Saudi Cultural Missions Theses & Dissertations
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Item Restricted Optimal Design In Multi-State Models For Clinical Trials(King's College London, 2025) Alzahrani, Hanan; Gilmour, StevenClinical trials are crucial for medical research and evidence-based healthcare. Tradition- ally focused on simple outcomes, many health conditions need more complex analysis to capture various patient states. Multi-state models address this by representing dynamic health transitions as a stochastic process. This research focuses on designing optimal experiments for multi-state models in survival data (i.e. time-to-event data), specifically exploring D-, weighted A-, and Ds- optimal designs for simple two-state model and competing risks model. Both complete (non-censored) data and type-I censored data scenarios with varying levels of censoring are considered. The aim is to optimise clinical trial designs within the multi-state model framework to achieve the most accurate parameter estimation. For the simple multi-state model, random data from the Weibull regression model fits into a nonlinear survival model. For competing risk models, bootstrap sampling methods improve precision and speed. An exchange algorithm constructs exact optimal designs, accommodating both censored and non-censored data. The sample covariance matrix of parameter estimators is derived, and an exchange algorithm is implemented to construct exact optimal designs for both the simple two-state model and the competing risks three-state model. These designs accommodate both censored and non-censored data. Extensive experiments using the developed algorithm, with various initial designs and prior points, consistently show that the optimal design typically includes points at the extremes, with proportions dependent on the optimality criterion and censoring percentage. The convergence of different designs to the same optimal design across experiments provides strong evidence of the optimality of the reported design.9 0Item Restricted Optimal Design In Multi-State Models For Clinical Trials(King's College London, 2025) Alzahrani, Hanan; Gilmour, StevenClinical trials are crucial for medical research and evidence-based healthcare. Tradition- ally focused on simple outcomes, many health conditions need more complex analysis to capture various patient states. Multi-state models address this by representing dynamic health transitions as a stochastic process. This research focuses on designing optimal experiments for multi-state models in survival data (i.e. time-to-event data), specifically exploring D-, weighted A-, and Ds- optimal designs for simple two-state model and competing risks model. Both complete (non-censored) data and type-I censored data scenarios with varying levels of censoring are considered. The aim is to optimise clinical trial designs within the multi-state model framework to achieve the most accurate parameter estimation. For the simple multi-state model, random data from the Weibull regression model fits into a nonlinear survival model. For competing risk models, bootstrap sampling methods improve precision and speed. An exchange algorithm constructs exact optimal designs, accommodating both censored and non-censored data. The sample covariance matrix of parameter estimators is derived, and an exchange algorithm is implemented to construct exact optimal designs for both the simple two-state model and the competing risks three-state model. These designs accommodate both censored and non-censored data. Extensive experiments using the developed algorithm, with various initial designs and prior points, consistently show that the optimal design typically includes points at the extremes, with proportions dependent on the optimality criterion and censoring percentage. The convergence of different designs to the same optimal design across experiments provides strong evidence of the optimality of the reported design.43 0Item Restricted Real-World Data Synergy: Optimizing Clinical Trials Through Evidence Integration(King's College London, 2024-08-13) Alharrah, Abdullah; Prapopoulou, MariaBackground Integration of real-world evidence into clinical trials is an emerging approach, which attempts to increase the generalizability, credibility, and efficiency of clinical research. RWE, derived from sources such as EHRs, patient registries, and insurance claims, will provide real-world effectiveness and safety information for medical interventions. While it has a lot of potential, the best way to incorporate RWE into clinical studies remains relatively unexplored, and challenges associated with data quality, standardization, and adherence to the regulation are significant. Methods A systematic review was used to examine the current literature on the integration of Real-world evidence (RWE) in clinical trials and a stakeholder review to identify the methods, opportunities and challenges for this integration. The literature review aimed to examine studies from the past 10 years, focusing in the practical benefits in using RWE to enhance patient recruitment and site selection and evaluated the methods of integration and their challenges. Case studies from pharmaceutical industry and research institutions were analyzed to showcase the real-world applications of RWE. Results The research further identified key