arXiv subjects

Lorin Crawford

Publications and source records attributed to Lorin Crawford.

16 recordsLinked to original sources

arXiv2026

JASPR: Joint Spatial Representation learning of histology and spatial genomics for improved virtual genomic screening and clinical prognostication

Recent studies have shown that spatial properties of tumors are critical for understanding disease biology and predicting patient outcomes. These spatial properties are increasingly uncovered through complementary modalities: spatial transcriptomics (ST) captures spatially-resolved molecular states, while hematoxylin and eosin-stained whole slide images (HE) reveal tissue morphology. While approaches are emerging to fuse these modalities, effective methods that learn not only joint representations but also incorporate spatial context across modalities are lacking. Here, we present JASPR (Joint Spatial Representation learning), a self-supervised deep learning framework that integrates HE images and ST data through a cross-modal reconstruction objective that incorporates spatial context within HE images and ST profiles. It employs shared modules to capture universal spatial properties across modalities, while modality-specific experts encode features unique to morphological and genomic data. We train and validate JASPR on breast cancer datasets, demonstrating that its learned joint representation substantially improves HE-based prediction of 9,248 genes and provides prognostic value for breast cancer outcomes.

cs.CV↗

arXiv2026

MorphoHELM: A Comprehensive Benchmark for Evaluating Representations for Microscopy-Based Morphology Assays

Microscopy images contain rich information about how cells respond to perturbations, making them essential to applications like drug screening. To quantify images, researchers often use representation extraction methods, and recent years have seen a proliferation of deep learning methods. While measuring the quality of these representations is essential, evaluation remains fragmented, with each proposed model evaluated on different tasks and datasets, using custom pipelines and metrics, making it difficult to fairly compare models. Here, we introduce MorphoHELM, a comprehensive open benchmark for evaluating feature extraction methods for Cell Painting, the most widely-used morphological profiling assay. MorphoHELM consolidates evaluation standards in the field, extends and corrects them to be more robust, and evaluates on the widest range of methods to date. A defining feature of the benchmark is that each task is evaluated at different degrees of batch effects (or technical noise), directly quantifying how the ability of methods to detect biological signal degrades as noise increases. Together, these properties enable MorphoHELM to detect trade-offs between methods, and we demonstrate that models that excel at certain kinds of biological signal are weaker at others. We show that no existing model outperforms classic computer vision analytic strategies across all settings, which remain the strongest general use-case representations. All datasets, code, and evaluation tools are publicly available at https://github.com/microsoft/MorphoHELM.

cs.CV↗

arXiv2026

Multimodal Alignment Improves Generalizability of Genomic Biomarker Prediction in Computational Pathology

Computational pathology models that use digitized histopathology whole-slide images have the potential to become a cost-effective and scalable alternative to molecular assays for the prediction of genomic biomarkers, a key task in precision oncology. However, as new genomic biomarkers are discovered or quantified, large, labeled datasets must be prospectively collected to train new models. To address this challenge, we developed MARBLE, a multimodal contrastive pretraining strategy that integrates structured biomarker knowledge into representation learning of histopathology images. MARBLE aligns histopathology-derived representations with representations of genomic biomarkers generated by a large language model (LLM) and a protein language model (PLM). This biologically informed alignment enables data-efficient generalization to novel, out-of-distribution biomarkers. Using the MSK-IMPACT cohort of over 40,000 patients across multiple biomarker panel versions, we design experiments grounded in real-world data to demonstrate the value of our proposed approach.

q-bio.QM↗

arXiv2025

A Large-Scale Benchmark of Cross-Modal Learning for Histology and Gene Expression in Spatial Transcriptomics

