencing becomes more common, medically actionable secondary findings will increasingly be returned to health care providers (HCPs), who will be faced with managing the resulting patient ...care. These findings are generally unsolicited, ie, unrelated to the sequencing indication and/or ordered by another clinician.
To understand the impact of receiving unsolicited results, we interviewed HCPs who received genomic results for patients enrolled in the Electronic Medical Records and Genomics (eMERGE) Phase III Network, which returned results on >100 actionable genes to eMERGE participants and HCPs.
In total, 16 HCPs across 3 eMERGE sites were interviewed about their experience of receiving a positive (likely pathogenic or pathogenic), negative, or variant of uncertain significance result for a patient enrolled in eMERGE Phase III and about managing their patient on the basis of the result. Although unsolicited, HCPs felt responsible for managing the patient’s resulting medical care. HCPs indicated that clinical utility depended on the actionability of results, and whereas comfort levels varied, confidence was improved by the availability of subspecialist consults. HCPs were concerned about patient anxiety, insurability, and missing an actionable result in the electronic health record.
Our findings help inform best practices for return of unsolicited genomic screening findings in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on ...specific results or weighed deliberations against relevant local contextual factors.
The Electronic Medical Records and Genomics (eMERGE) Network, which includes five biorepositories conducting genome-wide association studies, convened a return of results oversight committee to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision making.
Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The return of results oversight committee identified two sex chromosomal anomalies, Klinefelter syndrome and Turner syndrome, as well as homozygosity for factor V Leiden, as findings that could warrant reporting. Views about returning findings of HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of electronic medical records suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site).
The eMERGE experience reveals the complexity of return of results decision making and provides a potential deliberative model for adoption in other collaborative contexts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A patient is described who rapidly progressed from primary human immunodeficiency virus (HIV) type 1 infection to death without seroconversion but with consistently high plasma viremia. His ...asymptomatic sex partner had been HIV-1 seropositive for >8 years prior to transmission. Analysis of viral sequences from these subjects and controls confirmed the transmission event. Although the biologic properties of the patient's virus were unremarkable, he had poor functional immune responses to HIV and an HLA haplotype associated with rapid disease progression. The disparity between immune responses and clinical course in this transmission pair, coupled with infection with an unremarkable HIV-1 isolate, underscores the crucial importance of host factors in HIV-1 pathogenesis.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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