arXiv subjects

Manuel Middendorf

Publications and source records attributed to Manuel Middendorf.

7 recordsLinked to original sources

arXiv2007

Motif Discovery through Predictive Modeling of Gene Regulation

We present MEDUSA, an integrative method for learning motif models of transcription factor binding sites by incorporating promoter sequence and gene expression data. We use a modern large-margin machine learning approach, based on boosting, to enable feature selection from the high-dimensional search space of candidate binding sequences while avoiding overfitting. At each iteration of the algorithm, MEDUSA builds a motif model whose presence in the promoter region of a gene, coupled with activity of a regulator in an experiment, is predictive of differential expression. In this way, we learn motifs that are functional and predictive of regulatory response rather than motifs that are simply overrepresented in promoter sequences. Moreover, MEDUSA produces a model of the transcriptional control logic that can predict the expression of any gene in the organism, given the sequence of the promoter region of the target gene and the expression state of a set of known or putative transcription factors and signaling molecules. Each motif model is either a $k$-length sequence, a dimer, or a PSSM that is built by agglomerative probabilistic clustering of sequences with similar boosting loss. By applying MEDUSA to a set of environmental stress response expression data in yeast, we learn motifs whose ability to predict differential expression of target genes outperforms motifs from the TRANSFAC dataset and from a previously published candidate set of PSSMs. We also show that MEDUSA retrieves many experimentally confirmed binding sites associated with environmental stress response from the literature.

q-bio.GN↗

arXiv2005

Systematic identification of statistically significant network measures

We present a novel graph embedding space (i.e., a set of measures on graphs) for performing statistical analyses of networks. Key improvements over existing approaches include discovery of "motif-hubs" (multiple overlapping significant subgraphs), computational efficiency relative to subgraph census, and flexibility (the method is easily generalizable to weighted and signed graphs). The embedding space is based on {\it scalars}, functionals of the adjacency matrix representing the network. {\it Scalars} are global, involving all nodes; although they can be related to subgraph enumeration, there is not a one-to-one mapping between scalars and subgraphs. Improvements in network randomization and significance testing--we learn the distribution rather than assuming gaussianity--are also presented. The resulting algorithm establishes a systematic approach to the identification of the most significant scalars and suggests machine-learning techniques for network classification.

cond-mat.dis-nn↗

arXiv2004

An Information-Theoretic Approach to Network Modularity

Exploiting recent developments in information theory, we propose, illustrate, and validate a principled information-theoretic algorithm for module discovery and resulting measure of network modularity. This measure is an order parameter (a dimensionless number between 0 and 1). Comparison is made to other approaches to module-discovery and to quantifying network modularity using Monte Carlo generated Erdos-like modular networks. Finally, the Network Information Bottleneck (NIB) algorithm is applied to a number of real world networks, including the "social" network of coauthors at the APS March Meeting 2004.

q-bio.QM↗

arXiv2004

Predicting Genetic Regulatory Response Using Classification

We present a novel classification-based method for learning to predict gene regulatory response. Our approach is motivated by the hypothesis that in simple organisms such as Saccharomyces cerevisiae, we can learn a decision rule for predicting whether a gene is up- or down-regulated in a particular experiment based on (1) the presence of binding site subsequences (``motifs'') in the gene's regulatory region and (2) the expression levels of regulators such as transcription factors in the experiment (``parents''). Thus our learning task integrates two qualitatively different data sources: genome-wide cDNA microarray data across multiple perturbation and mutant experiments along with motif profile data from regulatory sequences. We convert the regression task of predicting real-valued gene expression measurement to a classification task of predicting +1 and -1 labels, corresponding to up- and down-regulation beyond the levels of biological and measurement noise in microarray measurements. The learning algorithm employed is boosting with a margin-based generalization of decision trees, alternating decision trees. This large-margin classifier is sufficiently flexible to allow complex logical functions, yet sufficiently simple to give insight into the combinatorial mechanisms of gene regulation. We observe encouraging prediction accuracy on experiments based on the Gasch S. cerevisiae dataset, and we show that we can accurately predict up- and down-regulation on held-out experiments. Our method thus provides predictive hypotheses, suggests biological experiments, and provides interpretable insight into the structure of genetic regulatory networks.

q-bio.QM↗

arXiv2004

Inferring Network Mechanisms: The Drosophila melanogaster Protein Interaction Network

Naturally occurring networks exhibit quantitative features revealing underlying growth mechanisms. Numerous network mechanisms have recently been proposed to reproduce specific properties such as degree distributions or clustering coefficients. We present a method for inferring the mechanism most accurately capturing a given network topology, exploiting discriminative tools from machine learning. The Drosophila melanogaster protein network is confidently and robustly (to noise and training data subsampling) classified as a duplication-mutation-complementation network over preferential attachment, small-world, and other duplication-mutation mechanisms. Systematic classification, rather than statistical study of specific properties, provides a discriminative approach to understand the design of complex networks.

q-bio.QM↗

arXiv2004

Predicting Genetic Regulatory Response using Classification: Yeast Stress Response

We present a novel classification-based algorithm called GeneClass for learning to predict gene regulatory response. Our approach is motivated by the hypothesis that in simple organisms such as Saccharomyces cerevisiae, we can learn a decision rule for predicting whether a gene is up- or down-regulated in a particular experiment based on (1) the presence of binding site subsequences (``motifs'') in the gene's regulatory region and (2) the expression levels of regulators such as transcription factors in the experiment (``parents''). Thus our learning task integrates two qualitatively different data sources: genome-wide cDNA microarray data across multiple perturbation and mutant experiments along with motif profile data from regulatory sequences. Rather than focusing on the regression task of predicting real-valued gene expression measurements, GeneClass performs the classification task of predicting +1 and -1 labels, corresponding to up- and down-regulation beyond the levels of biological and measurement noise in microarray measurements. GeneClass uses the Adaboost learning algorithm with a margin-based generalization of decision trees called alternating decision trees. In computational experiments based on the Gasch S. cerevisiae dataset, we show that the GeneClass method predicts up- and down-regulation on held-out experiments with high accuracy. We explore a range of experimental setups related to environmental stress response, and we retrieve important regulators, binding site motifs, and relationships between regulators and binding sites that are known to be associated to specific stress response pathways. Our method thus provides predictive hypotheses, suggests biological experiments, and provides interpretable insight into the structure of genetic regulatory networks.

q-bio.QM↗

arXiv2004

Discriminative Topological Features Reveal Biological Network Mechanisms

Recent genomic and bioinformatic advances have motivated the development of numerous random network models purporting to describe graphs of biological, technological, and sociological origin. The success of a model has been evaluated by how well it reproduces a few key features of the real-world data, such as degree distributions, mean geodesic lengths, and clustering coefficients. Often pairs of models can reproduce these features with indistinguishable fidelity despite being generated by vastly different mechanisms. In such cases, these few target features are insufficient to distinguish which of the different models best describes real world networks of interest; moreover, it is not clear a priori that any of the presently-existing algorithms for network generation offers a predictive description of the networks inspiring them. To derive discriminative classifiers, we construct a mapping from the set of all graphs to a high-dimensional (in principle infinite-dimensional) ``word space.'' This map defines an input space for classification schemes which allow us for the first time to state unambiguously which models are most descriptive of the networks they purport to describe. Our training sets include networks generated from 17 models either drawn from the literature or introduced in this work, source code for which is freely available. We anticipate that this new approach to network analysis will be of broad impact to a number of communities.

q-bio.MN↗