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A poster presented at the 36th European Immunogenetics and Histocompatibility Conference by the RDA / EOSC Future Domain Ambassador for Health Ethics. It describes the main challenges the discipline faces and describes the tools available to make data FAIR. It gives some recommendations for EFI to take onboard as Open Sciences becomes a major policy aspect.&nbsp

DFS by tumor stage stratified by genomic classifier

Supplementary Methods

Clinical information and 12 gene mutation status for cohorts C1-C3

Somatic mutations detected in 12 interrogated genes for cohorts C1-C3

Supplementary Tables S3-S13

Purpose:Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing.Experimental Design:The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework.Results:Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy.Conclusions:Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design.

Disease-Free Survival outcomes amongst genomic groups when applied to the 247 VHL mutated ccRCCs from the TCGA dataset

DFS amongst Leibovich risk groups stratified by genomic classifier

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in

Renal cell carcinomas (RCC) are characterized by their heterogenous clinical outcomes, and due to their indeterminate behavior and the absence of routine biomarkers, it is difficult to identify patients who are at high-risk for relapse after curative nephrectomy. To identify genomic biomarkers for clear cell RCC (ccRCC) risk-stratification we interrogated somatic mutation status of 12 RCC-relevant genes using next-generation sequencing (NGS) in tumor-normal pairs from 943 patients with matched follow up data from the Cancer Genomics of the Kidney (CAGEKID) study. We examined associations between genomically-defined patient groups, explained below, and disease-free as well as RCC-specific survival independently in two cohorts of patients (N=469 for cohort 1; 474 for cohort 2). We used the Kaplan-Meier method with log-rank tests to compare survival functions, and Cox proportional hazards models to stratify for patient stage and age to estimate association of each group with survival. RCC-specific survival was assessed with a competing-risks method to include deaths from other causes. Within these cohorts, 76.4% of patients harbored somatic mutations in VHL, the most common driver gene in ccRCC. The most commonly mutated genes within VHL-mutated tumors were PBRM1 (39.7%), SETD2 (19%), BAP1 (14.3%), and KDM5C (8.3%). Less frequently mutated genes included ATM, COL11A1, DMD, TP53, and TRRAP (~3-5%).Among VHL-driven tumors, we identified a new genomic classifier on the basis of the number of mutations in additional RCC driver genes in the panel examined. Patients were classified based on the presence of mutations only in VHL (VHL+0), those with mutations in VHL and one other driver gene (VHL+1), two other driver genes (VHL+2), and 3 or more other driver genes (VHL≥3). We observed within both cohorts that both the risk of disease recurrence as well as RCC-specific death were associated with an increased number of mutations within this classification. When stratified for patient stage and age, the hazard-ratio for 5-year disease-free survival for VHL≥3 patients was 6.69 (p=0.000212), 4.31 for VHL+2 (p=0.000862), and 2.43 for VHL+1 (p=0.035662), compared to patients with only mutations in VHL. These observations were replicated in the second patient cohort, with hazards ratios of 4.55, 2.49, and 1.40, for VHL≥3, VHL+2, and VHL+1 classified patients respectively, indicating that risk of disease recurrence increases with the number of driver mutations. Notably, tumor mutational burden (TMB) was not significantly different between the aforementioned groups, demonstrating that our classifier is independent of TMB. We created a model based on a set of 12 RCC-relevant genes, which can predict risk of relapse for the ~80% of patients with ccRCC that are VHL-driven. This classification can be defined based on a small panel of genes, making it easily applicable to the clinic, in the context of tumor or liquid biopsy analysis. Citation Format: Kate I. Glennon, Naveen S. Vasudev, Ghislaine Scelo, Michelle Wilson, Louis Letourneau, Robert Eveleigh, Nazanin Nourbehesht, Madeleine Arseneault, Antoine Paccard, Lars Egevad, Juris Viksna, Edgars Celms, Sharon M. Jackson, Behnoush Abedi-Ardekani, Anne Y. Warren, Peter J. Selby, Sebastian Trainor, Michael Kimuli, Naeem Soomro, Adebanji Adeyoju, Poulam Patel, Magdalena B. Wozniak, Ivana Holcatova, Antonin Brisuda, Vladimir Janout, Estelle Chanudet, David Zaridze, Anush Moukeria, Oxana Shangina, Lenka Foretova, Marie Navratilova, Dana Mates, Viorel Jinga, Ljiljana Bogdanovic, Bozidar Kovacevic, Anne Cambon-Thomsen, Guillaume Bourque, Alvis Brazma, Jörg Tost, Paul Brennan, Mark Lathrop, Yasser Riazalhosseini, Rosamonde E. Banks. Genomic classification to refine prognosis in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB113.

Research data are a vital component of the scientific record. Discovering and assessing data for possible reuse in future research is challenging. The Belmont Forum has recently awarded funds to th...

