The Israeli National Genetic database: a 10-year experience

BACKGROUND: The Israeli National and Ethnic Mutation database ( http://server.goldenhelix.org/israeli ) was launched in September 2006 on the ETHNOS software to include clinically relevant genomic variants reported among Jewish and Arab Israeli patients. In 2016, the database was reviewed and corrected according to ClinVar ( https://www.ncbi.nlm.nih.gov/clinvar ) and ExAC ( http://exac.broadinstitute.org ) database entries. The present article summarizes some key aspects from the development and continuous update of the database over a 10-year period, which could serve as a paradigm of successful database curation for other similar resources.RESULTS: In September 2016, there were 2444 entries in the database, 890 among Jews, 1376 among Israeli Arabs, and 178 entries among Palestinian Arabs, corresponding to an ~4× data content increase compared to when originally launched. While the Israeli Arab population is much smaller than the Jewish population, the number of pathogenic variants causing recessive disorders reported in the database is higher among Arabs (934) than among Jews (648). Nevertheless, the number of pathogenic variants classified as founder mutations in the database is smaller among Arabs (175) than among Jews (192). In 2016, the entire database content was compared to that of other databases such as ClinVar and ExAC. We show that a significant difference in the percentage of pathogenic variants from the Israeli genetic database that were present in ExAC was observed between the Jewish population (31.8%) and the Israeli Arab population (20.6%).CONCLUSIONS: The Israeli genetic database was launched in 2006 on the ETHNOS software and is available online ever since. It allows querying the database according to the disorder and the ethnicity; however, many other features are not available, in particular the possibility to search according to the name of the gene. In addition, due to the technical limitations of the previous ETHNOS software, new features and data are not included in the present online version of the database and upgrade is currently ongoing

Exome-wide analysis of the discovehr cohort reveals novel candidate pharmacogenomic variants for clinical pharmacogenomics

Recent advances in next-generation sequencing technology have led to the production of an unprecedented volume of genomic data, thus further advancing our understanding of the role of genetic variation in clinical pharmacogenomics. In the present study, we used whole exome sequencing data from 50,726 participants, as derived from the DiscovEHR cohort, to identify pharmacogenomic variants of potential clinical relevance, according to their occurrence within the PharmGKB database. We further assessed the distribution of the identified rare and common pharmacogenomics variants amongst different GnomAD subpopulations. Overall, our findings show that the use of publicly available sequence data, such as the DiscovEHR dataset and GnomAD, provides an opportunity for a deeper understanding of genetic variation in pharmacogenes with direct implications in clinical pharmacogenomics

Medical education in pharmacogenomics-results from a survey on pharmacogenetic knowledge in healthcare professionals within the European pharmacogenomics clinical implementation project Ubiquitous Pharmacogenomics (U-PGx)

Personalised Therapeutic

A Novel Text-Mining Approach for Retrieving Pharmacogenomics Associations From the Literature

Text mining in biomedical literature is an emerging field which has already been shown to have a variety of implementations in many research areas, including genetics, personalized medicine, and pharmacogenomics. In this study, we describe a novel text-mining approach for the extraction of pharmacogenomics associations. The code that was used toward this end was implemented using R programming language, either through custom scripts, where needed, or through utilizing functions from existing libraries. Articles (abstracts or full texts) that correspond to a specified query were extracted from PubMed, while concept annotations were derived by PubTator Central. Terms that denote a Mutation or a Gene as well as Chemical compound terms corresponding to drug compounds were normalized and the sentences containing the aforementioned terms were filtered and preprocessed to create appropriate training sets. Finally, after training and adequate hyperparameter tuning, four text classifiers were created and evaluated (FastText, Linear kernel SVMs, XGBoost, Lasso, and Elastic-Net Regularized Generalized Linear Models) with regard to their performance in identifying pharmacogenomics associations. Although further improvements are essential toward proper implementation of this text-mining approach in the clinical practice, our study stands as a comprehensive, simplified, and up-to-date approach for the identification and assessment of research articles enriched in clinically relevant pharmacogenomics relationships. Furthermore, this work highlights a series of challenges concerning the effective application of text mining in biomedical literature, whose resolution could substantially contribute to the further development of this field

ETHNOS: A versatile electronic tool for the development and curation of national genetic databases

National and ethnic mutation databases (NEMDBs) are emerging online repositories, recording extensive information about the described genetic heterogeneity of an ethnic group or population. These resources facilitate the provision of genetic services and provide a comprehensive list of genomic variations among different populations. As such, they enhance awareness of the various genetic disorders. Here, we describe the features of the ETHNOS software, a simple but versatile tool based on a flat-file database that is specifically designed for the development and curation of NEMDBs. ETHNOS is a freely available softw

ETHNOS : A versatile electronic tool for the development and curation of national genetic databases.

