In the past few years, biomarkers such as progression free survival (PFS) and time to progression (TTP), have been increasingly used as surrogate endpoints for overall survival (OS) in clinical trials in oncology. An issue occurs when clinical trials which demonstrated statistically significant treatment effect for the surrogate marker, shows no significant effect on the true outcome of interest, OS. It is possible that this lack of concordant results was due to informative censoring. Although it is known that informative censoring may bias the observed results, it is not clear what impact informative censoring has on the surrogacy of one marker in relation to a true outcome. In this thesis, we investigated how informative censoring could affect the results of a surrogate endpoint, and how would that affect the surrogacy of that endpoint. A simulation study was conducted to evaluate the impact of informative censoring on the treatment effect on TTP and the outcomes of the surrogate validation methods relative effect (RE), surrogate threshold effect (STE), and the difference between the treatment effect on TTP and on OS (IRE). The results of the simulation showed that having informative censoring for TTP will indeed bias the treatment effect on TTP as well as the results for the validation methods, RE, STE, and IRE. Hence, we conclude that the effect of informative censoring can greatly influence the ability to validate a surrogate marker, and additionally can bias the ability to determine the efficacy of a new therapy from a clinical trial using a surrogate marker as the primary outcome. / Thesis / Master of Science (MSc)

The selection of the best response variables in a clinical trial is often not straightforward; the primary endpoint of a trial should be clinically relevant, directly related to the primary objective of the trial, and with favorable efficiency to detect the treatment benefit with a reasonable sample size and duration of the trial. With the recent success in the management of heart failure, the mortality rate has dropped significantly compared to two decades ago, and patients with heart failure have high rates of hospitalization and morbid complications along with multiple symptoms and severe limitations in daily activities. Although mortality still remains important as a measure of the clinically relevant benefit and the safety of the intervention, with the low event rate of mortality, it requires large and longer clinical trials to detect treatment benefit of new intervention using mortality as the sole primary endpoint. Thus most heart failure trials use the combined endpoint of death and a second efficacy outcome, such as hospitalizations. This is often analyzed with time-to-first-event survival analysis which ignores possible subsequent hospitalization events and treating the death and first hospitalization equally in the importance and hierarchy of clinical relevance. Accounting for the recurrent events or subsequent death after the hospitalization(s) provides more detailed information on the disease-control process and treatment benefit. In this dissertation we propose a hierarchical endpoint with death in the higher priority and number of hospitalization events in the lower priority as primary endpoint to assess experimental treatment benefit versus a control using a non-parametric generalized Gehan-Wilcoxon test. In addition to the hierarchical endpoint, we also evaluated assessment of experimental treatment benefit on recurrent events with a multi-state model using extended stratified Cox model, considering the multi-states in which patients might transition during the study. We compared the false positive rate and power of the above mentioned methods with the composite endpoint approach and recurrent event endpoint approach analyzed using Andersen-Gill, WLW, and PWP models in simulation studies. Finally we applied all evaluated procedures to the Digitalis Investigation Group (DIG) trial.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany and Ecology Candidate: Bc. Renáta Čeganová Supervisor: RNDr. Jitka Vytlačilová, Ph.D. Title of diploma thesis: Ecotoxicological evaluation of biologically active substances For the observation of the ecotoxicological effects was selected griseofulvin that can be used as antifungal drug and local anesthetic dibucaine hydrochloride. Their analysis was performed by using a multigenerational test with a protozoan Tetrahymena thermophila, Rotoxkit F test with a rotifer Brachionus calyciflorus and algal test with Desmodesmus subspicatus. The mortality or inhibitory effects of the test substances on the growth of organisms was observed. The most sensitive of the test organisms for dibucaine hydrochloride was rotifer Brachionus calyciflorus and for griseofulvin it was alga Desmodesmus subspicatus. Keywords: ecotoxicity, biologically active substances, endpoint, biotests

Ingeniera Civil en Computación / Un endpoint es una aplicación similar a un servicio web que permite consultas estructuradas. Estas aplicaciones trabajan con el lenguaje de consulta SPARQL para consultar los datos y entender su semántica. Hoy día la mayoría de estas aplicaciones no tiene un sistema de seguridad que permita restringir el acceso de usuarios que tienen permisos para modificar estos datos. Este problema fue tomado como proyecto de memoria, y se implementó una solución genérica que permitire a los endpoints hoy existentes, agregar seguridad y administrar roles y usuarios mediante una interfaz gráfica. La implementación de esta solución consistió en tres grandes módulos. La primera parte fue una investigación del estado del arte, donde se estudió lo que otros académicos han investigado sobre el tema. Aquí se contactó a dos grupos de investigadores que han estado involucrados en la Web Semántica y han desarrollado soluciones parciales a este problema. La segunda, consistió en el diseño de la solución, donde se tomó varios conceptos encontrados en la etapa anterior, y en la implementación de ésta. Finalmente, se validó la solución en términos de usabilidad, aplicando dos métodos (Observación y Cuestionario de Usuario Final), y también en términos de rendimiento. La aplicación mostró resolver el problema planteado. Quedó a disposición de la comunidad con código abierto y licencia Atribución 4.0 Internacional de Creative Commons.

The objective of this thesis is to design and implement a speech recognition system for one hundred thousand Chinese names. Mel frequency cepstrum coefficient, hidden Markov model and lexicon search strategy are utilized to choose the name candidates. Furthermore, a mandarin intonation technique is also incorporated into this system to increase the final speech recognition accuracy. The experimental results indicate that for the speaker dependent case, an 85% correct rate can be achieved by use of the proposed intonation classification scheme and the balanced monosyllable training database. The above correct rate has an increase of 8% over the previous method without using these two techniques. Under Redhat Linux 9.0 environment, a mandarin name can be recognized within 2 seconds by the use of a computer with Intel Celeron 2.4 GHz CPU.

