arXiv subjects

Wesley Tansey

Publications and source records attributed to Wesley Tansey.

At least 19 recordsLinked to original sources

arXiv2026

ScreenShot: A Foundation Model for Few-Shot Combination Drug Screening

Treating patients with combinations of drugs reduces the risk of resistance to any individual drug. Finding effective combinations is difficult because the large search space makes combinatorial screens prohibitively expensive, time consuming, and often technically infeasible. Predictive models can fill this gap, yet existing methods typically require molecular profiling of each sample and per-cohort training, limiting their applicability when time and tissue are scarce. To address this challenge, we introduce ScreenShot, a hierarchical transformer pretrained on 40 drug screening datasets covering 3,700 drugs and 6,000 biological samples, whose architecture mirrors the nested structure of screening data. Given a few-shot context of observations from a new patient, ScreenShot predicts the response of the sample to combination therapies through in-context learning, operating directly on functional measurements with no fine-tuning and no molecular profiling. On four held-out datasets, ScreenShot outperforms all baselines in both prediction accuracy and identification of selectively effective treatments. ScreenShot's internal representations are directly useful for experimental design: we use them to drive a weighted k-means++ active learning strategy that selects which experiments to run, achieving the same hit detection as uniform screening with a third of the budget. Source code and interactive dashboard: https://github.com/tansey-lab/screenshot.

cs.LG↗

arXiv2026

Empirically Calibrated Conditional Independence Tests

Conditional independence tests (CIT) are widely used for causal discovery and feature selection. Even with false discovery rate (FDR) control procedures, they often fail to provide frequentist guarantees in practice. We highlight two common failure modes: (i) in small samples, asymptotic guarantees for many CITs can be inaccurate and even correctly specified models fail to estimate the noise levels and control the error, and (ii) when sample sizes are large but models are misspecified, unaccounted dependencies skew the test's behavior and fail to return uniform p-values under the null. We propose Empirically Calibrated Conditional Independence Tests (ECCIT), a method that measures and corrects for miscalibration. For a chosen base CIT (e.g., GCM, HRT), ECCIT optimizes an adversary that selects features and response functions to maximize a miscalibration metric. ECCIT then fits a monotone calibration map that adjusts the base-test p-values in proportion to the observed miscalibration. Across empirical benchmarks on synthetic and real data, ECCIT achieves valid FDR with higher power than existing calibration strategies while remaining test agnostic.

stat.ME↗

arXiv2025

Distilled Protein Backbone Generation

Diffusion- and flow-based generative models have recently demonstrated strong performance in protein backbone generation tasks, offering unprecedented capabilities for de novo protein design. However, while achieving notable performance in generation quality, these models are limited by their generating speed, often requiring hundreds of iterative steps in the reverse-diffusion process. This computational bottleneck limits their practical utility in large-scale protein discovery, where thousands to millions of candidate structures are needed. To address this challenge, we explore the techniques of score distillation, which has shown great success in reducing the number of sampling steps in the vision domain while maintaining high generation quality. However, a straightforward adaptation of these methods results in unacceptably low designability. Through extensive study, we have identified how to appropriately adapt Score identity Distillation (SiD), a state-of-the-art score distillation strategy, to train few-step protein backbone generators which significantly reduce sampling time, while maintaining comparable performance to their pretrained teacher model. In particular, multistep generation combined with inference time noise modulation is key to the success. We demonstrate that our distilled few-step generators achieve more than a 20-fold improvement in sampling speed, while achieving similar levels of designability, diversity, and novelty as the Proteina teacher model. This reduction in inference cost enables large-scale in silico protein design, thereby bringing diffusion-based models closer to real-world protein engineering applications. The PyTorch implementation is available at https://github.com/LY-Xie/SiD_Protein

cs.LG↗

arXiv2025

A Hierarchical Variational Graph Fused Lasso for Recovering Relative Rates in Spatial Compositional Data

