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The design of efficient combination therapies is a difficult key challenge in the treatment of complex diseases such as cancers. The large heterogeneity of cancers and the large number of available drugs renders exhaustive in vivo or even in vitro investigation of possible treatments impractical. In recent years, sophisticated mechanistic, ordinary differential equation-based pathways models that can predict treatment responses at a molecular level have been developed. However, surprisingly little effort has been put into leveraging these models to find novel therapies. In this paper we use for the first time, to our knowledge, a large-scale state-of-the-art pan-cancer signaling pathway model to identify candidates for novel combination therapies to treat individual cancer cell lines from various tissues (e.g., minimizing proliferation while keeping dosage low to avoid adverse side effects) and populations of heterogeneous cancer cell lines (e.g., minimizing the maximum or average proliferation across the cell lines while keeping dosage low). We also show how our method can be used to optimize the drug combinations used in sequential treatment plans—that is, optimized sequences of potentially different drug combinations—providing additional benefits. In order to solve the treatment optimization problems, we combine the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) algorithm with a significantly more scalable sampling scheme for truncated Gaussian distributions, based on a Hamiltonian Monte-Carlo method. These optimization techniques are independent of the signaling pathway model, and can thus be adapted to find treatment candidates for other complex diseases than cancers as well, as long as a suitable predictive model is available., Author summary Combination therapies are a promising approach to counter complex diseases such as cancers. Two key difficulties in the design of effective cancer combination therapies are the large number of available drugs and the heterogeneity of cancers which render exhaustive laboratory studies impractical. In recent years, sophisticated signaling pathway models that can predict responses to combination treatments at a molecular level have been developed. This motivates the question of how one can leverage mechanistic models to identify candidates for novel combination treatments. In this paper we propose a combination treatment optimization framework which employs a large-scale pan-cancer pathway model. We formulate treatment optimization problems for single cell lines and heterogeneous populations of cancer cells. We further investigate sequential treatment plans and combine an existing evolutionary algorithm with an efficient Hamiltonian Monte-Carlo based sampling scheme. During extensive simulation studies our approach identified combination therapies which are predicted to be more effective than conventional treatments. We hope that one day in silico experiments will be used to identify a small set of promising treatment candidates which can then form a starting point for laboratory studies, allowing for an efficient use of limited resources and accelerated discovery of effective therapies.

In their Commentary paper, Villaverde and Massonis (On testing structural identifiability by a simple scaling method: relying on scaling symmetries can be misleading) have commented on our paper in which we proposed a simple scaling method to test structural identifiability. Our scaling invariance method (SIM) tests for scaling symmetries only, and Villaverde and Massonis correctly show the SIM may fail to detect identifiability problems when a model has other types of symmetries. We agree with the limitations raised by these authors but, also, we emphasize that the method is still valuable for its applicability to a wide variety of models, its simplicity, and even as a tool to introduce the problem of identifiability to investigators with little training in mathematics.

Surveillance is critical to mounting an appropriate and effective response to pandemics. However, aggregated case report data suffers from reporting delays and can lead to misleading inferences. Different from aggregated case report data, line list data is a table contains individual features such as dates of symptom onset and reporting for each reported case and a good source for modeling delays. Current methods for modeling reporting delays are not particularly appropriate for line list data, which typically has missing symptom onset dates that are non-ignorable for modeling reporting delays. In this paper, we develop a Bayesian approach that dynamically integrates imputation and estimation for line list data. Specifically, this Bayesian approach can accurately estimate the epidemic curve and instantaneous reproduction numbers, even with most symptom onset dates missing. The Bayesian approach is also robust to deviations from model assumptions, such as changes in the reporting delay distribution or incorrect specification of the maximum reporting delay. We apply the Bayesian approach to COVID-19 line list data in Massachusetts and find the reproduction number estimates correspond more closely to the control measures than the estimates based on the reported curve., Author summary Interventions meant to control infectious diseases are often determined and judged using surveillance data on the number of new cases of disease. In many diseases, there are substantial delays between the time when an individual is infected or shows symptoms and when the case is actually reported to a public health authority, such as the CDC. This reported data often collects information on symptom onset dates for some individuals. In this paper, we describe a method that imputes missing onset dates for all individuals and recreates the history of the disease progression in a population according to symptom onset dates, which are the best observable proxy available for infection dates. Our method also estimates the instantaneous reproduction number and is robust to many deviations from the assumptions of the model. We show, using a COVID-19 dataset from Massachusetts that our method accurately follows the implementation of control measures in the state.

Identification of mutations of the genes that give cancer a selective advantage is an important step towards research and clinical objectives. As such, there has been a growing interest in developing methods for identification of driver genes and their temporal order within a single patient (intra-tumor) as well as across a cohort of patients (inter-tumor). In this paper, we develop a probabilistic model for tumor progression, in which the driver genes are clustered into several ordered driver pathways. We develop an efficient inference algorithm that exhibits favorable scalability to the number of genes and samples compared to a previously introduced ILP-based method. Adopting a probabilistic approach also allows principled approaches to model selection and uncertainty quantification. Using a large set of experiments on synthetic datasets, we demonstrate our superior performance compared to the ILP-based method. We also analyze two biological datasets of colorectal and glioblastoma cancers. We emphasize that while the ILP-based method puts many seemingly passenger genes in the driver pathways, our algorithm keeps focused on truly driver genes and outputs more accurate models for cancer progression., Author summary Cancer is a disease caused by the accumulation of somatic mutations in the genome. This process is mainly driven by mutations in certain genes that give the harboring cells some selective advantage. The rather few driver genes are usually masked amongst an abundance of so-called passenger mutations. Identification of the driver genes and the temporal order in which the mutations occur is of great importance towards research and clinical objectives. In this paper, we introduce a probabilistic model for cancer progression and devise an efficient inference algorithm to train the model. We show that our method scales favorably to large datasets and provides superior performance compared to an ILP-based counterpart on a wide set of synthetic data simulations. Our Bayesian approach also allows for systematic model selection and confidence quantification procedures in contrast to the previous non-probabilistic progression models. We also study two large datasets on colorectal and glioblastoma cancers and validate our inferred model in comparison to the ILP-based method.

