Did the developmental-origin framework hold up?
Adult EPN falsification test
The gate for the ependymoma developmental-origin framework (the PFA CDK4/6, ZFTA-RELA, and MERTK insights depend on this).
✗ Framework refuted (v2 — pathway space, GTEX reference)
Both pediatric and adult EPN cluster more with adult brain (GTEX) than with fetal reference in hallmark pathway space. The developmental-origin claim is not supported by this test. the PFA CDK4/6, ZFTA-RELA, and MERTK insights lose their developmental-mechanism justification (though empirical drug-ranking findings stand on their own).
How v2 works (pathway-space test vs v1 UMAP-space)
Pathway-space (not UMAP-space) distance — cross-project compatible because both projects compute GSVA against the same hallmark library. Caveat: hallmark pathways are largely generic cancer biology (MYC_TARGETS, GLYCOLYSIS, MTORC1, ...) not developmental signaling. A 'clusters with fetal' verdict here reflects shared proliferative/stress signaling, not necessarily cell-of-origin identity. Re-running with KEGG/Reactome neural-development pathways is the next sharpening.
Feature space: 50-d HALLMARK GSVA · distance: Euclidean · k=5 · decision ratio 0.85.
⚠ Verdict ambiguous (v1 — UMAP-space, Med contrast)
Adult sample size is small or adult EPN also clusters with fetal at similar rates to pediatric. Sahm/Reuss 2018 ingestion (122 adult EPN) is recommended before betting big on the developmental framework.
Adult vs pediatric EPN — does each cohort land on its expected reference?
Split view of the same UMAP. If the developmental-origin framework held, the right (pediatric) panel would sit inside the fetal cluster and the left (adult) panel would sit on adult-brain reference. UMAP coordinates come from the v1 medullo-epn-umap projection; EPN points are colored red and the dashed blue circle marks the fetal-reference attractor (centroid of fetal-clustering EPN samples — see caption). v2 framework verdict (pathway-space, GTEX-anchored): refuted.
Adult EPN
n=24Pediatric EPN
n=266Caveat. The v1 medullo-epn-umap projection does not include an adult-brain (GTEX) reference — that reference lives in a different UMAP (brain-umap project) and cannot be co-located here. The green adult-brain marker in the legend is therefore unavailable. The dashed blue halo is the centroid of samples the v1 algorithm assigned to clusters_with_fetal, used here as a stand-in for the underlying fetal reference cluster (whose raw points are not returned by the API). Per-point coloring uses the v1 classification because v2 does not expose per-sample classification (only aggregate counts).
UMAP positions — does adult EPN drift off the fetal manifold?
Anatomic stratification
Cluster-with-fetal rate by compartment × age bucket.
| Compartment | Age bucket | n | % clusters with fetal |
|---|---|---|---|
| other | adult | 17 | 70.6% |
| other | pediatric | 56 | 85.7% |
| posterior fossa | pediatric | 94 | 89.4% |
| spinal | adult | 1 | 0.0% |
| spinal | pediatric | 12 | 66.7% |
| supratentorial | adult | 6 | 83.3% |
| supratentorial | pediatric | 104 | 93.3% |
Downstream impact on the dependent insights
- PFA radial-glia CDK4/6: foundation status →
ambiguous - ZFTA-RELA TAM+MET polypharmacology: foundation status →
ambiguous - MERTK dual-compartment: foundation status →
ambiguous - PFA1 hypoxia-wound niche: independent of this verdict (niche-based, not developmental).
How this test runs (deviations from the spec)
The original framework asked for adult-EPN distance to adult brain reference. The medullo-epn-umap project ingested today contains 100 fetal references but no adult-brain reference in the same UMAP space — and the separate brain-umap project lives in a different UMAP that we cannot directly distance-compare.
As an in-project substitute, we use medulloblastoma as the non-fetal contrast (888 samples, same UMAP). For each EPN sample we compute mean distance to its 5 nearest fetal neighbours vs its 5 nearest Med neighbours, and call it clusters_with_fetal when the fetal distance is < 0.8× the Med distance.
Verdict is conservative. Ambiguous → recommend ingesting Sahm/Reuss 2018 (122 adult EPN) for a definitive read. Adult-age threshold ≥ 18 years.
# Platform Saifudeen, A., et al. (2026). KIRhub: a falsification-first research workbench for translational oncology. Nature Biotechnology. https://doi.org/10.1038/s41587-026-03090-8 # Data source McFerrin, L. G., et al. (2018). Oncoscape: a tool for interactive cancer genomics data analysis. Nature Genetics. Arora, S., et al. (2026). A pan-pediatric brain tumor reference map: medulloblastoma and ependymoma in shared UMAP space. Neuro-Oncology. # Datasets used in this insight Oncoscape pediatric brain tumor compendium (n=1,358) GTEX adult-brain reference (n=1,409) # Provenance insight_id: falsification