Univariate and Multivariate Survival Models with Flexible Hazard Functions

Our research focuses on exploring and developing flexible Bayesian methodologies to model both univariate and multivariate survival data. When developing a Bayesian survival model, the most desirable properties are often flexibility of hazard functions, a proper posterior distribution and efficient implementation. The novelty of our work can be classified into three sections: first, we introduce a new distribution to model univariate and bivariate survival data. Although extreme value theory and subsequently the Generalized Extreme Value (GEV) distribution have been explored in the past to model rare events, our work is the first of its kind to extend GEV framework into the foray of survival analysis. We develop a cure rate model and apply it to various types of univariate cancer survival data. Second, we provide a novel method of estimating the copula association parameter for bivariate survival data using an empirical Bayes approach. Lastly we propose a novel Bayesian R-Vine approach to model multivariate survival data. The thesis consists of five chapters. Chapter 1 introduces the problem of survival data analysis and provides a brief overview of both the frequentist and Bayesian methods developed over the past few decades. Chapter 2 briefly introduces the univariate extreme value analysis. In Chapter 3, we use both forms of the GEV distribution, the Maxima and the Minima to develop a Bayesian modeling technique to analyze right-censored log survival data for populations with a surviving fraction. Next in Chapter 4, we consider bivariate survival data and use copula structures to model the association between the survival times. A novel empirical Bayesian method for estimating the copula function has been proposed. Using our model, we enable the user to use different copula functions to model the same data and hence introduce the concept of copula choice using the Bayesian model selection approach. We demonstrate through extensive simulations that the empirical Bayesian approach provides tighter HPD intervals for the copula parameter of association as compared to full Bayesian and two-stage estimation procedures. Lastly, chapter 5 introduces a novel approach to model multivariate survival data using a Bayesian R-vine copula approach. We show that this method provides flexibility and easy computation even for dimensions 3 and higher as compared to direct extension of bivariate copula families to multivariate dimensions

A randomized Phase II trial evaluating efficacy, safety, and tolerability of oral BI 409306 in attenuated psychosis syndrome: Design and rationale.

AimAttenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first-episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase-9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated.MethodsIn this Phase II, multinational, double-blind, parallel-group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout.ConclusionsThis trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence-based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers

A randomized Phase II trial evaluating efficacy, safety, and tolerability of oral BI 409306 in attenuated psychosis syndrome:Design and rationale

AIM: Attenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders‐5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first‐episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase‐9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated. METHODS: In this Phase II, multinational, double‐blind, parallel‐group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout. CONCLUSIONS: This trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence‐based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers

A randomized Phase II trial evaluating efficacy, safety, and tolerability of oral BI 409306 in attenuated psychosis syndrome: Design and rationale

Aim Attenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first-episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase-9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated. Methods In this Phase II, multinational, double-blind, parallel-group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout. Conclusions This trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence-based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers