5,323 research outputs found
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
Prediction of protein-protein interactions using one-class classification methods and integrating diverse data
This research addresses the problem of prediction of protein-protein interactions (PPI)
when integrating diverse kinds of biological information. This task has been commonly
viewed as a binary classification problem (whether any two proteins do or do not interact)
and several different machine learning techniques have been employed to solve this
task. However the nature of the data creates two major problems which can affect results.
These are firstly imbalanced class problems due to the number of positive examples (pairs
of proteins which really interact) being much smaller than the number of negative ones.
Secondly the selection of negative examples can be based on some unreliable assumptions
which could introduce some bias in the classification results.
Here we propose the use of one-class classification (OCC) methods to deal with the task of
prediction of PPI. OCC methods utilise examples of just one class to generate a predictive
model which consequently is independent of the kind of negative examples selected; additionally
these approaches are known to cope with imbalanced class problems. We have
designed and carried out a performance evaluation study of several OCC methods for this
task, and have found that the Parzen density estimation approach outperforms the rest. We
also undertook a comparative performance evaluation between the Parzen OCC method
and several conventional learning techniques, considering different scenarios, for example
varying the number of negative examples used for training purposes. We found that the
Parzen OCC method in general performs competitively with traditional approaches and in
many situations outperforms them. Finally we evaluated the ability of the Parzen OCC
approach to predict new potential PPI targets, and validated these results by searching for
biological evidence in the literature
Nonlinear Models Using Dirichlet Process Mixtures
We introduce a new nonlinear model for classification, in which we model the
joint distribution of response variable, y, and covariates, x,
non-parametrically using Dirichlet process mixtures. We keep the relationship
between y and x linear within each component of the mixture. The overall
relationship becomes nonlinear if the mixture contains more than one component.
We use simulated data to compare the performance of this new approach to a
simple multinomial logit (MNL) model, an MNL model with quadratic terms, and a
decision tree model. We also evaluate our approach on a protein fold
classification problem, and find that our model provides substantial
improvement over previous methods, which were based on Neural Networks (NN) and
Support Vector Machines (SVM). Folding classes of protein have a hierarchical
structure. We extend our method to classification problems where a class
hierarchy is available. We find that using the prior information regarding the
hierarchical structure of protein folds can result in higher predictive
accuracy
Iterative Random Forests to detect predictive and stable high-order interactions
Genomics has revolutionized biology, enabling the interrogation of whole
transcriptomes, genome-wide binding sites for proteins, and many other
molecular processes. However, individual genomic assays measure elements that
interact in vivo as components of larger molecular machines. Understanding how
these high-order interactions drive gene expression presents a substantial
statistical challenge. Building on Random Forests (RF), Random Intersection
Trees (RITs), and through extensive, biologically inspired simulations, we
developed the iterative Random Forest algorithm (iRF). iRF trains a
feature-weighted ensemble of decision trees to detect stable, high-order
interactions with same order of computational cost as RF. We demonstrate the
utility of iRF for high-order interaction discovery in two prediction problems:
enhancer activity in the early Drosophila embryo and alternative splicing of
primary transcripts in human derived cell lines. In Drosophila, among the 20
pairwise transcription factor interactions iRF identifies as stable (returned
in more than half of bootstrap replicates), 80% have been previously reported
as physical interactions. Moreover, novel third-order interactions, e.g.
between Zelda (Zld), Giant (Gt), and Twist (Twi), suggest high-order
relationships that are candidates for follow-up experiments. In human-derived
cells, iRF re-discovered a central role of H3K36me3 in chromatin-mediated
splicing regulation, and identified novel 5th and 6th order interactions,
indicative of multi-valent nucleosomes with specific roles in splicing
regulation. By decoupling the order of interactions from the computational cost
of identification, iRF opens new avenues of inquiry into the molecular
mechanisms underlying genome biology
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