Relevance of pharmacogenomics for developing countries in Europe : implementation in the Maltese population

Pharmacogenomics is a promising new discipline that can realize personalized treatment for patients suffering from many common diseases, particularly those with multiple treatment modalities. Recent advances in the deciphering of the human genome sequence and high throughput genotyping technology have led to the reduction of the overall genotyping costs and enabled the inclusion of genotype-related dosing recommendations into drug package inserts, hence allowing the integration of pharmacogenomics into clinical practice. Although, pharmacogenomics gradually assumes an integral part in mainstream medical practice in developed countries, many countries, particularly from the developing world, still do not have access either to the knowledge or the resources to individualize drug treatment. The PharmacoGenetics for Every Nation Initiative (PGENI) aims to fill in this gap, by making pharmacogenomics globally applicable, not only by defining population-specific pharmacogenomic marker frequency profiles and formulating country-specific recommendations for drug efficacy and safety but also by increasing general public and healthcare professionals’ awareness over pharmacogenomics and genomic medicine. This article highlights the PGENI activities in Europe and its implementation in the Maltese population, in an effort to make pharmacogenomics readily applicable in European healthcare systems.peer-reviewe

A concealed carcinoid cardiac metastasis uncovered by comprehensive cardiovascular magnetic resonance-based tissue characterization: a case report.

oai:serval.unil.ch:BIB_EFAC9560DFE5Cardiac metastases of carcinoid tumours are extremely rare, and their diagnosis poses a significant challenge. A variety of techniques has been reported in the literature for this purpose, ranging from echocardiogram to the Indium-111 Octreotide, positron emission tomography using specific tracers, and biopsy. Occasionally, the diagnosis is only made post-mortem. Recently, CMR (cardiovascular magnetic resonance) has been added to the diagnostic toolkit. This case report describes the CMR sequences that can be used to characterize cardiac metastases of carcinoid tumours. A 55-year-old woman with an antecedent history of resected carcinoid tumour of the ileocecal junction underwent whole-body In-111 Octreoscan single-photon emission computed tomography in the context of her follow-up. This raised the suspicion of pericardial involvement, which prompted a CMR study. Comprehensive CMR findings were consistent with isolated carcinoid tumour metastasis embedded within the anterior papillary muscle. We describe the CMR sequences that were used to characterize the metastasis. The rarity of cardiac metastasis of carcinoid tumour makes its diagnosis challenging and warrants a high level of clinical suspicion. Cardiovascular magnetic resonance imaging proves to be an indispensable tool in the tissue characterization of such tumours

Ethics and equity in rare disease research and healthcare

Rapid advances in next-generation sequencing technology, particularly whole exome sequencing and whole genome sequencing, have greatly affected our understanding of genetic variation underlying rare genetic diseases. Herein, we describe ethical principles of guiding consent and sharing of genomics research data. We also discuss ethical dilemmas in rare diseases research and patient recruitment policies and address bioethical and societal aspects influencing the ethical framework for genetic testing. Moreover, we focus on addressing ethical issues surrounding research in low- and middle-income countries. Overall, this perspective aims to address key aspects and issues for building proper ethical frameworks, when conducting research involving genomics data with a particular emphasis on rare diseases and genetics testing

Exercise tolerance and quality of life in patients with known or suspected coronary artery disease

Background: Coronary artery disease (CAD) is known to impact on patients’ physical and mental health. The relationship between performance on treadmill exercise tolerance test (ETT) and health-related quality of life (HRQL)has never been specifically investigated in the setting of CAD. Methods: Consecutive patients undergoing an ETT with the Bruce protocol during a diagnostic workup for CAD (n = 1,631, age 55 ± 12 years) were evaluated. Exercise-related indices were recorded. Detailed information on cardiovascular risk factors and past medical history were obtained. HRQLwas assessed with the use of the validated 36-Item Short Form Survey (SF-36) questionnaire. Results: Increasing age and the presence of cardiovascular risk factors and comorbidities correlated with lower scores on the physical and mental health component of SF-36(all P < 0.05). Subjects with arrhythmias during exercise and slow recovery of systolic blood pressure had lower scores on the physical health indices or the Social Role Functioning component (P < 0.05). Achieved target heart rate and good exercise tolerance were independently associated with better scores of the physical and mental health domains of SF-36 and overall HRQLscores (β = 0.05 for target HR and PCS-36, β = 1.86 and β = 1.66 per increasing stage of exercise tolerance and PCS-36 and MCS-36, respectively, P < 0.001 for all associations). Ischemic ECG changes were associated with worse scores on Physical Functioning (β = − 3.2, P = 0.02) and Bodily Pain (β = − 4.55, P = 0.026). Conclusion: ETT parameters are associated with HRQL indices in patients evaluated for possible CAD. Physical conditioning may increase patient well-being and could serve as a complementary target in conjunction with cardiovascular drug therapy

Application of economic evaluation to assess feasibility for reimbursement of genomic testing as part of personalized medicine interventions

