Christina Mitropoulou

Personalized pharmacogenomics profiling using whole-genome sequencing

AIM Pharmacogenomics holds promise to rationalize drug use by minimizing drug toxicity and at the same time increase drug efficacy. There are currently several assays to screen for known pharmacogenomic biomarkers for the most commonly prescribed drugs. However, these genetic screening assays cannot account for other known or novel pharmacogenomic markers. MATERIALS & METHODS We analyzed whole-genome sequences of 482 unrelated individuals of various ethnic backgrounds to obtain their personalized pharmacogenomics profiles. RESULTS Bioinformatics analysis revealed 408,964 variants in 231 pharmacogenes, from which 26,807 were residing on exons and proximal regulatory sequences, whereas 16,487 were novel. In silico analyses indicated that 1012 novel pharmacogene-related variants possibly abolish protein function. We have also performed whole-genome sequencing analysis in a seven-member family of Greek origin in an effort to explain the variable response rate to acenocoumarol treatment in two family members. CONCLUSION Overall, our data demonstrate that whole-genome sequencing, unlike conventional genetic screening methods, is necessary to determine an individuals pharmacogenomics profile in a more comprehensive manner, which, combined with the gradually decreasing whole-genome sequencing costs, would expedite bringing personalized medicine closer to reality.

Economic evaluation of pharmacogenomics: A value-based approach to pragmatic decision making in the face of complexity

Evidence of the value of pharmacogenomic testing is needed to inform policymakers and clinicians for decision making related to adoption and coverage, and to facilitate prioritization for research and development. Pharmacogenomics has an important role in creating a more efficient healthcare system, and this article addresses how economic evaluation can strategically target evidence gaps for public health priorities with examples from pharmacogenomic medicine. This article begins with a review of the need for and use of economic evaluations in value-based decision making for pharmacogenomic testing. Three important gaps are described with examples demonstrating how they can be addressed: (1) projected impact of hypothetical new technology, (2) pre-implementation assessment of a specific technology, and (3) post-implementation assessment from relevant analytical stakeholder perspectives. Additional needs, challenges and approaches specific to pharmacogenomic economic evaluation in the developing world are also identified. These pragmatic approaches can provide much needed evidence to support real-world value-based decision making for pharmacogenomic-based screening and treatment strategies.

Locus‐specific database domain and data content analysis: evolution and content maturation toward clinical usea

Genetic variation databases have become indispensable in many areas of health care. In addition, more and more experts are depositing published and unpublished disease‐causing variants of particular genes into locus‐specific databases (LSDBs). Some of these databases contain such extensive information that they have become known as knowledge bases. Here, we analyzed 1,188 LSDBs and their content for the presence or absence of 44 content criteria related to database features (general presentation, locus‐specific information, database structure) and data content (data collection, summary table of variants, database querying). Our analyses revealed that several elements have helped to advance the field and reduce data heterogeneity, such as the development of specialized database management systems and the creation of data querying tools. We also identified a number of deficiencies, namely, the lack of detailed disease and phenotypic descriptions for each genetic variant and links to relevant patient organizations, which, if addressed, would allow LSDBs to better serve the clinical genetics community. We propose a structure, based on LSDBs and closely related repositories (namely, clinical genetics databases), which would contribute to a federated genetic variation browser and also allow the maintenance of variation data. Hum Mutat 31:1–8, 2010.

Key challenges for next-generation pharmacogenomics

The “post‐genomic revolution” has advanced our understanding of the molecular etiology of a range of human genetic diseases, which might lead to improved disease prognosis and treatment. Over the past decade, genomics research has revealed the genomic variants underlying diseases, from single nucleotide variations to complex genome rearrangements, and/or altered gene expression patterns that lead directly to pathogenesis. These findings have enormous potential to guide physicians in their task of estimating disease risk and deciding on the most efficient and safe treatment options. More generally, genomic research could catalyze the maturation of individualized healthcare by considering each persons genomic profile alongside his or her clinical condition to personalize therapeutic interventions. These developments have been enabled by the rapid technological progress from the low‐ and medium‐throughput genetic screening methods of yesteryear to the new high‐throughput genome‐wide approaches of today, including microarray assays and next‐generation sequencing. In particular, as the costs for sequencing are steadily decreasing and the data analysis tools are constantly improving, whole‐genome sequencing is an attractive and potentially very efficient method to determine an individuals pharmacogenomic profile. In several cases, whole exome and whole‐genome re‐sequencing has helped researchers to correlate specific genomic variants with disease predisposition and other clinical features or physiological traits. However, such developments have yet to make their way into clinical practice, as various factors slow down the transition from research into patient care and public health benefits. Most notably, healthcare professionals still lack sufficient education and training to make better use of genomics services. Furthermore, patients and the general public tend to have low genetic literacy, which impairs their ability to meaningfully integrate their genomic information into their lifestyle and health decisions. Lastly, there are legislative gaps, ethical concerns and a dearth of economic studies to support the integration …

A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant inter-population pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective.

