Burkhard Hoeckendorf

Cheng Jiang, Brady Ryan, Megan Crow et al.

Genome-Wide Association Studies (GWAS) identify associations between genetic variants and disease; however, moving beyond associations to causal mechanisms is critical for therapeutic target prioritization. The recently proposed Knowledge Graph GWAS (KGWAS) framework addresses this challenge by linking genetic variants to downstream gene-gene interactions via a knowledge graph (KG), thereby improving detection power and providing mechanistic insights. However, the original KGWAS implementation relies on a large general-purpose KG, which can introduce spurious correlations. We hypothesize that cell-type specific KGs from disease-relevant cell types will better support disease mechanism discovery. Here, we show that the general-purpose KG in KGWAS can be substantially pruned with no loss of statistical power on downstream tasks, and that performance further improves by incorporating gene-gene relationships derived from perturb-seq data. Importantly, using a sparse, context-specific KG from direct perturb-seq evidence yields more consistent and biologically robust disease-critical networks.

Taro Makino, Ji Won Park, Natasa Tagasovska et al.

Real-world datasets often combine data collected under different experimental conditions. This yields larger datasets, but also introduces spurious correlations that make it difficult to model the phenomena of interest. We address this by learning two embeddings to independently represent the phenomena of interest and the spurious correlations. The embedding representing the phenomena of interest is correlated with the target variable $y$, and is invariant to the environment variable $e$. In contrast, the embedding representing the spurious correlations is correlated with $e$. The invariance to $e$ is difficult to achieve on real-world datasets. Our primary contribution is an algorithm called Supervised Contrastive Block Disentanglement (SCBD) that effectively enforces this invariance. It is based purely on Supervised Contrastive Learning, and applies to real-world data better than existing approaches. We empirically validate SCBD on two challenging problems. The first problem is domain generalization, where we achieve strong performance on a synthetic dataset, as well as on Camelyon17-WILDS. We introduce a single hyperparameter $α$ to control the degree of invariance to $e$. When we increase $α$ to strengthen the degree of invariance, out-of-distribution performance improves at the expense of in-distribution performance. The second problem is batch correction, in which we apply SCBD to preserve biological signal and remove inter-well batch effects when modeling single-cell perturbations from 26 million Optical Pooled Screening images.

Sukwon Yun, Heming Yao, Burkhard Hoeckendorf et al.

Vision Transformers ($\text{ViTs}$) have become the backbone of vision foundation models, yet their optimization for multi-channel domains - such as cell painting or satellite imagery - remains underexplored. A key challenge in these domains is capturing interactions between channels, as each channel carries different information. While existing works have shown efficacy by treating each channel independently during tokenization, this approach naturally introduces a major computational bottleneck in the attention block - channel-wise comparisons leads to a quadratic growth in attention, resulting in excessive $\text{FLOPs}$ and high training cost. In this work, we shift focus from efficacy to the overlooked efficiency challenge in cross-channel attention and ask: "Is it necessary to model all channel interactions?". Inspired by the philosophy of Sparse Mixture-of-Experts ($\text{MoE}$), we propose MoE-ViT, a Mixture-of-Experts architecture for multi-channel images in $\text{ViTs}$, which treats each channel as an expert and employs a lightweight router to select only the most relevant experts per patch for attention. Proof-of-concept experiments on real-world datasets - JUMP-CP and So2Sat - demonstrate that $\text{MoE-ViT}$ achieves substantial efficiency gains without sacrificing, and in some cases enhancing, performance, making it a practical and attractive backbone for multi-channel imaging.

Heming Yao, Phil Hanslovsky, Jan-Christian Huetter et al.

Optical Pooled Screening (OPS) is a powerful tool combining high-content microscopy with genetic engineering to investigate gene function in disease. The characterization of high-content images remains an active area of research and is currently undergoing rapid innovation through the application of self-supervised learning and vision transformers. In this study, we propose a set-level consistency learning algorithm, Set-DINO, that combines self-supervised learning with weak supervision to improve learned representations of perturbation effects in single-cell images. Our method leverages the replicate structure of OPS experiments (i.e., cells undergoing the same genetic perturbation, both within and across batches) as a form of weak supervision. We conduct extensive experiments on a large-scale OPS dataset with more than 5000 genetic perturbations, and demonstrate that Set-DINO helps mitigate the impact of confounders and encodes more biologically meaningful information. In particular, Set-DINO recalls known biological relationships with higher accuracy compared to commonly used methods for morphological profiling, suggesting that it can generate more reliable insights from drug target discovery campaigns leveraging OPS.