% ABM Atlas — Literature Validation of 12 Associations % Expert cascade (EPIC) vs unsupervised classifiers (k-means / GMM / LCA / HDBSCAN) % v20 model · June 2026 ## Purpose Ten randomly-selected associations plus two Effect (E) examples were checked against the published scientific literature, to judge whether the **expert cascade** classification and the **unsupervised** cluster assignment are biologically accurate. EPIC: **E** = Effect (drug causes the ADR), **P** = Predisposition, **I** = Indication (confounding by indication), **C** = inConclusive (low-evidence residual). --- # Part A — 10 random associations ## 1. simvastatin × varicose veins (I83.1) × DUSP7 — Expert **E** vs unsupervised **P / P / P / I** The expert cascade calls this **Effect** (drug causes the event) on FAERS=STRONG, tissue=enriched, N_INDEPENDENT=3. The literature points the opposite way: statins **suppress** varicose remodeling — HMG-CoA reductase inhibitors block varicose vein development in mice, atorvastatin/rosuvastatin inhibit wall-stress AP-1 activity in venous smooth-muscle cells, and simvastatin has been trialled *for* venous ulcers. The curator agrees: "not an indication; shared vascular risk factors (age, obesity, sedentary lifestyle); weak comorbidity." DUSP7 (a dual-specificity phosphatase) has no venous mechanism. This is the clearest case where the **expert classification is likely wrong**: labelling a protective/confounded association as a drug-caused Effect inverts the biology. The unsupervised methods, pulling it away from Effect toward Predisposition (3/4) or Indication (HDBSCAN), show appropriate skepticism — though none lands on the most defensible label, inConclusive/comorbidity (shared metabolic risk driving both statin use and varicose veins). **Verdict: expert E is biologically backwards; true class is confounding (C).** ## 2. atenolol × psoriasis (L40.9) × MICAL3 — Expert **C** vs unsupervised **P / P / P / P** Beta-blockers including atenolol are historically among the drugs most strongly tied to drug-induced/aggravated psoriasis (~20% of psoriasis patients; calcium/cAMP keratinocyte mechanism), with atenolol prominent in adverse-event reports (Cohen *BJD* 2008; Brauchli *BJD* 2008, OR 1.31). However, a 2022+ multi-method reanalysis (NHANES + FDA) found **no significant signal**, arguing the label may be inappropriate. So this is a real-but-contested drug-induced effect. The expert calls it **Comorbidity** — but if atenolol genuinely induces psoriasis, that is an *Effect*, not coincidental co-occurrence. The cascade is internally inconsistent: the curator quotes strong causal evidence yet the tier lands on the weakest causal class. **All four unsupervised methods say Predisposition** — closer to "drug-related" than the expert's Comorbidity. **Verdict: expert undercalls a plausible drug-induced ADR; unsupervised P is more defensible, though the honest answer is "contested."** MICAL3 is almost certainly incidental. ## 3. lisinopril × oesophagitis (K20) × GNG13 — Expert **C** vs unsupervised **P / P / P / P** ACE-inhibitor cough is a well-known class effect that can clinically mimic GERD/oesophagitis — the "diagnostic confounding" the curator flags. There is no mechanism by which lisinopril causes true oesophageal inflammation, and GNG13 (a G-protein γ-subunit in taste/neural tissue) has no oesophageal role; the signal is weak (FAERS weak, tissue low, N_INDEPENDENT=1). Here the **expert Comorbidity/inConclusive call is the more defensible one** — it correctly reads the association as confounding rather than a real drug mechanism. The unanimous unsupervised "Predisposition" reflects the systematic bias: the rare-variant axis (GNG13 is a rare variant) pulls these signals toward P regardless of biology. **Verdict: expert right, unsupervised over-calling.** ## 4. amlodipine × pain, unspecified (R52.9) × NPAS3 — Expert **P** vs unsupervised **P / P / P / I** The outcome is the problem: "unspecified pain" is maximally non-specific, and NPAS3 is a neurodevelopmental transcription factor (brain-expressed) with no link to amlodipine or pain. The Predisposition call was driven by tissue="specific" (a brain-expression artifact), with otherwise weak evidence. Neither classification is trustworthy because the association is near-noise — a vague outcome plus an incidental rare variant. Expert P and three unsupervised P agree, but on thin grounds; HDBSCAN's dissent to Indication is no better supported. **Verdict: low confidence on both sides; should be flagged uninterpretable.** ## 5. atorvastatin × hypertrophic skin disorders (L91.8) × GALNT12 — Expert **C** vs unsupervised **P / P / P / P** L91.8 (keloids and other hypertrophic skin disorders) has no established statin association, and GALNT12 (a GalNAc-transferase, colorectal-cancer gene) has no skin-hypertrophy mechanism. Evidence is weak throughout; the curator notes "no indication." The **expert Comorbidity/inConclusive is appropriate** — it reads a weak, mechanism-less association as low-confidence co-occurrence. The unanimous unsupervised Predisposition is again the rare-variant pull misfiring. **Verdict: expert correct, unsupervised systematically over-calling P.