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BT 15.000 718.042 Td /F2 21.0 Tf  [(Testing of VKORC1 and CYP2C9 alleles to guide warfarin )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(dosing)] TJ ET
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BT 15.000 671.524 Td /F2 13.5 Tf  [(Test Category: Pharmacogenomic \(Treatment\))] TJ ET
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BT 15.000 653.050 Td /F3 9.8 Tf  [(September 14, 2010)] TJ ET
BT 26.250 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 37.092 641.209 Td /F1 9.8 Tf  [(Daurice Grossniklaus)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 629.304 Td /F1 9.8 Tf  [(Grossniklaus D. Testing of VKORC1 and CYP2C9 alleles to guide warfarin dosing: Test Category: Pharmacogenomic )] TJ ET
BT 26.250 617.400 Td /F1 9.8 Tf  [(\(Treatment\). PLOS Currents Evidence on Genomic Tests. 2010 Sep 14 . Edition 1. doi: 10.1371/currents.RRN1155.)] TJ ET
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BT 26.250 588.297 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 568.343 Td /F1 9.8 Tf  [(Warfarin is an oral anticoagulant that is widely prescribed to prevent thromboembolic events in persons at increased risk. The )] TJ ET
BT 26.250 556.438 Td /F1 9.8 Tf  [(optimal dose is difficult to establish because it can vary 10-fold among individuals due to clinical and demographic factors. )] TJ ET
BT 26.250 544.533 Td /F1 9.8 Tf  [(Testing for variants of the vitamin K epoxide reductase complex 1 \(VKORC1\) and cytochrome P450 2C9 \(CYP2C9\) genes has )] TJ ET
BT 26.250 532.629 Td /F1 9.8 Tf  [(been proposed for use in guiding the initial dose of warfarin, thus achieving optimal dosing more quickly and with lower risk of )] TJ ET
BT 26.250 520.724 Td /F1 9.8 Tf  [(bleeding.)] TJ ET
BT 26.250 484.121 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 464.167 Td /F1 9.8 Tf  [(Pharmacogenetic testing to guide warfarin dose selection for individuals at risk of a thromboembolic event with the goal of )] TJ ET
BT 26.250 452.262 Td /F1 9.8 Tf  [(shortening the time required to achieve a stable, effective dose and minimizing the risk of adverse effects. )] TJ ET
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0.271 0.267 0.267 rg
BT 26.250 415.660 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 395.706 Td /F1 9.8 Tf  [(Analysis of multiple single nucleotide polymorphisms \(SNPs\) in )] TJ ET
BT 300.410 395.706 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 340.502 395.706 Td /F1 9.8 Tf  [( and )] TJ ET
BT 362.186 395.706 Td /F5 9.8 Tf  [(CYP2C9)] TJ ET
BT 400.114 395.706 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 359.103 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 339.149 Td /F1 9.8 Tf  [(Over 31 million warfarin prescriptions were dispensed in 2004. Bleeding from warfarin use is a common adverse event and can )] TJ ET
BT 26.250 327.244 Td /F1 9.8 Tf  [(cause substantial morbidity and mortality. )] TJ ET
0.267 0.267 0.267 rg
BT 207.775 327.244 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 290.642 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 270.687 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
0.271 0.267 0.267 RG
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40.337 254.697 40.154 255.141 39.838 255.457 c
39.522 255.773 39.078 255.957 38.631 255.957 c
38.185 255.957 37.741 255.773 37.425 255.457 c
37.109 255.141 36.925 254.697 36.925 254.250 c
36.925 253.804 37.109 253.360 37.425 253.044 c
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39.078 252.544 39.522 252.728 39.838 253.044 c
40.154 253.360 40.337 253.804 40.337 254.250 c f
BT 45.750 251.283 Td /F1 9.8 Tf  [(Rapid ACCE review )] TJ ET
0.267 0.267 0.267 rg
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0.271 0.267 0.267 rg
BT 145.444 251.283 Td /F1 9.8 Tf  [( from 2008 includes a discussion of ELSI issues and identifies knowledge gaps.)] TJ ET
BT 26.250 228.128 Td /F4 9.8 Tf  [(Recommendations by independent group*)] TJ ET
40.337 211.691 m 
40.337 212.137 40.154 212.581 39.838 212.897 c
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38.185 213.397 37.741 213.213 37.425 212.897 c
37.109 212.581 36.925 212.137 36.925 211.691 c
36.925 211.244 37.109 210.800 37.425 210.484 c
37.741 210.168 38.185 209.985 38.631 209.985 c
39.078 209.985 39.522 210.168 39.838 210.484 c
40.154 210.800 40.337 211.244 40.337 211.691 c f
BT 45.750 208.723 Td /F1 9.8 Tf  [(None identified)] TJ ET
BT 26.250 185.568 Td /F4 9.8 Tf  [(Guidelines by professional group)] TJ ET
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40.337 169.578 40.154 170.022 39.838 170.338 c
39.522 170.654 39.078 170.838 38.631 170.838 c
38.185 170.838 37.741 170.654 37.425 170.338 c
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39.078 167.425 39.522 167.609 39.838 167.925 c
40.154 168.241 40.337 168.685 40.337 169.131 c f
BT 45.750 166.164 Td /F1 9.8 Tf  [(2008 American College of Medical Genetics \(ACMG\) policy statement: �There is insufficient evidence, at this time, to )] TJ ET
BT 45.750 154.259 Td /F1 9.8 Tf  [(recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients.� )] TJ ET
0.267 0.267 0.267 rg
BT 442.945 154.259 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 131.104 Td /F1 9.8 Tf  [(2008 American College of Chest Physicians guideline statement: �We suggest against pharmacogeneitc-based dosing until )] TJ ET
BT 26.250 119.199 Td /F1 9.8 Tf  [(randomized data indicate that it is beneficial.� )] TJ ET
0.267 0.267 0.267 rg
