The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems.

Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.

Attitudes of clinicians following large-scale pharmacogenomics implementation.

Clinician attitudes toward multiplexed genomic testing may be vital to the success of translational programs. We surveyed clinicians at an academic medical center about their views on a large pharmacogenomics implementation, the PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) program. Participants were asked about test ordering, major factors influencing use of results, expectations of efficacy and responsibility for applying results to patient care. Virtually all respondents (99%) agreed that pharmacogenomics variants influence patients' response to drug therapy. The majority (92%) favored immediate, active notification when a clinically significant drug-genome interaction was present. However, clinicians were divided on which providers were responsible for acting on a result when a prescription change was indicated and whether patients should be directly notified of a significant result. We concluded genotype results were valued for tailoring prescriptions, but clinicians do not agree on how to appropriately assign clinical responsibility for actionable results from a multiplexed panel.The Pharmacogenomics Journal advance online publication, 11 August 2015; doi:10.1038/tpj.2015.57.

Physician response to implementation of genotype-tailored antiplatelet therapy.

Physician responses to genomic information are vital to the success of precision medicine initiatives. We prospectively studied a pharmacogenomics implementation program for the propensity of clinicians to select antiplatelet therapy based on CYP2C19 loss-of-function variants in stented patients. Among 2,676 patients, 514 (19.2%) were found to have a CYP2C19 variant affecting clopidogrel metabolism. For the majority (93.6%) of the cohort, cardiologists received active and direct notification of CYP2C19 status. Over 12 months, 57.6% of poor metabolizers and 33.2% of intermediate metabolizers received alternatives to clopidogrel. CYP2C19 variant status was the most influential factor impacting the prescribing decision (hazard ratio [HR] in poor metabolizers 8.1, 95% confidence interval [CI] [5.4, 12.2] and HR 5.0, 95% CI [4.0, 6.3] in intermediate metabolizers), followed by patient age and type of stent implanted. We conclude that cardiologists tailored antiplatelet therapy for a minority of patients with a CYP2C19 variant and considered both genomic and nongenomic risks in their clinical decision-making.

Clinically actionable genotypes among 10,000 patients with preemptive pharmacogenomic testing.

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.

Optimizing drug outcomes through pharmacogenetics: a case for preemptive genotyping.

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.

Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project.

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.

Predicting clopidogrel response using DNA samples linked to an electronic health record.

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.

What can paper-based clinical information systems tell us about the design of computerized clinical information systems (CIS) in the ICU?

BACKGROUND: Screen designs in computerized clinical information systems (CIS) have been modeled on their paper predecessors. However, limited understanding about how paper forms support clinical work means that we risk repeating old mistakes and creating new opportunities for error and inefficiency as illustrated by problems associated with computerized provider order entry systems. PURPOSE: This study was designed to elucidate principles underlying a successful ICU paper-based CIS. The research was guided by two exploratory hypotheses: (1) paper-based artefacts (charts, notes, equipment, order forms) are used differently by nurses, doctors and other healthcare professionals in different (formal and informal) conversation contexts and (2) different artefacts support different decision processes that are distributed across role-based conversations. METHOD: All conversations undertaken at the bedsides of five patients were recorded with any supporting artefacts for five days per patient. Data was coded according to conversational role-holders, clinical decision process, conversational context and artefacts. 2133 data points were analyzed using Poisson logistic regression analyses. RESULTS: Results show significant interactions between artefacts used during different professional conversations in different contexts (chi(2)((df=16))=55.8, p<0.0001). The interaction between artefacts used during different professional conversations for different clinical decision processes was not statistically significant although all two-way interactions were statistically significant. CONCLUSIONS: Paper-based CIS have evolved to support complex interdisciplinary decision processes. The translation of two design principles - support interdisciplinary perspectives and integrate decision processes - from paper to computerized CIS may minimize the risks associated with computerization.

Adjustment for selection bias in observational studies with application to the analysis of autopsy data.

BACKGROUND: The interpretation of neuropathological studies of dementia and Alzheimer's disease is complicated by potential selection mechanisms that can drive whether or not a study participant is observed to undergo autopsy. Notwithstanding this, there appears to have been little emphasis placed on potential selection bias in published reports from population-based neuropathological studies of dementia. METHODS: We provide an overview of methodological issues relating to the identification of and adjustment for selection bias. When information is available on factors that govern selection, inverse-probability weighting provides an analytic approach to adjust for selection bias. The weights help alleviate bias by serving to bridge differences between the population from which the observed data may be viewed as a representative sample and the target population, identified as being of scientific interest. RESULTS: We illustrate the methods with data obtained from the Adult Changes in Thought study. Adjustment for potential selection bias yields substantially strengthened association between neuropathological measurements and risk of dementia. CONCLUSIONS: Armed with analytic techniques to adjust for selection bias and to ensure generalizability of results from population-based neuropathological studies, researchers should consider incorporating information related to selection into their data collection schemes.

