Clustering and graph mining techniques for classification of complex structural variations in cancer genomes

For many years, a major question in cancer genomics has been the identification of those variations that can have a functional role in cancer, and distinguish from the majority of genomic changes that have no functional consequences. This is particularly challenging when considering complex chromosomal rearrangements, often composed of multiple DNA breaks, resulting in difficulties in classifying and interpreting them functionally. Despite recent efforts towards classifying structural variants (SVs), more robust statistical frames are needed to better classify these variants and isolate those that derive from specific molecular mechanisms. We present a new statistical approach to analyze SVs patterns from 2392 tumor samples from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium and identify significant recurrence, which can inform relevant mechanisms involved in the biology of tumors. The method is based on recursive KDE clustering of 152,926 SVs, randomization methods, graph mining techniques and statistical measures. The proposed methodology was able not only to identify complex patterns across different cancer types but also to prove them as not random occurrences. Furthermore, a new class of pattern that was not previously described has been identified.Among others, this study has been supported by projects: SAF2017-89450-R (TransTumVar) and PID2020-119797RB-100 (BenchSV) from Science and Innovation Spanish Minstry. It has also been supported by the Spanish Goverment (contract PID2019-107255GB), Generalitat de Catalunya (contract 2014-SGR-1051) and Universitat Politècnica de Catalunya (45-FPIUPC2018).Peer ReviewedPostprint (published version

Doctor of Philosophy

dissertationCongenital heart defects are classes of birth defects that affect the structure and function of the heart. These defects are attributed to the abnormal or incomplete development of a fetal heart during the first few weeks following conception. The overall detection rate of congenital heart defects during routine prenatal examination is low. This is attributed to the insufficient number of trained personnel in many local health centers where many cases of congenital heart defects go undetected. This dissertation presents a system to identify congenital heart defects to improve pregnancy outcomes and increase their detection rates. The system was developed and its performance assessed in identifying the presence of ventricular defects (congenital heart defects that affect the size of the ventricles) using four-dimensional fetal chocardiographic images. The designed system consists of three components: 1) a fetal heart location estimation component, 2) a fetal heart chamber segmentation component, and 3) a detection component that detects congenital heart defects from the segmented chambers. The location estimation component is used to isolate a fetal heart in any four-dimensional fetal echocardiographic image. It uses a hybrid region of interest extraction method that is robust to speckle noise degradation inherent in all ultrasound images. The location estimation method's performance was analyzed on 130 four-dimensional fetal echocardiographic images by comparison with manually identified fetal heart region of interest. The location estimation method showed good agreement with the manually identified standard using four quantitative indexes: Jaccard index, Sørenson-Dice index, Sensitivity index and Specificity index. The average values of these indexes were measured at 80.70%, 89.19%, 91.04%, and 99.17%, respectively. The fetal heart chamber segmentation component uses velocity vector field estimates computed on frames contained in a four-dimensional image to identify the fetal heart chambers. The velocity vector fields are computed using a histogram-based optical flow technique which is formulated on local image characteristics to reduces the effect of speckle noise and nonuniform echogenicity on the velocity vector field estimates. Features based on the velocity vector field estimates, voxel brightness/intensity values, and voxel Cartesian coordinate positions were extracted and used with kernel k-means algorithm to identify the individual chambers. The segmentation method's performance was evaluated on 130 images from 31 patients by comparing the segmentation results with manually identified fetal heart chambers. Evaluation was based on the Sørenson-Dice index, the absolute volume difference and the Hausdorff distance, with each resulting in per patient average values of 69.92%, 22.08%, and 2.82 mm, respectively. The detection component uses the volumes of the identified fetal heart chambers to flag the possible occurrence of hypoplastic left heart syndrome, a type of congenital heart defect. An empirical volume threshold defined on the relative ratio of adjacent fetal heart chamber volumes obtained manually is used in the detection process. The performance of the detection procedure was assessed by comparison with a set of images with confirmed diagnosis of hypoplastic left heart syndrome and a control group of normal fetal hearts. Of the 130 images considered 18 of 20 (90%) fetal hearts were correctly detected as having hypoplastic left heart syndrome and 84 of 110 (76.36%) fetal hearts were correctly detected as normal in the control group. The results show that the detection system performs better than the overall detection rate for congenital heart defect which is reported to be between 30% and 60%

Non-invasive localization of atrial ectopic beats by using simulated body surface P-wave integral maps

Non-invasive localization of continuous atrial ectopic beats remains a cornerstone for the treatment of atrial arrhythmias. The lack of accurate tools to guide electrophysiologists leads to an increase in the recurrence rate of ablation procedures. Existing approaches are based on the analysis of the P-waves main characteristics and the forward body surface potential maps (BSPMs) or on the inverse estimation of the electric activity of the heart from those BSPMs. These methods have not provided an efficient and systematic tool to localize ectopic triggers. In this work, we propose the use of machine learning techniques to spatially cluster and classify ectopic atrial foci into clearly differentiated atrial regions by using the body surface P-wave integral map (BSPiM) as a biomarker. Our simulated results show that ectopic foci with similar BSPiM naturally cluster into differentiated non-intersected atrial regions and that new patterns could be correctly classified with an accuracy of 97% when considering 2 clusters and 96% for 4 clusters. Our results also suggest that an increase in the number of clusters is feasible at the cost of decreasing accuracy.This work was partially supported by The "Programa Prometeu" from Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana (www.edu.gva.es/fio/index_es.asp) Award Number: PROMETEU/2016/088 to JS; The "Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016" from the Ministerio de Economia, Industria y Competitividad of Spain, Agencia Estatal de Investigacion (www.mineco.gob.es) and the European Commission (European Regional Development Funds - ERDF -FEDER) (ec.europa.eu/regional_policy/es/funding/erdf/) Award Number: DPI2016-75799-R to JS and The "Programa Estatal de Investigacion, Desarrollo e Innovacion Orientado a los Retos de la Sociedad" from the Ministerio de Economia y Competitividad of Spain, Agencia Estatal de Investigacion (www.mineco.gob.es) and the European Commission (European Regional Development Funds - ERDF -FEDER) (ec.europa.eu/regional_policy/es/funding/erdf/) Award Number: TIN2014-59932-JIN to AFA and RS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ferrer Albero, A.; Godoy, EJ.; Lozano, M.; Martínez Mateu, L.; Alonso Atienza, F.; Saiz Rodríguez, FJ.; Sebastián Aguilar, R. (2017). Non-invasive localization of atrial ectopic beats by using simulated body surface P-wave integral maps. PLoS ONE. 12(7):1-23. https://doi.org/10.1371/journal.pone.0181263S12312

