Connections between signal processing and complex analysis

We describe one of the research lines of the Grup de Teoria de Funcions de la UAB UB, which deals with sampling and interpolation problems in signal analysis and their connections with complex function theory.

Rewarding civil service performance through team bonuses : findings, analysis and recommendations

Performance-related pay within public organizations is continuing to spread. Although it can help to strengthen an entrepreneurial spirit in civil servants, its implementation is marred by technical, financial, managerial and cultural problems. This article identifies an added problem, namely the contradiction that exists between a managerial discourse that emphasizes the team and collective performance, on the one hand, and the use of appraisal and reward tools that are above all individual, on the other. Based on an empirical survey carried out within Swiss public organizations, the analysis shows that the team is currently rarely taken into account and singles out the principal routes towards an integrated system for the management and rewarding of civil servants.

Advanced geostatistical and machine-learning models for spatial data analysis of radioactively contaminated regions

Radioactive soil-contamination mapping and risk assessment is a vital issue for decision makers. Traditional approaches for mapping the spatial concentration of radionuclides employ various regression-based models, which usually provide a single-value prediction realization accompanied (in some cases) by estimation error. Such approaches do not provide the capability for rigorous uncertainty quantification or probabilistic mapping. Machine learning is a recent and fast-developing approach based on learning patterns and information from data. Artificial neural networks for prediction mapping have been especially powerful in combination with spatial statistics. A data-driven approach provides the opportunity to integrate additional relevant information about spatial phenomena into a prediction model for more accurate spatial estimates and associated uncertainty. Machine-learning algorithms can also be used for a wider spectrum of problems than before: classification, probability density estimation, and so forth. Stochastic simulations are used to model spatial variability and uncertainty. Unlike regression models, they provide multiple realizations of a particular spatial pattern that allow uncertainty and risk quantification. This paper reviews the most recent methods of spatial data analysis, prediction, and risk mapping, based on machine learning and stochastic simulations in comparison with more traditional regression models. The radioactive fallout from the Chernobyl Nuclear Power Plant accident is used to illustrate the application of the models for prediction and classification problems. This fallout is a unique case study that provides the challenging task of analyzing huge amounts of data ('hard' direct measurements, as well as supplementary information and expert estimates) and solving particular decision-oriented problems.

Model-based Segmentation and Image Fusion of 3D Computed Tomography and 3D Ultrasound of the Eye for Radiotherapy Planning

For radiotherapy treatment planning of retinoblastoma inchildhood, Computed Tomography (CT) represents thestandard method for tumor volume delineation, despitesome inherent limitations. CT scan is very useful inproviding information on physical density for dosecalculation and morphological volumetric information butpresents a low sensitivity in assessing the tumorviability. On the other hand, 3D ultrasound (US) allows ahigh accurate definition of the tumor volume thanks toits high spatial resolution but it is not currentlyintegrated in the treatment planning but used only fordiagnosis and follow-up. Our ultimate goal is anautomatic segmentation of gross tumor volume (GTV) in the3D US, the segmentation of the organs at risk (OAR) inthe CT and the registration of both. In this paper, wepresent some preliminary results in this direction. Wepresent 3D active contour-based segmentation of the eyeball and the lens in CT images; the presented approachincorporates the prior knowledge of the anatomy by usinga 3D geometrical eye model. The automated segmentationresults are validated by comparing with manualsegmentations. Then, for the fusion of 3D CT and USimages, we present two approaches: (i) landmark-basedtransformation, and (ii) object-based transformation thatmakes use of eye ball contour information on CT and USimages.

