In 2013, the American College of Medical Genetics (ACMG) examined the issue of incidental findings in whole exome and whole genome sequencing, and introduced recommendations to search for, evaluate and report medically actionable variants in a set of 56 genes. At a debate held during the 2014 European Society for Human Genetics Conference (ESHG) in Milan, Italy, the first author of that paper presented this view in a debate session that did not end with a conclusive vote from the mainly European audience for or against reporting back actionable incidental findings. In this meeting report, we elaborate on the discussions held during a special meeting hosted at the ESHG in 2013 from posing the question ‘How to reach a (European) consensus on reporting incidental findings and unclassified variants in diagnostic next generation sequencing'. We ask whether an European consensus exists on the reporting of incidental findings in genome diagnostics, and present a series of key issues that require discussion at both a national and European level in order to develop recommendations for handling incidental findings and unclassified variants in line with the legal and cultural particularities of individual European member states.
Even though an increasing portion of biomedical research today relies on the use of bioresources, at present biobankers are not able to trace this use in scientific literature and measure its impact with a variety of citation metrics. The “BRIF (Bioresource Research Impact Factor) and journal editors” subgroup was created precisely with the aim to study this issue and to build a standardized system to cite bioresources in journal articles. This report aims at presenting a guideline for Citation of BioResources in journal Articles (CoBRA). The guideline offers for the first time a standard for citing bioresources (including biobanks) within journal articles. It will increase their visibility and promote their sharing.
To group HLA-DRB1 alleles based on acid–base properties of amino acids at positions 13, 70 and 71 and analyse their association with the presence of anticitrullinated peptide antibodies (ACPA) and structural progression in 2 cohorts of early rheumatoid arthritis (RA).
Patients with RA (N=612) from ESPOIR cohort and from EAC cohort (n=624) were genotyped for HLA-DRB1 alleles. The alleles containing the RAA sequence at positions 72–74 were classified into 3 groups according to the amino acid at positions 13, 70 and 71: BB encoding basic amino acids at positions 13, 70 and 71; A encoding acidic amino acids at positions 70 and 71; and BN encoding either neutral amino acids at position 13 and basic amino acids at positions 70 and 71, or basic amino acid at position 13 and neutral amino acids at positions 70 and 71. The associations between the different alleles and (1) the ACPA presence, and (2) the structural progression were assessed by χ2 test; a meta-analysis was performed on the 2 cohorts using the Mantel-Haenszel method.
After meta-analysis, BB alleles were significantly associated with ACPA presence (OR (95% CI) 4.08 (3.14 to 5.31)) and structural progression (OR (95% CI) 2.33 (1.76 to 3.09)). The alleles protected significantly against ACPA presence (OR (95% CI) 0.37 (0.28 to 0.50)) and structural progression (OR (95% CI) 0.34 (0.23 to 0.50)). This acid–base classification allowed to separate another group BN with an intermediate risk of ACPA production (OR (95% CI) 1.14 (0.91 to 1.44)) and structural progression (OR (95% CI) 1.01 (0.77 to 1.33)).
This new classification permitted to make a hierarchy of HLA-DRB1 alleles in terms of association with ACPA presence or structural progression in early RA.
Ant-CCP; Gene Polymorphism; Rheumatoid Arthritis
Introduction: The use of genetic predictive markers in medical practice does not necessarily bear the same kind of medical and ethical consequences than that of genes directly involved in monogenic diseases. However, the French bioethics law framed in the same way the production and use of any genetic information. It seems therefore necessary to explore the practical and ethical context of the actual use of predictive markers in order to highlight their specific stakes. In this study, we document the uses of HLA-B*27, which are an interesting example of the multiple features of genetic predictive marker in general medical practice.
Materials and Methods: The aims of this monocentric and qualitative study were to identify concrete and ethical issues of using the HLA-B*27 marker and the interests and limits of the legal framework as perceived by prescribers. In this regard, a thematic and descriptive analysis of five rheumatologists' semi-structured and face-to-face interviews was performed.
Results: According to most of the interviewees, HLA-B*27 is an “overframed” test because they considered that this test is not really genetic or at least does not have the same nature as “classical genetic tests”; HLA-B*27 is not concerned by the ethical challenges of genetic test; the major ethics stake of this marker is not linked to its genetic nature but rather to the complexity of the probabilistic information. This study allows also showing that HLA-B*27, validated for a certain usage, may be used in different ways in practice.