BT 224.048 119.199 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 99.795 Td /F1 9.8 Tf  [(Some additional guidelines and recommendations can be found at Centers for Medicare & Medicaid Services Decision Memo )] TJ ET
BT 26.250 87.890 Td /F1 9.8 Tf  [(for Pharmacogenomic Testing for Warfarin Response \(CAG-00400N\)\(dated 8/3/2009\):)] TJ ET
BT 26.250 68.485 Td /F1 9.8 Tf  [(https://www.cms.gov/mcd/viewdecisionmemo.asp?from2=viewdecisionmemo.asp&id=224)] TJ ET
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BT 15.000 718.042 Td /F2 21.0 Tf  [(Testing of VKORC1 and CYP2C9 alleles to guide warfarin )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(dosing)] TJ ET
0.271 0.267 0.267 rg
BT 15.000 671.524 Td /F2 13.5 Tf  [(Test Category: Pharmacogenomic \(Treatment\))] TJ ET
Q
BT 15.000 653.050 Td /F3 9.8 Tf  [(September 14, 2010)] TJ ET
BT 26.250 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 37.092 641.209 Td /F1 9.8 Tf  [(Daurice Grossniklaus)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 629.304 Td /F1 9.8 Tf  [(Grossniklaus D. Testing of VKORC1 and CYP2C9 alleles to guide warfarin dosing: Test Category: Pharmacogenomic )] TJ ET
BT 26.250 617.400 Td /F1 9.8 Tf  [(\(Treatment\). PLOS Currents Evidence on Genomic Tests. 2010 Sep 14 . Edition 1. doi: 10.1371/currents.RRN1155.)] TJ ET
q
15.000 27.295 577.500 587.724 re W n
0.271 0.267 0.267 rg
BT 26.250 588.297 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 568.343 Td /F1 9.8 Tf  [(Warfarin is an oral anticoagulant that is widely prescribed to prevent thromboembolic events in persons at increased risk. The )] TJ ET
BT 26.250 556.438 Td /F1 9.8 Tf  [(optimal dose is difficult to establish because it can vary 10-fold among individuals due to clinical and demographic factors. )] TJ ET
BT 26.250 544.533 Td /F1 9.8 Tf  [(Testing for variants of the vitamin K epoxide reductase complex 1 \(VKORC1\) and cytochrome P450 2C9 \(CYP2C9\) genes has )] TJ ET
BT 26.250 532.629 Td /F1 9.8 Tf  [(been proposed for use in guiding the initial dose of warfarin, thus achieving optimal dosing more quickly and with lower risk of )] TJ ET
BT 26.250 520.724 Td /F1 9.8 Tf  [(bleeding.)] TJ ET
BT 26.250 484.121 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 464.167 Td /F1 9.8 Tf  [(Pharmacogenetic testing to guide warfarin dose selection for individuals at risk of a thromboembolic event with the goal of )] TJ ET
BT 26.250 452.262 Td /F1 9.8 Tf  [(shortening the time required to achieve a stable, effective dose and minimizing the risk of adverse effects. )] TJ ET
0.267 0.267 0.267 rg
BT 484.168 452.262 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 415.660 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 395.706 Td /F1 9.8 Tf  [(Analysis of multiple single nucleotide polymorphisms \(SNPs\) in )] TJ ET
BT 300.410 395.706 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 340.502 395.706 Td /F1 9.8 Tf  [( and )] TJ ET
BT 362.186 395.706 Td /F5 9.8 Tf  [(CYP2C9)] TJ ET
BT 400.114 395.706 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 359.103 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 339.149 Td /F1 9.8 Tf  [(Over 31 million warfarin prescriptions were dispensed in 2004. Bleeding from warfarin use is a common adverse event and can )] TJ ET
BT 26.250 327.244 Td /F1 9.8 Tf  [(cause substantial morbidity and mortality. )] TJ ET
0.267 0.267 0.267 rg
BT 207.775 327.244 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 290.642 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 270.687 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
0.271 0.267 0.267 RG
40.337 254.250 m 
40.337 254.697 40.154 255.141 39.838 255.457 c
39.522 255.773 39.078 255.957 38.631 255.957 c
38.185 255.957 37.741 255.773 37.425 255.457 c
37.109 255.141 36.925 254.697 36.925 254.250 c
36.925 253.804 37.109 253.360 37.425 253.044 c
37.741 252.728 38.185 252.544 38.631 252.544 c
39.078 252.544 39.522 252.728 39.838 253.044 c
40.154 253.360 40.337 253.804 40.337 254.250 c f
BT 45.750 251.283 Td /F1 9.8 Tf  [(Rapid ACCE review )] TJ ET
0.267 0.267 0.267 rg
BT 134.602 251.283 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 145.444 251.283 Td /F1 9.8 Tf  [( from 2008 includes a discussion of ELSI issues and identifies knowledge gaps.)] TJ ET
BT 26.250 228.128 Td /F4 9.8 Tf  [(Recommendations by independent group*)] TJ ET
40.337 211.691 m 
40.337 212.137 40.154 212.581 39.838 212.897 c
39.522 213.213 39.078 213.397 38.631 213.397 c
38.185 213.397 37.741 213.213 37.425 212.897 c
37.109 212.581 36.925 212.137 36.925 211.691 c
36.925 211.244 37.109 210.800 37.425 210.484 c
37.741 210.168 38.185 209.985 38.631 209.985 c
39.078 209.985 39.522 210.168 39.838 210.484 c
40.154 210.800 40.337 211.244 40.337 211.691 c f
BT 45.750 208.723 Td /F1 9.8 Tf  [(None identified)] TJ ET
BT 26.250 185.568 Td /F4 9.8 Tf  [(Guidelines by professional group)] TJ ET
40.337 169.131 m 
40.337 169.578 40.154 170.022 39.838 170.338 c
39.522 170.654 39.078 170.838 38.631 170.838 c
38.185 170.838 37.741 170.654 37.425 170.338 c
37.109 170.022 36.925 169.578 36.925 169.131 c
36.925 168.685 37.109 168.241 37.425 167.925 c
37.741 167.609 38.185 167.425 38.631 167.425 c
39.078 167.425 39.522 167.609 39.838 167.925 c
40.154 168.241 40.337 168.685 40.337 169.131 c f
BT 45.750 166.164 Td /F1 9.8 Tf  [(2008 American College of Medical Genetics \(ACMG\) policy statement: �There is insufficient evidence, at this time, to )] TJ ET
BT 45.750 154.259 Td /F1 9.8 Tf  [(recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients.� )] TJ ET
0.267 0.267 0.267 rg