Computational drug repositioning and drug-target prediction have become essential tasks in the early stage of drug discovery. In previous studies, these two tasks have often been considered separately. However, the entities studied in these two tasks (i.e., drugs, targets, and diseases) are inherently related. On one hand, drugs interact with targets in cells to modulate target activities, which in turn alter biological pathways to promote healthy functions and to treat diseases. On the other hand, both drug repositioning and drug-target prediction involve the same drug feature space, which naturally connects these two problems and the two domains (diseases and targets). By using the wisdom of the crowds, it is possible to transfer knowledge from one of the domains to the other. The existence of relationships among drug-target-disease motivates us to jointly consider drug repositioning and drug-target prediction in drug discovery. In this paper, we present a novel approach called iDrug, which seamlessly integrates drug repositioning and drug-target prediction into one coherent model via cross-network embedding. In particular, we provide a principled way to transfer knowledge from these two domains and to enhance prediction performance for both tasks. Using real-world datasets, we demonstrate that iDrug achieves superior performance on both learning tasks compared to several state-of-the-art approaches. Our code and datasets are available at: https://github.com/Case-esaC/iDrug., Author summary Traditional high-throughput techniques for drug discovery are often expensive, time-consuming, and with high failure rates. Computational drug repositioning and drug-target prediction have thus become essential tasks in the early stage drug discovery. The emergence of large-scale heterogeneous biological networks has offered unprecedented opportunities for developing machine learning approaches to identify novel drug-disease or drug-target interactions. However, most existing works focused either on the drug-disease network or on the drug-target network, thus failed to capture the inherent dependencies between these two networks. These two biological networks are naturally connected since they involve the same drug feature space. In our opinion, ignoring this rich source of information is a major shortcoming of some existing works. In this paper, we present a novel approach called iDrug, which seamlessly integrates the drug-disease network and the drug-target network into one coherent model via cross-network embedding. As a result, iDrug is able to take full usage of the knowledge within these two biological networks to better exploit new biomedical insights of drug-target-disease. Therefore, iDrug has broad applications in drug discovery.

Surveillance plays a crucial role in preventing emerging infectious diseases from becoming epidemic. In circumstances where it is possible to monitor the infection status of certain people, transport hubs, or hospitals, early detection of the disease allows interventions to be implemented before most of the damage can occur, or at least its impact can be mitigated. This paper addresses the question of which nodes we should select in a network of individuals susceptible to some infectious disease in order to minimize the number of casualties. By simulating disease outbreaks on a collection of empirical and synthetic networks we show that the best strategy depends on topological characteristics of the network. For highly modular or spatially embedded networks it is better to place the sentinels on nodes distributed across different regions. However, if the degree heterogeneity is high, then a strategy that targets network hubs is preferred. We further consider the consequences of having an incomplete sample of the network and demonstrate that the value of new information diminishes as more data is collected. Finally we find further marginal improvements using two heuristics informed by known results in graph theory that exploit the fragmented structure of sparse network data., Author summary In a network of individuals susceptible to some infectious disease, what are the best locations to monitor in order to detect the infection before most damage can be done? In this paper we address this question by considering various heuristic strategies for sentinel placement that can potentially be implemented in real-world situations without requiring excessive amounts of computation, or even having perfect data about the structure of the network. We find that strategies that attempt to distribute sentinels over different regions of the network perform best in highly modular or spatially embedded networks, whereas the strategy of targeting the most well connected individuals works best when there is a considerable amount of contact heterogeneity between individuals. Our results may be used as a guideline to help decide when certain strategies should, or should not, be implemented.

Stochastic models of biomolecular reaction networks are commonly employed in systems and synthetic biology to study the effects of stochastic fluctuations emanating from reactions involving species with low copy-numbers. For such models, the Kolmogorov’s forward equation is called the chemical master equation (CME), and it is a fundamental system of linear ordinary differential equations (ODEs) that describes the evolution of the probability distribution of the random state-vector representing the copy-numbers of all the reacting species. The size of this system is given by the number of states that are accessible by the chemical system, and for most examples of interest this number is either very large or infinite. Moreover, approximations that reduce the size of the system by retaining only a finite number of important chemical states (e.g. those with non-negligible probability) result in high-dimensional ODE systems, even when the number of reacting species is small. Consequently, accurate numerical solution of the CME is very challenging, despite the linear nature of the underlying ODEs. One often resorts to estimating the solutions via computationally intensive stochastic simulations. The goal of the present paper is to develop a novel deep-learning approach for computing solution statistics of high-dimensional CMEs by reformulating the stochastic dynamics using Kolmogorov’s backward equation. The proposed method leverages superior approximation properties of Deep Neural Networks (DNNs) to reliably estimate expectations under the CME solution for several user-defined functions of the state-vector. This method is algorithmically based on reinforcement learning and it only requires a moderate number of stochastic simulations (in comparison to typical simulation-based approaches) to train the “policy function”. This allows not just the numerical approximation of various expectations for the CME solution but also of its sensitivities with respect to all the reaction network parameters (e.g. rate constants). We provide four examples to illustrate our methodology and provide several directions for future research., Author summary We develop a deep learning framework for estimating solutions of the chemical master equation (CME) that is fundamental to stochastic analysis of reaction networks. The CME is a system of ordinary differential equations that describes the time-evolution of the probability density of the random state-vector, and owing to an inherent curse of dimensionality, directly solving the CME is generally impractical with existing approaches. Moreover, the commonly employed simulation-based approaches for estimating CME solutions often require an exorbitant amount of computational time, even for moderately-sized networks. To counter these issues, we develop a deep reinforcement learning based method, called DeepCME, in this paper. DeepCME not only estimates function expectations based on the CME solution, but it also solves the more challenging problem of estimating their sensitivities with respect to all the model parameters. We illustrate our approach with four carefully chosen reaction network examples with varying sizes. Our results demonstrate that DeepCME reliably estimates the expectations of interest, along with all the parametric sensitivities, at a fraction of the computational cost of simulation-based estimators. We present many directions for future research and suggest further improvements to DeepCME that can greatly enhance its accuracy and applicability.

