Bortezomib-based induction therapies have shown to increase complete response rates and are used as an upfront therapy for newly diagnosed multiple myeloma patients. The standard treatment uses twice a week bortezomib at 1.3 mg/m^2 with dexamethasone PO on the day of and day after bortezomib, however, peripheral neuropathy is often a dose-limiting factor. For elderly patients with multiple co-morbidities and polypharmacy, we propose an alternate schedule of once a week bortezomib IV at 1.6 mg/m^2 with dexamethasone PO on the day of and day after bortezomib. In this phase II, open-labeled, multi-site study, we hypothesize that patients receiving weekly bortezomib will have comparable efficacy as the standard twice a week schedule with increased convenience and lower toxicity profile, especially related to peripheral neuropathy. METHODS: 50 patients with newly diagnosed symptomatic multiple myeloma who were ineligible for transplant or postponed transplant were enrolled from 12 Veterans Affairs hospitals. One cycle consisted of once a week 1.6 mg/m2 bortezomib IV (days 1, 8, 15, 22) plus dexamethasone PO on the day of and after bortezomib (days 1, 2, 8, 9, 15, 16, 22, 23) for 4 weeks, with the 5th week off of treatment. Responding patients could receive up to 6 cycles. RESULTS: The median age of patients was 71 ± 1.46 years (range: 50-89) with β-2 microglobulin of 5.80 ± 0.46 mg/L and c-reactive protein of 10.61 ± 5.54 mg/L. Patients also had multiple co-morbidities including cardiovascular disease (76%) renal insufficiency (54%) and pulmonary problems (36%) and were receiving a median of 13 concurrent medications at baseline. Of the fifty patients, 43 patients were evaluable for response. Seven patients received <1 cycle or died before response could be evaluated. An objective response rate of 79% was observed in 43 evaluable patients with 14% achieving nCR/CR, and at least VGPR in 44% of patients. The median progression-free survival was 9.6 months and overall survival was 46.5 months. The most common toxicity of all grades was thrombocytopenia (42%), lymphopenia (46%), asthenia (48%), and constipation (38%). Peripheral neuropathy occurred in 24% with grade 3 neuropathy occurring only in 6% of patients. In conclusion, a weekly bortezomib plus dexamethasone regimen is efficacious and safe, with lower neurotoxicity in elderly patients with newly diagnosed multiple myeloma complicated by extensive co-morbidities and polypharmacy.

Background: Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune inflammatory disorder of the central nervous system, with significant morbidity and mortality. The lymphocyte depleting, anti-CD52 monoclonal antibody alemtuzumab is a highly effective treatment option in RRMS, though associated with high rates of secondary autoimmune disorders. As alemtuzumab is now in routine clinical use, following licensing in Europe and the US, understanding the effects of repeated treatment cycles and reducing the risk of secondary autoimmunity is timely and essential. In this thesis, I explore how repeated treatment impacts the extent of lymphodepletion. I also study the role of soluble CD52, recently described as suppressive via interaction with Siglec-10, in the mechanism of secondary autoimmunity, and determine the biomarker potential of pre-treatment cytokine levels. Findings: CD4 and CD8 lymphocytes are less effectively depleted with repeated treatment cycles. Lymphocyte surface CD52 density was found by flow cytometry to be significantly lower after alemtuzumab treatment, although CD52-negative clones are not seen. In a cytolysis assay, reduced CD52 density was shown to correlate with reduced susceptibility to alemtuzumab. In addition, activated proliferating T lymphocytes, as observed after treatment, downregulated CD52 expression in a gene expression assay and shed the antigen from cell surface as demonstrated by ELISA and flow cytometry. The development of immunoassays to detect and quantify anti-idiotype antibodies to alemtuzumab is presented. The occurrence of antibodies at retreatment did not reduce lymphocyte depletion. A regulatory role for soluble CD52 was not found in suppression assays, and the proportion of antigen-activated CD52hi T cells did not vary between healthy controls and RRMS individuals. Siglec-10 was not seen on cell surface of activated T cells by flow cytometry and gene expression; thus concluding that soluble CD52 does not play a role in post-alemtuzumab induced autoimmunity. Prior to treatment, the only serum cytokine found to distinguish individuals who develop autoimmunity from those who do not was IL-21 (higher in the autoimmune cohort), however currently commercially available IL-21 immunoassays have no utility as predictive biomarker tests.

