E-prescription and invisible work in genomics in France.

This article aims to analyze the transformations in medical prescription work and infrastructures brought by digitalization. Our fieldwork takes place in the context of precision medicine development based on genomics High Throughput Sequencing (HTS) in France, through the Plan France Médecine Génomique (PFMG 2025). The Plan aims at industrializing the production of genomic testing in clinical context at a national scale, particularly in oncology. To ensure the intensified flow of information between hospitals and HTS platforms required, a centralized process has been organized around two sequencing platforms and the introduction of a new e-prescription software (E-PRES). We start by analyzing how the e-prescription software changes the practices of health professionals by imposing new technological and professional standards. We show that, more than a mere prescription tool, this software is also a monitoring tool for the platforms and prescribers' work, and a support tool for the logistical and work organization. Secondly, we question the division of labor among the different professionals involved in the organizational or technical tasks required. We show that the feasibility of this new form of digitalized prescription relies on an important datawork performed by "small hands" to select, translate and process a vast amount of heterogeneous data.

Genomic susceptibility in practice: The regulatory trajectory of non-rare thrombophilia (NRT) genetic tests in the clinical management of venous thrombo-embolism (VTE).

The use of individual genomic risk factors to predict the onset of common diseases is one of the main promises of personalized medicine. This paper aims to contribute to the understanding of how genetic susceptibility shapes clinical practice, by drawing on non-rare thrombophilia (NRT) tests, a common diagnostic technique for congenital predisposition to venous thromboembolism (VTE). Adopting a diachronic approach, we describe the trajectory of NRT usage and its professional regulation since the discovery of NRT variants in the mid-90s. Empirical materials combine biomedical literature, guidelines and recommendations, and interviews with key actors. We show a rapid adoption of these tests by clinicians, followed by a controversy over their clinical utility after epidemiological evaluations of NRT test demonstrated a low capacity to predict VTE in individual carriers. Indeed, alternative views on what should count as clinical utility led to heterogeneous professional regulations. Some clinicians favoured statistical and individualized predictions of risk and proposed a cessation of test prescription in the management of VTE. Others praised the context-specific clinical values of the tests that integrated their connection with aetiology and implications for prevention in healthy relatives, and therefore adopted less stringent regulatory principles. We identify three features of these genetic susceptibility tests that are central in this regulatory trajectory: two epistemological interpretations of the tests - as a molecular determinant of disease and as a multifactorial risk factor for VTE - that are alternatively aligned or opposed to each other; the connections established between different clinical contexts through test use and the correlated possibility of proposing preventive actions "for relatives; the centrality of the tests" in various clinical contexts regarding decisions about pharmacological treatment.

Appraising screening, making risk in/visible. The medical debate over Non-Rare Thrombophilia (NRT) testing before prescribing the pill.

Non-rare thrombophilia (NRT) are hereditary predispositions to thromboembolism, the most severe side effect of combined hormonal contraception. In the mid-1990s, the identification of NRT stirred up a controversy over the possibility of investigating these genetic variants in women wishing to use contraception. Through a review of literature, this article reconstructs the debate over whether and how this genetic test should be prescribed as a way to reconfigure the risk visibility on pharmacological contraception. The main arguments identified concern the epidemiological, social, economic and clinical aspects of the test. In a context where the overall thrombotic risk for hormonal contraception is largely invisible, the genetic tests turn to embody the thrombotic risk itself. Those who opt for selective screening argue that a better estimation of risk implies a test prescription embed in a global medical assessment of women's individual risk. To advocates of universal or 'extended' screening, the tests are valuable tools to inform women on the thrombotic risk and, as such, appraised as a moral/legal obligation, whatever their predictive power. Risk visibility thus appears as an insightful concept to analyse a complex setting associating clinical, political, social and cultural considerations that touches upon medical power, women's responsibility and drug safety.

[Susceptibility genetics of common conditions in clinical practice]. / Des tests génétiques pour prédire des maladies communes.

