# Known Limitations

The honest list of what would break this MVP at scale or in a different disease. Useful for the
next pharma conversation: "yes, we know these are limitations, here's how v2 addresses them."
Source: PLAN.md §9.

1. **Cell-composition confound in sickle cell expression data.** Whole-blood differential
   expression partly reflects different blood cell ratios, not disease biology. v1 acknowledges
   this; v2 should deconvolve cell types.

2. **LINCS L1000 cell-line limitations.** The 978 landmark genes were measured mostly in cancer
   cell lines (MCF7, A375, PC3, …). Signatures for non-oncology diseases may be noisy. A
   field-wide limitation, not unique to Reverso.

3. **L-glutamine probably has no LINCS signature.** Amino acids and metabolites weren't LINCS
   priorities. If true, the ground-truth test effectively rests on hydroxyurea alone, which is
   weaker. _Status: TBD — record the actual finding here once LINCS is pulled (Week 2)._

4. **Connectivity scoring surfaces broad-effect drugs as false positives.** HDAC inhibitors and
   broad kinase inhibitors often top connectivity rankings simply because they perturb many
   genes. The mechanistic prior (Week 3) helps filter, but does not eliminate this.

5. **Hydroxyurea will probably pass the recovery test by construction.** Sickle cell +
   hydroxyurea is a well-studied pair. Passing is necessary but not sufficient to claim the
   platform generalizes. The next disease is the real test — do not sell sickle cell results as
   proving the platform.

6. **No mechanistic validation layer.** Pure ML matching is not sufficient for extrapolation
   (flagged by multiple experts). The MVP knowingly omits the mechanistic layer; it is a phase-2
   addition. Position the MVP as "discovery hypothesis generation," not "validated prediction."

7. **Top-ranked novel candidates are not wet-lab validated.** They are computational hypotheses
   to test, not discoveries. Use careful language in any write-up.

## Drug-specific gaps (fill in during Week 2–3)

| Drug | Issue | Handling |
|---|---|---|
| TBD | e.g. no LINCS signature | flagged "not scored, no signature available" |