This thesis focuses on (1) the statistical methodologies for the estimation of spatial data with outliers and (2) classification accuracy of disease diagnosis. Chapter I, Robust Estimation for Spatial Markov Random Field Models: Markov Random Field (MRF) models are useful in analyzing spatial lattice data collected from semiconductor device fabrication and printed circuit board manufacturing processes or agricultural field trials. When outliers are present in the data, classical parameter estimation techniques (e.g., least squares) can be inefficient and potentially mislead the analyst. This chapter extends the MRF model to accommodate outliers and proposes robust parameter estimation methods such as the robust M- and RA-estimates. Asymptotic distributions of the estimates with differentiable and non-differentiable robustifying function are derived. Extensive simulation studies explore robustness properties of the proposed methods in situations with various amounts of outliers in different patterns. Also provided are studies of analysis of grid data with and without the edge information. Three data sets taken from the literature illustrate advantages of the methods. Chapter II, Extending the Skill Test for Disease Diagnosis: For diagnostic tests, we present an extension to the skill plot introduced by Mozer and Briggs (2003). The method is motivated by diagnostic measures for osteoporosis in a study. By restricting the area under the ROC curve (AUC) according to the skill statistic, we have an improved diagnostic test for practical applications by considering the misclassification costs. We also construct relationships, using the Koziol-Green model and mean-shift model, between the diseased group and the healthy group for improving the skill statistic. Asymptotic properties of the skill statistic are provided. Simulation studies compare the theoretical results and the estimates under various disease rates and misclassification costs. We apply the proposed method in classification of osteoporosis data.

Nous proposons dans cette thèse la méthode STREE de construction d'arbres de décision avec des données symboliques. Ce type de données permet de caractériser des individus de niveau supérieur qui peuvent être des classes ou catégories d’individus ou des concepts au sens des treillis de Galois. Les valeurs des variables, appelées variables symboliques, peuvent être des ensembles, des intervalles ou des histogrammes. Le critère de partitionnement récursif est une combinaison d'un critère par rapport aux variables explicatives et d'un critère par rapport à la variable à expliquer. Le premier critère est la variation de la variance des variables explicatives. Quand il est appliqué seul, STREE correspond à une méthode descendante de classification non supervisée. Le second critère permet de construire un arbre de décision. Il s'agit de la variation de l'indice de Gini si la variable à expliquer est nominale et de la variation de la variance si la variable à expliquer est continue ou bien est une variable symbolique. Les données classiques sont un cas particulier de données symboliques sur lesquelles STREE peut aussi obtenir de bons résultats. Il en ressort de bonnes performances sur plusieurs jeux de données UCI par rapport à des méthodes classiques de Data Mining telles que CART, C4.5, Naive Bayes, KNN, MLP et SVM. STREE permet également la construction d'ensembles d'arbres de décision symboliques soit par bagging soit par boosting. L'utilisation de tels ensembles a pour but de pallier les insuffisances liées aux arbres de décisions eux-mêmes et d'obtenir une décision finale qui est en principe plus fiable que celle obtenue à partir d'un arbre unique. / In this thesis, we propose the STREE methodology for the construction of decision trees with symbolic data. This data type allows us to characterize individuals of higher levels which may be classes or categories of individuals or concepts within the meaning of the Galois lattice. The values of the variables, called symbolic variables, may be sets, intervals or histograms. The criterion of recursive partitioning is a combination of a criterion related to the explanatory variables and a criterion related to the dependant variable. The first criterion is the variation of the variance of the explanatory variables. When it is applied alone, STREE acts as a top-down clustering methodology. The second criterion enables us to build a decision tree. This criteron is expressed as the variation of the Gini index if the dependant variable is nominal, and as the variation of the variance if thedependant variable is continuous or is a symbolic variable. Conventional data are a special case of symbolic data on which STREE can also get good results. It has performed well on multiple sets of UCI data compared to conventional methodologies of Data Mining such as CART, C4.5, Naive Bayes, KNN, MLP and SVM. The STREE methodology also allows for the construction of ensembles of symbolic decision trees either by bagging or by boosting. The use of such ensembles is designed to overcome shortcomings related to the decisions trees themselves and to obtain a finaldecision that is in principle more reliable than that obtained from a single tree.