Background: The incorporation of genomic testing into clinical practice constitutes an opportunity to improve patients’ lives, as it makes possible the implementation of innovative, individualized clinical interventions that maximize efficacy and/or minimize the risk of adverse drug reactions. In order to ensure equal access to genomic testing for all patients, the costs associated with these tests should be reimbursed by their respective national healthcare systems. Given that funding for the public health sector is decreasing in real terms, it is of paramount importance that the emerging interventions are thoroughly evaluated both in terms of their clinical effectiveness and their full economic cost. Objective: The aim of this study was to identify those genome-guided interventions that could be adopted and reimbursed by national healthcare systems. Further, we recorded the underlying factors determining the broad adoption of genome-guided interventions in clinical practice, in order to identify potential reimbursement criteria. Methods: We performed a systematic review of published (PubMed-listed) scientific articles on the economic evaluation of those individualized clinical interventions that include genomic tests. Information on genomic tests reimbursed by the US Medicare program was also included. Subsequently, we correlated the regulatory guidance given for the interventions collated in our systematic review with the corresponding economic evaluation results and policies of the Medicare program. Regulatory guidance information was collected from the PharmGKB online knowledgebase and the Clinical Pharmacogenetics Implementation Consortium (CPIC). Results: Most of the included studies constitute cost-utility analyses, in which the outcome of the interventions has been measured in quality-adjusted life years (QALYs) whereas an estimate of the total cost has been based upon direct medical cost data. Favorable economic evaluation results, as well as concrete evidence demonstrating the clinical utility of pre-emptive genotyping, are considered as prerequisites for the broad adoption and reimbursement of the costs incurred during genomic testing. Indicatively, pre-emptive HLA-B*5701 and TPMT testing before administration of abacavir and azathioprine, respectively, is reimbursed by Medicare based on both economic and efficacy evidence. Likewise, the medical necessary screening for MMR and BRCA1/2 genes are reimbursed for high-risk populations. Conclusions: Our findings further underline the need for further cost-utility analyses within different national healthcare systems, in order to promote the reimbursement of the cost of innovative genome-guided therapeutic interventions

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 Microsoft’s 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 above mentioned updates further enhance the impact of FINDbase, as a key resource for Genomic Medicine applications

Integrating Next-Generation Sequencing in the Clinical Pharmacogenomics Workflow

Pharmacogenomics has been recognized as a fundamental tool in the era of personalized medicine with up to 266 drug labels, approved by major regulatory bodies, currently containing pharmacogenomics information. Next-generation sequencing analysis assumes a critical role in personalized medicine, providing a comprehensive profile of an individual’s variome, particularly that of clinical relevance, comprising of pathogenic variants and pharmacogenomic biomarkers. Here, we propose a strategy to integrate next-generation sequencing into the current clinical pharmacogenomics workflow from deep resequencing to pharmacogenomics consultation, according to the existing guidelines and recommendations

Genomic medicine without borders: which strategies should developing countries employ to invest in precision medicine? A new "fast-second winner" strategy

Genomic medicine has greatly matured in terms of its technical capabilities, but the diffusion of genomic innovations worldwide faces significant barriers beyond mere access to technology. New global development strategies are sorely needed for biotechnologies such as genomics and their applications toward precision medicine without borders. Moreover, diffusion of genomic medicine globally cannot adhere to a “one-size-fits-all-countries” development strategy, in the same way that drug treatments should be customized. This begs a timely, difficult but crucial question: How should developing countries, and the resource-limited regions of developed countries, invest in genomic medicine? Although a full-scale investment in infrastructure from discovery to the translational implementation of genomic science is ideal, this may not always be feasible in all countries at all times. A simple “transplantation of genomics” from developed to developing countries is unlikely to be feasible. Nor should developing countries be seen as simple recipients and beneficiaries of genomic medicine developed elsewhere because important advances in genomic medicine have materialized in developing countries as well. There are several noteworthy examples of genomic medicine success stories involving resource-limited settings that are contextualized and described in this global genomic medicine innovation analysis. In addition, we outline here a new long-term development strategy for global genomic medicine in a way that recognizes the individual country's pressing public health priorities and disease burdens. We term this approach the “Fast-Second Winner” model of innovation that supports innovation commencing not only “upstream” of discovery science but also “mid-stream,” building on emerging highly promising biomarker and diagnostic candidates from the global science discovery pipeline, based on the unique needs of each country. A mid-stream entry into innovation can enhance collective learning from other innovators' mistakes upstream in discovery science and boost the probability of success for translation and implementation when resources are limited. This à la carte model of global innovation and development strategy offers multiple entry points into the global genomics innovation ecosystem for developing countries, whether or not extensive and expensive discovery infrastructures are already in place. Ultimately, broadening our thinking beyond the linear model of innovation will help us to enable the vision and practice of genomics without borders in both developed and resource-limited settings

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 leadingmostly tomonogenic 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/ethnicmutation databases, all built around Microsoft's 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 FIND-base, as a key resource for Genomic Medicine applications