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 abovementioned updates further enhance the impact of FINDbase, as a key resource for Genomic Medicine applications.

Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach.

Cancer, like many common disorders, has a complex etiology, often with a strong genetic component and with multiple environmental factors contributing to susceptibility. A considerable number of genomic variants have been previously reported to be causative of, or associated with, an increased risk for various types of cancer. Here, we adopted a next-generation sequencing approach in 11 members of two families of Greek descent to identify all genomic variants with the potential to predispose family members to cancer. Cross-comparison with data from the Human Gene Mutation Database identified a total of 571 variants, from which 47 % were disease-associated polymorphisms, 26 % disease-associated polymorphisms with additional supporting functional evidence, 19 % functional polymorphisms with in vitro/laboratory or in vivo supporting evidence but no known disease association, 4 % putative disease-causing mutations but with some residual doubt as to their pathological significance, and 3 % disease-causing mutations. Subsequent analysis, focused on the latter variant class most likely to be involved in cancer predisposition, revealed two variants of prime interest, namely MSH2 c.2732T>A (p.L911R) and BRCA1 c.2955delC, the first of which is novel. KMT2D c.13895delC and c.1940C>A variants are additionally reported as incidental findings. The next-generation sequencing-based family genomics approach described herein has the potential to be applied to other types of complex genetic disorder in order to identify variants of potential pathological significance.

Developments in FINDbase worldwide database for clinically relevant genomic variation allele frequencies.

FINDbase (http://www.findbase.org) aims to document frequencies of clinically relevant genomic variations, namely causative mutations and pharmacogenomic markers, worldwide. Each database record includes the population, ethnic group or geographical region, the disorder name and the related gene, accompanied by links to any related databases and the genetic variation together with its frequency in that population. Here, we report, in addition to the regular data content updates, significant developments in FINDbase, related to data visualization and querying, data submission, interrelation with other resources and a new module for genetic disease summaries. In particular, (i) we have developed new data visualization tools that facilitate data querying and comparison among different populations, (ii) we have generated a new FINDbase module, built around Microsoft's PivotViewer (http://www.getpivot.com) software, based on Microsoft Silverlight technology (http://www.silverlight.net), that includes 259 genetic disease summaries from five populations, systematically collected from the literature representing the documented genetic makeup of these populations and (iii) the implementation of a generic data submission tool for every module currently available in FINDbase.

Updates of the HbVar database of human hemoglobin variants and thalassemia mutations.

HbVar (http://globin.bx.psu.edu/hbvar) is one of the oldest and most appreciated locus-specific databases launched in 2001 by a multi-center academic effort to provide timely information on the genomic alterations leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. Database records include extensive phenotypic descriptions, biochemical and hematological effects, associated pathology and ethnic occurrence, accompanied by mutation frequencies and references. Here, we report updates to >600 HbVar entries, inclusion of population-specific data for 28 populations and 27 ethnic groups for α-, and ß-thalassemias and additional querying options in the HbVar query page. HbVar content was also inter-connected with two other established genetic databases, namely FINDbase (http://www.findbase.org) and Leiden Open-Access Variation database (http://www.lovd.nl), which allows comparative data querying and analysis. HbVar data content has contributed to the realization of two collaborative projects to identify genomic variants that lie on different globin paralogs. Most importantly, HbVar data content has contributed to demonstrate the microattribution concept in practice. These updates significantly enriched the database content and querying potential, enhanced the database profile and data quality and broadened the inter-relation of HbVar with other databases, which should increase the already high impact of this resource to the globin and genetic database community.

Challenges and opportunities for ELSI early career researchers.

BACKGROUND: Over the past 25 years, there has been growing recognition of the importance of studying the Ethical, Legal and Social Implications (ELSI) of genetic and genomic research. A large investment into ELSI research from the National Institutes of Health (NIH) Human Genomic Project budget in 1990 stimulated the growth of this emerging field; ELSI research has continued to develop and is starting to emerge as a field in its own right. The evolving subject matter of ELSI research continues to raise new research questions as well as prompt re-evaluation of earlier work and a growing number of scholars working in this area now identify themselves as ELSI scholars rather than with a particular discipline. MAIN TEXT: Due to the international and interdisciplinary nature of ELSI research, scholars can often find themselves isolated from disciplinary or regionally situated support structures. We conducted a workshop with Early Career Researchers (ECRs) in Oxford, UK, and this paper discusses some of the particular challenges that were highlighted. While ELSI ECRs may face many of the universal challenges faced by ECRs, we argue that a number of challenges are either unique or exacerbated in the case of ELSI ECRs and discuss some of the reasons as to why this may be the case. We identify some of the most pressing issues for ELSI ECRs as: interdisciplinary angst and expertise, isolation from traditional support structures, limited resources and funding opportunities, and uncertainty regarding how research contributions will be measured. We discuss the potential opportunity to use web 2.0 technologies to transform academic support structures and address some of the challenges faced by ELSI ECRs, by helping to facilitate mentoring and support, access to resources and new accreditation metrics. CONCLUSION: As our field develops it is crucial for the ELSI community to continue looking forward to identify how emerging digital solutions can be used to facilitate the international and interdisciplinary research we perform, and to offer support for those embarking on, progressing through, and transitioning into an ELSI research career.

