Challenges in the Pharmacogenomic Annotation of Whole Genomes

Altman, Russ B.; Whirl‐Carrillo, Michelle; Klein, Teri E.

doi:10.1038/clpt.2013.111

Cited by 22 publications

(11 citation statements)

References 6 publications

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“…By preemptive, we mean that the test result is available in the medical record as a pre-prescription patient characteristic: the test result has not been ordered because a specific pharmacogenetically high-risk drug is being contemplated, but the result is available because a broad screening of multiple genes has already been performed. This preemptive approach may counteract many of the disadvantages of reactive pharmacogenetic testing (27-29). The recent availability of high-quality genotyping arrays and other multiplex approaches that are oriented to pharmacogenetics and reasonably priced makes preemptive genotyping financially feasible.…”

Section: Introductionmentioning

confidence: 99%

Preemptive Clinical Pharmacogenetics Implementation: Current Programs in Five US Medical Centers

Dunnenberger¹,

Crews²,

Hoffman³

et al. 2015

Annu. Rev. Pharmacol. Toxicol.

437

381

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Although the field of pharmacogenetics has existed for decades, the implementation of, pharmacogenetic testing in clinical care has been slow. There are numerous publications, describing the barriers to clinical implementation of pharmacogenetics. Recently, several freely, available resources have been developed to help address these barriers. In this review we, discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of, patients. Array-based preemptive testing includes a large number of relevant pharmacogenes, that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to, be available prior to any prescribing decision so that genomic variation may be considered as, an inherent patient characteristic in the planning of therapy. This review describes the common, elements among programs that have implemented preemptive genotyping and highlights key, processes for implementation, including clinical decision support.

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Section: Introductionmentioning

confidence: 99%

Preemptive Clinical Pharmacogenetics Implementation: Current Programs in Five US Medical Centers

Dunnenberger¹,

Crews²,

Hoffman³

et al. 2015

Annu. Rev. Pharmacol. Toxicol.

437

381

View full text Add to dashboard Cite

show abstract

“…[Relling and Klein, ; Swen et al, ]. To be immediately available to guide prescribing decisions at any time, pharmacogenetic test results should be available pre‐emptively [Altman, ; Altman et al, ; Shuldiner et al, ]. The availability of high‐quality genotyping arrays focused on pharmacogenes at a reasonable cost facilitates this pre‐emptive approach [Altman et al, ].…”

Section: Introductionmentioning

confidence: 99%

PG4KDS: A model for the clinical implementation of pre‐emptive pharmacogenetics

Hoffman¹,

Haidar²,

Wilkinson³

et al. 2014

American J of Med Genetics Pt C

237

209

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Pharmacogenetics is frequently cited as an area for initial focus of the clinical implementation of genomics. Through the PG4KDS protocol, St. Jude Children’s Research Hospital pre-emptively genotypes patients for 230 genes using the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array supplemented with a CYP2D6 copy number assay. The PG4KDS protocol provides a rational, stepwise process for implementing gene/drug pairs, organizing data, and obtaining consent from patients and families. Through August 2013, 1559 patients have been enrolled, and 4 gene tests have been released into the electronic health record (EHR) for clinical implementation: TPMT, CYP2D6, SLCO1B1, and CYP2C19. These genes are coupled to 12 high-risk drugs. Of the 1016 patients with genotype test results available, 78% of them had at least one high-risk (i.e., actionable) genotype result placed in their EHR. Each diplotype result released to the EHR is coupled with an interpretive consult that is created in a concise, standardized format. To support-gene based prescribing at the point of care, 55 interruptive clinical decision support (CDS) alerts were developed. Patients are informed of their genotyping result and its relevance to their medication use through a letter. Key elements necessary for our successful implementation have included strong institutional support, a knowledgeable clinical laboratory, a process to manage any incidental findings, a strategy to educate clinicians and patients, a process to return results, and extensive use of informatics, especially CDS. Our approach to pre-emptive clinical pharmacogenetics has proven feasible, clinically useful, and scalable.

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“…Despite successful identification of several pharmacogenetic markers, the functional annotation of these variants—such as the combined effect of gain-of-function and loss-of-function genetic variants on the drug phenotype—is unknown and, in the context of multiple drugs that have interactions with each other, the effect of pharmacogenetic variation on overall drug phenotype is also unknown. 99 Ensuring the validity of the pharmacogenetic marker is, therefore, critically important before implementation of the marker into clinical practice. Adequately powered, pragmatic, prospective RCTs are required to translate the use of pharmacogenetic markers into clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Genotype-based clinical trials in cardiovascular disease

et al. 2015

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Consensus practice guidelines and the implementation of clinical therapeutic advances are usually based on the results of large, randomized clinical trials (RCTs). However, RCTs generally inform us on an average treatment effect for a presumably homogeneous population, but therapeutic interventions rarely benefit the entire population targeted. Indeed, multiple RCTs have demonstrated that interindividual variability exists both in drug response and in the development of adverse effects. The field of pharmacogenomics promises to deliver the right drug to the right patient. Substantial progress has been made in this field, with advances in technology, statistical and computational methods, and the use of cell and animal model systems. However, clinical implementation of pharmacogenetic principles has been difficult because RCTs demonstrating benefit are lacking. For patients, the potential benefits of performing such trials include the individualization of therapy to maximize efficacy and minimize adverse effects. These trials would also enable investigators to reduce sample size and hence contain costs for trial sponsors. Multiple ethical, legal, and practical issues need to be considered for the conduct of genotype-based RCTs. Whether pre-emptive genotyping embedded in electronic health records will preclude the need for performing genotype-based RCTs remains to be seen.

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Challenges in the Pharmacogenomic Annotation of Whole Genomes

Abstract: Next-generation sequencing technologies have enabled the sequencing of an entire genome for less than $4,000. With access to all the genetic variation in an individual, our task will be to use this information to assess the genetic influences on drug efficacy, toxicity, and dosage.

Cited by 22 publications

References 6 publications

Preemptive Clinical Pharmacogenetics Implementation: Current Programs in Five US Medical Centers

Preemptive Clinical Pharmacogenetics Implementation: Current Programs in Five US Medical Centers

PG4KDS: A model for the clinical implementation of pre‐emptive pharmacogenetics

Genotype-based clinical trials in cardiovascular disease

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