18/08/2026
Bouhedadja et al https://doi.org/10.2298/ABS260805020B externally validated two published pharmacogenetic acenocoumarol dosing equations, and one matched clinical equation in 119 Algerian adults receiving stable therapy. Published coefficients were applied without refitting, and performance was assessed using prediction error, calibration, prediction R², tolerance-based accuracy, dose-group analyses and prespecified sensitivity analyses.
All three equations systematically underpredicted stable weekly dose, showed inadequate calibration and produced negative prediction R² values. Accuracy was particularly poor among participants requiring more than 21 mg/week. These findings show that dose-prediction equations may not retain their validity after geographical and clinical transport and that recalibration or model updating is required before use in comparable Algerian patients. The study provides clinically relevant evidence from a North African population that remains underrepresented in pharmacogenetic model-validation research.
The authors’ earlier article from the same cohort is published by Archives of Biological Sciences (doi: 10.2298/ABS260719018B). The article examined associations between selected VKORC1 variants and stable dose. The present manuscript addresses a distinct question: the external validity and transportability of published dosing equations. It incorporates subsequently generated CYP2C9 and CYP4F2 genotype data and evaluates calibration, prediction error, tolerance-based accuracy, dose-group performance, and sensitivity analyses. The previously reported VKORC1 association findings are not presented as new results, and the earlier article is fully cited.
Fig. 2. Observed versus predicted weekly acenocoumarol doses in the common 109-participant subset. A – Tong pharmacogenetic equation; B – Tong clinical equation; C – Bulgarian pharmacogenetic equation. Each open circle represents one participant. The dashed diagonal line represents perfect agreement between observed and predicted doses, the thin solid line represents the linear calibration regression of observed dose on predicted dose, and the dash-dot line represents a locally weighted non-parametric smoothing curve (LOWESS; span 0.60) across the empirical prediction range. Calibration lines and smoothing curves were estimated separately for each equation and were used for descriptive evaluation only; the published equations were not refitted. Identical axis limits and scales were used in all panels. Non-positive predictions generated by the Bulgarian equation were retained and displayed at their original values.