Discussion: This marker and its clinical uses underline the challenges of translating both statistical concepts and unifying legal framework in clinical practice. This study allows identifying some new aspects and stakes of genetics in medicine and shows the need of additional studies about the use of predictive genetic markers, in order to provide a better basis for decisions and legal framework regarding these practices.
HLA-B27; rheumatology; ankylosing spondylitis; predictive genetic marker; multifactorial disease; statistical prediction; ethics; legal framework
Many biomedical publications refer to data obtained from collections of biosamples. Sharing such bioresources (biological samples, data, and databases) is paramount for the present governance of research. Recognition of the effort involved in generating, maintaining, and sharing high quality bioresources is poorly organized, which does not encourage sharing. At publication level, the recognition of such resources is often neglected and/or highly heterogeneous. This is a true handicap for the traceability of bioresource use. The aim of this article is to propose, for the first time, a guideline for reporting bioresource use in research articles, named CoBRA: Citation of BioResources in journal Articles.
As standards for citing bioresources are still lacking, the members of the journal editors subgroup of the Bioresource Research Impact Factor (BRIF) initiative developed a standardized and appropriate citation scheme for such resources by informing stakeholders about the subject and raising awareness among scientists and in science editors’ networks, mapping this topic among other relevant initiatives, promoting actions addressed to stakeholders, launching surveys, and organizing focused workshops.
The European Association of Science Editors has adopted BRIF’s suggestion to incorporate statements on biobanks in the Methods section of their guidelines. The BRIF subgroup agreed upon a proposed citation system: each individual bioresource that is used to perform a study and that is mentioned in the Methods section should be cited as an individual “reference [BIORESOURCE]” according to a delineated format. The EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network mentioned the proposed reporting guideline in their “guidelines under development” section.
Evaluating bioresources’ use and impact requires that publications accurately cite such resources. Adopting the standard citation scheme described here will improve the quality of bioresource reporting and will allow their traceability in scientific publications, thus increasing the recognition of bioresources’ value and relevance to research.
Please see related article: http://dx.doi.org/10.1186/s12916-015-0284-9.
Biobanks; Bioresource; Bioresource Research Impact Factor; CoBRA; Data sharing; Guideline; Open policies; Repository; Standardized citation; Traceability
We need an international infrastructure for the ethical, legal and social implications of genomic research.
recommendations; whole-genome sequencing; policy
recommendations; whole-genome sequencing; policy
Recently many international initiatives have been developed to improve access to scientific information and to promote open data sharing. In the complex field of bioresources, the BRIF (Bioresource Research Impact Factor) project aims to create suitable methods to recognise and measure the use and impact of biological resources in scientific/academic work, in order to maximize access by researchers to collections of biological materials and attached databases, and to recognize efforts involved in their maintenance. The lack of a proper recognition of scientific contribution is in fact a major obstacle which impedes bioresource sharing. In this context, the BRIF initiative can be considered as a tool to facilitate research resource sharing.
Bioresources; citations; data sharing; editors; open access; open research data.
Translating the knowledge from biomedical science into clinical applications that help patients has been compared to crossing a valley of death because of the many issues that separate the bench from the bedside and threaten to stall progress. But translation is also inhibited by a science policy environment with its own impediments. Mapping these policy impediments give a more complete picture of the valley of death. Stem cell science is one example where success in moving from the bench to the bedside has confronted policy challenges generating difficulties as challenging as those facing scientists and clinicians. We highlight some of the characteristics and challenges of the science policy valley of death common to the U.S. and Europe, illustrate them with a recent example from stem cell science, and describe some promising strategies for traversing the valley.
Science policy; Ethics; Valley of death; Stem cell research
An increasing portion of biomedical research relies on the use of biobanks and databases. Sharing of such resources is essential for optimizing knowledge production. A major obstacle for sharing bioresources is the lack of recognition for the efforts involved in establishing, maintaining and sharing them, due to, in particular, the absence of adequate tools. Increasing demands on biobanks and databases to improve access should be complemented with efforts of end-users to recognize and acknowledge these resources. An appropriate set of tools must be developed and implemented to measure this impact.
To address this issue we propose to measure the use in research of such bioresources as a value of their impact, leading to create an indicator: Bioresource Research Impact Factor (BRIF). Key elements to be assessed are: defining obstacles to sharing samples and data, choosing adequate identifier for bioresources, identifying and weighing parameters to be considered in the metrics, analyzing the role of journal guidelines and policies for resource citing and referencing, assessing policies for resource access and sharing and their influence on bioresource use. This work allows us to propose a framework and foundations for the operational development of BRIF that still requires input from stakeholders within the biomedical community.
