Cette thèse est consacrée à l'inférence de certains modèles statistiques mal spécifiés. Chaque résultat obtenu trouve son application dans une étude sur les facteurs pronostiques dans le cancer du sein, grâce à des données collectées par l'Institut Curie. Dans un premier temps, nous nous intéressons au modèle à risques non proportionnels, et exploitons la connaissance de la survie marginale du temps de décès. Ce modèle autorise la variation dans le temps du coefficient de régression, généralisant ainsi le modèle à hasards proportionnels. Dans un deuxième temps, nous étudions un modèle à hasards non proportionnels ayant un coefficient de régression constant par morceaux. Nous proposons une méthode d'inférence pour un modèle à un unique point de rupture, et une méthode d'estimation pour un modèle à plusieurs points de rupture. Dans un troisième temps, nous étudions l'influence du sous-échantillonnage sur la performance des forêts médianes et essayons de généraliser les résultats obtenus aux forêts aléatoires de survie à travers une application. Enfin, nous présentons un travail indépendant où nous développons une nouvelle méthode de recherche de doses, dans le cadre des essais cliniques de phase I à ordre partiel. / The thesis focuses on inference of statistical misspecified models. Every result finds its application in a prognostic factors study for breast cancer, thanks to the data collection of Institut Curie. We consider first non-proportional hazards models, and make use of the marginal survival of the failure time. This model allows a time-varying regression coefficient, and therefore generalizes the proportional hazards model. On a second time, we study step regression models. We propose an inference method for the changepoint of a two-step regression model, and an estimation method for a multiple-step regression model. Then, we study the influence of the subsampling rate on the performance of median forests and try to extend the results to random survival forests through an application. Finally, we present a new dose-finding method for phase I clinical trials, in case of partial ordering.

Die laufenden Aufrüstungsarbeiten des Large Hadron Colliders haben das Ziel, die Luminosität der Teilchenkollisionen zu erhöhen. Die erhöhte Luminosität liefert zwar neue Möglichkeiten für Präzisionsmessungen und Teilchensuchen, stellt aber gleichzeitig eine große Herausforderung an die beteiligten Experimente. Aus diesem Grund wird auch der ATLAS-Detektor aufgerüstet. Der Fokus ist dabei, eine hohe Effizienz des Triggers sicherzustellen, der die interessanten Physikereignisse in Echtzeit auswählt. Dafür wird das Flüssig-Argon-Kalorimeter des ATLAS-Detektors mit einer neuen Ausleseelektronik ausgerüstet. Um die Funktionsfähigkeit zu testen, wurde ein Demonstrationsaufbau der zukünftigen Ausleseelektronik installiert und von 2014 bis 2018 parallel zur ATLAS- Datennahme betrieben. In dieser Arbeit werden die Daten, die mit dem Aufbau aufgezeichnet wurden, analysiert. Die neue Ausleseelektronik erlaubt es, komplexere Algorithmen zur Erkennung von Signal- und Untergrundereignissen zu nutzen. Es handelt sich dabei um Variablen zur Beschreibung der Form von elektromagnetischen und hadronischen Teilchenschauern im Flüssig-Argon-Kalorimeter. Die Effizienz dieser Variablen wird untersucht. Dabei wird nach Kombination mehrerer Variablen eine Untergrundunterdrückung hadronischer Jets von 75 % bei einer Elektronenerkennungseffizienz von 90 % erreicht. Die zukünftige, erhöhte Luminosität führt dazu, dass sich bei Teilchenkollisionen die Zahl der Ereignisse, die sich sowohl zeitlich als auch räumlich überlappen, erhöht. Der Effekt dieser Überlappereignisse hat Auswirkungen auf die Energierekonstruktion. Daher wird eine Untersuchung der Überlappereignisse durchgeführt, um eine möglichst genaue Kenntnis über diese zu erhalten. Für die Rekonstruktion aus den Signalen der im Detektor deponierten Energie stehen verschiedene digitale Signalfilter zur Auswahl. Die Performanz hinsichtlich der Signalerkennung dieser Algorithmen wird überprüft. Es zeigt sich, dass neue digitale Signalfilter zwar den Effekt des zeitlichen Überlapps von Detektorpulsen reduzieren, jedoch sehr sensitiv auf die genaue Pulsmodellierung sind. / The ongoing upgrade activities at the Large Hadron Collider aim for an increase of the luminosity in the particle collisions. The increased