Improving Identification of Key Players in Aging via Network De-Noising and Core Inference.

Current "ground truth" knowledge about human aging has been obtained by transferring aging-related knowledge from well-studied model species via sequence homology or by studying human gene expression data. Since proteins function by interacting with each other, analyzing protein-protein interaction (PPI) networks in the context of aging is promising. Unlike existing static network research of aging, since cellular functioning is dynamic, we recently integrated the static human PPI network with aging-related gene expression data to form dynamic, age-specific networks. Then, we predicted as key players in aging those proteins whose network topologies significantly changed with age. Since current networks are noisy , here, we use link prediction to de-noise the human network and predict improved key players in aging from the de-noised data. Indeed, de-noising gives more significant overlap between the predicted data and the "ground truth" aging-related data. Yet, we obtain novel predictions, which we validate in the literature. Also, we improve the predictions by an alternative strategy: removing "redundant" edges from the age-specific networks and using the resulting age-specific network "cores" to study aging. We produce new knowledge from dynamic networks encompassing multiple data types, via network de-noising or core inference, complementing the existing knowledge obtained from sequence or expression data.

Global Network Alignment in the Context of Aging.

Analogous to sequence alignment, network alignment (NA) can be used to transfer biological knowledge across species between conserved network regions. NA faces two algorithmic challenges: 1) Which cost function to use to capture "similarities" between nodes in different networks? 2) Which alignment strategy to use to rapidly identify "high-scoring" alignments from all possible alignments? We "break down" existing state-of-the-art methods that use both different cost functions and different alignment strategies to evaluate each combination of their cost functions and alignment strategies. We find that a combination of the cost function of one method and the alignment strategy of another method beats the existing methods. Hence, we propose this combination as a novel superior NA method. Then, since human aging is hard to study experimentally due to long lifespan, we use NA to transfer aging-related knowledge from well annotated model species to poorly annotated human. By doing so, we produce novel human aging-related knowledge, which complements currently available knowledge about aging that has been obtained mainly by sequence alignment. We demonstrate significant similarity between topological and functional properties of our novel predictions and those of known aging-related genes. We are the first to use NA to learn more about aging.

An automated framework for hypotheses generation using literature.

BACKGROUND: In bio-medicine, exploratory studies and hypothesis generation often begin with researching existing literature to identify a set of factors and their association with diseases, phenotypes, or biological processes. Many scientists are overwhelmed by the sheer volume of literature on a disease when they plan to generate a new hypothesis or study a biological phenomenon. The situation is even worse for junior investigators who often find it difficult to formulate new hypotheses or, more importantly, corroborate if their hypothesis is consistent with existing literature. It is a daunting task to be abreast with so much being published and also remember all combinations of direct and indirect associations. Fortunately there is a growing trend of using literature mining and knowledge discovery tools in biomedical research. However, there is still a large gap between the huge amount of effort and resources invested in disease research and the little effort in harvesting the published knowledge. The proposed hypothesis generation framework (HGF) finds "crisp semantic associations" among entities of interest - that is a step towards bridging such gaps. METHODOLOGY: The proposed HGF shares similar end goals like the SWAN but are more holistic in nature and was designed and implemented using scalable and efficient computational models of disease-disease interaction. The integration of mapping ontologies with latent semantic analysis is critical in capturing domain specific direct and indirect "crisp" associations, and making assertions about entities (such as disease X is associated with a set of factors Z). RESULTS: Pilot studies were performed using two diseases. A comparative analysis of the computed "associations" and "assertions" with curated expert knowledge was performed to validate the results. It was observed that the HGF is able to capture "crisp" direct and indirect associations, and provide knowledge discovery on demand. CONCLUSIONS: The proposed framework is fast, efficient, and robust in generating new hypotheses to identify factors associated with a disease. A full integrated Web service application is being developed for wide dissemination of the HGF. A large-scale study by the domain experts and associated researchers is underway to validate the associations and assertions computed by the HGF.