Segmentation and classification of lung nodules from Thoracic CT scans : methods based on dictionary learning and deep convolutional neural networks.

Lung cancer is a leading cause of cancer death in the world. Key to survival of patients is early diagnosis. Studies have demonstrated that screening high risk patients with Low-dose Computed Tomography (CT) is invaluable for reducing morbidity and mortality. Computer Aided Diagnosis (CADx) systems can assist radiologists and care providers in reading and analyzing lung CT images to segment, classify, and keep track of nodules for signs of cancer. In this thesis, we propose a CADx system for this purpose. To predict lung nodule malignancy, we propose a new deep learning framework that combines Convolutional Neural Networks (CNN) and Recurrent Neural Networks (RNN) to learn best in-plane and inter-slice visual features for diagnostic nodule classification. Since a nodule\u27s volumetric growth and shape variation over a period of time may reveal information regarding the malignancy of nodule, separately, a dictionary learning based approach is proposed to segment the nodule\u27s shape at two time points from two scans, one year apart. The output of a CNN classifier trained to learn visual appearance of malignant nodules is then combined with the derived measures of shape change and volumetric growth in assigning a probability of malignancy to the nodule. Due to the limited number of available CT scans of benign and malignant nodules in the image database from the National Lung Screening Trial (NLST), we chose to initially train a deep neural network on the larger LUNA16 Challenge database which was built for the purpose of eliminating false positives from detected nodules in thoracic CT scans. Discriminative features that were learned in this application were transferred to predict malignancy. The algorithm for segmenting nodule shapes in serial CT scans utilizes a sparse combination of training shapes (SCoTS). This algorithm captures a sparse representation of a shape in input data through a linear span of previously delineated shapes in a training repository. The model updates shape prior over level set iterations and captures variabilities in shapes by a sparse combination of the training data. The level set evolution is therefore driven by a data term as well as a term capturing valid prior shapes. During evolution, the shape prior influence is adjusted based on shape reconstruction, with the assigned weight determined from the degree of sparsity of the representation. The discriminative nature of sparse representation, affords us the opportunity to compare nodules\u27 variations in consecutive time points and to predict malignancy. Experimental validations of the proposed segmentation algorithm have been demonstrated on 542 3-D lung nodule data from the LIDC-IDRI database which includes radiologist delineated nodule boundaries. The effectiveness of the proposed deep learning and dictionary learning architectures for malignancy prediction have been demonstrated on CT data from 370 biopsied subjects collected from the NLST database. Each subject in this database had at least two serial CT scans at two separate time points one year apart. The proposed RNN CAD system achieved an ROC Area Under the Curve (AUC) of 0.87, when validated on CT data from nodules at second sequential time point and 0.83 based on dictionary learning method; however, when nodule shape change and appearance were combined, the classifier performance improved to AUC=0.89

A Likelihood Based Approach to the Assessment of Large Sample Convergence and Model Based Clustering.

The likelihood is a function of model parameter(s) and data using a pre-defined probability density function (pdf). Thus, the likelihood can be viewed as model-data combination that can be utilized to address questions of interest. The relative likelihood function is the likelihood function scaled by its mode so as to have its maximum at one. Unlike likelihood functions, relative likelihood functions have attracted little attention and use by statisticians. The proposed dissertation work explores the properties and applications of relative likelihood functions in examining the large-sample convergence properties of maximum likelihood estimator (MLE) and in relation to clustering. The dissertation consists of three chapters. The first chapter presents a simulation based approach to examine the relationship between sample size and the asymptotic behavior of the MLE. The convergence of the observed relative likelihood function (RLF) to the asymptotic relative likelihood function (RLF) is assessed for different sample sizes using two measures of convergence; difference in areas and dissimilarity in shape. The proposed approach has been applied to data from the literature as well as to data simulated from different exponential family distributions. The second chapter proposes a novel clustering approach based on the observed RLFs. Observations in the dataset are assumed to follow a known distribution and observed RLFs are obtained. The observed RLFs are further scaled by the inverse of the asymptotic variation (Fisher Information) evaluated at the mode of the likelihood functions. The weighted RLFs reflect information based similarity among observations in the data. A data matrix is then developed by evaluating the weighted RLFs at different values in the parameter space. The data matrix allows for direct application of standard clustering algorithms such as k-means algorithm. This clustering approach was applied to simulated dataset based on real data and to datasets simulated from known distributions. The third chapter examines the proposed RLF based clustering approach to a publicly available gene expression dataset consisting of 70 gene expression profiles used to classify patients into prognostic groups. The agreement between the RLF clustering results and previous classification is also presented. The clusters obtained are also examined in relation to differences in two clinical features – time to overall survival; and time to metastases

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)