Table 2. . Pharmacogenetic dosing algorithms and their performance in observational studies.
| Study (year) | n† | Treatment of race in the model | Clinical and genetic predictors | R2 explained (%) | Assessed prediction with the IWPC or Gage'08 algorithm | Ref. | ||
|---|---|---|---|---|---|---|---|---|
| Genetic | Clinical | Total | ||||||
| Kamali et al. (2004) | E: 119 | Restricted to EA | Age, CYP2C9*2, *3 | 6 | 17 | 20 | – | [24] |
| Hillman et al. (2004) | E: 453 | Restricted to EA | Age, BSA, valve replacement, diabetes, CYP2C9*2, *3 | – | – | 34 | – | [88] |
| Gage et al. (2004) | E: 261 | Adjusted for race | Age, gender, BSA, race, target INR, amiodarone, simvastatin, CYP2C9*2, *3 | 10 (includes CYP2C9*5) | – | 39 | – | [71] |
| A: 108 | ||||||||
| Voora et al. (2005) | E: 40 | Adjusted for race | Age, gender, race, weight, height, simvastatin, amiodarone, CYP2C9*2, *3 | – | – | 42 | – | [67] |
| A: 5 | ||||||||
| Sconce et al. (2006) | E: 297 | Restricted to EA | Age, height, CYP2C9*2, *3; VKORC1-1639A | – | – | 55 | – | [89] |
| Herman et al. (2006) | E: 165 | Restricted to EA | Age, BSA, CYP2C9*2, *3; VKORC1-1639A | – | – | 60 | – | [90] |
| Carlquist et al. (2006) | E: 213 | Restricted to EA | Age, gender, weight, CYP2C9*2, *3; VKORC1-1639A | 33 | 12 | 45 | – | [91] |
| Aquilante et al. (2006) | E: 319 | Unadjusted for race | Age, weight, smoking status, mean and goal INR, vitamin K intake, enzyme inhibitors and inducers, CYP2C9*2, *3, *5; VKORC1-1639A; Factor VII I/D, Factor X I/D | – | – | 51 | – | [66] |
| A: 25 | ||||||||
| Caldwell et al. (2007) | E: 570 | Restricted to EA | Age, gender, BSA, valve replacement, diabetes, CYP2C9*2, *3; VKORC1-6853C | – | – | 56 | – | [92] |
| Limdi et al. (2007) | E:249 | Stratified by race | Age, gender, BMI, drug interactions, average alcohol intake, average vitamin K intake, # comorbid conditions, CYP2C9 *2, *3, *5, *6, *10 or *11 | 6 | – | 19 | – | [60] |
| A:239 | 1 | – | ||||||
| 28 | – | |||||||
| Momary et al. (2007) | A: 115 | Restricted to AA | Age, BSA, CYP2C9*2, *3, *5 | – | – | 33 | – | [93] |
| Zhu et al. (2007) | E: 65 | Restricted to EA | Age, gender, weight, CYP2C9*2, *3; VKORC1-1639A | – | – | 61 | – | [94] |
| Gage et al. (2008) | E: 838 | Adjusted for race | Age, race, BSA, current smoking, target INR, VTE, amiodarone, CYP2C9*2, *3; VKORC1-1639A | – | 17 | 57 | 53 | [38] |
| A: 153 | 31 | |||||||
| Perini et al. (2008) | E: 196 | Unadjusted for race | Age, weight, valve replacement, VTE, amiodarone, simvastatin, CYP2C9*2, *3, *5, *11; VKORC1-1639A | – | – | 51 | – | [61] |
| A: 76 | ||||||||
| Limdi et al. (2008) | E: 302 | Stratified by race | Age, gender, BMI, follow-up clinic, income, smoking status, education, health insurance, drug interactions, alcohol intake, vitamin K intake, comorbid conditions, CYP2C9*2, *3, *5, *6, *11 and VKORC1-1173C>T | – | – | 42 | – | [25] |
| A: 273 | – | – | 36 | – | ||||
| Schelleman et al. (2008) | E: 147 | Stratified by race | E: Age, gender, BMI, # medications that potentiate warfarin, most # drinks on one occasion, h/o DVT, CYP2C9*2, *3 and VKORC1 -1173C>T | – | – | 43 | 42 | [75] |
| A: 112 | A: Age, BMI, # medications that potentiate warfarin, VKORC1 -1173C>T, Factor VII -401 G>T, APOE | – | – | 28 | 34 | |||
| Wu et al. (2008) | E: 33 | Adjusted for race | Age, race, gender, height, weight, smoking, amiodarone, sulfamethoxazole, CYP2C9*2, *3; VKORC1-1639A, 2255T | – | – | 59 | – | [62] |
| A: 31 | ||||||||
| Michaud et al. (2008) | E: 131 | Restricted to EA | Age, BSA, INR and Model 1: S:R-warfarin ratio at 14 h Model 2: dose-adjusted INR at day 4, CYP2C9*2, *3 VKORC1-1639A, 3730T |
– | – | 51 | – | [95] |
| Wadelius et al. (2009) | E: 1496 | Restricted to EA | Age, gender, drugs that increase INR, CYP2C9*2, *3; VKORC1-1639A | – | – | 59 | – | [96] |
| Klein et al. (2009) (IWPC) | E: 2233 | Adjusted for race | Age, race, height, weight, amiodarone, enzyme inducers, CYP2C9*2, *3; VKORC1-1639A | – | 27 | 45 | 47 | [43] |
| A: 353 | 26 | |||||||
| Cavallari et al. (2010) | A: 226 | Restricted to AA | Age, BSA, stroke/TIA, CYP2C9 *2, *3, *5, *6, *8, or *11, VKORC1 -1639G>A | 15 | – | 36 | – | [48] |
