Analytics of the clinical implementation of pharmacogenomics testing in 12 758 individuals.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC8571952 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPharmacogenomics (PGx) holds promise to revolutionize modern healthcare. Although there are several prospective clinical studies in oncology and cardiology, demonstrating a beneficial effect of PGx-guided treatment in reducing adverse drug reactions, there are very few such studies in psychiatry, none of which spans across all main psychiatric indications, namely schizophrenia, major depressive disorder and bipolar disorder. In this study we aim to investigate the clinical effectiveness of PGx-guided treatment (occurrence of adverse drug reactions, hospitalisations and re-admissions, polypharmacy) and perform a cost analysis of the intervention.MethodsWe report our findings from a multicenter, large-scale, prospective study of pre-emptive genome-guided treatment named as PREemptive Pharmacogenomic testing for preventing Adverse drug REactions (PREPARE) in a large cohort of psychiatric patients (n = 1076) suffering from schizophrenia, major depressive disorder and bipolar disorder.FindingsWe show that patients with an actionable phenotype belonging to the PGx-guided arm (n = 25) present with 34.1% less adverse drug reactions compared to patients belonging to the control arm (n = 36), 41.2% less hospitalisations (n = 110 in the PGx-guided arm versus n = 187 in the control arm) and 40.5% less re-admissions (n = 19 in the PGx-guided arm versus n = 32 in the control arm), less duration of initial hospitalisations (n = 3305 total days of hospitalisation in the PGx-guided arm from 110 patients, versus n = 6517 in the control arm from 187 patients) and duration of hospitalisation upon readmission (n = 579 total days of hospitalisation upon readmission in the PGx-guided arm, derived from 19 patients, versus n = 928 in the control arm, from 32 patients respectively). It was also shown that in the vast majority of the cases, there was less drug dose administrated per drug in the PGx-guided arm compared to the control arm and less polypharmacy (n = 124 patients prescribed with at least 4 psychiatric drugs in the PGx-guided arm versus n = 143 in the control arm) and smaller average number of co-administered psychiatric drugs (2.19 in the PGx-guided arm versus 2.48 in the control arm. Furthermore, less deaths were reported in the PGx-guided arm (n = 1) compared with the control arm (n = 9). Most importantly, we observed a 48.5% reduction of treatment costs in the PGx-guided arm with a reciprocal slight increase of the quality of life of patients suffering from major depressive disorder (0.935 versus 0.925 QALYs in the PGx-guided and control arm, respectively).InterpretationWhile only a small proportion (∼25%) of the entire study sample had an actionable genotype, PGx-guided treatment can have a beneficial effect in psychiatric patients with a reciprocal reduction of treatment costs. Although some of these findings did not remain significant when all patients were considered, our data indicate that genome-guided psychiatric treatment may be successfully integrated in mainstream healthcare.FundingEuropean Union Horizon 2020.
| S-EPMC10879811 | biostudies-literature
Project description:ObjectiveTo comprehensively assess the pharmacogenomic evidence of routinely used drugs for clinical utility.MethodsBetween January 2, 2011, and May 31, 2013, we assessed 71 drugs by identifying all drug/genetic variant combinations with published clinical pharmacogenomic evidence. Literature supporting each drug/variant pair was assessed for study design and methods, outcomes, statistical significance, and clinical relevance. Proposed clinical summaries were formally scored using a modified AGREE (Appraisal of Guidelines for Research and Evaluation) II instrument, including recommendation for or against guideline implementation.ResultsPositive pharmacogenomic findings were identified for 51 of 71 cardiovascular drugs (71.8%), representing 884 unique drug/variant pairs from 597 publications. After analysis for quality and clinical relevance, 92 drug/variant pairs were proposed for translation into clinical summaries, encompassing 23 drugs (32.4% of drugs reviewed). All were recommended for clinical implementation using AGREE II, with mean ± SD overall quality scores of 5.18±0.91 (of 7.0; range, 3.67-7.0). Drug guidelines had highest mean ± SD scores in AGREE II domain 1 (Scope) (91.9±6.1 of 100) and moderate but still robust mean ± SD scores in domain 3 (Rigor) (73.1±11.1), domain 4 (Clarity) (67.8±12.5), and domain 5 (Applicability) (65.8±10.0). Clopidogrel (CYP2C19), metoprolol (CYP2D6), simvastatin (rs4149056), dabigatran (rs2244613), hydralazine (rs1799983, rs1799998), and warfarin (CYP2C9/VKORC1) were distinguished by the highest scores. Seven of the 9 most commonly prescribed drugs warranted translation guidelines summarizing clinical pharmacogenomic information.ConclusionConsiderable clinically actionable pharmacogenomic information for cardiovascular drugs exists, supporting the idea that consideration of such information when prescribing is warranted.
