Understanding cellular responses to chemical interventions is critical to the discovery of effective therapeutics. Because individual biological techniques often measure only one axis of cellular response at a time, high-quality multimodal datasets are needed to unlock a holistic understanding of how cells respond to treatments and to advance computational methods that integrate modalities. However, many techniques destroy cells and thus preclude paired measurements, and attempts to match disparate unimodal datasets are often confounded by data being generated in incompatible experimental settings. Here we introduce scGeneScope, a multimodal single‑cell RNA sequencing (scRNA-seq) and Cell Painting microscopy image dataset conditionally paired by chemical treatment, designed to facilitate the development and benchmarking of unimodal, multimodal, and multiple profile machine learning methods for cellular profiling. 28 chemicals, each acting on distinct biological pathways or mechanisms of action (MoAs), were applied to U2-OS cells in two experimental data generation rounds, creating paired sets of replicates that were then profiled independently by scRNA‑seq or Cell Painting. Using scGeneScope, we derive a replicate- and experiment-split treatment identification benchmark simulating MoA discovery under realistic laboratory variability conditions and evaluate unimodal, multimodal, and multiprofile models ranging in complexity from linear approaches to recent foundation models. Multiprofile integration improved performance in both the unimodal and multimodal settings, with gains more consistent in the former. Evaluation of unimodal models for MoA identification demonstrated that recent scRNA-seq foundation models deployed zero-shot were consistently outperformed by classic fit-to-data methods, underscoring the need for careful, realistic benchmarking in machine learning for biology. We release the scGeneScope dataset and benchmarking code to support further research.

Large Language Models (LLMs) have demonstrated remarkable proficiency in understanding and generating natural language. However, their capabilities wane in highly specialized domains underrepresented in the pretraining corpus, such as physical and biomedical sciences. This work explores how to repurpose general LLMs into effective task solvers for specialized domains. We introduce a novel, model-agnostic framework for learning custom input tags, which are parameterized as continuous vectors appended to the LLM’s embedding layer, to condition the LLM. We design two types of input tags: domain tags are used to delimit specialized representations (e.g., chemical formulas) and provide domain-relevant context; function tags are used to represent specific functions (e.g., predicting molecular properties) and compress function-solving instructions. We develop a three-stage protocol to learn these tags using auxiliary data and domain knowledge. By explicitly disentangling task domains from task functions, our method enables zero-shot generalization to unseen problems through diverse combinations of the input tags. It also boosts LLM’s performance in various specialized domains, such as predicting protein or chemical properties and modeling drug-target interactions, outperforming expert models tailored to these tasks.

The rising growth of deep neural networks (DNNs) and datasets in size motivates the need for efficient solutions for simultaneous model selection and training. Many methods for hyperparameter optimization (HPO) of iterative learners, including DNNs, attempt to solve this problem by querying and learning a response surface while searching for the optimum of that surface. However, many of these methods make myopic queries, do not consider prior knowledge about the response structure, and/or perform a biased cost-aware search, all of which exacerbate identifying the best-performing model when a total cost budget is specified. This paper proposes a novel approach referred to as Budget-Aware Planning for Iterative Learners (BAPI) to solve HPO problems under a constrained cost budget. BAPI is an efficient non-myopic Bayesian optimization solution that accounts for the budget and leverages the prior knowledge about the objective function and cost function to select better configurations and to take more informed decisions during the evaluation (training). Experiments on diverse HPO benchmarks for iterative learners show that BAPI performs better than state-of-the-art baselines in most cases.

Network Architecture Search (NAS) methods have recently gathered much attention. They design networks with better performance and use a much shorter search time compared to traditional manual tuning. Despite their efficiency in model deployments, most NAS algorithms target a single task on a fixed hardware system. However, real-life few-shot learning environments often cover a great number of tasks ($T$) and deployments on a wide variety of hardware platforms ($H$). The combinatorial search complexity $T \times H$ creates a fundamental search efficiency challenge if one naively applies existing NAS methods to these scenarios. To overcome this issue, we show, for the first time, how to rapidly adapt model architectures to new tasks in a \emph{many-task many-hardware} few-shot learning setup by integrating Model Agnostic Meta Learning (MAML) into the NAS flow. The proposed NAS method (H-Meta-NAS) is hardware-aware and performs optimisation in the MAML framework. MetaNAS shows a Pareto dominance compared to a variety of NAS and manual baselines in popular few-shot learning benchmarks with various hardware platforms and constraints. In particular, on the 5-way 1-shot Mini-ImageNet classification task, the proposed method outperforms the best manual baseline by a large margin ($5.21\%$ in accuracy) using $60\%$ less computation.