The genetic tests for "non-rare thrombophilias" (TNR) were introduced into clinical setting immediately after the identification of genetic variants in the mid-90s to predict and prevent venous thromboembolism (VTE). Although being a rare example of a genetic test of susceptibility for complex diseases that has been integrated in medical routine, it is the most widespread post-natal genetics inquiry in France nowadays. Yet, determining whom to test and how to use the results is still controversial. This article outlines the trajectory of its clinical regulation and illustrates the importance of the context of use to understand its diffusion. This analysis is intended to feed a more general reflection on the issues raised by the clinical integration of genetic surveys for common diseases, particularly with regard to the clinical utility of a test (statistical vs. biological), the subjects to be tested (the case index and/or her/his relatives), and the criteria underlying access to these tests (modalities of medico-economic assessment).

TITLE: Des tests génétiques pour prédire des maladies communes. ABSTRACT: Introduit au lendemain de l'identification des « thrombophilies non rares ¼ (TNR), au milieu des années 1990 afin de prédire et de prévenir la maladie thromboembolique veineuse (MTEV), le bilan génétique pour ces thrombophilies est un exemple assez rare de test génétique de susceptibilité pour une maladie complexe, à avoir franchi le pas d'un véritable usage de routine en clinique. Bien que ce test soit le plus répandu des tests de génétique post-natale en France, son usage (À qui proposer le test ? Que faire des résultats ?) fait encore l'objet de débats. Cet article analyse la trajectoire de régulation clinique de ce test et illustre l'importance du contexte spécifique d'usage pour comprendre sa diffusion. Cette analyse vise à nourrir une réflexion plus générale sur les enjeux que pose l'intégration clinique des tests génétiques pour les maladies communes, en considérant notamment les modalités de définition de l'utilité clinique d'un test (statistique versus biologique), des sujets du test (le cas index versus ses apparentés), et des critères en sous-tendant l'accès (modalités des calculs médico-économiques).

Geneva Statement on Heritable Human Genome Editing: The Need for Course Correction.

As public interest advocates, policy experts, bioethicists, and scientists, we call for a course correction in public discussions about heritable human genome editing. Clarifying misrepresentations, centering societal consequences and concerns, and fostering public empowerment will support robust, global public engagement and meaningful deliberation about altering the genes of future generations.

Imperfect biomarkers for adjuvant chemotherapy in early stage breast cancer with good prognosis.

The proliferation of biomarkers has raised concerns regarding the possibility for clinical judgment to be improperly removed from clinician's jurisdiction and included in laboratory tests. To evaluate the ways in which the diffusion of biomarkers questions the autonomy of clinicians, we consider the case of chemotherapy prescription to women with early stage breast cancer and a good prognosis. Drawing on a qualitative study of clinicians working in a diversity of institutional contexts, we follow three biomarkers available to guide this routinely made decision. We show that, biomarkers able to reduce all the uncertainties associated with, what we analyse as an uncomfortable decision, are sought more than dreaded by clinicians. If such ideal tools are unavailable, the fact is well acknowledged by the profession. Rather than precluding their usage, the imperfection of existing biomarkers is controlled by the profession, through their integration as additional tools in the decision process. The fact that the biomarkers are recognized as imperfect biomedical entities reinforces the importance of local material, organizational and financial constraints over that of international science, technology and clinical data, in their diffusion. The regulation of the uncertainties associated with these imperfections is organized at the professional level. Through an important work, relying on guidelines and enforced in collective bodies, the series of heterogeneous bioclinical evidences available are articulated. Biomarkers tend to be subordinated to the clinic. While maintaining the professional autonomy, the process also strengthens the internal professional hierarchy. When the most expert clinicians manage to inhabit a space for clinical autonomy, the nonexpert are torn between stronger professional rules and patient preferences. In this alliance between biomarkers and experts, their clinical autonomy tends to be the price for the professional autonomy.

'It has to become true genetics': tumour genetics and the division of diagnostic labour in the clinic.