BT 442.945 154.259 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 131.104 Td /F1 9.8 Tf  [(2008 American College of Chest Physicians guideline statement: �We suggest against pharmacogeneitc-based dosing until )] TJ ET
BT 26.250 119.199 Td /F1 9.8 Tf  [(randomized data indicate that it is beneficial.� )] TJ ET
0.267 0.267 0.267 rg
BT 224.048 119.199 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 99.795 Td /F1 9.8 Tf  [(Some additional guidelines and recommendations can be found at Centers for Medicare & Medicaid Services Decision Memo )] TJ ET
BT 26.250 87.890 Td /F1 9.8 Tf  [(for Pharmacogenomic Testing for Warfarin Response \(CAG-00400N\)\(dated 8/3/2009\):)] TJ ET
BT 26.250 68.485 Td /F1 9.8 Tf  [(https://www.cms.gov/mcd/viewdecisionmemo.asp?from2=viewdecisionmemo.asp&id=224)] TJ ET
Q
q
15.000 662.316 577.500 75.684 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(Testing of VKORC1 and CYP2C9 alleles to guide warfarin )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(dosing)] TJ ET
0.271 0.267 0.267 rg
BT 15.000 671.524 Td /F2 13.5 Tf  [(Test Category: Pharmacogenomic \(Treatment\))] TJ ET
Q
BT 15.000 653.050 Td /F3 9.8 Tf  [(September 14, 2010)] TJ ET
BT 26.250 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 37.092 641.209 Td /F1 9.8 Tf  [(Daurice Grossniklaus)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 629.304 Td /F1 9.8 Tf  [(Grossniklaus D. Testing of VKORC1 and CYP2C9 alleles to guide warfarin dosing: Test Category: Pharmacogenomic )] TJ ET
BT 26.250 617.400 Td /F1 9.8 Tf  [(\(Treatment\). PLOS Currents Evidence on Genomic Tests. 2010 Sep 14 . Edition 1. doi: 10.1371/currents.RRN1155.)] TJ ET
q
15.000 27.295 577.500 587.724 re W n
0.271 0.267 0.267 rg
BT 26.250 588.297 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 568.343 Td /F1 9.8 Tf  [(Warfarin is an oral anticoagulant that is widely prescribed to prevent thromboembolic events in persons at increased risk. The )] TJ ET
BT 26.250 556.438 Td /F1 9.8 Tf  [(optimal dose is difficult to establish because it can vary 10-fold among individuals due to clinical and demographic factors. )] TJ ET
BT 26.250 544.533 Td /F1 9.8 Tf  [(Testing for variants of the vitamin K epoxide reductase complex 1 \(VKORC1\) and cytochrome P450 2C9 \(CYP2C9\) genes has )] TJ ET
BT 26.250 532.629 Td /F1 9.8 Tf  [(been proposed for use in guiding the initial dose of warfarin, thus achieving optimal dosing more quickly and with lower risk of )] TJ ET
BT 26.250 520.724 Td /F1 9.8 Tf  [(bleeding.)] TJ ET
BT 26.250 484.121 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 464.167 Td /F1 9.8 Tf  [(Pharmacogenetic testing to guide warfarin dose selection for individuals at risk of a thromboembolic event with the goal of )] TJ ET
BT 26.250 452.262 Td /F1 9.8 Tf  [(shortening the time required to achieve a stable, effective dose and minimizing the risk of adverse effects. )] TJ ET
0.267 0.267 0.267 rg
BT 484.168 452.262 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 415.660 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 395.706 Td /F1 9.8 Tf  [(Analysis of multiple single nucleotide polymorphisms \(SNPs\) in )] TJ ET
BT 300.410 395.706 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 340.502 395.706 Td /F1 9.8 Tf  [( and )] TJ ET
BT 362.186 395.706 Td /F5 9.8 Tf  [(CYP2C9)] TJ ET
BT 400.114 395.706 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 359.103 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 339.149 Td /F1 9.8 Tf  [(Over 31 million warfarin prescriptions were dispensed in 2004. Bleeding from warfarin use is a common adverse event and can )] TJ ET
BT 26.250 327.244 Td /F1 9.8 Tf  [(cause substantial morbidity and mortality. )] TJ ET
0.267 0.267 0.267 rg
BT 207.775 327.244 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 290.642 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 270.687 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
0.271 0.267 0.267 RG
40.337 254.250 m 
40.337 254.697 40.154 255.141 39.838 255.457 c
39.522 255.773 39.078 255.957 38.631 255.957 c
38.185 255.957 37.741 255.773 37.425 255.457 c
37.109 255.141 36.925 254.697 36.925 254.250 c
36.925 253.804 37.109 253.360 37.425 253.044 c
37.741 252.728 38.185 252.544 38.631 252.544 c
39.078 252.544 39.522 252.728 39.838 253.044 c
40.154 253.360 40.337 253.804 40.337 254.250 c f
BT 45.750 251.283 Td /F1 9.8 Tf  [(Rapid ACCE review )] TJ ET
0.267 0.267 0.267 rg
BT 134.602 251.283 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 145.444 251.283 Td /F1 9.8 Tf  [( from 2008 includes a discussion of ELSI issues and identifies knowledge gaps.)] TJ ET
BT 26.250 228.128 Td /F4 9.8 Tf  [(Recommendations by independent group*)] TJ ET
40.337 211.691 m 
40.337 212.137 40.154 212.581 39.838 212.897 c
39.522 213.213 39.078 213.397 38.631 213.397 c
38.185 213.397 37.741 213.213 37.425 212.897 c
37.109 212.581 36.925 212.137 36.925 211.691 c
36.925 211.244 37.109 210.800 37.425 210.484 c
37.741 210.168 38.185 209.985 38.631 209.985 c
39.078 209.985 39.522 210.168 39.838 210.484 c
40.154 210.800 40.337 211.244 40.337 211.691 c f
BT 45.750 208.723 Td /F1 9.8 Tf  [(None identified)] TJ ET
BT 26.250 185.568 Td /F4 9.8 Tf  [(Guidelines by professional group)] TJ ET
40.337 169.131 m 
40.337 169.578 40.154 170.022 39.838 170.338 c
39.522 170.654 39.078 170.838 38.631 170.838 c
38.185 170.838 37.741 170.654 37.425 170.338 c
37.109 170.022 36.925 169.578 36.925 169.131 c
36.925 168.685 37.109 168.241 37.425 167.925 c
37.741 167.609 38.185 167.425 38.631 167.425 c
39.078 167.425 39.522 167.609 39.838 167.925 c
40.154 168.241 40.337 168.685 40.337 169.131 c f