Next-generation sequencing techniques enable unsolicited findings to be detected. This discovery raises ethical questions concerning the return of these findings. Our study aimed to highlight the views of the general public, patients under supervision and health professionals concerning the acceptability of disclosing unsolicited results to patients. In total, 449 participants assessed scenarios, consisted of all combinations of three factors (patient’s information and consent, prevention and treatment of the unsolicited disease and doctor’s decision). The response profiles were grouped into six clusters. The participants took ethical aspects into account, but health professionals also considered the medical aspects to a greater extent.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

Le terme de biobanque designe une collection d’echantillons biologiques associes a des donnees personnelles, destinee a servir la recherche scientifique. Les pratiques de recueil et de conservation du materiel biologique sont en constante evolution. Elles s’adaptent a la fois aux contextes changeants des institutions scientifiques, aux innovations d’ordre technologique et a l’emergence de nouvelles formes d’organisations. Ces adaptations doivent aussi permettre de valoriser les collections en multipliant les usages possibles des ressources biologiques et leur reutilisation future.Les orientations favorisant le developpement des biobanques sur le long terme posent cependant probleme du point de vue de l’ethique de la recherche biomedicale. Parce que nul n’est en mesure de predire pour quelle etude specifique les echantillons et donnees recueillis au sein des biobanques serviront precisement dans l’avenir, les eventuels participants des « nouvelles biobanques » se trouvent dans l’impossibilite de consentir a des recherches dont on ne peut anticiper ni la nature, ni la finalite. Les incertitudes relatives aux directions, methodes et enjeux de la recherche a venir empechent de proposer une procedure de « consentement eclaire » adaptee au present.Alors que l’anticipation constitue un enjeu technique et scientifique de taille dans la realisation des « nouvelles biobanques », nous proposons de l’envisager comme une dimension a part entiere de l’ethique appliquee aux biobanques. L’etude de pratiques scientifiques qui inscrivent les biobanques dans le temps long nous amene a penser le lien entre organisation, technologie et ethique.

Genomic technologies are developing at a time when greater public involvement in research and clinical governance is sought. To this end, empirical bioethics studies, although conceptualized as academic endeavors, may draw on the inclusion of laypeople to justify informing policy. Doing so, they face similar concerns as those addressed to public consultations which cannot be termed democratic a priori and may reinforce the authority of experts. We reflect on these concerns in the process of analyzing the results of a qualitative analysis of eight focus groups (64 participants) held in France during 2010–2012, designed to understand laypeople's views of the ethical debates surrounding genomic medicine. We examine how the notions of “lay” and “expert” play in the framework of the study and how participants situate themselves along this divide. This understanding of the social context in which the publics are situated enables a more reflexive and accurate ethical analysis.

The systemic challenges of the COVID-19 pandemic require cross-disciplinary collaboration in a global and timely fashion. Such collaboration needs open research practices and the sharing of research outputs, such as data and code, thereby facilitating research and research reproducibility and timely collaboration beyond borders. The Research Data Alliance COVID-19 Working Group recently published a set of recommendations and guidelines on data sharing and related best practices for COVID-19 research. These guidelines include recommendations for clinicians, researchers, policy- and decision-makers, funders, publishers, public health experts, disaster preparedness and response experts, infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations), and other potential users. These guidelines include recommendations for researchers, policymakers, funders, publishers and infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations). Several overarching themes have emerged from this document such as the need to balance the creation of data adherent to FAIR principles (findable, accessible, interoperable and reusable), with the need for quick data release; the use of trustworthy research data repositories; the use of well-annotated data with meaningful metadata; and practices of documenting methods and software. The resulting document marks an unprecedented cross-disciplinary, cross-sectoral, and cross-jurisdictional effort authored by over 160 experts from around the globe. This letter summarises key points of the Recommendations and Guidelines, highlights the relevant findings, shines a spotlight on the process, and suggests how these developments can be leveraged by the wider scientific community.

As next-generation sequencing technologies (NGS) are increasingly used in the clinic, one issue often pointed out in the literature is the fact that their implementation "blurs the line" between research and healthcare. Indeed, NGS data obtained through research study may have clinical significance, and patients may consent that their data is shared in international databases used in research. This blurred line may increase the risk of therapeutic misconception, or that of over-reporting incidental findings. The law has been used to impose a distinction between the two contexts, but this distinction may not always be as clear in the practice of clinical genomics. To illustrate this, we reviewed the legal frameworks in France and Quebec on the matter, and asked the opinion of stakeholders who use NGS to help cancer and rare disease patients in practice. We found that while there are clear legal distinctions between research and clinical care, bridges between the two contexts exist, and the law focuses on providing appropriate protections to persons, whether they are patients or research participants. The technology users we interviewed expressed that their use of NGS was designed to help patients, but harbored elements pertaining to research as well as care. We hence saw that NGS technologies are often used with a double objective, both individual care and the creation of collective knowledge. Our results highlight the importance of moving towards research-based care, where clinical information can be progressively enriched with evolutive research results. We also found that there can be a misalignment between scientific experts' views and legal norms of what constitutes research or care, which should be addressed. Our method allowed us to shed light on a grey zone at the edge between research and care, where the full benefits of NGS can be yielded. We believe that this and other evidence from the realities of clinical research practice can be used to design more stable and responsible personalized medicine policies.

