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1. Gene regulation network inference using k-nearest neighbor-based mutual information estimation: revisiting an old DREAM

   https://doi.org/10.1186/s12859-022-05047-5  

   Shachaf, Lior I. ; Roberts, Elijah ; Cahan, Patrick ; Xiao, Jie ( March 2023 , BMC Bioinformatics)

   A cell exhibits a variety of responses to internal and external cues. These responses are possible, in part, due to the presence of an elaborate gene regulatory network (GRN) in every single cell. In the past 20 years, many groups worked on reconstructing the topological structure of GRNs from large-scale gene expression data using a variety of inference algorithms. Insights gained about participating players in GRNs may ultimately lead to therapeutic benefits. Mutual information (MI) is a widely used metric within this inference/reconstruction pipeline as it can detect any correlation (linear and non-linear) between any number of variables (n-dimensions). However, the use of MI with continuous data (for example, normalized fluorescence intensity measurement of gene expression levels) is sensitive to data size, correlation strength and underlying distributions, and often requires laborious and, at times, ad hoc optimization.

   In this work, we first show that estimating MI of a bi- and tri-variate Gaussian distribution usingk-nearest neighbor (kNN) MI estimation results in significant error reduction as compared to commonly used methods based on fixed binning. Second, we demonstrate that implementing the MI-based kNN Kraskov–Stoögbauer–Grassberger (KSG) algorithm leads to a significant improvement in GRN reconstruction for popular inference algorithms, such as Context Likelihood of Relatedness (CLR). Finally, through extensive in-silico benchmarking we show that a new inference algorithm CMIA (Conditional Mutual Information Augmentation), inspired by CLR, in combination with the KSG-MI estimator, outperforms commonly used methods.

   Using three canonical datasets containing 15 synthetic networks, the newly developed method for GRN reconstruction—which combines CMIA, and the KSG-MI estimator—achieves an improvement of 20–35% in precision-recall measures over the current gold standard in the field. This new method will enable researchers to discover new gene interactions or better choose gene candidates for experimental validations.

    

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2. An automatic integrative method for learning interpretable communities of biological pathways

   https://doi.org/10.1093/nargab/lqac044  

   Beebe-Wang, Nicasia ; Dincer, Ayse B. ; Lee, Su-In ( June 2022 , NAR Genomics and Bioinformatics)

   Although knowledge of biological pathways is essential for interpreting results from computational biology studies, the growing number of pathway databases complicates efforts to efficiently perform pathway analysis due to high redundancies among pathways from different databases, and inconsistencies in how pathways are created and named. We introduce the PAthway Communities (PAC) framework, which reconciles pathways from different databases and reduces pathway redundancy by revealing informative groups with distinct biological functions. Uniquely applying the Louvain community detection algorithm to a network of 4847 pathways from KEGG, REACTOME and Gene Ontology databases, we identify 35 distinct and automatically annotated communities of pathways and show that they are consistent with expert-curated pathway categories. Further, we demonstrate that our pathway community network can be queried with new gene sets to provide biological context in terms of related pathways and communities. Our approach, combined with an interpretable web tool we provide, will help computational biologists more efficiently contextualize and interpret their biological findings.

    

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3. Geometric deep optical sensing

   https://doi.org/10.1126/science.ade1220  

   Yuan, Shaofan ; Ma, Chao ; Fetaya, Ethan ; Mueller, Thomas ; Naveh, Doron ; Zhang, Fan ; Xia, Fengnian ( March 2023 , Science)

   BACKGROUND Optical sensing devices measure the rich physical properties of an incident light beam, such as its power, polarization state, spectrum, and intensity distribution. Most conventional sensors, such as power meters, polarimeters, spectrometers, and cameras, are monofunctional and bulky. For example, classical Fourier-transform infrared spectrometers and polarimeters, which characterize the optical spectrum in the infrared and the polarization state of light, respectively, can occupy a considerable portion of an optical table. Over the past decade, the development of integrated sensing solutions by using miniaturized devices together with advanced machine-learning algorithms has accelerated rapidly, and optical sensing research has evolved into a highly interdisciplinary field that encompasses devices and materials engineering, condensed matter physics, and machine learning. To this end, future optical sensing technologies will benefit from innovations in device architecture, discoveries of new quantum materials, demonstrations of previously uncharacterized optical and optoelectronic phenomena, and rapid advances in the development of tailored machine-learning algorithms. ADVANCES Recently, a number of sensing and imaging demonstrations have emerged that differ substantially from conventional sensing schemes in the way that optical information is detected. A typical example is computational spectroscopy. In this new paradigm, a compact spectrometer first collectively captures the comprehensive spectral information of an incident light beam using multiple elements or a single element under different operational states and generates a high-dimensional photoresponse vector. An advanced algorithm then interprets the vector to achieve reconstruction of the spectrum. This scheme shifts the physical complexity of conventional grating- or interference-based spectrometers to computation. Moreover, many of the recent developments go well beyond optical spectroscopy, and we discuss them within a common framework, dubbed “geometric deep optical sensing.” The term “geometric” is intended to emphasize that in this sensing scheme, the physical properties of an unknown light beam and the corresponding photoresponses can be regarded as points in two respective high-dimensional vector spaces and that the sensing process can be considered to be a mapping from one vector space to the other. The mapping can be linear, nonlinear, or highly entangled; for the latter two cases, deep artificial neural networks represent a natural choice for the encoding and/or decoding processes, from which the term “deep” is derived. In addition to this classical geometric view, the quantum geometry of Bloch electrons in Hilbert space, such as Berry curvature and quantum metrics, is essential for the determination of the polarization-dependent photoresponses in some optical sensors. In this Review, we first present a general perspective of this sensing scheme from the viewpoint of information theory, in which the photoresponse measurement and the extraction of light properties are deemed as information-encoding and -decoding processes, respectively. We then discuss demonstrations in which a reconfigurable sensor (or an array thereof), enabled by device reconfigurability and the implementation of neural networks, can detect the power, polarization state, wavelength, and spatial features of an incident light beam. OUTLOOK As increasingly more computing resources become available, optical sensing is becoming more computational, with device reconfigurability playing a key role. On the one hand, advanced algorithms, including deep neural networks, will enable effective decoding of high-dimensional photoresponse vectors, which reduces the physical complexity of sensors. Therefore, it will be important to integrate memory cells near or within sensors to enable efficient processing and interpretation of a large amount of photoresponse data. On the other hand, analog computation based on neural networks can be performed with an array of reconfigurable devices, which enables direct multiplexing of sensing and computing functions. We anticipate that these two directions will become the engineering frontier of future deep sensing research. On the scientific frontier, exploring quantum geometric and topological properties of new quantum materials in both linear and nonlinear light-matter interactions will enrich the information-encoding pathways for deep optical sensing. In addition, deep sensing schemes will continue to benefit from the latest developments in machine learning. Future highly compact, multifunctional, reconfigurable, and intelligent sensors and imagers will find applications in medical imaging, environmental monitoring, infrared astronomy, and many other areas of our daily lives, especially in the mobile domain and the internet of things. Schematic of deep optical sensing. The n -dimensional unknown information ( w ) is encoded into an m -dimensional photoresponse vector ( x ) by a reconfigurable sensor (or an array thereof), from which w′ is reconstructed by a trained neural network ( n ′ = n and w′   ≈   w ). Alternatively, x may be directly deciphered to capture certain properties of w . Here, w , x , and w′ can be regarded as points in their respective high-dimensional vector spaces ℛ n , ℛ m , and ℛ n ′ . 

