Since September 2010, more than 10,000 patients have undergone preemptive, panel‐based pharmacogenomic testing through the Vanderbilt Pharmacogenomic Resource for Enhanced Decisions in Care and ...Treatment program. Analysis of the genetic data from the first 9,589 individuals reveals that the frequency of genetic variants is concordant with published allele frequencies. Based on five currently implemented drug–gene interactions, the multiplexed test identified one or more actionable variants in 91% of the genotyped patients and in 96% of African American patients. Using medication exposure data from electronic medical records, we compared a theoretical “reactive,” prescription‐triggered, serial single‐gene testing strategy with our preemptive, multiplexed genotyping approach. Reactive genotyping would have generated 14,656 genetic tests. These data highlight three advantages of preemptive genotyping: (i) the vast majority of patients carry at least one pharmacogenetic variant; (ii) data are available at the point of care; and (iii) there is a substantial reduction in testing burden compared with a reactive strategy.
Clinical Pharmacology & Therapeutics (2014); 95 4, 423–431. doi:10.1038/clpt.2013.229
Routine integration of genotype data into drug decision making could improve patient safety, particularly if many relevant genetic variants can be assayed simultaneously before prescribing the target ...drug. The frequency of opportunities for pharmacogenetic prescribing and the potential adverse events (AEs) mitigated are unknown. We examined the frequency with which 56 medications with known outcomes influenced by variant alleles were prescribed in a cohort of 52,942 medical home patients at Vanderbilt University Medical Center (VUMC). Within a 5‐year window, we estimated that 64.8% (95% confidence interval (CI): 64.4–65.2%) of individuals were exposed to at least one medication with an established pharmacogenetic association. Using previously published results for six medications with severe, well‐characterized, genetically linked AEs, we estimated that 383 events (95% CI, 212–552) could have been prevented with an effective preemptive genotyping program. Our results suggest that multiplexed, preemptive genotyping may represent an efficient alternative approach to current single‐use (“reactive”) methods and may also improve safety.
Clinical Pharmacology & Therapeutics (2012); 92 2, 235–242. doi:10.1038/clpt.2012.66
Emerging evidence associates dysfunction in the dopamine (DA) transporter (DAT) with the pathophysiology of autism spectrum disorder (ASD). The human DAT (hDAT; SLC6A3) rare variant with an Ala to ...Val substitution at amino acid 559 (hDAT A559V) was previously reported in individuals with bipolar disorder or attention-deficit hyperactivity disorder (ADHD). We have demonstrated that this variant is hyper-phosphorylated at the amino (N)-terminal serine (Ser) residues and promotes an anomalous DA efflux phenotype. Here, we report the novel identification of hDAT A559V in two unrelated ASD subjects and provide the first mechanistic description of its impaired trafficking phenotype. DAT surface expression is dynamically regulated by DAT substrates including the psychostimulant amphetamine (AMPH), which causes hDAT trafficking away from the plasma membrane. The integrity of DAT trafficking directly impacts DA transport capacity and therefore dopaminergic neurotransmission. Here, we show that hDAT A559V is resistant to AMPH-induced cell surface redistribution. This unique trafficking phenotype is conferred by altered protein kinase C β (PKCβ) activity. Cells expressing hDAT A559V exhibit constitutively elevated PKCβ activity, inhibition of which restores the AMPH-induced hDAT A559V membrane redistribution. Mechanistically, we link the inability of hDAT A559V to traffic in response to AMPH to the phosphorylation of the five most distal DAT N-terminal Ser. Mutation of these N-terminal Ser to Ala restores AMPH-induced trafficking. Furthermore, hDAT A559V has a diminished ability to transport AMPH, and therefore lacks AMPH-induced DA efflux. Pharmacological inhibition of PKCβ or Ser to Ala substitution in the hDAT A559V background restores AMPH-induced DA efflux while promoting intracellular AMPH accumulation. Although hDAT A559V is a rare variant, it has been found in multiple probands with neuropsychiatric disorders associated with imbalances in DA neurotransmission, including ADHD, bipolar disorder, and now ASD. These findings provide valuable insight into a new cellular phenotype (altered hDAT trafficking) supporting dysregulated DA function in these disorders. They also provide a novel potential target (PKCβ) for therapeutic interventions in individuals with ASD.