** ## 6. ramipril × disorientation (R41.0) × GJB6 — Expert **P** vs unsupervised **P / P / P / I** This has a genuine pathway: ACE inhibitors can cause hyponatremia/SIADH, and severe hyponatremia (Na⁺ <120 mEq/L) produces confusion/disorientation in the elderly — documented in case reports where confusion resolved on drug withdrawal. So ramipril can cause disorientation, but **indirectly via electrolytes**, not through GJB6 (connexin-30, a deafness/skin gene). Signal moderately strong (FAERS=STRONG, tissue enriched, N_INDEPENDENT=2). The drug→ADR link is real, making the expert **Predisposition** plausible (arguably edging to Effect). But the *gene-level* claim is spurious — the causal chain is drug→hyponatremia→confusion, independent of GJB6. **Verdict: drug-ADR plausible (P defensible), gene incidental; strong FAERS justifies taking the signal seriously while distrusting the variant.** ## 7. atorvastatin × fatty liver (K76.0) × FBLIM1 — Expert **I** vs unsupervised **P / P / P / I** Statins are not *formally* indicated for NAFLD but are safe and beneficial (atorvastatin reduces aminotransferases, ameliorates NASH; recommended for the accompanying dyslipidemia). NAFLD is a strong metabolic-syndrome marker, so statin users are enriched for fatty liver: **confounding by (metabolic) indication.** The expert **Indication** call is the right read — it identifies confounding-by-indication even if "indication" is slightly loose (statins aren't indicated *for* NAFLD specifically). The unsupervised split (3×P, HDBSCAN I) shows the methods catching the rare-variant signal (FBLIM1, incidental) rather than the confounding structure. **Verdict: expert I more defensible.** ## 8. ramipril × acute myocardial infarction (I21.9) × KLF12 — Expert **I** vs unsupervised **I / I / I / I** ✅ A textbook positive control. ACE inhibitors post-MI are a **Class I ESC indication** (AIRE, HOPE, SAVE — prevention of ventricular remodeling); ramipril is prescribed *because of* the MI. The curator labels it "direct indication"; KLF12 is incidental. **Expert and all four unsupervised methods agree on Indication** — the cleanest result in the set. When the truth is unambiguous confounding-by-indication, the rule cascade and the data-driven clustering converge. **Verdict: correct and unanimous — a reassuring validation that the pipeline gets clear cases right.** ## 9. clopidogrel × prosthetic-device complications (T82.8) × HPSE2 — Expert **I** vs unsupervised **I / P / P / I** Dual antiplatelet therapy (clopidogrel + aspirin) after coronary stenting is **Class I ESC** — clopidogrel is given *because* the patient has the device, the curator's "maximum confounding." FAERS is STRONG (heavy co-reporting), HPSE2 (heparanase-2, urinary/bladder gene) incidental. The expert **Indication** call is correct. The unsupervised methods are **split** (k-means + HDBSCAN agree I; GMM + LCA drift to P) — the GMM/LCA dissent is the rare-variant axis mistaking a confounded indication for predisposition. **Verdict: expert right; exposes a real weakness — strong confounding-by-indication can be misread as Predisposition when the variant is rare.** ## 10. ramipril × psoriasis (L40.9) × GLP1R — Expert **C** vs unsupervised **P / P / P / I** The most biologically interesting — both drug and gene have real literature. ACE inhibitors are associated with psoriasis (meta-analysis pooled OR 1.52, 95% CI 1.16–2.00; MR + pharmacovigilance). Independently, **GLP1R has genuine psoriasis biology**: GLP-1R expression is increased in psoriatic plaques, and genetic proxies of GLP1R expression are associated with psoriasis/psoriatic-arthritis risk. Unlike the other nine genes, GLP1R is *not* obviously incidental. Yet the expert labels this **Comorbidity/inConclusive** and the statistics are thin (FAERS weak, **N_INDEPENDENT=0** — no replication). A fascinating tension: the **biology is more compelling than the statistics.** The expert undercalls it (driven by weak replication); the unsupervised methods scatter without recognizing the GLP1R–psoriasis link, because that biology isn't in their feature space. **Verdict: both classifiers miss the interesting signal — a case where manual, biology-aware review outperforms either automated classifier; deserves follow-up despite weak replication.