Determining significance of pairwise co-occurrences of events in bursty sequences

<p>Abstract</p> <p>Background</p> <p>Event sequences where different types of events often occur close together arise, e.g., when studying potential transcription factor binding sites (TFBS, events) of certain transcription factors (TF, types) in a DNA sequence. These events tend to occur in bursts: in some genomic regions there are more genes and therefore potentially more binding sites, while in some, possibly very long regions, hardly any events occur. Also some types of events may occur in the sequence more often than others.</p> <p>Tendencies of co-occurrence of binding sites of two or more TFs are interesting, as they may imply a co-operative role between the TFs in regulatory processes. Determining a numerical value to summarize the tendency for co-occurrence between two TFs can be done in a number of ways. However, testing for the significance of such values should be done with respect to a relevant null model that takes into account the global sequence structure.</p> <p>Results</p> <p>We extend the existing techniques that have been considered for determining the significance of co-occurrence patterns between a pair of event types under different null models. These models range from very simple ones to more complex models that take the burstiness of sequences into account. We evaluate the models and techniques on synthetic event sequences, and on real data consisting of potential transcription factor binding sites.</p> <p>Conclusion</p> <p>We show that simple null models are poorly suited for bursty data, and they yield many false positives. More sophisticated models give better results in our experiments. We also demonstrate the effect of the window size, i.e., maximum co-occurrence distance, on the significance results.</p

On the use of resampling tests for evaluating statistical significance of binding-site co-occurrence.

BACKGROUND: In eukaryotes, most DNA-binding proteins exert their action as members of large effector complexes. The presence of these complexes are revealed in high-throughput genome-wide assays by the co-occurrence of the binding sites of different complex components. Resampling tests are one route by which the statistical significance of apparent co-occurrence can be assessed. RESULTS: We have investigated two resampling approaches for evaluating the statistical significance of binding-site co-occurrence. The permutation test approach was found to yield overly favourable p-values while the independent resampling approach had the opposite effect and is of little use in practical terms. We have developed a new, pragmatically-devised hybrid approach that, when applied to the experimental results of an Polycomb/Trithorax study, yielded p-values consistent with the findings of that study. We extended our investigations to the FL method developed by Haiminen et al, which derives its null distribution from all binding sites within a dataset, and show that the p-value computed for a pair of factors by this method can depend on which other factors are included in that dataset. Both our hybrid method and the FL method appeared to yield plausible estimates of the statistical significance of co-occurrences although our hybrid method was more conservative when applied to the Polycomb/Trithorax dataset.A high-performance parallelized implementation of the hybrid method is available. CONCLUSIONS: We propose a new resampling-based co-occurrence significance test and demonstrate that it performs as well as or better than existing methods on a large experimentally-derived dataset. We believe it can be usefully applied to data from high-throughput genome-wide techniques such as ChIP-chip or DamID. The Cooccur package, which implements our approach, accompanies this paper.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Detecting multineuronal temporal patterns in parallel spike trains

We present a non-parametric and computationally efficient method that detects spatiotemporal firing patterns and pattern sequences in parallel spike trains and tests whether the observed numbers of repeating patterns and sequences on a given timescale are significantly different from those expected by chance. The method is generally applicable and uncovers coordinated activity with arbitrary precision by comparing it to appropriate surrogate data. The analysis of coherent patterns of spatially and temporally distributed spiking activity on various timescales enables the immediate tracking of diverse qualities of coordinated firing related to neuronal state changes and information processing. We apply the method to simulated data and multineuronal recordings from rat visual cortex and show that it reliably discriminates between data sets with random pattern occurrences and with additional exactly repeating spatiotemporal patterns and pattern sequences. Multineuronal cortical spiking activity appears to be precisely coordinated and exhibits a sequential organization beyond the cell assembly concept

Fouille de séquences temporelles pour la maintenance prédictive : application aux données de véhicules traceurs ferroviaires