Spatial transcriptomics enables simultaneous measurement of gene expression and tissue morphology, offering unprecedented insights into cellular organization and disease mechanisms. However, the field lacks comprehensive benchmarks for evaluating multimodal learning methods that leverage both histology images and gene expression data. Here, we present HESCAPE, a large-scale benchmark for cross-modal contrastive pretraining in spatial transcriptomics, built on a curated pan-organ dataset spanning 6 different gene panels and 54 donors. We systematically evaluated state-of-the-art image and gene expression encoders across multiple pretraining strategies and assessed their effectiveness on two downstream tasks: gene mutation classification and gene expression prediction. Our benchmark demonstrates that gene expression encoders are the primary determinant of strong representational alignment, and that gene models pretrained on spatial transcriptomics data outperform both those trained without spatial data and simple baseline approaches. However, downstream task evaluation reveals a striking contradiction: while contrastive pretraining consistently improves gene mutation classification performance, it degrades direct gene expression prediction compared to baseline encoders trained without cross-modal objectives. We identify batch effects as a key factor that interferes with effective cross-modal alignment. Our findings highlight the critical need for batch-robust multimodal learning approaches in spatial transcriptomics. To accelerate progress in this direction, we release HESCAPE, providing standardized datasets, evaluation protocols, and benchmarking tools for the community

q-bio.GN↗

arXiv2025

Structural causal influence (SCI) captures the forces of social inequality in models of disease dynamics

Mathematical modeling has played a central role in understanding how infectious disease transmission manifests in populations. These models have demonstrated the importance of key community-level factors in structuring epidemic risk, and are now routinely used in public health for decision support. One barrier to their broader utility is that the existing canon does not often accommodate social inequalities as distinct formal drivers of variability in transmission dynamics. Given decades of evidence supporting the organizational effects of inequalities in structuring society more generally, and infectious disease risk more specifically, addressing this modeling gap is of critical importance. In this study, we build on previous efforts to integrate social forces into computational epidemiology by introducing a metric, the structural causal influence (SCI). The SCI uses causal analysis to provide a measure of the relative vulnerability of sub-communities within a susceptible population, shaped by differences in characteristics such as access to therapy, exposure to disease, and other determinants driven by social forces. We develop our metric in a simple case and apply it to a context of public health importance: Hepatitis C virus in a population of persons who inject drugs. In addition, we demonstrate the flexibility of the SCI using an agent-based model of an infectious disease. Our use of the SCI reveals that, under specific parameters in a multi-community model, the "less vulnerable" community may achieve a basic reproduction number below one, ensuring disease extinction. However, even minimal transmission between communities can increase this number, leading to sustained epidemics within both communities.

q-bio.QM↗

arXiv2024

BetaExplainer: A Probabilistic Method to Explain Graph Neural Networks

Graph neural networks (GNNs) are powerful tools for conducting inference on graph data but are often seen as "black boxes" due to difficulty in extracting meaningful subnetworks driving predictive performance. Many interpretable GNN methods exist, but they cannot quantify uncertainty in edge weights and suffer in predictive accuracy when applied to challenging graph structures. In this work, we proposed BetaExplainer which addresses these issues by using a sparsity-inducing prior to mask unimportant edges during model training. To evaluate our approach, we examine various simulated data sets with diverse real-world characteristics. Not only does this implementation provide a notion of edge importance uncertainty, it also improves upon evaluation metrics for challenging datasets compared to state-of-the art explainer methods.

stat.ML↗

arXiv2024

Randomness of Shapes and Statistical Inference on Shapes via the Smooth Euler Characteristic Transform

In this article, we establish the mathematical foundations for modeling the randomness of shapes and conducting statistical inference on shapes using the smooth Euler characteristic transform. Based on these foundations, we propose two chi-squared statistic-based algorithms for testing hypotheses on random shapes. Simulation studies are presented to validate our mathematical derivations and to compare our algorithms with state-of-the-art methods to demonstrate the utility of our proposed framework. As real applications, we analyze a data set of mandibular molars from four genera of primates and show that our algorithms have the power to detect significant shape differences that recapitulate known morphological variation across suborders. Altogether, our discussions bridge the following fields: algebraic and computational topology, probability theory and stochastic processes, Sobolev spaces and functional analysis, analysis of variance for functional data, and geometric morphometrics.

stat.ME↗

arXiv2023

Should I Stop or Should I Go: Early Stopping with Heterogeneous Populations

Randomized experiments often need to be stopped prematurely due to the treatment having an unintended harmful effect. Existing methods that determine when to stop an experiment early are typically applied to the data in aggregate and do not account for treatment effect heterogeneity. In this paper, we study the early stopping of experiments for harm on heterogeneous populations. We first establish that current methods often fail to stop experiments when the treatment harms a minority group of participants. We then use causal machine learning to develop CLASH, the first broadly-applicable method for heterogeneous early stopping. We demonstrate CLASH's performance on simulated and real data and show that it yields effective early stopping for both clinical trials and A/B tests.

