Joint and individual analysis of breast cancer histologic images and genomic covariates

A key challenge in modern data analysis is understanding connections between complex and differing modalities of data. For example, two of the main approaches to the study of breast cancer are histopathology (analyzing visual characteristics of tumors) and genetics. While histopathology is the gold standard for diagnostics and there have been many recent breakthroughs in genetics, there is little overlap between these two fields. We aim to bridge this gap by developing methods based on Angle-based Joint and Individual Variation Explained (AJIVE) to directly explore similarities and differences between these two modalities. Our approach exploits Convolutional Neural Networks (CNNs) as a powerful, automatic method for image feature extraction to address some of the challenges presented by statistical analysis of histopathology image data. CNNs raise issues of interpretability that we address by developing novel methods to explore visual modes of variation captured by statistical algorithms (e.g. PCA or AJIVE) applied to CNN features. Our results provide many interpretable connections and contrasts between histopathology and genetics

Training artificial neural networks directly on the concordance index for censored data using genetic algorithms.

OBJECTIVE: The concordance index (c-index) is the standard way of evaluating the performance of prognostic models in the presence of censored data. Constructing prognostic models using artificial neural networks (ANNs) is commonly done by training on error functions which are modified versions of the c-index. Our objective was to demonstrate the capability of training directly on the c-index and to evaluate our approach compared to the Cox proportional hazards model. METHOD: We constructed a prognostic model using an ensemble of ANNs which were trained using a genetic algorithm. The individual networks were trained on a non-linear artificial data set divided into a training and test set both of size 2000, where 50% of the data was censored. The ANNs were also trained on a data set consisting of 4042 patients treated for breast cancer spread over five different medical studies, 2/3 used for training and 1/3 used as a test set. A Cox model was also constructed on the same data in both cases. The two models' c-indices on the test sets were then compared. The ranking performance of the models is additionally presented visually using modified scatter plots. RESULTS: Cross validation on the cancer training set did not indicate any non-linear effects between the covariates. An ensemble of 30 ANNs with one hidden neuron was therefore used. The ANN model had almost the same c-index score as the Cox model (c-index=0.70 and 0.71, respectively) on the cancer test set. Both models identified similarly sized low risk groups with at most 10% false positives, 49 for the ANN model and 60 for the Cox model, but repeated bootstrap runs indicate that the difference was not significant. A significant difference could however be seen when applied on the non-linear synthetic data set. In that case the ANN ensemble managed to achieve a c-index score of 0.90 whereas the Cox model failed to distinguish itself from the random case (c-index=0.49). CONCLUSIONS: We have found empirical evidence that ensembles of ANN models can be optimized directly on the c-index. Comparison with a Cox model indicates that near identical performance is achieved on a real cancer data set while on a non-linear data set the ANN model is clearly superior

Computational and Imaging Methods for Studying Neuronal Populations during Behavior

One of the central questions in neuroscience is how the nervous system generates and regulates behavior. To understand the neural code for any behavior, an ideal experiment would entail (i) quantitatively defining that behavior, (ii) recording neuronal activity in relevant brain regions to identify the underlying neuronal circuits and eventually (iii) manipulating them to test their function. Novel methods in neuroscience have greatly advanced our abilities to conduct such experiments but are still insufficient. In this thesis, I developed methods for these three goals. In Chapter 2, I describe an automatic behavior identification and classification method for the cnidarian Hydra vulgaris using machine learning. In Chapter 3, I describe a fast volumetric two-photon microscope with dual-color laser excitation that can image in 3D the activity of populations of neurons from visual cortex of awake mice. In Chapter 4, I present a machine learning method that identifies cortical ensembles and pattern completion neurons in mouse visual cortex, using two-photon calcium imaging data. These methods advance current technologies, providing opportunities for new discoveries

