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Pankaj Mehta

Publications and source records attributed to Pankaj Mehta.

At least 73 records · Page 4Linked to original sources

Fast Bayesian Feature Selection for High Dimensional Linear Regression in Genomics via the Ising Approximation

Feature selection, identifying a subset of variables that are relevant for predicting a response, is an important and challenging component of many methods in statistics and machine learning. Feature selection is especially difficult and computationally intensive when the number of variables approaches or exceeds the number of samples, as is often the case for many genomic datasets. Here, we introduce a new approach -- the Bayesian Ising Approximation (BIA) -- to rapidly calculate posterior probabilities for feature relevance in L2 penalized linear regression. In the regime where the regression problem is strongly regularized by the prior, we show that computing the marginal posterior probabilities for features is equivalent to computing the magnetizations of an Ising model. Using a mean field approximation, we show it is possible to rapidly compute the feature selection path described by the posterior probabilities as a function of the L2 penalty. We present simulations and analytical results illustrating the accuracy of the BIA on some simple regression problems. Finally, we demonstrate the applicability of the BIA to high dimensional regression by analyzing a gene expression dataset with nearly 30,000 features.

q-bio.QM↗

From Intracellular Signaling to Population Oscillations: Bridging Scales in Collective Behavior

Collective behavior in cellular populations is coordinated by biochemical signaling networks within individual cells. Connecting the dynamics of these intracellular networks to the population phenomena they control poses a considerable challenge because of network complexity and our limited knowledge of kinetic parameters. However, from physical systems we know that behavioral changes in the individual constituents of a collectively-behaving system occur in a limited number of well-defined classes, and these can be described using simple models. Here we apply such an approach to the emergence of collective oscillations in cellular populations of the social amoeba Dictyostelium discoideum. Through direct tests of our model with quantitative in vivo measurements of single-cell and population signaling dynamics, we show how a simple model can effectively describe a complex molecular signaling network and its effects at multiple size and temporal scales. The model predicts novel noise-driven single-cell and population-level signaling phenomena that we then experimentally observe. Our results suggest that like physical systems, collective behavior in biology may be universal and described using simple mathematical models.

physics.bio-ph↗

Zipf's law and criticality in multivariate data without fine-tuning

The joint probability distribution of many degrees of freedom in biological systems, such as firing patterns in neural networks or antibody sequence composition in zebrafish, often follow Zipf's law, where a power law is observed on a rank-frequency plot. This behavior has recently been shown to imply that these systems reside near to a unique critical point where the extensive parts of the entropy and energy are exactly equal. Here we show analytically, and via numerical simulations, that Zipf-like probability distributions arise naturally if there is an unobserved variable (or variables) that affects the system, e. g. for neural networks an input stimulus that causes individual neurons in the network to fire at time-varying rates. In statistics and machine learning, these models are called latent-variable or mixture models. Our model shows that no fine-tuning is required, i.e. Zipf's law arises generically without tuning parameters to a point, and gives insight into the ubiquity of Zipf's law in a wide range of systems.

q-bio.NC↗

A phase transition between the niche and neutral regimes in ecology

An ongoing debate in ecology concerns the impacts of ecological drift and selection on community assembly. Here, we show that there is a sharp phase transition in diverse ecological communities between a selection dominated regime (the niche phase) and a drift dominated regime (the neutral phase). Simulations and analytic arguments show that the niche phase is favored in communities with large population sizes and relatively constant environments, whereas the neutral phase is favored in communities with small population sizes and fluctuating environments. Our results demonstrate how apparently neutral populations may arise even in communities inhabited by species with varying traits.

q-bio.PE↗

Identifying Keystone Species in the Human Gut Microbiome from Metagenomic Timeseries using Sparse Linear Regression

