Data-Driven Soft Labeling Scales DNA Read Classification to Whole-Body Cell-Type Deconvolution

Cell-type deconvolution, the task of estimating the proportions of constituent cell types in a heterogeneous biological sample, is a core problem in computational biology. Methods that rely on epigenetic marks such as DNA methylation typically operate on aggregated methylation estimates, discarding the pattern-level information carried by individual DNA reads. Existing read-level approaches that exploit this information are scarce, and all remain restricted to few-class settings; scaling them further is an open problem because, at scale, non-discriminative reads dominate and hard labels conflict with the many-to-many mapping between methylation patterns and cell types, preventing classifier convergence. To overcome this, we propose data-driven soft labels that estimate the conditional cell-type distribution for each read, and integrate this scheme into Syto, a new modular framework for read-level classification-based deconvolution. On a whole-body atlas of 39 human cell types, Syto reduces MSE by 2.56$\times$ over SoTA, with gains transferring to an out-of-distribution dataset spanning 16 tissues. Syto lays the foundation for modeling increasingly large cell-type panels, with improved applications in biology and healthcare. The proposed soft-labeling scheme is further translatable to any setting with a many-to-many signal-to-label mapping.

Querying Counterfactuals on Tissue Graphs with Supervised Disentanglement

\textit{Tissue graph counterfactuals} ask how a cell's expression would change under altered spatial neighbor contexts. Such queries are central to predicting cell behavior in tissues, but lack a unified definition, with existing methods targeting specific intervention types or treating cells as i.i.d. In this work, we first formalize \textit{tissue graph counterfactuals} as a class of spatial interventions that either rewire connections between cells (\textit{edge perturbation}) or modify the expression of their neighbors (\textit{node perturbation}). We then introduce \textit{Cellina} {\renewcommand{\thefootnote}‡\footnote{https://cellina.readthedocs.io}\addtocounter{footnote}{-1}}, a framework that uses supervised disentanglement to decompose a cell's intrinsic state from its spatial context, using the latter as a conditioning input for counterfactual predictions. Across benchmarks spanning over 2.5 million spatially-resolved cells in colorectal cancer and mouse brain, \textit{Cellina} outperforms spatially-informed and non-spatial competitors in tissue perturbations, disentanglement, and scalability. Additionally, we show that \textit{Cellina} reveals biologically distinct cancer subdomains in an unsupervised manner and enables targeted neighbor perturbation simulations.

Matrix factorization with Binary Components

Motivated by an application in computational biology, we consider low-rank matrix factorization with $\{0,1\}$-constraints on one of the factors and optionally convex constraints on the second one. In addition to the non-convexity shared with other matrix factorization schemes, our problem is further complicated by a combinatorial constraint set of size $2^{m \cdot r}$, where $m$ is the dimension of the data points and $r$ the rank of the factorization. Despite apparent intractability, we provide - in the line of recent work on non-negative matrix factorization by Arora et al. (2012) - an algorithm that provably recovers the underlying factorization in the exact case with $O(m r 2^r + mnr + r^2 n)$ operations for $n$ datapoints. To obtain this result, we use theory around the Littlewood-Offord lemma from combinatorics.