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4. A multimodal graph neural network framework for cancer molecular subtype classification

   https://doi.org/10.1186/s12859-023-05622-4  

   Li, Bingjun ; Nabavi, Sheida ( January 2024 , BMC Bioinformatics)

   The recent development of high-throughput sequencing has created a large collection of multi-omics data, which enables researchers to better investigate cancer molecular profiles and cancer taxonomy based on molecular subtypes. Integrating multi-omics data has been proven to be effective for building more precise classification models. Most current multi-omics integrative models use either an early fusion in the form of concatenation or late fusion with a separate feature extractor for each omic, which are mainly based on deep neural networks. Due to the nature of biological systems, graphs are a better structural representation of bio-medical data. Although few graph neural network (GNN) based multi-omics integrative methods have been proposed, they suffer from three common disadvantages. One is most of them use only one type of connection, either inter-omics or intra-omic connection; second, they only consider one kind of GNN layer, either graph convolution network (GCN) or graph attention network (GAT); and third, most of these methods have not been tested on a more complex classification task, such as cancer molecular subtypes.

   In this study, we propose a novel end-to-end multi-omics GNN framework for accurate and robust cancer subtype classification. The proposed model utilizes multi-omics data in the form of heterogeneous multi-layer graphs, which combine both inter-omics and intra-omic connections from established biological knowledge. The proposed model incorporates learned graph features and global genome features for accurate classification. We tested the proposed model on the Cancer Genome Atlas (TCGA) Pan-cancer dataset and TCGA breast invasive carcinoma (BRCA) dataset for molecular subtype and cancer subtype classification, respectively. The proposed model shows superior performance compared to four current state-of-the-art baseline models in terms of accuracy, F1 score, precision, and recall. The comparative analysis of GAT-based models and GCN-based models reveals that GAT-based models are preferred for smaller graphs with less information and GCN-based models are preferred for larger graphs with extra information.

    

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5. EnGRaiN : a supervised ensemble learning method for recovery of large-scale gene regulatory networks

   https://doi.org/10.1093/bioinformatics/btab829  

   Aluru, Maneesha ; Shrivastava, Harsh ; Chockalingam, Sriram P. ; Shivakumar, Shruti ; Aluru, Srinivas ; Martelli, ed., Pier Luigi ( December 2021 , Bioinformatics)

   Reconstruction of genome-scale networks from gene expression data is an actively studied problem. A wide range of methods that differ between the types of interactions they uncover with varying trade-offs between sensitivity and specificity have been proposed. To leverage benefits of multiple such methods, ensemble network methods that combine predictions from resulting networks have been developed, promising results better than or as good as the individual networks. Perhaps owing to the difficulty in obtaining accurate training examples, these ensemble methods hitherto are unsupervised.

   In this article, we introduce EnGRaiN, the first supervised ensemble learning method to construct gene networks. The supervision for training is provided by small training datasets of true edge connections (positives) and edges known to be absent (negatives) among gene pairs. We demonstrate the effectiveness of EnGRaiN using simulated datasets as well as a curated collection of Arabidopsis thaliana datasets we created from microarray datasets available from public repositories. EnGRaiN shows better results not only in terms of receiver operating characteristic and PR characteristics for both real and simulated datasets compared with unsupervised methods for ensemble network construction, but also generates networks that can be mined for elucidating complex biological interactions.

   EnGRaiN software and the datasets used in the study are publicly available at the github repository: https://github.com/AluruLab/EnGRaiN.

   Supplementary data are available at Bioinformatics online.

    

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