Human associated microbial communities exert tremendous influence over human health and disease. With modern metagenomic sequencing methods it is possible to follow the relative abundance of microbes in a community over time. These microbial communities exhibit rich ecological dynamics and an important goal of microbial ecology is to infer the interactions between species from sequence data. Any algorithm for inferring species interactions must overcome three obstacles: 1) a correlation between the abundances of two species does not imply that those species are interacting, 2) the sum constraint on the relative abundances obtained from metagenomic studies makes it difficult to infer the parameters in timeseries models, and 3) errors due to experimental uncertainty, or mis-assignment of sequencing reads into operational taxonomic units, bias inferences of species interactions. Here we introduce an approach, Learning Interactions from MIcrobial Time Series (LIMITS), that overcomes these obstacles. LIMITS uses sparse linear regression with boostrap aggregation to infer a discrete-time Lotka-Volterra model for microbial dynamics. We tested LIMITS on synthetic data and showed that it could reliably infer the topology of the inter-species ecological interactions. We then used LIMITS to characterize the species interactions in the gut microbiomes of two individuals and found that the interaction networks varied significantly between individuals. Furthermore, we found that the interaction networks of the two individuals are dominated by distinct "keystone species", Bacteroides fragilis and Bacteroided stercosis, that have a disproportionate influence on the structure of the gut microbiome even though they are only found in moderate abundance. Based on our results, we hypothesize that the abundances of certain keystone species may be responsible for individuality in the human gut microbiome.

q-bio.QM↗

Intrinsic noise of microRNA-regulated genes and the ceRNA hypothesis

MicroRNAs are small noncoding RNAs that regulate genes post-transciptionally by binding and degrading target eukaryotic mRNAs. We use a quantitative model to study gene regulation by inhibitory microRNAs and compare it to gene regulation by prokaryotic small non-coding RNAs (sRNAs). Our model uses a combination of analytic techniques as well as computational simulations to calculate the mean-expression and noise profiles of genes regulated by both microRNAs and sRNAs. We find that despite very different molecular machinery and modes of action (catalytic vs stoichiometric), the mean expression levels and noise profiles of microRNA-regulated genes are almost identical to genes regulated by prokaryotic sRNAs. This behavior is extremely robust and persists across a wide range of biologically relevant parameters. We extend our model to study crosstalk between multiple mRNAs that are regulated by a single microRNA and show that noise is a sensitive measure of microRNA-mediated interaction between mRNAs. We conclude by discussing possible experimental strategies for uncovering the microRNA-mRNA interactions and testing the competing endogenous RNA (ceRNA) hypothesis.

q-bio.MN↗

Efficiency bounds for nonequilibrium heat engines

We analyze the efficiency of thermal engines (either quantum or classical) working with a single heat reservoir like atmosphere. The engine first gets an energy intake, which can be done in arbitrary non-equilibrium way e.g. combustion of fuel. Then the engine performs the work and returns to the initial state. We distinguish two general classes of engines where the working body first equilibrates within itself and then performs the work (ergodic engine) or when it performs the work before equilibrating (non-ergodic engine). We show that in both cases the second law of thermodynamics limits their efficiency. For ergodic engines we find a rigorous upper bound for the efficiency, which is strictly smaller than the equivalent Carnot efficiency. I.e. the Carnot efficiency can be never achieved in single reservoir heat engines. For non-ergodic engines the efficiency can be higher and can exceed the equilibrium Carnot bound. By extending the fundamental thermodynamic relation to nonequilibrium processes, we find a rigorous thermodynamic bound for the efficiency of both ergodic and non-ergodic engines and show that it is given by the relative entropy of the non-equilibrium and initial equilibrium distributions.These results suggest a new general strategy for designing more efficient engines. We illustrate our ideas by using simple examples.

cond-mat.stat-mech↗

The Energetic Costs of Cellular Computation

Cells often perform computations in response to environmental cues. A simple example is the classic problem, first considered by Berg and Purcell, of determining the concentration of a chemical ligand in the surrounding media. On general theoretical grounds (Landuer's Principle), it is expected that such computations require cells to consume energy. Here, we explicitly calculate the energetic costs of computing ligand concentration for a simple two-component cellular network that implements a noisy version of the Berg-Purcell strategy. We show that learning about external concentrations necessitates the breaking of detailed balance and consumption of energy, with greater learning requiring more energy. Our calculations suggest that the energetic costs of cellular computation may be an important constraint on networks designed to function in resource poor environments such as the spore germination networks of bacteria.