In order to meet the mounting social and economic demands, railway operators and manufacturers are striving for a longer availability and a better reliability of railway transportation systems. Commercial trains are being equipped with state-of-the-art onboard intelligent sensors monitoring various subsystems all over the train. These sensors provide real-time flow of data, called floating train data, consisting of georeferenced events, along with their spatial and temporal coordinates. Once ordered with respect to time, these events can be considered as long temporal sequences which can be mined for possible relationships. This has created a neccessity for sequential data mining techniques in order to derive meaningful associations rules or classification models from these data. Once discovered, these rules and models can then be used to perform an on-line analysis of the incoming event stream in order to predict the occurrence of target events, i.e, severe failures that require immediate corrective maintenance actions. The work in this thesis tackles the above mentioned data mining task. We aim to investigate and develop various methodologies to discover association rules and classification models which can help predict rare tilt and traction failures in sequences using past events that are less critical. The investigated techniques constitute two major axes: Association analysis, which is temporal and Classification techniques, which is not temporal. The main challenges confronting the data mining task and increasing its complexity are mainly the rarity of the target events to be predicted in addition to the heavy redundancy of some events and the frequent occurrence of data bursts. The results obtained on real datasets collected from a fleet of trains allows to highlight the effectiveness of the approaches and methodologies usedDe nos jours, afin de répondre aux exigences économiques et sociales, les systèmes de transport ferroviaire ont la nécessité d'être exploités avec un haut niveau de sécurité et de fiabilité. On constate notamment un besoin croissant en termes d'outils de surveillance et d'aide à la maintenance de manière à anticiper les défaillances des composants du matériel roulant ferroviaire. Pour mettre au point de tels outils, les trains commerciaux sont équipés de capteurs intelligents envoyant des informations en temps réel sur l'état de divers sous-systèmes. Ces informations se présentent sous la forme de longues séquences temporelles constituées d'une succession d'événements. Le développement d'outils d'analyse automatique de ces séquences permettra d'identifier des associations significatives entre événements dans un but de prédiction d'événement signant l'apparition de défaillance grave. Cette thèse aborde la problématique de la fouille de séquences temporelles pour la prédiction d'événements rares et s'inscrit dans un contexte global de développement d'outils d'aide à la décision. Nous visons à étudier et développer diverses méthodes pour découvrir les règles d'association entre événements d'une part et à construire des modèles de classification d'autre part. Ces règles et/ou ces classifieurs peuvent ensuite être exploités pour analyser en ligne un flux d'événements entrants dans le but de prédire l'apparition d'événements cibles correspondant à des défaillances. Deux méthodologies sont considérées dans ce travail de thèse: La première est basée sur la recherche des règles d'association, qui est une approche temporelle et une approche à base de reconnaissance de formes. Les principaux défis auxquels est confronté ce travail sont principalement liés à la rareté des événements cibles à prédire, la redondance importante de certains événements et à la présence très fréquente de "bursts". Les résultats obtenus sur des données réelles recueillies par des capteurs embarqués sur une flotte de trains commerciaux permettent de mettre en évidence l'efficacité des approches proposée

Metastability and Dynamics of Stem Cells: From Direct Observations to Inference at the Single Cell Level

Organismal development, homeostasis, and pathology are rooted in inherently probabilistic events. From gene expression to cellular differentiation, rates and likelihoods shape the form and function of biology. Processes ranging from growth to cancer homeostasis to reprogramming of stem cells all require transitions between distinct phenotypic states, and these occur at defined rates. Therefore, measuring the fidelity and dynamics with which such transitions occur is central to understanding natural biological phenomena and is critical for therapeutic interventions. While these processes may produce robust population-level behaviors, decisions are made by individual cells. In certain circumstances, these minuscule computing units effectively roll dice to determine their fate. And while the 'omics' era has provided vast amounts of data on what these populations are doing en masse, the behaviors of the underlying units of these processes get washed out in averages. Therefore, in order to understand the behavior of a sample of cells, it is critical to reveal how its underlying components, or mixture of cells in distinct states, each contribute to the overall phenotype. As such, we must first define what states exist in the population, determine what controls the stability of these states, and measure in high dimensionality the dynamics with which these cells transition between states. To address a specific example of this general problem, we investigate the heterogeneity and dynamics of mouse embryonic stem cells (mESCs). While a number of reports have identified particular genes in ES cells that switch between 'high' and 'low' metastable expression states in culture, it remains unclear how levels of many of these regulators combine to form states in transcriptional space. Using a method called single molecule mRNA fluorescent in situ hybridization (smFISH), we quantitatively measure and fit distributions of core pluripotency regulators in single cells, identifying a wide range of variabilities between genes, but each explained by a simple model of bursty transcription. From this data, we also observed that strongly bimodal genes appear to be co-expressed, effectively limiting the occupancy of transcriptional space to two primary states across genes studied here. However, these states also appear punctuated by the conditional expression of the most highly variable genes, potentially defining smaller substates of pluripotency. Having defined the transcriptional states, we next asked what might control their stability or persistence. Surprisingly, we found that DNA methylation, a mark normally associated with irreversible developmental progression, was itself differentially regulated between these two primary states. Furthermore, both acute or chronic inhibition of DNA methyltransferase activity led to reduced heterogeneity among the population, suggesting that metastability can be modulated by this strong epigenetic mark. Finally, because understanding the dynamics of state transitions is fundamental to a variety of biological problems, we sought to develop a high-throughput method for the identification of cellular trajectories without the need for cell-line engineering. We achieved this by combining cell-lineage information gathered from time-lapse microscopy with endpoint smFISH for measurements of final expression states. Applying a simple mathematical framework to these lineage-tree associated expression states enables the inference of dynamic transitions. We apply our novel approach in order to infer temporal sequences of events, quantitative switching rates, and network topology among a set of ESC states. Taken together, we identify distinct expression states in ES cells, gain fundamental insight into how a strong epigenetic modifier enforces the stability of these states, and develop and apply a new method for the identification of cellular trajectories using scalable in situ readouts of cellular state.</p

Statistical Mechanics and Information-Theoretic Perspectives on Complexity in the Earth System

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