BN-BacArena: Bayesian network extension of BacArena for the dynamic simulation of microbial communities.

MOTIVATION: Simulating gut microbial dynamics is extremely challenging. Several computational tools, notably the widely used BacArena, enable modeling of dynamic changes in the microbial environment. These methods, however, do not comprehensively account for microbe-microbe stimulant or inhibitory effects or for nutrient-microbe inhibitory effects, typically observed in different compounds present in the daily diet. RESULTS: Here, we present BN-BacArena, an extension of BacArena consisting on the incorporation within the native computational framework of a Bayesian network model that accounts for microbe-microbe and nutrient-microbe interactions. Using in vitro experiments, 16S rRNA gene sequencing data and nutritional composition of 55 foods, the output Bayesian network showed 23 significant nutrient-bacteria interactions, suggesting the importance of compounds such as polyols, ascorbic acid, polyphenols and other phytochemicals, and 40 bacteria-bacteria significant relationships. With test data, BN-BacArena demonstrates a statistically significant improvement over BacArena to predict the time-dependent relative abundance of bacterial species involved in the gut microbiota upon different nutritional interventions. As a result, BN-BacArena opens new avenues for the dynamic modeling and simulation of the human gut microbiota metabolism. AVAILABILITY AND IMPLEMENTATION: MATLAB and R code are available in https://github.com/PlanesLab/BN-BacArena.

Learning massive interpretable gene regulatory networks of the human brain by merging Bayesian networks.

We present the Fast Greedy Equivalence Search (FGES)-Merge, a new method for learning the structure of gene regulatory networks via merging locally learned Bayesian networks, based on the fast greedy equivalent search algorithm. The method is competitive with the state of the art in terms of the Matthews correlation coefficient, which takes into account both precision and recall, while also improving upon it in terms of speed, scaling up to tens of thousands of variables and being able to use empirical knowledge about the topological structure of gene regulatory networks. To showcase the ability of our method to scale to massive networks, we apply it to learning the gene regulatory network for the full human genome using data from samples of different brain structures (from the Allen Human Brain Atlas). Furthermore, this Bayesian network model should predict interactions between genes in a way that is clear to experts, following the current trends in explainable artificial intelligence. To achieve this, we also present a new open-access visualization tool that facilitates the exploration of massive networks and can aid in finding nodes of interest for experimental tests.

NeuroSuites: An online platform for running neuroscience, statistical, and machine learning tools.

Nowadays, an enormous amount of high dimensional data is available in the field of neuroscience. Handling these data is complex and requires the use of efficient tools to transform them into useful knowledge. In this work we present NeuroSuites, an easy-access web platform with its own architecture. We compare our platform with other software currently available, highlighting its main strengths. Thanks to its defined architecture, it is able to handle large-scale problems common in some neuroscience fields. NeuroSuites has different neuroscience-oriented applications and tools to integrate statistical data analysis and machine learning algorithms commonly used in this field. As future work, we want to further expand the list of available software tools as well as improve the platform interface according to user demands.

Feature Saliencies in Asymmetric Hidden Markov Models.

Many real-life problems are stated as nonlabeled high-dimensional data. Current strategies to select features are mainly focused on labeled data, which reduces the options to select relevant features for unsupervised problems, such as clustering. Recently, feature saliency models have been introduced and developed as clustering models to select and detect relevant variables/features as the model is learned. Usually, these models assume that all variables are independent, which narrows their applicability. This article introduces asymmetric hidden Markov models with feature saliencies, i.e., models capable of simultaneously determining during their learning phase relevant variables/features and probabilistic relationships between variables. The proposed models are compared with other state-of-the-art approaches using synthetic data and real data related to grammatical face videos and wear in ball bearings. We show that the proposed models have better or equal fitness than other state-of-the-art models and provide further data insights.

Autoregressive Asymmetric Linear Gaussian Hidden Markov Models.