Ultrasound technology allows in vivo estimation of carcass composition. Successful genetic evaluation of ultrasonic measures depends upon technician certification guidelines and a viable common-endpoint adjustment strategy for field data. Four technicians and three image interpreters ultrasonically evaluated 172 lambs to determine accuracy and repeatability of loin eye area (LEA), backfat thickness (BF), and body wall thickness (BW) estimations. Correlations between ultrasonic and carcass measurements were 0.66, 0.78, and 0.73 for LEA, BF, and BW, respectively. Performance was similar among technicians and interpreters. Mean bias ranged from -1.30 to -2.66 cm2, -0.12 to -0.17 cm, and 0.14 to -0.03 cm, for LEA, BF, and BW, respectively; prediction standard errors ranged from 1.86 to 2.22 cm2, 0.12 to 0.14 cm, and 0.35 to 0.38 cm, respectively. Repeatability standard errors ranged from 1.61 to 2.45 cm2, 0.07 to 0.11 cm, and 0.36 to 0.42 cm for LEA, BF, and BW, respectively. Changes in ultrasonic measurements were evaluated using seven serial scans on 24 growing Suffolk ram lambs. All equations had similar goodness of fit. Equations were tested on other populations, including similarly-managed rams across breeds and years and ewe lambs fed for slower gain. Correlations between predicted and actual measures ranged from 0.78 to 0.87 for BF and 0.66 to 0.93 for LEA in winter-born rams, were only slightly lower in fall-born rams, and ranged from 0.72 to 0.74 for BF and 0.54 to 0.76 for LEA in ewe lambs. Of the equations tested, linear and allometric forms appear best for general use. / Master of Science

No description available.

In recent years, adaptive designs in clinical trials have been attractive due to their efficiency and flexibility. Response adaptive randomization procedures in phase II or III clinical trials are proposed to appeal ethical concerns by skewing the probability of patient assignments based on the responses obtained thus far, so that more patients will be assigned to a superior treatment group. General response-adaptive randomizations usually assume that the primary endpoint can be obtained quickly after the treatment. However, in real clinical trials, the primary outcome is delayed, making it unusable for adaptation. Therefore, we utilize surrogate and primary endpoints simultaneously to adaptively assign subjects between treatment groups for clinical trials with continuous responses. We explore two types of primary endpoints commonly used in clinical tirials: normally distributed outcome and time-to-event outcome. We establish a connection between the surrogate and primary endpoints through a Bayesian model, and then update the allocation ratio based on the accumulated data. Through simulation studies, we find that our proposed response adaptive randomization is more effective in assigning patients to better treatments as compared with equal allocation randomization and standard response adaptive randomization which is solely based on the primary endpoint.

Master of Science / Department of Animal Sciences & Industry / Elizabeth A. Boyle / Quality attributes of vacuum packaged, skinless smoked sausage made with a combination of pork, turkey, and beef, cooked to 64, 68, or 72°C internal endpoint temperature following USDA FSIS Appendix A, and displayed at 4°C for up to 120 days under light emitting diode (LED) and fluorescent (FLS) lighting were evaluated. External color, pH, thiobarbituric acid reactive substances (TBARS), proximate analysis, reheat yield, and sensory attributes were measured on day 0, 90, and 120 of display. Purge amount and color were measured on day 10, 90, and 120. Product was displayed in LED or FLS retail display cases set to the same operational and temperature profiles. Lighting type had no effect (P>0.05) on any of the measured attributes. Instrumental external color was less (P<0.05) red by 0.63 units in product thermally processed to 64°C than product processed to 68°C. Product cooked to 72°C was less (P<0.05) yellow externally compared to those processed to 64 and 68°C. Purge color lightness increased (P<0.05) in product thermally processed to 72 compared to 64°C. Purge was more red by 0.36 units (P<0.05) on day 120 compared to day 10. Yellowness of purge color increased at 72°C compared to 64°C by 0.66 units. Purge was more yellow (P<0.05) on d 120 compared to d 10 and 90. TBARS values decreased (P<0.05) from 0.70 mg of malonaldehyde/100g on day 0 to 0.35 and 0.23 on d 90 and 120, respectively. Sensory panel scores showed that flavor intensity decreased (P<0.05) as day of storage increased, and saltiness decreased from d 0 to d 90. Purge content increased (P<0.05) from 1.45% to 1.90% in products cooked to 64 and 68°C, respectively. The amount of purge increased (P<0.05) from 1.58% to 1.92% on day 10 and 90, respectively. While there were slight changes found in quality characteristics of smoked sausages during storage, many of these were minimal. Processors could reduce their internal endpoint temperature following USDA FSIS Appendix A guidelines with minimal effect on product quality. Vacuum packaged pre-cooked smoked sausages could be displayed under LED or FLS lighting with no effect on product quality.

Three-dimensional kinematic analysis was used to precisely quantify alterations in gait and compensatory behaviors in rat performance on beamwalk and treadmill tasks following moderate traumatic brain injury. Measures included limb height, joint angles, adduction, flexion, and swing/stance phase duration. Injury-associated changes on the treadmill included postural and hip angle change, and increases in hip height and adduction. The beamwalk presented as a more sensitive measure when coupled with kinematic analysis, as differences between injury groups were evident on measures including knee, ankle, elbow, and mid hip height. Animal response was diverse, possibly reflecting individual compensatory strategies which varied among injured animals. Kinematic analysis was ultimately shown to be a useful tool in characterizing and dissociating initial impairment, compensation, and recovery.