High-throughput data such as metabolomics, genomics, transcriptomics, and proteomics have become familiar data types within the “-omics” family. For this work, we focus on subsets that interact with one another and represent these “pathways” as graphs. Observed pathways often have disjoint components, i.e., nodes or sets of nodes (metabolites, etc.) not connected to any other within the pathway, which notably lessens testing power. In this paper we propose the Pathway Integrated Regression-based Kernel Association Test (PaIRKAT), a new kernel machine regression method for incorporating known pathway information into the semi-parametric kernel regression framework. This work extends previous kernel machine approaches. This paper also contributes an application of a graph kernel regularization method for overcoming disconnected pathways. By incorporating a regularized or “smoothed” graph into a score test, PaIRKAT can provide more powerful tests for associations between biological pathways and phenotypes of interest and will be helpful in identifying novel pathways for targeted clinical research. We evaluate this method through several simulation studies and an application to real metabolomics data from the COPDGene study. Our simulation studies illustrate the robustness of this method to incorrect and incomplete pathway knowledge, and the real data analysis shows meaningful improvements of testing power in pathways. PaIRKAT was developed for application to metabolomic pathway data, but the techniques are easily generalizable to other data sources with a graph-like structure., Author summary PaIRKAT is a tool for improving testing power on high dimensional data by including graph topography in the kernel machine regression setting. Studies on high-dimensional data can struggle to include the complex relationships between variables. The semi-parametric kernel machine regression model is a powerful tool for capturing these types of relationships. They provide a framework for testing for relationships between outcomes of interest and high dimensional data such as metabolomic, genomic, or proteomic pathways. Our paper proposes a kernel machine method for including known biological connections between high dimensional variables by representing them as edges of ‘graphs’ or ‘networks.’ It is common for nodes (e.g., metabolites) to be disconnected from all others within the graph, which leads to meaningful decreases in testing power when graph information is ignored. We include a graph regularization or ‘smoothing’ approach for managing this issue. We demonstrate the benefits of this approach through simulation studies and an application to the metabolomic data from the COPDGene study.

The cerebral vasculature has a complex and hierarchical network, ranging from vessels of a few millimeters to superficial cortical vessels with diameters of a few hundred micrometers, and to the microvasculature (arteriole/venule) and capillary beds in the cortex. In standard imaging techniques, it is difficult to segment all vessels in the network, especially in the case of the human brain. This study proposes a hybrid modeling approach that determines these networks by explicitly segmenting the large vessels from medical images and employing a novel vascular generation algorithm. The framework enables vasculatures to be generated at coarse and fine scales for individual arteries and veins with vascular subregions, following the personalized anatomy of the brain and macroscale vasculatures. In this study, the vascular structures of superficial cortical (pial) vessels before they penetrate the cortex are modeled as a mesoscale vasculature. The validity of the present approach is demonstrated through comparisons with partially observed data from existing measurements of the vessel distributions on the brain surface, pathway fractal features, and vascular territories of the major cerebral arteries. Additionally, this validation provides some biological insights: (i) vascular pathways may form to ensure a reasonable supply of blood to the local surface area; (ii) fractal features of vascular pathways are not sensitive to overall and local brain geometries; and (iii) whole pathways connecting the upstream and downstream entire-scale cerebral circulation are highly dependent on the local curvature of the cerebral sulci., Author summary Cerebral autoregulation in the complex vascular networks of the brain is an amazing achievement. We believe that numerical analysis of the cerebral blood circulation using an anatomically precise vascular model provides a powerful tool for evaluating the direct relationships between local- and global-scale blood flows. However, there is a lack of information about the overall vascular pathways in the human brain, preventing a monolithic model of the human cerebrovasculature from being established. This paper presents a multiscale model of human cerebrovasculature based on a hybrid approach that uses image-based geometries and a newly developed mathematical algorithm. One important argument of this paper is the validity of the cerebrovasculature represented in the model, which reflects anatomical features of major cerebral vasculatures and brain shape, and has strong similarities with available data for human superficial cortical vessels. Investigations of the reconstructed model allow us to derive some biological insights and associated hypotheses for the cerebral vasculature. The authors believe the present cerebrovascular model can be applied to numerical simulations of the entire-scale cerebral blood flow.

Phylogenetic networks generalize phylogenetic trees by allowing the modelization of events of reticulate evolution. Among the different kinds of phylogenetic networks that have been proposed in the literature, the subclass of binary tree-child networks is one of the most studied ones. However, very little is known about the combinatorial structure of these networks. In this paper we address the problem of generating all possible binary tree-child (BTC) networks with a given number of leaves in an efficient way via reduction/augmentation operations that extend and generalize analogous operations for phylogenetic trees, and are biologically relevant. Since our solution is recursive, this also provides us with a recurrence relation giving an upper bound on the number of such networks. We also show how the operations introduced in this paper can be employed to extend the evolutive history of a set of sequences, represented by a BTC network, to include a new sequence. An implementation in python of the algorithms described in this paper, along with some computational experiments, can be downloaded from https://github.com/bielcardona/TCGenerators., Research of GC and JCP has been partially supported by the Spanish Ministry of Science, Innovation and Universities (http://www.ciencia.gob.es/) and European Regional Development Fund (https://ec.europa.eu/regional_policy/es/funding/erdf/) projects DPI2015-67082-P and PGC2018-096956-B-C43. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The presence of treatment-resistant cells is an important factor that limits the efficacy of cancer therapy, and the prospect of resistance is considered the major cause of the treatment strategy. Several recent studies have employed mathematical models to elucidate the dynamics of generating resistant cancer cells and attempted to predict the probability of emerging resistant cells. The purpose of this paper is to present numerical approach to compute the number of resistant cells and the emerging probability of resistance. Stochastic model was designed and developed a method to approximately but efficiently compute the number of resistant cells and the probability of resistance. To model the progression of cancer, a discrete-state, two-dimensional Markov process whose states are the total number of cells and the number of resistant cells was employed. Then exact analysis and approximate aggregation approaches were proposed to calculate the number of resistant cells and the probability of resistance when the cell population reaches detection size. To confirm the accuracy of computed results of approximation, relative errors between exact analysis and approximation were computed. The numerical values of our approximation method were very close to those of exact analysis calculated in the range of small detection size M = 500, 100, and 1500. Then computer simulation was performed to confirm the accuracy of computed results of approximation when the detection size was M = 10000,30000,50000,100000 and 1000000. All the numerical results of approximation fell between the upper level and the lower level of 95% confidential intervals and our method took less time to compute over a broad range of cell size. The effects of parameter change on emerging probabilities of resistance were also investigated by computed values using approximation method. The results showed that the number of divisions until the cell population reached the detection size is important for emerging the probability of resistance. The next step of numerical approach is to compute the emerging probabilities of resistance under drug administration and with multiple mutation. Another effective approximation would be necessary for the analysis of the latter case., Author summary Drug therapies for cancer have dramatically succeeded since molecular-targeted drugs have been introduced in medical practice; however, drug treatment often fails owing to the emergence of drug-resistant cells. A variety of approaches, including mathematical modeling, has been undertaken to clarify the mechanism of resistance and subsequently avoid resistance to therapy. This paper proposes one of the mathematical approaches that uses a stochastic model and provides the emerging probabilities of resistance at detection size.

