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Caroline Uhler

Publications and source records attributed to Caroline Uhler.

At least 37 records · Page 2Linked to original sources
arXiv2024

Causal Imputation for Counterfactual SCMs: Bridging Graphs and Latent Factor Models

We consider the task of causal imputation, where we aim to predict the outcomes of some set of actions across a wide range of possible contexts. As a running example, we consider predicting how different drugs affect cells from different cell types. We study the index-only setting, where the actions and contexts are categorical variables with a finite number of possible values. Even in this simple setting, a practical challenge arises, since often only a small subset of possible action-context pairs have been studied. Thus, models must extrapolate to novel action-context pairs, which can be framed as a form of matrix completion with rows indexed by actions, columns indexed by contexts, and matrix entries corresponding to outcomes. We introduce a novel SCM-based model class, where the outcome is expressed as a counterfactual, actions are expressed as interventions on an instrumental variable, and contexts are defined based on the initial state of the system. We show that, under a linearity assumption, this setup induces a latent factor model over the matrix of outcomes, with an additional fixed effect term. To perform causal prediction based on this model class, we introduce simple extension to the Synthetic Interventions estimator (Agarwal et al., 2020). We evaluate several matrix completion approaches on the PRISM drug repurposing dataset, showing that our method outperforms all other considered matrix completion approaches.

stat.ML↗
arXiv2024

Causal Discovery under Off-Target Interventions

Causal graph discovery is a significant problem with applications across various disciplines. However, with observational data alone, the underlying causal graph can only be recovered up to its Markov equivalence class, and further assumptions or interventions are necessary to narrow down the true graph. This work addresses the causal discovery problem under the setting of stochastic interventions with the natural goal of minimizing the number of interventions performed. We propose the following stochastic intervention model which subsumes existing adaptive noiseless interventions in the literature while capturing scenarios such as fat-hand interventions and CRISPR gene knockouts: any intervention attempt results in an actual intervention on a random subset of vertices, drawn from a distribution dependent on attempted action. Under this model, we study the two fundamental problems in causal discovery of verification and search and provide approximation algorithms with polylogarithmic competitive ratios and provide some preliminary experimental results.

cs.LG↗
arXiv2023

Unsupervised Protein-Ligand Binding Energy Prediction via Neural Euler's Rotation Equation

Protein-ligand binding prediction is a fundamental problem in AI-driven drug discovery. Prior work focused on supervised learning methods using a large set of binding affinity data for small molecules, but it is hard to apply the same strategy to other drug classes like antibodies as labelled data is limited. In this paper, we explore unsupervised approaches and reformulate binding energy prediction as a generative modeling task. Specifically, we train an energy-based model on a set of unlabelled protein-ligand complexes using SE(3) denoising score matching and interpret its log-likelihood as binding affinity. Our key contribution is a new equivariant rotation prediction network called Neural Euler's Rotation Equations (NERE) for SE(3) score matching. It predicts a rotation by modeling the force and torque between protein and ligand atoms, where the force is defined as the gradient of an energy function with respect to atom coordinates. We evaluate NERE on protein-ligand and antibody-antigen binding affinity prediction benchmarks. Our model outperforms all unsupervised baselines (physics-based and statistical potentials) and matches supervised learning methods in the antibody case.

q-bio.BM↗
arXiv2023

Removing Biases from Molecular Representations via Information Maximization

High-throughput drug screening -- using cell imaging or gene expression measurements as readouts of drug effect -- is a critical tool in biotechnology to assess and understand the relationship between the chemical structure and biological activity of a drug. Since large-scale screens have to be divided into multiple experiments, a key difficulty is dealing with batch effects, which can introduce systematic errors and non-biological associations in the data. We propose InfoCORE, an Information maximization approach for COnfounder REmoval, to effectively deal with batch effects and obtain refined molecular representations. InfoCORE establishes a variational lower bound on the conditional mutual information of the latent representations given a batch identifier. It adaptively reweighs samples to equalize their implied batch distribution. Extensive experiments on drug screening data reveal InfoCORE's superior performance in a multitude of tasks including molecular property prediction and molecule-phenotype retrieval. Additionally, we show results for how InfoCORE offers a versatile framework and resolves general distribution shifts and issues of data fairness by minimizing correlation with spurious features or removing sensitive attributes. The code is available at https://github.com/uhlerlab/InfoCORE.