In a real life process evolving over time, the relationship between its relevant variables may change. Therefore, it is advantageous to have different inference models for each state of the process. Asymmetric hidden Markov models fulfil this dynamical requirement and provide a framework where the trend of the process can be expressed as a latent variable. In this paper, we modify these recent asymmetric hidden Markov models to have an asymmetric autoregressive component in the case of continuous variables, allowing the model to choose the order of autoregression that maximizes its penalized likelihood for a given training set. Additionally, we show how inference, hidden states decoding and parameter learning must be adapted to fit the proposed model. Finally, we run experiments with synthetic and real data to show the capabilities of this new model.

Identifying Parkinson's disease subtypes with motor and non-motor symptoms via model-based multi-partition clustering.

Identification of Parkinson's disease subtypes may help understand underlying disease mechanisms and provide personalized management. Although clustering methods have been previously used for subtyping, they have reported generic subtypes of limited relevance in real life practice because patients do not always fit into a single category. The aim of this study was to identify new subtypes assuming that patients could be grouped differently according to certain sets of related symptoms. To this purpose, a novel model-based multi-partition clustering method was applied on data from an international, multi-center, cross-sectional study of 402 Parkinson's disease patients. Both motor and non-motor symptoms were considered. As a result, eight sets of related symptoms were identified. Each of them provided a different way to group patients: impulse control issues, overall non-motor symptoms, presence of dyskinesias and pyschosis, fatigue, axial symptoms and motor fluctuations, autonomic dysfunction, depression, and excessive sweating. Each of these groups could be seen as a subtype of the disease. Significant differences between subtypes (P< 0.01) were found in sex, age, age of onset, disease duration, Hoehn & Yahr stage, and treatment. Independent confirmation of these results could have implications for the clinical management of Parkinson's disease patients.

Patient specific prediction of temporal lobe epilepsy surgical outcomes.

OBJECTIVE: Drug-resistant temporal lobe epilepsy (TLE) is the most common type of epilepsy for which patients undergo surgery. Despite the best clinical judgment and currently available prediction algorithms, surgical outcomes remain variable. We aimed to build and to evaluate the performance of multidimensional Bayesian network classifiers (MBCs), a type of probabilistic graphical model, at predicting probability of seizure freedom after TLE surgery. METHODS: Clinical, neurophysiological, and imaging variables were collected from 231 TLE patients who underwent surgery at the University of California, San Francisco (UCSF) or the Montreal Neurological Institute (MNI) over a 15-year period. Postsurgical Engel outcomes at year 1 (Y1), Y2, and Y5 were analyzed as primary end points. We trained an MBC model on combined data sets from both institutions. Bootstrap bias corrected cross-validation (BBC-CV) was used to evaluate the performance of the models. RESULTS: The MBC was compared with logistic regression and Cox proportional hazards according to the area under the receiver-operating characteristic curve (AUC). The MBC achieved an AUC of 0.67 at Y1, 0.72 at Y2, and 0.67 at Y5, which indicates modest performance yet superior to what has been reported in the state-of-the-art studies to date. SIGNIFICANCE: The MBC can more precisely encode probabilistic relationships between predictors and class variables (Engel outcomes), achieving promising experimental results compared to other well-known statistical methods. Multisite application of the MBC could further optimize its classification accuracy with prospective data sets. Online access to the MBC is provided, paving the way for its use as an adjunct clinical tool in aiding pre-operative TLE surgical counseling.

Comparing the Electrophysiology and Morphology of Human and Mouse Layer 2/3 Pyramidal Neurons With Bayesian Networks.