National and ethnic mutation databases (NEMDBs) are emerging online repositories, recording extensive information about the described genetic heterogeneity of an ethnic group or population. These resources facilitate the provision of genetic services and provide a comprehensive list of genomic variations among different populations. As such, they enhance awareness of the various genetic disorders. Here, we describe the features of the ETHNOS software, a simple but versatile tool based on a flat-file database that is specifically designed for the development and curation of NEMDBs. ETHNOS is a freely available software which runs more than half of the NEMDBs currently available. Given the emerging need for NEMDB in genetic testing services and the fact that ETHNOS is the only off-the-shelf software available for NEMDB development and curation, its adoption in subsequent NEMDB development would contribute towards data content uniformity, unlike the diverse contents and quality of the available gene (locus)-specific databases. Finally, we allude to the potential applications of NEMDBs, not only as worldwide central allele frequency repositories, but also, and most importantly, as data warehouses of individual-level genomic data, hence allowing for a comprehensive ethnicity-specific documentation of genomic variation

A Rare Disease Patient Manager

ABSTRACT publicado: 6th International Conference on Practical Applications of Computational Biology & Bioinformatics (PACBB. Salamanca, 28-30 Março 2012The personal health implications behind rare diseases are seldom considered in widespread medical care. The low incidence rate and complex treatment process makes rare disease research an underrated field in the life sciences. However, it is in these particular conditions that the strongest relations between genotypes and phenotypes are identified. The rare disease patient manager, detailed in this manuscript, presents an innovative perspective for a patient-centric portal integrating genetic and medical data. With this strategy, patient’s digital records are transparently integrated and connected to wet-lab genetics research in a seamless working environment. The resulting knowledge base offers multiple data views, geared towards medical staff, with patient treatment and monitoring data; genetics researchers, through a custom locus-specific database; and patients, who for once play an active role in their treatment and rare diseases research

A Dual Reporter Mouse Model of the Human β-Globin Locus: Applications and Limitations

The human β-globin locus contains the β-like globin genes (i.e. fetal γ-globin and adult β-globin), which heterotetramerize with α-globin subunits to form fetal or adult hemoglobin. Thalassemia is one of the commonest inherited disorders in the world, which results in quantitative defects of the globins, based on a number of genome variations found in the globin gene clusters. Hereditary persistence of fetal hemoglobin (HPFH) also caused by similar types of genomic alterations can compensate for the loss of adult hemoglobin. Understanding the regulation of the human γ-globin gene expression is a challenge for the treatment of thalassemia. A mouse model that facilitates high-throughput assays would simplify such studies. We have generated a transgenic dual reporter mouse model by tagging the γ- and β-globin genes with GFP and DsRed fluorescent proteins respectively in the endogenous human β-globin locus. Erythroid cell lines derived from this mouse model were tested for their capacity to reactivate the γ-globin gene. Here, we discuss the applications and limitations of this fluorescent reporter model to study the genetic basis of red blood cell disorders and the potential use of such model systems in high-throughput screens for hemoglobinopathies therapeutics

Economic evaluation of pharmacogenomic-guided antiplatelet treatment in Spanish patients suffering from acute coronary syndrome participating in the U-PGx PREPARE study

BackgroundCardiovascular diseases and especially Acute Coronary Syndrome (ACS) constitute a major health issue impacting millions of patients worldwide. Being a leading cause of death and hospital admissions in many European countries including Spain, it accounts for enormous amounts of healthcare expenditures for its management. Clopidogrel is one of the oldest antiplatelet medications used as standard of care in ACS.MethodsIn this study, we performed an economic evaluation study to estimate whether a genome-guided clopidogrel treatment is cost-effective compared to conventional one in a large cohort of 243 individuals of Spanish origin suffering from ACS and treated with clopidogrel. Data were derived from the U-PGx PREPARE clinical trial. Effectiveness was measured as survival of individuals while study data on safety and efficacy, as well as on resource utilization associated with each adverse drug reaction were used to measure costs to treat these adverse drug reactions. A generalized linear regression model was used to estimate cost differences for both study groups.ResultsBased on our findings, PGx-guided treatment group is cost-effective. PGx-guided treatment demonstrated to have 50% less hospital admissions, reduced emergency visits and almost 13% less ADRs compared to the non-PGx approach with mean QALY 1.07 (95% CI, 1.04-1.10) versus 1.06 (95% CI, 1.03-1.09) for the control group, while life years for both groups were 1.24 (95% CI, 1.20-1.26) and 1.23 (95% CI, 1.19-1.26), respectively. The mean total cost of PGx-guided treatment was 50% less expensive than conventional therapy with clopidogrel [euro883 (95% UI, euro316-euro1582), compared to euro1,755 (95% UI, euro765-euro2949)].ConclusionThese findings suggest that PGx-guided clopidogrel treatment represents a cost-effective option for patients suffering from ACS in the Spanish healthcare setting.Personalised Therapeutic

Clinically relevant updates of the HbVar database of human hemoglobin variants and thalassemia mutations

HbVar (http://globin.bx.psu.edu/hbvar) is a widely-used locus-specific database (LSDB) launched 20 years ago by a multi-center academic effort to provide timely information on the numerous genomic variants leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. Here, we report several advances for the database. We made clinically relevant updates of HbVar, implemented as additional querying options in the HbVar query page, allowing the user to explore the clinical phenotype of compound heterozygous patients. We also made significant improvements to the HbVar front page, making comparative data querying, analysis and output more user-friendly. We continued to expand and enrich the regular data content, involving 1820 variants, 230 of which are new entries. We also increased the querying potential and expanded the usefulness of HbVar database in the clinical setting. These several additions, expansions and updates should improve the utility of HbVar both for the globin research community and in a clinical setting