The analysis of spatial data from biological imaging technology, such as imaging mass spectrometry (IMS) or imaging mass cytometry (IMC), is challenging because of a competitive sampling process which convolves signals from molecules in a single pixel. To address this, we develop a scalable Bayesian framework that leverages natural sparsity in spatial signal patterns to recover relative rates for each molecule across the entire image. Our method relies on the use of a heavy-tailed variant of the graphical lasso prior and a novel hierarchical variational family, enabling efficient inference via automatic differentiation variational inference. Simulation results show that our approach outperforms state-of-the-practice point estimate methodologies in IMS, and has superior posterior coverage than mean-field variational inference techniques. Results on real IMS data demonstrate that our approach better recovers the true anatomical structure of known tissue, removes artifacts, and detects active regions missed by the standard analysis approach.

stat.ML↗

arXiv2025

Addressing the Cold-Start Problem for Personalized Combination Drug Screening

Personalizing combination therapies in oncology requires navigating an immense space of possible drug and dose combinations, a task that remains largely infeasible through exhaustive experimentation. Recent developments in patient-derived models have enabled high-throughput ex vivo screening, but the number of feasible experiments is limited. Further, a tight therapeutic window makes gathering molecular profiling information (e.g. RNA-seq) impractical as a means of guiding drug response prediction. This leads to a challenging cold-start problem: how do we select the most informative combinations to test early, when no prior information about the patient is available? We propose a strategy that leverages a pretrained deep learning model built on historical drug response data. The model provides both embeddings for drug combinations and dose-level importance scores, enabling a principled selection of initial experiments. We combine clustering of drug embeddings to ensure functional diversity with a dose-weighting mechanism that prioritizes doses based on their historical informativeness. Retrospective simulations on large-scale drug combination datasets show that our method substantially improves initial screening efficiency compared to baselines, offering a viable path for more effective early-phase decision-making in personalized combination drug screens.

cs.LG↗

arXiv2025

Controllable diffusion-based generation for multi-channel biological data

Spatial profiling technologies in biology, such as imaging mass cytometry (IMC) and spatial transcriptomics (ST), generate high-dimensional, multi-channel data with strong spatial alignment and complex inter-channel relationships. Generative modeling of such data requires jointly capturing intra- and inter-channel structure, while also generalizing across arbitrary combinations of observed and missing channels for practical application. Existing diffusion-based models generally assume low-dimensional inputs (e.g., RGB images) and rely on simple conditioning mechanisms that break spatial correspondence and ignore inter-channel dependencies. This work proposes a unified diffusion framework for controllable generation over structured and spatial biological data. Our model contains two key innovations: (1) a hierarchical feature injection mechanism that enables multi-resolution conditioning on spatially aligned channels, and (2) a combination of latent-space and output-space channel-wise attention to capture inter-channel relationships. To support flexible conditioning and generalization to arbitrary subsets of observed channels, we train the model using a random masking strategy, enabling it to reconstruct missing channels from any combination of inputs. We demonstrate state-of-the-art performance across both spatial and non-spatial prediction tasks, including protein imputation in IMC and gene-to-protein prediction in single-cell datasets, and show strong generalization to unseen conditional configurations.

cs.LG↗

arXiv2025

Treatment response as a latent variable

Scientists often need to analyze the samples in a study that responded to treatment in order to refine their hypotheses and find potential causal drivers of response. Natural variation in outcomes makes teasing apart responders from non-responders a statistical inference problem. To handle latent responses, we introduce the causal two-groups (C2G) model, a causal extension of the classical two-groups model. The C2G model posits that treated samples may or may not experience an effect, according to some prior probability. We propose two empirical Bayes procedures for the causal two-groups model, one under semi-parametric conditions and another under fully nonparametric conditions. The semi-parametric model assumes additive treatment effects and is identifiable from observed data. The nonparametric model is unidentifiable, but we show it can still be used to test for response in each treated sample. We show empirically and theoretically that both methods for selecting responders control the false discovery rate at the target level with near-optimal power. We also propose two novel estimands of interest and provide a strategy for deriving estimand intervals in the unidentifiable nonparametric model. On a cancer immunotherapy dataset, the nonparametric C2G model recovers clinically-validated predictive biomarkers of both positive and negative outcomes. Code is available at https://github.com/tansey-lab/causal2groups.