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arXiv2023

Identifiability Guarantees for Causal Disentanglement from Soft Interventions

Causal disentanglement aims to uncover a representation of data using latent variables that are interrelated through a causal model. Such a representation is identifiable if the latent model that explains the data is unique. In this paper, we focus on the scenario where unpaired observational and interventional data are available, with each intervention changing the mechanism of a latent variable. When the causal variables are fully observed, statistically consistent algorithms have been developed to identify the causal model under faithfulness assumptions. We here show that identifiability can still be achieved with unobserved causal variables, given a generalized notion of faithfulness. Our results guarantee that we can recover the latent causal model up to an equivalence class and predict the effect of unseen combinations of interventions, in the limit of infinite data. We implement our causal disentanglement framework by developing an autoencoding variational Bayes algorithm and apply it to the problem of predicting combinatorial perturbation effects in genomics.

stat.ML↗
arXiv2023

Meek Separators and Their Applications in Targeted Causal Discovery

Learning causal structures from interventional data is a fundamental problem with broad applications across various fields. While many previous works have focused on recovering the entire causal graph, in practice, there are scenarios where learning only part of the causal graph suffices. This is called $targeted$ causal discovery. In our work, we focus on two such well-motivated problems: subset search and causal matching. We aim to minimize the number of interventions in both cases. Towards this, we introduce the $Meek~separator$, which is a subset of vertices that, when intervened, decomposes the remaining unoriented edges into smaller connected components. We then present an efficient algorithm to find Meek separators that are of small sizes. Such a procedure is helpful in designing various divide-and-conquer-based approaches. In particular, we propose two randomized algorithms that achieve logarithmic approximation for subset search and causal matching, respectively. Our results provide the first known average-case provable guarantees for both problems. We believe that this opens up possibilities to design near-optimal methods for many other targeted causal structure learning problems arising from various applications.

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arXiv2023

Unpaired Multi-Domain Causal Representation Learning

The goal of causal representation learning is to find a representation of data that consists of causally related latent variables. We consider a setup where one has access to data from multiple domains that potentially share a causal representation. Crucially, observations in different domains are assumed to be unpaired, that is, we only observe the marginal distribution in each domain but not their joint distribution. In this paper, we give sufficient conditions for identifiability of the joint distribution and the shared causal graph in a linear setup. Identifiability holds if we can uniquely recover the joint distribution and the shared causal representation from the marginal distributions in each domain. We transform our identifiability results into a practical method to recover the shared latent causal graph.

stat.ML↗
arXiv2023

Active Learning for Optimal Intervention Design in Causal Models

Sequential experimental design to discover interventions that achieve a desired outcome is a key problem in various domains including science, engineering and public policy. When the space of possible interventions is large, making an exhaustive search infeasible, experimental design strategies are needed. In this context, encoding the causal relationships between the variables, and thus the effect of interventions on the system, is critical for identifying desirable interventions more efficiently. Here, we develop a causal active learning strategy to identify interventions that are optimal, as measured by the discrepancy between the post-interventional mean of the distribution and a desired target mean. The approach employs a Bayesian update for the causal model and prioritizes interventions using a carefully designed, causally informed acquisition function. This acquisition function is evaluated in closed form, allowing for fast optimization. The resulting algorithms are theoretically grounded with information-theoretic bounds and provable consistency results for linear causal models with known causal graph. We apply our approach to both synthetic data and single-cell transcriptomic data from Perturb-CITE-seq experiments to identify optimal perturbations that induce a specific cell state transition. The causally informed acquisition function generally outperforms existing criteria allowing for optimal intervention design with fewer but carefully selected samples.

cs.LG↗
arXiv2023

The DeCAMFounder: Non-Linear Causal Discovery in the Presence of Hidden Variables

Many real-world decision-making tasks require learning causal relationships between a set of variables. Traditional causal discovery methods, however, require that all variables are observed, which is often not feasible in practical scenarios. Without additional assumptions about the unobserved variables, it is not possible to recover any causal relationships from observational data. Fortunately, in many applied settings, additional structure among the confounders can be expected. In particular, pervasive confounding is commonly encountered and has been utilized for consistent causal estimation in linear causal models. In this paper, we present a provably consistent method to estimate causal relationships in the non-linear, pervasive confounding setting. The core of our procedure relies on the ability to estimate the confounding variation through a simple spectral decomposition of the observed data matrix. We derive a DAG score function based on this insight, prove its consistency in recovering a correct ordering of the DAG, and empirically compare it to previous approaches. We demonstrate improved performance on both simulated and real datasets by explicitly accounting for both confounders and non-linear effects.