| S-EPMC4475352 | biostudies-literature
Project description:Introduction: Next-generation sequencing (NGS) technologies have been widely used in clinical genomic testing for drug response phenotypes. However, the inherent limitations of short reads make accurate inference of diplotypes still challenging, which may reduce the effectiveness of genotype-guided drug therapy. Methods: An automated Pharmacogenomics Annotation tool (PAnno) was implemented, which reports prescribing recommendations and phenotypes by parsing the germline variant call format (VCF) file from NGS and the population to which the individual belongs. Results: A ranking model dedicated to inferring diplotypes, developed based on the allele (haplotype) definition and population allele frequency, was introduced in PAnno. The predictive performance was validated in comparison with four similar tools using the consensus diplotype data of the Genetic Testing Reference Materials Coordination Program (GeT-RM) as ground truth. An annotation method was proposed to summarize prescribing recommendations and classify drugs into avoid use, use with caution, and routine use, following the recommendations of the Clinical Pharmacogenetics Implementation Consortium (CPIC), etc. It further predicts phenotypes of specific drugs in terms of toxicity, dosage, efficacy, and metabolism by integrating the high-confidence clinical annotations in the Pharmacogenomics Knowledgebase (PharmGKB). PAnno is available at https://github.com/PreMedKB/PAnno. Discussion: PAnno provides an end-to-end clinical pharmacogenomics decision support solution by resolving, annotating, and reporting germline variants.
| S-EPMC9909284 | biostudies-literature
Project description:The National Institutes of Health Clinical Center (NIH CC) is the largest hospital in the United States devoted entirely to clinical research, with a highly diverse spectrum of patients. Patient safety and clinical quality are major goals of the hospital, and therapy is often complicated by multiple cotherapies and comorbidities. To this end, we implemented a pharmacogenomics program in 2 phases. In the first phase, we implemented genotyping for HLA-A and HLA-B gene variations with clinical decision support (CDS) for abacavir, carbamazepine, and allopurinol. In the second phase, we implemented genotyping for drug-metabolizing enzymes and transporters: SLCO1B1 for CDS of simvastatin and TPMT for CDS of mercaptopurine, azathioprine, and thioguanine. The purpose of this review is to describe the implementation process, which involves clinical, laboratory, informatics, and policy decisions pertinent to the NIH CC.
| S-EPMC5657584 | biostudies-literature
Project description:PURPOSE:Greater clinical validity and economic feasibility are driving the more widespread use of multiplex genetic technologies in routine clinical care, especially for applications in pharmacogenomics. Empirical data on the numbers and types of incidental findings generated through such testing are needed to develop policies and practices related to their clinical use. Of particular importance are disparities in findings relevant to different ancestry groups. METHODS:The Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment Resource, or PREDICT, is an institutional program to implement prospective clinical genotyping of 34 pharmacogenomic-related genes to guide drug selection and dosing. We curated 5,566 journal articles to quantify and characterize the incidental, non-pharmacogenomic genotype-phenotype associations that could be generated through this clinical genotyping project. RESULTS:We identified 372 putative incidental genotype-phenotype associations that might be revealed in patients undergoing clinical genotyping for pharmacogenomic purposes. Of these, 287 associations were supported by at least one study demonstrating an odds ratio ?2.0 or ?0.5. Numbers of potentially relevant findings varied widely by ancestry group. CONCLUSION:Rigorous clinical policies for the clinical management of incidental findings are needed because the sheer number of significant findings could prove overwhelming to health-care institutions, providers, and patients.
| S-EPMC3648626 | biostudies-literature
Project description:BackgroundPharmacogenomics (PGx) testing is increasingly used in clinical practice to optimize drug therapies. This study aims to understand the involvement of clinical pharmacists in PGx testing at tertiary hospitals in China and their self-assessed capacity to deliver such services.MethodsWe developed a questionnaire exploring clinical pharmacists' involvement and self-assessed level of capacity of performing PGx tests. A random sample was obtained from the Pharmaceutical Affairs Management Professional Committee of the Chinese Hospital Association.ResultsA total of 1005 clinical pharmacists completed the survey. Of these, 996 (99.1%) had heard of PGx tests and 588 (59.0%) had been involved in PGx testing and related services. Some clinical pharmacists (28.9%) provided PGx services at the rate of "1-5 cases/year" while 21.9% of clinical pharmacists provided PGx services at the rate of ">30 cases/year". Clinical pharmacists most frequently provided PGx testing for cardiovascular diseases. "Consult relevant guidelines/literature" (90.1%) was the most frequently used method to familiarize oneself with PGx testing. About 60% of the pharmacists considered themselves to have poor or fair capacity to provide PGx testing and related services.ConclusionsMore than half of the pharmacists had been involved in PGx testing and related services. However, pharmacists generally had little confidence in their knowledge level of and capacity to provide PGx-related services.