stat.ME↗

arXiv2023

Statistical Inference on Grayscale Images via the Euler-Radon Transform

Tools from topological data analysis have been widely used to represent binary images in many scientific applications. Methods that aim to represent grayscale images (i.e., where pixel intensities instead take on continuous values) have been relatively underdeveloped. In this paper, we introduce the Euler-Radon transform, which generalizes the Euler characteristic transform to grayscale images by using o-minimal structures and Euler integration over definable functions. Coupling the Karhunen-Loeve expansion with our proposed topological representation, we offer hypothesis-testing algorithms based on the chi-squared distribution for detecting significant differences between two groups of grayscale images. We illustrate our framework via extensive numerical experiments and simulations.

stat.ME↗

arXiv2023

A Simple Approach for Local and Global Variable Importance in Nonlinear Regression Models

The ability to interpret machine learning models has become increasingly important as their usage in data science continues to rise. Most current interpretability methods are optimized to work on either (\textit{i}) a global scale, where the goal is to rank features based on their contributions to overall variation in an observed population, or (\textit{ii}) the local level, which aims to detail on how important a feature is to a particular individual in the data set. In this work, a new operator is proposed called the "GlObal And Local Score" (GOALS): a simple \textit{post hoc} approach to simultaneously assess local and global feature variable importance in nonlinear models. Motivated by problems in biomedicine, the approach is demonstrated using Gaussian process regression where the task of understanding how genetic markers are associated with disease progression both within individuals and across populations is of high interest. Detailed simulations and real data analyses illustrate the flexible and efficient utility of GOALS over state-of-the-art variable importance strategies.

stat.ME↗

arXiv2020

Generalizing Variational Autoencoders with Hierarchical Empirical Bayes

Variational Autoencoders (VAEs) have experienced recent success as data-generating models by using simple architectures that do not require significant fine-tuning of hyperparameters. However, VAEs are known to suffer from over-regularization which can lead to failure to escape local maxima. This phenomenon, known as posterior collapse, prevents learning a meaningful latent encoding of the data. Recent methods have mitigated this issue by deterministically moment-matching an aggregated posterior distribution to an aggregate prior. However, abandoning a probabilistic framework (and thus relying on point estimates) can both lead to a discontinuous latent space and generate unrealistic samples. Here we present Hierarchical Empirical Bayes Autoencoder (HEBAE), a computationally stable framework for probabilistic generative models. Our key contributions are two-fold. First, we make gains by placing a hierarchical prior over the encoding distribution, enabling us to adaptively balance the trade-off between minimizing the reconstruction loss function and avoiding over-regularization. Second, we show that assuming a general dependency structure between variables in the latent space produces better convergence onto the mean-field assumption for improved posterior inference. Overall, HEBAE is more robust to a wide-range of hyperparameter initializations than an analogous VAE. Using data from MNIST and CelebA, we illustrate the ability of HEBAE to generate higher quality samples based on FID score than existing autoencoder-based approaches.

stat.ML↗

arXiv2020

Interpreting Deep Neural Networks Through Variable Importance

While the success of deep neural networks (DNNs) is well-established across a variety of domains, our ability to explain and interpret these methods is limited. Unlike previously proposed local methods which try to explain particular classification decisions, we focus on global interpretability and ask a universally applicable question: given a trained model, which features are the most important? In the context of neural networks, a feature is rarely important on its own, so our strategy is specifically designed to leverage partial covariance structures and incorporate variable dependence into feature ranking. Our methodological contributions in this paper are two-fold. First, we propose an effect size analogue for DNNs that is appropriate for applications with highly collinear predictors (ubiquitous in computer vision). Second, we extend the recently proposed "RelATive cEntrality" (RATE) measure (Crawford et al., 2019) to the Bayesian deep learning setting. RATE applies an information theoretic criterion to the posterior distribution of effect sizes to assess feature significance. We apply our framework to three broad application areas: computer vision, natural language processing, and social science.

stat.ML↗

arXiv2019

Predicting Clinical Outcomes in Glioblastoma: An Application of Topological and Functional Data Analysis