stat.ME↗
arXiv2023

Causal Imputation via Synthetic Interventions

Consider the problem of determining the effect of a compound on a specific cell type. To answer this question, researchers traditionally need to run an experiment applying the drug of interest to that cell type. This approach is not scalable: given a large number of different actions (compounds) and a large number of different contexts (cell types), it is infeasible to run an experiment for every action-context pair. In such cases, one would ideally like to predict the outcome for every pair while only having to perform experiments on a small subset of pairs. This task, which we label "causal imputation", is a generalization of the causal transportability problem. To address this challenge, we extend the recently introduced synthetic interventions (SI) estimator to handle more general data sparsity patterns. We prove that, under a latent factor model, our estimator provides valid estimates for the causal imputation task. We motivate this model by establishing a connection to the linear structural causal model literature. Finally, we consider the prominent CMAP dataset in predicting the effects of compounds on gene expression across cell types. We find that our estimator outperforms standard baselines, thus confirming its utility in biological applications.

stat.ME↗
arXiv2023

Linear Causal Disentanglement via Interventions

Causal disentanglement seeks a representation of data involving latent variables that relate to one another via a causal model. A representation is identifiable if both the latent model and the transformation from latent to observed variables are unique. In this paper, we study observed variables that are a linear transformation of a linear latent causal model. Data from interventions are necessary for identifiability: if one latent variable is missing an intervention, we show that there exist distinct models that cannot be distinguished. Conversely, we show that a single intervention on each latent variable is sufficient for identifiability. Our proof uses a generalization of the RQ decomposition of a matrix that replaces the usual orthogonal and upper triangular conditions with analogues depending on a partial order on the rows of the matrix, with partial order determined by a latent causal model. We corroborate our theoretical results with a method for causal disentanglement that accurately recovers a latent causal model.

stat.ML↗
arXiv2023

Positivity in Linear Gaussian Structural Equation Models

We study a notion of positivity of Gaussian directed acyclic graphical models corresponding to a non-negativity constraint on the coefficients of the associated structural equation model. We prove that this constraint is equivalent to the distribution being conditionally increasing in sequence (CIS), a well-known subclass of positively associated random variables. These distributions require knowledge of a permutation, a CIS ordering, of the nodes for which the constraint of non-negativity holds. We provide an algorithm and prove in the noise-less setting that a CIS ordering can be recovered when it exists. We extend this result to the noisy setting and provide assumptions for recovering the CIS orderings. In addition, we provide a characterization of Markov equivalence for CIS DAG models. Further, we show that when a CIS ordering is known, the corresponding class of Gaussians lies in a family of distributions in which maximum likelihood estimation is a convex problem.

math.ST↗
arXiv2022

Causal Structure Learning: a Combinatorial Perspective

In this review, we discuss approaches for learning causal structure from data, also called causal discovery. In particular, we focus on approaches for learning directed acyclic graphs (DAGs) and various generalizations which allow for some variables to be unobserved in the available data. We devote special attention to two fundamental combinatorial aspects of causal structure learning. First, we discuss the structure of the search space over causal graphs. Second, we discuss the structure of equivalence classes over causal graphs, i.e., sets of graphs which represent what can be learned from observational data alone, and how these equivalence classes can be refined by adding interventional data.

stat.ME↗
arXiv2022

Maximum Likelihood Estimation for Brownian Motion Tree Models Based on One Sample

We study the problem of maximum likelihood estimation given one data sample ($n=1$) over Brownian Motion Tree Models (BMTMs), a class of Gaussian models on trees. BMTMs are often used as a null model in phylogenetics, where the one-sample regime is common. Specifically, we show that, almost surely, the one-sample BMTM maximum likelihood estimator (MLE) exists, is unique, and corresponds to a fully observed tree. Moreover, we provide a polynomial time algorithm for its exact computation. We also consider the MLE over all possible BMTM tree structures in the one-sample case and show that it exists almost surely, that it coincides with the MLE over diagonally dominant M-matrices, and that it admits a unique closed-form solution that corresponds to a path graph. Finally, we explore statistical properties of the one-sample BMTM MLE through numerical experiments.