luminosity delivers new capabilities for precision measurements and searches for signatures of new physics. At the same time, challenges arise for the experiments. For this reason, the ATLAS detector is upgraded. The focus is on maintaining the high efficiency of the trigger that selects interesting physics events in real-time. Therefore, the Liquid-Argon calorimeter of the ATLAS detector is upgraded with new readout electronics. To evaluate the performance, a demonstrator readout was installed and operated in parallel to the data taking of the main readout between 2014 and 2018. In this thesis, the data recorded with the demonstrator is analyzed. The new readout electronics allow more sophisticated algorithms to distinguish between signal and background events. They are based on variables that describe electromagnetic and hadronic showers. The proposed shower-shape variables are studied concerning their trigger efficiency and background rejection power. With a combination of the shower-shape variables, a background rejection power of 75 % for hadronic jets is achieved while keeping the electron trigger efficiency at 90 %. The increase in luminosity will lead to an increase in in-time and out-of-time pile-up effects. These have an impact on the energy reconstruction. Therefore, pile-up events are investigated, to gain precise knowledge about their effects. For the energy reconstruction of the detector signals, different digital filter algorithms are available. The signal detection efficiency of these algorithms is examined. While new filter algorithms are capable of reducing the effect of out-of-time pile-up, they depend greatly on the correct phase of the pulse shape.

Dans les Antilles françaises, une proportion anormalement élevée de parkinsonismes atypiques sporadiques – des tauopathies – est observée. Un lien avec la consommation de plantes de la famille des Annonaceae, en particulier Annona muricata L. (corossol) a été démontré. Les acétogénines d’Annonaceae, des inhibiteurs puissants du complexe I de la chaine respiratoire mitochondriale, sont considérées comme des toxines candidates. L’annonacine, une acétogénine représentative, majoritaire dans A. muricata, est neurotoxique in vitro et in vivo. L’Agence Française de Sécurité Sanitaire des Aliments a exprimé ses doutes quant à ce problème de santé publique. Elle insiste sur l’importance d’évaluer l’exposition des consommateurs d’Annonaceae aux acétogénines, et de déterminer les paramètres pharmacocinétiques de ces molécules. Au cours de cette thèse, nous avons cherché à répondre à ces interrogations, avec l’annonacine pour modèle. Après l’analyse structurale d’acétogénines étalons, une méthode de déréplication puissante et innovante a été mise au point par CLHP-ESI-LTQ-Orbitrap® avec infusion post-colonne de lithium. Les profils complets des acétogénines d’extraits bruts issus d’un nectar d’A. muricata et d’un alcool d’Annona cherimolia Mill. (annone, chérimole) ont été élucidés, mettant en évidence une composition plus complexe et plus variée que celle envisagée dans la littérature. A. cherimolia n’avait pas été identifiée comme une source d’exposition jusqu’à maintenant. Des données quantitatives ont été obtenues par CLHP-DAD-MS, à partir d’une quinzaine d’échantillons de produits commerciaux, confirmant une exposition humaine importante à ces molécules par voie alimentaire, via des produits d’origines géographiques, de statuts et de modes d’obtention variés. Des travaux préliminaires d’étude du passage de l’annonacine à travers des membranes biologiques ont été amorcés (modèles de barrières intestinale – Caco-2 – et hémato-encéphalique – hCMEC/D3). Une étude de métabolisation de phase I de l’annonacine sur microsomes de foie de Rat a permis d'identifier 25 métabolites mono-hydroxylés par CLHP-ESI-LTQ-Orbitrap®. Seuls trois d’entre eux sont observés avec des microsomes humains. Ces métabolites ont été obtenus par hémisynthèse (bioconversion, catalyse par porphyrines) et leur structure a été déterminée. Les résultats montrent que cette étape de métabolisation n’est pas cruciale dans le devenir de l’annonacine, et ne peut expliquer de susceptibilité différentielle aux acétogénines. Après la présentation de rappels concernant les Annonaceae, les parkinsonismes et leurs formes atypiques guadeloupéennes et tropicales, puis d’aspects méthodologiques en spectrométrie de