Data sharing; Bioresource; Biobank; Identifier; Metrics; Traceability; Impact factor; Biology; Science policy; Open data
The participation of minors in biobank research can offer great benefits for science and
health care. However, as minors are a vulnerable population they are also in need of
adequate protective measures when they are enrolled in research. Research using biobanked
biological samples from children poses additional ethical issues to those raised by
research using adult biobanks. For example, small children have only limited capacity, if
any, to understand the meaning and implications of the research and to give a documented
agreement to it. Older minors are gradually acquiring this capacity. We describe
principles for good practice related to the inclusion of minors in biobank research,
focusing on issues related to benefits and subsidiarity, consent, proportionality and
return of results. Some of these issues are currently heavily debated, and we conclude by
providing principles for good practice for policy makers of biobanks, researchers and
anyone involved in dealing with stored tissue samples from children. Actual implementation
of the principles will vary according to different jurisdictions.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
A few months ago, the controversial debate on connection between genetic variants and antisocial behaviour gained renewed prominence after the sentence of an Italian judge who decided to further reduce the prison sentence of a person convicted of murder by 1 year – from 9 to 8 years – because he was found to be a carrier of a few genetic variants thought to be associated with a predisposition to aggressiveness. We discuss the social implication of this view, the lack of evidence of the clinical utility of this test, and in particular the risks of offering susceptibility testing in the context of legal proceedings.
An extensive family-based study of linkage disequilibrium (LD) in the killer cell immunoglobulin-like receptors (KIR) cluster was performed. We aimed to describe the LD structure in the KIR gene cluster using a sample of 418 founder haplotypes identified by segregation in a group of 106 families from Northern Ireland. The LD was studied at two levels of polymorphism: the structural level (presence or absence of KIR genes) and the allelic level (between alleles of KIR genes). LD was further assessed using the predictive value of one KIR polymorphism for another one in order to provide an interpretative framework for the LD effect in association studies. In line with previous research, distinct patterns of KIR genetic diversity within the genomic region centromeric to KIR2DL4 (excluding KIR2DL4) and within the telomeric region including KIR2DL4 were found. In a comprehensive PPV/NPV-based LD analysis within the KIR cluster, robust tag markers were found that can be used to identify which genes are concomitantly present or absent and to further identify groups of associated KIR alleles. Several extended KIR haplotypes in the study population were identified (KIR2DS2*POS–KIR2DL2*001–KIR2DL5B*002–KIR2DS3*00103–KIR2DL1*00401; KIR2DL4*011–KIR3DL1/S1*005–KIR2DS4*003–KIR3DL2*003; KIR2DL4*00802–KIR3DL1/S1*004–KIR2DS4*006–KIR3DL2*005; KIR2DL4*00801–KIR3DL1/S1*00101–KIR2DS4*003–KIR3DL2*001; KIR2DL4*00103–KIR3DL1/S1*008–KIR2DS4*003–KIR3DL2*009; KIR2DL4*00102–KIR3DL1/S1*01502/*002–KIR2DS4*00101–KIR3DL2*002; KIR2DL4*00501–KIR3DL1/S1*013–KIR2DL5A*001–KIR2DS5*002–KIR2DS1*002–KIR3DL2*007). The present study provides a rationale for analyzing associations of KIR polymorphisms by taking into account the complex LD structure of the KIR region.
Electronic supplementary material
The online version of this article (doi:10.1007/s00251-010-0478-4) contains supplementary material, which is available to authorized users.
KIR; Linkage disequilibrium; Tagging; Association studies
Rheumatoid arthritis (RA) is a complex polygenic disease of unknown etiology. HLA-DRB1 alleles encoding the shared epitope (SE) (RAA amino acid pattern in positions 72 to 74 of the third hypervariable region of the DRβ1 chain) are associated with RA susceptibility. A new classification of HLA-DRB1 SE alleles has been developed by Tezenas du Montcel and colleagues to refine the association between HLA-DRB1 and RA. In the present study, we used RA samples collected worldwide to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility across various Caucasoid and non-Caucasoid patients.
Eighteen subsamples were defined from a total number of 759 cases and 789 controls and grouped in 10 samples on the basis of their ethnic origin. HLA-DRB1 alleles were divided into five groups (S1, S2, S3D, S3P, and X) according to the new HLA-DRB1 allele classification. The whole analysis was performed by comparing carrier frequencies for the five HLA-DRB1 allele groups between RA patients and controls across the 10 Caucasoid and non-Caucasoid samples. The Mantel-Haenszel method of meta-analysis provided a global odds ratio (OR) estimate with 95% confidence interval (CI).