Made available in DSpace on 2016-06-02T20:06:03Z (GMT). No. of bitstreams: 1 2711.pdf: 1912872 bytes, checksum: 297e56759e248cb7127eae6094c0d821 (MD5) Previous issue date: 2009-03-03 / Financiadora de Estudos e Projetos / Diagnostic tests are methods capable of indicating the presence or absence of a disease, with a probability of error. The performance of a diagnostic test can be verified by some indicator, as: the specificity, the sensitivity and the ROC curve. A graph of the specificity complement versus sensitivity is called as ROC curve. The ROC curve demonstrates the test s ability to discriminate the different disease diagnosis, therefore it is a graphical tool that is used to assess the performance of a test. We define three types of confidence regions around the ROC curve: the punctual, the regional and the global. In some instances, depending on the clinical needs, the decision is taken under an specific region of the ROC curve. We review some procedures for estimating confidence region for the ROC curve and we propose two new methods (optimized averages and averages thresholds optimized) to estimating that region. We use the bootstrap method to search for a confidence region around the ROC curve. Using numerical examples, we apply the methods an compare their performance. / Testes diagnósticos são métodos capazes de indicar a presença ou ausência de uma doença, com uma probabilidade de erro. O desempenho de um teste diagnóstico pode ser verificado por algum indicador, como: a especificidade, a sensibilidade e a curva ROC. Um gráfico do complemento da especificidade versus sensibilidade é chamado de curva ROC. A curva ROC demonstra a habilidade do teste em discriminar os diferentes diagnósticos da doença, logo é uma ferramenta gráfica que serve para avaliar o desempenho de um teste. Definimos três tipos de regiões de confiança em torno da curva ROC: as pontuais, as regionais e as globais. Em algumas situações, de acordo com a necessidade do clínico, uma decisão é tomada sobre uma determinada região específica da curva ROC. Revisamos alguns procedimentos para estimar a região de confiança para a curva ROC e propomos dois novos métodos (médias otimizadas e médias limiares otimizadas) para estimar essa região. Usamos o método bootstrap para buscar uma região de confiança em torno da curva ROC. Usando exemplos numéricos, aplicamos os métodos para comparar seus desempenhos.

The aim of this thesis is comparison of selected classification methods which are logistic regression (binary and multinominal), multilayer perceptron and classification trees, CHAID and CRT. The first part is reminiscent of the theoretical basis of these methods and explains the nature of parameters of the models. The next section applies the above classification methods to the six data sets and then compares the outputs of these methods. Particular emphasis is placed on the discriminatory power rating models, which a separate chapter is devoted to. Rating discriminatory power of the model is based on the overall accuracy, F-measure and size of the area under the ROC curve. The benefit of this work is not only a comparison of selected classification methods based on statistical models evaluating discriminatory power, but also an overview of the strengths and weaknesses of each method.

The thesis discusses the methods of determination of tumor markers and their clinical importance in medical diagnostics. The theoretical part describes clinically important tumor markers and also the chemiluminescent immunoassay methods used for their determination. The practical part of the thesis describes the introduction of new chemiluminescent methods for the determination of tumor markers in routine operation, evaluates its basic analytical parameters and compares it with the existing immunoturbidimetric method. The practical part also presents results of monitoring of cancer patients with various tumors, which is performed by evaluation of the values of tumor markers. Comparison of our method with other methods within the context of System of external quality control is also documented.