The subject of this thesis is the use of Magnetic Resonance (MR) Imaging to quantify biometric MR indices in the Multiple Sclerosis (MS) fixed post-mortem central nervous system (CNS) tissue. Evaluating these indices in fixed tissue allows for the use of histology to verify the findings of MRI. However, it must first be discovered if the indices can be evaluated in fixed post-mortem spinal cord tissue. There is very little literature in this specific area, though some in the fixed brain, the results of which have been assumed to be equivalent in the spinal cord without proof. Therefore, the methodology must first be verified before the consideration of any index as useful and translatable to in-vivo spinal cord. This thesis concentrates on the evaluation of MR relaxometry methods using the indices T1 and T2 by themselves and to evaluate the myelin content of fixed post-mortem CNS tissue. The Carr-Purcell-Meiboom-Gill (CPMG) and Multicomponent Driven Equilibrium Single Pulse Observation of T1 & T2 (mcDESPOT) sequences are used to calculate T1, T2 and the Myelin Water Fraction (MWF) which is believed to be proportional to myelin content in the CNS. This is performed at 3T in a clinical scanner and at 7T in a small animal and wholebody scanner. The methods are first evaluated for use in fixed post-mortem CNS tissue. The two myelin measurement methods are then compared to histological staining if appropriate and where available to verify that the results obtained are proportional to myelin content. The T1 and T2 values in fixed tissue were found to be shortened in fixed tissue, T2 values were so short as to be at the limits of measurement by a clinical scanner, and values converged in white and grey matter, and therefore contrast was found to be limited between these tissues. Proton density images provided the most contrast between tissues. However, even with shortened T2 values, the CPMG sequence was able to identify the myelin water component in fixed tissue. The mcDESPOT algorithm struggled to separate the myelin water component due to clinical scanner limitations and the shortened, converging T1 and T2 values. However, the mcDESPOT algorithm was successful in discerning the myelin water component in the high signal situation of a small bore 7T peclinical scanner. An evaluation was then made of the usefulness of these indices for translation into clinical imaging. The CPMG sequence was found to be proportional to myelin content under all conditions, and therefore useful for disease monitoring in demyelinating diseases. The mcDESPOT sequence, was found to be proportional to myelin in some conditions, and is likely to be useful for monitoring myelination, though the sequence could not be fully validated in this thesis.

The case is presented of a female patient with history of anaemia (haemoglobin 9 g/dL) of 4 years onset, who was referred to the Internal Medicine department complaining of fatigue, dyspnoea, and syncope. She also had a burning pain in the costal region radiating to dorsal and lumbar spine, and lower limbs, which persisted for more than 6 months. The laboratory results reported a haemoglobin value of 8.4 g / dL. There were also high levels of immunoglobulin A (2087). The serum protein electrophoresis revealed the presence of a monoclonal peak, with immunofixation showing the presence of Kappa type IgA. The histopathological examination of the bone marrow biopsy showed the presence of osteosclerosis and few plasma cells. Multiple myeloma was confirmed by CD 138 immunohistochemical staining. A review is presented on multiple myeloma, its clinical presentation, and differential diagnosis. / Revisión por pares

