20,531 research outputs found
Systems approaches and algorithms for discovery of combinatorial therapies
Effective therapy of complex diseases requires control of highly non-linear
complex networks that remain incompletely characterized. In particular, drug
intervention can be seen as control of signaling in cellular networks.
Identification of control parameters presents an extreme challenge due to the
combinatorial explosion of control possibilities in combination therapy and to
the incomplete knowledge of the systems biology of cells. In this review paper
we describe the main current and proposed approaches to the design of
combinatorial therapies, including the empirical methods used now by clinicians
and alternative approaches suggested recently by several authors. New
approaches for designing combinations arising from systems biology are
described. We discuss in special detail the design of algorithms that identify
optimal control parameters in cellular networks based on a quantitative
characterization of control landscapes, maximizing utilization of incomplete
knowledge of the state and structure of intracellular networks. The use of new
technology for high-throughput measurements is key to these new approaches to
combination therapy and essential for the characterization of control
landscapes and implementation of the algorithms. Combinatorial optimization in
medical therapy is also compared with the combinatorial optimization of
engineering and materials science and similarities and differences are
delineated.Comment: 25 page
Module networks revisited: computational assessment and prioritization of model predictions
The solution of high-dimensional inference and prediction problems in
computational biology is almost always a compromise between mathematical theory
and practical constraints such as limited computational resources. As time
progresses, computational power increases but well-established inference
methods often remain locked in their initial suboptimal solution. We revisit
the approach of Segal et al. (2003) to infer regulatory modules and their
condition-specific regulators from gene expression data. In contrast to their
direct optimization-based solution we use a more representative centroid-like
solution extracted from an ensemble of possible statistical models to explain
the data. The ensemble method automatically selects a subset of most
informative genes and builds a quantitatively better model for them. Genes
which cluster together in the majority of models produce functionally more
coherent modules. Regulators which are consistently assigned to a module are
more often supported by literature, but a single model always contains many
regulator assignments not supported by the ensemble. Reliably detecting
condition-specific or combinatorial regulation is particularly hard in a single
optimum but can be achieved using ensemble averaging.Comment: 8 pages REVTeX, 6 figure
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