Collections intended for purely academic purposes are run on a nonprofit basis, whereas commercially managed collections are intended to make a profit for their owners by placing on the market samples private researchers can buy when they do not have their own source of research materials. In recent years, researchers using collections for multicentric projects have been reflecting on how collections can best be used. Calls for applications for European research programs stipulate that consortia conduct their research in accordance with European and international ethical guidelines.

OBJECTIVE: For patients with metastatic renal cell cancer (mRCC), treatment choice is mainly based on clinical parameters. With many treatments available and the limited response to treatment and associated toxicities, there is much interest in identifying better biomarkers for personalized treatment. EuroTARGET aims to identify and characterize host- and tumor-related biomarkers for prediction of response to tyrosine kinase inhibitor therapy in mRCC. Here, we describe the EuroTARGET mRCC patient cohort. METHODS AND MATERIALS: EuroTARGET is a European collaborative project designed as an observational study for which patients with mRCC were recruited prospectively in 62 centers. In addition, 462 patients with mRCC from previous studies were included. Detailed clinical information (baseline and follow-up) from all patients was entered in web-based case record forms. Blood was collected for germline DNA and pharmacokinetic/pharmacodynamic analyses and, where available, fresh-frozen tumor material was collected to perform tumor DNA, RNA, kinome, and methylome analyses. RESULTS: In total, 1,210 patients with mRCC were included. Of these, 920 received a tyrosine kinase inhibitor as first-line targeted treatment (sunitinib [N = 713, 78%], sorafenib [N = 41, 4%], or pazopanib [N = 166, 18%]) and had at least 6 months of outcome assessment (median follow-up 15.3 months [interquartile range: 8.5-30.2 months]). Germline DNA samples were available from 824 of these patients, fresh-frozen tumor material from 142 patients, fresh-frozen normal kidney tissue from 95 patients, and tissue microarrays created from formalin-fixed paraffin-embedded tumor material from 247 patients. Of the 920 patients, germline DNA variant chip data were successfully generated for 811 patients (Illumina HumanOmniExpress BeadChip). For 80 patients, next-generation exome sequencing of germline and tumor DNA was performed, tumor RNA sequencing was performed for 124 patients, kinome activity measured and processed for 121 patients (PamChip), and methylome data (Illumina Infinium HumanMethylation450 BeadChip) were created for 116 RCC tissues (and 23 normal kidney tissues). For 73 out of the 920 patients, all platform data types were generated. In addition, 40 patients were included in a pharmacokinetic/pharmacodynamic phase IV substudy. CONCLUSIONS: Analysis of EuroTARGET cohort data will contribute to personalization of therapy for patients with mRCC. The extensive clinical data and multiplatform EuroTARGET data will be freely available. We would like to thank all patients who participated and their treating physicians for inviting them. Sí

Resume Objectifs Determiner l’impact des polymorphismes nucleotidiques simples (SNP) dans les genes IL-2RA (rs2104286) et IL-2RB (rs743777 et rs3218253) sur les risques d’erosion chez les patients atteints de polyarthrite rhumatoide (PR). Methodes Ce travail derive de deux cohortes prospectives de PR precoce : les cohortes ESPOIR (n = 439) et RMP (n = 180). Les proportions de patients avec erosion au depart et a un an en fonction des genotypes de l’IL-2RA (rs2104286) ou des haplotypes generes par les deux SNP de l’IL-2RB ont ete comparees dans la population totale et chez les patients positifs pour les ACPA. Une meta-analyse determinant le risque erosif en fonction des haplotypes des deux SNP de l’IL-2RB a ete realisee en utilisant la methode de Mantel-Haenszel. Un modele multivarie a ete utilise afin de determiner l’effet independant des haplotypes d’IL-2RB sur le risque erosif. Resultats L’haplotype AC d’IL-2RB etait associe de maniere significative avec les taux d’erosion chez les patients positifs pour les ACPA dans la cohorte ESPOIR (taux d’erosion : AC/AC : 78 % contre GC ou GT/GC ou GT : 44 %, p = 0,001). Une meta-analyse des cohortes ESPOIR et RMP a confirme que le fait de porter l’haplotype AC etait significativement associe au taux d’erosion a un an dans la population totale (OR [IC95 %] = 1,92 [1,14–3,22], p = 0,01) et chez les patients ACPA-positifs (OR [IC95 %] = 3,34 [1,68–6,67], p = 0,0006). Un modele multivarie dans la cohorte ESPOIR a demontre l’effet independant de l’haplotype AC (6,03 [1,94–18,69], p = 0,002) sur le risque erosif chez les patients ACPA-positifs. Conclusion Un haplotype forme par deux SNP localises dans le gene IL-2RB etait associe a l’etat erosif dans la PR precoce.

Online availability of direct-to-consumer health genetic testing services for various diseases and behavioural traits appears to have created a business dynamic since its beginning around the turn of the millennium. What are the marketing strategies implemented by the companies commercialising these tests and the social expectations they feed on? From a quantitative and qualitative analysis of the websites offering such tests for health, it appears that these companies have based their expansion on a triple-branch market: 'healthism', contemporary claims revolving around the individuation of 'biopolitics', and biosocial bonding. Each of these three marketing strategies raises a number of socio-ethical issues that require careful consideration in the face of an unprecedented surge of the genetic testing market.