masse, nos travaux de phytochimie analytique, d’analyse métabolique, d’hémisynthèse et de détermination structurale sont présentés, et discutés en regard d’un problème de santé publique potentiellement large et préoccupant. / In the French West Indies, an unusually high proportion of atypical sporadic parkinsonisms - tauopathies - is observed. A link between these atypical parkinsonisms and the consumption of plants of the Annonacea family, Annona muricata L. (soursop) was demonstrated. The Annonaceous acetogenins are potent inhibitors of complex I of mitochondrial respiratory chain and are considered to be in vitro toxins candidate. The major acetogenin in Annona muricata, annonacin, is neurotoxic in in vitro and in vivo models. Afssa (Agence Française de Sécurité Sanitaire des Aliments) expressed its concern regarding this public health problem. The Agency reports the importance of assessing consumers ‘exposure to Annonaceous acetogenins, and of determining the pharmacokinetic of these molecules. In this thesis, we sintended to answer these questions, with annonacine as a model. After the structural analysis of acetogenins standards, a powerful and innovative method of dereplication was developed by HPLC-ESI-LTQ-Orbitrap ® with post-column infusion of lithium. Complete acetogenins profile in crude extracts from nectar of A. muricata and from an alcohol of Annona cherimolia Mill. (Annona, cherimoya) were elucidated, revealing a more complex and more varied composition than that proposed in the literature. A. cherimolia had not been identified as a source of exposure to date. Quantitative data were obtained by HPLC-DAD-MS, from fifteen samples of commercial products, confirming an important human exposure to these molecules through food products of varied geographical origins, status and methods. Preliminary works to study ability of annonacin to cross biological membranes have been initiated (intestinal barrier models - Caco-2 - and blood-brain barrier - hCMEC/D3). A study of phase I metabolism of annonacin in rat liver microsomes allowed the identification of 25 mono-hydroxylated metabolites by HPLC-ESI-LTQ-Orbitrap®. Only three of them were observed with human microsomes. These metabolites were obtained by semisynthesis (bioconversion, porphyrin mediated catalysis) and their structure was determined. The results show that phase metabolism is not critical in the becoming of annonacin, and cannot explain a differential susceptibility of acetogenins. After a presentation of the Annonaceae family, of parkinsonism – including atypical and guadeloupean forms then of and methodological aspects of mass spectrometry, analytical phytochemistry of our work, metabolic analysis, semisynthesis and structure determination are proposed, and discussed in the context of a public health problem and potentially broad concern.

Made available in DSpace on 2016-06-02T20:18:19Z (GMT). No. of bitstreams: 1 4875.pdf: 19049146 bytes, checksum: c54256037244fb411763a05e459a625a (MD5) Previous issue date: 2011-02-28 / There are very few published studies evaluating the effect of a protocol of graded exercise of short duration, during phase I cardiac rehabilitation (CR) on the cardiac autonomic modulation in patients after acute myocardial infarction (AMI), thus three investigations were undertaken in order to evaluate the safety of the protocol of cardiovascular therapy (CPT) phase I, as well as observing the behavior of heart rate (HR), blood pressure (BP) and autonomic modulation of HR through HR variability (HRV) in time domain (TD) and frequency (DF) in patients undergoing phase I protocol CPT after the 1st AMI. Physical therapy in phase I of the CR can be initiated 12 to 24 hours after AMI, however, it is common to prolonged bed rest due to fears of instability of the patient. So the goal of the 1st study was to evaluate the hemodynamic and autonomic responses to post-AMI patients undergoing day 1 of phase I protocol of CPT, as well as their safety. We studied 51 patients with first AMI uncomplicated, 5511 years, 76% men and submitted to the 1st day of the protocol CPT Stage I, on average, 24 hours after AMI, consisting of 10 minutes of rest before and after exercises, followed by 4 min of breathing exercises and 5 min of dynamic exercise. The results indicate that the exercise was safe because it caused hemodynamic and autonomic modulation in these