LncRNA-protein interactions play important roles in post-transcriptional gene regulation, poly-adenylation, splicing and translation. Identification of lncRNA-protein interactions helps to understand lncRNA-related activities. Existing computational methods utilize multiple lncRNA features or multiple protein features to predict lncRNA-protein interactions, but features are not available for all lncRNAs or proteins; most of existing methods are not capable of predicting interacting proteins (or lncRNAs) for new lncRNAs (or proteins), which don’t have known interactions. In this paper, we propose the sequence-based feature projection ensemble learning method, “SFPEL-LPI”, to predict lncRNA-protein interactions. First, SFPEL-LPI extracts lncRNA sequence-based features and protein sequence-based features. Second, SFPEL-LPI calculates multiple lncRNA-lncRNA similarities and protein-protein similarities by using lncRNA sequences, protein sequences and known lncRNA-protein interactions. Then, SFPEL-LPI combines multiple similarities and multiple features with a feature projection ensemble learning frame. In computational experiments, SFPEL-LPI accurately predicts lncRNA-protein associations and outperforms other state-of-the-art methods. More importantly, SFPEL-LPI can be applied to new lncRNAs (or proteins). The case studies demonstrate that our method can find out novel lncRNA-protein interactions, which are confirmed by literature. Finally, we construct a user-friendly web server, available at http://www.bioinfotech.cn/SFPEL-LPI/., Author summary LncRNA-protein interactions play important roles in post-transcriptional gene regulation, poly-adenylation, splicing and translation. Identification of lncRNA-protein interactions helps to understand lncRNA-related activities. In this paper, we propose a novel computational method “SFPEL-LPI” to predict lncRNA-protein interactions. SFPEL-LPI makes use of lncRNA sequences, protein sequences and known lncRNA-protein associations to extract features and calculate similarities for lncRNAs and proteins, and then combines them with a feature projection ensemble learning frame. SFPEL-LPI can predict unobserved interactions between lncRNAs and proteins, and also can make predictions for new lncRNAs (or proteins), which have no interactions with any proteins (or lncRNAs). SFPEL-LPI produces high-accuracy performances on the benchmark dataset when evaluated by five-fold cross validation, and outperforms state-of-the-art methods. The case studies demonstrate that SFPEL-LPI can find out novel associations, which are confirmed by literature. To facilitate the lncRNA-protein interaction prediction, we develop a user-friendly web server, available at http://www.bioinfotech.cn/SFPEL-LPI/.

This paper uses mathematical modeling to study the mechanisms of surround suppression in the primate visual cortex. We present a large-scale neural circuit model consisting of three interconnected components: LGN and two input layers (Layer 4Ca and Layer 6) of the primary visual cortex V1, covering several hundred hypercolumns. Anatomical structures are incorporated and physiological parameters from realistic modeling work are used. The remaining parameters are chosen to produce model outputs that emulate experimentally observed size-tuning curves. Our two main results are: (i) we discovered the character of the long-range connections in Layer 6 responsible for surround effects in the input layers; and (ii) we showed that a net-inhibitory feedback, i.e., feedback that excites I-cells more than E-cells, from Layer 6 to Layer 4 is conducive to producing surround properties consistent with experimental data. These results are obtained through parameter selection and model analysis. The effects of nonlinear recurrent excitation and inhibition are also discussed. A feature that distinguishes our model from previous modeling work on surround suppression is that we have tried to reproduce realistic lengthscales that are crucial for quantitative comparison with data. Due to its size and the large number of unknown parameters, the model is computationally challenging. We demonstrate a strategy that involves first locating baseline values for relevant parameters using a linear model, followed by the introduction of nonlinearities where needed. We find such a methodology effective, and propose it as a possibility in the modeling of complex biological systems., Author summary The visual cortex is a part of the cortex that processes visual signal. The visual signal from the retina is relayed through the lateral geniculate nucleus (LGN), and enters the primary visual cortex directly. The primary visual cortex consists of many layers. A phenomenon called surround suppression, which means a reduction of neuronal activities in response to stimuli of increasing size, is well-observed in all layers of the primate primary visual cortex. In this paper, we built a large scale mathematical model consisting of the LGN input and tens of thousands of neuron groups in Layer 4 and Layer 6 of the primary visual cortex to study the mechanism of surround suppression. This model is constrained by both anatomical structures and realistic physiological parameters. Remaining unknown parameters are reverse-engineered from experimental data. We showed how the character of the surround suppression depends on the long-range connections in the feedback layer, as well as the feedback current from Layer 6 to Layer 4.