Santé en milieu pénitentiaire: vulnérabilité partagée entre détenus et professionnels de la santé [Health in prison: shared vulnerability between detainees and health professionals]

In prison, the health professional has to take the sanitary needs of a temporary of chronically vulnerable population. His practice has to meet laws and recommendations, as well as the field reality and its numerous constraints. This puts him in a "shared vulnerability and stigmatization". He attempts to maintain or restore a health status in a deteriorating environment, at least psychologically. He is in the penitentiary world's eye which he depends upon in many ways to achieve his mandate. His activity is scarcely known and recognised by his peers from whom he can be very out of touch. To ensure a humanistic, efficient and equivalent-of-care practice, the health professional must rely on sound knowledge of general healthcare, ethics, deontology and medical laws. Basic and continuous training is a mainspring, like networking and development of federal recommendations.

Economic and legal analysis of mandatory non-recourse mortgages with applications to Spain

“The liquidity crisis of the Spanish banks is largely due to the lack of confidence of foreign investors and, therefore, the changes that occur in the legislation should not affect the credibility, stability, legal certainty, predictability that markets expect”.Sergio Nasarre (2011)In the current situation of economic crisis, many people have found they can no longer pay back the mortgage loans that were granted to them in order to purchase a dwelling. It is for this reason that, in light of the economic, political and social problems this poses, our paper studies the state of the Spanish real-estate system and of foreclosure, paying special attention to the solution that has been proposed recently as the best option for debtors that cannot make their mort-gage payments: non-recourse mortgaging. We analyze this proposal from legal and economic perspectives in order to fully understand the effects that this change could imply. At the same time, this paper will also examine several alternatives we believe would ameliorate the situation of mortgage-holders, among them legal reforms, mortgage insurance, and non-recourse mortgaging itself.

Safety and efficacy of chronic therapy with captopril in hypertensive patients: an update

Captopril, an orally active angiotensin-converting enzyme inhibitor, has been administered to 81 patients with different types of clinical hypertension. Most of the patients had previously uncontrollable high blood pressure. In order to achieve a satisfactory blood pressure control during long-term captopril therapy, a concomitant decrease in total body sodium was required in more than half of the patients. During our first two years of clinical experience with this new antihypertensive agent, side effects developed in 46.9 per cent of the patients and necessitated the withdrawal of the drug in 23.4 per cent of all patients. Only a few side effects such as hypotensive or syncopal episodes and cold extremities appeared to be due to the chronic blockade of the renin-angiotensin system. The most frequent and the most serious adverse reactions such as skin rash, altered taste, pancytopenia, and pemphigus foliaceus seemed to be specifically drug related. The incidence of cutaneous and taste problems was markedly higher in patients with impaired renal function in whom retention of captopril has been previously demonstrated. This suggests that the occurrence of adverse reactions to captopril could be lowered in the future by using smaller daily doses and by titrating them according to the renal function.

Specificity of psychosis, mania and major depression in a contemporary family study.

There has been increasing attention to the subgroups of mood disorders and their boundaries with other mental disorders, particularly psychoses. The goals of the present paper were (1) to assess the familial aggregation and co-aggregation patterns of the full spectrum of mood disorders (that is, bipolar, schizoaffective (SAF), major depression) based on contemporary diagnostic criteria; and (2) to evaluate the familial specificity of the major subgroups of mood disorders, including psychotic, manic and major depressive episodes (MDEs). The sample included 293 patients with a lifetime diagnosis of SAF disorder, bipolar disorder and major depressive disorder (MDD), 110 orthopedic controls, and 1734 adult first-degree relatives. The diagnostic assignment was based on all available information, including direct diagnostic interviews, family history reports and medical records. Our findings revealed specificity of the familial aggregation of psychosis (odds ratio (OR)=2.9, confidence interval (CI): 1.1-7.7), mania (OR=6.4, CI: 2.2-18.7) and MDEs (OR=2.0, CI: 1.5-2.7) but not hypomania (OR=1.3, CI: 0.5-3.6). There was no evidence for cross-transmission of mania and MDEs (OR=.7, CI:.5-1.1), psychosis and mania (OR=1.0, CI:.4-2.7) or psychosis and MDEs (OR=1.0, CI:.7-1.4). The strong familial specificity of psychotic, manic and MDEs in this largest controlled contemporary family study challenges the growing assertion that the major types of mood disorders are manifestations of a common underlying diathesis.