Tumour genetics is currently turning into a massive clinical approach. This paper is an enquiry into its practices as they expand beyond expert and experimental contexts and become routinised in clinical hospital settings. Studying a French university hospital, we unpack the content and everyday organization of diagnostic labour in this context. Exploring the sociotechnical frictions that arise in the process, we describe the ways in which they are collectively controlled, and stabilized through organizational fictions, that are instrumental in making tumour genetics doable in the hospital, at a large scale. We further show that the new role of external regulations in the production of clinical values for mutations has a strong impact on diagnostic work, making it possible to be performed locally without resorting to expert bioclinical collectives, and outside the professional jurisdiction of clinical geneticists. This division of labour appears as a necessary condition for the rise in clinical productivity required by a new function assigned to genetics: to guide the prescription of drugs for common diseases. This turn in the way genetics is embedded in the clinic calls for a thorough reassessment of its impacts on clinical discourses, practices and decisions.

[Genomics from bench to bedside: a change in perspective]. / Génomique, de la recherche à la clinique - questions autour d'un changement de perspective.

While genomics is sometimes presented as an area of ​​research where results can be rapidly translated into clinical practice, the facts are more ambiguous. To illustrate some of the pitfalls of translation, this article focuses on the applications of genome-wide association studies (GWAS) results. Following a brief scientific contextualization of GWAS, two emblematic examples are presented as illustrations. The case of Crohn's disease emphasizes the limits of GWAS results for individual risk prediction. The case of warfarin highlights the difficulties of demonstrating the clinical utility of genetic data in treatment decisions. The article outlines the simplification of disease causation that underlies the GWAS methodology. Whereas this reductionist approach is fruitful for exploratory research purposes, it shows its limits when applied to clinical conditions.

Quantitative damage-benefit evaluation of drug effects: major discrepancies between the general population, users and experts.

AIMS: This study sought to quantify the perceptions of damage and benefit, for users and society, associated with five addictive substances (alcohol, tobacco, cannabis, cocaine and heroin) and one addictive behavior (gambling), in a large sample representative of the French population. We compared with expert assessments and investigated the effects of substance consumption on these perceptions. FINDINGS: The ranking of substances by the lay public is very divergent from that of experts. The public overestimates damage to users and to society and underestimates the benefit, in comparison with experts, for all substances. Alcohol is the only exception, with damage and benefit perceptions similar to those of experts. Heroin and cocaine are perceived as the two most dangerous substances. The damage of cannabis and alcohol are judged to be equivalent. The three legal substances are associated with the highest overall benefit, although cannabis has the highest perceived benefit for users. Substances with the highest perceived benefit tend to be associated with perception of lower levels of damage. Individuals with an history of substance use have a perception of the damage and the benefit for that substance which is more congruent with experts, including a similar ranking of substances. CONCLUSIONS: Prevention campaigns focused on perceptions of damage alone have reached their limits. The perception of benefit should be taken into account in early interventions with illegal substance users.

Genetic and environmental factors influencing the Placental Growth Factor (PGF) variation in two populations.

Placental Growth Factor (PGF) is a key molecule in angiogenesis. Several studies have revealed an important role of PGF primarily in pathological conditions (e.g.: ischaemia, tumour formation, cardiovascular diseases and inflammatory processes) suggesting its use as a potential therapeutic agent. However, to date, no information is available regarding the genetics of PGF variability. Furthermore, even though the effect of environmental factors (e.g.: cigarette smoking) on angiogenesis has been explored, no data on the influence of these factors on PGF levels have been reported so far. Here we have first investigated PGF variability in two cohorts focusing on non-genetic risk factors: a study sample from two isolated villages in the Cilento region, South Italy (N=871) and a replication sample from the general Danish population (N=1,812). A significant difference in PGF mean levels was found between the two cohorts. However, in both samples, we observed a strong correlation of PGF levels with ageing and sex, men displaying PGF levels significantly higher than women. Interestingly, smoking was also found to influence the trait in the two populations, although differently. We have then focused on genetic risk factors. The association between five single nucleotide polymorphisms (SNPs) located in the PGF gene and the plasma levels of the protein was investigated. Two polymorphisms (rs11850328 and rs2268614) were associated with the PGF plasma levels in the Cilento sample and these associations were strongly replicated in the Danish sample. These results, for the first time, support the hypothesis of the presence of genetic and environmental factors influencing PGF plasma variability.