<p>Uvod: Hronični subduralni hematom (HSDH) je učestala i nezanemarljiva traumatska/netraumatska intrakranijalna lezija, naročito kod pacijenata starije životne dobi. Simptomi pacijenata sa HSDH su raznovrsni i često pogre&scaron;no protumačeni i lečeni. Zbog navedenih činjenica, HSDH predstavlja veliki izazov u dijagnostici i terapiji. Različiti autori ističu značaj radiolo&scaron;kih parametara tokom dijagnostike ovog oboljenja i povezanost sa kliničkom slikom I neurolo&scaron;kim statusom pacijenta, pa je ovo istraživanje bilo usmereno u preciznoj evaluaciji pomenutih parametara, njihovoj prediktivnoj vrednosti i uticaju na prognozu ishoda lečenja. Cilj: Generalni cilj istraživanja je bio da se ispita učestalost pacijenata sa hroničnim subduralnim hematomom na teritoriji Vojvodine u periodu od tri godine; da se analizira starosna dob pacijenata, polna distribucija oboljenja, uticaj komorbiditeta ili faktora rizika na nastanak HSDH; prisustvo ili odsustvo traume koja je doprinela nastanku HSDH, vremenski interval od traume do pojave simpotoma ili znakova bolesti i da se omogući praćenje efekta terapije pacijenata sa ovim oboljenjem. Specifični ciljevi su obuhvatili: 1. Da se utvrde parametri kompjuterizovane tomografije koji imaju prediktivni značaj u pozitivnom ishodu lečenja pacijenata sa hroničnim subduralnim hematomom. 2. Da se utvrde klinički parametri koji imaju prediktivni značaj u pozitivnom ishodu lečenja pacijenata sa hroničnim subduralnim hematomom. 3. Da se dobije model sa najvećom specifično&scaron;ću i senzitivno&scaron;ću za predikciju ishoda lečenja, kombinacijom kliničkih i parametrara kompjuterizovane tomografije kod pacijenata sa hroničnim subduralnim hematomom. Materijal i metode: Istraživanje je obavljeno kao prospektivna trogodi&scaron;nja studija u periodu od aprila 2010. do aprila 2013. godine u Kliničkom Centru Vojvodine- Centru za radiologiju i Klinici za neurohirurgiju i obuvatila je 83 pacijenata sa dijagnozom hroničnog subduralnog hematoma. Svi ispitanici su dijagnostikovani upotrebom kompjuterizovane tomografije glave (CT) i lečeni na Klinici za neurohirurgiju KCV. Izvori podataka su celokupna medicinska dokumentacija svakog pacijenta od perioda prve hospitalizacije do njihovog otpusta, a uključuje i podatke vezane za subjektivni osećaj o zdravstvenom stanju koje su pacijenti usmeno izneli &scaron;est meseci nakon hospitalnog otpusta. Rezultati: Rezultati istraživanja pokazuju da je Glasgow Coma Scala (GCS) tj. nivo svesti pacijenta na hospitalnom prijemu jedini parametar sa visokom prediktivnom vredno&scaron;ću za klinički ishod lečenja pacijenata sa HSDH procenjen preko Glasgow Outcome Scale (GOS). Preostali radiolo&scaron;ki i klinički parametri (&scaron;irina hematoma, pomeraj mediosagitalne linije, denzitet hematoma, starost pacijenta) nemaju visoku prediktivnu vrednost za klinički ishod pacijenata sa hroničnim subduralnim hematomom. Zaključak: Na osnovu grupe analiziranih pacijenata sa HSDH nije bilo moguće napraviti optimalan model za predikciju ishoda lečenja kombinujući radiolo&scaron;ke i kliničke parametre. Pojedinačno posmatrani radiolo&scaron;ki parametri nisu imali visoku prediktivnu vrednost za ishod lečenja pacijenata sa HSDH. Izolovan klinički parametar- GCS- je jedini visoko prediktivni faktor za ishod lečenja pacijenata sa HSDH. Kombinacija kliničkih i radiolo&scaron;kih parametara daje visoku vrednost predviđanja kliničkog ishoda lečenja, ali samo zahvaljujući izrazito visokoj prediktivnoj vrednosti GCS. Iz svega navedenog, kompjuterizovana tomografija (CT) ima veliki značaj u ranoj dijagnostici i praćenju terapije pacijenata sa HSDH, ali CT parametri ponaosob nemaju značaj u predviđanju ishoda lečenja.