<p>Karcinom bronha je danas u svetu najče&scaron;ći uzrok smrti povezanih sa malignim bolestima. U XX veku je registrovan značajan porast kako incidence, tako i mortaliteta karcinoma bronha u većini zemalja. Medijana&nbsp; preživljavanja u svim stadijumima bolesti se značajno pobolj&scaron;ala poslednjih godina XX veka, ali nedovoljno u odnosu na očekivano. U najvećem broju slučajeva, bolest se otkriva u uznapredovalom stadijumu, kada je radikalno hirur&scaron;ko lečenje kao optimalan vid lečenja nemoguće. Određivanje stadijuma bolesti (stejdžing) je najbitniji segment u evaluaciji svakog bolesnika s karcinomom bronha. Utvrđivanje zahvaćenosti medijastinalnih&nbsp; limfnih čvorova karcinomom je od posebne važnosti, jer je u velikom broju slučajeva upravo nodalni status faktor koji određuje svsishodnost primene hirur&scaron;kog lečenja, radioterapije i hemioterapije, a samim tim i jedan od bitnih faktora prognoze bolesnika sa nemikrocelularnim karcinomom bronha NSCLC. Bolesnici sa dokazanom zahvaćeno&scaron;ću N2 medijastinalnih limfnih čvorova se svrstavaju u IIIA stadijum NSCLC koji je potencijalno resektabilan, dok se bolesnici sa dokazanom zahvaćeno&scaron;ću N3 medijastinalnih limfnih čvorova svrstavaju u IIIB stadijum NSCLC, koji se smatra neresektabilnim. Cilj ove doktorske disertacije je bio da se utvrdi da li postoje prognostički značajni faktori za rezultat lečenja medijastinoskopski dokazanog N2 i N3 stadijuma NSCLC. Studija je bila nerandomizovana, delom retrospektivnog, a delom prospektivnog karaktera. U ispitivanje je uključeno 60 bolesnika lečenih u Institutu za plućne bolesti Vojvodine tokom&nbsp; 2006., 2007. i 2008. godine. Kod svih uključenih bolesnika medijastinoskopijom je dokazana propagacija NSCLC u medijastinalne limfne čvorove. U radu su analizirani sledeći faktori: pol, starost, ECOG performans status, pridružena hronična opstruktivna bolest pluća (HOBP), pridruženo kardiovaskularno oboljenje sa simtomatologijom klasifikovanom prema NYHA, T faktor, lokalizacija i broj medijastinoskopski dokazanih metastatski zahvaćenih limfnih čvorova, vrsta primenjenog&nbsp; lečenja (hemioradioterapija, hemioterapija, operacija), rezultat lečenja (odgovor na terapiju i preživljavanje). Univarijantnom analizom je utvrđeno da su kod bolesnika sa medijastinoskopski dokazanim N2 i N3 stadijumom NSCLC prognostički faktori koji su imali uticaj na lo&scaron;ije preživljavanje bili: ECOG PS 2 (p=0,00000), pridruženo kardivaskularno oboljenja sa simptomatologijom klase NYHA II (p=0,00113), zahvaćenost kontralateralnih medijastinalnih medijastinalnih limfnih čvorova (N3 stadijum) (p=0,000003), dok je uticaj zahvaćenosti vi&scaron;e pozicija ipsilateralnih medijastinalnih limfnih čvorova (multi station N2) bio na granici statističke značajnosti (p=0,05385). Utvrđeno je da bolesnici sa N2 i N3 stadijumom NSCLC lečeni hemioradioterapijom imaju bolju stopu odgovora na primenjenu terapiju u odnosu na bolesnike lečene samo hemioterapijom (p=0,03118), kao i da operativno lečenje primenjeno kod bolesnika koji su imali dobar odgovor na sprovedenu terapiju ima statistički značajan uticaj u vidu boljeg preživljavanja (p=0,00121). Univarijantnom analizom nije utvrđen značajan uticaj sledećih faktora na preživljavanje bolesnika sa N2 i N3 stadijomom NSCLC: pol, starost, pridružena HOBP, skvamozni tip NSCLC i T faktor. Multivarijantnom analizom su kao nezavisni prognostički faktori na preživljavanje bolesnika sa N2 i N3 stadijumom NSCLC utvrđeni klinički N status (bolje preživljavanje ima N2 u odnosu na N3 stadijum) i sprovedena terapija (bolje preživljavanje ima hemioradioterapija u odnosu na hemioterapiju). Dobijeni rezultati navode nas na zaključak da su pozicija i broj zahvaćenih pozicija medijastinalnih limfnih čvorova, koji su utvrđeni medijastinoskopski, kao i sprovođenje multimodalnog lečenja ključni prognostički faktori za preživljavanje bolesnika sa N2 i N3 stadijumom NSCLC.