Les études d'association à grande échelle sont devenus un outil très performant pour détecter les variants génétiques associés aux maladies. Ce manuscrit de doctorat s'intéresse à plusieurs des aspects clés des nouvelles problématiques informatiques et statistiques qui ont émergé grâce à de telles recherches. Les résultats des études d'association à grande échelle sont critiqués, en partie, à cause du biais induit par la stratification des populations. Nous proposons une étude de comparaison des stratégies qui existent pour prendre en compte ce problème. Leurs avantages et limites sont discutés en s'appuyant sur divers scénarios de structure des populations dans le but de proposer des conseils et indications pratiques. Nous nous intéressons ensuite à l'interférence de la structure des populations dans la recherche génétique. Nous avons développé au cours de cette thèse un nouvel algorithme appelé SHIPS (Spectral Hierarchical clustering for the Inference of Population Structure). Cet algorithme a été appliqué à un ensemble de jeux de données simulés et réels, ainsi que de nombreux autres algorithmes utilisés en pratique à titre de comparaison. Enfin, la question du test multiple dans ces études d'association est abordée à plusieurs niveaux. Nous proposons une présentation générale des méthodes de tests multiples et discutons leur validité pour différents designs d'études. Nous nous concertons ensuite sur l'obtention de résultats interprétables aux niveaux de gènes, ce qui correspond à une problématique de tests multiples avec des tests dépendants. Nous discutons et analysons les différentes approches dédiées à cette fin. / Genome-Wide association studies have become powerful tools to detect genetic variants associated with diseases. This PhD thesis focuses on several key aspects of the new computational and methodological problematics that have arisen with such research. The results of Genome-Wide association studies have been questioned, in part because of the bias induced by population stratification. Many stratégies are available to account for population stratification scenarios are highlighted in order to propose pratical guidelines to account for population stratification. We then focus on the inference of population structure that has many applications for genetic research. We have developed and present in this manuscript a new clustering algoritm called Spectral Hierarchical clustering for the Inference of Population Structure (SHIPS). This algorithm in the field to propose a comparison of their performances. Finally, the issue of multiple-testing in Genome-Wide association studies is discussed on several levels. We propose a review of the multiple-testing corrections and discuss their validity for different study settings. We then focus on deriving gene-wise interpretation of the findings that corresponds to multiple-stategy to obtain valid gene-disease association measures.

Chau Sze-lok. / Thesis submitted in: December 2002. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 221-245). / Abstracts in English and Chinese. / ABSTRACT (English) --- p.i / ABSTRACT (Chinese) --- p.iii / ACKNOWLEDGMENT --- p.v / LIST OF CONTENTS --- p.vii / LIST OF TABLES --- p.xiv / LIST OF FIGURES --- p.xvii / ABBREVIATIONS --- p.xx / TERMS --- p.xxi / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / (PART A) / Chapter 1.1 --- Acinetobacter spp --- p.1 / Chapter 1.2 --- Clinical importance of Acinetobacter --- p.4 / Chapter 1.3 --- Resistance mechanisms / Chapter 1.3.1 --- Intrinsic resistance --- p.7 / Chapter 1.3.2 --- Acquired resistance --- p.15 / Chapter 1.4 --- Resistance in Acinetobacter --- p.21 / Chapter 1.4.1 --- The efflux system in Acinetobacter --- p.22 / Chapter 1.4.2 --- Other antibiotic resistance mechanisms in Acinetobacter --- p.23 / (PART B) / Chapter 1.5 --- Methods used in this study --- p.29 / Chapter 1.6 --- Rationale of this study --- p.35 / Chapter 1.7 --- Objectives --- p.37 