Glioblastoma multiforme (GBM) is an aggressive form of human brain cancer that is under active study in the field of cancer biology. Its rapid progression and the relative time cost of obtaining molecular data make other readily-available forms of data, such as images, an important resource for actionable measures in patients. Our goal is to utilize information given by medical images taken from GBM patients in statistical settings. To do this, we design a novel statistic---the smooth Euler characteristic transform (SECT)---that quantifies magnetic resonance images (MRIs) of tumors. Due to its well-defined inner product structure, the SECT can be used in a wider range of functional and nonparametric modeling approaches than other previously proposed topological summary statistics. When applied to a cohort of GBM patients, we find that the SECT is a better predictor of clinical outcomes than both existing tumor shape quantifications and common molecular assays. Specifically, we demonstrate that SECT features alone explain more of the variance in GBM patient survival than gene expression, volumetric features, and morphometric features. The main takeaways from our findings are thus twofold. First, they suggest that images contain valuable information that can play an important role in clinical prognosis and other medical decisions. Second, they show that the SECT is a viable tool for the broader study of medical imaging informatics.

stat.AP↗

arXiv2019

Tropical Sufficient Statistics for Persistent Homology

We show that an embedding in Euclidean space based on tropical geometry generates stable sufficient statistics for barcodes. In topological data analysis, barcodes are multiscale summaries of algebraic topological characteristics that capture the `shape' of data; however, in practice, they have complex structures that make them difficult to use in statistical settings. The sufficiency result presented in this work allows for classical probability distributions to be assumed on the tropical geometric representation of barcodes. This makes a variety of parametric statistical inference methods amenable to barcodes, all while maintaining their initial interpretations. More specifically, we show that exponential family distributions may be assumed, and that likelihood functions for persistent homology may be constructed. We conceptually demonstrate sufficiency and illustrate its utility in persistent homology dimensions 0 and 1 with concrete parametric applications to human immunodeficiency virus and avian influenza data.

math.ST↗

arXiv2018

Variable Prioritization in Nonlinear Black Box Methods: A Genetic Association Case Study

The central aim in this paper is to address variable selection questions in nonlinear and nonparametric regression. Motivated by statistical genetics, where nonlinear interactions are of particular interest, we introduce a novel and interpretable way to summarize the relative importance of predictor variables. Methodologically, we develop the "RelATive cEntrality" (RATE) measure to prioritize candidate genetic variants that are not just marginally important, but whose associations also stem from significant covarying relationships with other variants in the data. We illustrate RATE through Bayesian Gaussian process regression, but the methodological innovations apply to other "black box" methods. It is known that nonlinear models often exhibit greater predictive accuracy than linear models, particularly for phenotypes generated by complex genetic architectures. With detailed simulations and two real data association mapping studies, we show that applying RATE enables an explanation for this improved performance.

stat.ME↗

arXiv2017

Bayesian Approximate Kernel Regression with Variable Selection

Nonlinear kernel regression models are often used in statistics and machine learning because they are more accurate than linear models. Variable selection for kernel regression models is a challenge partly because, unlike the linear regression setting, there is no clear concept of an effect size for regression coefficients. In this paper, we propose a novel framework that provides an effect size analog of each explanatory variable for Bayesian kernel regression models when the kernel is shift-invariant --- for example, the Gaussian kernel. We use function analytic properties of shift-invariant reproducing kernel Hilbert spaces (RKHS) to define a linear vector space that: (i) captures nonlinear structure, and (ii) can be projected onto the original explanatory variables. The projection onto the original explanatory variables serves as an analog of effect sizes. The specific function analytic property we use is that shift-invariant kernel functions can be approximated via random Fourier bases. Based on the random Fourier expansion we propose a computationally efficient class of Bayesian approximate kernel regression (BAKR) models for both nonlinear regression and binary classification for which one can compute an analog of effect sizes. We illustrate the utility of BAKR by examining two important problems in statistical genetics: genomic selection (i.e. phenotypic prediction) and association mapping (i.e. inference of significant variants or loci). State-of-the-art methods for genomic selection and association mapping are based on kernel regression and linear models, respectively. BAKR is the first method that is competitive in both settings.

stat.ME↗