Retinal vessel segmentation using textons

Segmenting vessels from retinal images, like segmentation in many other medical image domains, is a challenging task, as there is no unified way that can be adopted to extract the vessels accurately. However, it is the most critical stage in automatic assessment of various forms of diseases (e.g. Glaucoma, Age-related macular degeneration, diabetic retinopathy and cardiovascular diseases etc.). Our research aims to investigate retinal image segmentation approaches based on textons as they provide a compact description of texture that can be learnt from a training set. This thesis presents a brief review of those diseases and also includes their current situations, future trends and techniques used for their automatic diagnosis in routine clinical applications. The importance of retinal vessel segmentation is particularly emphasized in such applications. An extensive review of previous work on retinal vessel segmentation and salient texture analysis methods is presented. Five automatic retinal vessel segmentation methods are proposed in this thesis. The first method focuses on addressing the problem of removing pathological anomalies (Drusen, exudates) for retinal vessel segmentation, which have been identified by other researchers as a problem and a common source of error. The results show that the modified method shows some improvement compared to a previously published method. The second novel supervised segmentation method employs textons. We propose a new filter bank (MR11) that includes bar detectors for vascular feature extraction and other kernels to detect edges and photometric variations in the image. The k-means clustering algorithm is adopted for texton generation based on the vessel and non-vessel elements which are identified by ground truth. The third improved supervised method is developed based on the second one, in which textons are generated by k-means clustering and texton maps representing vessels are derived by back projecting pixel clusters onto hand labelled ground truth. A further step is implemented to ensure that the best combinations of textons are represented in the map and subsequently used to identify vessels in the test set. The experimental results on two benchmark datasets show that our proposed method performs well compared to other published work and the results of human experts. A further test of our system on an independent set of optical fundus images verified its consistent performance. The statistical analysis on experimental results also reveals that it is possible to train unified textons for retinal vessel segmentation. In the fourth method a novel scheme using Gabor filter bank for vessel feature extraction is proposed. The ii method is inspired by the human visual system. Machine learning is used to optimize the Gabor filter parameters. The experimental results demonstrate that our method significantly enhances the true positive rate while maintaining a level of specificity that is comparable with other approaches. Finally, we proposed a new unsupervised texton based retinal vessel segmentation method using derivative of SIFT and multi-scale Gabor filers. The lack of sufficient quantities of hand labelled ground truth and the high level of variability in ground truth labels amongst experts provides the motivation for this approach. The evaluation results reveal that our unsupervised segmentation method is comparable with the best other supervised methods and other best state of the art methods

Deformable meshes for shape recovery: models and applications

With the advance of scanning and imaging technology, more and more 3D objects become available. Among them, deformable objects have gained increasing interests. They include medical instances such as organs, a sequence of objects in motion, and objects of similar shapes where a meaningful correspondence can be established between each other. Thus, it requires tools to store, compare, and retrieve them. Many of these operations depend on successful shape recovery. Shape recovery is the task to retrieve an object from the environment where its geometry is hidden or implicitly known. As a simple and versatile tool, mesh is widely used in computer graphics for modelling and visualization. In particular, deformable meshes are meshes which can take the deformation of deformable objects. They extend the modelling ability of meshes. This dissertation focuses on using deformable meshes to approach the 3D shape recovery problem. Several models are presented to solve the challenges for shape recovery under different circumstances. When the object is hidden in an image, a PDE deformable model is designed to extract its surface shape. The algorithm uses a mesh representation so that it can model any non-smooth surface with an arbitrary precision compared to a parametric model. It is more computational efficient than a level-set approach. When the explicit geometry of the object is known but is hidden in a bank of shapes, we simplify the deformation of the model to a graph matching procedure through a hierarchical surface abstraction approach. The framework is used for shape matching and retrieval. This idea is further extended to retain the explicit geometry during the abstraction. A novel motion abstraction framework for deformable meshes is devised based on clustering of local transformations and is successfully applied to 3D motion compression

Biometric Systems

Biometric authentication has been widely used for access control and security systems over the past few years. The purpose of this book is to provide the readers with life cycle of different biometric authentication systems from their design and development to qualification and final application. The major systems discussed in this book include fingerprint identification, face recognition, iris segmentation and classification, signature verification and other miscellaneous systems which describe management policies of biometrics, reliability measures, pressure based typing and signature verification, bio-chemical systems and behavioral characteristics. In summary, this book provides the students and the researchers with different approaches to develop biometric authentication systems and at the same time includes state-of-the-art approaches in their design and development. The approaches have been thoroughly tested on standard databases and in real world applications