Teaching Motivational Interviewing to Medical Students to Improve Behavior Change Counseling Skills - Results of a Pilot Test

BACKGROUND: Patient behavior accounts for half or more of the variance in health, disease, mortality and treatment outcome and costs. Counseling using motivational interviewing (MI) effectively improves the substance use and medical compliance behavior of patients. Medical training should include substantial focus on this key issue of health promotion. The objective of the study is to test the efficacy of teaching MI to medical students. METHODS: Thirteen fourth-year medical students volunteered to participate. Seven days before and after an 8-hour interactive MI training workshop, each student performed a video-recorded interview with two standardized patients: a 60 year-old alcohol dependent female consulting a primary care physician for the first time about fatigue and depression symptoms; and a 50 year-old male cigarette smoker hospitalized for myocardial infarction. All 52 videos (13 students×2 interviews before and after training) were independently coded by two blinded clinicians using the Motivational Interviewing Training Integrity (MITI, 3.0). MITI scores consist of global spirit (Evocation, Collaboration, Autonomy/Support), global Empathy and Direction, and behavior count summary scores (% Open questions, Reflection to question ratio, % Complex reflections, % MI-adherent behaviors). A "beginning proficiency" threshold (BPT) is defined for each of these 9 scores. The proportion of students reaching BPT before and after training was compared using McNemar exact tests. Inter-rater reliability was evaluated by comparing double coding, and test-retest analyses were conducted on a sub-sample of 10 consecutive interviews by each coder. Weighted Kappas were used for global rating scales and intra-class correlations (ICC) were computed for behavior count summary scores. RESULTS: The percent of counselors reaching BPT before and after MI training increased significantly for Evocation (15% to 65%, p<.001), Collaboration (27% to 77%, p=.001), Autonomy/Support (15% to 54%, p=.006), and % Open questions (4% to 38%, p=.004). Proportions increased, but were not statistically significant for Empathy (38% to 58%, p=.18), Reflection to question ratio (0% to 15%, p=.12), % Complex reflection (35% to 54%, p=.23), and % MI-adherent behaviors (8% to 15%, p=.69). There was virtually no change for the Direction scale (92% to 88%, p=1.00). The reliability analyses produced mixed results. Weighted kappas for inter-rater reliability ranged from .14 for Direction to .51 for Collaboration, and from .27 for Direction to .80 for Empathy for test-retest. ICCs ranged from .20 for Complex reflections to .89 for Open questions (inter-rater), and from .67 for Complex reflections to .99 for Reflection to question ratio (test-retest). CONCLUSION: This pilot study indicates that a single 8-hour training in motivational interviewing for voluntary fourth-year medical students results in significant improvement of some MI skills. A larger sample of randomly selected medical students observed over longer periods should be studied to test if MI training generalizes to medical students. Inter-rater reliability and test-retest findings indicate a need for caution when interpreting the present results, as well as for more intensive training to help appropriately capture more dimensions of the process in future studies.

Evaluation gériatrique des patients agés candidats a un remplacement valvulaire aortique percutané [Geriatric assessment in old patients candidate to transcatheter aortic implantation].

Aortic stenosis mostly occurs among old-old patients. Once symptoms appear, prognosis is guarded, with 2-year mortality as high as 50%. Transcatheter Aortic Valve Implantation (TAVI) is a new therapeutic option in patients at very high surgical risk, who are mostly older persons. However, TAVI is associated with some complications, and patient selection remains a challenge. Comprehensive geriatric assessment (CGA) identifies patients with medical and functional problems likely to affect the TAVI post-operative course. Collaboration between cardiologists and geriatricians will likely become a standard approach to enhance the assessment of these frail patients and identify those most likely to benefit from TAVI.

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.

