345 research outputs found
ProbCD: enrichment analysis accounting for categorization uncertainty
As in many other areas of science, systems biology makes extensive use of statistical association and significance estimates in contingency tables, a type of categorical data analysis known in this field as enrichment (also over-representation or enhancement) analysis. In spite of efforts to create probabilistic annotations, especially in the Gene Ontology context, or to deal with uncertainty in high throughput-based datasets, current enrichment methods largely ignore this probabilistic information since they are mainly based on variants of the Fisher Exact Test. We developed an open-source R package to deal with probabilistic categorical data analysis, ProbCD, that does not require a static contingency table. The contingency table for
the enrichment problem is built using the expectation of a Bernoulli Scheme stochastic process given the categorization probabilities. An on-line interface was created to allow usage by non-programmers and is available at: http://xerad.systemsbiology.net/ProbCD/. We present an analysis framework and software tools to address the issue of uncertainty in categorical data analysis. In particular, concerning the enrichment analysis, ProbCD can accommodate: (i) the stochastic nature of the high-throughput experimental techniques and (ii) probabilistic gene annotation
A generalizable data-driven multicellular model of pancreatic ductal adenocarcinoma.
BACKGROUND: Mechanistic models, when combined with pertinent data, can improve our knowledge regarding important molecular and cellular mechanisms found in cancer. These models make the prediction of tissue-level response to drug treatment possible, which can lead to new therapies and improved patient outcomes. Here we present a data-driven multiscale modeling framework to study molecular interactions between cancer, stromal, and immune cells found in the tumor microenvironment. We also develop methods to use molecular data available in The Cancer Genome Atlas to generate sample-specific models of cancer.
RESULTS: By combining published models of different cells relevant to pancreatic ductal adenocarcinoma (PDAC), we built an agent-based model of the multicellular pancreatic tumor microenvironment, formally describing cell type-specific molecular interactions and cytokine-mediated cell-cell communications. We used an ensemble-based modeling approach to systematically explore how variations in the tumor microenvironment affect the viability of cancer cells. The results suggest that the autocrine loop involving EGF signaling is a key interaction modulator between pancreatic cancer and stellate cells. EGF is also found to be associated with previously described subtypes of PDAC. Moreover, the model allows a systematic exploration of the effect of possible therapeutic perturbations; our simulations suggest that reducing bFGF secretion by stellate cells will have, on average, a positive impact on cancer apoptosis.
CONCLUSIONS: The developed framework allows model-driven hypotheses to be generated regarding therapeutically relevant PDAC states with potential molecular and cellular drivers indicating specific intervention strategies
Simcluster: clustering enumeration gene expression data on the simplex space
Transcript enumeration methods such as SAGE, MPSS, and sequencing-by-synthesis EST "digital northern", are important high-throughput techniques for digital gene expression measurement. As other counting or voting processes, these measurements constitute compositional data exhibiting properties particular to the simplex space where the summation of the components is constrained. These properties are not present on regular Euclidean spaces, on which hybridization-based microarray data is often modeled. Therefore, pattern recognition methods commonly used for microarray data analysis may be non-informative for the data generated by transcript enumeration techniques since they ignore certain fundamental properties of this space.

Here we present a software tool, Simcluster, designed to perform clustering analysis for data on the simplex space. We present Simcluster as a stand-alone command-line C package and as a user-friendly on-line tool. Both versions are available at: http://xerad.systemsbiology.net/simcluster.

Simcluster is designed in accordance with a well-established mathematical framework for compositional data analysis, which provides principled procedures for dealing with the simplex space, and is thus applicable in a number of contexts, including enumeration-based gene expression data
Should We Learn Probabilistic Models for Model Checking? A New Approach and An Empirical Study
Many automated system analysis techniques (e.g., model checking, model-based
testing) rely on first obtaining a model of the system under analysis. System
modeling is often done manually, which is often considered as a hindrance to
adopt model-based system analysis and development techniques. To overcome this
problem, researchers have proposed to automatically "learn" models based on
sample system executions and shown that the learned models can be useful
sometimes. There are however many questions to be answered. For instance, how
much shall we generalize from the observed samples and how fast would learning
converge? Or, would the analysis result based on the learned model be more
accurate than the estimation we could have obtained by sampling many system
executions within the same amount of time? In this work, we investigate
existing algorithms for learning probabilistic models for model checking,
propose an evolution-based approach for better controlling the degree of
generalization and conduct an empirical study in order to answer the questions.
One of our findings is that the effectiveness of learning may sometimes be
limited.Comment: 15 pages, plus 2 reference pages, accepted by FASE 2017 in ETAP
CRI iAtlas: an interactive portal for immuno-oncology research.