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.39 / Chapter 2.1 --- Bacterial strains and isolates / Chapter 2.1.1 --- Isolates for studying blaIMP-4 --- p.39 / Chapter 2.1.2 --- Isolates for studying adeB --- p.39 / Chapter 2.1.3 --- Isolates for investigation of other efflux pump(s)in Acinetobacter GDG3 --- p.40 / Chapter 2.1.4 --- Isolates for studying the distribution of efflux pumps --- p.40 / Chapter 2.1.5 --- Reference strains --- p.41 / Chapter 2.2 --- Materials / Chapter 2.2.1 --- Sources of materials --- p.42 / Chapter 2.2.2 --- Buffers and solutions --- p.45 / Chapter 2.3 --- Instruments and software --- p.46 / Chapter 2.4 --- General bacteriological techniques / Chapter 2.4.1 --- Bacteriological dientification --- p.47 / Chapter 2.4.2 --- Stock isolates --- p.48 / Chapter 2.4.3 --- Retrieval of isolates --- p.48 / Chapter 2.5 --- General molecular biology techniques / Chapter 2.5.1 --- Agarose gel electrophoresis --- p.49 / Chapter 2.5.2 --- Polymerase chain reaction (PCR) --- p.50 / Chapter 2.5.3 --- Amplified Ribosomal Restriction DNA Analysis (ARDRA) --- p.51 / Chapter 2.5.4 --- Pulsed field gel electrophoresis (PFGE) --- p.53 / Chapter 2.5.5 --- Minimal inhibitory concentration (MIC) --- p.55 / Chapter 2.5.6 --- Antibiotic sensitivity test - disc diffusion test --- p.56 / Chapter 2.5.7 --- Detection of the presence of the common resistance mechanisms --- p.57 / Chapter 2.5.8 --- TA Cloning --- p.60 / Chapter 2.5.9 --- DNA Sequencing --- p.62 / Chapter 2.5.10 --- Sequence analysis --- p.64 / Chapter 2.5.11 --- CYBR Green Assay --- p.65 / Chapter 2.5.12 --- Complementary DNA (cDNA) preparation --- p.66 / Chapter 2.5.13 --- Real time RT-PCR --- p.67 / Chapter 2.5.14 --- Construction of Genome Walker Libraries --- p.69 / Chapter 2.6 --- "Selection of acinetobacters from ICU, blood culture and other clinical isolates" / Chapter 2.6.1 --- Isolates from existing stock cultures --- p.71 / Chapter 2.6.2 --- New isolates obtained for this study --- p.71 / Chapter 2.7 --- Study of expression level of the blaIMP-4 gene / Chapter 2.7.1a --- Verification of the specificity of primers for blaIMP-4 --- p.72 / Chapter 2.7.1b --- Verfication of the specificity of primers for 16S rRNA gene --- p.73 / Chapter 2.7.1c --- Construction of standard curve --- p.76 / Chapter 2.7.2 --- Expression levels of blaIMP-4 and meropenem MICin blaIMP-4+ blood culture isolates --- p.77 / Chapter 2.7.3 --- Intra-assay reproducibility --- p.11 / Chapter 2.7.4 --- Detection of the production of metallo-β-lactamase --- p.77 / Chapter 2.8 --- Study of adeABC expression / Chapter 2.8.1 --- Determination of the presence of the adeB gene --- p.78 / Chapter 2.8.2 --- Entirety of the adeABC operon --- p.79 / Chapter 2.8.3 --- Expression level of the adeB gene --- p.82 / Chapter 2.8.4 --- Expression levels of adeB in sets of serial isolates --- p.84 / Chapter 2.8.5 --- Intra-assay reproducibility --- p.84 / Chapter 2.8.6 --- Inter-assay reproducibility --- p.84 / Chapter 2.9 --- Investigation of other efflux pumps in acinetobacter genomic DNA group3 / Chapter 2.9.1 --- Detection of adeB homologue in a genomic DNA group 3isolate --- p.85 / Chapter 2.9.2 --- Chromosome walking of the adeB-like genes --- p.87 / Chapter 2.9.3 --- Sequences of AdeE and AdeY and their comparison --- p.105 / Chapter 2.9.4 --- Topology prediction of AdeE and AdeY --- p.105 / Chapter 2.9.5 --- The role of the putative pump AdeE --- p.106 / Chapter 2.10 --- Distribution of AdeB and the putative efflux pumps AdeE and AdeY in acinetobacters from different bacterial collections / Chapter 2.10.1 --- Distribution of adeB and the putative pumps (adeE and adeY) in blood cultures (1997-2000) --- p.113 / Chapter 2.10.2 --- Confirmation of the identity of the amplification products of adeE and ade Y in blood culture isolate (1997-2000) --- p.115 / Chapter 2.10.3 --- The presence of adeE in GDG 3 acinetobacters from different sources --- p.116 / Chapter 2.10.4 --- "The presence of adeB, adeE and adeY in antibiotic susceptibility" --- p.116 / Chapter 2.10.5 --- "adeB, adeE and adeY and the clonally and epidemiologically related sets of isolates" --- p.116 / Chapter 2.10.6 --- "adeB, adeE and adeY and the blaIMP-4+ isolates" --- p.116 / Chapter CHAPTER 3 --- "SELECTION OF ACINETOBACTERS FROM ICU, BLOOD CULTURE AND OTHER CLINICAL ISOLATES" --- p.119 / Chapter 3.1 --- Results / Chapter 3.1.1 --- Isolates from existing stock cultures --- p.119 / Chapter 3.1.2 --- New isolates obtained for this study --- p.127 / Chapter 3.2 --- Discussion / Chapter 3.2.1 --- Identification of clonally related isolates by PFGE --- p.129 / Chapter 3.2.2 --- Correlation between the presence of common resistance mechanisms and the changes in antimicrobial susceptibility --- p.129 / Chapter 3.2.3 --- Development of resistance in serial isolates --- p.131 / Chapter CHAPTER 4 --- STUDY OF blaIMP-4 EXPRESSION --- p.133 / Chapter 4.1 --- Results / Chapter 4.1.1 --- Study of expression level of the blaIMP-4 gene --- p.134 / Chapter 4.1.2 --- Expression levels of blaIMP-4 and meropenem MIC in blaIMP-4+ blood culture isolates --- p.136 / Chapter 4.1.3 --- Intra-assay reproducibility \ --- p.37 / Chapter 4.1.4 --- Detection of the production of metallo-β-lactamase --- p.140 / Chapter 4.2 --- Discussion / Chapter 4.2.1 --- Dissociation curve --- p.140 / Chapter 4.2.2 --- Reproducibility of real time RT-PCR --- p.140 / Chapter 4.2.3 --- Relationship between mRNA level of blaIMP-4 and the meropenem MIC --- p.142 / Chapter CHAPTER 5 --- STUDY OF adeABC EXPRESSION --- p.145 / Chapter 5.1 --- Results / Chapter 5.1.1 --- Determination of the presence of the adeB gene --- p.145 / Chapter 5.1.2 --- Entirety of the adeABC operon --- p.146 / Chapter 5.1.3 --- Expression level of the adeB gene --- p.148 / Chapter 5.1.4 --- Expression levels of adeB in sets of serial isolates --- p.151 / Chapter 5.1.5 --- Intra-assay reproducibility --- p.154 / Chapter 5.1.6 --- Inter-assay reproducibility --- p.154 / Chapter 5.2 --- Discussion / Chapter 5.2.1 --- Detection of adeB --- p.156 / Chapter 5.2.2 --- Entirety of the adeABC operon --- p.156 / Chapter 5.2.3 --- Reproducibility of real time RT-PCR --- p.157 / Chapter 5.2.4 --- Relationship between adeB-mRNA level and antimicrobial susceptibility --- p.157 / Chapter CHAPTER 6 --- INVESTIGATION OF OTHER EFFLUX PUMPS IN ACINETOBACTER GENOMIC DNA GROUP3 --- p.159 / Chapter 6.1 --- Results / Chapter 6.1.1 --- Detection of adeB homologue in a genomic DNA group3 isolate --- p.159 / Chapter 6.1.2 --- Chromosome walking of the adeB-like genes --- p.162 / Chapter 6.1.3 --- Sequences of AdeE and AdeY and their comparison --- p.173 / Chapter 6.1.4 --- Topology prediction of AdeE and AdeY --- p.175 / Chapter 6.1.5 --- The role of the putative pump AdeE --- p.177 / Chapter 6.2 --- Discussion / Chapter 6.2.1 --- The AdeE RND transporter --- p.181 / Chapter 6.2.2 --- The theoretical AdeY protein --- p.183 / Chapter CHAPTER 7 --- DISTRIBUTION OF AdeB AND THE PUTATIVE EFFLUX PUMPS AdeE and AdeY IN ACINETOBACTERS FROM DIFFERENT BACTERIAL COLLECTIONS --- p.184 / Chapter 7.1 --- Results / Chapter 7.1.1 --- Distribution of adeB and the putative pumps (adeE and ade Y) in blood cultures (1997-2000) --- p.184 / Chapter 7.1.2 --- Confirmation of the identity of the amplification products of adeE and adeY in blood culture isolates (1997-2000) --- p.187 / Chapter 7.1.3 --- The presence of adeE in GDG 3 acinetobacters from different sources --- p.195 / Chapter 7.1.4 --- "The presence of adeB, adeE and ade Y in antibiotic susceptibility" --- p.196 / Chapter 7.1.5 --- "adeB, adeE and adeY and the clonally and epidemiologically related sets of