1,023 research outputs found
Modeling cumulative biological phenomena with Suppes-Bayes Causal Networks
Several diseases related to cell proliferation are characterized by the
accumulation of somatic DNA changes, with respect to wildtype conditions.
Cancer and HIV are two common examples of such diseases, where the mutational
load in the cancerous/viral population increases over time. In these cases,
selective pressures are often observed along with competition, cooperation and
parasitism among distinct cellular clones. Recently, we presented a
mathematical framework to model these phenomena, based on a combination of
Bayesian inference and Suppes' theory of probabilistic causation, depicted in
graphical structures dubbed Suppes-Bayes Causal Networks (SBCNs). SBCNs are
generative probabilistic graphical models that recapitulate the potential
ordering of accumulation of such DNA changes during the progression of the
disease. Such models can be inferred from data by exploiting likelihood-based
model-selection strategies with regularization. In this paper we discuss the
theoretical foundations of our approach and we investigate in depth the
influence on the model-selection task of: (i) the poset based on Suppes' theory
and (ii) different regularization strategies. Furthermore, we provide an
example of application of our framework to HIV genetic data highlighting the
valuable insights provided by the inferred
Efficient computational strategies to learn the structure of probabilistic graphical models of cumulative phenomena
Structural learning of Bayesian Networks (BNs) is a NP-hard problem, which is
further complicated by many theoretical issues, such as the I-equivalence among
different structures. In this work, we focus on a specific subclass of BNs,
named Suppes-Bayes Causal Networks (SBCNs), which include specific structural
constraints based on Suppes' probabilistic causation to efficiently model
cumulative phenomena. Here we compare the performance, via extensive
simulations, of various state-of-the-art search strategies, such as local
search techniques and Genetic Algorithms, as well as of distinct regularization
methods. The assessment is performed on a large number of simulated datasets
from topologies with distinct levels of complexity, various sample size and
different rates of errors in the data. Among the main results, we show that the
introduction of Suppes' constraints dramatically improve the inference
accuracy, by reducing the solution space and providing a temporal ordering on
the variables. We also report on trade-offs among different search techniques
that can be efficiently employed in distinct experimental settings. This
manuscript is an extended version of the paper "Structural Learning of
Probabilistic Graphical Models of Cumulative Phenomena" presented at the 2018
International Conference on Computational Science
Parallel Implementation of Efficient Search Schemes for the Inference of Cancer Progression Models
The emergence and development of cancer is a consequence of the accumulation
over time of genomic mutations involving a specific set of genes, which
provides the cancer clones with a functional selective advantage. In this work,
we model the order of accumulation of such mutations during the progression,
which eventually leads to the disease, by means of probabilistic graphic
models, i.e., Bayesian Networks (BNs). We investigate how to perform the task
of learning the structure of such BNs, according to experimental evidence,
adopting a global optimization meta-heuristics. In particular, in this work we
rely on Genetic Algorithms, and to strongly reduce the execution time of the
inference -- which can also involve multiple repetitions to collect
statistically significant assessments of the data -- we distribute the
calculations using both multi-threading and a multi-node architecture. The
results show that our approach is characterized by good accuracy and
specificity; we also demonstrate its feasibility, thanks to a 84x reduction of
the overall execution time with respect to a traditional sequential
implementation
The Temporal Order of Genetic and Pathway Alterations in Tumorigenesis
Cancer evolves through the accumulation of mutations, but the order in which mutations occur is poorly understood. Inference of a temporal ordering on the level of genes is challenging because clinically and histologically identical tumors often have few mutated genes in common. This heterogeneity may at least in part be due to mutations in different genes having similar phenotypic effects by acting in the same functional pathway. We estimate the constraints on the order in which alterations accumulate during cancer progression from cross-sectional mutation data using a probabilistic graphical model termed Hidden Conjunctive Bayesian Network (H-CBN). The possible orders are analyzed on the level of genes and, after mapping genes to functional pathways, also on the pathway level. We find stronger evidence for pathway order constraints than for gene order constraints, indicating that temporal ordering results from selective pressure acting at the pathway level. The accumulation of changes in core pathways differs among cancer types, yet a common feature is that progression appears to begin with mutations in genes that regulate apoptosis pathways and to conclude with mutations in genes involved in invasion pathways. H-CBN models provide a quantitative and intuitive model of tumorigenesis showing that the genetic events can be linked to the phenotypic progression on the level of pathways
Computational Cancer Biology: An Evolutionary Perspective
ISSN:1553-734XISSN:1553-735
Algorithmic methods to infer the evolutionary trajectories in cancer progression
The genomic evolution inherent to cancer relates directly to a renewed focus on the voluminous next-generation sequencing data and machine learning for the inference of explanatory models of how the (epi)genomic events are choreographed in cancer initiation and development. However, despite the increasing availability of multiple additional -omics data, this quest has been frustrated by various theoretical and technical hurdles, mostly stemming from the dramatic heterogeneity of the disease. In this paper, we build on our recent work on the 'selective advantage' relation among driver mutations in cancer progression and investigate its applicability to the modeling problem at the population level. Here, we introduce PiCnIc (Pipeline for Cancer Inference), a versatile, modular, and customizable pipeline to extract ensemble-level progression models from cross-sectional sequenced cancer genomes. The pipeline has many translational implications because it combines state-of-the-art techniques for sample stratification, driver selection, identification of fitness-equivalent exclusive alterations, and progression model inference. We demonstrate PiCnIc's ability to reproduce much of the current knowledge on colorectal cancer progression as well as to suggest novel experimentally verifiable hypotheses
Efficient sampling for Bayesian inference of conjunctive Bayesian networks
Motivation: Cancer development is driven by the accumulation of advantageous mutations and subsequent clonal expansion of cells harbouring these mutations, but the order in which mutations occur remains poorly understood. Advances in genome sequencing and the soon-arriving flood of cancer genome data produced by large cancer sequencing consortia hold the promise to elucidate cancer progression. However, new computational methods are needed to analyse these large datasets. Results: We present a Bayesian inference scheme for Conjunctive Bayesian Networks, a probabilistic graphical model in which mutations accumulate according to partial order constraints and cancer genotypes are observed subject to measurement noise. We develop an efficient MCMC sampling scheme specifically designed to overcome local optima induced by dependency structures. We demonstrate the performance advantage of our sampler over traditional approaches on simulated data and show the advantages of adopting a Bayesian perspective when reanalyzing cancer datasets and comparing our results to previous maximum-likelihood-based approaches. Availability: An R package including the sampler and examples is available at http://www.cbg.ethz.ch/software/bayes-cbn. Contacts: [email protected]
Learning mutational graphs of individual tumour evolution from single-cell and multi-region sequencing data
Background. A large number of algorithms is being developed to reconstruct
evolutionary models of individual tumours from genome sequencing data. Most
methods can analyze multiple samples collected either through bulk multi-region
sequencing experiments or the sequencing of individual cancer cells. However,
rarely the same method can support both data types.
Results. We introduce TRaIT, a computational framework to infer mutational
graphs that model the accumulation of multiple types of somatic alterations
driving tumour evolution. Compared to other tools, TRaIT supports multi-region
and single-cell sequencing data within the same statistical framework, and
delivers expressive models that capture many complex evolutionary phenomena.
TRaIT improves accuracy, robustness to data-specific errors and computational
complexity compared to competing methods.
Conclusions. We show that the application of TRaIT to single-cell and
multi-region cancer datasets can produce accurate and reliable models of
single-tumour evolution, quantify the extent of intra-tumour heterogeneity and
generate new testable experimental hypotheses
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