Brainstem circuits involved in skilled forelimb movements

Movement is the main output of the nervous system as well as the fundamental form of interaction animals have with their environment. Due to its function and scope, movement has to be characterized by both stability and flexibility. Such apparently conflicting attributes are reflected in the complex organization of the motor system, composed of a vast network of widely distributed circuits interacting with each other to generate an appropriate motor output. Different neuronal structures, located throughout the brain, are responsible for producing a broad spectrum of actions, ranging from simple locomotion to complex goal directed movements such as reaching for food or playing a musical instrument. The brainstem is one of such structures, holding considerable importance in the generation of the motor output, but also largely unexplored, due to its less-than-accessible anatomic location, functional intricacies and the lack of appropriate techniques to investigate its complexity. Despite recent advances, a deeper understanding of the role of brainstem neuronal circuits in skilled movements is still missing. In this dissertation, we investigated the involvement of the lateral rostral medulla (LatRM) in the construction of skilled forelimb behaviors. The focus of my work was centered on elucidating the anatomical and functional relationships between LatRM and the caudal brainstem, and specifically on the interactions with the medullary reticular formation, considering both its ventral (MdV) and dorsal subdivisions (MdD). In summary, we reveal the existence of anatomically segregated subpopulations of neurons in the lower brainstem which encode different aspects of skilled forelimb movements. Moreover, we show that LatRM neurons are necessary for the correct execution of skilled motor programs and their activation produces complex coordinated actions. All this evidence suggests that LatRM may be a key orchestrator for skilled movements by functioning as integration center for upstream signals as well as coordinator by selecting the appropriate effectors in the lower medulla and the spinal cord

Artificial Intelligence and Bank Soundness: Between the Devil and the Deep Blue Sea - Part 2

Banks have experienced chronic weaknesses as well as frequent crisis over the years. As bank failures are costly and affect global economies, banks are constantly under intense scrutiny by regulators. This makes banks the most highly regulated industry in the world today. As banks grow into the 21st century framework, banks are in need to embrace Artificial Intelligence (AI) to not only to provide personalized world class service to its large database of customers but most importantly to survive. The chapter provides a taxonomy of bank soundness in the face of AI through the lens of CAMELS where C (Capital), A(Asset), M(Management), E(Earnings), L(Liquidity), S(Sensitivity). The taxonomy partitions challenges from the main strand of CAMELS into distinct categories of AI into 1(C), 4(A), 17(M), 8 (E), 1(L), 2(S) categories that banks and regulatory teams need to consider in evaluating AI use in banks. Although AI offers numerous opportunities to enable banks to operate more efficiently and effectively, at the same time banks also need to give assurance that AI ‘do no harm’ to stakeholders. Posing many unresolved questions, it seems that banks are trapped between the devil and the deep blue sea for now

Prediction of Sudden Cardiac Death Using Ensemble Classifiers

Sudden Cardiac Death (SCD) is a medical problem that is responsible for over 300,000 deaths per year in the United States and millions worldwide. SCD is defined as death occurring from within one hour of the onset of acute symptoms, an unwitnessed death in the absence of pre-existing progressive circulatory failures or other causes of deaths, or death during attempted resuscitation. Sudden death due to cardiac reasons is a leading cause of death among Congestive Heart Failure (CHF) patients. The use of Electronic Medical Records (EMR) systems has made a wealth of medical data available for research and analysis. Supervised machine learning methods have been successfully used for medical diagnosis. Ensemble classifiers are known to achieve better prediction accuracy than its constituent base classifiers. In an effort to understand the factors contributing to SCD, data on 2,521 patients were collected for the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). The data included 96 features that were gathered over a period of 5 years. The goal of this dissertation was to develop a model that could accurately predict SCD based on available features. The prediction model used the Cox proportional hazards model as a score and then used the ExtraTreesClassifier algorithm as a boosting mechanism to create the ensemble. We tested the system at prediction points of 180 days and 365 days. Our best results were at 180-days with accuracy of 0.9624, specificity of 0.9915, and F1 score of 0.9607