Background: Survival analysis is sometimes called time-to-event analysis. The Cox model is used widely in survival analysis, where the covariates act multiplicatively on unknown baseline hazards. However, the Cox model requires the proportionality assumption, which limits its applications. The additive hazards model has been used as an alternative to the Cox model, where the covariates act additively on unknown baseline hazards. Objectives and methods: In this thesis, performance of the Cox multiplicative hazards model and the additive hazards model have been demonstrated and applied to the transfer, lifting and repositioning (TLR) injury prevention study. The TLR injury prevention study was a retrospective, pre-post intervention study that utilized a non-randomized control group. There were 1,467 healthcare workers from six hospitals in Saskatchewan, Canada who were injured from January 1, 1999 to December 1, 2006. De-identified data sets were received from the Saskatoon Health Region and Regina Quappelle Health Region. Time to repeated TLR injury was considered as the outcome variable. The models goodness of fit was also assessed. Results: Of a total of 1,467 individuals, 149 (56.7%) in the control group and 114 (43.3%) in the intervention group had repeated injuries during the study period. Nurses and nursing aides had the highest repeated TLR injuries (84.8%) among occupations. Back, neck and shoulders were the most common body parts injured (74.9%). These covariates were significant in both Cox multiplicative and additive hazards models. The intervention group had 27% fewer repeated injuries than the control group in the multiplicative hazards model (HR= 0.63; 95% CI=0.48-0.82; p-value=0.0002). In the additive model, the hazard difference between the intervention and the control groups was 0.002. Conclusion: Both multiplicative and additive hazards models showed similar results, indicating that the TLR injury prevention intervention was effective in reducing repeated injuries. The additive hazards model is not widely used, but the coefficient of the covariates is easy to interpret in an additive manner. The additive hazards model should be considered when the proportionality assumption of the Cox model is doubtful.

The field of survival analysis has experienced tremendous growth during the latter half of the 20th century. The methodological developments of survival analysis that have had the most profound impact are the Kaplan-Meier method for estimating the survival function, the log-rank test for comparing the equality of two or more survival distributions, and the Cox proportional hazards (PH) model for examining the covariate effects on the hazard function. The accelerated failure time (AFT) model was proposed but seldom used. In this thesis, we present the basic concepts, nonparametric methods (the Kaplan-Meier method and the log-rank test), semiparametric methods (the Cox PH model, and Cox model with time-dependent covariates) and parametric methods (Parametric PH model and the AFT model) for analyzing survival data.<p> We apply these methods to a randomized placebo-controlled trial to prevent Tuberculosis (TB) in Ugandan adults infected with Human Immunodificiency Virus (HIV). The objective of the analysis is to determine whether TB preventive therapies affect the rate of AIDS progression and survival in HIV-infected adults. Our conclusion is that TB preventive therapies appear to have no effect on AIDS progression, death and combined event of AIDS progression and death. The major goal of this paper is to support an argument for the consideration of the AFT model as an alternative to the PH model in the analysis of some survival data by means of this real dataset. We critique the PH model and assess the lack of fit. To overcome the violation of proportional hazards, we use the Cox model with time-dependent covariates, the piecewise exponential model and the accelerated failure time model. After comparison of all the models and the assessment of goodness-of-fit, we find that the log-logistic AFT model fits better for this data set. We have seen that the AFT model is a more valuable and realistic alternative to the PH model in some situations. It can provide the predicted hazard functions, predicted survival functions, median survival times and time ratios. The AFT model can easily interpret the results into the effect upon the expected median duration of illness for a patient in a clinical setting. We suggest that the PH model may not be appropriate in some situations and that the AFT model could provide a more appropriate description of the data.