Pyramidal neurons are the most common neurons in the cerebral cortex. Understanding how they differ between species is a key challenge in neuroscience. We compared human temporal cortex and mouse visual cortex pyramidal neurons from the Allen Cell Types Database in terms of their electrophysiology and dendritic morphology. We found that, among other differences, human pyramidal neurons had a higher action potential threshold voltage, a lower input resistance, and larger dendritic arbors. We learned Gaussian Bayesian networks from the data in order to identify correlations and conditional independencies between the variables and compare them between the species. We found strong correlations between electrophysiological and morphological variables in both species. In human cells, electrophysiological variables were correlated even with morphological variables that are not directly related to dendritic arbor size or diameter, such as mean bifurcation angle and mean branch tortuosity. Cortical depth was correlated with both electrophysiological and morphological variables in both species, and its effect on electrophysiology could not be explained in terms of the morphological variables. For some variables, the effect of cortical depth was opposite in the two species. Overall, the correlations among the variables differed strikingly between human and mouse neurons. Besides identifying correlations and conditional independencies, the learned Bayesian networks might be useful for probabilistic reasoning regarding the morphology and electrophysiology of pyramidal neurons.

Comparing basal dendrite branches in human and mouse hippocampal CA1 pyramidal neurons with Bayesian networks.

Pyramidal neurons are the most common cell type in the cerebral cortex. Understanding how they differ between species is a key challenge in neuroscience. A recent study provided a unique set of human and mouse pyramidal neurons of the CA1 region of the hippocampus, and used it to compare the morphology of apical and basal dendritic branches of the two species. The study found inter-species differences in the magnitude of the morphometrics and similarities regarding their variation with respect to morphological determinants such as branch type and branch order. We use the same data set to perform additional comparisons of basal dendrites. In order to isolate the heterogeneity due to intrinsic differences between species from the heterogeneity due to differences in morphological determinants, we fit multivariate models over the morphometrics and the determinants. In particular, we use conditional linear Gaussian Bayesian networks, which provide a concise graphical representation of the independencies and correlations among the variables. We also extend the previous study by considering additional morphometrics and by formally testing whether a morphometric increases or decreases with the distance from the soma. This study introduces a multivariate methodology for inter-species comparison of morphology.

A community-based transcriptomics classification and nomenclature of neocortical cell types.

To understand the function of cortical circuits, it is necessary to catalog their cellular diversity. Past attempts to do so using anatomical, physiological or molecular features of cortical cells have not resulted in a unified taxonomy of neuronal or glial cell types, partly due to limited data. Single-cell transcriptomics is enabling, for the first time, systematic high-throughput measurements of cortical cells and generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data reveal clusters that often correspond to cell types previously defined by morphological or physiological criteria and that appear conserved across cortical areas and species. To capitalize on these new methods, we propose the adoption of a transcriptome-based taxonomy of cell types for mammalian neocortex. This classification should be hierarchical and use a standardized nomenclature. It should be based on a probabilistic definition of a cell type and incorporate data from different approaches, developmental stages and species. A community-based classification and data aggregation model, such as a knowledge graph, could provide a common foundation for the study of cortical circuits. This community-based classification, nomenclature and data aggregation could serve as an example for cell type atlases in other parts of the body.

Classification of GABAergic interneurons by leading neuroscientists.

There is currently no unique catalog of cortical GABAergic interneuron types. In 2013, we asked 48 leading neuroscientists to classify 320 interneurons by inspecting images of their morphology. That study was the first to quantify the degree of agreement among neuroscientists in morphology-based interneuron classification, showing high agreement for the chandelier and Martinotti types, yet low agreement for most of the remaining types considered. Here we present the dataset containing the classification choices by the neuroscientists according to interneuron type as well as to five prominent morphological features. These data can be used as crisp or soft training labels for learning supervised machine learning interneuron classifiers, while further analyses can try to pinpoint anatomical characteristics that make an interneuron especially difficult or especially easy to classify.

Towards a supervised classification of neocortical interneuron morphologies.

BACKGROUND: The challenge of classifying cortical interneurons is yet to be solved. Data-driven classification into established morphological types may provide insight and practical value. RESULTS: We trained models using 217 high-quality morphologies of rat somatosensory neocortex interneurons reconstructed by a single laboratory and pre-classified into eight types. We quantified 103 axonal and dendritic morphometrics, including novel ones that capture features such as arbor orientation, extent in layer one, and dendritic polarity. We trained a one-versus-rest classifier for each type, combining well-known supervised classification algorithms with feature selection and over- and under-sampling. We accurately classified the nest basket, Martinotti, and basket cell types with the Martinotti model outperforming 39 out of 42 leading neuroscientists. We had moderate accuracy for the double bouquet, small and large basket types, and limited accuracy for the chandelier and bitufted types. We characterized the types with interpretable models or with up to ten morphometrics. CONCLUSION: Except for large basket, 50 high-quality reconstructions sufficed to learn an accurate model of a type. Improving these models may require quantifying complex arborization patterns and finding correlates of bouton-related features. Our study brings attention to practical aspects important for neuron classification and is readily reproducible, with all code and data available online.