Dengue is an arbovirus affecting global populations. Frequent outbreaks occur, especially in equatorial cities such as Singapore, where year-round tropical climate, large daily influx of travelers and population density provide the ideal conditions for dengue to transmit. Little work has, however, quantified the peaks of dengue outbreaks, when health systems are likely to be most stretched. Nor have methods been developed to infer differences in exogenous factors which lead to the rise and fall of dengue case counts across extreme and non-extreme periods. In this paper, we developed time varying extreme mixture (tvEM) methods to account for the temporal dependence of dengue case counts across extreme and non-extreme periods. This approach permits inference of differences in climatic forcing across non-extreme and extreme periods of dengue case counts, quantification of their temporal dependence as well as estimation of thresholds with associated uncertainties to determine dengue case count extremities. Using tvEM, we found no evidence that weather affects dengue case counts in the near term for non-extreme periods, but that it has non-linear and mixed signals in influencing dengue through tvEM parameters in the extreme periods. Using the most appropriate tvEM specification, we found that a threshold at the 70th (95% credible interval 41.1, 83.8) quantile is optimal, with extreme events of 526.6, 1052.2 and 1183.6 weekly case counts expected at return periods of 5, 50 and 75 years. Weather parameters at a 1% scaled increase was found to decrease the long-run expected case counts, but larger increases would lead to a drastic expected rise from the baseline correspondingly. The tvEM approach can provide valuable inference on the extremes of time series, which in the case of infectious disease notifications, allows public health officials to understand the likely scale of outbreaks in the long run., Author summary Dengue is an arbovirus affecting populations across much of the globe. Frequent outbreaks occur, especially in equatorial cities such as Singapore, where the year-round tropical climate, large daily influx of travelers and population density provide the ideal conditions for dengue transmission. Little work has however quantified the peaks of dengue outbreaks, when health systems are likely to be most stretched. Nor have methods been developed to infer differences in exogenous factors which lead to the rise and fall of dengue case counts across extreme and non extreme periods. In this paper, we developed time varying extreme mixture (tvEM) methods to account for the temporal dependence of dengue case counts across extreme and non-extreme periods. tvEM is able to infer differences in climatic forcing across non-extreme and extreme periods of dengue case counts, their temporal dependence as well as estimate suitable thresholds with associated uncertainties to determine dengue case count extremities. Using tvEM, we found no evidence that weather affects dengue case counts in the near term for non extreme periods, but has non-linear and mixed signals in influencing dengue through tvEM parameters in the extreme periods. Using the most appropriate tvEM specification, we found that a high percentile threshold is estimated, with dengue outbreak events far larger than currently observed to be expected in 5, 50 and 75 years. Weather parameters at a 1% scaled increase was found to decrease the long-run expected case counts, but larger increases would lead to a drastic expected rise from the baseline correspondingly. tvEM can provide valuable inference on the extremes of time series, which in the case of infectious disease data, allows public health officials to understand factors and the likely scale of infectious disease outbreaks in the long run.

Humans are able to track multiple objects at any given time in their daily activities—for example, we can drive a car while monitoring obstacles, pedestrians, and other vehicles. Several past studies have examined how humans track targets simultaneously and what underlying behavioral and neural mechanisms they use. At the same time, computer-vision researchers have proposed different algorithms to track multiple targets automatically. These algorithms are useful for video surveillance, team-sport analysis, video analysis, video summarization, and human–computer interaction. Although there are several efficient biologically inspired algorithms in artificial intelligence, the human multiple-target tracking (MTT) ability is rarely imitated in computer-vision algorithms. In this paper, we review MTT studies in neuroscience and biologically inspired MTT methods in computer vision and discuss the ways in which they can be seen as complementary., Author summary Multiple-target tracking (MTT) is a challenging task vital for both a human’s daily life and for many artificial intelligent systems, such as those used for urban traffic control. Neuroscientists are interested in discovering the underlying neural mechanisms that successfully exploit cognitive resources, e.g., spatial attention or memory, during MTT. Computer-vision specialists aim to develop powerful MTT algorithms based on advanced models or data-driven computational methods. In this paper, we review MTT studies from both communities and discuss how findings from cognitive studies can inspire developers to construct higher performing MTT algorithms. Moreover, some directions have been proposed through which MTT algorithms could raise new questions in the cognitive science domain, and answering them can shed light on neural processes underlying MTT.

Integrated Information Theory (IIT) has become nowadays the most sensible general theory of consciousness. In addition to very important statements, it opens the door for an abstract (mathematical) formulation of the theory. Given a mechanism in a particular state, IIT identifies a conscious experience with a conceptual structure, an informational object which exists, is composed of identified parts, is informative, integrated and maximally irreducible. This paper introduces a space-time continuous version of the concept of integrated information. To this aim, a graph and a dynamical systems treatment is used to define, for a given mechanism in a state for which a dynamics is settled, an Informational Structure, which is associated to the global attractor at each time of the system. By definition, the informational structure determines all the past and future behavior of the system, possesses an informational nature and, moreover, enriches all the points of the phase space with cause-effect power by means of its associated Informational Field. A detailed description of its inner structure by invariants and connections between them allows to associate a transition probability matrix to each informational structure and to develop a measure for the level of integrated information of the system., Author summary In this paper we introduce a space-time continuous version for the level of integrated information of a network on which a dynamics is defined. The concept of integrated information comes from the IIT of consciousness. By a strict mathematical formulation, we complement the existing IIT theoretical framework from a dynamical systems perspective. In other words, we develop the bases for a continuous mathematical approach to IIT introducing a dynamical system as the driving rule of a given mechanism. We also introduce and define the concepts of Informational Structure and Informational Field as the complex network with the power to ascertain the dynamics (past and future scenarios) of the studied phenomena. The detailed description of an informational structure is showing the cause-effect power of a mechanism in a state and thus, a characterization of the quantity and quality of information, and the way this is integrated. We firstly introduce how network patterns arise from dynamic phenomena on networks, leading to the concept of informational structure. Then, we formally introduce the mathematical objects supporting the theory, from graphs to informational structures, throughout the integration of dynamics on graphs with a global model of differential equations. After this, we formally present some of the IIT’s postulates associated to a given mechanism. Finally, we provide the quantitative and qualitative characterization of the integrated information, and how it depends on the geometry of the mechanism.

