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Abstract MotivationCell function is regulated by gene regulatory networks (GRNs) defined by protein-mediated interaction between constituent genes. Despite advances in experimental techniques, we can still measure only a fraction of the processes that govern GRN dynamics. To infer the properties of GRNs using partial observation, unobserved sequential processes can be replaced with distributed time delays, yielding non-Markovian models. Inference methods based on the resulting model suffer from the curse of dimensionality. ResultsWe develop a simulation-based Bayesian MCMC method employing an approximate likelihood for the efficient and accurate inference of GRN parameters when only some of their products are observed. We illustrate our approach using a two-step activation model: an activation signal leads to the accumulation of an unobserved regulatory protein, which triggers the expression of observed fluorescent proteins. With prior information about observed fluorescent protein synthesis, our method successfully infers the dynamics of the unobserved regulatory protein. We can estimate the delay and kinetic parameters characterizing target regulation including transcription, translation, and target searching of an unobserved protein from experimental measurements of the products of its target gene. Our method is scalable and can be used to analyze non-Markovian models with hidden components. Availability and implementationOur code is implemented in R and is freely available with a simple example data at https://github.com/Mathbiomed/SimMCMC. 

Abstract Probabilistic graphical models provide a powerful tool to describe complex statistical structure, with many real-world applications in science and engineering from controlling robotic arms to understanding neuronal computations. A major challenge for these graphical models is that inferences such as marginalization are intractable for general graphs. These inferences are often approximated by a distributed message-passing algorithm such as Belief Propagation, which does not always perform well on graphs with cycles, nor can it always be easily specified for complex continuous probability distributions. Such difficulties arise frequently in expressive graphical models that include intractable higher-order interactions. In this paper we define the Recurrent Factor Graph Neural Network (RF-GNN) to achieve fast approximate inference on graphical models that involve many-variable interactions. Experimental results on several families of graphical models demonstrate the out-of-distribution generalization capability of our method to different sized graphs, and indicate the domain in which our method outperforms Belief Propagation (BP). Moreover, we test the RF-GNN on a real-world Low-Density Parity-Check dataset as a benchmark along with other baseline models including BP variants and other GNN methods. Overall we find that RF-GNNs outperform other methods under high noise levels. 

Abstract Probabilistic graphical models have become an important unsupervised learning tool for detecting network structures for a variety of problems, including the estimation of functional neuronal connectivity from two‐photon calcium imaging data. However, in the context of calcium imaging, technological limitations only allow for partially overlapping layers of neurons in a brain region of interest to be jointly recorded. In this case, graph estimation for the full data requires inference for edge selection when many pairs of neurons have no simultaneous observations. This leads to the graph quilting problem, which seeks to estimate a graph in the presence of block‐missingness in the empirical covariance matrix. Solutions for the graph quilting problem have previously been studied for Gaussian graphical models; however, neural activity data from calcium imaging are often non‐Gaussian, thereby requiring a more flexible modelling approach. Thus, in our work, we study two approaches for nonparanormal graph quilting based on the Gaussian copula graphical model, namely, a maximum likelihood procedure and a low rank‐based framework. We provide theoretical guarantees on edge recovery for the former approach under similar conditions to those previously developed for the Gaussian setting, and we investigate the empirical performance of both methods using simulations as well as real data calcium imaging data. Our approaches yield more scientifically meaningful functional connectivity estimates compared to existing Gaussian graph quilting methods for this calcium imaging data set. 

Abstract Backpropagation is widely used to train artificial neural networks, but its relationship to synaptic plasticity in the brain is unknown. Some biological models of backpropagation rely on feedback projections that are symmetric with feedforward connections, but experiments do not corroborate the existence of such symmetric backward connectivity. Random feedback alignment offers an alternative model in which errors are propagated backward through fixed, random backward connections. This approach successfully trains shallow models, but learns slowly and does not perform well with deeper models or online learning. In this study, we develop a meta-learning approach to discover interpretable, biologically plausible plasticity rules that improve online learning performance with fixed random feedback connections. The resulting plasticity rules show improved online training of deep models in the low data regime. Our results highlight the potential of meta-learning to discover effective, interpretable learning rules satisfying biological constraints. 