With the human genome project running from 1989 until its completion in 2003, and the incredible advances in sequencing technology and in bioinformatics during the last decade, there has been a shift towards an increase focus on studying common complex disorders which develop due to the interplay of many different genes as well as environmental factors. Although some susceptibility genes have been identified in some populations for disorders such as cancer, diabetes and cardiovascular diseases, the integration of this information into the health care system has proven to be much more problematic than for single gene disorders. Furthermore, with the 1000$ genome supposedly just around the corner, and whole genome sequencing gradually being integrated into research protocols as well as in the clinical context, there is a strong push for the uptake of additional genomic testing. Indeed, the advent of public health genomics, wherein genomics would be integrated in all aspects of health care and public health, should be taken seriously. Although laudable, these advances also bring with them a slew of ethical and social issues that challenge the normative frameworks used in clinical genetics until now. With this in mind, we highlight herein 5 principles that are used as a primer to discuss the ethical introduction of genome-based information and genome-based technologies into public health.

In recent years, the cost of generating genome information has shown a rapid decline.1, 2 High-throughput genomic technologies make it possible to sequence the whole exome or genome of a person at a price that is affordable for some health-care systems. More services based on these technologies are now becoming available for patients, raising the issue of how to ensure that these are provided appropriately. In order to determine both the clinical utility of genetic testing and assure a high quality of the analysis, the interpretation and communication of the results must be discussed so that patients can receive appropriate advice and genetic testing. The Public and Professional Policy Committee (PPPC) and the Quality Committee of the European Society of Human Genetics (ESHG) addressed these challenges at a joint workshop in Gothenburg, Sweden, in 2010.3 PPPC also organised workshops in Amsterdam, the Netherlands (January 2011 in collaboration with the EU-funded project TECHGENE, January 2012). A report for the Health Council of the Netherlands served as a background document for the PPPC's reflections.4 Focusing on the clinical diagnostics setting, this paper is intended to contribute to the discussion and the development of guidelines in this fast-moving field, and provide recommendations for health-care professionals. The paper and recommendations were posted on the ESHG website from 20 June to 1 August 2012 for comment by the membership. The final version was approved by the ESHG Board in December 2012.

Next-generation sequencing is radically changing how DNA diagnostic laboratories operate. What started as a single-gene profession is now developing into gene panel sequencing and whole exome and genome sequencing (WES/WGS) analyses. With further advances in sequencing technology and concomitant price reductions, whole genome sequencing (WGS) will soon become the standard and be routinely offered. Here we focus on the critical steps involved in performing WGS, with a particular emphasis on points where WGS differs from WES, the important variables that should be taken into account, and the quality control measures that can be taken to monitor the process. The points discussed here, combined with recent publications on guidelines for reporting variants, will facilitate the routine implementation of WGS into a diagnostic setting. This article is protected by copyright. All rights reserved. ispartof: Human Mutation vol:38 issue:8 pages:912-921 ispartof: location:United States status: published

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.

Un phenomene nouveau reliant les avancees de la biotechnologie aux technologies de l’information et de la communication semble s’etre produit sans qu’on en ait anticipe la nature et l’ampleur. Il s’agit de la mise a disposition, sur Internet, d’une genomique dite personnalisee. Les usagers peuvent acheter directement aupres de diverses compagnies une offre combinee de tests genetiques pour de multiples maladies, associant parfois des informations relatives a l’ancestralite, sans qu’il soit necessairement requis de prescription medicale et sans que l’usager soit systematiquement assiste par un professionnel de sante pour l’interpretation des resultats. Quels types de strategies commerciales utilisent les entreprises offrant des tests genetiques en libre acces sur Internet et sur quelles categories d’attentes sociales jouent-elles parallelement ? Par une analyse tant quantitative que qualitative des sites Internet qui proposent ces tests, on constate que ces compagnies visent un triple marche : celui du healthism (santeisme) qui a hisse la sante et l’hygiene au pantheon des valeurs sociales ; celui des revendications contemporaines des usagers des systemes de sante a devenir de veritables acteurs des decisions de sante ; et enfin celui du lien (bio-)social. Ces trois strategies commerciales recouvrent differents enjeux ethiques et societaux qu’il convient d’analyser.

Advances in genomics have crucial implications for public health, offering new ways of differentiating individuals and groups within populations that go beyond the measures normally used by public health professionals, such as gender, age, socio-economic status, physiological measurements or clinical biomarkers.1 While public health has traditionally been concerned with interventions at a population level, genomic medicine seems to promote a vision for health care that encourages individualism rather than collectivism.2 This tension is apparent in weighing up its consequences. Thus, it may bring benefits in stratifying individuals according to genetic risk, enabling better targeting of preventive and therapeutic interventions. But it may also have harmful consequences undermining the imperative to tackle social and environmental determinants of disease and the collective provision of health care potentially leading to overdiagnosis/overtreatment; it may fragment the risk pooling that underpins social solidarity; and it may increase the probability of stigmatization and discrimination. Consequently, the public health community, with its commitment to equity, must take the opportunity to engage with genomic knowledge, ensuring that it advances the population’s health. These issues were explored in January 2014 at the inaugural meeting of an international working group on ‘Beyond Public Health Genomics’, convening leading experts in genomics, public health, clinical sciences, systems medicine, law and bioethics, from many disciplines and countries, at the Universita Cattolica del Sacro Cuore in Rome. Its goal, inspired by the 2005 Bellagio statement on public health genomics, defined as the ‘responsible and effective translation of genome-based discovery into population health,3 was to generate high value-based proposals to foster the evidence base for implementing genomic discoveries in public health policy and practice, and to ensure necessary action while accounting for the challenge of needing to fund these workstreams in the current environment of diminishing resources. The contribution of genomics to …

