Junior B.
3417f85eb1
Post-hoc improvement after the pre-registered v1 recovery test failed. Two changes, diagnosing v1's failure: - score on the full 12,328-gene LINCS space (week2_lincs_extract.py), lifting signature overlap from 12% to 85% (brings erythroid markers in) - src/scoring.py: KS connectivity + per-drug specificity z-score (spec_z = SDs below a 1,000 random-query null). Primary ranking is now spec_z. (Textbook tau saturated at +/-100 for a coherent query — documented; needs a reference-signature library, a v2 item.) - week3_scoring.py: spec_z primary + WTCS reference + prior-blended - tests: tau/spec_z calibration test; 19 passing - scripts/exp_genespace.py: the BING vs all-12,328 comparison Result: hydroxyurea recovers (rank 40 -> 18, top 6%, passes top-10%), confirming the v1 failure was the landmark bottleneck not the algorithm. Overall STILL FAILS: L-glutamine does not reverse (rank 213, metabolite), and negative controls (norethindrone, ciprofloxacin) rank top-3 — connectivity != therapeutic relatedness. v1.1 is post-hoc/exploratory, not a confirmatory test; reported as such in recovery_test_report.md. Co-Authored-By: Claude Opus 4.8 (1M context) <noreply@anthropic.com>
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75 lines
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Markdown
# Data Sources
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> Fill in version + download date for every source actually used. This file is the artifact
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> that proves reproducibility (PLAN.md §6, Week 4 task 4). Record date and version for **all**
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> downloads.
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| Source | URL | Access | License | Use in MVP | Version | Download date |
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| Open Targets | https://platform.opentargets.org | API, bulk Parquet | CC0 | Target-disease graph | TBD | TBD |
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| MONDO | http://www.obofoundry.org/ontology/mondo.html | OBO file | CC BY 4.0 | Disease ID | TBD | TBD |
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| Orphanet | https://www.orpha.net | Bulk XML | CC BY 4.0 | Rare disease metadata | TBD | TBD |
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| OMIM | https://omim.org | Free for academic | License for commercial | Disease genetics | TBD | TBD |
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| GEO (GSE35007) | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE35007 | GEOparse, FTP | Public domain | Disease signature (study 1) | GPL10558 | 2026-06-23 |
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| GEO (GSE16728) | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE16728 | GEOparse, FTP | Public domain | Disease signature (study 2) | GPL570 | 2026-06-23 |
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| ChEMBL | https://www.ebi.ac.uk/chembl | chembl_webresource_client | CC BY-SA 3.0 | Drug structures, MoA, targets | API (live) | 2026-06-23 |
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| LINCS L1000 Phase I | GSE92742 (GEO) | GEOparse/FTP + cmapPy | CC0 (GEO) | Drug signatures (incl. L-glutamine) | GSE92742 | 2026-06-23 |
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| LINCS L1000 Phase II | GSE70138 (GEO) | GEOparse/FTP + cmapPy | CC0 (GEO) | Drug signatures (incl. hydroxyurea) | GSE70138 | 2026-06-23 |
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| ClinicalTrials.gov | https://clinicaltrials.gov | API | Public domain | Trial history | TBD | TBD |
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| FDA DailyMed | https://dailymed.nlm.nih.gov | API | Public domain | Approved labels | TBD | TBD |
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| Reactome | https://reactome.org | API, bulk | CC0 | Pathway data (Week 3 prior) | TBD | TBD |
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## Chosen GEO datasets (disease signature, Tier A via 2-study concordance)
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The signature is the cross-study concordance of two independent whole-blood studies (genes
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significant at q<0.05 in **both** with the same direction). Whole-blood tissue was required so
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concordance is meaningful; the two differ by platform and population, which strengthens
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robustness.
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| Study | Platform | Tissue | Disease group | Healthy group | n disease / healthy |
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| **GSE35007** | Illumina HumanHT-12 V4 (GPL10558) | whole blood | hb phenotype = SS | hb phenotype = AA | 190 / 12 |
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| **GSE16728** | Affymetrix HG-U133 Plus 2.0 (GPL570) | whole blood (PAXgene) | sickle-cell patient | control | 10 / 10 |
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- DE method: per-gene Welch t-test + Benjamini–Hochberg (microarray, pure Python).
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- Probes collapsed to HGNC symbol (keep max-mean-expression probe) before concordance.
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- Result: 16,208 genes tested in both → **671 concordant** (444 up / 227 down). Signature =
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top 250 up + all 227 down by worst-case q-value.
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- **Rejected candidates:** GSE53441 (PBMC — tissue mismatch with the whole-blood anchor);
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GSE84633/GSE84634 (PBMC, no healthy controls).
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- **Tier caveat:** GSE16728 is exactly 10/group (two PAXgene preps merged), below the strict
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n>10 rule; Tier A is assigned on cross-study concordance, documented in the signature JSON.
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Reproduce with `scripts/week1_explore.py` (download + DE + concordance) then
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`scripts/week1_finalize.py` (mygene mapping + persist).
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## Drug profiles (Week 2)
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300-drug set (`drug_set_v1.csv`), composed and restricted to LINCS-scorable compounds:
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| Inclusion reason | n | Notes |
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| ground_truth | 2 | hydroxyurea (Phase II), L-glutamine = "glutamine" (Phase I) |
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| related_mechanism | 32 | HbF inducers (decitabine, azacitidine, vorinostat, panobinostat, romidepsin…), NO donors, antioxidants, anti-inflammatories |
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| negative_control | 26 | antifungals, antihistamines, antibiotics, hormones |
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| general_sample | 240 | random from LINCS catalog, seed=42 |
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- **LINCS signatures:** per-drug consensus = mean of Level-5 MODZ z-scores across the drug's
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sig_ids (cell lines/doses/times), restricted to the 978 landmark genes. Drawn from BOTH
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phases (hydroxyurea is Phase-II-only; L-glutamine is Phase-I-only). All 300 drugs scored.
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- **ChEMBL:** matched by InChIKey — 145/300 (curated drugs ~90%, random research compounds
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38%, as expected). 43 drugs carry target annotations; 46 carry mechanism-of-action.
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- **Tier:** all signature-backed drugs are Tier B (LINCS is a single source → fails Tier A's
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not-single-source rule).
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- **Gene space (v1.1):** scoring uses the full **12,328-gene** LINCS space, not just the 978
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landmarks. Signature overlap is 406/477 (85%) vs 56/477 (12%) for landmark-only — the larger
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space is what recovers hydroxyurea (see recovery_test_report.md). HBG1/HBG2 are absent from
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LINCS entirely and remain unscoreable.
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- Reproduce: `week2_curate_drugset.py` → `week2_chembl.py` → download Level-5 GCTX →
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`week2_lincs_extract.py` → `week2_assemble.py`.
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## Licensing note for LINCS
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Read the LINCS data use terms before commercial use. For the MVP (research / proof-of-concept)
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the terms are permissive. For productization this needs legal review.
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