BT 45.750 166.164 Td /F1 9.8 Tf  [(2008 American College of Medical Genetics \(ACMG\) policy statement: �There is insufficient evidence, at this time, to )] TJ ET
BT 45.750 154.259 Td /F1 9.8 Tf  [(recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients.� )] TJ ET
0.267 0.267 0.267 rg
BT 442.945 154.259 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 131.104 Td /F1 9.8 Tf  [(2008 American College of Chest Physicians guideline statement: �We suggest against pharmacogeneitc-based dosing until )] TJ ET
BT 26.250 119.199 Td /F1 9.8 Tf  [(randomized data indicate that it is beneficial.� )] TJ ET
0.267 0.267 0.267 rg
BT 224.048 119.199 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 99.795 Td /F1 9.8 Tf  [(Some additional guidelines and recommendations can be found at Centers for Medicare & Medicaid Services Decision Memo )] TJ ET
BT 26.250 87.890 Td /F1 9.8 Tf  [(for Pharmacogenomic Testing for Warfarin Response \(CAG-00400N\)\(dated 8/3/2009\):)] TJ ET
BT 26.250 68.485 Td /F1 9.8 Tf  [(https://www.cms.gov/mcd/viewdecisionmemo.asp?from2=viewdecisionmemo.asp&id=224)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(1)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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0.271 0.267 0.267 rg
40.337 608.708 m 
40.337 609.155 40.154 609.599 39.838 609.915 c
39.522 610.231 39.078 610.415 38.631 610.415 c
38.185 610.415 37.741 610.231 37.425 609.915 c
37.109 609.599 36.925 609.155 36.925 608.708 c
36.925 608.262 37.109 607.818 37.425 607.502 c
37.741 607.186 38.185 607.002 38.631 607.002 c
39.078 607.002 39.522 607.186 39.838 607.502 c
40.154 607.818 40.337 608.262 40.337 608.708 c f
BT 45.750 605.741 Td /F1 9.8 Tf  [(College of American Pathology \(CAP\)/American College of Medical Genetics proficiency testing program for warfarin )] TJ ET
BT 45.750 593.836 Td /F1 9.8 Tf  [(pharmacogenetic testing may improve access to analytic validity data. )] TJ ET
0.267 0.267 0.267 rg
BT 349.745 593.836 Td /F1 9.8 Tf  [([3][4])] TJ ET
BT 45.750 581.931 Td /F1 9.8 Tf  [(https://www.cap.org/apps/docs/proficiency_testing/surveys_catalog/2010_surveys_catalog.pdf#page=214)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 558.777 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 558.777 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 558.777 Td /F1 9.8 Tf  [( Test accuracy and reliability in predicting appropriate warfarin dose \(predictive value\).)] TJ ET
40.337 542.339 m 
40.337 542.786 40.154 543.230 39.838 543.546 c
39.522 543.862 39.078 544.046 38.631 544.046 c
38.185 544.046 37.741 543.862 37.425 543.546 c
37.109 543.230 36.925 542.786 36.925 542.339 c
36.925 541.893 37.109 541.449 37.425 541.133 c
37.741 540.817 38.185 540.633 38.631 540.633 c
39.078 540.633 39.522 540.817 39.838 541.133 c
40.154 541.449 40.337 541.893 40.337 542.339 c f
BT 45.750 539.372 Td /F1 9.8 Tf  [(Published studies have examined the relationship of CYP2C9 alleles to warfarin dose. )] TJ ET
0.267 0.267 0.267 rg
BT 419.126 539.372 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 526.685 m 
59.837 527.131 59.654 527.575 59.338 527.891 c
59.022 528.207 58.578 528.391 58.131 528.391 c
57.685 528.391 57.241 528.207 56.925 527.891 c
56.609 527.575 56.425 527.131 56.425 526.685 c
56.425 526.238 56.609 525.794 56.925 525.478 c
57.241 525.162 57.685 524.978 58.131 524.978 c
58.578 524.978 59.022 525.162 59.338 525.478 c
59.654 525.794 59.837 526.238 59.837 526.685 c s
0.267 0.267 0.267 rg
BT 65.250 523.717 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.271 0.267 0.267 rg
BT 136.230 523.717 Td /F1 9.8 Tf  [(: query �)] TJ ET
0.267 0.267 0.267 rg
BT 171.993 523.717 Td /F1 9.8 Tf  [(warfarin and CYP2C9)] TJ ET
0.271 0.267 0.267 rg
BT 266.275 523.717 Td /F1 9.8 Tf  [(�)] TJ ET
40.337 499.780 m 
40.337 500.227 40.154 500.671 39.838 500.987 c
39.522 501.302 39.078 501.486 38.631 501.486 c
38.185 501.486 37.741 501.302 37.425 500.987 c
37.109 500.671 36.925 500.227 36.925 499.780 c
36.925 499.333 37.109 498.889 37.425 498.573 c
37.741 498.258 38.185 498.074 38.631 498.074 c
39.078 498.074 39.522 498.258 39.838 498.573 c
40.154 498.889 40.337 499.333 40.337 499.780 c f
BT 45.750 496.812 Td /F1 9.8 Tf  [(Published studies have examined the relationship of VKORC1 alleles to warfarin dose. )] TJ ET
0.267 0.267 0.267 rg
BT 421.291 496.812 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 484.125 m 
59.837 484.572 59.654 485.016 59.338 485.332 c
59.022 485.648 58.578 485.831 58.131 485.831 c
57.685 485.831 57.241 485.648 56.925 485.332 c
56.609 485.016 56.425 484.572 56.425 484.125 c
56.425 483.679 56.609 483.235 56.925 482.919 c
57.241 482.603 57.685 482.419 58.131 482.419 c
58.578 482.419 59.022 482.603 59.338 482.919 c
59.654 483.235 59.837 483.679 59.837 484.125 c s
0.267 0.267 0.267 rg
BT 65.250 481.158 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.271 0.267 0.267 rg
BT 136.230 481.158 Td /F1 9.8 Tf  [(: query �)] TJ ET
0.267 0.267 0.267 rg
BT 171.993 481.158 Td /F1 9.8 Tf  [(warfarin and VKORC1)] TJ ET
0.271 0.267 0.267 rg
BT 268.440 481.158 Td /F1 9.8 Tf  [(�)] TJ ET
40.337 457.220 m 
40.337 457.667 40.154 458.111 39.838 458.427 c
39.522 458.743 39.078 458.927 38.631 458.927 c
38.185 458.927 37.741 458.743 37.425 458.427 c
37.109 458.111 36.925 457.667 36.925 457.220 c
36.925 456.774 37.109 456.330 37.425 456.014 c
37.741 455.698 38.185 455.514 38.631 455.514 c
39.078 455.514 39.522 455.698 39.838 456.014 c
40.154 456.330 40.337 456.774 40.337 457.220 c f
BT 45.750 454.253 Td /F1 9.8 Tf  [(The ACCE review and ACMG guideline reported that there is evidence that CYP2C9 and VKORC1 variants are correlated )] TJ ET