stat.ME↗

arXiv2023

Scalable Causal Structure Learning via Amortized Conditional Independence Testing

Controlling false positives (Type I errors) through statistical hypothesis testing is a foundation of modern scientific data analysis. Existing causal structure discovery algorithms either do not provide Type I error control or cannot scale to the size of modern scientific datasets. We consider a variant of the causal discovery problem with two sets of nodes, where the only edges of interest form a bipartite causal subgraph between the sets. We develop Scalable Causal Structure Learning (SCSL), a method for causal structure discovery on bipartite subgraphs that provides Type I error control. SCSL recasts the discovery problem as a simultaneous hypothesis testing problem and uses discrete optimization over the set of possible confounders to obtain an upper bound on the test statistic for each edge. Semi-synthetic simulations demonstrate that SCSL scales to handle graphs with hundreds of nodes while maintaining error control and good power. We demonstrate the practical applicability of the method by applying it to a cancer dataset to reveal connections between somatic gene mutations and metastases to different tissues.

stat.ME↗

arXiv2023

DIET: Conditional independence testing with marginal dependence measures of residual information

Conditional randomization tests (CRTs) assess whether a variable $x$ is predictive of another variable $y$, having observed covariates $z$. CRTs require fitting a large number of predictive models, which is often computationally intractable. Existing solutions to reduce the cost of CRTs typically split the dataset into a train and test portion, or rely on heuristics for interactions, both of which lead to a loss in power. We propose the decoupled independence test (DIET), an algorithm that avoids both of these issues by leveraging marginal independence statistics to test conditional independence relationships. DIET tests the marginal independence of two random variables: $F(x \mid z)$ and $F(y \mid z)$ where $F(\cdot \mid z)$ is a conditional cumulative distribution function (CDF). These variables are termed "information residuals." We give sufficient conditions for DIET to achieve finite sample type-1 error control and power greater than the type-1 error rate. We then prove that when using the mutual information between the information residuals as a test statistic, DIET yields the most powerful conditionally valid test. Finally, we show DIET achieves higher power than other tractable CRTs on several synthetic and real benchmarks.

stat.ME↗

arXiv2022

Targeted active learning for probabilistic models

A fundamental task in science is to design experiments that yield valuable insights about the system under study. Mathematically, these insights can be represented as a utility or risk function that shapes the value of conducting each experiment. We present PDBAL, a targeted active learning method that adaptively designs experiments to maximize scientific utility. PDBAL takes a user-specified risk function and combines it with a probabilistic model of the experimental outcomes to choose designs that rapidly converge on a high-utility model. We prove theoretical bounds on the label complexity of PDBAL and provide fast closed-form solutions for designing experiments with common exponential family likelihoods. In simulation studies, PDBAL consistently outperforms standard untargeted approaches that focus on maximizing expected information gain over the design space. Finally, we demonstrate the scientific potential of PDBAL through a study on a large cancer drug screen dataset where PDBAL quickly recovers the most efficacious drugs with a small fraction of the total number of experiments.

cs.LG↗

arXiv2021

The Holdout Randomization Test for Feature Selection in Black Box Models

We propose the holdout randomization test (HRT), an approach to feature selection using black box predictive models. The HRT is a specialized version of the conditional randomization test (CRT; Candes et al., 2018) that uses data splitting for feasible computation. The HRT works with any predictive model and produces a valid $p$-value for each feature. To make the HRT more practical, we propose a set of extensions to maximize power and speed up computation. In simulations, these extensions lead to greater power than a competing knockoffs-based approach, without sacrificing control of the error rate. We apply the HRT to two case studies from the scientific literature where heuristics were originally used to select important features for predictive models. The results illustrate how such heuristics can be misleading relative to principled methods like the HRT. Code is available at https://github.com/tansey/hrt.