Under the auspices of a multi-national European scientific project involving whole genome sequencing, GEUVADIS, we set out to investigate the attitudes of the participating scientists of having their own genome sequenced. The views of such researchers on this subject have not been fully explored before and we utilized questionnaires and discussion groups to elicit their opinions. Many said that it was the first time that they had an opportunity to discuss ethical and social issues about sequencing. The many ongoing multi-national science projects present a good opportunity for social science research involving scientists and would benefit from rigorous research methodology, taking into account any language barriers.

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.

Resume La loi de bioethique, votee pour la premiere fois en France en 1994 et revisee en 2004, est a nouveau en revision. La preparation de cette revision a suscite de nombreux debats, dans les spheres professionnelles, institutionnelles et sociales. Le gouvernement a aussi pour la premiere fois sur ce sujet organise un debat auquel a participe un panel de citoyens formes par un comite d’experts : les Etats generaux de la bioethique (EGB). Nous avons analyse les contributions de six instances publiques – l’Office parlementaire d’evaluation des choix scientifiques et technologiques (OPECST), le Comite consultatif national d’ethique pour les sciences de la vie et de la sante (CCNE), le Conseil d’Etat (CE), l’Agence de la biomedecine, le Senat et la Mission parlementaire d’information sur la revision des lois de bioethique (MPI) – au debat sur la revision, ainsi que le rapport final des EGB. Dans cet article, nous presentons et comparons leurs propositions sur trois themes : assistance medicale a la procreation (AMP), gestation pour autrui (GPA) et transplantation. Si les avis des instances sont parfois consensuels – excepte le Senat, tous semblent etre en faveur du maintien de l’interdiction de la gestation pour autrui – ils different parfois fortement – comment faut-il ouvrir l’acces a l’AMP, selon quelles modalites est-il possible d’ouvrir l’acces a certaines categories de donnees concernant des donneurs de gametes, comment definir les criteres de la mort dans le cas difficile d’un arret cardiaque avec possibilite de don d’organes a cœur arrete, faut-il amenager le regime de consentement presume au don d’organes post mortem -. Les parlementaires doivent debattre de la revision de la loi au premier semestre 2010, et auront alors la difficile tâche de trancher dans des domaines porteurs de nombreuses interrogations aussi bien medicales et scientifiques, que sociales, philosophiques et morales.

HLA class II alleles were identified in 181 healthy unrelated Ethiopian children of both sexes and in 350 European controls from the South of France. The Ethiopian individuals belonged to the two major ethnic groups of the country: Oromo (N=83) and Amhara (N=98). In both panels, genetic polymorphism of HLA class II alleles was analysed for the first time by molecular typing of DRB1, DQA1 and DQB1 loci. Allelic and phenotypic frequencies were compared with those of European controls and other African populations. Construction of HLA class II three-locus haplo-types was also performed. The study revealed some differences between the two groups. Characteristic features of Central and North African populations appeared on the Ethiopian HLA genotypes. Surprisingly, DRB1*11 presented one of the lowest gene frequencies in both Ethiopian ethnic groups in contrast to Europeans and West Africans. Furthermore, this decrease was more marked than those observed using serological techniques in other geographically close East African countries. Oromo and Amhara only showed minor differences in spite of their different origins and histories. One significant difference consisted of a lower DRB1*01 gene frequency in Oromo as reported in most West African people. Some new or rare haplotypes were also observed in the Oromo group. Our results underline the distinctive features of the Ethiopian populations among the few HLA genotyping data available for East African groups and emphasise the major interest of such investigations in this region of Africa.

Resume Introduction Les aspects medicoeconomiques de la polyarthrite rhumatoide (PR) ont ete largement modifies depuis l’utilisation des agents inhibiteurs du TNFα. Le but de notre etude a ete d’estimer l’influence de la prescription d’etanercept, en terme de consommation de soins, au sein d’une cohorte regionale de patients atteints de PR en France. Methodes Nous avons etudie 148 patients atteints de PR, pour lesquels le suivi moyen a ete de 343 jours avant et apres l’initiation d’un traitement anti-TNF. Les donnees ont ete recueillies de maniere anonyme a partir de la base de donnees ERASME de la caisse regionale d’assurance maladie Midi-Pyrenees. Nous avons effectue une analyse microeconomique des couts financiers, patient par patient. Resultats Le cout annuel moyen par patient, imputable a la PR, a ete multiplie par un facteur de 2,8 apres l’initiation du traitement par etanercept par rapport a la periode anterieure (15 148,57 versus 5248,95 euros). Le pourcentage du cout des produits pharmaceutiques est passe de 11,7 % des couts medicaux directs avant etanercept a 69,7 % apres etanercept (120,12 versus 9995,23 euros). Le cout de certains autres traitements a legerement diminue : anti-inflammatoires non steroidiens (142,14 versus 102,21 euros), kinesitherapie (286,40 versus 138,77 euros). Le cout des actes medicaux et les couts indirects imputables n’ont pas ete differents avant et apres l’initiation de l’etanercept. Conclusion Dans cette etude effectuee sur une courte periode, la mise en route d’un traitement par etanercept n’a pas entraine de baisse de la consommation des soins donnes aux patients. Des etudes a plus long terme apparaissent necessaires pour determiner un eventuel avantage medicoeconomique lie a l’efficacite clinique, structurale et fonctionnelle d’un traitement anti-TNF.