BT 45.750 442.348 Td /F1 9.8 Tf  [(with the stable warfarin dose. There is limited evidence for an association between CYP2C9 and severe bleeding events, )] TJ ET
BT 45.750 430.443 Td /F1 9.8 Tf  [(and an absence of evidence for bleeding events associated with VKORC1. )] TJ ET
0.267 0.267 0.267 rg
BT 370.376 430.443 Td /F1 9.8 Tf  [([3][4])] TJ ET
0.271 0.267 0.267 rg
BT 45.750 407.289 Td /F1 9.8 Tf  [(Recent additions to the literature:)] TJ ET
40.337 390.851 m 
40.337 391.298 40.154 391.742 39.838 392.058 c
39.522 392.374 39.078 392.558 38.631 392.558 c
38.185 392.558 37.741 392.374 37.425 392.058 c
37.109 391.742 36.925 391.298 36.925 390.851 c
36.925 390.405 37.109 389.961 37.425 389.645 c
37.741 389.329 38.185 389.145 38.631 389.145 c
39.078 389.145 39.522 389.329 39.838 389.645 c
40.154 389.961 40.337 390.405 40.337 390.851 c f
BT 45.750 387.884 Td /F1 9.8 Tf  [(A study designed to compare a clinical algorithm versus a pharmacogenetic algorithm using INR values \(day 4 or 5 of )] TJ ET
BT 45.750 375.979 Td /F1 9.8 Tf  [(treatment\), clinical factors and genotype to predict warfarin dose. In the derivation set \(N=969\), the clinical algorithm had an )] TJ ET
BT 45.750 364.074 Td /F1 9.8 Tf  [(coefficient of determination R\(2\) of 48% and the pharmacogenetic algorithm had an R\(2\) of 63% in predicting warfarin )] TJ ET
BT 45.750 352.170 Td /F1 9.8 Tf  [(dose. In independent validation sets, the clinical algorithm had an R\(2\) of 26-43% and the pharmacogenetic algorithm had )] TJ ET
BT 45.750 340.265 Td /F1 9.8 Tf  [(an R\(2\) of 42-58% in predicting warfarin dose. )] TJ ET
0.267 0.267 0.267 rg
BT 247.331 340.265 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
40.337 327.578 m 
40.337 328.024 40.154 328.468 39.838 328.784 c
39.522 329.100 39.078 329.284 38.631 329.284 c
38.185 329.284 37.741 329.100 37.425 328.784 c
37.109 328.468 36.925 328.024 36.925 327.578 c
36.925 327.131 37.109 326.687 37.425 326.371 c
37.741 326.055 38.185 325.872 38.631 325.872 c
39.078 325.872 39.522 326.055 39.838 326.371 c
40.154 326.687 40.337 327.131 40.337 327.578 c f
BT 45.750 324.610 Td /F1 9.8 Tf  [(A retrospective cohort study designed to examine the accuracy of pharmacogenetic warfarin dosing algorithms in predicting )] TJ ET
BT 45.750 312.705 Td /F1 9.8 Tf  [(warfarin dose. Data from 71 adult patients at an outpatient anticoagulation clinic on a stable, therapeutic warfarin dose were )] TJ ET
BT 45.750 300.801 Td /F1 9.8 Tf  [(included in the analysis. Six pharmacogenetic warfarin dosing algorithms and a 5 mg fixed dose approach were evaluated. )] TJ ET
BT 45.750 288.896 Td /F1 9.8 Tf  [(The algorithms published by Gage et al. 2008 and the IWPC 2009 were the most accurate in predicting warfarin dose in the )] TJ ET
BT 45.750 276.991 Td /F1 9.8 Tf  [(study population. )] TJ ET
0.267 0.267 0.267 rg
BT 122.171 276.991 Td /F1 9.8 Tf  [([8])] TJ ET
0.271 0.267 0.267 rg
40.337 264.304 m 
40.337 264.751 40.154 265.195 39.838 265.511 c
39.522 265.826 39.078 266.010 38.631 266.010 c
38.185 266.010 37.741 265.826 37.425 265.511 c
37.109 265.195 36.925 264.751 36.925 264.304 c
36.925 263.857 37.109 263.413 37.425 263.097 c
37.741 262.782 38.185 262.598 38.631 262.598 c
39.078 262.598 39.522 262.782 39.838 263.097 c
40.154 263.413 40.337 263.857 40.337 264.304 c f
BT 45.750 261.336 Td /F1 9.8 Tf  [(A study designed to compare the International Warfarin Pharmacogenetics Consoritum \(IWPC\) algorithm versus a clinical )] TJ ET
BT 45.750 249.432 Td /F1 9.8 Tf  [(algorithm in cohort of Japanese patients \(n=200\). The purpose was to determine the percentage of Japanese patients for )] TJ ET
BT 45.750 237.527 Td /F1 9.8 Tf  [(whom the predicted dose deviated by less than 7mg/week from the actual dose. The IWPC algorithm identified a larger )] TJ ET
BT 45.750 225.622 Td /F1 9.8 Tf  [(percentage of patients to achieve the target INR than did the clinical algorithm. )] TJ ET
0.267 0.267 0.267 rg
BT 386.630 225.622 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
40.337 212.935 m 
40.337 213.382 40.154 213.826 39.838 214.142 c
39.522 214.457 39.078 214.641 38.631 214.641 c
38.185 214.641 37.741 214.457 37.425 214.142 c
37.109 213.826 36.925 213.382 36.925 212.935 c
36.925 212.488 37.109 212.044 37.425 211.728 c
37.741 211.413 38.185 211.229 38.631 211.229 c
39.078 211.229 39.522 211.413 39.838 211.728 c
40.154 212.044 40.337 212.488 40.337 212.935 c f
BT 45.750 209.967 Td /F1 9.8 Tf  [(A study by the International Warfarin Pharmacogenetics Consortium reported a comprehensive assessment of the )] TJ ET
BT 45.750 198.063 Td /F1 9.8 Tf  [(influence of six )] TJ ET
BT 112.947 198.063 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 153.039 198.063 Td /F1 9.8 Tf  [( SNPs and haplotypes on warfarin dose prediction in a cohort of Asians \(n=1103\), blacks \(n=670\), )] TJ ET
BT 45.750 186.158 Td /F1 9.8 Tf  [(and whites \(n=3113\). )] TJ ET
0.267 0.267 0.267 rg
BT 139.779 186.158 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 173.471 m 
59.837 173.917 59.654 174.361 59.338 174.677 c
59.022 174.993 58.578 175.177 58.131 175.177 c
57.685 175.177 57.241 174.993 56.925 174.677 c
56.609 174.361 56.425 173.917 56.425 173.471 c
56.425 173.024 56.609 172.580 56.925 172.264 c
57.241 171.948 57.685 171.764 58.131 171.764 c
58.578 171.764 59.022 171.948 59.338 172.264 c
59.654 172.580 59.837 173.024 59.837 173.471 c s
BT 65.250 170.503 Td /F1 9.8 Tf  [(VKORC1-1639G>A and 1173C>T individually explained the greatest variance in warfarin dose across the three racial )] TJ ET