Comparative study and meta-analysis of meta-analysis studies for the correlation of genomic markers with early cancer detection.

A large number of common disorders, including cancer, have complex genetic traits, with multiple genetic and environmental components contributing to susceptibility. A literature search revealed that even among several meta-analyses, there were ambiguous results and conclusions. In the current study, we conducted a thorough meta-analysis gathering the published meta-analysis studies previously reported to correlate any random effect or predictive value of genome variations in certain genes for various types of cancer. The overall analysis was initially aimed to result in associations (1) among genes which when mutated lead to different types of cancer (e.g. common metabolic pathways) and (2) between groups of genes and types of cancer. We have meta-analysed 150 meta-analysis articles which included 4,474 studies, 2,452,510 cases and 3,091,626 controls (5,544,136 individuals in total) including various racial groups and other population groups (native Americans, Latinos, Aborigines, etc.). Our results were not only consistent with previously published literature but also depicted novel correlations of genes with new cancer types. Our analysis revealed a total of 17 gene-disease pairs that are affected and generated gene/disease clusters, many of which proved to be independent of the criteria used, which suggests that these clusters are biologically meaningful.

Culturomics: A New Kid on the Block of OMICS to Enable Personalized Medicine.

This innovation analysis highlights the underestimated and versatile potential of the new field of culturomics and examines its relation to other OMICS system sciences such as infectiomics, metabolomics, phenomics, and pharmacomicrobiomics. The advent of molecular biology, followed by the emergence of various disciplines of the genomics, and most importantly metagenomics, brought about the sharp decline of conventional microbiology methods. Emergence of culturomics has a natural synergy with therapeutic and clinical genomic approaches so as to realize personalized medicine. Notably, the concept of culturomics expands on that of phenomics and allows a reintroduction of the culture-based phenotypic characterization into the 21st century research repertoire, bolstered by robust technology for automated and massive execution, but its potential is largely unappreciated at present; the few available references show unenthusiastic pursuit and in narrow applications. This has not to be so: depending on the specific brand of culturomics, the scope of applications may extend to medicine, agriculture, environmental sciences, pharmacomicrobiomics, and biotechnology innovation. Moreover, culturomics may produce Big Data. This calls for a new generation of data scientists and innovative ways of harnessing and valorizing Big Data beyond classical genomics. Much more detailed and objective classification and identification of microbiota may soon be at hand through culturomics, thus enabling precision diagnosis toward truly personalized medicine. Culturomics may both widen the scope of microbiology and improve its contributions to diagnostics and personalized medicine, characterizing microbes and determining their associations with health and disease dynamics.

Nutrigenomics 2.0: The Need for Ongoing and Independent Evaluation and Synthesis of Commercial Nutrigenomics Tests' Scientific Knowledge Base for Responsible Innovation.

Nutrigenomics is an important strand of precision medicine that examines the bidirectional interactions of the genome and nutritional exposures, and attendant health and disease outcomes. This perspectives article presents the new concept of "Nutrigenomics 2.0," so as to cultivate and catalyze the next generation research and funding priorities for responsible and sustainable knowledge-based innovations. We further contextualize our recent study of the 38 genes included in commercially available nutrigenomics tests, and offer additional context in relation to the 2014 American Academy of Nutrition and Dietetics position. Finally, we make a call in the best interest of the nutrigenomics science community, governments, global society, and commercial nutrigenomics test providers that new evidence evaluation and synthesis platforms are created concerning nutrigenomics tests before they become commercially available. The proposed assessment and synthesis of nutrigenomics data should be carried out on an ongoing dynamic basis with periodic intervals and/or when there is a specific demand for evidence synthesis, and importantly, in ways that are transparent where conflict of interests are disclosed fully by the involved parties, be they scientists, industry, governments, citizens, social scientists, or ethicists. We submit that this will cultivate responsible innovation, and business models that are sustainable, robust, and stand the test of time and context.