A positive association with RA susceptibility was found for S2 allele carriers (OR 2.15, 95% CI 1.54 to 3.00; p < 10-5) and S3P allele carriers (OR 2.74, 95% CI 2.01 to 3.74; p < 10-5). A negative association was found for S1 alleles (OR 0.60, 95% CI 0.48 to 0.76; p < 10-4) and X alleles (OR 0.58, 95% CI 0.39 to 0.84; p = 4 × 10-3). No significant association was highlighted for the S3D group of alleles (OR 0.89, 95% CI 0.69 to 1.14; p = 0.89). The complementary genotype analysis fit with the genotype risk hierarchy previously reported in Caucasoid RA patients.
So far, the present study is the first attempt to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility on both Caucasoid and non-Caucasoid samples. Our results support the hypothesis of a differential role played by different HLA-DRB1 allele groups in RA susceptibility across different ethnic backgrounds and confirm the interest of such an HLA-DRB1 classification in differentiating predisposing and protective alleles.
The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity.
We investigated the relevance of this new classification of HLA-DRB1 SE+ alleles in terms of rheumatoid factor (RF) and ACPA production in a sample of French RA patients.
We studied 160 early RA patients included in a prospective longitudinal cohort of French Caucasian patients with recent-onset arthritis. RF, anticyclic citrullinated peptide 2 (anti-CCP2) and antideiminated human fibrinogen autoantibodies (AhFibA) were assessed in all patients at inclusion. The HLA-DRB1 gene was typed by PCR-sequence specific oligonucleotides probes (PCR-SSOP), and SE+ alleles were classified into four groups (S1, S2, S3P, S3D) according to the new classification.
The new classification of HLA-DRB1 SE+ alleles distinguishes predisposing and protective alleles for RF, anti-CCP2 or AhFibA production. The presence of S2 or S3P alleles is associated with both RF, anti-CCP2 or AhFibA positivity, whereas the presence of S3D or S1 alleles appears to be protective for RF, anti-CCP2 or AhFibA positivity.
The new classification of HLA-DRB1 SE+ alleles is relevant in terms of autoantibody production in early RA patients by differentiating predisposing and protective alleles for RF or ACPA production.
Biobanks include biological samples and attached databases. Human biobanks occur in research, technological development and medical activities. Population genomics
is highly dependent on the availability of large biobanks. Ethical issues must be
considered: protecting the rights of those people whose samples or data are in
biobanks (information, autonomy, confidentiality, protection of private life), assuring
the non-commercial use of human body elements and the optimal use of samples
and data. They balance other issues, such as protecting the rights of researchers
and companies, allowing long-term use of biobanks while detailed information on
future uses is not available. At the level of populations, the traditional form of
informed consent is challenged. Other dimensions relate to the rights of a group
as such, in addition to individual rights. Conditions of return of results and/or
benefit to a population need to be defined. With ‘large-scale biobanking’ a marked
trend in genomics, new societal dimensions appear, regarding communication, debate,
regulation, societal control and valorization of such large biobanks. Exploring how
genomics can help health sector biobanks to become more rationally constituted
and exploited is an interesting perspective. For example, evaluating how genomic
approaches can help in optimizing haematopoietic stem cell donor registries using
new markers and high-throughput techniques to increase immunogenetic variability
in such registries is a challenge currently being addressed. Ethical issues in such
contexts are important, as not only individual decisions or projects are concerned,
but also national policies in the international arena and organization of democratic
debate about science, medicine and society.
More than 1,000 Web-based locus-specific variation databases (LSDBs) are listed on the Website of the Human Genetic Variation Society (HGVS). These individual efforts, which often relate phenotype to genotype, are a valuable source of information for clinicians, patients, and their families, as well as for basic research. The initiators of the Human Variome Project recently recognized that having access to some of the immense resources of unpublished information already present in diagnostic laboratories would provide critical data to help manage genetic disorders. However, there are significant ethical issues involved in sharing these data worldwide. An international working group presents second-generation guidelines addressing ethical issues relating to the curation of human LSDBs that provide information via a Web-based interface. It is intended that these should help current and future curators and may also inform the future decisions of ethics committees and legislators. These guidelines have been reviewed by the Ethics Committee of the Human Genome Organization (HUGO). Hum Mutat 31:–6, 2010. © 2010 Wiley-Liss, Inc.
phenotype; LSDB; data-sharing; ethics; curators; guidelines; diagnostic test; consent