</p> / <p>Lung&nbsp; cancer&nbsp; is&nbsp; the&nbsp; most&nbsp; common cause of cancer&nbsp; related mortality&nbsp; worldwide.&nbsp; Increase&nbsp; in&nbsp; both&nbsp; incidence&nbsp; and mortality&nbsp; of&nbsp; lung&nbsp; cancer&nbsp; was&nbsp; registered&nbsp; throughout&nbsp; 20th century. The median survival in every stage of lung cancer has been improved in last years of 20th century but it is still not satisfactory. In most cases, lung cancer is diagnosed in advanced&nbsp; stage&nbsp; when&nbsp; surgical&nbsp; treatment&nbsp; as&nbsp; the&nbsp; optimal approach&nbsp; is&nbsp; not&nbsp; possible. Staging&nbsp; is&nbsp; the&nbsp; most&nbsp; important element&nbsp; in&nbsp; the&nbsp; evaluation&nbsp; of&nbsp; every&nbsp; lung&nbsp; cancer&nbsp; patient. Mediastinal lymph node involvement is crucial, because in most of the cases nodal staging is factor which determines appropriate use of surgery, radiotherapy and chemotherapy and it is one of the important factors influencing prognosis of lung cancer patients. Patients with proven involvement of ipsilateral&nbsp; mediastinal&nbsp; lymph&nbsp; nodes&nbsp; (N2&nbsp; stage)&nbsp; are categorized&nbsp; in&nbsp; IIIA&nbsp; stage&nbsp; which&nbsp; is&nbsp; considered&nbsp; to&nbsp; be potentially resectable, and patients with proven involvement of&nbsp; contralateral&nbsp; mediastinal&nbsp; lymph&nbsp; nodes&nbsp; (N3&nbsp; stage)&nbsp; are categorized&nbsp; in&nbsp; IIIB&nbsp; stage,&nbsp; which&nbsp; is&nbsp; considered&nbsp; to&nbsp; be nonresectable. The aim of this study was the determination of&nbsp; significant&nbsp; prognostic&nbsp; factors&nbsp; that&nbsp; have&nbsp; influence&nbsp; on treatment&nbsp; and&nbsp; survival&nbsp; of&nbsp; non-small&nbsp; cell&nbsp; lung&nbsp; cancer (NSCLC)&nbsp; patients&nbsp; in&nbsp; stage&nbsp; N2&nbsp; and&nbsp; N3.&nbsp; Study&nbsp; was nonrandomized,&nbsp;&nbsp; partially&nbsp;&nbsp; retrospective&nbsp;&nbsp; and&nbsp;&nbsp; partially prospective. It included 60 patients treated at the Institute for Pulmonary&nbsp; Diseases&nbsp; of&nbsp; Vojvodina&nbsp; during&nbsp; 2006,&nbsp; 2007&nbsp; and 2008. Cancer involvement of mediastinal lymph nodes was determined by mediastinoscopy in every patient. In study we analyzed following factors: gender, age, ECOG performance&nbsp;&nbsp; status,&nbsp;&nbsp; associated&nbsp;&nbsp; chronic&nbsp;&nbsp; obstructive pulmonary&nbsp; disease&nbsp; (COPD),&nbsp; associated&nbsp; cardiovascular disease with symptoms graded by NYHA classification, T status, position and number of involved mediastinal lymph nodes,&nbsp; applied&nbsp; treatment&nbsp; (surgery,&nbsp; chemoradiotherapy, chemotherapy alone), treatment result (response to treatment and&nbsp; survival).&nbsp; Prognostic&nbsp; factors&nbsp; for&nbsp; poorer&nbsp; survival&nbsp; on univariant analysis were ECOG PS 2 (p=0,0000), associated cardiovascular&nbsp;&nbsp; disease&nbsp;&nbsp; with&nbsp;&nbsp; symptoms&nbsp;&nbsp; NYHA&nbsp;&nbsp; II (p=0,00113)&nbsp; and&nbsp; involvement of&nbsp; contralateral&nbsp; mediastinal lymph nodes (N3 stage) (p=0,00003) while multi station N2 disease was borderline significant at level of p=0,05385. It was determined that patients treated with chemoradiotherapy achieved better response to treatment compared to patients treated&nbsp; with&nbsp; chemotherapy&nbsp; alone&nbsp; (p=0,03118).