patients, without causing any medical complications. The 2nd study aimed to characterize the autonomic and hemodynamic responses to CPT in patients with stage I of an AMI. We studied 21 patients with first uncomplicated AMI, age 5212 years, 81% men, six days a progressive exercise program (phase I CPT), consisting of a daily standard protocol (10 min rest in supine position pre-and post-exercise and 4 min of breathing exercises) and a protocol for dynamic graded exercise, progressing to active-assisted movements of the legs in the first days after AMI, even walking in the last days of hospitalization. The protocol applied CPT promoted hemodynamic and autonomic changes during the course of the year, allowing early mobilization of the patient and gradually preparing to return to their activity of daily living after discharge from hospital, without being observed the presence of any sign and / or symptoms of exercise intolerance. The 3rd study was to evaluate the effects of a progressive exercise protocol used in phase I of RCV on HRV at rest in patients after AMI. We studied thirty-seven patients who were admitted to hospital with first uncomplicated AMI. The treated group (TG) (n= 21, age= 52±12 years) conducted a five-day program of progressive exercises during phase I of the RCV, while the control group (CG) (n= 16, age= 54±11 years) had only breathing exercises. The progressive exercise program performed during the first phase of cardiac rehabilitation associated with clinical treatment increased cardiac vagal modulation and reduced cardiac sympathetic modulation in patients after AMI. Overall Conclusion: The results of the three studies suggest that the protocol is safe when applied CPT started after 24 hours of AMI not complicated, and allows early mobilization of patients and gradually prepare them to return their activity of daily living after discharge, without being observed the presence of any sign and / or symptoms of exercise intolerance. In addition the progressive exercise program that compose the physiotherapy intervention associated with clinical treatment caused an increase in cardiac vagal modulation and reduction of cardiac sympathetic modulation at rest in the patients studied. / Há carência de estudos na literatura que avaliem o efeito de um protocolo de exercício físico progressivo (EFP) de curta duração, durante fase I da reabilitação cardiovascular (RCV), sobre a modulação autonômica cardíaca em pacientes pós-infarto agudo do miocárdio (IAM), deste modo, uma investigação dividida em três partes foi desenvolvida no intuito de avaliar a segurança do protocolo de fisioterapia cardiovascular (FTCV) fase I, bem como, observar o comportamento da frequência cardíaca (FC), da pressão arterial (PA) e da modulação autonômica da FC, por meio da variabilidade da FC (VFC) nos domínios do tempo (DT) e da freqüência (DF), em pacientes submetidos ao protocolo de FTCV fase I após o 1º IAM. A fisioterapia na fase I da RCV pode ser iniciada de 12 a 24 horas após o IAM, no entanto, é comum o repouso prolongado no leito devido ao receio de instabilização do paciente. Assim o objetivo do 1º estudo foi avaliar as respostas autonômicas e hemodinâmicas de pacientes pós-IAM submetidos ao 1º dia de protocolo de FTCV fase I, bem como, sua segurança. Foram estudados 51 pacientes com 1o IAM não-complicado, 5511 anos, 76% homens e submetidos ao 1º dia do protocolo de FTCV fase I, em média, 24 horas pós-IAM, composto de 10 min de repouso pré e pós-exercícios, 4 min de exercícios respiratórios e 5 min de exercícios físicos dinâmicos (EFD) de membros inferiores (MMII). Os resultados obtidos indicam que o exercício realizado foi seguro, pois promoveu alterações hemodinâmicas e na modulação autonômica da FC nestes pacientes, sem ocasionar qualquer intercorrência clínica. O 2º estudo teve como objetivo caracterizar as respostas autonômicas e hemodinâmicas a FTCV fase I em pacientes com 1º IAM. Foram estudados 21 pacientes com 1o IAM não-complicado, idade 5212 anos, 81% homens, durante 6 dias de um programa de EFP (FTCV fase I), composto por um protocolo padrão diário (10 min de repouso na posição supina pré e pós-exercícios e 4 min de exercícios respiratórios) e um protocolo de EFD gradativos, progredindo de movimentos ativo-assistidos de MMII no 1o dia pós-IAM até deambulação nos últimos dias de internação. O protocolo de FTCV aplicado