A regularity index for dendrites - local statistics of a neuron's input space.

Neurons collect their inputs from other neurons by sending out arborized dendritic structures. However, the relationship between the shape of dendrites and the precise organization of synaptic inputs in the neural tissue remains unclear. Inputs could be distributed in tight clusters, entirely randomly or else in a regular grid-like manner. Here, we analyze dendritic branching structures using a regularity index R, based on average nearest neighbor distances between branch and termination points, characterizing their spatial distribution. We find that the distributions of these points depend strongly on cell types, indicating possible fundamental differences in synaptic input organization. Moreover, R is independent of cell size and we find that it is only weakly correlated with other branching statistics, suggesting that it might reflect features of dendritic morphology that are not captured by commonly studied branching statistics. We then use morphological models based on optimal wiring principles to study the relation between input distributions and dendritic branching structures. Using our models, we find that branch point distributions correlate more closely with the input distributions while termination points in dendrites are generally spread out more randomly with a close to uniform distribution. We validate these model predictions with connectome data. Finally, we find that in spatial input distributions with increasing regularity, characteristic scaling relationships between branching features are altered significantly. In summary, we conclude that local statistics of input distributions and dendrite morphology depend on each other leading to potentially cell type specific branching features.

3D morphology-based clustering and simulation of human pyramidal cell dendritic spines.

The dendritic spines of pyramidal neurons are the targets of most excitatory synapses in the cerebral cortex. They have a wide variety of morphologies, and their morphology appears to be critical from the functional point of view. To further characterize dendritic spine geometry, we used in this paper over 7,000 individually 3D reconstructed dendritic spines from human cortical pyramidal neurons to group dendritic spines using model-based clustering. This approach uncovered six separate groups of human dendritic spines. To better understand the differences between these groups, the discriminative characteristics of each group were identified as a set of rules. Model-based clustering was also useful for simulating accurate 3D virtual representations of spines that matched the morphological definitions of each cluster. This mathematical approach could provide a useful tool for theoretical predictions on the functional features of human pyramidal neurons based on the morphology of dendritic spines.

MultiMap: A Tool to Automatically Extract and Analyse Spatial Microscopic Data From Large Stacks of Confocal Microscopy Images.

The development of 3D visualization and reconstruction methods to analyse microscopic structures at different levels of resolutions is of great importance to define brain microorganization and connectivity. MultiMap is a new tool that allows the visualization, 3D segmentation and quantification of fluorescent structures selectively in the neuropil from large stacks of confocal microscopy images. The major contribution of this tool is the posibility to easily navigate and create regions of interest of any shape and size within a large brain area that will be automatically 3D segmented and quantified to determine the density of puncta in the neuropil. As a proof of concept, we focused on the analysis of glutamatergic and GABAergic presynaptic axon terminals in the mouse hippocampal region to demonstrate its use as a tool to provide putative excitatory and inhibitory synaptic maps. The segmentation and quantification method has been validated over expert labeled images of the mouse hippocampus and over two benchmark datasets, obtaining comparable results to the expert detections.

Patterns of Dendritic Basal Field Orientation of Pyramidal Neurons in the Rat Somatosensory Cortex.

