Classification of GPCRs using family specific motifs

The classification of G-Protein Coupled Receptor (GPCR) sequences is an important problem that arises from the need to close the gap between the large number of orphan receptors and the relatively small number of annotated receptors. Equally important is the characterization of GPCR Class A subfamilies and gaining insight into the ligand interaction since GPCR Class A encompasses a very large number of drug-targeted receptors. In this thesis, a method for Class A subfamily classification using sequence-derived motifs which characterizes the subfamilies by discovering receptor-ligand interaction sites is proposed. The motifs that best characterize a subfamily are selected by the proposed Distinguishing Power Evaluation (DPE) technique. The experiments performed on GPCR sequence databases show that the proposed method outperforms state-of-the-art classification techniques for GPCR Class A subfamily prediction. An important contribution of this thesis is to discover key receptor-ligand interaction sites which is very important for drug design

PROBABILISTIC LATENT FACTOR MODELS FOR TRANSFORMATIVE DRUG DISCOVERY

The cost of discovering a new drug has doubled every 9 years since the 1950s. This can change by using machine learning to guide experimentation. The idea I have developed over the course of my PhD is that using latent factor modeling (LFM) of the drug-target interaction network, we can guide drug repurposable efforts to achieve transformative improvements. By better characterizing the drug-target interaction network, it is possible to use currently approved drugs to achieve therapies for diseases that currently are not optimally treated. These drugs might be directly used through repurposing, or they can serve as a starting point for new drug discovery efforts where they are optimized through medicinal chemistry methods. To achieve this goal, I have developed LFM-based techniques applicable to existing databases of drug-target interaction networks. Specifically, I have started out by establishing that probabilistic matrix factorization (PMF; one type of LFM algorithm) can be used as descriptors by showing they capture therapeutic function similarities that state-of-the-art 3D chemical similarity methods could not capture. Then I have shown that PMF can effectively predict unknown drug-target interactions. Furthermore, I have used newly developed computational techniques for discovering repurposable drugs for two diseases, α1 antitrypsin (1-AT) deficiency (ATD) and Huntington’s disease (HD) leading to successful discoveries in both. For ATD, two sets of data generated by the David Perlmutter and Gary Silverman laboratories have been used as input to deduce potential targets and repurposable drugs: (i) a high throughput screening data from a genome-wide RNAi knockdown in a C. elegans model for studying ATZ (Z-allele of 1-AT), and (ii) data from Prestwick library screen for the same model. We have predicted that the antidiabetic drug glibenclamide would be beneficial against ATZ aggregation, and data collected to date in Mus musculus models are promising. We have worked on HD with the Robert Friedlander lab, by examining the potential drugs and implicated pathways for 15 neuroprotective (repurposable) drugs that they have identified in a two-stage screening study. Based on LFM-based analysis of the targets of these drugs, we have developed a number of hypotheses to be tested. Among them, the antihypertensive drug sodium nitroprusside appears to be effective against HD based on neuronal cell death inhibition experiments that were conducted at the University of Pittsburgh Drug Discovery Institute as well as the Friedlander lab. Finally, we have built a web server, named BalestraWeb, for facilitating the use of PMF in repurposable drug identification by the broader community. BalestraWeb enables users to extract information on known and potential targets (or drugs) for any approved drug (or target), simply by entering the name of the query drug (or target). I have also laid out the framework for developing an integrated resource for quantitative systems pharmacology, Balestra toolkit (BalestraTK), which would take advantage of existing databases such as STITCH, UniProt, and PubChem. Collectively, our results provide firm evidence for the potential utility of machine learning techniques for assisting in drug discovery

Deep Learning Development Environment in Virtual Reality

Virtual reality (VR) offers immersive visualization and intuitive interaction. We leverage VR to enable any biomedical professional to deploy a deep learning (DL) model for image classification. While DL models can be powerful tools for data analysis, they are also challenging to understand and develop. To make deep learning more accessible and intuitive, we have built a virtual reality-based DL development environment. Within our environment, the user can move tangible objects to construct a neural network only using their hands. Our software automatically translates these configurations into a trainable model and then reports its resulting accuracy on a test dataset in real-time. Furthermore, we have enriched the virtual objects with visualizations of the model's components such that users can achieve insight about the DL models that they are developing. With this approach, we bridge the gap between professionals in different fields of expertise while offering a novel perspective for model analysis and data interaction. We further suggest that techniques of development and visualization in deep learning can benefit by integrating virtual reality

