We consider the problem of discovering gene regulatory networks from time-series microarray data. Recently, graphical Granger modeling has gained considerable attention as a promising direction for addressing this problem. These methods apply graphical modeling methods on time-series data and invoke the notion of ‘Granger causality’ to make assertions on causality through inference on time-lagged effects. Existing algorithms, however, have neglected an important aspect of the problem—the group structure among the lagged temporal variables naturally imposed by the time series they belong to. Specifically, existing methods in computational biology share this shortcoming, as well as additional computational limitations, prohibiting their effective applications to the large datasets including a large number of genes and many data points. In the present article, we propose a novel methodology which we term ‘grouped graphical Granger modeling method’, which overcomes the limitations mentioned above by applying a regression method suited for high-dimensional and large data, and by leveraging the group structure among the lagged temporal variables according to the time series they belong to. We demonstrate the effectiveness of the proposed methodology on both simulated and actual gene expression data, specifically the human cancer cell (HeLa S3) cycle data. The simulation results show that the proposed methodology generally exhibits higher accuracy in recovering the underlying causal structure. Those on the gene expression data demonstrate that it leads to improved accuracy with respect to prediction of known links, and also uncovers additional causal relationships uncaptured by earlier works.Contact: aclozano@us.ibm.com

The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). TADs are demarcated by boundaries mostly conserved across cell types and even across species. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we first use fused two-dimensional lasso as a machine learning method to improve Hi-C contact matrix reproducibility, and, subsequently, we categorize TAD boundaries based on their insulation score. We demonstrate that higher TAD boundary insulation scores are associated with elevated CTCF levels and that they may differ across cell types. Intriguingly, we observe that super-enhancers are preferentially insulated by strong boundaries. Furthermore, we demonstrate that strong TAD boundaries and super-enhancer elements are frequently co-duplicated in cancer patients. Taken together, our findings suggest that super-enhancers insulated by strong TAD boundaries may be exploited, as a functional unit, by cancer cells to promote oncogenesis.

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State-space smoothing has found many applications in science and engineering. Under linear and Gaussian assumptions, smoothed estimates can be obtained using efficient recursions, for example Rauch-Tung-Striebel and Mayne-Fraser algorithms. Such schemes are equivalent to linear algebraic techniques that minimize a convex quadratic objective function with structure induced by the dynamic model. These classical formulations fall short in many important circumstances. For instance, smoothers obtained using quadratic penalties can fail when outliers are present in the data, and cannot track impulsive inputs and abrupt state changes. Motivated by these shortcomings, generalized Kalman smoothing formulations have been proposed in the last few years, replacing quadratic models with more suitable, often nonsmooth, convex functions. In contrast to classical models, these general estimators require use of iterated algorithms, and these have received increased attention from control, signal processing, machine learning, and optimization communities. In this survey we show that the optimization viewpoint provides the control and signal processing community great freedom in the development of novel modeling and inference frameworks for dynamical systems. We discuss general statistical models for dynamic systems, making full use of nonsmooth convex penalties and constraints, and providing links to important models in signal processing and machine learning. We also survey optimization techniques for these formulations, paying close attention to dynamic problem structure. Modeling concepts and algorithms are illustrated with numerical examples.

Attribution of climate change to causal factors has been based predominantly on simulations using physical climate models, which have inherent limitations in describing such a complex and chaotic system. We propose an alternative, data centric, approach that relies on actual measurements of climate observations and human and natural forcing factors. Specifically, we develop a novel method to infer causality from spatial-temporal data, as well as a procedure to incorporate extreme value modeling into our method in order to address the attribution of extreme climate events, such as heatwaves. Our experimental results on a real world dataset indicate that changes in temperature are not solely accounted for by solar radiance, but attributed more significantly to CO2 and other greenhouse gases. Combined with extreme value modeling, we also show that there has been a significant increase in the intensity of extreme temperatures, and that such changes in extreme temperature are also attributable to greenhouse gases. These preliminary results suggest that our approach can offer a useful alternative to the simulation-based approach to climate modeling and attribution, and provide valuable insights from a fresh perspective.