Most objects and vegetation making up the habitats of echolocating bats return a multitude of overlapping echoes. Recent evidence suggests that the limited temporal and spatial resolution of bio-sonar prevents bats from separately perceiving the objects giving rise to these overlapping echoes. Therefore, bats often operate under conditions where their ability to localize obstacles is severely limited. Nevertheless, bats excel at avoiding complex obstacles. In this paper, we present a robotic model of bat obstacle avoidance using interaural level differences and distance to the nearest obstacle as the minimal set of cues. In contrast to previous robotic models of bats, the current robot does not attempt to localize obstacles. We evaluate two obstacle avoidance strategies. First, the Fixed Head Strategy keeps the acoustic gaze direction aligned with the direction of flight. Second, the Delayed Linear Adaptive Law (DLAL) Strategy uses acoustic gaze scanning, as observed in hunting bats. Acoustic gaze scanning has been suggested to aid the bat in hunting for prey. Here, we evaluate its adaptive value for obstacle avoidance when obstacles can not be localized. The robot’s obstacle avoidance performance is assessed in two environments mimicking (highly cluttered) experimental setups commonly used in behavioral experiments: a rectangular arena containing multiple complex cylindrical reflecting surfaces and a corridor lined with complex reflecting surfaces. The results indicate that distance to the nearest object and interaural level differences allows steering the robot clear of obstacles in environments that return non-localizable echoes. Furthermore, we found that using acoustic gaze scanning reduced performance, suggesting that gaze scanning might not be beneficial under conditions where the animal has limited access to angular information, which is in line with behavioral evidence., Author summary The sonar system of bats provides only limited information about the location of obstacles. In particular, it is unlikely that bats can localize multiple, complex obstacles that return a multitude of interfering echoes. Nevertheless, these animals can fly swiftly through densely cluttered habits. To explain how bats do this, we proposed they only need to compare the loudness of the echoes at the left and the right ear. If the echoes at the left ear are louder than at the right ear, obstacles are probably located to the left. Therefore, the bat should bank right (and vice versa). In this paper, we test whether such a simple strategy would allow bats to avoid obstacles. We equipped a robot with a sonar system resembling that of a bat, and we implemented the obstacle avoidance strategy above. We tested this robotic bat in environments mimicking those used in experimental studies of their sonar behavior. The robot was able to avoid most of the obstacles in both environments. Therefore, we conclude that bats could rely on a simple strategy when avoiding obstacles in complex environments.

Manually curating biomedical knowledge from publications is necessary to build a knowledge based service that provides highly precise and organized information to users. The process of retrieving relevant publications for curation, which is also known as document triage, is usually carried out by querying and reading articles in PubMed. However, this query-based method often obtains unsatisfactory precision and recall on the retrieved results, and it is difficult to manually generate optimal queries. To address this, we propose a machine-learning assisted triage method. We collect previously curated publications from two databases UniProtKB/Swiss-Prot and the NHGRI-EBI GWAS Catalog, and used them as a gold-standard dataset for training deep learning models based on convolutional neural networks. We then use the trained models to classify and rank new publications for curation. For evaluation, we apply our method to the real-world manual curation process of UniProtKB/Swiss-Prot and the GWAS Catalog. We demonstrate that our machine-assisted triage method outperforms the current query-based triage methods, improves efficiency, and enriches curated content. Our method achieves a precision 1.81 and 2.99 times higher than that obtained by the current query-based triage methods of UniProtKB/Swiss-Prot and the GWAS Catalog, respectively, without compromising recall. In fact, our method retrieves many additional relevant publications that the query-based method of UniProtKB/Swiss-Prot could not find. As these results show, our machine learning-based method can make the triage process more efficient and is being implemented in production so that human curators can focus on more challenging tasks to improve the quality of knowledge bases., Author summary As the volume of literature on genomic variants continues to grow at an increasing rate, it is becoming more difficult for a curator of a variant knowledge base to keep up with and curate all the published papers. Here, we suggest a deep learning-based literature triage method for genomic variation resources. Our method achieves state-of-the-art performance on the triage task. Moreover, our model does not require any laborious preprocessing or feature engineering steps, which are required for traditional machine learning triage methods. We applied our method to the literature triage process of UniProtKB/Swiss-Prot and the NHGRI-EBI GWAS Catalog for genomic variation by collaborating with the database curators. Both the manual curation teams confirmed that our method achieved higher precision than their previous query-based triage methods without compromising recall. Both results show that our method is more efficient and can replace the traditional query-based triage methods of manually curated databases. Our method can give human curators more time to focus on more challenging tasks such as actual curation as well as the discovery of novel papers/experimental techniques to consider for inclusion.

Phylogenetic networks are rooted, directed, acyclic graphs that model reticulate evolutionary histories. Recently, statistical methods were devised for inferring such networks from either gene tree estimates or the sequence alignments of multiple unlinked loci. Bi-allelic markers, most notably single nucleotide polymorphisms (SNPs) and amplified fragment length polymorphisms (AFLPs), provide a powerful source of genome-wide data. In a recent paper, a method called SNAPP was introduced for statistical inference of species trees from unlinked bi-allelic markers. The generative process assumed by the method combined both a model of evolution for the bi-allelic markers, as well as the multispecies coalescent. A novel component of the method was a polynomial-time algorithm for exact computation of the likelihood of a fixed species tree via integration over all possible gene trees for a given marker. Here we report on a method for Bayesian inference of phylogenetic networks from bi-allelic markers. Our method significantly extends the algorithm for exact computation of phylogenetic network likelihood via integration over all possible gene trees. Unlike the case of species trees, the algorithm is no longer polynomial-time on all instances of phylogenetic networks. Furthermore, the method utilizes a reversible-jump MCMC technique to sample the posterior of phylogenetic networks given bi-allelic marker data. Our method has a very good performance in terms of accuracy and robustness as we demonstrate on simulated data, as well as a data set of multiple New Zealand species of the plant genus Ourisia (Plantaginaceae). We implemented the method in the publicly available, open-source PhyloNet software package., Author summary The availability of genomic data has revolutionized the study of evolutionary histories and phylogeny inference. Inferring evolutionary histories from genomic data requires, in most cases, accounting for the fact that different genomic regions could have evolutionary histories that differ from each other as well as from that of the species from which the genomes were sampled. In this paper, we introduce a method for inferring evolutionary histories while accounting for two processes that could give rise to such differences across the genomes, namely incomplete lineage sorting and hybridization. We introduce a novel algorithm for computing the likelihood of phylogenetic networks from bi-allelic genetic markers and use it in a Bayesian inference method. Analyses of synthetic and empirical data sets show a very good performance of the method in terms of the estimates it obtains.

