# Domain-Adversarial Neural Network and Explainable AI for Reducing Tissue-of-Origin Signal in Pan-cancer Mortality Classification

arXiv: https://arxiv.org/abs/2504.10343 · HTML: https://mlsanity.com/paper/2504.10343/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 6 of its 56 references that are in the map.
- First posted on arXiv 14 Apr 2025.

## Builds on (most cited first, 6 of 6)

- [Axiomatic Attribution for Deep Networks](https://mlsanity.com/paper/1703.01365/) (2017)
- [Domain-Adversarial Training of Neural Networks](https://mlsanity.com/paper/1505.07818/) (2015)
- [When Explainability Meets Adversarial Learning: Detecting Adversarial Examples using SHAP Signatures](https://mlsanity.com/paper/1909.03418/) (2019)
- [Deep learning for unsupervised domain adaptation in medical imaging: Recent advancements and future perspectives](https://mlsanity.com/paper/2308.01265/) (2023)
- [Visualizing the PHATE of Neural Networks](https://mlsanity.com/paper/1908.02831/) (2019)
- [Balanced background and explanation data are needed in explaining deep learning models with SHAP: An empirical study on clinical decision making](https://mlsanity.com/paper/2206.04050/) (2022)

## Abstract (arXiv)

Tissue-of-origin signals dominate pan-cancer gene expression, often obscuring molecular features linked to patient survival. This hampers the discovery of generalizable biomarkers, as models tend to overfit tissue-specific patterns rather than capture survival-relevant signals. To address this, we propose a Domain-Adversarial Neural Network (DANN) trained on TCGA RNA-seq data to learn representations less biased by tissue and more focused on survival. Identifying tissue-independent genetic profiles is key to revealing core cancer programs. We assess the DANN using: (1) Standard SHAP, based on the original input space and DANN's mortality classifier; (2) A layer-aware strategy applied to hidden activations, including an unsupervised manifold from raw activations and a supervised manifold from mortality-specific SHAP values. Standard SHAP remains confounded by tissue signals due to biases inherent in its computation. The raw activation manifold was dominated by high-magnitude activations, which masked subtle tissue and mortality-related signals. In contrast, the layer-aware SHAP manifold offers improved low-dimensional representations of both tissue and mortality signals, independent of activation strength, enabling subpopulation stratification and pan-cancer identification of survival-associated genes.