Association between a polymorphism in the promoter of a glutamate receptor subunit gene (GRIN2A) and alcoholism.

A variable (GT)(n) repeat in the 5'-regulatory region of N-methyl-D-aspartate GRIN2A subtype has recently been identified and associated with psychiatric disorders. In this study, we examined the association of this polymorphism with alcohol dependence. Subject-control analysis included 206 alcohol-dependent and 168 control subjects. Average observed repeat numbers and genotype distributions were significantly different (P-value = 0.001) in alcohol-dependent subjects versus control subjects. Short alleles were significantly less frequent among alcohol-dependent subjects (odds ratio = 0.58, P-value = 7 × 10(-4)). These results could be replicated in an independent sample of 116 alcohol-dependent subjects. For the first time, a significant association was identified between this polymorphism and alcoholism.

A damage/benefit evaluation of addictive product use.

AIMS: To obtain damage/benefit assessments of eight commonly used addictive products and one addictive behaviour from French addiction experts and link these to overall evaluations. DESIGN AND SETTING: Criteria-based evaluation by experts in addiction. Specific statistical modelling to estimate the relative contribution of various criteria to formulating expert general opinion on products. PARTICIPANTS: Forty-eight French experts in addiction. MEASUREMENTS: Twelve criteria covering the whole spectrum of damages and benefits to users and to society evaluated using visual analogue scales (VAS). Direct measure of expert overall subjective opinions on products from user and from social perspectives. FINDINGS: Damage scoring identified alcohol (damage score = 48.1), heroin (damage score = 44.9) and cocaine (damage score = 38.5) as the most harmful products to users and to society; gambling was considered the least harmful (score = 22.5), replicating previous results. Damage scoring correlated poorly with legal status or with overall subjective expert opinions of products. Benefit perception scores indicated alcohol as a clear outlier (benefit score = 45.5) followed by tobacco (benefit score = 34.3) and cannabis (benefit score = 31.1). Statistical modelling suggested that experts attributed 10 times more importance to benefit perception than to damages when making their subjective opinion from a user perspective and two times more importance to benefit perception than to damages in formulating their opinion from a social perspective. CONCLUSIONS: The perceived benefits of addictive products appear to have a major impact on the opinion of those products expressed by a number of French addiction experts.

Genetics of VEGF serum variation in human isolated populations of cilento: importance of VEGF polymorphisms.

Vascular Endothelial Growth Factor (VEGF) is the main player in angiogenesis. Because of its crucial role in this process, the study of the genetic factors controlling VEGF variability may be of particular interest for many angiogenesis-associated diseases. Although some polymorphisms in the VEGF gene have been associated with a susceptibility to several disorders, no genome-wide search on VEGF serum levels has been reported so far. We carried out a genome-wide linkage analysis in three isolated populations and we detected a strong linkage between VEGF serum levels and the 6p21.1 VEGF region in all samples. A new locus on chromosome 3p26.3 significantly linked to VEGF serum levels was also detected in a combined population sample. A sequencing of the gene followed by an association study identified three common single nucleotide polymorphisms (SNPs) influencing VEGF serum levels in one population (Campora), two already reported in the literature (rs3025039, rs25648) and one new signal (rs3025020). A fourth SNP (rs41282644) was found to affect VEGF serum levels in another population (Cardile). All the identified SNPs contribute to the related population linkages (35% of the linkage explained in Campora and 15% in Cardile). Interestingly, none of the SNPs influencing VEGF serum levels in one population was found to be associated in the two other populations. These results allow us to exclude the hypothesis that the common variants located in the exons, intron-exon junctions, promoter and regulative regions of the VEGF gene may have a causal effect on the VEGF variation. The data support the alternative hypothesis of a multiple rare variant model, possibly consisting in distinct variants in different populations, influencing VEGF serum levels.

