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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. MFBO-SSM: Multi-Fidelity Bayesian Optimization for Fast Inference in State-Space Models

   Imani, M ; Ghoreishi, S.F. ; Allaire, D. ; Braga-Neto, U ( July 2019 , Proceedings of the ... AAAI Conference on Artificial Intelligence)

   Nonlinear state-space models are ubiquitous in modeling real-world dynamical systems. Sequential Monte Carlo (SMC) techniques, also known as particle methods, are a well-known class of parameter estimation methods for this general class of state-space models. Existing SMC-based techniques rely on excessive sampling of the parameter space, which makes their computation intractable for large systems or tall data sets. Bayesian optimization techniques have been used for fast inference in state-space models with intractable likelihoods. These techniques aim to find the maximum of the likelihood function by sequential sampling of the parameter space through a single SMC approximator. Various SMC approximators with different fidelities and computational costs are often available for sample- based likelihood approximation. In this paper, we propose a multi-fidelity Bayesian optimization algorithm for the inference of general nonlinear state-space models (MFBO-SSM), which enables simultaneous sequential selection of parameters and approximators. The accuracy and speed of the algorithm are demonstrated by numerical experiments using synthetic gene expression data from a gene regulatory network model and real data from the VIX stock price index. 

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3. INFERENCE OF GENE REGULATORY NETWORKS BY MAXIMUM-LIKELIHOOD ADAPTIVE FILTERING AND DISCRETE FISH SCHOOL SEARCH

   https://doi.org/10.1109/MLSP.2018.8516967  

   Tan, Yukun ; Lima Neto, Fernando B. ; Braga Neto, Ulisses ( September 2018 , 2018 IEEE 28th International Workshop on Machine Learning for Signal Processing (MLSP))

   We propose a new algorithm for inference of gene regulatory networks (GRN) from noisy gene expression data based on maximum-likelihood (ML) adaptive filtering and the discrete fish school search algorithm (DFSS). The approach is based on the general partially-observed Boolean dynamical system (POBDS) model, and as such can be used for simultaneous state and parameter estimation for any Boolean dynamical system observed in noise. The proposed DFSS-ML-BKF algorithm combines the ML adaptive Boolean Kalman Filter (ML-BKF) with DFSS, a version of the Fish School Search algorithm tailored for discrete parameter spaces. Results based on synthetic gene expression time-series data using the well-known p53-MDM2 negative-feedback loop GRN demonstrate that DFSS-ML-BKF can infer the network topology accurately and efficiently. 

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4. JRmGRN: joint reconstruction of multiple gene regulatory networks with common hub genes using data from multiple tissues or conditions

   https://doi.org/10.1093/bioinformatics/bty354  

   Deng, Wenping ; Zhang, Kui ; Liu, Sanzhen ; Zhao, Patrick X. ; Xu, Shizhong ; Wei, Hairong ; Birol, ed., Inanc ( April 2018 , Bioinformatics)

   Joint reconstruction of multiple gene regulatory networks (GRNs) using gene expression data from multiple tissues/conditions is very important for understanding common and tissue/condition-specific regulation. However, there are currently no computational models and methods available for directly constructing such multiple GRNs that not only share some common hub genes but also possess tissue/condition-specific regulatory edges.

   In this paper, we proposed a new graphic Gaussian model for joint reconstruction of multiple gene regulatory networks (JRmGRN), which highlighted hub genes, using gene expression data from several tissues/conditions. Under the framework of Gaussian graphical model, JRmGRN method constructs the GRNs through maximizing a penalized log likelihood function. We formulated it as a convex optimization problem, and then solved it with an alternating direction method of multipliers (ADMM) algorithm. The performance of JRmGRN was first evaluated with synthetic data and the results showed that JRmGRN outperformed several other methods for reconstruction of GRNs. We also applied our method to real Arabidopsis thaliana RNA-seq data from two light regime conditions in comparison with other methods, and both common hub genes and some conditions-specific hub genes were identified with higher accuracy and precision.

   JRmGRN is available as a R program from: https://github.com/wenpingd.

   Supplementary data are available at Bioinformatics online.

    

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5. Inference of Protein-Protein Interaction Networks from Liquid-Chromatography Mass-Spectrometry Data by Approximate Bayesian Computation-Sequential Monte Carlo Sampling

   https://doi.org/10.1109/MLSP49062.2020.9231824  

   Tan, Yukun ; Lima Neto, Fernando B. ; Neto, Ulisses Braga ( September 2020 , 2020 IEEE 30th International Workshop on Machine Learning for Signal Processing (MLSP))

   null (Ed.)

   We propose a new algorithm for inference of protein-protein interaction (PPI) networks from noisy time series of Liquid- Chromatography Mass-Spectrometry (LC-MS) proteomic expression data based on Approximate Bayesian Computation - Sequential Monte Carlo sampling (ABC-SMC). The algorithm is an extension of our previous framework PALLAS. The proposed algorithm can be easily modified to handle other complex models of expression data, such as LC-MS data, for which the likelihood function is intractable. Results based on synthetic time series of cytokine LC-MS measurements cor- responding to a prototype immunomic network demonstrate that our algorithm is capable of inferring the network topology accurately. 

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