** --- # Part B — two Effect (E) examples ## 11. citalopram × osteoporosis (M81.9) × DLEU1 — Expert **E** vs unsupervised **P / P / P / I** This is a genuine drug-induced effect. SSRI-associated bone loss is well documented: a meta-analytic fracture RR ≈ 1.6, decreased bone mineral density, and FDA/EMA warnings. The mechanism is biologically specific — serotonin transporters are present on osteoblasts, osteoclasts and osteocytes; SSRIs impair osteoclast function peripherally but trigger a central serotonin-dependent sympathetic rise that increases bone resorption, with a *net* effect of bone loss. Notably, the gene **DLEU1 is a documented regulator of osteoclastogenesis** — so unlike most atlas genes, this one has a plausible bone mechanism, and the curator flags the "tissue rescue" by literature. The **expert Effect call is biologically correct** — citalopram causes osteoporosis through an established serotonin–bone pathway. Strikingly, **all four unsupervised methods miss it**, calling Predisposition (3/4) or Indication (HDBSCAN). This is the concrete manifestation of the structural finding that Effect does not separate as a cluster: even a literature-validated, mechanism-supported drug-induced effect gets absorbed into the rare-variant Predisposition axis. **Verdict: expert E correct; unsupervised methods systematically fail to recover Effect.** ## 12. diazepam × COPD (J44.9) × PDE1C — Expert **E** vs unsupervised **P / P / P / I** Benzodiazepines in COPD are a clinically important, well-established hazard: benzodiazepine use is associated with a ~45% increased risk of COPD exacerbations, respiratory failure, and increased mortality, via GABA-A-mediated central respiratory depression (hypoxemia, reduced respiratory drive, hypercapnia). PDE1C (a phosphodiesterase) is expressed in airway/vascular smooth muscle, giving the gene-level signal more plausibility than most. The curator notes the dual reality: benzodiazepines are relatively contraindicated in COPD (respiratory depression), yet heavily *used* in this anxious/dyspneic population — so both a real ADR and confounded co-prescription are present. The **expert Effect call is defensible** — diazepam mechanistically worsens respiratory outcomes in COPD. Again, **all four unsupervised methods miss it** (P/P/P/I), confirming that the data-driven approach cannot recover the Effect class even when the causality is clinically established. **Verdict: expert E correct (with a confounding caveat from co-prescription); unsupervised methods fail to recover Effect, as in example 11.** --- # Honest advice — patterns across all 12 **1. Gene-level calls are mostly noise.** Of twelve genes, only three have real biology (GLP1R–psoriasis, DLEU1–osteoclastogenesis, PDE1C–airway). The other nine are incidental rare variants. **This is the single biggest caveat for the atlas:** it treats gene-level GWAS hits as meaningful, but at the individual-association level most are spurious. The real, checkable signal is almost always the *drug→ADR epidemiology*, not the specific variant. **2. The expert cascade's Effect tier is largely sound.** Two of the three Effect cases examined (SSRI/osteoporosis, benzodiazepine/COPD) are genuine, literature-validated drug-induced effects with plausible mechanisms; only one (statin/varicose) was biologically backwards. The cascade also reads confounding-by-indication correctly (#7, #8, #9). Its main weakness is being **conservative on drug-induced ADRs** — calling real/contested effects (atenolol & ramipril psoriasis, ramipril disorientation) "Comorbidity." **3. The unsupervised methods cannot recover Effect, and over-call Predisposition.** In **both** genuine Effect cases (#11, #12) all four methods said P or I, never E. And for confounded indications with rare variants (#3, #5, #9) they over-call P. The rare-variant standard-error axis dominates their behaviour, biasing them toward Predisposition regardless of biology. This is the concrete, literature-grounded version of the T4-recovery failure documented quantitatively elsewhere. **4. Neither classifier is ground truth — use as a screen.** Treat the classification (either version) as a **prioritization layer**, not a verdict. Every association destined for the manuscript needs the manual triage performed here: (a) is the drug→ADR link real, protective, or confounded? (b) is the gene plausible or incidental? The cases worth manual follow-up are the **disagreements** (#1, #2, #10) and the biology-rich outliers (#10 GLP1R, #11 DLEU1) — not the unanimous ones. --- ## Sources - Beta-blocker psoriasis: Azzouz, *Br J Clin Pharmacol* 2022 (doi 10.1111/bcp.15330); reanalysis (no signal), HMP Global; mechanisms, PMC7398737. - ACE inhibitor psoriasis: meta-analysis OR 1.52, *Sci Rep* 2021 (s41598-021-89490-z); MR + pharmacovigilance, *Expert Rev Clin Pharmacol* 2024 (PubMed 38078460). - Statins / NAFLD: PMC5998729; atorvastatin in NAFLD, PubMed 38304133. - ACEi hyponatremia / confusion: PMC6368929. - Statins / venous disease: HMG-CoA inhibitors suppress varicose remodeling, PubMed 26908399; IntechOpen review. - GLP1R / psoriasis: increased in plaques, PubMed 23362875; genetic proxies, medRxiv 2025.10.12.25337838. - SSRI / bone loss: serotonin reuptake inhibitors and bone, PMC6372777; central/peripheral mechanism, PMC5053870; meta-analysis, PMC9568413. - Benzodiazepines / COPD: ~45% exacerbation risk, *Eur Respir J* 44(2):332; *Ann Am Thorac Soc* PMC6344455.