</p> / <p>Introduction: Chronic subdural hematoma (CSDH) is common traumatic/no traumatic intracranial lesion, especially in older patients. Symptomatology of this disease is variable and often is misdiagnosed and treated with specially challenges in diagnostic and therapy. Different authors pointed on importance of radiological parameters during diagnostic of this disease and connections with clinic and neurological status in patients with chronic subdural hematoma (CSDH), so this thesis was directed to evaluate radiological and clinical parameters of CSDHs and to show their predictive values and their significance on patient&rsquo;s outcome. Aim: General aim of this thesis was to examine frequency of patients with chronic subdural hematoma in Vojvodina, during the period of three years, to analyze the age of population with CSDHs, the gender distribution, an impact of comorbidity or risk factors for patients with CSDHs, the presence or absence of trauma which has contributed to CSDH, to determine time interval from trauma to appearance of symptoms and signs of disease, monitoring the effect of therapy. Specific aims were: 1. To determine clinical parameters with a positive predictive significance on patients outcome 2. To determine radiological parameters with a positive predictive significance on patients outcome 3. To determine optimal prognostic model with high specificity and sensitivity, using combination of radiological and clinical parameters for positive prediction outcome. Material and methods: The study was performed as three-year prospective study from April 2010 to April 2013 in Clinical Centre of Vojvodina, Centre for Radiology and Clinic of Neurosurgery and includes 83 patients with chronic subdural hematoma. All patients were diagnosed using computed tomography of the brain (CT scan) and all were treated in Clinic of Neurosurgery (KCV). Data sources included the medical records of each patient from the time of first hospitalization to period of their discharge and included data related to the subjective feeling of the health that patients verbally present six months after hospital discharge. Results: The results showed that the Glasgow Coma Scale (GCS) - a level of consciousness of the patient on the hospital admission was the only parameter with a high predictive value for clinical outcome of patients with CSDH assessed through Glasgow Outcome Scale (GOS). Other evaluated radiological and clinical parameters (width of the CSDH, mediosagital line displacement, a density of the CSDH, the age of the patient) did not have high predictive values for the clinical outcome in patients with chronic subdural hematoma. Conclusion: Based on the analyzed group of patients with CSDH it was not possible to make optimal predictive model for outcome by combining radiological and clinical parameters. Radiographic parameters did not have high predictive values for treatment outcome in patients with CSDH. Glasgow Coma Scale (GCS) is the only highly predictive factor for treatment outcome in patients with CSDH. The combination of clinical and radiological parameters gives high predictive value for clinical outcome, but only because of extremely high predictive value of GCS. Therefore, computed tomography (CT) is of great importance in early diagnosis and therapy monitoring of patients with CSDH, but CT parameters did not have the high predictive values for the patient&rsquo;s clinical outcome.</p>

Introdução: Atualmente, o diagnóstico das reações de hipersensibilidade a anti-inflamatórios não esteroidais (AINEs) baseia-se na história relatada pelo paciente e, em determinados casos, é realizado o Teste de Provocação. Todavia, este teste pode expor os pacientes a riscos graves, inclusive anafilaxia. Em busca de ferramenta mais segura, tem-se estudado o Teste de Ativação de Basófilos (BAT). Trata-se de um teste in vitro, no qual é possível testar diversos estímulos em uma única amostra de sangue, avaliando a ativação dos basófilos (indicativo de reação de hipersensibilidade), através do aumento da expressão de moléculas na superfície desses leucócitos, como o CD63. Objetivo: Padronizar e validar o BAT para ácido acetilsalicílico (AAS), diclofenaco, dipirona e