Effectiveness of early coronary angioplasty and abciximab for failed thrombolysis (reteplase or alteplase) during acute myocardial infarction (results from the GUSTO-III trial). Global Use of Strategies To Open occluded coronary arteries.

We evaluated the effects of abciximab treatment during early angioplasty after clinically failed thrombolysis for acute myocardial infarction. In the Global Use of Strategies To Open occluded coronary arteries (GUSTO-III) trial of reteplase versus alteplase for acute infarction (n = 15,059), 392 patients underwent angioplasty a median of 3.5 hours after thrombolysis and had complete procedural data. We compared 30-day mortality and in-hospital outcomes between patients who received abciximab (n = 83) and those who did not (n = 309), and (among patients given abciximab) between those randomized to alteplase versus reteplase. Patients given abciximab had anterior infarction less often, but were more often in Killip classes III or IV. The 30-day mortality rate tended to be lower with abciximab (3.6% vs 9.7%, p = 0.076), more so after adjustment for baseline differences (p = 0.042). The composite of death, stroke, or reinfarction did not differ significantly with abciximab treatment (12% vs 14%, p = 0.7), but it occurred less often among abciximab-treated patients who had been randomized to reteplase (n = 55) versus alteplase (n = 28) (7% vs 21%, p = 0.08). Severe bleeding was increased among abciximab-treated patients (3.6% vs 1.0%, p = 0.08), despite less heparin use. No intracranial hemorrhages occurred with abciximab. The use of abciximab for early angioplasty after clinically failed thrombolysis resulted in trends toward lower 30-day mortality and increased bleeding.

Predicting rodent carcinogenicity using potency measures of the in vitro sister chromatid exchange and chromosome aberration assays.

In vitro sister chromatid exchange (SCE) and chromosome aberration (ABS) tests have been extensively used to identify potential rodent carcinogens. A number of measures of potency were developed to describe in vitro SCE and ABS test results: the dose needed to induce a unit increase over the control; the lowest effective dose; the slope of the ordinary linear regression; the maximum observed slope; and the maximum fold increase over background. The ability of these potency measures to predict the qualitative and quantitative carcinogenicity of chemicals was compared to the predictivity of the qualitative in vitro responses. The results of the analyses showed that the quantitative measures of the SCE or ABS responses only minimally increased the predictivity of carcinogenesis when compared to the predictivity using the qualitative responses.

Predicting rodent carcinogenicity from mutagenic potency measured in the Ames Salmonella assay.

Many in vitro tests have been developed to identify chemicals that can damage cellular DNA or cause mutations, and secondarily to identify potential carcinogens. The test receiving by far the most use and attention has been the Salmonella (SAL) mutagenesis test developed by Ames and colleagues [(1973): Proc Natl Acad Sci USA 70:2281-2285; (1975): Mutat Res 31:347-364], because of its initial promise of high qualitative (YES/NO) predictivity for cancer in rodents and, by extension, in humans. In addition to the initial reports of high qualitative predictivity, there was also an early report by Meselson and Russell [in Hiatt HH et al (1977): "Origins of Human Cancer, Book C: Human Risk Assessment," pp 1473-1481] of a quantitative relationship between mutagenic potency measured in SAL and carcinogenic potency measured in rodents, for a small number of chemicals. However, other reports using larger numbers of chemicals have found only very weak correlations. The primary purpose of this study was to determine whether mutagenic potency, as measured in a number of different ways, could be used to improve predictivity of carcinogenicity, either qualitatively or quantitatively. To this end, eight measures of SAL mutagenic potency were used. This study firmly establishes that the predictive relationship between mutagenic potency in SAL and rodent carcinogenicity is, at best, weak. When predicting qualitative carcinogenicity, only qualitative mutagenicity is useful; none of the quantitative measures of potency considered improves the carcinogenicity prediction. In fact, when qualitative mutagenicity is forced out of the model, the quantitative measures are still not predictive of carcinogenicity. When predicting quantitative carcinogenicity, several possible methods were considered for summarizing potency over all experiments; however, in all cases, the relationship between mutagenic potency predictors and quantitative carcinogenicity is very weak.