BACKGROUND/AIMS: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. METHODS: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. RESULTS: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. CONCLUSIONS: This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.

Is Internet use unhealthy? A cross-sectional study of adolescent Internet overuse.

OBJECTIVE: To assess whether problematic internet use is associated with somatic complaints and whether this association remains when checking for internet activity among a random sample of adolescents living in the canton of Vaud, Switzerland. METHODS: Cross-sectional survey of 3,067 8th graders (50.3% females) divided into average (n = 2,708) and problematic (n = 359) Internet users and compared for somatic complaints (backache, overweight, headaches, musculoskeletal pain, sleep problems and sight problems) controlling for sociodemographic and internet-related variables. Logistic regressions were performed for each complaint and for all of them simultaneously controlling variables significant at the bivariate level. RESULTS: At the multivariate level, when taken separately, problematic internet users were more likely to have a chronic condition (adjusted odds ratio [aOR] with 95% CI: 1.58 [1.11:2.23]) and to report back pain (aOR: 1.46 [1.04:2.05]), overweight (aOR: 1.74 [1.03:2.93]), musculoskeletal pain (aOR: 1.36 [1.00:1.84]) and sleep problems (aOR: 2.16 [1.62:2.88]). When considered in the full model, only sleep problems remained significant (aOR: 2.03 [1.50:2.74]). CONCLUSIONS: Our results confirm that problematic internet users report health problems more frequently, with lack of sleep being the most strongly associated and seeming to act as mediator regarding the other ones. Clinicians should remember to screen for excessive internet use their patients complaining of sleep-related problems, back or musculoskeletal pain or overweight. Clinicians should advise parents to limit the amount of time their adolescent children can spend online for leisure activities. Furthermore, limiting the number of devices used to connect to the internet could help warrant enough sleeping time.

Exhaled breath condensate as a matrix for combustion-based nanoparticle exposure and health effect evaluation

Health assessment and medical surveillance of workers exposed to combustion nanoparticles are challenging. The aim was to evaluate the feasibility of using exhaled breath condensate (EBC) from healthy volunteers for (1) assessing the lung deposited dose of combustion nanoparticles and (2) determining the resulting oxidative stress by measuring hydrogen peroxide (H2O2) and malondialdehyde (MDA). Methods: Fifteen healthy nonsmoker volunteers were exposed to three different levels of sidestream cigarette smoke under controlled conditions. EBC was repeatedly collected before, during, and 1 and 2 hr after exposure. Exposure variables were measured by direct reading instruments and by active sampling. The different EBC samples were analyzed for particle number concentration (light-scattering-based method) and for selected compounds considered oxidative stress markers. Results: Subjects were exposed to an average airborne concentration up to 4.3×10(5) particles/cm(3) (average geometric size ∼60-80 nm). Up to 10×10(8) particles/mL could be measured in the collected EBC with a broad size distribution (50(th) percentile ∼160 nm), but these biological concentrations were not related to the exposure level of cigarette smoke particles. Although H2O2 and MDA concentrations in EBC increased during exposure, only H2O2 showed a transient normalization 1 hr after exposure and increased afterward. In contrast, MDA levels stayed elevated during the 2 hr post exposure. Conclusions: The use of diffusion light scattering for particle counting proved to be sufficiently sensitive to detect objects in EBC, but lacked the specificity for carbonaceous tobacco smoke particles. Our results suggest two phases of oxidation markers in EBC: first, the initial deposition of particles and gases in the lung lining liquid, and later the start of oxidative stress with associated cell membrane damage. Future studies should extend the follow-up time and should remove gases or particles from the air to allow differentiation between the different sources of H2O2 and MDA.

