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1. DCI: learning causal differences between gene regulatory networks

   https://doi.org/10.1093/bioinformatics/btab167  

   Belyaeva, Anastasiya; Squires, Chandler; Uhler, Caroline (March 2021, Bioinformatics)

   Cowen, Lenore (Ed.)

   Abstract Summary Designing interventions to control gene regulation necessitates modeling a gene regulatory network by a causal graph. Currently, large-scale gene expression datasets from different conditions, cell types, disease states, and developmental time points are being collected. However, application of classical causal inference algorithms to infer gene regulatory networks based on such data is still challenging, requiring high sample sizes and computational resources. Here, we describe an algorithm that efficiently learns the differences in gene regulatory mechanisms between different conditions. Our difference causal inference (DCI) algorithm infers changes (i.e. edges that appeared, disappeared, or changed weight) between two causal graphs given gene expression data from the two conditions. This algorithm is efficient in its use of samples and computation since it infers the differences between causal graphs directly without estimating each possibly large causal graph separately. We provide a user-friendly Python implementation of DCI and also enable the user to learn the most robust difference causal graph across different tuning parameters via stability selection. Finally, we show how to apply DCI to single-cell RNA-seq data from different conditions and cell states, and we also validate our algorithm by predicting the effects of interventions. Availability and implementation Python package freely available at http://uhlerlab.github.io/causaldag/dci. Supplementary information Supplementary data are available at Bioinformatics online. 

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2. The effective graph reveals redundancy, canalization, and control pathways in biochemical regulation and signaling

   https://doi.org/10.1073/pnas.2022598118  

   Gates, Alexander J.; Brattig Correia, Rion; Wang, Xuan; Rocha, Luis M. (March 2021, Proceedings of the National Academy of Sciences)

   null (Ed.)

   The ability to map causal interactions underlying genetic control and cellular signaling has led to increasingly accurate models of the complex biochemical networks that regulate cellular function. These network models provide deep insights into the organization, dynamics, and function of biochemical systems: for example, by revealing genetic control pathways involved in disease. However, the traditional representation of biochemical networks as binary interaction graphs fails to accurately represent an important dynamical feature of these multivariate systems: some pathways propagate control signals much more effectively than do others. Such heterogeneity of interactions reflects canalization—the system is robust to dynamical interventions in redundant pathways but responsive to interventions in effective pathways. Here, we introduce the effective graph, a weighted graph that captures the nonlinear logical redundancy present in biochemical network regulation, signaling, and control. Using 78 experimentally validated models derived from systems biology, we demonstrate that 1) redundant pathways are prevalent in biological models of biochemical regulation, 2) the effective graph provides a probabilistic but precise characterization of multivariate dynamics in a causal graph form, and 3) the effective graph provides an accurate explanation of how dynamical perturbation and control signals, such as those induced by cancer drug therapies, propagate in biochemical pathways. Overall, our results indicate that the effective graph provides an enriched description of the structure and dynamics of networked multivariate causal interactions. We demonstrate that it improves explainability, prediction, and control of complex dynamical systems in general and biochemical regulation in particular. 

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3. Efficient and passive learning of networked dynamical systems driven by non-white exogenous inputs

   Harish Doddi, Deepjyoti Deka (May 2022, Proceedings of The 25th International Conference on Artificial Intelligence and Statistics)

   We consider a networked linear dynamical system with p agents/nodes. We study the problem of learning the underlying graph of interactions/dependencies from observations of the nodal trajectories over a time-interval T. We present a regularized non-casual consistent estimator for this problem and analyze its sample complexity over two regimes: (a) where the interval T consists of n i.i.d. observation windows of length T/n (restart and record), and (b) where T is one continuous observation window (consecutive). Using the theory of M-estimators, we show that the estimator recovers the underlying interactions, in either regime, in a time-interval that is logarithmic in the system size p. To the best of our knowledge, this is the first work to analyze the sample complexity of learning linear dynamical systems driven by unobserved not-white wide-sense stationary (WSS) inputs. 

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4. Efficient and passive learning of networked dynamical systems driven by non-white exogenous inputs

   Harish Doddi, Deepjyoti Deka (May 2022, Proceedings of The 25th International Conference on Artificial Intelligence and Statistics)

   We consider a networked linear dynamical system with p agents/nodes. We study the problem of learning the underlying graph of interactions/dependencies from observations of the nodal trajectories over a time-interval T. We present a regularized non-casual consistent estimator for this problem and analyze its sample complexity over two regimes: (a) where the interval T consists of n i.i.d. observation windows of length T/n (restart and record), and (b) where T is one continuous observation window (consecutive). Using the theory of M-estimators, we show that the estimator recovers the underlying interactions, in either regime, in a time-interval that is logarithmic in the system size p. To the best of our knowledge, this is the first work to analyze the sample complexity of learning linear dynamical systems driven by unobserved not-white wide-sense stationary (WSS) inputs. 

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5. Minimax rates for heterogeneous causal effect estimation

   https://doi.org/10.1214/24-AOS2369  

   Kennedy, Edward H; Balakrishnan, Sivaraman; Robins, James M; Wasserman, Larry (April 2024, The Annals of Statistics)

   Estimation of heterogeneous causal effects—that is, how effects of policies and treatments vary across subjects—is a fundamental task in causal inference. Many methods for estimating conditional average treatment effects (CATEs) have been proposed in recent years, but questions surrounding optimality have remained largely unanswered. In particular, a minimax theory of optimality has yet to be developed, with the minimax rate of convergence and construction of rate-optimal estimators remaining open problems. In this paper, we derive the minimax rate for CATE estimation, in a Hölder-smooth nonparametric model, and present a new local polynomial estimator, giving high-level conditions under which it is minimax optimal. Our minimax lower bound is derived via a localized version of the method of fuzzy hypotheses, combining lower bound constructions for nonparametric regression and functional estimation. Our proposed estimator can be viewed as a local polynomial R-Learner, based on a localized modification of higher-order influence function methods. The minimax rate we find exhibits several interesting features, including a nonstandard elbow phenomenon and an unusual interpolation between nonparametric regression and functional estimation rates. The latter quantifies how the CATE, as an estimand, can be viewed as a regression/functional hybrid. 

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