Critical appraisal of the views of healthcare professionals with respect to pharmacogenomics and personalized medicine in Greece

AIM In the postgenomic era, in many European countries, very little is known regarding the level of awareness of healthcare professionals with respect to pharmacogenomics and personalized medicine. METHODS Here, we report the findings of an in-depth study, involving 86 pharmacists and 208 physicians, to assess their level of awareness of pharmacogenomics and personalized medicine. RESULTS Our findings indicate that approximately 60% of pharmacists consider their level of knowledge of personalized medicine to be very low, while over half of the pharmacists and physicians intimate that they would be unable to explain the results of pharmacogenomic tests to their customers or patients, respectively. This situation may be directly related to the low level of their undergraduate education in genetics and pharmacogenomics. CONCLUSION These findings provide the basis for assessing the views of healthcare professionals in relation to personalized medicine in Greece, and should help to facilitate the integration of genomics into the medical decision-making process.

Stakeholder analysis in pharmacogenomics and genomic medicine in Greece

Background: The pace of discoveries and advances in genomic research is not reflected in the pace of their translation and incorporation into day-to-day clinical medicine to individualize healthcare decision-making processes. One of the main obstacles is the poor understanding of the policies and the key stakeholders involved in these translation processes. Methods: We used the computerized version of the PolicyMaker political mapping tool to collect and organize important information about the pharmacogenomics and genomic medicine policy environment, serving as a database for assessments of the policys content, the major players, their power and policy positions, their interests, and networks and coalitions that interconnect them. Results and Conclusions: Our findings indicate that the genomic medicine policy environment in Greece seems to be rather positive, as the vast majority of the stakeholders express their medium to high support in the initially set goals of genomic medicine policy environment. The Ministry of Health and public healthcare insurance funds seem to oppose it, most likely due to financial constrains. These findings would contribute in selecting and implementing policy measures that will expedite the adoption of genomics into conventional medical interventions.

Economic evaluation of pharmacogenomic-guided warfarin treatment for elderly Croatian atrial fibrillation patients with ischemic stroke.

BACKGROUND & METHODS Economic evaluation in genomic medicine is an emerging discipline to assess the cost-effectiveness of genome-guided treatment. Here, we developed a pharmaco-economic model to assess whether pharmacogenomic (PGx)-guided warfarin treatment of elderly ischemic stroke patients with atrial fibrillation in Croatia is cost effective compared with non-PGx therapy. The time horizon of the model was set at 1 year. RESULTS Our primary analysis indicates that 97.07% (95% CI: 94.08-99.34%) of patients belonging to the PGx-guided group have not had any major complications, compared with the control group (89.12%; 95% CI: 84.00-93.87%, p < 0.05). The total cost per patient was estimated at €538.7 (95% CI: €526.3-551.2) for the PGx-guided group versus €219.7 (95% CI: €137.9-304.2) for the control group. In terms of quality-adjusted life-years (QALYs) gained, total QALYs was estimated at 0.954 (95% CI: 0.943-0.964) and 0.944 (95% CI: 0.931-0.956) for the PGx-guided and the control groups, respectively. The true difference in QALYs was estimated at 0.01 (95% CI: 0.005-0.015) in favor of the PGx-guided group. The incremental cost-effectiveness ratio of the PGx-guided versus the control groups was estimated at €31,225/QALY. CONCLUSION Overall, our data indicate that PGx-guided warfarin treatment may represent a cost-effective therapy option for the management of elderly patients with atrial fibrillation who developed ischemic stroke in Croatia.

Test Pricing and Reimbursement in Genomic Medicine: Towards a General Strategy.

This paper aims to provide an overview of the rationale and basic principles guiding the governance of genomic testing services, to clarify their objectives, and allocate and define responsibilities among stakeholders in a health-care system, with a special focus on the EU countries. Particular attention is paid to issues pertaining to pricing and reimbursement policies, the availability of essential genomic tests which differs between various countries owing to differences in disease prevalence and public health relevance, the prescribing and use of genomic testing services according to existing or new guidelines, budgetary and fiscal control, the balance between price and access to innovative testing, monitoring and evaluation for cost-effectiveness and safety, and the development of research capacity. We conclude that addressing the specific items put forward in this article will help to create a robust policy in relation to pricing and reimbursement in genomic medicine. This will contribute to an effective and sustainable health-care system and will prove beneficial to the economy at large.

Expanded national database collection and data coverage in the FINDbase worldwide database for clinically relevant genomic variation allele frequencies

FINDbase (http://www.findbase.org) is a comprehensive data repository that records the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants leading mostly to monogenic disorders and pharmacogenomics biomarkers. The database also records the incidence of rare genetic diseases in various populations, all in well-distinct data modules. Here, we report extensive data content updates in all data modules, with direct implications to clinical pharmacogenomics. Also, we report significant new developments in FINDbase, namely (i) the release of a new version of the ETHNOS software that catalyzes development curation of national/ethnic genetic databases, (ii) the migration of all FINDbase data content into 90 distinct national/ethnic mutation databases, all built around Microsofts PivotViewer (http://www.getpivot.com) software (iii) new data visualization tools and (iv) the interrelation of FINDbase with DruGeVar database with direct implications in clinical pharmacogenomics. The abovementioned updates further enhance the impact of FINDbase, as a key resource for Genomic Medicine applications.