Nutrigenomics: A controversy.

Nutrigenomics is an emerging science which investigates a certain area of nutrition that uses molecular tools to search access and understand the several responses obtained through a certain diet applied between individual and population groups. The increased need for the use of personalised nutrition in patients is increasing and research is being made on its possible effects. However, research on nutrigenomics and in particular, obesity is still ongoing. Following a current metanalysis on thirty-eight nutrigenomics genes, it seems that a definite association between the genes usually examined in nutrigenomics testing and several diet-related diseases is lacking, even though there is a limited number of studies associating them. In 2014, literature search results in a great number of studies on several polymorphisms. This heterogeneity could only show the way towards new research aims. Nutrigenomics was born due to the need to move from Epidemiology and Physiology to Molecular Biology and Genetics. Currently, there are steps that need to be considered in order for nutrigenomics to be applied: the genes, the gene/protein network, and the strategy towards the determination of the nutrients' influence on gene/protein expression. It is certainly an interesting evolving science with many areas to be investigated further and from different perspectives, as it involves ethics, medicine, genetics and nutrition.

Meta-Analysis of Genes in Commercially Available Nutrigenomic Tests Denotes Lack of Association with Dietary Intake and Nutrient-Related Pathologies.

Nutrigenomics is an emerging discipline that aims to investigate how individual genetic composition correlates with dietary intake, as well as how nutrition influences gene expression. Herein, the fundamental question relates to the value of nutrigenomics testing on the basis of the currently available scientific evidence. A thorough literature search has been conducted in PubMed scientific literature database for nutrigenomics research studies on 38 genes included in nutrigenomics tests provided by various private genetic testing laboratories. Data were subsequently meta-analyzed to identify possible associations between the genes of interest and dietary intake and/or nutrient-related pathologies. Data analysis occurred according to four different models due to data sparsity and inconsistency. Data from 524,592 individuals (361,153 cases and 163,439 controls) in a total of 1,170 entries were obtained. Conflicting findings indicated that there was a great incompatibility regarding the associations (or their absence) identified. No specific--and statistically significant-association was identified for any of the 38 genes of interest. In those cases, where a weak association was demonstrated, evidence was based on a limited number of studies. As solid scientific evidence is currently lacking, commercially available nutrigenomics tests cannot be presently recommended. Notwithstanding, the need for a thorough and continuous nutrigenomics research is evident as it is a highly promising tool towards precision medicine.

Clinical application of pharmacogenomics: the example of HLA-based drug-induced toxicity.

Pharmacogenomics is gradually becoming more and more indispensable in modern medicine. In several cases, a pharmacogenomics test may alleviate serious drug-induced adverse reactions, if it precedes drug prescription. In this article, we provide an overview of the well-established HLA-based carbamazepine- and allopurinol-induced adverse reactions, as one of the most characteristic examples of the clinical application of pharmacogenomics, highlighting its regional impact in Southeast Asian populations in preventing adverse reactions of certain drug/allele pairs. This example provides useful insights towards evidence generation for policy implementation, including economic evaluation analysis, the implementation of pharmacogenomics testing procedures and monitoring of policy effectiveness, hence serving, per se or in the context of international collaborative efforts, as a model for similar cases in several national healthcare systems worldwide.

Ascertainment and critical assessment of the views of the general public and healthcare professionals on nutrigenomics in Greece.

AIM: The aim of this study was to understand the general public's and healthcare professionals' views on nutrigenomics. PATIENTS & METHODS: We designed a cross-sectional survey of healthcare professionals (n = 87) and the general public (n = 1504) in the three largest cities in Greece (Athens, Thessaloniki and Patras). RESULTS: Our data revealed that only 11.5% of respondents from the general public had been advised to take a genetic test in order to explore the relationship between their genes and their nutritional status. Although 80.5% of healthcare professionals would have been willing to recommend their patients/clients to undergo nutrigenomic analysis to correlate their genetic profile with their diet, only 17.2% of respondents had actually done so. In general, the general public was opposed to direct-access nutrigenomics testing. CONCLUSION: The application of genomic information in the context of nutritional choice requires the continuing education of healthcare professionals and the dissemination of accurate and reliable information to the general public.