Computational and statistical analysis of copy number variants in normal and cancer genomes

AbstractAlthough the genomes from any two human individuals are more than 99.99% identical at the sequence level, some structural variation can be observed. Differences between genomes include single nucleotide polymorphism (SNP), inversion and copy number changes (gain or loss of DNA). The latter can range from submicroscopic events (CNVs, at least 1kb in size) to complete chromosomal aneuploidies. Small copy number variations have often no (lethal) consequences to the cell, but a few were associated to disease susceptibility and phenotypic variations. Larger re-arrangements (i.e. complete chromosome gain) are frequently associated with more severe consequences on health such as genomic disorders and cancer. High-throughput technologies like DNA microarrays enable the detection of CNVs in a genome-wide fashion. Since the initial catalogue of CNVs in the human genome in 2006, there has been tremendous interest in CNVs both in the context of population and medical genetics. Understanding CNV patterns within and between human populations is essential to elucidate their possible contribution to disease. But genome analysis is a challenging task; the technology evolves rapidly creating needs for novel, efficient and robust analytical tools which need to be compared with existing ones. Also, while the link between CNV and disease has been established, the relative CNV contribution is not fully understood and the predisposition to disease from CNVs of the general population has not been yet investigated.During my PhD thesis, I worked on several aspects related to CNVs. As l will report in chapter 3, ! was interested in computational methods to detect CNVs from the general population. I had access to the CoLaus dataset, a population-based study with more than 6,000 participants from the Lausanne area. All these individuals were analysed on SNP arrays and extensive clinical information were available. My work explored existing CNV detection methods and I developed a variety of metrics to compare their performance. Since these methods were not producing entirely satisfactory results, I implemented my own method which outperformed two existing methods. I also devised strategies to combine CNVs from different individuals into CNV regions.I was also interested in the clinical impact of CNVs in common disease (chapter 4). Through an international collaboration led by the Centre Hospitalier Universitaire Vaudois (CHUV) and the Imperial College London I was involved as a main data analyst in the investigation of a rare deletion at chromosome 16p11 detected in obese patients. Specifically, we compared 8,456 obese patients and 11,856 individuals from the general population and we found that the deletion was accounting for 0.7% of the morbid obesity cases and was absent in healthy non- obese controls. This highlights the importance of rare variants with strong impact and provides new insights in the design of clinical studies to identify the missing heritability in common disease.Furthermore, I was interested in the detection of somatic copy number alterations (SCNA) and their consequences in cancer (chapter 5). This project was a collaboration initiated by the Ludwig Institute for Cancer Research and involved other groups from the Swiss Institute of Bioinformatics, the CHUV and Universities of Lausanne and Geneva. The focus of my work was to identify genes with altered expression levels within somatic copy number alterations (SCNA) in seven metastatic melanoma ceil lines, using CGH and SNP arrays, RNA-seq, and karyotyping. Very few SCNA genes were shared by even two melanoma samples making it difficult to draw any conclusions at the individual gene level. To overcome this limitation, I used a network-guided analysis to determine whether any pathways, defined by amplified or deleted genes, were common among the samples. Six of the melanoma samples were potentially altered in four pathways and five samples harboured copy-number and expression changes in components of six pathways. In total, this approach identified 28 pathways. Validation with two external, large melanoma datasets confirmed all but three of the detected pathways and demonstrated the utility of network-guided approaches for both large and small datasets analysis.RésuméBien que le génome de