isolates" --- p.202 / Chapter 7.1.6 --- "adeB, adeE and adeY and the blaIMP-4+ isolates" --- p.202 / Chapter 7.2 --- Discussion / Chapter 7.2.1 --- PCR-RFLP typing --- p.205 / Chapter 7.2.2 --- Distribution of adeB --- p.205 / Chapter 7.2.3 --- Distribution of adeE --- p.206 / Chapter 7.2.4 --- Distribution of adeY --- p.207 / Chapter 7.2.5 --- Distribution of adeE and adeY in GDG 3 isolates --- p.207 / Chapter CHAPTER 8 --- GENERAL DISCUSSION --- p.209 / Chapter 8.1 --- Significance of adeB and the putative pumps (adeE and adeY) --- p.211 / Chapter CHAPTER 9 --- CONCLUSION --- p.218 / Chapter 9.1 --- Conclusion --- p.218 / Chapter 9.2 --- Future Plan --- p.219 / REFERENCES --- p.221 / APPENDIX --- p.246 / Appendix1 --- p.246 / Appendix2 --- p.247 / Appendix3 --- p.252 / Appendix4 --- p.253 / Appendix5 --- p.259

Chan Ka Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 46-48). / Abstracts in English and Chinese. / Abstract --- p.i / Acknowledgement --- p.iii / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Multiple comparison procedures and their applications --- p.1 / Chapter 1.2 --- Different types of error control --- p.3 / Chapter 1.3 --- Single-step and stepwise procedures --- p.5 / Chapter 1.4 --- From familywise error rate control to false discovery rate control --- p.8 / Chapter 1.5 --- The FDR procedure of BH --- p.10 / Chapter 1.6 --- Application of the FDR procedure --- p.11 / Chapter 1.7 --- Family size and family size robustness --- p.16 / Chapter 1.8 --- Objectives of the thesis --- p.17 / Chapter 2 --- The Familywise Robustness Criteria --- p.18 / Chapter 2.1 --- The basic idea of familywise robustness --- p.18 / Chapter 2.2 --- Definitions and notations --- p.19 / Chapter 2.3 --- The measurement of robustness to changing family size --- p.21 / Chapter 2.4 --- Main Theorems --- p.21 / Chapter 2.5 --- Example --- p.23 / Chapter 2.6 --- Summary --- p.24 / Chapter 3 --- FDR and FWR --- p.26 / Chapter 3.1 --- Positive false discovery rate --- p.26 / Chapter 3.2 --- A unified approach to FDR --- p.29 / Chapter 3.3 --- The S procedure --- p.30 / Chapter 3.4 --- Family wise robustness criteria and the S procedure --- p.32 / Chapter 4 --- Simulation Study --- p.41 / Chapter 4.1 --- The setup --- p.41 / Chapter 4.2 --- Simulation result --- p.43 / Chapter 4.3 --- Conclusions --- p.44 / Bibliography --- p.46

Kwan Ho-yuet. / "April 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (p. 98-[103]). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Chan, Kin Kwok. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 68-69). / Abstract also in Chinese. / Chapter 1 --- Introduction --- p.1 / Chapter 2 --- The effect of using a default error model --- p.8 / Chapter 2.1 --- Formulae to measure the prediction error --- p.9 / Chapter 2.2 --- The effect of autoregressive parameter on SD of prediction error --- p.10 / Chapter 2.3 --- Misspecification error of SD of prediction error when using a default error model --- p.12 / Chapter 2.4 --- Reporting error of SD of prediction error when using a default error model --- p.23 / Chapter 3 --- Error modelling by using benchmarks --- p.30 / Chapter 3.1 --- Review of an existing method --- p.30 / Chapter 3.2 --- Introduction of Benchmark Forecasting Method --- p.32 / Chapter 3.3 --- Comparison of estimation methods --- p.36 / Chapter 4 --- Performance of using fitted error model --- p.41 / Chapter 4.1 --- Fitted value and reporting value of SD of prediction error when using a fitted error model --- p.41 / Chapter 4.2 --- Misspecification error and reporting error when using a fitted error model --- p.45 / Chapter 4.3 --- Suggestions on the selection of default and fitted error model --- p.51 / Chapter 5 --- Benchmarking performance of using fitted AR(1) model for usual ARMA survey error --- p.55 / Chapter 5.1 --- Model settings for two usual ARMA survey error --- p.56 / Chapter 5.2 --- Simulation studies --- p.57 / Chapter 6 --- An illustrative example: Traveller Accommodation series --- p.62 / Chapter 7 --- Conclusion --- p.66 / Bibliography --- p.68