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
Variants in ABCB1 and CYP2C19 have been identified as predictors of cardiac events during clopidogrel therapy initiated after myocardial infarction (MI) or percutaneous coronary intervention (PCI). ...In addition, PON1 has recently been associated with stent thrombosis. The reported effects of these variants have not yet been replicated in a real–world setting. We used BioVU, the Vanderbilt DNA repository linked to de–identified electronic health records (EHRs), to find data on patients who were on clopidogrel treatment after an MI and/or a PCI; among these, we identified those who had experienced one or more recurrent cardiac events while on treatment (cases, n = 225) and those who had not experienced any cardiac event while on treatment (controls, n = 468). We found that CYP2C19*2 (hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.16–2.06, P = 0.003) and ABCB1 (HR 1.28, 95% CI 1.04–1.57, P = 0.018), but not PON1 (HR 0.91, 95% CI 0.73–1.12, P = 0.370), were associated with recurrent events. In this population, genetic signals for clopidogrel resistance in ABCB1 and CYP2C19 were replicated, supporting the use of EHRs for pharmacogenomic studies. Our data do not show an association between PON1 and recurrent cardiovascular events.
Clinical Pharmacology & Therapeutics (2012); 91 2, 257–263. doi:10.1038/clpt.2011.221
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
In a multicenter trial in 566 patients with critical illness who had delirium, the use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the duration of delirium ...or coma. Side effects and extrapyramidal disorders occurred at similar rates in all groups.
For over two decades, physicians have attempted to define the best methods of discontinuing mechanical ventilation in patients recovering from respiratory failure. An early study of weaning
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noted ...that the clinical decision to discontinue mechanical ventilation is often arbitrary, based on “judgment and experience.” With increasing recognition of the risks and economic consequences of prolonged ventilation, identifying strategies that reduce the duration of mechanical ventilation remains a high priority,
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,
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but no single approach has been established as the best one. Many measures have been proposed to identify patients ready for extubation,
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,
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ranging from simple maneuvers, such as . . .
A respiratory therapist-driven weaning protocol incorporating daily screens, spontaneous breathing trials (SBT), and prompts to caregivers has been associated with superior outcomes in mechanically ...ventilated medical patients. To determine the effectiveness of this approach in neurosurgical (NSY) patients, we conducted a randomized controlled trial involving 100 patients over a 14-mo period. All had daily screens of weaning parameters. If these were passed, a 2-h SBT was performed in the Intervention group. Study physicians communicated positive SBT results, and the decision to extubate was made by the primary NSY team. Patients in the Intervention (n = 49) and Control (n = 51) groups had similar demographic characteristics, illness severity, and neurologic injuries. Among all patients, 87 (45 in the Control and 42 in the Intervention group) passed at least one daily screen. Forty (82%) patients in the Intervention group passed SBT, but a median of 2 d passed before attempted extubation, primarily because of concerns about the patient's sensorium (84%). Of 167 successful SBT, 126 (75%) did not lead to attempted extubation on the same day. The median time of mechanical ventilation was 6 d in both study groups, and there were no differences in outcomes. Overall complications included death (36%), reintubation (16%), and pneumonia (9%). Tracheostomies were created in 29% of patients. Multivariate analysis showed that Glasgow Coma Scale (GCS) score (p < 0.0001) and partial pressure of arterial oxygen/fraction of inspired oxygen ratio (p < 0.0001) were associated with extubation success. The odds of successful extubation increased by 39% with each GCS score increment. A GCS score > or = 8 at extubation was associated with success in 75% of cases, versus 33% for a GCS score < 8 (p < 0.0001). Implementation of a weaning protocol based on traditional respiratory physiologic parameters had practical limitations in NSY patients, owing to concerns about neurologic impairment. Whether protocols combining respiratory parameters with neurologic measures lead to superior outcomes in this population requires further investigation.
Procedure instruction for physicians-in-training is usually nonstandardized. The authors observed that during insertion of central venous catheters (CVCs), few physicians used full-size sterile ...drapes (an intervention proven to reduce the risk for CVC-related infection).
To improve standardization of infection control practices and techniques during invasive procedures.
Nonrandomized pre-post observational trial.
Six intensive care units and one step-down unit at Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina.
Third-year medical students and physicians completing their first postgraduate year.
A 1-day course on infection control practices and procedures given in June 1996 and June 1997.
Surveys assessing physician attitudes toward use of sterile techniques during insertion of CVCs were administered during the baseline year and just before, immediately after, and 6 months after the first course. Preintervention and postintervention use of full-size sterile drapes was measured, and surveillance for vascular catheter-related infection was performed.
The perceived need for full-size sterile drapes was 22% in the year before the course and 73% 6 months after the course (P < 0.001). The perceived need for small sterile towels at the insertion site decreased reciprocally (P < 0.001). Documented use of full-size sterile drapes increased from 44% to 65% (P < 0.001). The rate of catheter-related infection decreased from 4.51 infections per 1000 patient-days before the first course to 2.92 infections per 1000 patient-days 18 months after the first course (average decrease, 3.23 infections per 1000 patient-days; P < 0.01). The estimated cost savings of this 28% decrease was at least $63000 and may have exceeded $800000.
Standardization of infection control practices through a course is a cost-effective way to decrease related adverse outcomes. If these findings can be reproduced, this approach may serve as a model for physicians-in-training.
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