Various machine learning tasks, from generative modeling to domain adaptation, revolve around the concept of dataset transformation and manipulation. While various methods exist for transforming unlabeled datasets, principled methods to do so for labeled (e.g., classification) datasets are missing. In this work, we propose a novel framework for dataset transformation, which we cast as optimization over data-generating joint probability distributions. We approach this class of problems through Wasserstein gradient flows in probability space, and derive practical and efficient particle-based methods for a flexible but well-behaved class of objective functions. Through various experiments, we show that this framework can be used to impose constraints on classification datasets, adapt them for transfer learning, or to re-purpose fixed or black-box models to classify {—}with high accuracy{—} previously unseen datasets.

In this paper, we introduce Differentiable Feature Selection, a gradient-based search algorithm for feature selection. Our approach extends a recent result on the estimation of learnability in the sublinear data regime by showing that the calculation can be performed iteratively (i.e. in mini-batches) and in linear time and space with respect to both the number of features D and the sample size N. This, along with a discrete-to-continuous relaxation of the search domain, allows for an efficient, gradient-based search algorithm among feature subsets for very large datasets. Our algorithm utilizes higher-order correlations between features and targets for both the N>D and N Cite this Paper BibTeX @InProceedings{pmlr-v108-sheth20a, title = {Differentiable Feature Selection by Discrete Relaxation}, author = {Sheth, Rishit and Fusi, Nicol\'o}, booktitle = {Proceedings of the Twenty Third International Conference on Artificial Intelligence and Statistics}, pages = {1564--1572}, year = {2020}, editor = {Chiappa, Silvia and Calandra, Roberto}, volume = {108}, series = {Proceedings of Machine Learning Research}, month = {26--28 Aug}, publisher = {PMLR}, pdf = {http://proceedings.mlr.press/v108/sheth20a/sheth20a.pdf}, url = {https://proceedings.mlr.press/v108/sheth20a.html}, abstract = {In this paper, we introduce Differentiable Feature Selection, a gradient-based search algorithm for feature selection. Our approach extends a recent result on the estimation of learnability in the sublinear data regime by showing that the calculation can be performed iteratively (i.e. in mini-batches) and in linear time and space with respect to both the number of features D and the sample size N. This, along with a discrete-to-continuous relaxation of the search domain, allows for an efficient, gradient-based search algorithm among feature subsets for very large datasets. Our algorithm utilizes higher-order correlations between features and targets for both the N>D and N Copy to Clipboard Download Endnote %0 Conference Paper %T Differentiable Feature Selection by Discrete Relaxation %A Rishit Sheth %A Nicoló Fusi %B Proceedings of the Twenty Third International Conference on Artificial Intelligence and Statistics %C Proceedings of Machine Learning Research %D 2020 %E Silvia Chiappa %E Roberto Calandra %F pmlr-v108-sheth20a %I PMLR %P 1564--1572 %U https://proceedings.mlr.press/v108/sheth20a.html %V 108 %X In this paper, we introduce Differentiable Feature Selection, a gradient-based search algorithm for feature selection. Our approach extends a recent result on the estimation of learnability in the sublinear data regime by showing that the calculation can be performed iteratively (i.e. in mini-batches) and in linear time and space with respect to both the number of features D and the sample size N. This, along with a discrete-to-continuous relaxation of the search domain, allows for an efficient, gradient-based search algorithm among feature subsets for very large datasets. Our algorithm utilizes higher-order correlations between features and targets for both the N>D and N Copy to Clipboard Download APA Sheth, R. & Fusi, N.. (2020). Differentiable Feature Selection by Discrete Relaxation. Proceedings of the Twenty Third International Conference on Artificial Intelligence and Statistics, in Proceedings of Machine Learning Research 108:1564-1572 Available from https://proceedings.mlr.press/v108/sheth20a.html. Copy to Clipboard Download Related Material Download PDF This site last compiled Sun, 05 Jul 2026 14:49:58 +0000 Github Account Copyright © The authors and PMLR 2026. MLResearchPress

The notion of task similarity is at the core of various machine learning paradigms, such as domain adaptation and meta-learning. Current methods to quantify it are often heuristic, make strong assumptions on the label sets across the tasks, and many are architecture-dependent, relying on task-specific optimal parameters (e.g., require training a model on each dataset). In this work we propose an alternative notion of distance between datasets that (i) is model-agnostic, (ii) does not involve training, (iii) can compare datasets even if their label sets are completely disjoint and (iv) has solid theoretical footing. This distance relies on optimal transport, which provides it with rich geometry awareness, interpretable correspondences and well-understood properties. Our results show that this novel distance provides meaningful comparison of datasets, and correlates well with transfer learning hardness across various experimental settings and datasets.