paracetamol em pacientes com hipersensibilidade a AINEs. Metodologia: Participaram 20 (testados com os quatro AINEs) + 33 (testados somente com AAS) pacientes atendidos no Serviço de Imunologia Clínica e Alergia do HCFMUSP, que apresentaram manifestações cutâneas em até 24 horas após exposição a um ou múltiplos AINEs, bem como 13 (quatro AINEs) + 26 (AAS) controles. A técnica consistiu em incubar sangue total com os AINEs já mencionados e, depois, marcar as amostras com anticorpos monoclonais (CD45, anti-IgE e CD63) para posterior leitura por citometria de fluxo. Os resultados obtidos foram comparados com as histórias clínicas e os testes de provocação oral, quando realizados. Resultados: Utilizando os critérios de positividade do BAT empregados na literatura (isto é, porcentagem de CD45+IgE+highCD63+ e índice de estimulação), a sensibilidade e a especificidade variaram de acordo com o AINE: para ácido acetilsalicílico foram 75,0% e 16,7%, respectivamente, diclofenaco, 100% e 0%, dipirona, 23,5% e 66,7%, paracetamol, 40,0% e 42,9%. Após a realização de curvas dose-resposta e tempo-resposta somente com AAS, foi encontrado novo critério de positividade: média de intensidade de fluorescência (MFI) menor do que 6575 representava BAT positivo; com isso, os valores de sensibilidade e especificidade foram: 84,4% e 34,6%, respectivamente. O BAT foi mais sensível em pacientes cuja última reação ocorreu há menos de um ano da data de execução do BAT (93,7%). Conclusão: Devido aos baixos valores de sensibilidade e/ou especificidade, não foi possível padronizar e, por conseguinte, validar o BAT para ácido acetilsalicílico, diclofenaco, dipirona e paracetamol. / Introduction: Currently, the diagnosis of nonsteroidal antiinflammatory drugs (NSAIDs) hypersensivitity is based on patients´ clinical history and drug provocation tests, which are done in selected cases. Nevertheless, this test may expose patients to severe risks, including anaphylaxis. Looking for a safer tool, Basophil Activation Test (BAT) for allergy diagnosis has been studied in the last years. It is an in vitro method where a wide variety of stimuli can be tested, incubating them with the patient\'s blood sample, and observing basophil activation (indication of hypersensitivity) through upregulation of CD63 (or other basophil activation markers) on this leucocyte\'s membrane. Objective: To standardize and validate BAT stimulated with acetylsalicylic acid (ASA), diclophenac, dipyrone and paracetamol in NSAID hypersensitive patients. Methods: Patients which reported immediate reactions (less than 24 hours) after exposure to one or multiple NSAIDs, with cutaneous symptoms were enrolled from Clinical Immunology and Allergy outpatient clinic from HC-FMUSP. BAT with the four NSAIDs was tested on 20 patients and 13 controls and BAT with ASA only, on 33 patients and 26 controls. BAT consisted of incubating whole blood with NSAIDs, then triple-labeled with monoclonal antibodies (CD45, anti-IgE, CD63) for analysis by flow cytometry. BAT results were compared to clinical history and oral provocation tests, when available. Results: According to literature\'s positivity criteria (percentage of CD45+IgE+highCD63+ and stimulation index), sensitivity and specificity varied according to the NSAID tested: for ASA was 75.0% and 16.7% respectively, diclophenac, 100.0% and 0.0%, dipyrone, 23.5% and 66.7%, paracetamol, 40.0% and 42.9%. A new positivity criterion was possible to be defined after further dose-response and time-response curves only for ASA: Mean Fluorescence Intensity lower than 6575 (positive BAT). Accordingly, new sensitivity and specificity for BAT in ASA hypersensitivity were 84,4% and 34,6%. Patients that presented the last reaction in the last year were more likely to present a positive BAT (93.7%). Conclusion: Due to low values for sensitivity and/or specificity, it was not possible to standardize and validate BAT for ASA, diclophenac, dipyrone and paracetamol.