Background: Survival analysis is sometimes called time-to-event analysis. The Cox model is used widely in survival analysis, where the covariates act multiplicatively on unknown baseline hazards. However, the Cox model requires the proportionality assumption, which limits its applications. The additive hazards model has been used as an alternative to the Cox model, where the covariates act additively on unknown baseline hazards. Objectives and methods: In this thesis, performance of the Cox multiplicative hazards model and the additive hazards model have been demonstrated and applied to the transfer, lifting and repositioning (TLR) injury prevention study. The TLR injury prevention study was a retrospective, pre-post intervention study that utilized a non-randomized control group. There were 1,467 healthcare workers from six hospitals in Saskatchewan, Canada who were injured from January 1, 1999 to December 1, 2006. De-identified data sets were received from the Saskatoon Health Region and Regina Quappelle Health Region. Time to repeated TLR injury was considered as the outcome variable. The models goodness of fit was also assessed. Results: Of a total of 1,467 individuals, 149 (56.7%) in the control group and 114 (43.3%) in the intervention group had repeated injuries during the study period. Nurses and nursing aides had the highest repeated TLR injuries (84.8%) among occupations. Back, neck and shoulders were the most common body parts injured (74.9%). These covariates were significant in both Cox multiplicative and additive hazards models. The intervention group had 27% fewer repeated injuries than the control group in the multiplicative hazards model (HR= 0.63; 95% CI=0.48-0.82; p-value=0.0002). In the additive model, the hazard difference between the intervention and the control groups was 0.002. Conclusion: Both multiplicative and additive hazards models showed similar results, indicating that the TLR injury prevention intervention was effective in reducing repeated injuries. The additive hazards model is not widely used, but the coefficient of the covariates is easy to interpret in an additive manner. The additive hazards model should be considered when the proportionality assumption of the Cox model is doubtful.

Målsättning Att utreda skillnader i tillgänglighet till insulinpump mellan olika patientgrupper samt vad som orsakar ett byte till insulinpump. Metod Data från 7224 individer med typ 1 diabetes vid tio olika vårdenheter analyserades för att utreda effekterna av njurfunktion, kön, långtidsblodsocker, insulindos, diabetesduration samt ålder. Jämförelsen mellan patientgrupper utfördes med logistisk regression som en tvärsnittsstudie och Cox-regression för att utreda vad som föregått ett byte till pump. Resultat Genom logistisk regression erhölls en bild av hur skillnader mellan patienter som använder insulinpump och patienter som inte gör det ser ut i dagsläget. Cox-regressionen tar med ett tidsperspektiv och ger på så sätt svar på vad som föregått ett byte till insulinpump. Dessa analyser gav liknande resultat gällande variabler konstanta över tiden. Kvinnor använder pump i större utsträckning än män och andelen pumpanvändare skiljer sig åt vid olika vårdenheter. I dagsläget visar sig hög ålder sänka sannolikheten att använda insulinpump, vilket bekräftas vid den tidsberoende studien som visade hur sannolikheten att byta till pump är avsevärt lägre vid hög ålder. Långtidsblodsockret har också tydlig effekt på sannolikheten att gå över till pump där ett högt långtidsblodsocker medför hög sannolikhet att byta till insulinpump. Slutsatser I dagsläget finns det skillnader i andelen insulinpumpanvändare mellan olika patientgrupper och skillnader finns även i de olika gruppernas benägenhet att byta från andra insulinbehandlingar till insulinpump. Beroende av patienters njurfunktion, kön, långtidsblodsocker, insulindos, diabetesduration och ålder har dessa olika sannolikheter att byta till insulinpump.