Abstract Success in many real-world tasks depends on our ability to dynamically track hidden states of the world. We hypothesized that neural populations estimate these states by processing sensory history through recurrent interactions which reflect the internal model of the world. To test this, we recorded brain activity in posterior parietal cortex (PPC) of monkeys navigating by optic flow to a hidden target location within a virtual environment, without explicit position cues. In addition to sequential neural dynamics and strong interneuronal interactions, we found that the hidden state - monkey’s displacement from the goal - was encoded in single neurons, and could be dynamically decoded from population activity. The decoded estimates predicted navigation performance on individual trials. Task manipulations that perturbed the world model induced substantial changes in neural interactions, and modified the neural representation of the hidden state, while representations of sensory and motor variables remained stable. The findings were recapitulated by a task-optimized recurrent neural network model, suggesting that task demands shape the neural interactions in PPC, leading them to embody a world model that consolidates information and tracks task-relevant hidden states. 

Abstract Clustering has long been a popular unsupervised learning approach to identify groups of similar objects and discover patterns from unlabeled data in many applications. Yet, coming up with meaningful interpretations of the estimated clusters has often been challenging precisely due to their unsupervised nature. Meanwhile, in many real-world scenarios, there are some noisy supervising auxiliary variables, for instance, subjective diagnostic opinions, that are related to the observed heterogeneity of the unlabeled data. By leveraging information from both supervising auxiliary variables and unlabeled data, we seek to uncover more scientifically interpretable group structures that may be hidden by completely unsupervised analyses. In this work, we propose and develop a new statistical pattern discovery method named supervised convex clustering (SCC) that borrows strength from both information sources and guides towards finding more interpretable patterns via a joint convex fusion penalty. We develop several extensions of SCC to integrate different types of supervising auxiliary variables, to adjust for additional covariates, and to find biclusters. We demonstrate the practical advantages of SCC through simulations and a case study on Alzheimer's disease genomics. Specifically, we discover new candidate genes as well as new subtypes of Alzheimer's disease that can potentially lead to better understanding of the underlying genetic mechanisms responsible for the observed heterogeneity of cognitive decline in older adults. 

Summary Structural learning of Gaussian graphical models in the presence of latent variables has long been a challenging problem. Chandrasekaran et al. (2012) proposed a convex program for estimating a sparse graph plus a low-rank term that adjusts for latent variables; however, this approach poses challenges from both computational and statistical perspectives. We propose an alternative, simple solution: apply a hard-thresholding operator to existing graph selection methods. Conceptually simple and computationally attractive, the approach of thresholding the graphical lasso is shown to be graph selection consistent in the presence of latent variables under a simpler minimum edge strength condition and at an improved statistical rate. The results are extended to estimators for thresholded neighbourhood selection and constrained $$\ell_{1}$$-minimization for inverse matrix estimation as well. We show that our simple thresholded graph estimators yield stronger empirical results than existing methods for the latent variable graphical model problem, and we apply them to a neuroscience case study on estimating functional neural connections. 

In computational neuroscience, recurrent neural networks are widely used to model neural activity and learning. In many studies, fixed points of recurrent neural networks are used to model neural responses to static or slowly changing stimuli, such as visual cortical responses to static visual stimuli. These applications raise the question of how to train the weights in a recurrent neural network to minimize a loss function evaluated on fixed points. In parallel, training fixed points is a central topic in the study of deep equilibrium models in machine learning. A natural approach is to use gradient descent on the Euclidean space of weights. We show that this approach can lead to poor learning performance due in part to singularities that arise in the loss surface. We use a reparameterization of the recurrent network model to derive two alternative learning rules that produce more robust learning dynamics. We demonstrate that these learning rules avoid singularities and learn more effectively than standard gradient descent. The new learning rules can be interpreted as steepest descent and gradient descent, respectively, under a non-Euclidean metric on the space of recurrent weights. Our results question the common, implicit assumption that learning in the brain should be expected to follow the negative Euclidean gradient of synaptic weights.