Introduction Economical impact of rheumatoid arthritis (RA) has been widely modified thanks to TNF inhibitors. Our study aims to estimate the impact etanercept prescription, in term of health resources consumption, within a regional cohort of French RA patients. Methods The study included 148 RA patients, with a mean follow-up duration of 343 days before and after etanercept initiation. Data were anonymously collected from ERASME database of French Health Insurance in Midi-Pyrenees region. A patient-by-patient microcosting approach was performed. Results The average annual cost per patient, attributable to RA, was 2.8 times higher after treatment by etanercept than before (15,148.57€ versus 5248.95€). We observed a rise in pharmaceutical costs, from 11.7% of direct medical costs before to 69.7% after etanercept initiation (120.12€ versus 9995.23€). We observed a small decrease particularly for NSAIDs (142.14€ versus 102.21€) and physiotherapy (286.40€ versus 138.77€). Attributable act costs and indirect costs did not differ before and after etanercept initiation. Discussion In this short-term study, initiation of etanercept in RA patients did not come along with a decrease of consumption of health resources. Long-term studies are needed to reveal a potential economical advantage as a consequence of the clinical, structural and functional efficacy of anti-TNF.

Background Availability of a healthy, human-leukocyte-antigen-matched hematopoietic stem cell source is a prerequisite for successful allogenic hematopoietic stem cell transplantation. In 70% of cases, the search of hematopoietic stem cells shifts from siblings to unrelated donor registries. Given that the Human Leucocytes Antigens (HLA) system is highly polymorphic and that the cost of HLA typing remains high, the adequacy between registry content and patient needs must be assessed. Registries should be optimally organized to increase the probability for any given patient to find a donor. Methods A welfare function associated with the existence of an HLA registry was defined as was a measure of the advantage for laboratories having performed HLA typing. We hypothesized a way to formalize registry efficiency and applied it to the French Hematopoietic Stem Cell donors Registry. Results The model determined an implicit value for the stem cell graft and showed that efficiency increased very slowly with increasing number of potential donors in registries. The optimal size of a registry was found to be sensitive to model parameters. Conclusion Increased registry size, in terms of number of donors foreseeable in the French registry, would have a limited impact on registry efficiency and thus social effectiveness. Nevertheless, the calibration of the model justifies the goal of recruiting 100 000 new volunteer donors over the next 10 years as proposed by the French government in the “Graft Plan”. The policy of the regulatory agency should be oriented towards improving the probability a compatible potential donor identified during a preliminary search would become an actual fully compatible donor and towards reducing the cost of typing.

We have previously mapped a separate type 1 diabetes (T1D) association in the extended MHC class I region, marked by D6S2223, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype. The associated region encompasses a gene encoding a thymus-specific serine protease (PRSS16), presumably involved in positive selection of T cells or in T-cell regulation. Fourteen PRSS16 polymorphisms were genotyped in two steps using a total of six T1D family data sets, as well as case-control materials for both T1D and celiac disease (CD). An association with a 15 base-pair deletion in exon 12 of PRSS16 was found on the DRB1*03-DQA1*0501-DQB1*0201 haplotype for both T1D and CD, but it could not explain the more pronounced disease associations observed at marker D6S2223. We compared the performance of the 14 tested PRSS16 polymorphisms, selected after our previous comprehensive screen, against HapMap selected tag SNPs. Use of a HapMap based SNP selection strategy would result in loss of a large proportion of the genetic variation in PRSS16. Our data suggest that it is unlikely that polymorphisms within the PRSS16 gene are involved in the predisposition to T1D. However, we cannot rule out that regulatory polymorphisms located some distance away from the gene may be involved.

The analysis of Killer cell immunoglobulin-like receptors (KIRs) in terms of haplotypes have only been done through genotyping numerous and selected families. Consequently and schematically, KIR haplotypes have been roughly described by two groups (A and B) based on their gene contents. No further KIR adapted methods have been applied to the estimation of haplotype frequencies using unrelated data. We propose here a maximum likelihood (ML) estimation of KIR haplotype frequencies. ML estimation was developed as an extension of those successfully applied to human leukocyte antigen (HLA) data including the handling of missing values and HLA nomenclature. It has been implemented using an adapted Expectation Masimisation algorithm. KIR types on 11 loci in more than 40 Irish families were used to validate the method in a simulation study. Estimated haplotype frequencies are compared to the phase known. Various allele or gene frequency estimation methods were also compared. We demonstrated the interest and reliability of the haplotype method and underline the effect of the sample size on the quality of the estimation. The ML haplotype method also provides by collapsing more accurate estimation of allele or gene frequencies in population. Such an algorithm opens new perspectives in the analysis of KIR genotypes. Large sample size studies are required using phase-known data and/or simulations. It would allow a genotype-based approach to explore the KIR gene haplotype diversity. The haplotype frequencies may be used to compare populations.