deux individus soit similaire à plus de 99.99%, des différences de structure peuvent être observées. Ces différences incluent les polymorphismes simples de nucléotides, les inversions et les changements en nombre de copies (gain ou perte d'ADN). Ces derniers varient de petits événements dits sous-microscopiques (moins de 1kb en taille), appelés CNVs (copy number variants) jusqu'à des événements plus large pouvant affecter des chromosomes entiers. Les petites variations sont généralement sans conséquence pour la cellule, toutefois certaines ont été impliquées dans la prédisposition à certaines maladies, et à des variations phénotypiques dans la population générale. Les réarrangements plus grands (par exemple, une copie additionnelle d'un chromosome appelée communément trisomie) ont des répercutions plus grave pour la santé, comme par exemple dans certains syndromes génomiques et dans le cancer. Les technologies à haut-débit telle les puces à ADN permettent la détection de CNVs à l'échelle du génome humain. La cartographie en 2006 des CNV du génome humain, a suscité un fort intérêt en génétique des populations et en génétique médicale. La détection de différences au sein et entre plusieurs populations est un élément clef pour élucider la contribution possible des CNVs dans les maladies. Toutefois l'analyse du génome reste une tâche difficile, la technologie évolue très rapidement créant de nouveaux besoins pour le développement d'outils, l'amélioration des précédents, et la comparaison des différentes méthodes. De plus, si le lien entre CNV et maladie a été établit, leur contribution précise n'est pas encore comprise. De même que les études sur la prédisposition aux maladies par des CNVs détectés dans la population générale n'ont pas encore été réalisées.Pendant mon doctorat, je me suis concentré sur trois axes principaux ayant attrait aux CNV. Dans le chapitre 3, je détaille mes travaux sur les méthodes d'analyses des puces à ADN. J'ai eu accès aux données du projet CoLaus, une étude de la population de Lausanne. Dans cette étude, le génome de plus de 6000 individus a été analysé avec des puces SNP et de nombreuses informations cliniques ont été récoltées. Pendant mes travaux, j'ai utilisé et comparé plusieurs méthodes de détection des CNVs. Les résultats n'étant pas complètement satisfaisant, j'ai implémenté ma propre méthode qui donne de meilleures performances que deux des trois autres méthodes utilisées. Je me suis aussi intéressé aux stratégies pour combiner les CNVs de différents individus en régions.Je me suis aussi intéressé à l'impact clinique des CNVs dans le cas des maladies génétiques communes (chapitre 4). Ce projet fut possible grâce à une étroite collaboration avec le Centre Hospitalier Universitaire Vaudois (CHUV) et l'Impérial College à Londres. Dans ce projet, j'ai été l'un des analystes principaux et j'ai travaillé sur l'impact clinique d'une délétion rare du chromosome 16p11 présente chez des patients atteints d'obésité. Dans cette collaboration multidisciplinaire, nous avons comparés 8'456 patients atteint d'obésité et 11 '856 individus de la population générale. Nous avons trouvés que la délétion était impliquée dans 0.7% des cas d'obésité morbide et était absente chez les contrôles sains (non-atteint d'obésité). Notre étude illustre l'importance des CNVs rares qui peuvent avoir un impact clinique très important. De plus, ceci permet d'envisager une alternative aux études d'associations pour améliorer notre compréhension de l'étiologie des maladies génétiques communes.Egalement, j'ai travaillé sur la détection d'altérations somatiques en nombres de copies (SCNA) et de leurs conséquences pour le cancer (chapitre 5). Ce projet fut une collaboration initiée par l'Institut Ludwig de Recherche contre le Cancer et impliquant l'Institut Suisse de Bioinformatique, le CHUV et les Universités de Lausanne et Genève. Je me suis concentré sur l'identification de gènes affectés par des SCNAs et avec une sur- ou sous-expression dans des lignées cellulaires dérivées de mélanomes métastatiques. Les données utilisées ont été générées par des puces ADN (CGH et SNP) et du séquençage à haut débit du transcriptome. Mes recherches ont montrées que peu de gènes sont récurrents entre les mélanomes, ce qui rend difficile l'interprétation des résultats. Pour contourner ces limitations, j'ai utilisé une analyse de réseaux pour définir si