q-bio.MN↗

Kuramoto model with coupling through an external medium

Synchronization of coupled oscillators is often described using the Kuramoto model. Here we study a generalization of the Kuramoto model where oscillators communicate with each other through an external medium. This generalized model exhibits interesting new phenomena such as bistability between synchronization and incoherence and a qualitatively new form of synchronization where the external medium exhibits small-amplitude oscillations. We conclude by discussing the relationship of the model to other variations of the Kuramoto model including the Kuramoto model with a bimodal frequency distribution and the Millennium Bridge problem.

nlin.CD↗

Dynamical quorum-sensing and synchronization of nonlinear oscillators coupled through an external medium

Many biological and physical systems exhibit population-density dependent transitions to synchronized oscillations in a process often termed "dynamical quorum sensing". Synchronization frequently arises through chemical communication via signaling molecules distributed through an external media. We study a simple theoretical model for dynamical quorum sensing: a heterogenous population of limit-cycle oscillators diffusively coupled through a common media. We show that this model exhibits a rich phase diagram with four qualitatively distinct mechanisms fueling population-dependent transitions to global oscillations, including a new type of transition we term "dynamic death". We derive a single pair of analytic equations that allows us to calculate all phase boundaries as a function of population density and show that the model reproduces many of the qualitative features of recent experiments of BZ catalytic particles as well as synthetically engineered bacteria.

q-bio.CB↗

Statistical mechanics of transcription-factor binding site discovery using Hidden Markov Models

Hidden Markov Models (HMMs) are a commonly used tool for inference of transcription factor (TF) binding sites from DNA sequence data. We exploit the mathematical equivalence between HMMs for TF binding and the "inverse" statistical mechanics of hard rods in a one-dimensional disordered potential to investigate learning in HMMs. We derive analytic expressions for the Fisher information, a commonly employed measure of confidence in learned parameters, in the biologically relevant limit where the density of binding sites is low. We then use techniques from statistical mechanics to derive a scaling principle relating the specificity (binding energy) of a TF to the minimum amount of training data necessary to learn it.

cond-mat.stat-mech↗

Measurement of the copy number of the master quorum-sensing regulator of a bacterial cell

Quorum sensing is the mechanism by which bacteria communicate and synchronize group behaviors. Quantitative information on parameters such as the copy number of particular quorum-sensing proteins should contribute strongly to understanding how the quorum-sensing network functions. Here we show that the copy number of the master regulator protein LuxR in Vibrio harveyi, can be determined in vivo by exploiting small-number fluctuations of the protein distribution when cells undergo division. When a cell divides, both its volume and LuxR protein copy number N are partitioned with slight asymmetries. We have measured the distribution functions describing the partitioning of the protein fluorescence and the cell volume. The fluorescence distribution is found to narrow systematically as the LuxR population increases while the volume partitioning is unchanged. Analyzing these changes statistically, we have determined that N = 80-135 dimers at low cell density and 575 dimers at high cell density. In addition, we have measured the static distribution of LuxR over a large (3,000) clonal population. Combining the static and time-lapse experiments, we determine the magnitude of the Fano factor of the distribution. This technique has broad applicability as a general, in vivo technique for measuring protein copy number and burst size.

q-bio.QM↗

Information processing and signal integration in bacterial quorum sensing

Bacteria communicate using secreted chemical signaling molecules called autoinducers in a process known as quorum sensing. The quorum-sensing network of the marine bacterium {\it Vibrio harveyi} employs three autoinducers, each known to encode distinct ecological information. Yet how cells integrate and interpret the information contained within the three autoinducer signals remains a mystery. Here, we develop a new framework for analyzing signal integration based on Information Theory and use it to analyze quorum sensing in {\it V. harveyi}. We quantify how much the cells can learn about individual autoinducers and explain the experimentally observed input-output relation of the {\it V. harveyi} quorum-sensing circuit. Our results suggest that the need to limit interference between input signals places strong constraints on the architecture of bacterial signal-integration networks, and that bacteria likely have evolved active strategies for minimizing this interference. Here we analyze two such strategies: manipulation of autoinducer production and feedback on receptor number ratios.