BT 65.250 158.598 Td /F1 9.8 Tf  [(groups. Including additional )] TJ ET
BT 186.647 158.598 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 226.739 158.598 Td /F1 9.8 Tf  [( SNPS and haplotypes did not further improve warfarin dose prediction.)] TJ ET
0.39 w 1 J 1 j
59.837 145.911 m 
59.837 146.358 59.654 146.802 59.338 147.118 c
59.022 147.434 58.578 147.617 58.131 147.617 c
57.685 147.617 57.241 147.434 56.925 147.118 c
56.609 146.802 56.425 146.358 56.425 145.911 c
56.425 145.465 56.609 145.021 56.925 144.705 c
57.241 144.389 57.685 144.205 58.131 144.205 c
58.578 144.205 59.022 144.389 59.338 144.705 c
59.654 145.021 59.837 145.465 59.837 145.911 c s
BT 65.250 142.944 Td /F5 9.8 Tf  [(VKORC1 )] TJ ET
BT 108.053 142.944 Td /F1 9.8 Tf  [(explained greater variability in warfarin dose among whites than in Asians or blacks, a finding explained )] TJ ET
BT 65.250 131.039 Td /F1 9.8 Tf  [(largely by race-specific differences in the frequency of the -1639 A and 1173T alleles.)] TJ ET
40.337 107.102 m 
40.337 107.548 40.154 107.992 39.838 108.308 c
39.522 108.624 39.078 108.808 38.631 108.808 c
38.185 108.808 37.741 108.624 37.425 108.308 c
37.109 107.992 36.925 107.548 36.925 107.102 c
36.925 106.655 37.109 106.211 37.425 105.895 c
37.741 105.579 38.185 105.395 38.631 105.395 c
39.078 105.395 39.522 105.579 39.838 105.895 c
40.154 106.211 40.337 106.655 40.337 107.102 c f
BT 45.750 104.134 Td /F1 9.8 Tf  [(A study designed to examine the effect of)] TJ ET
BT 224.604 104.134 Td /F5 9.8 Tf  [( CYP2C9)] TJ ET
BT 265.242 104.134 Td /F1 9.8 Tf  [( and )] TJ ET
BT 286.926 104.134 Td /F5 9.8 Tf  [(VKORC1 )] TJ ET
BT 329.728 104.134 Td /F1 9.8 Tf  [(genotypes on rate of International Normalized Ratio \(INR\) )] TJ ET
BT 45.750 92.229 Td /F1 9.8 Tf  [(increase, anticoagulation maintenance, risk of over anticoagulation, and change in dose over 30 days. )] TJ ET
0.267 0.267 0.267 rg
BT 487.981 92.229 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 79.542 m 
59.837 79.989 59.654 80.433 59.338 80.749 c
59.022 81.065 58.578 81.248 58.131 81.248 c
57.685 81.248 57.241 81.065 56.925 80.749 c
56.609 80.433 56.425 79.989 56.425 79.542 c
56.425 79.096 56.609 78.652 56.925 78.336 c
57.241 78.020 57.685 77.836 58.131 77.836 c
58.578 77.836 59.022 78.020 59.338 78.336 c
59.654 78.652 59.837 79.096 59.837 79.542 c s
BT 65.250 76.575 Td /F1 9.8 Tf  [(The )] TJ ET
BT 84.760 76.575 Td /F5 9.8 Tf  [(VKORC1 )] TJ ET
BT 127.562 76.575 Td /F1 9.8 Tf  [(variant genotype \(with/without the )] TJ ET
BT 275.509 76.575 Td /F5 9.8 Tf  [(CYP2C9 )] TJ ET
BT 316.147 76.575 Td /F1 9.8 Tf  [(variant genotype\) was associated with higher risk of over )] TJ ET
BT 65.250 64.670 Td /F1 9.8 Tf  [(anti-coagulation in European Americans but not African Americans.)] TJ ET
0.39 w 1 J 1 j
59.837 51.983 m 
59.837 52.429 59.654 52.873 59.338 53.189 c
59.022 53.505 58.578 53.689 58.131 53.689 c
57.685 53.689 57.241 53.505 56.925 53.189 c
56.609 52.873 56.425 52.429 56.425 51.983 c
56.425 51.536 56.609 51.092 56.925 50.776 c
57.241 50.460 57.685 50.276 58.131 50.276 c
58.578 50.276 59.022 50.460 59.338 50.776 c
59.654 51.092 59.837 51.536 59.837 51.983 c s
BT 65.250 49.015 Td /F1 9.8 Tf  [(The risk of minor hemorrhage was not influenced by either)] TJ ET
BT 316.683 49.015 Td /F5 9.8 Tf  [( CYP2C9)] TJ ET
BT 357.321 49.015 Td /F1 9.8 Tf  [( or )] TJ ET
BT 371.410 49.015 Td /F5 9.8 Tf  [(VKORC1 )] TJ ET
BT 414.212 49.015 Td /F1 9.8 Tf  [(genotype.)] TJ ET
Q
q
15.000 42.884 577.500 734.116 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F5 9.8 Tf  [(* independent groups include the US Preventive Services Task Force \(USPSTF\) and Evaluation of Genomic)] TJ ET
BT 492.817 767.476 Td /F5 9.8 Tf  [(Applications in )] TJ ET
BT 26.250 755.571 Td /F5 9.8 Tf  [(Practice and Prevention \(EGAPP\) Working Group.)] TJ ET
BT 26.250 718.969 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 699.015 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 699.015 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 699.015 Td /F1 9.8 Tf  [(Test accuracy and reliability in identifying alleles at multiple SNPs \(analytic sensitivity and specificity\).)] TJ ET
0.271 0.267 0.267 RG
40.337 682.577 m 
40.337 683.024 40.154 683.468 39.838 683.784 c
39.522 684.100 39.078 684.284 38.631 684.284 c
38.185 684.284 37.741 684.100 37.425 683.784 c
37.109 683.468 36.925 683.024 36.925 682.577 c
36.925 682.131 37.109 681.687 37.425 681.371 c
37.741 681.055 38.185 680.871 38.631 680.871 c
39.078 680.871 39.522 681.055 39.838 681.371 c
40.154 681.687 40.337 682.131 40.337 682.577 c f
BT 45.750 679.610 Td /F1 9.8 Tf  [(Based on findings from a ACCE evidence review and ACMG policy statement: )] TJ ET
0.39 w 1 J 1 j
59.837 666.923 m 
59.837 667.369 59.654 667.813 59.338 668.129 c
59.022 668.445 58.578 668.629 58.131 668.629 c
57.685 668.629 57.241 668.445 56.925 668.129 c
56.609 667.813 56.425 667.369 56.425 666.923 c
56.425 666.476 56.609 666.032 56.925 665.716 c
57.241 665.400 57.685 665.216 58.131 665.216 c
58.578 665.216 59.022 665.400 59.338 665.716 c
59.654 666.032 59.837 666.476 59.837 666.923 c s
BT 65.250 663.955 Td /F1 9.8 Tf  [(Limited data on analytic validity are available from laboratories performing these tests. )] TJ ET
0.267 0.267 0.267 rg
BT 438.607 663.955 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 651.268 m 
59.837 651.715 59.654 652.159 59.338 652.475 c
59.022 652.790 58.578 652.974 58.131 652.974 c
57.685 652.974 57.241 652.790 56.925 652.475 c
56.609 652.159 56.425 651.715 56.425 651.268 c
