Finding Complex Biological Relationships in Recent PubMed Articles Using Bio-LDA

The overwhelming amount of available scholarly literature in the life sciences poses significant challenges to scientists wishing to keep up with important developments related to their research, but also provides a useful resource for the discovery of recent information concerning genes, diseases, compounds and the interactions between them. In this paper, we describe an algorithm called Bio-LDA that uses extracted biological terminology to automatically identify latent topics, and provides a variety of measures to uncover putative relations among topics and bio-terms. Relationships identified using those approaches are combined with existing data in life science datasets to provide additional insight. Three case studies demonstrate the utility of the Bio-LDA model, including association predication, association search and connectivity map generation. This combined approach offers new opportunities for knowledge discovery in many areas of biology including target identification, lead hopping and drug repurposing.Comment: 14 pages, 8 figures, 10 table

Dynamic Rearrangement of Cell States Detected by Systematic Screening of Sequential Anticancer Treatments

Signaling networks are nonlinear and complex, involving a large ensemble of dynamic interaction states that fluctuate in space and time. However, therapeutic strategies, such as combination chemotherapy, rarely consider the timing of drug perturbations. If we are to advance drug discovery for complex diseases, it will be essential to develop methods capable of identifying dynamic cellular responses to clinically relevant perturbations. Here, we present a Bayesian dose-response framework and the screening of an oncological drug matrix, comprising 10,000 drug combinations in melanoma and pancreatic cancer cell lines, from which we predict sequentially effective drug combinations. Approximately 23% of the tested combinations showed high-confidence sequential effects (either synergistic or antagonistic), demonstrating that cellular perturbations of many drug combinations have temporal aspects, which are currently both underutilized and poorly understood

Advancing discovery science with fair data stewardship:Findable, accessible, interoperable, reusable

This report summarizes a presentation by Dr. Michel Dumontier. It reviews innovative scientific research methods created by data science, and the need to develop infrastructure, methodologies, and user communities to advance data science. Stakeholders have proposed a set of principles to make digital resources findable, accessible, interoperable, and reusable—FAIR. FAIR principles provide guidelines, do not require specific technologies, and allow communities of stakeholders to define specific FAIR standards and develop metrics to quantify them. Libraries can be part of the new data ecosystemby providing education, data stewardship, and infrastructure

Gene Regulatory Networks: Modeling, Intervention and Context

abstract: Biological systems are complex in many dimensions as endless transportation and communication networks all function simultaneously. Our ability to intervene within both healthy and diseased systems is tied directly to our ability to understand and model core functionality. The progress in increasingly accurate and thorough high-throughput measurement technologies has provided a deluge of data from which we may attempt to infer a representation of the true genetic regulatory system. A gene regulatory network model, if accurate enough, may allow us to perform hypothesis testing in the form of computational experiments. Of great importance to modeling accuracy is the acknowledgment of biological contexts within the models -- i.e. recognizing the heterogeneous nature of the true biological system and the data it generates. This marriage of engineering, mathematics and computer science with systems biology creates a cycle of progress between computer simulation and lab experimentation, rapidly translating interventions and treatments for patients from the bench to the bedside. This dissertation will first discuss the landscape for modeling the biological system, explore the identification of targets for intervention in Boolean network models of biological interactions, and explore context specificity both in new graphical depictions of models embodying context-specific genomic regulation and in novel analysis approaches designed to reveal embedded contextual information. Overall, the dissertation will explore a spectrum of biological modeling with a goal towards therapeutic intervention, with both formal and informal notions of biological context, in such a way that will enable future work to have an even greater impact in terms of direct patient benefit on an individualized level.Dissertation/ThesisPh.D. Computer Science 201

DRUG-NEM: Optimizing drug combinations using single-cell perturbation response to account for intratumoral heterogeneity.

