Test whether fixing the cell-composition confound rescues the recovery
test. GSE35007 measured WBC/RBC/MCV per sample, so adjust DE directly
for them (per-gene OLS: expression ~ disease + WBC + RBC + MCV + age +
sex) — a measured-covariate deconvolution, compared vs unadjusted.
Finding (negative, informative): adjustment HURT hydroxyurea (rank
20 -> 35, fails top-10%) — it was recovering partly via composition
genes — and did NOT fix negative-control specificity (still 2/5). Only
gain: top hits become more mechanistically coherent (resveratrol,
aspirin enter). Conclusion: cleaning the disease signature does not
rescue connectivity; the binding constraint is matching-side (needs a
reference-signature library for proper specificity calibration), which
is a multi-disease investment. v1.1 signature NOT replaced.
Co-Authored-By: Claude Opus 4.8 (1M context) <noreply@anthropic.com>