promoveu alterações autonômicas e hemodinâmicas durante a realização do exercício, permitindo a mobilização precoce do paciente e gradativamente o preparando para o retorno a sua atividade de vida diária (AVD) após a alta hospitalar, sem ser observada presença de qualquer sinal e/ou sintoma de intolerância ao esforço. O 3º estudo teve por objetivo avaliar os efeitos de um protocolo de EFP utilizado na fase I da FTCV sobre a VFC de repouso de pacientes pós-IAM. Foram estudados 37 pacientes com 1º IAM não complicado. O grupo tratado (GT) (n=21, idade=52±12 anos) realizou 5 dias de um programa de EFP durante a fase I da FTCV, enquanto o grupo controle (GC) (n=16, idade=54±11 anos) realizou somente exercícios respiratórios. O programa de EFP realizado durante a fase I da FTCV associado ao tratamento clínico aumentou a modulação vagal cardíaca e reduziu a modulação simpática cardíaca em pacientes pós-IAM. Conclusão geral: Os resultados obtidos nas três partes do estudo sugerem que o protocolo de FTCV aplicado é seguro quando iniciado após 24 horas do IAM não complicado, além de permitir a mobilização precoce dos pacientes e gradativamente os preparar para o retorno as suas AVDs após a alta hospitalar, sem ser observada presença de qualquer sinal e/ou sintoma de intolerância ao esforço. Em adição o programa de EFP que compõem a FTCV fase I associado ao tratamento clínico promoveram aumento da modulação vagal cardíaca e redução da modulação simpática cardíaca em repouso nos pacientes estudados.

Made available in DSpace on 2016-06-02T20:19:28Z (GMT). No. of bitstreams: 1 DissMDBS.pdf: 1917686 bytes, checksum: 9d2cd0affae35c5474a851d16fe9b2e0 (MD5) Previous issue date: 2006-03-23 / Universidade Federal de Minas Gerais / The purpose of the present study was to evaluate the effects of physiotherapeutic intervention on the autonomic control of heart rate through heart rate variability (HRV) indices at rest (supine and seated positions), during deep breath test (DBT), during an exercise protocol and during walking, in patients with acute myocardial infarction (AMI) submitted to phase I of cardiac rehabilitation. Second, evaluate the effects of an inspiratory muscle training (IMT) on the maximal inspiratory pressure (PImax) and on the magnitude of respiratory sinus arrhythmia (RSA). Initially, thirty five patients of both genders were studied in the 1st stage of the cardiovascular physiotherapy (CPT), however, only eighteen of them performed all six stages of treatment (mean = 56± 13 year). These patients, who were admitted to the Coronary Care Unit (CCU) (two days) and the ward (four days) of the Santa Casa de Misericórdia de São Carlos with noncomplicated AMI, were hemodynamically stable and used conventional medications. The 1st stage was initiated 22± 5 hours after the CCU admission and the progression to other 5 stages was done based in the daily clinical evolution of each patient. This stage included 10 minutes of rest (pre and post-exercise protocol), 4 minutes of deep breathing test and 5 minutes of exercise protocol (active-assisted low extremities exercises) in the supine position. Furthermore, the 6th stage included 10 minutes of rest in the supine position (pre and post-intervention), 4 minutes of deep breathing test, 5 minutes of rest in the seated position (pre and post-intervention), 5 minutes of active low extremities exercises in the orthostatic position and 15 minutes of walking. The instantaneous heart rate (HR) and the R-R interval (RRi) were acquired by a HR monitor (Polar S810) during all stage and the blood pressure (BP) was measured before and after each stage. Additionally, the PImax was measured (in the seated position) through a manuvacuometer at the pre and post-IMT, which was performed at the 2nd to 6th stages. The intensity of IMT was settled at 40% of PImax pressure load. The HRV was analyzed by time (RMSSD and RMSM indices) and frequency (Fast Fourier Transform) domain methods. The power spectral density was expressed as normalized units (nu) at low (LF) and high (HF) frequencies, and as the LF/HF. Results: The cumulative effect of physiotherapeutic intervention caused increase of AFnu (p<0.05) and decrease of LFnu (p<0.05) when they were evaluated at the rest pre-intervention in the supine position and during exercise protocol of 1st and 6th stages. Additionally, decreased LF/HF was also observed at rest