An individual malignant tumor is composed of a heterogeneous collection of single cells with distinct molecular and phenotypic features, a phenomenon termed intratumoral heterogeneity. Intratumoral heterogeneity poses challenges for cancer treatment, motivating the need for combination therapies. Single-cell technologies are now available to guide effective drug combinations by accounting for intratumoral heterogeneity through the analysis of the signaling perturbations of an individual tumor sample screened by a drug panel. In particular, Mass Cytometry Time-of-Flight (CyTOF) is a high-throughput single-cell technology that enables the simultaneous measurements of multiple ([Formula: see text]40) intracellular and surface markers at the level of single cells for hundreds of thousands of cells in a sample. We developed a computational framework, entitled Drug Nested Effects Models (DRUG-NEM), to analyze CyTOF single-drug perturbation data for the purpose of individualizing drug combinations. DRUG-NEM optimizes drug combinations by choosing the minimum number of drugs that produce the maximal desired intracellular effects based on nested effects modeling. We demonstrate the performance of DRUG-NEM using single-cell drug perturbation data from tumor cell lines and primary leukemia samples

Two Measures of Non-Probabilistic Uncertainty

There are two reasons why uncertainty about the future yield of investments may not be adequately described by Probability Theory. The first one is due to unique or nearly-unique events, that either never realized or occurred too seldom for probabilities to be reliable. The second one arises when when one fears that something may happen, that one is not even able to figure out, e.g., if one asks: "Climate change, financial crises, pandemic, war, what next?" In both cases, simple one-to-one causal mappings between available alternatives and possible consequences eventually melt down. However, such destructions reflect into the changing narratives of business executives, employees and other stakeholders in specific, identifiable and differential ways. In particular, texts such as consultants' reports or letters to shareholders can be analysed in order to detect the impact of both sorts of uncertainty onto the causal relations that normally guide decision-making. We propose structural measures of causal mappings as a means to measure non-probabilistic uncertainty, eventually suggesting that automated text analysis can greatly augment the possibilities offered by these techniques. Prospective applications may concern statistical institutes, stock market traders, as well as businesses wishing to compare their own vision to those prevailing in their industry.Comment: 22 pages, 15 figure

Computation of context as a cognitive tool

In the field of cognitive science, as well as the area of Artificial Intelligence (AI), the role of context has been investigated in many forms, and for many purposes. It is clear in both areas that consideration of contextual information is important. However, the significance of context has not been emphasized in the Bayesian networks literature. We suggest that consideration of context is necessary for acquiring knowledge about a situation and for refining current representational models that are potentially erroneous due to hidden independencies in the data.In this thesis, we make several contributions towards the automation of contextual consideration by discovering useful contexts from probability distributions. We show how context-specific independencies in Bayesian networks and discovery algorithms, traditionally used for efficient probabilistic inference can contribute to the identification of contexts, and in turn can provide insight on otherwise puzzling situations. Also, consideration of context can help clarify otherwise counter intuitive puzzles, such as those that result in instances of Simpson's paradox. In the social sciences, the branch of attribution theory is context-sensitive. We suggest a method to distinguish between dispositional causes and situational factors by means of contextual models. Finally, we address the work of Cheng and Novick dealing with causal attribution by human adults. Their probabilistic contrast model makes use of contextual information, called focal sets, that must be determined by a human expert. We suggest a method for discovering complete focal sets from probabilistic distributions, without the human expert

Computational Methods for Knowledge Integration in the Analysis of Large-scale Biological Networks

abstract: As we migrate into an era of personalized medicine, understanding how bio-molecules interact with one another to form cellular systems is one of the key focus areas of systems biology. Several challenges such as the dynamic nature of cellular systems, uncertainty due to environmental influences, and the heterogeneity between individual patients render this a difficult task. In the last decade, several algorithms have been proposed to elucidate cellular systems from data, resulting in numerous data-driven hypotheses. However, due to the large number of variables involved in the process, many of which are unknown or not measurable, such computational approaches often lead to a high proportion of false positives. This renders interpretation of the data-driven hypotheses extremely difficult. Consequently, a dismal proportion of these hypotheses are subject to further experimental validation, eventually limiting their potential to augment existing biological knowledge. This dissertation develops a framework of computational methods for the analysis of such data-driven hypotheses leveraging existing biological knowledge. Specifically, I show how biological knowledge can be mapped onto these hypotheses and subsequently augmented through novel hypotheses. Biological hypotheses are learnt in three levels of abstraction -- individual interactions, functional modules and relationships between pathways, corresponding to three complementary aspects of biological systems. The computational methods developed in this dissertation are applied to high throughput cancer data, resulting in novel hypotheses with potentially significant biological impact.Dissertation/ThesisPh.D. Computer Science 201