challenges in integrating RWE into clinical trials, such as data quality, data standardiza)on, and regulatory acceptance. It also brought out practical benefits that are related to RWE, among them improved patient recruitment, better efficiency in conducting trials, and facilitating validation and complementation of RCT findings. Case studies illustrated successful applications of RWE in several therapeutic areas, specifically on how this could be used in the design and conduct of clinical trials to enhance generalizability and applicability. Stakeholder survey highlighted the need for collaboration between stakeholders. Conclusion Real-world evidence showed positive outcome regarding patient safety and reduction of clinical trials duration and costs. Although RWE proved beneficial, challenges such as data quality, standardization, and regulatory compliance need to be addressed. Suggesting modification to current methodologies and regulatory guidance for improved patient outcomes and more informed healthcare decisions.4 0Item Restricted Exploring Physiologic Markers for the Identification of Vasovagal Syncope(University of Calgary, 2024) Robert S Sheldon, Mohammed Alsaleh; Sheldon, Robert SBackground: Vasovagal Syncope (VVS) is a common cardiovascular disorder, with at least 40% of individuals experiencing at least one episode in their life and about 20% of adults experiencing recurrent episodes. Traditional diagnostic methods such as the Head-Up Tilt (HUT) test and Implantable Cardiac Monitors (ICM) have significant limitations, including limited availability, high costs, and intensive resource requirements. A novel wearable, beat-to-beat blood pressure (BP) monitor is being developed to address these issues. This device, worn on the ear, samples BP at 50 Hz, stores and streams data, and features a rechargeable battery lasting up to 30 hours. This innovative solution will offer a cost-effective, user-friendly alternative for VVS management, potentially improving diagnostic accuracy and patient outcomes. Aims: We aimed to investigate the potential of a wearable beat-to-beat BP monitor in diagnosing vasovagal syncope. The thesis is structured around the following objectives: Objective 1: Provide a detailed narrative review of vasovagal syncope physiology, the BezoldJarisch reflex, and the need for a wearable beat-to-beat BP monitor. Objective 2: Validate the short-term blood pressure fluctuations during scripted physiological changes with a wearable beat-to-beat BP monitor. Methods: The narrative review explores physiological mechanisms underlying VVS, highlighting serotonin's role. For Objective 2 data were collected from 14 participants during activities such as rhythmic breathing and hand grips to validate the ear BP monitor. Spectral and coherence analyses assessed synchronization between the ear monitor and the Modelflow system, with non-parametric methods evaluating statistical differences. ii Results: The narrative review identified key markers for monitoring VVS. The narrative review identified key markers for monitoring vasovagal syncope (VVS), which guided the validation of the ear BP monitor. Data was successfully collected from 14 out of 20 participants, comprising 47% male and 53% female subjects, with an average age of 24.29 ± 5.61 years. The device demonstrated high coherence values (>0.95) across all activities, indicating strong synchronization with the Modelflow system. No significant differences were observed in systolic BP measurements, with p-values of 0.37 for low-frequency components and 0.18 for high-frequency components, confirming the ear BP monitor's ability to capture BP fluctuations during dynamic physiological changes accurately. Further analysis identified the fundamental heartbeat frequency as 1.4 Hz, with harmonics at 2.8 Hz, 4.2 Hz, and beyond. The coherence of these harmonics highlighted the consistency of the heartbeat-induced waveform shapes, indicating that the arterial blood pressure measurements from the Modelflow and EarBP devices were stable and reliable. Coherence across frequencies revealed comparable signal synchronization between the two devices, with significant coherence observed at the fundamental frequency and its harmonics. Coherence values were tightly clustered near the median across all conditions, with the Valsalva maneuver showing slightly more significant variability due to lower coherence values in some participants. These results collectively validate the ear BP monitor as a reliable tool for arterial pressure measurement and synchronized waveform analysis. Conclusion: This thesis advances the understanding of vasovagal syncope (VVS) physiology and validates using a novel ear-based blood pressure monitor. The narrative review identified key physiological markers and mechanisms, including the Bezold-Jarisch reflex and serotonin signaling, central to VVS episodes. The validation study demonstrated high accuracy and synchronization of the ear BP monitor with established standards, offering a non-invasive, iii wearable alternative for real-time blood pressure monitoring. While promising, further research is required to expand its validation across diverse populations and address potential limitations such as motion artifacts. These findings support the use of an ear BP monitor as an innovative tool with the potential to diagnose vasovagal syncope2 0