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Identification of transcriptional programs using dense vector representations defined by mutual information with GeneVector.

ABSTRACT: Deciphering individual cell phenotypes from cell-specific transcriptional processes requires high dimensional single cell RNA sequencing. However, current dimensionality reduction methods aggregate sparse gene information across cells, without directly measuring the relationships that exist between genes. By performing dimensionality reduction with respect to gene co-expression, low-dimensional features can model these gene-specific relationships and leverage shared signal to overcome sparsity. We describe GeneVector, a scalable framework for dimensionality reduction implemented as a vector space model using mutual information between gene expression. Unlike other methods, including principal component analysis and variational autoencoders, GeneVector uses latent space arithmetic in a lower dimensional gene embedding to identify transcriptional programs and classify cell types. In this work, we show in four single cell RNA-seq datasets that GeneVector was able to capture phenotype-specific pathways, perform batch effect correction, interactively annotate cell types, and identify pathway variation with treatment over time.

SUBMITTER: Ceglia N

PROVIDER: S-EPMC10359421 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Identification of transcriptional programs using dense vector representations defined by mutual information with GeneVector.

Ceglia Nicholas N Sethna Zachary Z Freeman Samuel S SS Uhlitz Florian F Bojilova Viktoria V Rusk Nicole N Burman Bharat B Chow Andrew A Salehi Sohrab S Kabeer Farhia F Aparicio Samuel S Greenbaum Benjamin D BD Shah Sohrab P SP McPherson Andrew A

Nature communications 20230720 1

Deciphering individual cell phenotypes from cell-specific transcriptional processes requires high dimensional single cell RNA sequencing. However, current dimensionality reduction methods aggregate sparse gene information across cells, without directly measuring the relationships that exist between genes. By performing dimensionality reduction with respect to gene co-expression, low-dimensional features can model these gene-specific relationships and leverage shared signal to overcome sparsity. ...[more]

PMID: 37474509

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Project description:BackgroundProbability based statistical learning methods such as mutual information and Bayesian networks have emerged as a major category of tools for reverse engineering mechanistic relationships from quantitative biological data. In this work we introduce a new statistical learning strategy, MI3 that addresses three common issues in previous methods simultaneously: (1) handling of continuous variables, (2) detection of more complex three-way relationships and (3) better differentiation of causal versus confounding relationships. With these improvements, we provide a more realistic representation of the underlying biological system.ResultsWe test the MI3 algorithm using both synthetic and experimental data. In the synthetic data experiment, MI3 achieved an absolute sensitivity/precision of 0.77/0.83 and a relative sensitivity/precision both of 0.99. In addition, MI3 significantly outperformed the control methods, including Bayesian networks, classical two-way mutual information and a discrete version of MI3. We then used MI3 and control methods to infer a regulatory network centered at the MYC transcription factor from a published microarray dataset. Models selected by MI3 were numerically and biologically distinct from those selected by control methods. Unlike control methods, MI3 effectively differentiated true causal models from confounding models. MI3 recovered major MYC cofactors, and revealed major mechanisms involved in MYC dependent transcriptional regulation, which are strongly supported by literature. The MI3 network showed that limited sets of regulatory mechanisms are employed repeatedly to control the expression of large number of genes.ConclusionOverall, our work demonstrates that MI3 outperforms the frequently used control methods, and provides a powerful method for inferring mechanistic relationships underlying biological and other complex systems. The MI3 method is implemented in R in the "mi3" package, available under the GNU GPL from http://sysbio.engin.umich.edu/~luow/downloads.php and from the R package archive CRAN.

Project description:A longstanding challenge in epilepsy research and practice is the need to classify synchronization patterns hidden in multivariate electroencephalography (EEG) data that is routinely superimposed with intensive noise. It is essential to select a suitable feature extraction method to achieve high recognition performance. A typical approach is to extract the mutual information (MI) between pairs of channels. This calculation, which considers the differences between the sequence pairs to build a reasonable partition, can improve the classification performance. On this basis, however, it is even more difficult to adaptively classify the synchronization patterns hidden in multivariate EEG data under circumstances of insufficient a priori knowledge of domain dependency, such as denoising, feature extraction on a special patient, etc. To address these problems by (1) effectively calculating the MI matrix (synchronization pattern) and (2) accurately classifying the seizure or non-seizure state, this study first accurately measures the synchronization between channel pairs in terms of affinity propagation clustering partition MI (APCPMI). The global synchronization measurement is then obtained by organizing APCPMIs of all channel pairs into a correlation matrix. Finally, a cross-layer fully connected net is designed to characterize the synchronization dynamics correlation matrices adaptively and identify seizure or non-seizure states automatically. Experiments are performed using the CHB-MIT scalp EEG dataset to evaluate the proposed approach. Seizure states are identified with an accuracy, sensitivity, and specificity of 0.9793 ± 0.002, 0.9942 ± 0.0005, and 0.9676 ± 0.003, respectively; the resulting performance is superior to those achieved by most existing methods over the same dataset. Furthermore, the approach alleviates the necessity for strictly preprocessing (denoising, removing interferences and artifacts) the EEG data using prior knowledge, which is usually required by existing approaches.

Project description:PurposeEffective identification of electrical drivers within remodeled tissue is a key for improving ablation treatment for atrial fibrillation. We have developed a mutual information, graph-based approach to identify and propose fault tolerance metric of local efficiency as a distinguishing feature of rotational activation and remodeled atrial tissue.MethodsVoltage data were extracted from atrial tissue simulations (2D Karma, 3D physiological, and the Multiscale Cardiac Simulation Framework (MSCSF)) using multi-spline open and parallel regional mapping catheter geometries. Graphs were generated based on varied mutual information thresholds between electrode pairs and the local efficiency for each graph was calculated.ResultsHigh-resolution mapping catheter geometries can distinguish between rotational and irregular activation patterns using the derivative of local efficiency as a function of increasing mutual information threshold. The derivative is decreased for rotational activation patterns comparing to irregular activations in both a simplified 2D model (0.0017 ± 1 × 10-4 vs. 0.0032 ± 1 × 10-4, p < 0.01) and a more realistic 3D model (0.00092 ± 5 × 10-5 vs. 0.0014 ± 4 × 10-5, p < 0.01). Average local efficiency derivative can also distinguish between degrees of remodeling. Simulations using the MSCSF model, with 10 vs. 90% remodeling, display distinct derivatives in the grid design parallel spline catheter configuration (0.0015 ± 5 × 10-5 vs. 0.0019 ± 6 × 10-5, p < 0.01) and the flower shaped open spline configuration (0.0011 ± 5 × 10-5 vs. 0.0016 ± 4 × 10-5, p < 0.01).ConclusionA decreased derivative of local efficiency characterizes rotational activation and varies with atrial remodeling. This suggests a distinct communication pattern in cardiac rotational activation detectable via high-resolution regional mapping and could enable identification of electrical drivers for targeted ablation.

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Identification of transcriptional programs using dense vector representations defined by mutual information with GeneVector.

Publications

Identification of transcriptional programs using dense vector representations defined by mutual information with GeneVector.

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