The study of neuronal dendritic orientation is of interest because it is related to how neurons grow dendrites to establish the synaptic input that neurons receive. The dendritic orientations of neurons in the nervous system vary, ranging from rather heterogeneously distributed (asymmetric) to homogeneously distributed (symmetric) dendritic arbors. Here, we analyze the dendritic orientation of the basal dendrites of intracellularly labeled pyramidal neurons from horizontal sections of Layers II-VI of the hindlimb somatosensory (S1HL) cortex of 14-d-old (P14) rats. We used circular statistics and proposed two new graphical descriptive representations of the neuron. We found that the dendritic pattern of most neurons was asymmetric. Furthermore, we found that there is a mixture of different types of orientations within any given group of neurons in any cortical layer. In addition, we investigated whether dendritic orientation was related to the physical location within the brain with respect to the anterior, dorsal, posterior and ventral directions. Generally, there was a preference towards the anterior orientation. A comparison between layers revealed that the preference for the anterior orientation was more pronounced in neurons located in Layers II, III, IV, and Va than for the neurons located in Layers Vb and VI. The dorsal orientation was the least preferred orientation in all layers, except for Layers IV and Va, where the ventral orientation had the lowest preference. Therefore, the orientation of basal dendritic arbors of pyramidal cells is variable and asymmetric, although a majority has a single orientation with a preference for the anterior direction in P14 rats.

Parkinson's Disease Subtypes Identified from Cluster Analysis of Motor and Non-motor Symptoms.

Parkinson's disease is now considered a complex, multi-peptide, central, and peripheral nervous system disorder with considerable clinical heterogeneity. Non-motor symptoms play a key role in the trajectory of Parkinson's disease, from prodromal premotor to end stages. To understand the clinical heterogeneity of Parkinson's disease, this study used cluster analysis to search for subtypes from a large, multi-center, international, and well-characterized cohort of Parkinson's disease patients across all motor stages, using a combination of cardinal motor features (bradykinesia, rigidity, tremor, axial signs) and, for the first time, specific validated rater-based non-motor symptom scales. Two independent international cohort studies were used: (a) the validation study of the Non-Motor Symptoms Scale (n = 411) and (b) baseline data from the global Non-Motor International Longitudinal Study (n = 540). k-means cluster analyses were performed on the non-motor and motor domains (domains clustering) and the 30 individual non-motor symptoms alone (symptoms clustering), and hierarchical agglomerative clustering was performed to group symptoms together. Four clusters are identified from the domains clustering supporting previous studies: mild, non-motor dominant, motor-dominant, and severe. In addition, six new smaller clusters are identified from the symptoms clustering, each characterized by clinically-relevant non-motor symptoms. The clusters identified in this study present statistical confirmation of the increasingly important role of non-motor symptoms (NMS) in Parkinson's disease heterogeneity and take steps toward subtype-specific treatment packages.

Three-dimensional spatial modeling of spines along dendritic networks in human cortical pyramidal neurons.

We modeled spine distribution along the dendritic networks of pyramidal neurons in both basal and apical dendrites. To do this, we applied network spatial analysis because spines can only lie on the dendritic shaft. We expanded the existing 2D computational techniques for spatial analysis along networks to perform a 3D network spatial analysis. We analyzed five detailed reconstructions of adult human pyramidal neurons of the temporal cortex with a total of more than 32,000 spines. We confirmed that there is a spatial variation in spine density that is dependent on the distance to the cell body in all dendrites. Considering the dendritic arborizations of each pyramidal cell as a group of instances of the same observation (the neuron), we used replicated point patterns together with network spatial analysis for the first time to search for significant differences in the spine distribution of basal dendrites between different cells and between all the basal and apical dendrites. To do this, we used a recent variant of Ripley's K function defined to work along networks. The results showed that there were no significant differences in spine distribution along basal arbors of the same neuron and along basal arbors of different pyramidal neurons. This suggests that dendritic spine distribution in basal dendritic arbors adheres to common rules. However, we did find significant differences in spine distribution along basal versus apical networks. Therefore, not only do apical and basal dendritic arborizations have distinct morphologies but they also obey different rules of spine distribution. Specifically, the results suggested that spines are more clustered along apical than in basal dendrites. Collectively, the results further highlighted that synaptic input information processing is different between these two dendritic domains.