Machine Learning Methods To Identify Hidden Phenotypes In The Electronic Health Record

The widespread adoption of Electronic Health Records (EHRs) means an unprecedented amount of patient treatment and outcome data is available to researchers. Research is a tertiary priority in the EHR, where the priorities are patient care and billing. Because of this, the data is not standardized or formatted in a manner easily adapted to machine learning approaches. Data may be missing for a large variety of reasons ranging from individual input styles to differences in clinical decision making, for example, which lab tests to issue. Few patients are annotated at a research quality, limiting sample size and presenting a moving gold standard. Patient progression over time is key to understanding many diseases but many machine learning algorithms require a snapshot, at a single time point, to create a usable vector form. In this dissertation, we develop new machine learning methods and computational workflows to extract hidden phenotypes from the Electronic Health Record (EHR). In Part 1, we use a semi-supervised deep learning approach to compensate for the low number of research quality labels present in the EHR. In Part 2, we examine and provide recommendations for characterizing and managing the large amount of missing data inherent to EHR data. In Part 3, we present an adversarial approach to generate synthetic data that closely resembles the original data while protecting subject privacy. We also introduce a workflow to enable reproducible research even when data cannot be shared. In Part 4, we introduce a novel strategy to first extract sequential data from the EHR and then demonstrate the ability to model these sequences with deep learning

Comparative cellular analysis of motor cortex in human, marmoset and mouse

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals(1). Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.Cardiovascular Aspects of Radiolog

Comparative cellular analysis of motor cortex in human, marmoset and mouse

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations

Machine Learning Approaches and Web-Based System to the Application of Disease Modifying Therapy for Sickle Cell

Sickle cell disease (SCD) is a common serious genetic disease, which has a severe impact due to red blood cell (RBCs) abnormality. According to the World Health Organisation, 7 million newborn babies each year suffer either from the congenital anomaly or from an inherited disease, primarily from thalassemia and sickle cell disease. In the case of SCD, recent research has shown the beneficial effects of a drug called hydroxyurea/hydroxycarbamide in modifying the disease phenotype. The clinical management of this disease-modifying therapy is difficult and time consuming for clinical staff. This includes finding an optimal classifier that can help to solve the issues with missing values, multi-class datasets, and features selection. For the classification and discriminant analysis of SCD datasets, 7 classifiers based on machine learning models are selected representing linear and non-linear methods. After running these classifiers with a single model, the results revealed that a single classifier has provided us with effective outcomes in terms of the classification performance evaluation metric. In order to produce such an optimal outcome, this research proposed and designed combined classifiers (ensemble classifiers) among the neural network’s models, the random forest classifier, and the K-nearest neighbour classifier. In this aspect, combining the levenberg-marquardt algorithm, the voted perceptron classifier, the radial basis neural classifier, and random forest classifier obtain the highest rate of performance and accuracy. This ensemble classifier receives better results during the training set and testing set process. Recent technology advances based on smart devices have improved the medical facilities and become increasingly popular in association with real-time health monitoring and remote/personal health-care. The web-based system developed under the supervision of the haematology specialist at the Alder Hey Children’s Hospital in order to produce such an effective and useful system for both patients and clinicians. To sum up, the simulation experiment concludes that using machine learning and the web-based system platforms represents an alternative procedure that could assist healthcare professionals, particularly for the specialist nurse and junior doctor to improve the quality of care with sickle cell disorder