The Cancer Research Institute (CRI) iAtlas is an interactive web platform for data exploration and discovery in the context of tumors and their interactions with the immune microenvironment. iAtlas allows researchers to study immune response characterizations and patterns for individual tumor types, tumor subtypes, and immune subtypes. iAtlas supports computation and visualization of correlations and statistics among features related to the tumor microenvironment, cell composition, immune expression signatures, tumor mutation burden, cancer driver mutations, adaptive cell clonality, patient survival, expression of key immunomodulators, and tumor infiltrating lymphocyte (TIL) spatial maps. iAtlas was launched to accompany the release of the TCGA PanCancer Atlas and has since been expanded to include new capabilities such as (1) user-defined loading of sample cohorts, (2) a tool for classifying expression data into immune subtypes, and (3) integration of TIL mapping from digital pathology images. We expect that the CRI iAtlas will accelerate discovery and improve patient outcomes by providing researchers access to standardized immunogenomics data to better understand the tumor immune microenvironment and its impact on patient responses to immunotherapy
A self-organized model for cell-differentiation based on variations of molecular decay rates
Systemic properties of living cells are the result of molecular dynamics
governed by so-called genetic regulatory networks (GRN). These networks capture
all possible features of cells and are responsible for the immense levels of
adaptation characteristic to living systems. At any point in time only small
subsets of these networks are active. Any active subset of the GRN leads to the
expression of particular sets of molecules (expression modes). The subsets of
active networks change over time, leading to the observed complex dynamics of
expression patterns. Understanding of this dynamics becomes increasingly
important in systems biology and medicine. While the importance of
transcription rates and catalytic interactions has been widely recognized in
modeling genetic regulatory systems, the understanding of the role of
degradation of biochemical agents (mRNA, protein) in regulatory dynamics
remains limited. Recent experimental data suggests that there exists a
functional relation between mRNA and protein decay rates and expression modes.
In this paper we propose a model for the dynamics of successions of sequences
of active subnetworks of the GRN. The model is able to reproduce key
characteristics of molecular dynamics, including homeostasis, multi-stability,
periodic dynamics, alternating activity, differentiability, and self-organized
critical dynamics. Moreover the model allows to naturally understand the
mechanism behind the relation between decay rates and expression modes. The
model explains recent experimental observations that decay-rates (or turnovers)
vary between differentiated tissue-classes at a general systemic level and
highlights the role of intracellular decay rate control mechanisms in cell
differentiation.Comment: 16 pages, 5 figure
Modeling Stochasticity and Variability in Gene Regulatory Networks
Modeling stochasticity in gene regulatory networks is an important and
complex problem in molecular systems biology. To elucidate intrinsic noise,
several modeling strategies such as the Gillespie algorithm have been used
successfully. This paper contributes an approach as an alternative to these
classical settings. Within the discrete paradigm, where genes, proteins, and
other molecular components of gene regulatory networks are modeled as discrete
variables and are assigned as logical rules describing their regulation through
interactions with other components. Stochasticity is modeled at the biological
function level under the assumption that even if the expression levels of the
input nodes of an update rule guarantee activation or degradation there is a
probability that the process will not occur due to stochastic effects. This
approach allows a finer analysis of discrete models and provides a natural
setup for cell population simulations to study cell-to-cell variability. We
applied our methods to two of the most studied regulatory networks, the outcome
of lambda phage infection of bacteria and the p53-mdm2 complex.Comment: 23 pages, 8 figure
Forum on immune digital twins: a meeting report
Medical digital twins are computational models of human biology relevant to a
given medical condition, which can be tailored to an individual patient,
thereby predicting the course of disease and individualized treatments, an
important goal of personalized medicine. The immune system, which has a central
role in many diseases, is highly heterogeneous between individuals, and thus
poses a major challenge for this technology. If medical digital twins are to
faithfully capture the characteristics of a patient's immune system, we need to
answer many questions, such as: What do we need to know about the immune system
to build mathematical models that reflect features of an individual? What data
do we need to collect across the different scales of immune system action? What
are the right modeling paradigms to properly capture immune system complexity?
In February 2023, an international group of experts convened in Lake Nona, FL
for two days to discuss these and other questions related to digital twins of
the immune system. The group consisted of clinicians, immunologists,
biologists, and mathematical modelers, representative of the interdisciplinary
nature of medical digital twin development. A video recording of the entire
event is available. This paper presents a synopsis of the discussions, brief
descriptions of ongoing digital twin projects at different stages of progress.
It also proposes a 5-year action plan for further developing this technology.
The main recommendations are to identify and pursue a small number of promising
use cases, to develop stimulation-specific assays of immune function in a
clinical setting, and to develop a database of existing computational immune
models, as well as advanced modeling technology and infrastructure
- …