| S-EPMC9409798 | biostudies-literature
Project description:The mapping of the human genome and subsequent advancements in genetic technology had provided clinicians and scientists an understanding of the genetic basis of altered drug pharmacokinetics and pharmacodynamics, as well as some examples of applying genomic data in clinical practice. This has raised the public expectation that predicting patients' responses to drug therapy is now possible in every therapeutic area, and personalized drug therapy would come sooner than later. However, debate continues among most stakeholders involved in drug development and clinical decision-making on whether pharmacogenomic biomarkers should be used in patient assessment, as well as when and in whom to use the biomarker-based diagnostic tests. Currently, most would agree that achieving the goal of personalized therapy remains years, if not decades, away. Realistic application of genomic findings and technologies in clinical practice and drug development require addressing multiple logistics and challenges that go beyond discovery of gene variants and/or completion of prospective controlled clinical trials. The goal of personalized medicine can only be achieved when all stakeholders in the field work together, with willingness to accept occasional paradigm change in their current approach.
| S-EPMC3603526 | biostudies-literature
Project description:Since its approval by the U.S. Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections including the most common, aspergillosis and candidiasis. Despite voriconazole's widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole's pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity.
| S-EPMC4082739 | biostudies-other
Project description:PurposeDue to the diversity within Europe, the implementation of pharmacogenomic testing in clinical practice faces specific challenges. In the context of the European pharmacogenomics implementation project "Ubiquitous Pharmacogenomics" (U-PGx; funded by the European Commission), we studied the current educational background.MethodsWe developed a questionnaire including 29 questions. It was spread out to healthcare professionals working at the future implementation sites (in Austria, Greece, Italy, Netherlands, Slovenia, Spain and Great Britain) of the U-PGx project in preparation of an educational programme. Aim of the survey was to analyse the current educational situation at the implementation sites.ResultsIn total, 70 healthcare professionals participated in the survey. Of participants, 84.3% found pharmacogenomics relevant to their current practice, but experience was still rare. More than two-thirds (65.7%) did not order nor recommend a pharmacogenomic test in the past year. This was mainly attributed to not having enough knowledge on pharmacogenomics (40.0%). Needs were identified in application of pharmacogenomics (identifying drugs 41.4%, interpreting test results 37.2%) as well as in underlining mechanisms (better knowledge on drug metabolism 67.1%, better knowledge on basic principles of pharmacogenomics 60.0%).ConclusionsThis study analysed the specific attitudes, experience and education on pharmacogenomics of future users. There was a general positive attitude and interest towards pharmacogenomic testing. However, the grade of own experience, and knowledge about application and interpretation of pharmacogenomics caused uncertainty. Thus, education and training programmes may be helpful for implementation of pharmacogenomics at a homogenous level within Europe.
| S-EPMC5599468 | biostudies-literature
Project description:Pharmacogenomics (PGx) relates to the study of genetic factors determining variability in drug response. Implementing PGx testing in paediatric patients can enhance drug safety, helping to improve drug efficacy or reduce the risk of toxicity. Despite its clinical relevance, the implementation of PGx testing in paediatric practice to date has been variable and limited. As with most paediatric pharmacological studies, there are well-recognised barriers to obtaining high-quality PGx evidence, particularly when patient numbers may be small, and off-label or unlicensed prescribing remains widespread. Furthermore, trials enrolling small numbers of children can rarely, in isolation, provide sufficient PGx evidence to change clinical practice, so extrapolation from larger PGx studies in adult patients, where scientifically sound, is essential. This review paper discusses the relevance of PGx to paediatrics and considers implementation strategies from a child health perspective. Examples are provided from Canada, the Netherlands and the UK, with consideration of the different healthcare systems and their distinct approaches to implementation, followed by future recommendations based on these cumulative experiences. Improving the evidence base demonstrating the clinical utility and cost-effectiveness of paediatric PGx testing will be critical to drive implementation forwards. International, interdisciplinary collaborations will enhance paediatric data collation, interpretation and evidence curation, while also supporting dedicated paediatric PGx educational initiatives. PGx consortia and paediatric clinical research networks will continue to play a central role in the streamlined development of effective PGx implementation strategies to help optimise paediatric pharmacotherapy.
| S-EPMC9544158 | biostudies-literature