Family history of thyroid cancer and the risk of differentiated thyroid cancer in French polynesia.

BACKGROUND: Differentiated thyroid carcinoma is considered to be the nonhereditary cancer for which familial inheritance is the highest. To date, no familial aggregation analysis of this cancer has been performed in Maohi populations, which exhibit a very high incidence rate. Therefore, we evaluate the risk of differentiated thyroid cancer associated with a family history of thyroid cancer in natives of French Polynesia. METHODS: We investigated thyroid cancer incidence in the first-degree relatives of 225 cases of differentiated thyroid carcinomas diagnosed between 1979 and 2004 in patients born in French Polynesia, and 368 randomly selected population controls matched for sex and age, born and residing in French Polynesia. All but five thyroid cancers declared among relatives were validated. RESULTS: Twenty-four cases declared a family history of thyroid cancer, when compared with 11 controls. Individuals with an affected first-degree relative had a 4.5-fold (95% confidence interval [CI], 1.9-10.6) increased risk of differentiated thyroid cancer. This odds ratio (OR) was not significantly higher when a male first-degree relative was affected (OR, 10.0; 95% CI, 1.3-74.8) compared with a female (OR, 4.0; 95% CI, 1.5-10.3) and was not different for patients who had a nonaggressive thyroid microcarcinoma (OR, 3.5; 95% CI, 0.6-16.4) than those who had a larger cancer (OR, 6.0; 95% CI, 1.8-20.5). This OR was borderline significantly (p, 0.07) higher in Maohis (OR, 11.0; 95% CI, 2.4-48.8) than in individuals of mixed origin (OR, 2.1; 95% CI, 0.8-5.9). CONCLUSION: Our study shows that the familial inheritance of differentiated thyroid cancer is particularly high in Maohi populations.

A common SNP near BMP2 is associated with severity of the iron burden in HFE p.C282Y homozygous patients: a follow-up study.

BACKGROUND AND OBJECTIVES: It is now generally admitted that penetrance of the common HFE p.C282Y/p.C282Y genotype is incomplete, and identification of modifier genes is the concern of a growing number of research projects. We recently identified a significant association between pretherapeutic serum ferritin level and the common rs235756 single nucleotide polymorphism (SNP) of the BMP2 gene region. Our results further suggested an interactive effect between the BMP2 rs235756 SNP and the rs16827043 SNP in HJV, with a small additive effect of the rs4901474 SNP in BMP4. DESIGN AND METHODS: The present study has been designed as a replication study in an independent cohort of 450 HFE p.C282Y homozygous patients from a nearby French region (Brittany). Information on individual alcohol consumption and amount of iron removed by phlebotomy being available for a substantial part of this cohort, additional analyses were conducted. RESULTS: Only the use of the Amount of Iron Removed by phlebotomy (AIR) as marker of iron burden has provided positive results. Indeed, a significant association was detected between rs235756 and AIR adjusted for sex and age, with a mean AIR increasing with the number of BMP2 T alleles in the genotype groups. The effect of rs235657 was not strong enough to detect effects of gene combinations. Still, the trend in two-locus genotype risks involving BMP2 and HJV for AIR was concordant with the specific interactive effect described in the initial study. INTERPRETATION AND CONCLUSIONS: Although we failed to replicate results of the initial study, we argue that, altogether, our results help to consider genes involved in the regulation of hepcidin synthesis as potential modifiers of the p.C282Y/pC282Y genotype expression and especially BMP2.

Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis.