| Wells et al. (2010 ) | E: 232 | Restricted to EA | Age, BMI, height, exercise level, angiotensin II receptor antagonists, beta blockers, CYP2C9*2, *3; VKORC1-1639A; CYP4F2*3 | – | – | 58 | – | [97] |
| Lenzini et al. (2010) | E: 818 | Adjusted for race in the PGx model | Age, BSA, diabetes, stroke, amiodarone, fluvastatin, target INR, log INR, dose 2–4 days before INR measurement, CYP2C9*2, *3; VKORC1-1639A | – | 48 | 63 | – | [68] |
| A: 95 | ||||||||
| Zambon et al. (2011) | E: 274 | Restricted to EA | Age, BSA, CYP2C9*2, *3; VKORC1-1639A; CYP4F2*3 | – | – | 65 | 63 | [98] |
| Botton et al. (2011) | E: 279 | Restricted to EA | Age, weight, amiodarone, carbamazepine, beta blockers, amlodipine, diuretics, CYP2C9 *2, *3; VKORC1 haplotype based on -1639A, -1173T, -3730A; CYP4F2*3, F2 -494T | – | – | 63 | IWPC: 46 Gage: 42 |
[99] |
| Gong et al. (2011) | E:159 | Unadjusted for race | Age, weight, gender, amiodarone, CYP2C9*2, *3; VKORC1-1639A; CYP4F2*3 | – | – | 42 | – | [59] |
| A: 4 | ||||||||
| Perera et al. (2011) | A: 330 | Restricted to AA | Age, weight, DVT/PE, CYP2C9*2, *3, -18786T; VKORC1-1173T, -8191A | – | 22 | 40 | 26 | [49] |
| Avery et al. (2011) | E: 671 | Restricted to EA | Age, height, weight, amiodarone, CYP2C9*2, *3; VKORC1-1639A | – | – | 42 | – | [100] |
| Cini et al. (2012) | E: 55 | Restricted to EA | Age, height, weight, gender, smoking, dietary intake, VTE, diabetes, CYP2C9*2, *3; VKORC1 -1639A, 3730A | – | – | 44 | IWPC: 47 Gage: 54 |
[101] |
| Ramos et al. (2012) | E: 146 | Unadjusted for race | Age, PE, dose-adjusted INR at day 3, amiodarone, CYP2C9*2, *3, *5; VKORC1-1639A | 34 | – | 67 | 36 | [65] |
| A: 17 | ||||||||
| Horne et al. (2012) | E: 1115 | Unadjusted for race | Age, BSA, stroke, target INR, INR values, day of therapy, amiodarone, simvastatin, fluvastatin or enzyme inducers, CYP2C9*2, *3; VKORC1-1639A | – | 65 | 72 | 49 | [69] |
| A: 64 | ||||||||
| Ramirez et al. (2012) | E: 1022 | Stratified by race | Age, gender, BSA, smoking, atrial fibrillation vs. VTE, amiodarone, CYP2C9*2, *3, *6, *8; VKORC1 -1639A; CALU rs339097; CYP4F2*3 | – | 23 | 53 | 50 | [70] |
| A: 145 | – | 24 | 41 | 29 | ||||
| Shuen et al. (2012) | E: 264 | Unadjusted for race | Age, gender, target INR, CYP2C9*2, *3; VKORC1-1639A, VKORC1 Asp36Tyr | – | – | 54 | – | [63] |
| A: 52 | ||||||||
| Bress et al. (2012) | A: 260 | Restricted to AA | Age, BSA, hypertension, CYP2C9*2, *3, *5, *6, *8, *11; VKORC1 -1639A | – | 23 | 37 | – | [58] |
| Hernandez et al. (2014) | A: 349 | Restricted to AA | Age, weight, VTE, CYP2C9*2, *3, *5, *8, *11, 18786T, VKORC1 -1639A, -8191A; rs12777823 | – | – | 27 | IWPC Clinical: 16, Total: 15 |
[76] |
| Santos et al. (2015) | E: 574 | Adjusted for race | Age, gender, race, weight, height, amiodarone, enzyme inducers, CYP2C9*2, *3; VKORC1-1639A | – | – | 40 | – | [64] |
| A: 67 | ||||||||
| Limdi et al. (2015) | E: 762 | Stratified by race | Age, BSA, amiodarone, CKD, CYP2C9*2, *3, *5, *6, *11; VKORC1 -1639A, CYP4F2*3, rs12777823 | 35 | 16 | 54 | 51 | [46] |
| A: 595 | 10 | 23 | 34 | 29 | ||||
| Alzubiedi et al. (2016) | A: 163 | Restricted to AA | Age, height, weight, CHF, amiodarone, aspirin, paracetamol, enzyme inducers, CYP2C9*2, *3, *5; VKORC1 -1639A, CYP4F2*3, rs12777823 | – | – | 38 | 26 | [75] |
| Wiley et al. (2017) | E: 1928 | Four models related to race - unadjusted, adjusted, % ancestry and stratified | Age, BSA, smoking, amiodarone, enzyme inducers, CYP2C9*2, *3, *5, *6, *8, *11, VKORC1 -1639A; rs12777823 Other CYP2C9 and VKORC1 SNPs – either alone, combined or as haplotypes |
– | 20 | 56 | 45 | [73] |
| A: 253 | – | 22 | 40 | 20 | ||||
†Individuals of other race/ethnic groups are not listed in this table.
A: African descent; BMI: Body mass index; BSA: Body surface area; CHF: Congestive heart failure; CKD: Chronic kidney disease; DVT: deep vein thrombosis; E: European descent; INR: International normalized atio; IWPC: International Warfarin Pharmacogenetics Consortium; PE: Pulmonary embolism; VTE: Venous thromboembolism.