INTRODUÇÃO E OBJETIVO: A estenose de junção ureteropélvica (EJUP) é importante causa de obstrução do trato urinário e pode levar a deterioração progressiva da função renal. Há espaço para o aprimoramento de novos métodos diagnósticos capazes de discriminar hidronefrose e uropatia obstrutiva. Acredita-se que os biomarcadores urinários podem fornecer indícios de lesão renal precoce na obstrução urinária. Neste contexto, KIM-1 pode elevar-se na urina por lesão tubular proximal, NGAL por lesão no túbulo proximal, distal ou alça de Henle, CA19-9 por produção excessiva no túbulo obstruído e ?2-microglobulina (beta2M) por injúria ao glomérulo ou ao túbulo proximal. O objetivo do presente estudo foi avaliar as propriedades diagnósticas dos biomarcadores urinários citados em adultos com EJUP, sendo o primeiro estudo na literatura a avaliar tais moléculas nesta população. MÉTODOS: Foram estudados de modo prospectivo pacientes consecutivos acima de 18 anos com diagnóstico de EJUP submetidos a pieloplastia videolaparoscópica de dezembro de 2013 a fevereiro de 2015. Foram excluídos do estudo pacientes com EJUP bilateral, rim contralateral patológico, EJUP em rim único, antecedentes de tratamento cirúrgico para estenose de JUP ou taxa de filtração glomerular inferior a 60 ml/min/1,73m2. Cada paciente forneceu quatro amostras de urina para medição de biomarcadores, uma no pré-operatório e outras com 1, 3 e 6 meses de seguimento pós-operatório. O grupo controle foi constituído por voluntários saudáveis sem hidronefrose à ultrassonografia. RESULTADOS: Foram incluídos 47 pacientes com idade média de 38,6 ± 12,7 anos (intervalo 19 a 64 anos), sendo 17 (36,2%) do sexo masculino e 30 (62,8%) do sexo feminino. O grupo controle foi composto por 40 indivíduos semelhantes ao grupo com EJUP no que concerne idade (p = 0,95) e sexo (p = 0,82). KIM-1 foi o marcador com melhores propriedades diagnósticas, apresentando área sob a curva (AUC) de 0,79 (95% CI 0,70 a 0,89). O NGAL, por sua vez, teve AUC de 0,71 (95% CI 0,61 a 0,83), CA19- 9 teve AUC de 0,70 (95% CI 0,60 a 0,81) e (beta2M) apresentou AUC de 0,61 (95% CI 0,50 a 0,73), sendo o único biomarcador com propriedades inadequadas neste cenário. O KIM-1 foi o marcador mais sensível com o ponto de corte 170,4 pg/mg de creatinina (sensibilidade 91,4%, especificidade 59,1%) e o CA 19-9 o mais específico para o ponto de corte de 51,3 U/mg de creatinina (sensibilidade 48,9%, especificidade 88,0%), enquanto o NGAL foi o que apresentou maior queda após desobstrução, com 90,0% dos pacientes apresentando clareamento superior a 50%. CONCLUSÕES: A avaliação dos biomarcadores urinários é útil no diagnóstico de obstrução em adultos com EJUP submetidos a pieloplastia videolaparoscópica. O KIM-1 foi o marcador mais sensível e o CA 19-9 o mais específico, enquanto o NGAL foi o que apresentou maior que com a desobstrução. Houve queda das concentrações dos marcadores após pieloplastia no período estudado. O papel exato dos biomarcadores urinários no cenário de obstrução em adultos deve ser mais amplamente investigado / INTRODUCTION AND OBJECTIVE: Ureteropelvic junction obstruction (UPJO) is an important cause of urinary tract obstruction and can lead to progressive deterioration of renal function. Thus the development of novel non-invasive methods capable of discriminating obstruction and hydronephrosis may be useful. Elevation of urinary biomarkers may provide early evidence of kidney damage in urinary obstruction. In this scenario, urinary concentrations of KIM-1 may be elevated following proximal tubular injury, while NGAL may increase as result of injury to proximal or distal tubule as well as to loop of Henle, CA19-9 after overproduction in the obstructed tubule and ?2 microglobulin (beta2M) after injury to the glomerulus or the proximal tubule. The aim of this study was to evaluate the diagnostic properties of these urinary biomarkers in adults with UPJO. METHODS: We prospectively studied consecutive patients older