&nbsp; Univariant analyses&nbsp; did&nbsp; not&nbsp; confirm&nbsp; significance&nbsp; of&nbsp; gender,&nbsp; age, associate COPD, squamous cell lung cancer and T factor on survival. Multivariante&nbsp; analyses&nbsp; identified&nbsp; N&nbsp; status&nbsp; (better survival has N2 stage compared to N3 stage of NSCLC) and conducted treatment (better survival has&nbsp; chemoradiotherapy compared to chemotherapy alone) as independent prognostic factors.&nbsp; Our&nbsp; results&nbsp; suggest&nbsp; that&nbsp; position&nbsp; and&nbsp; number&nbsp; of cancer involved&nbsp; mediastinal lymph nodes position,&nbsp; proven by mediastinoscopy, as well as the conducted multimodality treatment are key prognostic factors which might influence the survival of patients with N2 and N3 stage of NSCLC.</p>

Dans ce travail, nous nous intéressons à l'inférence statistique dans deux modèles semi-paramétrique et non-paramétrique stratifiés de durées de vie censurées. Nous proposons tout d'abord une statistique de test d'ajustement pour le modèle de régression stratifié à risques proportionnels. Nous établissons sa distribution asymptotique sous l'hypothèse nulle d'un ajustement correct du modèle aux données. Nous étudions les propriétés numériques de ce test (niveau, puissance sous différentes alternatives) au moyen de simulations. Nous proposons ensuite une procédure permettant de stratifier le modèle à 1isques proportionnels suivant un seuil inconnu d'une variable de stratification. Cette procédure repose sur l'utilisation du test d'ajustement proposé précédemment. Une étude de simulation exhaustive est conduite pour évaluer les pe1fonnances de cette procédure. Dans une seconde partie de notre travail, nous nous intéressons à l'application du test du logrank stratifié dans un contexte de données manquantes (nous considérons la situation où les strates ne peuvent être observées chez tous les individus de l'échantillon). Nous construisons une version pondérée du logrank stratifié adaptée à ce problème. Nous en établissons la loi limite sous l'hypothèse nulle d'égalité des fonctions de risque dans les différents groupes. Les propriétés de cette nouvelle statistique de test sont évaluée au moyen de simulations. Le test est ensuite appliqué à un jeu de données médicales. / In this work, we are interested in the statistical inference in two semi-parametric and non-parametric stratified models for censored data. We first propose a goodnessof- fit test statistic for the stratified proportional hazards regression model. We establish its asymptotic distribution under the null hypothesis of a correct fit of the model. We investigate the numerical properties of this test (level, power under different alternatives) by means of simulations. Then, we propose a procedure allowing to stratify the proportional hazards model according to an unknown threshold in a stratification variable. This procedure is based on the goodness-of-fit test proposed earlier. An exhaustive simulation study is conducted to evaluate the performance of this procedure. In a second part of our work, we consider the stratified logrank test in a context of missing data (we consider the situation where strata can not be observed on all sample individuals). We construct a weighted version of the stratified logrank, adapted to this problem. We establish its asymptotic distribution under the null hypothesis of equality of the hazards functions in the different groups. The prope1ties of this new test statistic are assessed using simulatious. Finally, the test is applied to a medical dataset.

