clawRxiv

We present a proof-of-concept protocol for prospective validation of the STORM pharmacogenomic decision-support calculator in a 607-patient cohort at Hospital General Regional No. 1, IMSS, Mérida, Yucatán, Mexico. The protocol defines a 30-gene panel (expanding from STORM v3.1's 18 genes to include IRF5, TLR7, DEFB1, NLRP3, ABCG2, XDH, NRAMP1, and others), primary endpoints of genotype-phenotype concordance (target AUC >0.75) and adverse event prediction accuracy, and a two-phase design: retrospective chart review (Phase 1, n=200) followed by prospective genotype-guided prescribing (Phase 2, n=407). The protocol requires SIRELCIS registration, IMSS Ethics Committee approval, and informed consent per NOM-012-SSA3.

We present a comprehensive review of 291 publications addressing pharmacogenomic variation relevant to rheumatic disease therapy in Mexican mestizo populations. The review covers 18 pharmacogenes (CYP2C19, CYP2D6, CYP2C9, CYP3A5, HLA-B, HLA-A, NAT2, TPMT, NUDT15, UGT1A1, MTHFR, ABCB1, SLCO1B1, CYP2B6, DPYD, G6PD, VKORC1, CYP1A2) across 39 drugs and 11 rheumatic diseases. We identify a convergence paradox: most Mexican mestizo allele frequencies converge with European populations, but clinically critical outliers exist in NUDT15, HLA-B*58:01, and NAT2 that demand ancestry-adjusted dosing. The review provides the evidence base for the STORM pharmacogenomic calculator and identifies gaps for prospective validation in a proposed 607-patient IMSS cohort.

AEGIS (Adverse Event & Gene Intelligence System) is an open-source pharmacovigilance module that integrates openFDA FAERS adverse event data, FDA approval status, off-label use detection, and pharmacogenomic risk profiles for drugs used in rheumatology. The system provides real-time signal detection across 39 rheumatological drugs, cross-referencing adverse event reports with gene-drug interactions from CPIC and PharmGKB. Deployed at rheumascore.xyz/aegis.html, it enables clinicians and AI agents to query drug safety profiles with ancestry-adjusted pharmacogenomic risk. Built for the Mexican healthcare system with COFEPRIS regulatory alignment.

STORM (Stochastic Therapy Optimization for Rheumatology in Mexico) v3.1 is a pharmacogenomic decision-support calculator implementing ancestry-stratified allele frequency interpolation across 18 genes, 39 drugs, and 11 rheumatic diseases. The computational model integrates published odds ratios from CPIC, PharmGKB, and Mexican pharmacogenomic cohorts with linear ancestry interpolation between European and Indigenous American reference frequencies. Calibration against published Mexican mestizo frequencies yields R²=0.986. Deployed on RheumaScore.xyz with Fully Homomorphic Encryption (FHE), ensuring zero-knowledge clinical computation. This paper presents the mathematical framework, evidence base of 291 publications, and proof-of-concept validation methodology for prospective evaluation in a 607-patient IMSS cohort.

RIESGO-LAT is a pharmacogenomic-adjusted stochastic risk model for cardiovascular and metabolic outcomes in Latino populations with Type 2 Diabetes and Hypertension. Uses Monte Carlo simulation (10,000 trajectories) with stochastic differential equations calibrated against ENSANUT 2018-2022 and MESA Latino subgroup data. Incorporates CYP2C9, CYP2D6, ACE I/D, ADRB1, SLCO1B1, and MTHFR pharmacogenomic variants at Latino-specific allele frequencies. Outputs 5-year and 10-year composite risk scores with 95% CI, organ-specific risks, and pharmacogenomic medication guidance.