than 18 years diagnosed with UPJO undergoing laparoscopic pyeloplasty from December 2013 to February 2015 in our institution. Exclusion criteria included patients with bilateral UPJO, unilateral UPJO with contralateral pathologic kidney, solitary kidney, history of previous surgical treatment for UPJO or glomerular filtration rate below 60 ml/min/1,73m2. Each patient provided four voided urine samples for biomarker measurement, one at preoperative consultation and the others at 1, 3 and 6 months of postoperative follow-up. Healthy individuals with no hydronephrosis on ultrasound evaluation constituted our control group. RESULTS: We included 47 patients with a mean age of 38.6 ± 12.7 years (range 19-64 years), from which 17 (36.2%) were males and 30 (62.8%) were females. The control group consisted of 40 subjects with no statistical difference to the study group regarding age (p = 0.95) and gender (p = 0.82). KIM-1 had an area under the curve (AUC) of 0.79 (95% CI 0.70 to 0.89) and was the biomarker with the best diagnostic properties. CA19-9 had an AUC of 0.70 (95% CI 0.60 to 0.81), NGAL had an AUC of 0.71 (95% CI 0.61 to 0.83) and beta2M had an AUC of 0.61 (95% CI 0.50 to 0.73). KIM-1 was the most sensitive marker with a cutoff of 170.4 pg/mg creatinine (sensitivity 91.4%, specificity 59.1%) whereas CA 19-9 as the most specific one, displaying a cutoff of 51.3 U/mg creatinine (sensitivity 48.9%, specificity 88.0%). NGAL showed the greatest decrease in urinary concentrations after pyeloplasty, in which 90.0% of patients had a clearance greater than 50% in comparison to preoperative values. CONCLUSIONS: The evaluation of urinary biomarkers is useful in the assessment of UPJO in adults undergoing laparoscopic pyeloplasty. Urinary concentrations of CA 19-9, NGAL and KIM-1 were elevated in patients with UPJO and significantly decreased after pyeloplasty. The exact role of those biomarkers in the setting of obstruction in adults should be further evaluated

本論文的研究目標是建構一個由多標記複合成的最佳疾病診斷工具，所考慮的評估準則為操作者特徵曲線在特定特異度範圍之線下面積(pAUC)。在常態分布假設下，我們推導多標記線性組合之pAUC以及最佳線性組合之必要條件。由於函數本身過於複雜使得計算困難。除此之外，我們也發現其最佳解可能不唯一，以及局部極值存在，這些情況使得現有演算法的運用受限，我們因此提出多重初始值演算法。當母體參數未知時，我們利用最大概似估計量以獲得樣本pAUC以及令其極大化之最佳線性組合，並證明樣本最佳線性組合將一致性地收斂到母體最佳線性組合。在進一步的研究中，我們針對單標記的邊際判別能力、多標記的複合判別能力以及個別標記的條件判別能力，分別提出相關統計檢定方法。這些統計檢定被運用至兩個標記選取的方法，分別是前進選擇法與後退淘汰法。我們運用這些方法以選取與疾病檢測有顯著相關的標記。本論文透過模擬研究來驗證所提出的演算法、統計檢定方法以及標記選取的方法。另外，也將這些方法運用在數組實際資料上。 / The aim of this work is to construct a composite diagnostic tool based on multiple biomarkers under the criterion of the partial area under a ROC curve (pAUC) for a predetermined specificity range. Recently several studies are interested in the optimal linear combination maximizing the whole area under a ROC curve (AUC). In this study, we focus on finding the optimal linear combination by a direct maximization of the pAUC under normal assumption. In order to find an analytic solution, the first derivative of the pAUC is derived. The form is so complicated, that a further validation on the Hessian matrix is difficult. In addition, we find that the pAUC maximizer may not be unique and sometimes, local maximizers exist. As a result, the existing algorithms, which depend on the initial-point, are inadequate to serve our needs. We propose a new algorithm by adopting several initial points at one time. In addition, when the population parameters are unknown and only a random sample data set is available, the maximizer of the sample version of the pAUC is shown to be a strong consistent estimator of its theoretical counterpart. We further focus on determining whether a biomarker set, or one specific biomarker has a significant contribution to the disease diagnosis. We propose three statistical tests for the identification of the discriminatory power. The proposed tests are applied to biomarker selection for reducing the variable number in advanced analysis. Numerical studies are performed to validate the proposed algorithm and the proposed statistical procedures.

