Chapitre 8. Annoncer ou pas la découverte d'anomalies non sollicitées lors d'un test génétique à séquençage haut débit ?

OBJECTIVE: New genome sequencing techniques allow new approaches in medical genetics, in particular by facilitating the diagnosis of genetic diseases. However, their use also leads to unsolicited genetic findings being uncovered. This type of discovery raises ethical, legal and psychological considerations. The objective of this psychological research was to study the different positions of patients, health professionals and general public regarding the acceptability of the announcement of unsolicited findings revealed during a high-throughput sequencing genetic test. METHOD: the first exploratory study aimed, through non-directive research interviews conducted with 13 patients of a medical genetics service, to understand the psychological repercussions linked to the announcement of a result of a targeted genetic test and to know the patients’ desires regarding the announcement of unsolicited findings if the test had been a high-throughput genetic test. The second study, using a quantitative methodology, aimed to identify the judgment policies of 144 patients, 94 healthcare professionals and 211 people from the general public concerning the acceptability of this type of disclosure. RESULTS: The cluster analyses highlighted six judgment policies as to whether or not to disclose the discovery of unsolicited anomalies: “Tell everything”, “Tell even in part”, “Tell everything unless desperate”, “Undecided”, “Do not tell” and “Do not tell if no prevention”. The participants positioned themselves differently, in particular according to the patient’s consent. CONCLUSION: This research shows the variability of positioning and the importance of consent in the acceptability of the disclosure of unsolicited findings. However, one of the limitations of the study lies in the fact that in medical clinic, acceptability and acceptance may vary over time. A longitudinal study would undoubtedly afford a better understanding of the psychological progress of patients in this type of care pathway..

A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study.

BACKGROUND: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. METHODS: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. FINDINGS: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001). INTERPRETATION: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. FUNDING: European Union Horizon 2020.

Application of Genomic Sequencing to Refine Patient Stratification for Adjuvant Therapy in Renal Cell Carcinoma.

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.

Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib.

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 CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

Selection of data sets for FAIRification in drug discovery and development: Which, why, and how?

Despite the intuitive value of adopting the Findable, Accessible, Interoperable, and Reusable (FAIR) principles in both academic and industrial sectors, challenges exist in resourcing, balancing long- versus short-term priorities, and achieving technical implementation. This situation is exacerbated by the unclear mechanisms by which costs and benefits can be assessed when decisions on FAIR are made. Scientific and research and development (R&D) leadership need reliable evidence of the potential benefits and information on effective implementation mechanisms and remediating strategies. In this article, we describe procedures for cost-benefit evaluation, and identify best-practice approaches to support the decision-making process involved in FAIR implementation.

International transfers of personal data for health research following Schrems II: a problem in need of a solution.

On 16 July 2020, the Court of Justice of the European Union issued their decision in the Schrems II case concerning Facebook's transfers of personal data from the EU to the US. The decision may have significant effects on the legitimate transfer of personal data for health research purposes from the EU. This article aims: (i) to outline the consequences of the Schrems II decision for the sharing of personal data for health research between the EU and third countries, particularly in the context of the COVID-19 pandemic; and, (ii) to consider certain options available to address the consequences of the decision and to facilitate international data exchange for health research moving forward.

Attitudes of French populations towards the disclosure of unsolicited findings in medical genetics.

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.

Fostering global data sharing: highlighting the recommendations of the Research Data Alliance COVID-19 working group.

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.

Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations.

In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients' representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the "actionability" of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.

Is it research or is it clinical? Revisiting an old frontier through the lens of next-generation sequencing technologies.

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.

Including all voices in international data-sharing governance.

