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Rare Genomic Subtype Discovery from RNA-seq via Autoencoder Embeddings and Stability-Aware Clustering

Mezghiche, Alaa

arXiv.org Artificial Intelligence

Unsupervised learning on high-dimensional RNA-seq data can reveal molecular subtypes beyond standard labels. We combine an autoencoder-based representation with clustering and stability analysis to search for rare but reproducible genomic subtypes. On the UCI "Gene Expression Cancer RNA-Seq" dataset (801 samples, 20,531 genes; BRCA, COAD, KIRC, LUAD, PRAD), a pan-cancer analysis shows clusters aligning almost perfectly with tissue of origin (Cramer's V = 0.887), serving as a negative control. We therefore reframe the problem within KIRC (n = 146): we select the top 2,000 highly variable genes, standardize them, train a feed-forward autoencoder (128-dimensional latent space), and run k-means for k = 2-10. While global indices favor small k, scanning k with a pre-specified discovery rule (rare < 10 percent and stable with Jaccard >= 0.60 across 20 seeds after Hungarian alignment) yields a simple solution at k = 5 (silhouette = 0.129, DBI = 2.045) with a rare cluster C0 (6.85 percent of patients) that is highly stable (Jaccard = 0.787). Cluster-vs-rest differential expression (Welch's t-test, Benjamini-Hochberg FDR) identifies coherent markers. Overall, pan-cancer clustering is dominated by tissue of origin, whereas a stability-aware within-cancer approach reveals a rare, reproducible KIRC subtype.


Hypothesis Hunting with Evolving Networks of Autonomous Scientific Agents

Liu, Tennison, Estévez, Silas Ruhrberg, Bentley, David L., van der Schaar, Mihaela

arXiv.org Artificial Intelligence

Large-scale scientific datasets -- spanning health biobanks, cell atlases, Earth reanalyses, and more -- create opportunities for exploratory discovery unconstrained by specific research questions. We term this process hypothesis hunting: the cumulative search for insight through sustained exploration across vast and complex hypothesis spaces. To support it, we introduce AScience, a framework modeling discovery as the interaction of agents, networks, and evaluation norms, and implement it as ASCollab, a distributed system of LLM-based research agents with heterogeneous behaviors. These agents self-organize into evolving networks, continually producing and peer-reviewing findings under shared standards of evaluation. Experiments show that such social dynamics enable the accumulation of expert-rated results along the diversity-quality-novelty frontier, including rediscoveries of established biomarkers, extensions of known pathways, and proposals of new therapeutic targets. While wet-lab validation remains indispensable, our experiments on cancer cohorts demonstrate that socially structured, agentic networks can sustain exploratory hypothesis hunting at scale.