Variational autoencoders (VAE) are a powerful and widely-used class of models to learn complex data distributions in an unsupervised fashion. One important limitation of VAEs is the prior assumption that latent sample representations are independent and identically distributed. However, for many important datasets, such as time-series of images, this assumption is too strong: accounting for covariances between samples, such as those in time, can yield to a more appropriate model specification and improve performance in downstream tasks. In this work, we introduce a new model, the Gaussian Process (GP) Prior Variational Autoencoder (GPPVAE), to specifically address this issue. The GPPVAE aims to combine the power of VAEs with the ability to model correlations afforded by GP priors. To achieve efficient inference in this new class of models, we leverage structure in the covariance matrix, and introduce a new stochastic backpropagation strategy that allows for computing stochastic gradients in a distributed and low-memory fashion. We show that our method outperforms conditional VAEs (CVAEs) and an adaptation of standard VAEs in two image data applications.

In order to achieve state-of-the-art performance, modern machine learning techniques require careful data pre-processing and hyperparameter tuning. Moreover, given the ever increasing number of machine learning models being developed, model selection is becoming increasingly important. Automating the selection and tuning of machine learning pipelines, which can include different data pre-processing methods and machine learning models, has long been one of the goals of the machine learning community. In this paper, we propose to solve this meta-learning task by combining ideas from collaborative filtering and Bayesian optimization. Specifically, we use a probabilistic matrix factorization model to transfer knowledge across experiments performed in hundreds of different datasets and use an acquisition function to guide the exploration of the space of possible ML pipelines. In our experiments, we show that our approach quickly identifies high-performing pipelines across a wide range of datasets, significantly outperforming the current state-of-the-art.

MOTIVATION: Genomic studies have revealed a substantial heritable component of the transcriptional state of the cell. To fully understand the genetic regulation of gene expression variability, it is important to study the effect of genotype in the context of external factors such as alternative environmental conditions. In model systems, explicit environmental perturbations have been considered for this purpose, allowing to directly test for environment-specific genetic effects. However, such experiments are limited to species that can be profiled in controlled environments, hampering their use in important systems such as human. Moreover, even in seemingly tightly regulated experimental conditions, subtle environmental perturbations cannot be ruled out, and hence unknown environmental influences are frequent. Here, we propose a model-based approach to simultaneously infer unmeasured environmental factors from gene expression profiles and use them in genetic analyses, identifying environment-specific associations between polymorphic loci and individual gene expression traits. RESULTS: In extensive simulation studies, we show that our method is able to accurately reconstruct environmental factors and their interactions with genotype in a variety of settings. We further illustrate the use of our model in a real-world dataset in which one environmental factor has been explicitly experimentally controlled. Our method is able to accurately reconstruct the true underlying environmental factor even if it is not given as an input, allowing to detect genuine genotype-environment interactions. In addition to the known environmental factor, we find unmeasured factors involved in novel genotype-environment interactions. Our results suggest that interactions with both known and unknown environmental factors significantly contribute to gene expression variability. AVAILABILITY: and implementation: Software available at http://pmbio.github.io/envGPLVM/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Expression quantitative trait loci (eQTL) studies are an integral tool to investigate the genetic component of gene expression variation. A major challenge in the analysis of such studies are hidden confounding factors, such as unobserved covariates or unknown subtle environmental perturbations. These factors can induce a pronounced artifactual correlation structure in the expression profiles, which may create spurious false associations or mask real genetic association signals. Here, we report PANAMA (Probabilistic ANAlysis of genoMic dAta), a novel probabilistic model to account for confounding factors within an eQTL analysis. In contrast to previous methods, PANAMA learns hidden factors jointly with the effect of prominent genetic regulators. As a result, this new model can more accurately distinguish true genetic association signals from confounding variation. We applied our model and compared it to existing methods on different datasets and biological systems. PANAMA consistently performs better than alternative methods, and finds in particular substantially more trans regulators. Importantly, our approach not only identifies a greater number of associations, but also yields hits that are biologically more plausible and can be better reproduced between independent studies. A software implementation of PANAMA is freely available online at http://ml.sheffield.ac.uk/qtl/.