56.425 650.821 56.609 650.377 56.925 650.061 c
57.241 649.746 57.685 649.562 58.131 649.562 c
58.578 649.562 59.022 649.746 59.338 650.061 c
59.654 650.377 59.837 650.821 59.837 651.268 c s
BT 65.250 648.300 Td /F1 9.8 Tf  [(High analytic sensitivity and specificity is expected for testing of common CYP2C9 alleles. )] TJ ET
0.267 0.267 0.267 rg
BT 454.850 648.300 Td /F1 9.8 Tf  [([3] [4])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 635.613 m 
59.837 636.060 59.654 636.504 59.338 636.820 c
59.022 637.136 58.578 637.319 58.131 637.319 c
57.685 637.319 57.241 637.136 56.925 636.820 c
56.609 636.504 56.425 636.060 56.425 635.613 c
56.425 635.167 56.609 634.723 56.925 634.407 c
57.241 634.091 57.685 633.907 58.131 633.907 c
58.578 633.907 59.022 634.091 59.338 634.407 c
59.654 634.723 59.837 635.167 59.837 635.613 c s
BT 65.250 632.646 Td /F1 9.8 Tf  [(Few data are available for evaluation on analytic sensitivity and specificity of testing for VKORC1alleles. )] TJ ET
0.267 0.267 0.267 rg
BT 515.017 632.646 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
40.337 608.708 m 
40.337 609.155 40.154 609.599 39.838 609.915 c
39.522 610.231 39.078 610.415 38.631 610.415 c
38.185 610.415 37.741 610.231 37.425 609.915 c
37.109 609.599 36.925 609.155 36.925 608.708 c
36.925 608.262 37.109 607.818 37.425 607.502 c
37.741 607.186 38.185 607.002 38.631 607.002 c
39.078 607.002 39.522 607.186 39.838 607.502 c
40.154 607.818 40.337 608.262 40.337 608.708 c f
BT 45.750 605.741 Td /F1 9.8 Tf  [(College of American Pathology \(CAP\)/American College of Medical Genetics proficiency testing program for warfarin )] TJ ET
BT 45.750 593.836 Td /F1 9.8 Tf  [(pharmacogenetic testing may improve access to analytic validity data. )] TJ ET
0.267 0.267 0.267 rg
BT 349.745 593.836 Td /F1 9.8 Tf  [([3][4])] TJ ET
BT 45.750 581.931 Td /F1 9.8 Tf  [(https://www.cap.org/apps/docs/proficiency_testing/surveys_catalog/2010_surveys_catalog.pdf#page=214)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 558.777 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 558.777 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 558.777 Td /F1 9.8 Tf  [( Test accuracy and reliability in predicting appropriate warfarin dose \(predictive value\).)] TJ ET
40.337 542.339 m 
40.337 542.786 40.154 543.230 39.838 543.546 c
39.522 543.862 39.078 544.046 38.631 544.046 c
38.185 544.046 37.741 543.862 37.425 543.546 c
37.109 543.230 36.925 542.786 36.925 542.339 c
36.925 541.893 37.109 541.449 37.425 541.133 c
37.741 540.817 38.185 540.633 38.631 540.633 c
39.078 540.633 39.522 540.817 39.838 541.133 c
40.154 541.449 40.337 541.893 40.337 542.339 c f
BT 45.750 539.372 Td /F1 9.8 Tf  [(Published studies have examined the relationship of CYP2C9 alleles to warfarin dose. )] TJ ET
0.267 0.267 0.267 rg
BT 419.126 539.372 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 526.685 m 
59.837 527.131 59.654 527.575 59.338 527.891 c
59.022 528.207 58.578 528.391 58.131 528.391 c
57.685 528.391 57.241 528.207 56.925 527.891 c
56.609 527.575 56.425 527.131 56.425 526.685 c
56.425 526.238 56.609 525.794 56.925 525.478 c
57.241 525.162 57.685 524.978 58.131 524.978 c
58.578 524.978 59.022 525.162 59.338 525.478 c
59.654 525.794 59.837 526.238 59.837 526.685 c s
0.267 0.267 0.267 rg
BT 65.250 523.717 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.271 0.267 0.267 rg
BT 136.230 523.717 Td /F1 9.8 Tf  [(: query �)] TJ ET
0.267 0.267 0.267 rg
BT 171.993 523.717 Td /F1 9.8 Tf  [(warfarin and CYP2C9)] TJ ET
0.271 0.267 0.267 rg
BT 266.275 523.717 Td /F1 9.8 Tf  [(�)] TJ ET
40.337 499.780 m 
40.337 500.227 40.154 500.671 39.838 500.987 c
39.522 501.302 39.078 501.486 38.631 501.486 c
38.185 501.486 37.741 501.302 37.425 500.987 c
37.109 500.671 36.925 500.227 36.925 499.780 c
36.925 499.333 37.109 498.889 37.425 498.573 c
37.741 498.258 38.185 498.074 38.631 498.074 c
39.078 498.074 39.522 498.258 39.838 498.573 c
40.154 498.889 40.337 499.333 40.337 499.780 c f
BT 45.750 496.812 Td /F1 9.8 Tf  [(Published studies have examined the relationship of VKORC1 alleles to warfarin dose. )] TJ ET
0.267 0.267 0.267 rg
BT 421.291 496.812 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 484.125 m 
59.837 484.572 59.654 485.016 59.338 485.332 c
59.022 485.648 58.578 485.831 58.131 485.831 c
57.685 485.831 57.241 485.648 56.925 485.332 c
56.609 485.016 56.425 484.572 56.425 484.125 c
56.425 483.679 56.609 483.235 56.925 482.919 c
57.241 482.603 57.685 482.419 58.131 482.419 c
58.578 482.419 59.022 482.603 59.338 482.919 c
59.654 483.235 59.837 483.679 59.837 484.125 c s
0.267 0.267 0.267 rg
BT 65.250 481.158 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.271 0.267 0.267 rg
BT 136.230 481.158 Td /F1 9.8 Tf  [(: query �)] TJ ET
0.267 0.267 0.267 rg
BT 171.993 481.158 Td /F1 9.8 Tf  [(warfarin and VKORC1)] TJ ET
0.271 0.267 0.267 rg
BT 268.440 481.158 Td /F1 9.8 Tf  [(�)] TJ ET
40.337 457.220 m 
40.337 457.667 40.154 458.111 39.838 458.427 c
39.522 458.743 39.078 458.927 38.631 458.927 c
38.185 458.927 37.741 458.743 37.425 458.427 c
37.109 458.111 36.925 457.667 36.925 457.220 c
36.925 456.774 37.109 456.330 37.425 456.014 c
37.741 455.698 38.185 455.514 38.631 455.514 c
39.078 455.514 39.522 455.698 39.838 456.014 c
40.154 456.330 40.337 456.774 40.337 457.220 c f
BT 45.750 454.253 Td /F1 9.8 Tf  [(The ACCE review and ACMG guideline reported that there is evidence that CYP2C9 and VKORC1 variants are correlated )] TJ ET
BT 45.750 442.348 Td /F1 9.8 Tf  [(with the stable warfarin dose. There is limited evidence for an association between CYP2C9 and severe bleeding events, )] TJ ET