De nombreux travaux de recherches sont menés depuis quelques années dans le but de fournir une solution précise et intègre au problème de la localisation de véhicules routiers. Ces recherches sont en majorité fondées sur la théorie probabiliste de l’estimation. Elles utilisent la fusion multi-capteurs et le filtrage de Kalman mono-modèle, au travers de variantes adaptées aux systèmes non linéaires ; l’unique modèle complexe étant supposé décrire toute la dynamique du véhicule. Nous proposons dans cette thèse une approche multi-modèles. Cette étude dérive d’une analyse modulaire de la dynamique du véhicule, c’est-à-dire que l’espace d’évolution est pris comme un espace discret : plusieurs modèles simples et dédiés chacun à une manœuvre particulière sont générés, ce qui améliore la robustesse face aux défauts de modélisation du système. Il s’agit d’une variante de l’algorithme IMM, qui prend en compte l’asynchronisme des capteurs embarqués dans le processus d’estimation de l’état du véhicule. Pour cela, une nouvelle modélisation sous contraintes est développée, ce qui permet de mettre à jour la vraisemblance des modèles intégrés même en l’absence de mesures provenant de capteurs extéroceptifs. Toutefois, la performance d’un tel système nécessite d’utiliser des données capteurs de bonne qualité. Plusieurs opérations sont présentées, illustrant la correction du biais des capteurs, des bruits de mesures ainsi que la prise en compte de l’angle de dévers de la chaussée. La méthodologie développée est validée à travers une comparaison avec les algorithmes de fusion probabilistes EKF, UKF, DD1, DD2 et le filtrage particulaire. Cette comparaison est fondée sur des mesures courantes de précision et de confiance, puis sur l’utilisation de critères statistiques de consistance et de crédibilité, à partir de scénarios synthétiques et ensuite des données réelles. / Many research works have been devoted in the last years in order to provide an accurate and high integrity solution to the problem outdoor vehicles localization. These research efforts are mainly based on the probability estimation theory. They use multi-sensor fusion approach and a single-model based Kalman filtering, through some variants adapted to nonlinear systems. The single complex model that is used is assumed to describe the dynamics of the vehicle. We rather propose a multiple model approach in this thesis. The presented study derives from a modular analysis of the dynamics of the vehicle, ie the evolution of the vehicle is considered as a discrete process, which combines several simple models. Each model is dedicated to a particular manoeuvre of the vehicle. This evolution space discretizing will improves the system robustness to modelling defects. Our approach is a variant of the IMM algorithm, which takes into account the asynchronism of the embedded sensors. In order to achieve this goal, a new system constrained modelling is developed, which allows to update the various models likelihood even in absence of exteroceptive sensors. However, the performance of such a system requires the use of good quality data. Several operations are presented, illustrating the corrections on the sensors bias, measurements noise and taking into account the road bank angle. The developed methodology is validated through a comparison with the probabilistic fusion algorithms EKF, UKF, DD1, DD2 and particle filtering. This comparison is based on measurements of accuracy and confidence, then the use of statistical consistency and credibility measures, from simulation scenarios and then real data.