stat.ME↗

arXiv2021

A Bayesian Model of Dose-Response for Cancer Drug Studies

Exploratory cancer drug studies test multiple tumor cell lines against multiple candidate drugs. The goal in each paired (cell line, drug) experiment is to map out the dose-response curve of the cell line as the dose level of the drug increases. We propose Bayesian Tensor Filtering (BTF), a hierarchical Bayesian model for dose-response modeling in multi-sample, multi-treatment cancer drug studies. BTF uses low-dimensional embeddings to share statistical strength between similar drugs and similar cell lines. Structured shrinkage priors in BTF encourage smoothness in the dose-response curves while remaining adaptive to sharp jumps when the data call for it. We focus on a pair of cancer drug studies exhibiting a particular pathology in their experimental design, leading us to a non-conjugate monotone mixture-of-Gammas likelihood. To perform posterior inference, we develop a variant of the elliptical slice sampling algorithm for sampling from linearly-constrained multivariate normal priors with non-conjugate likelihoods. In benchmarks, BTF outperforms state-of-the-art methods for covariance regression and dynamic Poisson matrix factorization. On the two cancer drug studies, BTF outperforms the current standard approach in biology and reveals potential new biomarkers of drug sensitivity in cancer. Code is available at https://github.com/tansey/functionalmf.

stat.ML↗

arXiv2021

Smoothed Nested Testing on Directed Acyclic Graphs

We consider the problem of multiple hypothesis testing when there is a logical nested structure to the hypotheses. When one hypothesis is nested inside another, the outer hypothesis must be false if the inner hypothesis is false. We model the nested structure as a directed acyclic graph, including chain and tree graphs as special cases. Each node in the graph is a hypothesis and rejecting a node requires also rejecting all of its ancestors. We propose a general framework for adjusting node-level test statistics using the known logical constraints. Within this framework, we study a smoothing procedure that combines each node with all of its descendants to form a more powerful statistic. We prove a broad class of smoothing strategies can be used with existing selection procedures to control the familywise error rate, false discovery exceedance rate, or false discovery rate, so long as the original test statistics are independent under the null. When the null statistics are not independent but are derived from positively-correlated normal observations, we prove control for all three error rates when the smoothing method is arithmetic averaging of the observations. Simulations and an application to a real biology dataset demonstrate that smoothing leads to substantial power gains.

stat.ME↗

arXiv2020

Quantile regression with deep ReLU Networks: Estimators and minimax rates

Quantile regression is the task of estimating a specified percentile response, such as the median, from a collection of known covariates. We study quantile regression with rectified linear unit (ReLU) neural networks as the chosen model class. We derive an upper bound on the expected mean squared error of a ReLU network used to estimate any quantile conditional on a set of covariates. This upper bound only depends on the best possible approximation error, the number of layers in the network, and the number of nodes per layer. We further show upper bounds that are tight for two large classes of functions: compositions of Hölder functions and members of a Besov space. These tight bounds imply ReLU networks with quantile regression achieve minimax rates for broad collections of function types. Unlike existing work, the theoretical results hold under minimal assumptions and apply to general error distributions, including heavy-tailed distributions. Empirical simulations on a suite of synthetic response functions demonstrate the theoretical results translate to practical implementations of ReLU networks. Overall, the theoretical and empirical results provide insight into the strong performance of ReLU neural networks for quantile regression across a broad range of function classes and error distributions. All code for this paper is publicly available at https://github.com/tansey/quantile-regression.

