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Register a new userCross-Scale Sensitivity Analysis of a Non-Small Cell Lung Cancer Model: Linking Molecular Signaling Properties to Cellular Behavior
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Sensitivity analysis is an effective tool for systematically identifying specific perturbations in parameters that have significant effects on the behavior of a given biosystem, at the scale investigated. In this work, using a two-dimensional, multiscale non-small cell lung cancer (NSCLC) model, we examine the effects of perturbations in system parameters which span both molecular and cellular levels, i.e. across scales of interest. This is achieved by first linking molecular and cellular activities and then assessing the influence of parameters at the molecular level on the tumors spatio-temporal expansion rate, which serves as the output behavior at the cellular level. Overall, the algorithm operated reliably over relatively large variations of most parameters, hence confirming the robustness of the model. However, three pathway components (proteins PKC, MEK, and ERK) and eleven reaction steps were determined to be of critical importance by employing a sensitivity coefficient as an evaluation index. Each of these sensitive parameters exhibited a similar changing pattern in that a relatively larger increase or decrease in its value resulted in a lesser influence on the systems cellular performance. This study provides a novel cross-scaled approach to analyzing sensitivities of computational model parameters and proposes its application to interdisciplinary biomarker studies.
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To enable personalized cancer treatment, machine learning models have been developed to predict drug response as a function of tumor and drug features. However, most algorithm development efforts have relied on cross validation within a single study to assess model accuracy. While an essential first step, cross validation within a biological data set typically provides an overly optimistic estimate of the prediction performance on independent test sets. To provide a more rigorous assessment of model generalizability between different studies, we use machine learning to analyze five publicly available cell line-based data sets: NCI60, CTRP, GDSC, CCLE and gCSI. Based on observed experimental variability across studies, we explore estimates of prediction upper bounds. We report performance results of a variety of machine learning models, with a multitasking deep neural network achieving the best cross-study generalizability. By multiple measures, models trained on CTRP yield the most accurate predictions on the remaining testing data, and gCSI is the most predictable among the cell line data sets included in this study. With these experiments and further simulations on partial data, two lessons emerge: (1) differences in viability assays can limit model generalizability across studies, and (2) drug diversity, more than tumor diversity, is crucial for raising model generalizability in preclinical screening.
Mathematical methods of information theory constitute essential tools to describe how stimuli are encoded in activities of signaling effectors. Exploring the information-theoretic perspective, however, remains conceptually, experimentally and computationally challenging. Specifically, existing computational tools enable efficient analysis of relatively simple systems, usually with one input and output only. Moreover, their robust and readily applicable implementations are missing. Here, we propose a novel algorithm to analyze signaling data within the framework of information theory. Our approach enables robust as well as statistically and computationally efficient analysis of signaling systems with high-dimensional outputs and a large number of input values. Analysis of the NF-kB single - cell signaling responses to TNF-a uniquely reveals that the NF-kB signaling dynamics improves discrimination of high concentrations of TNF-a with a modest impact on discrimination of low concentrations. Our readily applicable R-package, SLEMI - statistical learning based estimation of mutual information, allows the approach to be used by computational biologists with only elementary knowledge of information theory.
If Electronic Health Records contain a large amount of information about the patients condition and response to treatment, which can potentially revolutionize the clinical practice, such information is seldom considered due to the complexity of its extraction and analysis. We here report on a first integration of an NLP framework for the analysis of clinical records of lung cancer patients making use of a telephone assistance service of a major Spanish hospital. We specifically show how some relevant data, about patient demographics and health condition, can be extracted; and how some relevant analyses can be performed, aimed at improving the usefulness of the service. We thus demonstrate that the use of EHR texts, and their integration inside a data analysis framework, is technically feasible and worth of further study.
Cells crawling through tissues migrate inside a complex fibrous environment called the extracellular matrix (ECM), which provides signals regulating motility. Here we investigate one such well-known pathway, involving mutually antagonistic signalling molecules (small GTPases Rac and Rho) that control the protrusion and contraction of the cell edges (lamellipodia). Invasive melanoma cells were observed migrating on surfaces with topography (array of posts), coated with adhesive molecules (fibronectin, FN) by Park et al., 2016. Several distinct qualitative behaviors they observed included persistent polarity, oscillation between the cell front and back, and random dynamics. To gain insight into the link between intracellular and ECM signaling, we compared experimental observations to a sequence of mathematical models encoding distinct hypotheses. The successful model required several critical factors. (1) Competition of lamellipodia for limited pools of GTPases. (2) Protrusion / contraction of lamellipodia influence ECM signaling. (3) ECM-mediated activation of Rho. A model combining these elements explains all three cellular behaviors and correctly predicts the results of experimental perturbations. This study yields new insight into how the dynamic interactions between intracellular signaling and the cells environment influence cell behavior.
Cell type (e.g. pluripotent cell, fibroblast) is the end result of many complex processes that unfold due to evolutionary, developmental, and transformational stimuli. A cells phenotype and the discrete, a priori states that define various cell subtypes (e.g. skin fibroblast, embryonic stem cell) are ultimately part of a continuum that may predict changes and systematic variation in cell subtypes. These features can be both observable in existing cellular states and hypothetical (e.g. unobserved). In this paper, a series of approaches will be used to approximate the continuous diversity of gene expression across a series of pluripotent, totipotent, and fibroblast cellular subtypes. We will use a series of previously-collected datasets and analyze them using three complementary approaches: the computation of distances based on the subsampling of diversity, assessing the separability of individual genes for a specific cell line both within and between cell types, and a hierarchical soft classification technique that will assign a membership value for specific genes in specific cell types given a number of different criteria. These approaches will allow us to assess the observed gene-expression diversity in these datasets, as well as assess how well a priori cell types characterize their constituent populations. In conclusion, the application of these findings to a broader biological context will be discussed.
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