En la presente investigación se analizan los determinantes de la duración del desempleo de los ocupados y desocupados de lima metropolitana para el período de estudio 2014 – 2020. Para ello se realiza un análisis de supervivencia usando estimaciones no paramétricas de Kaplan-Meier, el cual demuestra que a medida que se prolonga el período de desempleo, el riesgo de salida aumenta. Asimismo, se analiza la existencia de diferencia de género y el efecto de sus determinantes mediante la estimación Weibull. Los resultados muestran que ser mujer, en lima metropolitana, reduce las probabilidades de salir del desempleo. Dentro de los factores que incrementan la duración del desempleo se encuentran el ser mujer, tener un nivel educativo superior o tener más años de experiencia reducen las probabilidades de salir del desempleo. Por otro lado, las estimaciones paramétricas revelan que dentro de los factores que disminuyen la duración del desempleo se encuentra el pertenecer al grupo étnico mestizo, tener como lengua materna el castellano o poseer un seguro médico, incrementan el riesgo de salir del desempleo. Estas variables permiten identificar los grupos de la población más vulnerable al problema del desempleo. / In this research, the determinants of the duration of unemployment of the employed and unemployed of metropolitan lima for the study period 2014 - 2020 are analyzed. For this, a survival analysis is carried out using non-parametric Kaplan-Meier estimates, which shows that as the unemployment period lengthens, the risk of leaving increases. Likewise, the existence of gender difference and the effect of its determinants are analyzed using the Weibull estimation. The results show that being a woman, in metropolitan Lima, reduces the chances of getting out of unemployment. Among the factors that increase the duration of unemployment are being a woman, having a higher education level and having more years of experience reduce the chances of leaving unemployment. On the other hand, the parametric estimates reveal that among the factors that decrease the duration of unemployment, belonging to the mestizo ethnic group, having Spanish as their mother tongue, having health insurance, increase the risk of leaving unemployment. These variables make it possible to identify the groups of the population most vulnerable to the problem of unemployment. / Trabajo de investigación

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Survival analysis often includes dealing with data that are censored. This thesis focuses on censoring in the form of current status data. We discuss seve- ral methods of regression analysis of current status data and focus mainly on a method that assumes that the time to event follows the additive hazards mo- del. Under the assumption of proportional hazards for the monitoring time, this method does not require knowing the baseline hazard function and allows us to use the theory and software which were developed for Cox model. We also pre- sent a modification of this method, a two-step estimator, and show that it is asymptotically normal and has the advantage of lower asymptotic variance.

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Alzheimer's Disease (AD) affects nearly 5.4 million Americans as of 2016 and is the most common form of dementia. The disease is characterized by the presence of neurofibrillary tangles and amyloid plaques [1]. The amount of plaques are measured by Braak stage, post-mortem. It is known that AD is positively associated with hypercholesterolemia [16]. As statins are the most widely used cholesterol-lowering drug, there may be associations between statin use and AD. We hypothesize that those who use statins, specifically lipophilic statins, are more likely to have a low Braak stage in post-mortem analysis. In order to address this hypothesis, we wished to fit a regression model for ordinal outcomes (e.g., high, moderate, or low Braak stage) using data collected from the National Alzheimer's Coordinating Center (NACC) autopsy cohort. As the outcomes were matched on the length of follow-up, a conditional likelihood-based method is often used to estimate the regression coefficients. However, it can be challenging to solve the conditional-likelihood based estimating equation numerically, especially when there are many matching strata. Given that the likelihood of a conditional logistic regression model is equivalent to the partial likelihood from a stratified Cox proportional hazard model, the existing R function for a Cox model, coxph( ), can be used for estimation of a conditional logistic regression model. We would like to investigate whether this strategy could be extended to a regression model for ordinal outcomes. More specifically, our aims are to (1) demonstrate the equivalence between the exact partial likelihood of a stratified discrete time Cox proportional hazards model and the likelihood of a conditional logistic regression model, (2) prove equivalence, or lack there-of, between the exact partial likelihood of a stratified discrete time Cox proportional hazards model and the conditional likelihood of models appropriate for multiple ordinal outcomes: an adjacent categories model, a continuation-ratio model, and a cumulative logit model, and (3) clarify how to set up stratified discrete time Cox proportional hazards model for multiple ordinal outcomes with matching using the existing coxph( ) R function and interpret the regression coefficient estimates that result. We verified this theoretical proof through simulation studies. We simulated data from the three models of interest: an adjacent categories model, a continuation-ratio model, and a cumulative logit model. We fit a Cox model using the existing coxph( ) R function to the simulated data produced by each model. We then compared the coefficient estimates obtained. Lastly, we fit a Cox model to the NACC dataset. We used Braak stage as the outcome variables, having three ordinal categories. We included predictors for age at death, sex, genotype, education, comorbidities, number of days having taken lipophilic statins, number of days having taken hydrophilic statins, and time to death. We matched cases to controls on the length of follow up. We have discussed all findings and their implications in detail.