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world and Taiwan. The major factors involved in the molecular pathogenesis for the development of HCC had been explored in recent years. An extensive array of growth factors and their receptors had been identified and may act as positive and negative modulators in different stages of hepatocarcinogenesis. Current therapeutic approaches for HCC include surgical resection (include liver transplantation), trans-arterial embolization (TAE), alcohol injection, etc. However, the effect is limited due to most of the HCC patients present with advanced stages of the disease. Therefore, this underscores the need for the development of novel therapeutic strategies. It is pivotal to set up an orthotopic hepatoma model for the development of novel intervention strategies for HCC. Under the guidance of ultrasound, we are able to create hepatoma in the liver lobe of Sprague-Dawley (SD) rats by injection of Novikoff (N1-S1) hepatoma cells. In addition, sonographic technique was employed for the monitoring of tumor growth in this animal model in the following subprojects. The continuous, non-invasive measurement of orthotopic hepatoma development will be a valuable tool for the evaluation of effects of drugs for treatment of HCC. In Chapter 1, the study employed a relatively non-invasive approach to establish an orthotopic HCC model in immune-competent rats. This was done by ultrasound-guided implantation of cancer cells and the model was used to evaluate the therapeutic efficacy of short-term and low-dose epirubicin chemotherapy. Ultrasound-guided implantation of Novikoff hepatoma cells led to the formation of orthotopic HCC in 60.4% of the SD rats. Moreover, tumor sizes measured by ultrasound significantly correlated with those measured by calipers after sacrificing the animals (P < 0.00001). The rate of tumor induction by ultrasound-guided implantation was comparable to that of laparotomy (55/91, 60.4% vs. 39/52, 75%) and no significant difference in sizes of tumor was noted between the two groups. Moreover, there was a significant correlation in tumor size measurement by ultrasound and computerized tomography. In tumor-bearing rats, short-term and low-dose epirubicin chemotherapy caused a significant reduction in tumor growth, and was found to be associated with enhanced apoptosis and attenuated proliferation as well as a decrease in microvessel density in tumors. In chapter 2, we investigated the chemopreventive effects of celecoxib in the growth of orthotopic rat HCC and the possible signal pathways involved. The status of COX-2 expression in rat Novikoff HCC was consistent with that in human HCC. Both Western blot and PCR tests had proved that N1-S1 was a HCC model presenting with low COX-2 enzymes in tumor cells. Then, low doses of celecoxib was shown to effectively inhibited the proliferation and increased the apoptosis of N1-S1 cells in vitro, which were also safe to the normal hepatocytes. Moreover, chemoprevention by celecoxib inhibiting the HCC tumor growth was shown in rat orthotropic HCC model. Tumor incidence was not affected by the celecoxib prevention, but, tumor weight was found significantly suppressed by the drug. Possible mechanisms of chemoprevention by celecoxib seen in the animal model were thought to be related to the anti-angiogenic, anti-proliferative and anti-hCSC characters of the drug. In chapter 3, we tried to test the combined inhibitory effects of low doses of celecoxib and epirubicin on the growth of HCC. Combined low doses of epirubicin and celecoxib was effective in inhibiting the hepatic cancer stem cells, tumor angiogenesis, tumor cell proliferation, as well as promoting cancer apoptosis. These are compatible with the effects of the individual drugs on HCC growth shown in the previous two chapters. In general, combination therapy expressed more effectiveness in tumor suppression and less bone marrow suppression than the individual drugs used alone. Taken together, ultrasound-guided implantation of Novikoff hepatoma cells is an effective means of establishing orthotopic HCC in SD rats, which is suitable and convenient for therapeutic trial of anti-HCC treatment. In the current study, we had proved the efficacies of low doses of two drugs, epirubicin and celecoxib, acting individually, as well as the combined effects of them in treating HCC in this model.

Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. Interleukin-10 (IL-10) is a cytokine that downregulates the proinflammatory response and has a modulatory effect on hepatic fibrogenesis. The aim of this study was to investigate whether IL-10 gene therapy possesses anti-hepatic fibrogenesis in mice. Liver fibrosis was induced by long-term thioacetamide administration in mice. Human IL-10 expression plasmid was delivered via electroporation after liver fibrosis established. IL-10 gene therapy reversed hepatic fibrosis and prevented cell apoptosis in a thioacetamide-treated liver. RT-PCR revealed IL-10 gene therapy could reduce liver transforming growth factor-£]1¡]TGF-£]1¡^, tumor necrosis factor-£\¡]TNF-£\¡^, collagen £\1, cell adhesion molecule, and tissue inhibitors of metalloproteinase¡]TIMPs¡^mRNA upregulation. Following gene transfer, the activation of £\-smooth muscle actin¡]£\-SMA¡^and cyclooxygenase-2¡]COX-2¡^were significantly attenuated. In brief, electroporative IL-10 gene therapy might be an effective therapeutic reagent for liver fibrosis with potential future clinical applications.

The purpose of this study was to assess the prognostic significance and clinical correlations of cyclooxgenase-2 expression (COX) in a cohort of patients treated with radiation (RT) for post-mastectomy chest wall relapse (PMCWR). Between 1975 and 1999, 113 patients were treated for isolated PMCWR. All patients were treated with biopsy and/or excision of the CWR followed by RT. Median follow-up was 10 years. All clinical data including demographics, pathology, staging, receptor status, HER-2/neu status, and adjuvant therapy were entered into a computerized database. Paraffin-embedded CWR specimens were retrieved from 42 patients, of which 38 were evaluated, created into a tissue microarray, stained by immunohistochemical methods for COX, and graded 0-3+. A score of 2-3+ was considered positive. Overall survival from original diagnosis for the entire cohort was 44% at 10 years. Survival rate after chest wall recurrence was 28% at 10 years. The distant metastasis-free survival rate after CWR was 40% at 10 years. Local-regional control of disease was achieved in 79% at 10 years after CWR. COX was considered positive in 13 of 38 cases. COX was inversely correlated with ER (p= .045) and PR (p = .028), and positively correlated with HER-2/neu (p =.003). COX was also associated with a shorter time to PMCWR. The distant metastasis-free rate for COX negative patients was 70% at 10 years, compared with 31% at 10 years for COX-2 positive patients (p = 0.029). COX positive had a poorer local-regional progression-free rate of 19% at 10 years, compared with 81% at 10 years for COX negative (p = 0.003). Outcome following RT for PMCWR is relatively poor. Positive COX correlated with other markers of poor outcome including a shorter time to local relapse, negative ER/PR and positive Her-2/neu status. Positive COX correlated with higher distant metastasis and lower local-regional control of disease. If confirmed with larger studies, these data have implications with respect to the concurrent use of COX-2 inhibitors and radiation for PMCWR.

It is common practice to use Cox-Snell residuals to check for overall goodness of tin survival models. We evaluate the presumed relation of unit exponentially dis-tributed residuals for a good model t and evaluate under some violations of themodel. This is done graphically with the usual graphs of Cox-Snell residual andformally using Kolmogorov-Smirnov goodness of t test. It is observed that residu-als from a correctly tted model follow unit exponential distribution. However, theCox-Snell residuals do not seem to be sensitive to the violations of the model.

Šiame magistro darbe yra pateikiamas įmonės išgyvenamumą prognozuojantis Kokso proporcingųjų rizikų modelis. Pirmoje dalyje yra pateikiama trumpa modelių, susijusių su įmonių bankrotais ar nemokumu, apžvalga. Taip pat yra pristatomi balansinių ataskaitų ir įmonių finansų teoriniai pagrindai, įvairūs finansiniai rodikliai (įmonės pelnas/nuostolis, įsipareigojimai, turtas ir kt.) bei santykiniai finansiniai rodikliai (įmonės bendras skolos rodiklis, grynojo pelningumo koeficientas ir kt.). Be to, pateikiami išgyvenamumo analizės ir Kokso proporcingųjų rizikų modelio teoriniai pagrindai. Antroje darbo dalyje pateikiami empiriniai skaičiavimai. Čia parenkami statistiškai reikšmingi finansiniai ir santykiniai finansiniai rodikliai, įtakojantys įmonės gyvavimo trukmę, sudaromas bei tiriamas Kokso regresijos modelis, kuris vertina įmonės tikimybę išgyventi po tam tikro laiko. Ekonometrinė analizė atliekama naudojant SPSS, MS Excel ir SAS programinę įrangą. / This Master thesis develops survival of company prediction Cox proportional hazards model using the statistical methodology of Survival analysis. In the first part the short review of literature about models related with company’s bankruptcy, failure or financial distress is presented. Also the background of financial statement analysis, corporate finance, various financial variables (company’s profit/loss, liabilities, asset and other) and financial ratios (debt ratio, total asset turnover and other) are clarified. Furthermore, the theoretical background of Survival analysis and Cox proportional hazards model are presented. In the following part empirical computations are introduced. There are selected financial variables and financial ratios, which influence company’s survival and are statistically significant. Moreover, Cox regression model for estimating the probability of company’s survival after particular time is presented. Econometric analysis is performed using SPSS, MS Excel and SAS software.

Time-to-event data is used in this thesis to analyze private cars’ longevity in Sweden. Thedataset is provided by Trafikanalys and contains all registered, deregistered or temporary deregisteredcars in Sweden during the time period 2000 - 2012.A Cox proportional hazards model is fitted, including variables such as car manufacturer andcar body. The results show that directly imported cars have a much shorter median survivalcompared to non-imported cars. The convertible cars have the longest median survival amongthe five different car bodies. Sedan and station wagon body types have the shortest mediansurvival. Volvo and Mercedes have the longest survival while Renault, Ford and Opel have theshortest survival. The model fits the data reasonably well, and the assumption of proportionalhazards holds for most of the variables.