BACKGROUND: Governments, funding bodies, institutions, and publishers have developed a number of strategies to encourage researchers to facilitate access to datasets. The rationale behind this approach is that this will bring a number of benefits and enable advances in healthcare and medicine by allowing the maximum returns from the investment in research, as well as reducing waste and promoting transparency. As this approach gains momentum, these data-sharing practices have implications for many kinds of research as they become standard practice across the world. MAIN TEXT: The governance frameworks that have been developed to support biomedical research are not well equipped to deal with the complexities of international data sharing. This system is nationally based and is dependent upon expert committees for oversight and compliance, which has often led to piece-meal decision-making. This system tends to perpetuate inequalities by obscuring the contributions and the important role of different data providers along the data stream, whether they be low- or middle-income country researchers, patients, research participants, groups, or communities. As research and data-sharing activities are largely publicly funded, there is a strong moral argument for including the people who provide the data in decision-making and to develop governance systems for their continued participation. CONCLUSIONS: We recommend that governance of science becomes more transparent, representative, and responsive to the voices of many constituencies by conducting public consultations about data-sharing addressing issues of access and use; including all data providers in decision-making about the use and sharing of data along the whole of the data stream; and using digital technologies to encourage accessibility, transparency, and accountability. We anticipate that this approach could enhance the legitimacy of the research process, generate insights that may otherwise be overlooked or ignored, and help to bring valuable perspectives into the decision-making around international data sharing.

How to responsibly acknowledge research work in the era of big data and biobanks: ethical aspects of the Bioresource Research Impact Factor (BRIF).

Currently, a great deal of biomedical research in fields such as epidemiology, clinical trials and genetics is reliant on vast amounts of biological and phenotypic information collected and assembled in biobanks. While many resources are being invested to ensure that comprehensive and well-organised biobanks are able to provide increased access to, and sharing of biomedical samples and information, many barriers and challenges remain to such responsible and extensive sharing. Germane to the discussion herein is the barrier to collecting and sharing bioresources related to the lack of proper recognition of researchers and clinicians who developed the bioresource. Indeed, the efforts and resources invested to set up and sustain a bioresource can be enormous and such work should be easily traced and properly recognised. However, there is currently no such system that systematically and accurately traces and attributes recognition to those doing this work or the bioresource institution itself. As a beginning of a solution to the "recognition problem", the Bioresource Research Impact Factor/Framework (BRIF) initiative was proposed almost a decade and a half ago and is currently under further development. With the ultimate aim of increasing awareness and understanding of the BRIF, in this article, we contribute the following: (1) a review of the objectives and functions of the BRIF including the description of two tools that will help in the deployment of the BRIF, the CoBRA (Citation of BioResources in journal Articles) guideline, and the Open Journal of Bioresources (OJB); (2) the results of a small empirical study on stakeholder awareness of the BRIF and (3) a brief analysis of the ethical dimensions of the BRIF which allow it to be a positive contribution to responsible biobanking.

Critical points for an accurate human genome analysis.

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 whole-genome sequencing (WES/WGS) analyses. With further advances in sequencing technology and concomitant price reductions, 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.

Description of the EuroTARGET cohort: A European collaborative project on TArgeted therapy in renal cell cancer-GEnetic- and tumor-related biomarkers for response and toxicity.

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.

Mechanisms of the Development of Allergy (MeDALL): Introducing novel concepts in allergy phenotypes.

Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non-IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including in vivo and in vitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20 years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. A microarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), and transcriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4 years and 11,080 children aged 8 years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases.

Biobankers: Treat the Poison of Invisibility with CoBRA, a Systematic Way of Citing Bioresources in Journal Articles.

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.

Judging health risk as a function of risk factors and type of illness: Do people weight risk factors in a flexible way?

We examined the extent to which lay people and health professionals are able to assess occurrence risks for multifactorial diseases. We asked 341 participants to assess the risk of developing lung cancer, coronary artery disease or rheumatoid arthritis in 16 scenarios, each featuring a combination of four factors (family history, daily alcohol intake, daily tobacco consumption and genetic test results). Participants considered all factors. However, they accorded more weight to tobacco and genetic test results. Moreover, it appears that where one of the factors (e.g. the presence of the incriminated gene) exerted a strong influence, the influence of the other factor(s) was correspondingly weaker. The health risk judgements of health professionals were more dependent on the specific disease and were also influenced to a greater degree by genetic information than lay people.

A new classification of HLA-DRB1 alleles based on acid-base properties of the amino acids located at positions 13, 70 and 71: impact on ACPA status or structural progression, and meta-analysis on 1235 patients with rheumatoid from two cohorts (ESPOIR and EAC cohort).

OBJECTIVE: 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). METHODS: 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 χ(2) test; a meta-analysis was performed on the 2 cohorts using the Mantel-Haenszel method. RESULTS: 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)). CONCLUSIONS: 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.

Genetic markers as a predictive tool based on statistics in medical practice: ethical considerations through the analysis of the use of HLA-B(*)27 in rheumatology in France.

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.