q-bio.MN↗

A quantitative comparison of sRNA-based and protein-based gene regulation

Small, non-coding RNAs (sRNAs) play important roles as genetic regulators in prokaryotes. sRNAs act post-transcriptionally via complementary pairing with target mRNAs to regulate protein expression. We use a quantitative approach to compare and contrast sRNAs with conventional transcription factors (TFs) to better understand the advantages of each form of regulation. In particular, we calculate the steady-state behavior, noise properties, frequency-dependent gain (amplification), and dynamical response to large input signals of both forms of regulation. While the mean steady-state behavior of sRNA-regulated proteins exhibits a distinctive tunable threshold-linear behavior, our analysis shows that transcriptional bursting leads to significantly higher intrinsic noise in sRNA-based regulation than in TF-based regulation in a large range of expression levels and limits the ability of sRNAs to perform quantitative signaling. Nonetheless, we find that sRNAs are better than TFs at filtering noise in input signals. Additionally, we find that sRNAs allow cells to respond rapidly to large changes in input signals. These features suggest a niche for sRNAs in allowing cells to transition quickly yet reliably between distinct states. This functional niche is consistent with the widespread appearance of sRNAs in stress-response and quasi-developmental networks in prokaryotes.

q-bio.MN↗

Exponential sensitivity of noise-driven switching in genetic networks

Cells are known to utilize biochemical noise to probabilistically switch between distinct gene expression states. We demonstrate that such noise-driven switching is dominated by tails of probability distributions and is therefore exponentially sensitive to changes in physiological parameters such as transcription and translation rates. However, provided mRNA lifetimes are short, switching can still be accurately simulated using protein-only models of gene expression. Exponential sensitivity limits the robustness of noise-driven switching, suggesting cells may use other mechanisms in order to switch reliably.

q-bio.MN↗

Nonequilibrium quantum-impurities: from entropy production to information theory

Nonequilibrium steady-state currents, unlike their equilibrium counterparts, continuously dissipate energy into their physical surroundings leading to entropy production and time-reversal symmetry breaking. This letter discusses these issues in the context of quantum impurity models driven out of equilibrium by attaching the impurity to leads at different chemical potentials and temperatures. We start by pointing out that entropy production is often hidden in traditional treatments of quantum-impurity models. We then use simple thermodynamic arguments to define the rate of entropy production. Using the scattering framework recently developed by the authors we show that the rate of entropy production has a simple information theoretic interpretation in terms of the Shannon entropy and Kullback-Leibler divergence of nonequilibrium distribution function. This allows us to show that the entropy production is strictly positive for any nonequilibrium steady-state. We conclude by applying these ideas to the Resonance Level Model and the Kondo model.

cond-mat.str-el↗

Scattering approach to impurity thermodynamics

Recently the authors developed a scattering approach that allows for a complete description of the steady-state physics of quantum-impurities in and out of equilibrium. Quantum impurities are described using scattering eigenstates defined ab initio on the open, infinite line with asymptotic boundary conditions imposed by the leads. The scattering states on the open line are constructed for integrable quantum-impurity models by means of a significant generalization of the Bethe-Ansatz which we call the Scattering Bethe-Ansatz (SBA). The purpose of the paper is to present in detail the scattering approach to quantum-impurity models and the SBA and show that they reproduce well-known thermodynamic results for several widely studied models: the Resonance Level model, Interacting Resonance Level model and the Kondo model. Though the SBA is more complex than the traditional Thermodynamic Bethe Ansatz (TBA) when applied to thermodynamical questions, the scattering approach (SBA) allows access to an array of new questions that cannot be addressed otherwise, ranging from scattering of electrons off magnetic impurities to nonequilibrium dynamics.

cond-mat.str-el↗