1. |
- Horne, B D, et al.
(author)
-
Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy
- 2012
-
In: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 107:2, s. 232-240
-
Journal article (peer-reviewed)abstract
- By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
|
|
2. |
- Lenzini, P., et al.
(author)
-
Integration of genetic, clinical, and INR data to refine warfarin dosing
- 2010
-
In: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 87:5, s. 572-578
-
Journal article (peer-reviewed)abstract
- Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.
|
|
3. |
- Lindborg, Erik, et al.
(author)
-
Comment on "reinterpreting aircraft measurement in anisotropic scaling turbulence" by Lovejoy et al. (2009)
- 2010
-
In: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 10:3, s. 1401-1402
-
Journal article (peer-reviewed)abstract
- Recently, Lovejoy et al. (2009) argued that the steep ∼k-3 atmospheric kinetic energy spectrum at synoptic scales (≥1000 km) observed by aircraft is a spurious artefact of aircraft following isobars instead of isoheights. Without taking into account the earth's rotation they hypothesise that the horizontal atmospheric energy spectrum should scale as k-5/3 at all scales. We point out that the approximate k -3-spectrum at synoptic scales has been observed by a number of non-aircraft means since the 1960s and that general circulation models and other current models have successfully produced this spectrum. We also argue that the vertical movements of the aircraft are far too small to cause any strong effect on the measured spectrum at synoptic scales.
|
|