Resume Le traitement de la polyarthrite rhumatoide (PR) a ete profondement modifie avec l’apparition en 1999 des anti- TNFα. Peut-on faire l’hypothese que le cout de ces traitements innovants, dont la superiorite clinique par rapport aux traitements traditionnels est prouvee, est partiellement compense par une diminution de la consommation des autres ressources de sante ? Une etude observationnelle retrospective a ete realisee dans la region Midi-Pyrenees, du point de vue de l’Assurance Maladie pour comparer les ressources consommees entre deux cohortes de patients, l’une traitee par etanercept (Enbrel®) et l’autre par leflunomide (Arava®). Ont ete inclus 253 patients dans la cohorte etanercept et 539 dans la cohorte leflunomide. Le cout moyen annuel attribuable a la PR d’un patient traite par etanercept est de 13 936 € contre 5 764 € pour un patient traite par leflunomide. Les couts evites par le recours a l’etanercept ne permettent pas de compenser le cout eleve de la specialite pharmaceutique.

In the framework of the 2007 call to support the preparatory phase of the European biobank infrastructures, the European Commission funded a specific project aiming to prepare a pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) for biomedical and biological research in Europe and worldwide (Yuille et al. in Brief Bioinform 9:14–24, 2008). This infrastructure, which was to be built on new and existing national networks, resources and technologies, would be specifically complemented by innovative components and would be properly embedded into European ethical, legal and societal frameworks.

Within the major histocompatibility complex (MHC), the human leucocyte antigen (HLA)-DRB1 locus is clearly associated with rheumatoid arthritis (RA). Using a microsatellite (MSat) typing approach, we aimed to identify other loci associated with RA susceptibility and/or severity within the MHC. A panel of nine MSat HLA loci [D6S291, D6S2876 (G51152), D6S1666 (DQCAR II), D6S273, D6S2789 (TNFd), D6S2810 (MIB), D6S265, D6S2222, D6S2239], and HLA-A, -B and -DRB1 genes were typed in 170 RA cases and 282 controls. For susceptibility analysis, MSat and HLA allele distribution were compared between cases and controls, before and after stratification on HLA-DRB1*04. Haplotype frequencies were estimated using an expectation-maximization algorithm in a permutation test procedure. For severity analysis, we compared the distribution of structural damage score at onset and after 4 years of follow-up in RA cases carrying susceptibility alleles. Two MSat polymorphisms were positively associated with RA susceptibility: allele* 136 of D6S265 [odds ratio, OR (confidence interval, CI) = 1.55 (1.11-2.17), P = 0.007], allele*116 of D6S2239 [OR = 1.34 (1-1.79), P = 0.03] and HLA-A2 [OR = 1.46 (1.08-1.98), P = 0.01]. Two MSat polymorphisms were negatively associated with RA susceptibility: allele*133 of D6S273 [OR = 0.3 (0.1-0.75), P = 0.005] and allele*177 of D6S291 [OR = 0.72 (0.53-0.96), P = 0.02]. The association between allele* 136 of D6S265 and RA susceptibility remained unchanged after stratification on HLA-DRB1*04. The haplotypic analysis showed an overrepresentation of D6S265*136/HLA-A*02 haplotype, which suggests an effect independent of HLA-DRB1 locus in RA susceptibility. While HLA-A2 and HLA-DR4 were associated with RA severity, no MSat polymorphism was associated with structural damage score.

Major histocompatibility complex (MHC) region Microsatellites (Msat) have been extensively used in various applications, such as disease mapping, forensics, and population genetics. A comprehensive review of HLA Msat primers has been previously published based on literature and sequence analysis, but electronic tools are lacking to make it easily accessible and actually used by the community. We have integrated data from this review, with an overlapping set of 31 Msat markers used in the 13th International Histocompatibility and Immunogenetics Workshop (IHIWS) to create a public archive that will synchronize published descriptions to a common framework. http://www.ncbi.nlm.nih.gov/projects/mhc. Currently, the dbMHC contains 389 primer pairs across the extended MHC targeting 281 distinct repeat regions (approximately 1/45 kb). Literature review and analysis of the primers reveal that over 200 synonymous names have been published for these markers. Users may view or download specific Msat data sets using the portal. Query options include name or partial name, primer sequence, neighboring genes, and/or position. Query results include locus name(s), a graphic showing of the relative location of the marker in relation to the classical HLA genes, a listing of the constituent primer pairs and name, a link to UniSTS, aliases, allele range (bp), overlapping single nucleotide polymorphisms, a link to e-polymerase chain reaction, and physical mapping information. To increase the utility of this resource, researchers using Msat markers in the HLA region are encouraged by the authors to submit new primers to the dbMHC. The minimal Msat submission consists of primers sequences, a submitter's name and contact information. Additional information recommended but not required is the laboratory protocol(s), known allele size range (bp), known aliases, and an exemplar sequence. Assigned UniSTS numbers can be used for primer pair standard identification.