math.ST↗

arXiv2020

Interpreting Black Box Models via Hypothesis Testing

In science and medicine, model interpretations may be reported as discoveries of natural phenomena or used to guide patient treatments. In such high-stakes tasks, false discoveries may lead investigators astray. These applications would therefore benefit from control over the finite-sample error rate of interpretations. We reframe black box model interpretability as a multiple hypothesis testing problem. The task is to discover "important" features by testing whether the model prediction is significantly different from what would be expected if the features were replaced with uninformative counterfactuals. We propose two testing methods: one that provably controls the false discovery rate but which is not yet feasible for large-scale applications, and an approximate testing method which can be applied to real-world data sets. In simulation, both tests have high power relative to existing interpretability methods. When applied to state-of-the-art vision and language models, the framework selects features that intuitively explain model predictions. The resulting explanations have the additional advantage that they are themselves easy to interpret.

stat.ML↗

arXiv2020

Deep Direct Likelihood Knockoffs

Predictive modeling often uses black box machine learning methods, such as deep neural networks, to achieve state-of-the-art performance. In scientific domains, the scientist often wishes to discover which features are actually important for making the predictions. These discoveries may lead to costly follow-up experiments and as such it is important that the error rate on discoveries is not too high. Model-X knockoffs enable important features to be discovered with control of the FDR. However, knockoffs require rich generative models capable of accurately modeling the knockoff features while ensuring they obey the so-called "swap" property. We develop Deep Direct Likelihood Knockoffs (DDLK), which directly minimizes the KL divergence implied by the knockoff swap property. DDLK consists of two stages: it first maximizes the explicit likelihood of the features, then minimizes the KL divergence between the joint distribution of features and knockoffs and any swap between them. To ensure that the generated knockoffs are valid under any possible swap, DDLK uses the Gumbel-Softmax trick to optimize the knockoff generator under the worst-case swap. We find DDLK has higher power than baselines while controlling the false discovery rate on a variety of synthetic and real benchmarks including a task involving a large dataset from one of the epicenters of COVID-19.

stat.ML↗

arXiv2020

Dose-response modeling in high-throughput cancer drug screenings: An end-to-end approach

Personalized cancer treatments based on the molecular profile of a patient's tumor are an emerging and exciting class of treatments in oncology. As genomic tumor profiling is becoming more common, targeted treatments to specific molecular alterations are gaining traction. To discover new potential therapeutics that may apply to broad classes of tumors matching some molecular pattern, experimentalists and pharmacologists rely on high-throughput, in-vitro screens of many compounds against many different cell lines. We propose a hierarchical Bayesian model of how cancer cell lines respond to drugs in these experiments and develop a method for fitting the model to real-world high-throughput screening data. Through a case study, the model is shown to capture nontrivial associations between molecular features and drug response, such as requiring both wild type TP53 and overexpression of MDM2 to be sensitive to Nutlin-3(a). In quantitative benchmarks, the model outperforms a standard approach in biology, with ~20% lower predictive error on held out data. When combined with a conditional randomization testing procedure, the model discovers biomarkers of therapeutic response that recapitulate known biology and suggest new avenues for investigation. All code for the paper is publicly available at https://github.com/tansey/deep-dose-response.

stat.AP↗

arXiv2018

Black Box FDR

Analyzing large-scale, multi-experiment studies requires scientists to test each experimental outcome for statistical significance and then assess the results as a whole. We present Black Box FDR (BB-FDR), an empirical-Bayes method for analyzing multi-experiment studies when many covariates are gathered per experiment. BB-FDR learns a series of black box predictive models to boost power and control the false discovery rate (FDR) at two stages of study analysis. In Stage 1, it uses a deep neural network prior to report which experiments yielded significant outcomes. In Stage 2, a separate black box model of each covariate is used to select features that have significant predictive power across all experiments. In benchmarks, BB-FDR outperforms competing state-of-the-art methods in both stages of analysis. We apply BB-FDR to two real studies on cancer drug efficacy. For both studies, BB-FDR increases the proportion of significant outcomes discovered and selects variables that reveal key genomic drivers of drug sensitivity and resistance in cancer.

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