stat.ME↗
arXiv2022

Transfer Learning with Kernel Methods

Transfer learning refers to the process of adapting a model trained on a source task to a target task. While kernel methods are conceptually and computationally simple machine learning models that are competitive on a variety of tasks, it has been unclear how to perform transfer learning for kernel methods. In this work, we propose a transfer learning framework for kernel methods by projecting and translating the source model to the target task. We demonstrate the effectiveness of our framework in applications to image classification and virtual drug screening. In particular, we show that transferring modern kernels trained on large-scale image datasets can result in substantial performance increase as compared to using the same kernel trained directly on the target task. In addition, we show that transfer-learned kernels allow a more accurate prediction of the effect of drugs on cancer cell lines. For both applications, we identify simple scaling laws that characterize the performance of transfer-learned kernels as a function of the number of target examples. We explain this phenomenon in a simplified linear setting, where we are able to derive the exact scaling laws. By providing a simple and effective transfer learning framework for kernel methods, our work enables kernel methods trained on large datasets to be easily adapted to a variety of downstream target tasks.

cs.LG↗
arXiv2022

Geometry of Log-Concave Density Estimation

Shape-constrained density estimation is an important topic in mathematical statistics. We focus on densities on $\mathbb{R}^d$ that are log-concave, and we study geometric properties of the maximum likelihood estimator (MLE) for weighted samples. Cule, Samworth, and Stewart showed that the logarithm of the optimal log-concave density is piecewise linear and supported on a regular subdivision of the samples. This defines a map from the space of weights to the set of regular subdivisions of the samples, i.e. the face poset of their secondary polytope. We prove that this map is surjective. In fact, every regular subdivision arises in the MLE for some set of weights with positive probability, but coarser subdivisions appear to be more likely to arise than finer ones. To quantify these results, we introduce a continuous version of the secondary polytope, whose dual we name the Samworth body. This article establishes a new link between geometric combinatorics and nonparametric statistics, and it suggests numerous open problems.

stat.ME↗
arXiv2022

Causal Structure Discovery between Clusters of Nodes Induced by Latent Factors

We consider the problem of learning the structure of a causal directed acyclic graph (DAG) model in the presence of latent variables. We define latent factor causal models (LFCMs) as a restriction on causal DAG models with latent variables, which are composed of clusters of observed variables that share the same latent parent and connections between these clusters given by edges pointing from the observed variables to latent variables. LFCMs are motivated by gene regulatory networks, where regulatory edges, corresponding to transcription factors, connect spatially clustered genes. We show identifiability results on this model and design a consistent three-stage algorithm that discovers clusters of observed nodes, a partial ordering over clusters, and finally, the entire structure over both observed and latent nodes. We evaluate our method in a synthetic setting, demonstrating its ability to almost perfectly recover the ground truth clustering even at relatively low sample sizes, as well as the ability to recover a significant number of the edges from observed variables to latent factors. Finally, we apply our method in a semi-synthetic setting to protein mass spectrometry data with a known ground truth network, and achieve almost perfect recovery of the ground truth variable clusters.

stat.ME↗
arXiv2022

Wide and Deep Neural Networks Achieve Optimality for Classification

While neural networks are used for classification tasks across domains, a long-standing open problem in machine learning is determining whether neural networks trained using standard procedures are optimal for classification, i.e., whether such models minimize the probability of misclassification for arbitrary data distributions. In this work, we identify and construct an explicit set of neural network classifiers that achieve optimality. Since effective neural networks in practice are typically both wide and deep, we analyze infinitely wide networks that are also infinitely deep. In particular, using the recent connection between infinitely wide neural networks and Neural Tangent Kernels, we provide explicit activation functions that can be used to construct networks that achieve optimality. Interestingly, these activation functions are simple and easy to implement, yet differ from commonly used activations such as ReLU or sigmoid. More generally, we create a taxonomy of infinitely wide and deep networks and show that these models implement one of three well-known classifiers depending on the activation function used: (1) 1-nearest neighbor (model predictions are given by the label of the nearest training example); (2) majority vote (model predictions are given by the label of the class with greatest representation in the training set); or (3) singular kernel classifiers (a set of classifiers containing those that achieve optimality). Our results highlight the benefit of using deep networks for classification tasks, in contrast to regression tasks, where excessive depth is harmful.

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