Complex polygenic and multifactorial diseases remain a challenge for human geneticists. Here we aim to remind basic definitions of multifactorial diseases and the genetic related concepts underlying classical methods. Knowledge on pathophysiological process and the genetic information available conditions the design of study. The choice of methodology, between candidate gene approach and genome scan approach, between linkage and association studies, is the most important step. Both methods, linkage analysis and association studies are usually considered as complementary approaches for a given disease. For this reason, in this article, we present the most important classical methodologies in genetic epidemiology of complex disorders. References and examples are given to illustrate.

Human leukocyte antigen (HLA) matching remains a key issue in the outcome of transplantation. In hematopoietic stem cell transplantation with unrelated donors, the matching for compatible donors is based on the HLA phenotype information. In familial transplantation, the matching is achieved at the haplotype level because donor and recipient share the block-transmitted major histocompatibility complex region. We present a statistical method based on the HLA haplotype inference to refine the HLA information available in an unrelated situation. We implement a systematic statistical inference of the haplotype combinations at the individual level. It computes the most likely haplotype pair given the phenotype and its probability. The method is validated on 301 phase-known phenotypes from CEPH families (Centre d'Etude du Polymorphisme Humain). The method is further applied to 85,933 HLA-A B DR typed unrelated donors from the French Registry of hematopoietic stem cells donors (France Greffe de Moelle). The average value of prediction probability is 0.761 (SD 0.199) ranging from 0.26 to 1. Correlations between phenotype characteristics and predictions are also given. Homozygosity (OR = 2.08; [2.02-2.14] p

Reviews of microsatellite markers in the human leukocyte antigen region have been very useful in addressing the needs of the immunogenetics community. Nevertheless, characterization of the same microsatellite loci in different laboratories can lead to seemingly contradictory results, particularly in terms of nomenclature. Here we provide an update of previous reports, as well as a standardized characterization of primers for microsatellites located within the major histocompatibility complex (MHC). A uniform and extended inventory of 378 primer pairs from published reports was performed as well as a standardized characterization of the corresponding microsatellite loci according to the extended full-length consensus sequence of MHC region. The literature-based approach was complemented by a sequence-based analysis of each reported microsatellite locus. Iterative electronic polymerase chain reaction runs and an original algorithm that characterizes patterns of repeats within sequence were used. The sequence of primers was corrected according to the consensus sequence. Table of synonymous names for individual microsatellite loci is provided.

Haplotype frequency estimation in population data is an important problem in genetics and different methods including expectation maximisation (EM) methods have been proposed. The statistical properties of EM methods have been extensively assessed for data sets with no missing values. When numerous markers and/or individuals are tested, however, it is likely that some genotypes will be missing. Thus, it is of interest to investigate the behaviour of the method in the presence of incomplete genotype observations. We propose an extension of the EM method to handle missing genotypes, and we compare it with commonly used methods (such as ignoring individuals with incomplete genotype information or treating a missing allele as any other allele). Simulations were performed, starting from data sets of haematopoietic stem cell donors genotyped at three HLA loci. We deleted some data to create incomplete genotype observations in various proportions. We then compared the haplotype frequencies obtained on these incomplete data sets using the different methods to those obtained on the complete data. We found that the method proposed here provides better estimations, both qualitatively and quantitatively, but increases the computation time required. We discuss the influence of missing values on the algorithm's efficiency and the advantages and disadvantages of deleting incomplete genotypes. We propose guidelines for missing data handling in routine analysis.

Objective The gene encoding tumor necrosis factor receptor type II (TNFRII) is a strong candidate in the pathogenesis of rheumatoid arthritis (RA). An association between a single-nucleotide polymorphism (196M/R) in exon 6 of the TNFRII gene and familial RA was recently reported. The present study was undertaken to test the hypothesis that there is an association between this polymorphism and the severity of RA. Methods One hundred two white patients with early RA were included in this prospective study. The French version of the Health Assessment Questionnaire (F-HAQ) and a radiographic damage score (modified Sharp/van der Heijde method) were used to quantify the functional and structural severity of RA at baseline and after 4 years of followup. TNFRII 196M/R polymorphism genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism analysis. Results Among the 102 patients with RA, 63 (61.8%) were homozygous for the 196M allele, 36 (35.3%) were heterozygous for alleles 196M and 196R, and 3 (2.9%) were homozygous for the 196R allele. At baseline, the median radiographic and F-HAQ scores did not differ between RA patients who carried the 196R allele and those who did not. After 4 years of followup, the F-HAQ score was higher in RA patients carrying the 196R allele (median 1 [interquartile range (IQR) 0.125, 1.375]) than in noncarriers (0.375 [IQR 0, 1]) (P = 0.02), while the median radiographic score did not differ between RA patients who carried the 196R allele and those who did not. Conclusion The results of the present study support the hypothesis that there is an association between the TNFRII 196 M/R gene polymorphism and the functional severity of early RA.