CDS: Counterfactual Directionality Score for Structured Interventions in Spatial Graphs

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 tissue graph counterfactuals as a class of spatial interventions that either rewire connections between cells (edge perturbation) or modify the expression of their neighbors (node perturbation). We then introduce Cellina (https://cellina.readthedocs.io) - 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, Cellina outperforms spatially-informed and non-spatial competitors in in-silico graph perturbations, disentanglement, and scalability. Additionally, we show that Cellina reveals biologically distinct cancer subdomains in an unsupervised manner and enables targeted neighbor perturbation simulations.

Let $p(x)$ be the joint density of variables $X$, and let $ψ(x)=\nabla_x\log p(x)$ be its score field. Geometry constructed from $p$ and $ψ$ alone cannot identify causal direction: structural models with the same observational distribution have the same score geometry. I develop an interventional analogue. A hard intervention $\operatorname{do}(X_k=ξ)$ does not merely reweight the joint law; it restricts the distribution to the submanifold ${x_k=ξ}$. Its score should therefore be defined on the remaining $d-1$ free coordinates. I define causal influence $X_k\rightsquigarrow X_j$ as variation of the interventional marginal distribution of $X_j$ with $ξ$, and show that the corresponding derivative of the marginal interventional score gives a local sufficient condition for influence. Projecting the observational score onto admissible intervention directions does not generally recover causal response: two models may share the same observational score and admissible set yet respond differently. I therefore introduce an interventional response field supplied by structural information. A causal metric is defined as the Fisher information metric on a family of interventions with a common target, avoiding ill-posed comparisons across targets. The framework yields a geometric dictionary for randomized trials, instrumental variables, and conditional-independence designs, clarifying what each does and does not identify. A bivariate Gaussian example gives two models with the same observational score but different interventional score derivatives. The framework organizes relations among designs, interventions, and score fields, but adds no identification beyond the underlying assumptions. In Pearl's Ladder of Causation, observational score geometry belongs to association, intervention-indexed score fields to intervention, and unit-level counterfactual geometry is left for future work.

We introduce causal density functions: Radon-Nikodym derivatives that compare interventional laws to observational laws and therefore act as local density ratios for causal effects. Whereas many causal-strength measures compare whole distributions after graph surgery, causal density functions provide a pointwise change-of-measure object that can be estimated, calibrated, and used to score directed influence. The basic identity $$\mathbb{E}_{\mathrm{do}}[f(Y)] = \mathbb{E}_{\mathrm{obs}}\!\left[f(Y)ρ(X,Y)\right]$$ makes causal density directly testable: if the estimated density ratio is correct, observational expectations reweighted by $ρ$ reproduce interventional expectations. We derive practical estimators for do-curves and directed edge scores, relate the construction to Radon-Nikodym/Kan semantics for conditioning and intervention, and evaluate the resulting estimators on synthetic and real perturbation benchmarks.