des réseaux de signalisations enrichis en gènes amplifiés ou perdus, étaient communs aux différents échantillons. En fait, parmi les 28 réseaux détectés, quatre réseaux sont potentiellement dérégulés chez six mélanomes, et six réseaux supplémentaires sont affectés chez cinq mélanomes. La validation de ces résultats avec deux larges jeux de données publiques, a confirmée tous ces réseaux sauf trois. Ceci démontre l'utilité de cette approche pour l'analyse de petits et de larges jeux de données.Résumé grand publicL'avènement de la biologie moléculaire, en particulier ces dix dernières années, a révolutionné la recherche en génétique médicale. Grâce à la disponibilité du génome humain de référence dès 2001, de nouvelles technologies telles que les puces à ADN sont apparues et ont permis d'étudier le génome dans son ensemble avec une résolution dite sous-microscopique jusque-là impossible par les techniques traditionnelles de cytogénétique. Un des exemples les plus importants est l'étude des variations structurales du génome, en particulier l'étude du nombre de copies des gènes. Il était établi dès 1959 avec l'identification de la trisomie 21 par le professeur Jérôme Lejeune que le gain d'un chromosome supplémentaire était à l'origine de syndrome génétique avec des répercussions graves pour la santé du patient. Ces observations ont également été réalisées en oncologie sur les cellules cancéreuses qui accumulent fréquemment des aberrations en nombre de copies (telles que la perte ou le gain d'un ou plusieurs chromosomes). Dès 2004, plusieurs groupes de recherches ont répertorié des changements en nombre de copies dans des individus provenant de la population générale (c'est-à-dire sans symptômes cliniques visibles). En 2006, le Dr. Richard Redon a établi la première carte de variation en nombre de copies dans la population générale. Ces découvertes ont démontrées que les variations dans le génome était fréquentes et que la plupart d'entre elles étaient bénignes, c'est-à-dire sans conséquence clinique pour la santé de l'individu. Ceci a suscité un très grand intérêt pour comprendre les variations naturelles entre individus mais aussi pour mieux appréhender la prédisposition génétique à certaines maladies.Lors de ma thèse, j'ai développé de nouveaux outils informatiques pour l'analyse de puces à ADN dans le but de cartographier ces variations à l'échelle génomique. J'ai utilisé ces outils pour établir les variations dans la population suisse et je me suis consacré par la suite à l'étude de facteurs pouvant expliquer la prédisposition aux maladies telles que l'obésité. Cette étude en collaboration avec le Centre Hospitalier Universitaire Vaudois a permis l'identification d'une délétion sur le chromosome 16 expliquant 0.7% des cas d'obésité morbide. Cette étude a plusieurs répercussions. Tout d'abord elle permet d'effectuer le diagnostique chez les enfants à naître afin de déterminer leur prédisposition à l'obésité. Ensuite ce locus implique une vingtaine de gènes. Ceci permet de formuler de nouvelles hypothèses de travail et d'orienter la recherche afin d'améliorer notre compréhension de la maladie et l'espoir de découvrir un nouveau traitement Enfin notre étude fournit une alternative aux études d'association génétique qui n'ont eu jusqu'à présent qu'un succès mitigé.Dans la dernière partie de ma thèse, je me suis intéressé à l'analyse des aberrations en nombre de copies dans le cancer. Mon choix s'est porté sur l'étude de mélanomes, impliqués dans le cancer de la peau. Le mélanome est une tumeur très agressive, elle est responsable de 80% des décès des cancers de la peau et est souvent résistante aux traitements utilisés en oncologie (chimiothérapie, radiothérapie). Dans le cadre d'une collaboration entre l'Institut Ludwig de Recherche contre le Cancer, l'Institut Suisse de Bioinformatique, le CHUV et les universités de Lausanne et Genève, nous avons séquencés l'exome (les gènes) et le transcriptome (l'expression des gènes) de sept mélanomes métastatiques, effectués des analyses du nombre de copies par des puces à ADN et des caryotypes. Mes travaux ont permis le développement de nouvelles méthodes d'analyses adaptées au cancer, d'établir la liste des réseaux de signalisation cellulaire affectés de façon récurrente chez le mélanome et d'identifier deux cibles thérapeutiques potentielles jusqu'alors ignorées dans les cancers de la peau.