Spondyloarthritis (SpA) is a chronic inflammatory disorder with a strong genetic predisposition dominated by the role of HLA-B27. However, the contribution of other genes to the disease susceptibility has been clearly demonstrated. We previously reported significant evidence of linkage of SpA to chromosome 9q31-34. The current study aimed to characterize this locus, named SPA2. First, we performed a fine linkage mapping of SPA2 (24 cM) with 28 microsatellite markers in 149 multiplex families, which allowed us to reduce the area of investigation to an 18 cM (13 Mb) locus delimited by the markers D9S279 and D9S112. Second, we constructed a linkage disequilibrium (LD) map of this region with 1,536 tag single-nucleotide polymorphisms (SNPs) in 136 families (263 patients). The association was assessed using a transmission disequilibrium test. One tag SNP, rs4979459, yielded a significant P-value (4.9 x 10(-5)). Third, we performed an extension association study with rs4979459 and 30 surrounding SNPs in LD with it, in 287 families (668 patients), and in a sample of 139 cases and 163 controls. Strong association was observed in both familial and case/control datasets for several SNPs. In the replication study, carried with 8 SNPs in an independent sample of 232 cases and 149 controls, one SNP, rs6478105, yielded a nominal P-value<3 x 10(-2). Pooled case/control study (371 cases and 312 controls) as well as combined analysis of extension and replication data showed very significant association (P<5 x 10(-4)) for 6 of the 8 latter markers (rs7849556, rs10817669, rs10759734, rs6478105, rs10982396, and rs10733612). Finally, haplotype association investigations identified a strongly associated haplotype (P<8.8 x 10(-5)) consisting of these 6 SNPs and located in the direct vicinity of the TNFSF15 gene. In conclusion, we have identified within the SPA2 locus a haplotype strongly associated with predisposition to SpA which is located near to TNFSF15, one of the major candidate genes in this region.

Epidemiology, pathology, and genetics of histiocytic sarcoma in the Bernese mountain dog breed.

Histiocytic sarcoma (HS) refers to a highly aggressive and frequently disseminated neoplastic disease belonging to the class of canine histiocytic proliferative disorders. Disseminated HS (previously called malignant histiocytosis) is highly breed specific, with Bernese mountain dogs (BMDs), rottweilers, and retrievers having a high prevalence with a frequency of approximately 25% in the BMD breed. We collected DNA samples and clinical information from 800 BMDs, of which 200 are affected by HS. To better characterize the physiopathology and epidemiology, an in-depth analysis of 89 BMD cases has been performed. The mean age of onset was 6.5 years, males and females being equally affected. The clinical features, biochemical parameters, and pathological features have been determined. The life span after diagnosis has been estimated to be 49 days. A large BMD pedigree of 327 dogs, 121 of which are affected, was assembled. Using a subset of 160 BMDs, encompassing 21 complete sibships, we now propose an oligogenic transmission mode of the disease. Whole-genome linkage scans as well as association studies using a case/control analysis, in parallel with expression profiling of neoplastic versus normal histiocytes, are all underway. Altogether, these complementary approaches are expected to localize the genes for HS in the BMD, leading to advances in our knowledge of histiocyte diseases in dogs and humans.

Linkage analysis with dense SNP maps in isolated populations.

OBJECTIVE: SNP maps are becoming the gold standard for genetic markers, even for linkage analyses. However, because of the density of SNPs on most high throughput platforms, the resulting significant linkage disequilibrium (LD) can bias classical nonparametric multipoint linkage analyses. This problem may be even stronger in population isolates where LD can extend over larger distances and with a more stochastic pattern. We investigate the issue of linkage analysis with SNPs from the Affymetrix 500K GeneChip array in extended families from the isolated Hutterite population. METHODS: We minimized LD between SNPs by two methods based on a LD block pattern (Merlin and SNPLINK) and by MASEL, a new algorithm that we proposed to select SNP subsets with minimum LD and with no prior hypothesis about the LD pattern. RESULTS: Simulations, performed using the real LD pattern observed in the Hutterite population, show that sizeable inflation of linkage statistics persist when LD between SNPs is minimized by Merlin and SNPLINK. Inflation of linkage statistics is better controlled with MASEL. CONCLUSION: In this population, it may be difficult to extract from standard GeneChip arrays a SNP map without LD-driven bias that is more informative than a dense microsatellite map.