Introdução: Atualmente, o diagnóstico das reações de hipersensibilidade a anti-inflamatórios não esteroidais (AINEs) baseia-se na história relatada pelo paciente e, em determinados casos, é realizado o Teste de Provocação. Todavia, este teste pode expor os pacientes a riscos graves, inclusive anafilaxia. Em busca de ferramenta mais segura, tem-se estudado o Teste de Ativação de Basófilos (BAT). Trata-se de um teste in vitro, no qual é possível testar diversos estímulos em uma única amostra de sangue, avaliando a ativação dos basófilos (indicativo de reação de hipersensibilidade), através do aumento da expressão de moléculas na superfície desses leucócitos, como o CD63. Objetivo: Padronizar e validar o BAT para ácido acetilsalicílico (AAS), diclofenaco, dipirona e paracetamol em pacientes com hipersensibilidade a AINEs. Metodologia: Participaram 20 (testados com os quatro AINEs) + 33 (testados somente com AAS) pacientes atendidos no Serviço de Imunologia Clínica e Alergia do HCFMUSP, que apresentaram manifestações cutâneas em até 24 horas após exposição a um ou múltiplos AINEs, bem como 13 (quatro AINEs) + 26 (AAS) controles. A técnica consistiu em incubar sangue total com os AINEs já mencionados e, depois, marcar as amostras com anticorpos monoclonais (CD45, anti-IgE e CD63) para posterior leitura por citometria de fluxo. Os resultados obtidos foram comparados com as histórias clínicas e os testes de provocação oral, quando realizados. Resultados: Utilizando os critérios de positividade do BAT empregados na literatura (isto é, porcentagem de CD45+IgE+highCD63+ e índice de estimulação), a sensibilidade e a especificidade variaram de acordo com o AINE: para ácido acetilsalicílico foram 75,0% e 16,7%, respectivamente, diclofenaco, 100% e 0%, dipirona, 23,5% e 66,7%, paracetamol, 40,0% e 42,9%. Após a realização de curvas dose-resposta e tempo-resposta somente com AAS, foi encontrado novo critério de positividade: média de intensidade de fluorescência (MFI) menor do que 6575 representava BAT positivo; com isso, os valores de sensibilidade e especificidade foram: 84,4% e 34,6%, respectivamente. O BAT foi mais sensível em pacientes cuja última reação ocorreu há menos de um ano da data de execução do BAT (93,7%). Conclusão: Devido aos baixos valores de sensibilidade e/ou especificidade, não foi possível padronizar e, por conseguinte, validar o BAT para ácido acetilsalicílico, diclofenaco, dipirona e paracetamol. / Introduction: Currently, the diagnosis of nonsteroidal antiinflammatory drugs (NSAIDs) hypersensivitity is based on patients´ clinical history and drug provocation tests, which are done in selected cases. Nevertheless, this test may expose patients to severe risks, including anaphylaxis. Looking for a safer tool, Basophil Activation Test (BAT) for allergy diagnosis has been studied in the last years. It is an in vitro method where a wide variety of stimuli can be tested, incubating them with the patient\'s blood sample, and observing basophil activation (indication of hypersensitivity) through upregulation of CD63 (or other basophil activation markers) on this leucocyte\'s membrane. Objective: To standardize and validate BAT stimulated with acetylsalicylic acid (ASA), diclophenac, dipyrone and paracetamol in NSAID hypersensitive patients. Methods: Patients which reported immediate reactions (less than 24 hours) after exposure to one or multiple NSAIDs, with cutaneous symptoms were enrolled from Clinical Immunology and Allergy outpatient clinic from HC-FMUSP. BAT with the four NSAIDs was tested on 20 patients and 13 controls and BAT with ASA only, on 33 patients and 26 controls. BAT consisted of incubating whole blood with NSAIDs, then triple-labeled with monoclonal antibodies (CD45, anti-IgE, CD63) for analysis by flow cytometry. BAT results were compared to clinical history and oral provocation tests, when available. Results: According to literature\'s positivity criteria (percentage of CD45+IgE+highCD63+ and stimulation index), sensitivity and specificity varied according to the NSAID tested: for ASA was 75.0% and 16.7% respectively, diclophenac, 100.0% and 0.0%, dipyrone, 23.5% and 66.7%, paracetamol, 40.0% and 42.9%. A new positivity criterion was possible to be defined after further dose-response and time-response curves only for ASA: Mean Fluorescence Intensity lower than 6575 (positive BAT). Accordingly, new sensitivity and specificity for BAT in ASA hypersensitivity were 84,4% and 34,6%. Patients that presented the last reaction in the last year were more likely to present a positive BAT (93.7%). Conclusion: Due to low values for sensitivity and/or specificity, it was not possible to standardize and validate BAT for ASA, diclophenac, dipyrone and paracetamol.