Probabilistic uncertainty quantification and experiment design for nonlinear models: Applications in systems biology

Despite the ever-increasing interest in understanding biology at the system level, there are several factors that hinder studies and analyses of biological systems. First, unlike systems from other applied fields whose parameters can be effectively identified, biological systems are usually unidentifiable, even in the ideal case when all possible system outputs are known with high accuracy. Second, the presence of multivariate bifurcations often leads the system to behaviors that are completely different in nature. In such cases, system outputs (as function of parameters/inputs) are usually discontinuous or have sharp transitions across domains with different behaviors. Finally, models from systems biology are usually strongly nonlinear with large numbers of parameters and complex interactions. This results in high computational costs of model simulations that are required to study the systems, an issue that becomes more and more problematic when the dimensionality of the system increases. Similarly, wet-lab experiments to gather information about the biological model of interest are usually strictly constrained by research budget and experimental settings. The choice of experiments/simulations for inference, therefore, needs to be carefully addressed. ^ The work presented in this dissertation develops strategies to address theoretical and practical limitations in uncertainty quantification and experimental design of non-linear mathematical models, applied in the context of systems biology. This work resolves those issues by focusing on three separate but related approaches: (i) the use of probabilistic frameworks for uncertainty quantification in the face of unidentifiability (ii) the use of behavior discrimination algorithms to study systems with discontinuous model responses and (iii) the use of effective sampling schemes and optimal experimental design to reduce the computational/experimental costs. ^ This cumulative work also places strong emphasis on providing theoretical foundations for the use of the proposed framework: theoretical properties of algorithms at each step in the process are investigated carefully to give more insights about how the algorithms perform, and in many cases, to provide feedback to improve the performance of existing approaches. Through the newly developed procedures, we successfully created a general probabilistic framework for uncertainty quantification and experiment design for non-linear models in the face of unidentifiability, sharp model responses with limited number of model simulations, constraints on experimental setting, and even in the absence of data. The proposed methods have strong theoretical foundations and have also proven to be effective in studies of expensive high-dimensional biological systems in various contexts

Perforator Mapping of the Superficial and Deep Inferior Epigastric Artery in the Abdominal Region of the Vietnamese

BACKGROUND: Previous studies worldwide have investigated the anatomy of the perforators of the deep inferior epigastric arteries to figure out the navigation patterns of the perforators on the abdominal wall. This has been inconsistent amongst the researchers about how to select the perforator to increase the blood supply area for the flap. AIM: To explore the blood supply area of the perforators of the superficial and deep inferior epigastric artery in the abdominal region of the Vietnamese by dissection and 64-slice multislice computed tomography (64-slice MSCT). METHODS: A descriptive cross-sectional study Center from September 2014 to September 2016 on two groups including 30 cadavers fixed by formalin 10% in Anatomy Department of UPNT, and 37 patients getting the 64-slice MSCT abdominal arteries angiogram. RESULTS: The superficial epigastric arteries at the level of the inguinal ligament were located in the middle region, with 96% (right) and 88.5% (left). The anterior superior iliac spine level was in the middle, and lateral regions of 68% and 32% respectively. The level of the umbilical cord was in the lateral region with 66.7% and 85.7%, respectively. There were about 6 perforators of the deep inferior epigastric arteries located in the navel area. These perforators were 70% in the medial region and 30% in the middle region. CONCLUSION: Mapping the blood supply based on the fourth space in the abdominal region in which the superfical inferior epigastric arteries supplied the lateral area. The middle and the internal ones were the perforators of the deep inferior epigastric arteries

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

Despite their promise, circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection face challenges in test performance, due mostly to the limited abundance of ctDNA and its inherent variability. To address these challenges, published assays to date demanded a very high-depth sequencing, resulting in an elevated price of test. Herein, we developed a multimodal assay called SPOT-MAS (screening for the presence of tumor by methylation and size) to simultaneously profile methylomics, fragmentomics, copy number, and end motifs in a single workflow using targeted and shallow genome-wide sequencing (~0.55×) of cell-free DNA. We applied SPOT-MAS to 738 non-metastatic patients with breast, colorectal, gastric, lung, and liver cancer, and 1550 healthy controls. We then employed machine learning to extract multiple cancer and tissue-specific signatures for detecting and locating cancer. SPOT-MAS successfully detected the five cancer types with a sensitivity of 72.4% at 97.0% specificity. The sensitivities for detecting early-stage cancers were 73.9% and 62.3% for stages I and II, respectively, increasing to 88.3% for non-metastatic stage IIIA. For tumor-of-origin, our assay achieved an accuracy of 0.7. Our study demonstrates comparable performance to other ctDNA-based assays while requiring significantly lower sequencing depth, making it economically feasible for population-wide screening