A Path to Implement Precision Child Health Cardiovascular Medicine.

Congenital heart defects (CHDs) affect approximately 1% of live births and are a major source of childhood morbidity and mortality even in countries with advanced healthcare systems. Along with phenotypic heterogeneity, the underlying etiology of CHDs is multifactorial, involving genetic, epigenetic, and/or environmental contributors. Clear dissection of the underlying mechanism is a powerful step to establish individualized therapies. However, the majority of CHDs are yet to be clearly diagnosed for the underlying genetic and environmental factors, and even less with effective therapies. Although the survival rate for CHDs is steadily improving, there is still a significant unmet need for refining diagnostic precision and establishing targeted therapies to optimize life quality and to minimize future complications. In particular, proper identification of disease associated genetic variants in humans has been challenging, and this greatly impedes our ability to delineate gene-environment interactions that contribute to the pathogenesis of CHDs. Implementing a systematic multileveled approach can establish a continuum from phenotypic characterization in the clinic to molecular dissection using combined next-generation sequencing platforms and validation studies in suitable models at the bench. Key elements necessary to advance the field are: first, proper delineation of the phenotypic spectrum of CHDs; second, defining the molecular genotype/phenotype by combining whole-exome sequencing and transcriptome analysis; third, integration of phenotypic, genotypic, and molecular datasets to identify molecular network contributing to CHDs; fourth, generation of relevant disease models and multileveled experimental investigations. In order to achieve all these goals, access to high-quality biological specimens from well-defined patient cohorts is a crucial step. Therefore, establishing a CHD BioCore is an essential infrastructure and a critical step on the path toward precision child health cardiovascular medicine

Doctor of Philosophy

dissertationThe goal of machine learning is to develop efficient algorithms that use training data to create models that generalize well to unseen data. Learning algorithms can use labeled data, unlabeled data or both. Supervised learning algorithms learn a model using labeled data only. Unsupervised learning methods learn the internal structure of a dataset using only unlabeled data. Lastly, semisupervised learning is the task of finding a model using both labeled and unlabeled data. In this research work, we contribute to both supervised and semisupervised learning. We contribute to supervised learning by proposing an efficient high-dimensional space coverage scheme which is based on the disjunctive normal form. We use conjunctions of a set of half-spaces to create a set of convex polytopes. Disjunction of these polytopes can provide desirable coverage of space. Unlike traditional methods based on neural networks, we do not initialize the model parameters randomly. As a result, our model minimizes the risk of poor local minima and higher learning rates can be used which leads to faster convergence. We contribute to semisupervised learning by proposing 2 unsupervised loss functions that form the basis of a novel semisupervised learning method. The first loss function is called Mutual-Exclusivity. The motivation of this method is the observation that an optimal decision boundary lies between the manifolds of different classes where there are no or very few samples. Decision boundaries can be pushed away from training samples by maximizing their margin and it is not necessary to know the class labels of the samples to maximize the margin. The second loss is named Transformation/Stability and is based on the fact that the prediction of a classifier for a data sample should not change with respect to transformations and perturbations applied to that data sample. In addition, internal variations of a learning system should have little to no effect on the output. The proposed loss minimizes the variation in the prediction of the network for a specific data sample. We also show that the same technique can be used to improve the robustness of a learning model with respect to adversarial examples

Computational and Robotic Models of Early Language Development: A Review

We review computational and robotics models of early language learning and development. We first explain why and how these models are used to understand better how children learn language. We argue that they provide concrete theories of language learning as a complex dynamic system, complementing traditional methods in psychology and linguistics. We review different modeling formalisms, grounded in techniques from machine learning and artificial intelligence such as Bayesian and neural network approaches. We then discuss their role in understanding several key mechanisms of language development: cross-situational statistical learning, embodiment, situated social interaction, intrinsically motivated learning, and cultural evolution. We conclude by discussing future challenges for research, including modeling of large-scale empirical data about language acquisition in real-world environments. Keywords: Early language learning, Computational and robotic models, machine learning, development, embodiment, social interaction, intrinsic motivation, self-organization, dynamical systems, complexity.Comment: to appear in International Handbook on Language Development, ed. J. Horst and J. von Koss Torkildsen, Routledg