pre-intervention in the supine position. However, no changes were observed for these indices when the 1st and 6th stages were compared to during the RSA, in the rest post-intervention (supine position) and in the rest pre and post-intervention (seated position), and the 4th and 6th stages were compared to during the walking. In the time domain, RMSM and RMSSD diminished at 1st to 6th stages for rest post-intervention in supine position. The IMT augmented the PImax in 46% (P<0.05), but increased PImax and the RSA magnitude did not correlate among them. Conclusion: The CPT realized in the phase I of the cardiac rehabilitation caused increase in the vagal activity and decrease the sympathetic activity during rest and exercises conditions, since the beta-blockade and IECA medications dosages were not altered. Additionally, the intensity used in the IMT was able to improve the PImax, but it did not influence on the RSA magnitude. Financial support: FAPESP (04/05788-6) and CNPq (478799/2003-9). / O presente estudo teve como principal objetivo avaliar a modulação do sistema nervoso autônomo no coração, por meio do comportamento da variabilidade da freqüência cardíaca (VFC) em repouso, supino e sentado, durante manobra para acentuar a arritmia sinusal respiratória (ASR), exercício e deambulação em pacientes com infarto agudo do miocárdio (IAM) antes e após serem submetidos à fisioterapia: fase I da reabilitação cardiovascular. Como objetivo secundário foi avaliada a pressão inspiratória máxima (PImáx) antes e após um programa de treinamento muscular inspiratório (TMI), bem como, a influência do TMI na magnitude da ASR. Foram estudados 35 pacientes na 1ª etapa (controle) e 18 antes e após a fisioterapia cardiovascular (FTCV), com idade média de 56±13 anos, de ambos os sexos, internados na Unidade Coronariana (UCO) (2 dias) e enfermaria da Irmandade Santa Casa de Misericórdia de São Carlos (4 dias) com IAM não complicado. Todos estavam hemodinamicamente estáveis e em uso de medicações convencionais. Foram submetidos a 1ª etapa após 22±5 horas da chegada na UCO e progrediram na FTCV até a 6ª etapa, diariamente, baseado na evolução clínica. A 1ª etapa foi composta de 10 minutos (min) de repouso supino pré (R1) e pós-intervenção (R2), 4 min da manobra para acentuar a ASR (MASR) e 5 min de exercícios ativos-assistidos de membros inferiores (MMII) na postura supina. Já a 6ª etapa foi composta de 10 min de R1 e R2, 4 min da MASR, 5 min de repouso sentado pré (RS1) e pós-intervenção (RS2), 5 min de exercícios ativos de MMII na postura em pé e 15 min de deambulação. Os intervalos R-R (iRR) e a freqüência cardíaca (FC) foram obtidos, batimento a batimento, pelo freqüencímetro Polar® S810i e a pressão arterial (PA) foi aferida antes, durante e após a FTCV. A medida da PImáx foi realizada com um manovacuômetro, na posição sentada, na 2ª etapa e reavaliada na 6ª etapa. O TMI foi realizado, na posição sentada, da 2ª até a 6ª etapa, sendo que a carga pressórica foi de 40% da PImáx obtida na 2ª etapa. A VFC foi analisada nos domínios do tempo (DT - índices RMSSD e RMSM dos iRR em ms) e da freqüência (DF por meio da análise espectral), a qual forneceu as bandas de baixa freqüência (BF) e alta freqüência (AF), expressas em unidades normalizadas (un), e a razão BF/AF. Resultados: Com relação ao efeito cumulativo das seis etapas da FTCV, no DF, houve diminuição da BFun e aumento da AFun no R1 e durante o exercício e diminuição da razão BF/AF no R1 da 1ª para a 6ª etapa, não havendo alterações destas variáveis durante a MASR e no R2 da 1ª para a 6ª etapa, no RS1 e RS2 da 2ª para 6ª etapa e durante a deambulação da 4ª para 6ª etapa. No DT, os índices RMSSD e RMSM diminuíram no R2 da 1ª para a 6ª etapa. Houve aumento de 46% da PImáx com o TMI (p<0,05) e não houve correlação entre o aumento da PImáx e a magnitude de resposta da ASR. Conclusões: A FTCV fase I aplicada aos pacientes com IAM promoveu aumento da atuação vagal e redução da atuação simpática tanto na condição de repouso supino como durante a execução de exercício, uma vez que a dosagem das medicações betabloqueadores e inibidoras da enzima conversora de angiotensina permaneceram inalteradas durante o estudo. Ainda, o TMI promoveu aumento da PImáx na intensidade aplicada, no entanto, não influenciou a magnitude de resposta da ASR Suporte Financeiro: FAPESP Proc. 04/05788- 6, CNPq Proc. 478799/2003-9.