Type 2 diabetes leads to premature death and reduced quality of life for 8% of Americans. Nutrition management is critical to maintaining glycemic control, yet it is difficult to achieve due to the high individual differences in glycemic response to nutrition. Anticipating glycemic impact of different meals can be challenging not only for individuals with diabetes, but also for expert diabetes educators. Personalized computational models that can accurately forecast an impact of a given meal on an individual’s blood glucose levels can serve as the engine for a new generation of decision support tools for individuals with diabetes. However, to be useful in practice, these computational engines need to generate accurate forecasts based on limited datasets consistent with typical self-monitoring practices of individuals with type 2 diabetes. This paper uses three forecasting machines: (i) data assimilation, a technique borrowed from atmospheric physics and engineering that uses Bayesian modeling to infuse data with human knowledge represented in a mechanistic model, to generate real-time, personalized, adaptable glucose forecasts; (ii) model averaging of data assimilation output; and (iii) dynamical Gaussian process model regression. The proposed data assimilation machine, the primary focus of the paper, uses a modified dual unscented Kalman filter to estimate states and parameters, personalizing the mechanistic models. Model selection is used to make a personalized model selection for the individual and their measurement characteristics. The data assimilation forecasts are empirically evaluated against actual postprandial glucose measurements captured by individuals with type 2 diabetes, and against predictions generated by experienced diabetes educators after reviewing a set of historical nutritional records and glucose measurements for the same individual. The evaluation suggests that the data assimilation forecasts compare well with specific glucose measurements and match or exceed in accuracy expert forecasts. We conclude by examining ways to present predictions as forecast-derived range quantities and evaluate the comparative advantages of these ranges., Author summary Type 2 diabetes is a devastating disease that requires constant patient self-management of glucose, insulin, nutrition and exercise. Nevertheless, glucose and insulin dynamics are complicated, nonstationary, nonlinear, and individual-dependent, making self-management of diabetes a complex task. To help alleviate some of the difficulty for patients, we develop a method for personalized, real-time, glucose forecasting based on nutrition. Specifically, we create and evaluate the computational machinery based on both Gaussian process models and data assimilation that leverages the physiologic knowledge of two mechanistic models to produce a personalized, nutrition-based glucose forecast for individuals with type 2 diabetes in real time that is robust to sparse data and nonstationary patients. Our computational engine was conceived to be of potential use for diabetes self-management.

A recent paper by Karin et al. introduced a mathematical notion called dynamical compensation (DC) of biological circuits. DC was shown to play an important role in glucose homeostasis as well as other key physiological regulatory mechanisms. Karin et al. went on to provide a sufficient condition to test whether a given system has the DC property. Here, we show how DC can be formulated in terms of a well-known concept in systems biology, statistics, and control theory—that of parameter structural non-identifiability. Viewing DC as a parameter identification problem enables one to take advantage of powerful theoretical and computational tools to test a system for DC. We obtain as a special case the sufficient criterion discussed by Karin et al. We also draw connections to system equivalence and to the fold-change detection property., Author summary A recently introduced mathematical notion called dynamical compensation of biological circuits was shown to play an important role in glucose homeostasis and other key physiological regulatory mechanisms. This paper explains how dynamical compensation can be formulated in terms of a well-known concept in systems biology, statistics, and control theory—that of parameter structural non-identifiability. Viewing dynamical compensation as a parameter identification problem enables one to take advantage of powerful theoretical and computational tools to test a system for dynamical compensation. As a special case, one obtains the sufficient criterion for dynamical compensation. The paper also draws connections to system equivalence and to the fold-change detection property. The non-identifiability characterization brings up an interesting contrast in the way in which one thinks of these properties in the two fields. From the point of view of robustness of behavior, one wishes that parameters do not influence much the response of a system. On the other hand, from the systems and parameter identification point of view, the more that a parameter affects behavior, the easier it is to estimate it, and poor sensitivity is taken as an indication of a poorly parametrized model.

Integrative clustering is used to identify groups of samples by jointly analysing multiple datasets describing the same set of biological samples, such as gene expression, copy number, methylation etc. Most existing algorithms for integrative clustering assume that there is a shared consistent set of clusters across all datasets, and most of the data samples follow this structure. However in practice, the structure across heterogeneous datasets can be more varied, with clusters being joined in some datasets and separated in others. In this paper, we present a probabilistic clustering method to identify groups across datasets that do not share the same cluster structure. The proposed algorithm, Clusternomics, identifies groups of samples that share their global behaviour across heterogeneous datasets. The algorithm models clusters on the level of individual datasets, while also extracting global structure that arises from the local cluster assignments. Clusters on both the local and the global level are modelled using a hierarchical Dirichlet mixture model to identify structure on both levels. We evaluated the model both on simulated and on real-world datasets. The simulated data exemplifies datasets with varying degrees of common structure. In such a setting Clusternomics outperforms existing algorithms for integrative and consensus clustering. In a real-world application, we used the algorithm for cancer subtyping, identifying subtypes of cancer from heterogeneous datasets. We applied the algorithm to TCGA breast cancer dataset, integrating gene expression, miRNA expression, DNA methylation and proteomics. The algorithm extracted clinically meaningful clusters with significantly different survival probabilities. We also evaluated the algorithm on lung and kidney cancer TCGA datasets with high dimensionality, again showing clinically significant results and scalability of the algorithm., Author summary Integrative clustering is the task of identifying groups of samples by combining information from several datasets. An example of this task is cancer subtyping, where we cluster tumour samples based on several datasets, such as gene expression, proteomics and others. Most existing algorithms assume that all such datasets share a similar cluster structure, with samples outside these clusters treated as noise. The structure can, however, be much more heterogeneous: some meaningful clusters may appear only in some datasets. In the paper, we introduce the Clusternomics algorithm that identifies groups of samples across heterogeneous datasets. It models both cluster structure of individual datasets, and the global structure that appears as a combination of local structures. The algorithm uses probabilistic modelling to identify the groups and share information across the local and global levels. We evaluated the algorithm on both simulated and real world datasets, where the algorithm found clinically significant clusters with different survival outcomes.