GlyphLink: an interactive visualization approach for semantic graphs

Graph analysis by data visualization involves achieving a series of topology-based tasks. When the graph data belongs to a data domain that contains multiple node and link types, as in the case of semantic graphs, topology-based tasks become more challenging. To reduce visual complexity in semantic graphs, we propose an approach which is based on applying relational operations such as selecting and joining nodes of different types. We use node aggregation to reflect the relational operations to the graph. We introduce glyphs for representing aggregated nodes. Using glyphs lets us encode connectivity information of multiple nodes with a single glyph. We also use visual parameters of the glyph to encode node attributes or type specific information. Rather than doing the operations in the data abstraction layer and presenting the user with the resulting visualization, we propose an interactive approach where the user can iteratively apply the relational operations directly on the visualization. We present the efficiency of our method by the results of a usability study that includes a case study on a subset of the International Movie Database. The results of the controlled experiment in our usability study indicate a statistically significant contribution in reducing the completion time of the evaluation tasks

Classification of GPCRs using family specific motifs

The classification of G-Protein Coupled Receptor (GPCR) sequences is an important problem that arises from the need to close the gap between the large number of orphan receptors and the relatively small number of annotated receptors. Equally important is the characterization of GPCR Class A subfamilies and gaining insight into the ligand interaction since GPCR Class A encompasses a very large number of drug-targeted receptors. In this work, we propose a method for Class A subfamily classification using sequence-derived motifs which characterizes the subfamilies by discovering receptor-ligand interaction sites. The motifs that best characterize a subfamily are selected by the Distinguishing Power Evaluation (DPE) technique we propose. The experiments performed on GPCR sequence databases show that our method outperforms state-of-the-art classification techniques for GPCR Class A subfamily prediction. An important contribution of our work is to discover key receptor-ligand interaction sites which is very important for drug design

Comparison of mobile device navigation information display alternatives from the cognitive load perspective

In-vehicle information systems (IVIS) should minimize the cognitive load on the drivers to reduce any risk of accidents. For that purpose we built an experiment in which two alternatives for information display are compared. One alternative is the traditional information display method of showing a map with the target route highlighted in red. This is compared against a proposed alternative for information display in which prior to a junction a ground-level photo is displayed with a large red arrow pointing at the correct route the driver must take. The photo-enhanced information display method required 39% more time spent while gazing at the screen but provided a 10% reduction in the total number of headturns. Based on the participant comments, 80% of whom opted for the non-photo enhanced method, we concluded that the cognitive load brought on by the photo-enhancement is not worth the return

Predicting Drug–Target Interactions Using Probabilistic Matrix Factorization

Quantitative analysis of known drug–target interactions emerged in recent years as a useful approach for drug repurposing and assessing side effects. In the present study, we present a method that uses probabilistic matrix factorization (PMF) for this purpose, which is particularly useful for analyzing large interaction networks. DrugBank drugs clustered based on PMF latent variables show phenotypic similarity even in the absence of 3D shape similarity. Benchmarking computations show that the method outperforms those recently introduced provided that the input data set of known interactions is sufficiently largewhich is the case for enzymes and ion channels, but not for G-protein coupled receptors (GPCRs) and nuclear receptors. Runs performed on DrugBank after hiding 70% of known interactions show that, on average, 88 of the top 100 predictions hit the hidden interactions. De novo predictions permit us to identify new potential interactions. Drug–target pairs implicated in neurobiological disorders are overrepresented among de novo predictions

Clinical features and accompanying findings of Pseudo-Bartter Syndrome in cystic fibrosis

Background Pseudo-Bartter syndrome (PBS) is a rare complication of cystic fibrosis (CF) and there are limited data in the literature about it. We aimed to compare clinical features and accompanying findings of patients with PBS in a large patient population