Double sampling procedure is adapted from a statistical branch called acceptance sampling. The first Shewhart-type double sampling monitoring scheme was introduced in the statistical process monitoring (SPM) field in 1974. The double sampling monitoring scheme has been proven to effectively decrease the sampling effort and, at the same time, to decrease the time to detect potential out-of-control situations when monitoring the location, variability, joint location and variability using univariate or multivariate techniques. Consequently, an overview is conducted to give a full account of all 76 publications on double sampling monitoring schemes that exist in the SPM literature. Moreover, in the review conducted here, these are categorized and summarized so that any research gaps in the SPM literature can easily be identified. Next, based on the knowledge gained from the literature review about the existing designs for monitoring the process mean, a new type of double sampling design is proposed. The new charting region design lead to a class of a control charts called a side-sensitive double sampling (SSDS) monitoring schemes. In this study, the SSDS scheme is implemented to monitor the process mean when the underlying process parameters are known as well as when they are unknown. A variety of run-length properties (i.e., the 5th, 25th, 50th, 75th, 95th percentiles, the average run-length (𝐴𝑅𝐿), standard deviation of the run-length (𝑆𝐷𝑅𝐿), the average sample size (𝐴𝑆𝑆) and the average extra quadratic loss (𝐴𝐸𝑄𝐿) metrics) are used to design and implement the new SSDS scheme. Comparisons with other established monitoring schemes (when parameters are known and unknown) indicate that the proposed SSDS scheme has a better overall performance. Illustrative examples are also given to facilitate the real-life implementation of the proposed SSDS schemes. Finally, a list of possible future research ideas is given with hope that this will stimulate more future research on simple as well as complex double sampling schemes (especially using the newly proposed SSDS design) for monitoring a variety of quality characteristics in the future. / Statistics / M. Sc. (Statistics)

PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.

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(in English): The subject of my dissertation is the decision of the subjects to participate in the early phase of clinical trial. The aim of this disseration is to detect and understand the ethical aspects of decision making of subjects with oncological diseases to participate in the early phase of clinical trial. In the theoretical part of my dissertation, I define the field of clinical research, describe the phases of clinical research and ethical codes important for clinical research. The current ethical dilemmas related to the participation of subjects in the early phase of clinical trial, which are being discussed by the professional public, are presented. The research part contains the results of interviews with seventeen respondents whose content correlates with the aim of the research part and it is to understand the decision- making of subjects to participate in the early phase of clinical trial in terms of subjectively constructed realities, which are different for individual respondents. The results of the research show that fourteen respondents identified one of the most important aspects of the decision-making to participate in the early phase of clinical trial of the recommendation of principal investigator and trust in a physician. Twelve respondents stated the most frequent reason...

(in English): The subject of my dissertation is the decision of the subjects to participate in the early phase of clinical trial. The aim of this disseration is to detect and understand the ethical aspects of decision making of subjects with oncological diseases to participate in the early phase of clinical trial. In the theoretical part of my dissertation, I define the field of clinical research, describe the phases of clinical research and ethical codes important for clinical research. The current ethical dilemmas related to the participation of subjects in the early phase of clinical trial, which are being discussed by the professional public, are presented. The research part contains the results of interviews with seventeen respondents whose content correlates with the aim of the research part and it is to understand the decision- making of subjects to participate in the early phase of clinical trial in terms of subjectively constructed realities, which are different for individual respondents. The results of the research show that fourteen respondents identified one of the most important aspects of the decision-making to participate in the early phase of clinical trial of the recommendation of principal investigator and trust in a physician. Twelve respondents stated the most frequent reason...