Phylogenetic networks generalize phylogenetic trees by allowing the modelization of events of reticulate evolution. Among the different kinds of phylogenetic networks that have been proposed in the literature, the subclass of binary tree-child networks is one of the most studied ones. However, very little is known about the combinatorial structure of these networks. In this paper we address the problem of generating all possible binary tree-child (BTC) networks with a given number of leaves in an efficient way via reduction/augmentation operations that extend and generalize analogous operations for phylogenetic trees, and are biologically relevant. Since our solution is recursive, this also provides us with a recurrence relation giving an upper bound on the number of such networks. We also show how the operations introduced in this paper can be employed to extend the evolutive history of a set of sequences, represented by a BTC network, to include a new sequence. An implementation in python of the algorithms described in this paper, along with some computational experiments, can be downloaded from https://github.com/bielcardona/TCGenerators.

Neural Mass Models provide a compact description of the dynamical activity of cell populations in neocortical regions. Moreover, models of regional activity can be connected together into networks, and inferences made about the strength of connections, using M/EEG data and Bayesian inference. To date, however, Bayesian methods have been largely restricted to the Variational Laplace (VL) algorithm which assumes that the posterior distribution is Gaussian and finds model parameters that are only locally optimal. This paper explores the use of Annealed Importance Sampling (AIS) to address these restrictions. We implement AIS using proposals derived from Langevin Monte Carlo (LMC) which uses local gradient and curvature information for efficient exploration of parameter space. In terms of the estimation of Bayes factors, VL and AIS agree about which model is best but report different degrees of belief. Additionally, AIS finds better model parameters and we find evidence of non-Gaussianity in their posterior distribution., Author Summary The activity of populations of neurons in the human brain can be described using a set of differential equations known as a neural mass model. These models can then be connected to describe activity in multiple brain regions and, by fitting them to human brain imaging data, statistical inferences can be made about changes in macroscopic connectivity among brain regions. For example, the strength of a connection from one region to another may be more strongly engaged in a particular patient population or during a specific cognitive task. Current statistical inference approaches use a Bayesian algorithm based on principles of local optimization and the assumption that uncertainty about model parameters (e.g. connectivity), having seen the data, follows a Gaussian distribution. This paper evaluates current methods against a global Bayesian optimization algorithm and finds that the two approaches (local/global) agree about which model is best, but finds that the global approach produces better parameter estimates.

There is a current interest in quantifying time-varying connectivity (TVC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for TVC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exist many TVC methods it is difficult to assess differences in time-varying connectivity between studies. In this paper, we present tvc_benchmarker, which is a Python package containing four simulations to test TVC methods. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating TVC (sliding window, tapered sliding window, multiplication of temporal derivatives, spatial distance and jackknife correlation). These simulations were designed to test each method’s ability to track changes in covariance over time, which is a key property in TVC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future TVC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. Using tvc_benchmarker researchers can easily add, compare and submit their own TVC methods to evaluate its performance., Author summary Time-varying connectivity attempts to quantify the fluctuating covariance relationship between two or more regions through time. In recent years, it has become popular to do this with fMRI neuroimaging data. There have been many methods proposed to quantify time-varying connectivity, but very few attempts to systematically compare them. In this paper, we present tvc_benchmarker, which is a python package that consists of four simulations. The parameters of the data are justified on fMRI signal properties. Five different methods are evaluated in this paper, but other researchers can use tvc_benchmarker to evaluate their methodologies and their results can be submitted to be included in future reports. Methods are evaluated on their ability to track a fluctuating covariance parameter between time series. Of the evaluated methods, the jackknife correlation method performed the best at tracking a fluctuating covariance parameter in these four simulations.

13C metabolic flux analysis (13C-MFA) has been widely used to measure in vivo enzyme reaction rates (i.e., metabolic flux) in microorganisms. Mining the relationship between environmental and genetic factors and metabolic fluxes hidden in existing fluxomic data will lead to predictive models that can significantly accelerate flux quantification. In this paper, we present a web-based platform MFlux (http://mflux.org) that predicts the bacterial central metabolism via machine learning, leveraging data from approximately 100 13C-MFA papers on heterotrophic bacterial metabolisms. Three machine learning methods, namely Support Vector Machine (SVM), k-Nearest Neighbors (k-NN), and Decision Tree, were employed to study the sophisticated relationship between influential factors and metabolic fluxes. We performed a grid search of the best parameter set for each algorithm and verified their performance through 10-fold cross validations. SVM yields the highest accuracy among all three algorithms. Further, we employed quadratic programming to adjust flux profiles to satisfy stoichiometric constraints. Multiple case studies have shown that MFlux can reasonably predict fluxomes as a function of bacterial species, substrate types, growth rate, oxygen conditions, and cultivation methods. Due to the interest of studying model organism under particular carbon sources, bias of fluxome in the dataset may limit the applicability of machine learning models. This problem can be resolved after more papers on 13C-MFA are published for non-model species., Author Summary Metabolic information is important for disease treatment, bioprocess optimization, environmental remediation, biogeochemical cycle regulation, and our understanding of life’s origin and evolution. 13C-MFA can quantify microbial physiology at the level of metabolic reaction rates. To speed up microbial characterizations and fluxomic studies, we hypothesize that genetic and environmental factors generate specific fluxome patterns that can be recognized by machine learning. Aided by constraint programming and quadratic optimization, our platform based on machine learning (ML) can predict meaningful metabolic information about bacterial species in their environments. Further, it can offer constraints to improve the accuracy of flux balance analysis. This study infers that the bacterial metabolic network has a certain degree of rigidity in allocating carbon fluxes, and different microbial species may share common regulatory strategies for balancing carbon and energy metabolisms. As a proof of concept, we demonstrate that the use of data-driven artificial intelligence (AI) approaches, e.g., ML, may assist mechanistic based models to elucidate the topology of microbial fluxomes.