Calibrate sickle connectivity against a real disease-signature
reference population (Enrichr Disease_Signatures_from_GEO, 141 diseases)
instead of random gene-set nulls — proper CMap tau.
Finding: hydroxyurea still recovers (rank 25, top 8%), but negative-
control specificity is UNCHANGED (2/5; norethindrone + ciprofloxacin
still top). The reference-calibrated ranking is nearly identical to the
random-null ranking. Third independent fix (after gene-space expansion
and composition adjustment) that recovers hydroxyurea but does NOT fix
specificity.
Conclusion: unsupervised connectivity has a specificity ceiling — it
cannot distinguish therapeutic reversal from coincidental transcriptional
anti-correlation. Breaking it needs external signal (supervised labels
or mechanistic filtering), not more calibration. Disease-signature
library cached at data/raw/disease_sigs/.
Co-Authored-By: Claude Opus 4.8 (1M context) <noreply@anthropic.com>