BT 45.750 430.443 Td /F1 9.8 Tf  [(and an absence of evidence for bleeding events associated with VKORC1. )] TJ ET
0.267 0.267 0.267 rg
BT 370.376 430.443 Td /F1 9.8 Tf  [([3][4])] TJ ET
0.271 0.267 0.267 rg
BT 45.750 407.289 Td /F1 9.8 Tf  [(Recent additions to the literature:)] TJ ET
40.337 390.851 m 
40.337 391.298 40.154 391.742 39.838 392.058 c
39.522 392.374 39.078 392.558 38.631 392.558 c
38.185 392.558 37.741 392.374 37.425 392.058 c
37.109 391.742 36.925 391.298 36.925 390.851 c
36.925 390.405 37.109 389.961 37.425 389.645 c
37.741 389.329 38.185 389.145 38.631 389.145 c
39.078 389.145 39.522 389.329 39.838 389.645 c
40.154 389.961 40.337 390.405 40.337 390.851 c f
BT 45.750 387.884 Td /F1 9.8 Tf  [(A study designed to compare a clinical algorithm versus a pharmacogenetic algorithm using INR values \(day 4 or 5 of )] TJ ET
BT 45.750 375.979 Td /F1 9.8 Tf  [(treatment\), clinical factors and genotype to predict warfarin dose. In the derivation set \(N=969\), the clinical algorithm had an )] TJ ET
BT 45.750 364.074 Td /F1 9.8 Tf  [(coefficient of determination R\(2\) of 48% and the pharmacogenetic algorithm had an R\(2\) of 63% in predicting warfarin )] TJ ET
BT 45.750 352.170 Td /F1 9.8 Tf  [(dose. In independent validation sets, the clinical algorithm had an R\(2\) of 26-43% and the pharmacogenetic algorithm had )] TJ ET
BT 45.750 340.265 Td /F1 9.8 Tf  [(an R\(2\) of 42-58% in predicting warfarin dose. )] TJ ET
0.267 0.267 0.267 rg
BT 247.331 340.265 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
40.337 327.578 m 
40.337 328.024 40.154 328.468 39.838 328.784 c
39.522 329.100 39.078 329.284 38.631 329.284 c
38.185 329.284 37.741 329.100 37.425 328.784 c
37.109 328.468 36.925 328.024 36.925 327.578 c
36.925 327.131 37.109 326.687 37.425 326.371 c
37.741 326.055 38.185 325.872 38.631 325.872 c
39.078 325.872 39.522 326.055 39.838 326.371 c
40.154 326.687 40.337 327.131 40.337 327.578 c f
BT 45.750 324.610 Td /F1 9.8 Tf  [(A retrospective cohort study designed to examine the accuracy of pharmacogenetic warfarin dosing algorithms in predicting )] TJ ET
BT 45.750 312.705 Td /F1 9.8 Tf  [(warfarin dose. Data from 71 adult patients at an outpatient anticoagulation clinic on a stable, therapeutic warfarin dose were )] TJ ET
BT 45.750 300.801 Td /F1 9.8 Tf  [(included in the analysis. Six pharmacogenetic warfarin dosing algorithms and a 5 mg fixed dose approach were evaluated. )] TJ ET
BT 45.750 288.896 Td /F1 9.8 Tf  [(The algorithms published by Gage et al. 2008 and the IWPC 2009 were the most accurate in predicting warfarin dose in the )] TJ ET
BT 45.750 276.991 Td /F1 9.8 Tf  [(study population. )] TJ ET
0.267 0.267 0.267 rg
BT 122.171 276.991 Td /F1 9.8 Tf  [([8])] TJ ET
0.271 0.267 0.267 rg
40.337 264.304 m 
40.337 264.751 40.154 265.195 39.838 265.511 c
39.522 265.826 39.078 266.010 38.631 266.010 c
38.185 266.010 37.741 265.826 37.425 265.511 c
37.109 265.195 36.925 264.751 36.925 264.304 c
36.925 263.857 37.109 263.413 37.425 263.097 c
37.741 262.782 38.185 262.598 38.631 262.598 c
39.078 262.598 39.522 262.782 39.838 263.097 c
40.154 263.413 40.337 263.857 40.337 264.304 c f
BT 45.750 261.336 Td /F1 9.8 Tf  [(A study designed to compare the International Warfarin Pharmacogenetics Consoritum \(IWPC\) algorithm versus a clinical )] TJ ET
BT 45.750 249.432 Td /F1 9.8 Tf  [(algorithm in cohort of Japanese patients \(n=200\). The purpose was to determine the percentage of Japanese patients for )] TJ ET
BT 45.750 237.527 Td /F1 9.8 Tf  [(whom the predicted dose deviated by less than 7mg/week from the actual dose. The IWPC algorithm identified a larger )] TJ ET
BT 45.750 225.622 Td /F1 9.8 Tf  [(percentage of patients to achieve the target INR than did the clinical algorithm. )] TJ ET
0.267 0.267 0.267 rg
BT 386.630 225.622 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
40.337 212.935 m 
40.337 213.382 40.154 213.826 39.838 214.142 c
39.522 214.457 39.078 214.641 38.631 214.641 c
38.185 214.641 37.741 214.457 37.425 214.142 c
37.109 213.826 36.925 213.382 36.925 212.935 c
36.925 212.488 37.109 212.044 37.425 211.728 c
37.741 211.413 38.185 211.229 38.631 211.229 c
39.078 211.229 39.522 211.413 39.838 211.728 c
40.154 212.044 40.337 212.488 40.337 212.935 c f
BT 45.750 209.967 Td /F1 9.8 Tf  [(A study by the International Warfarin Pharmacogenetics Consortium reported a comprehensive assessment of the )] TJ ET
BT 45.750 198.063 Td /F1 9.8 Tf  [(influence of six )] TJ ET
BT 112.947 198.063 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 153.039 198.063 Td /F1 9.8 Tf  [( SNPs and haplotypes on warfarin dose prediction in a cohort of Asians \(n=1103\), blacks \(n=670\), )] TJ ET
BT 45.750 186.158 Td /F1 9.8 Tf  [(and whites \(n=3113\). )] TJ ET
0.267 0.267 0.267 rg
BT 139.779 186.158 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 173.471 m 
59.837 173.917 59.654 174.361 59.338 174.677 c
59.022 174.993 58.578 175.177 58.131 175.177 c
57.685 175.177 57.241 174.993 56.925 174.677 c
56.609 174.361 56.425 173.917 56.425 173.471 c
56.425 173.024 56.609 172.580 56.925 172.264 c
57.241 171.948 57.685 171.764 58.131 171.764 c
58.578 171.764 59.022 171.948 59.338 172.264 c
59.654 172.580 59.837 173.024 59.837 173.471 c s
BT 65.250 170.503 Td /F1 9.8 Tf  [(VKORC1-1639G>A and 1173C>T individually explained the greatest variance in warfarin dose across the three racial )] TJ ET
BT 65.250 158.598 Td /F1 9.8 Tf  [(groups. Including additional )] TJ ET
BT 186.647 158.598 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 226.739 158.598 Td /F1 9.8 Tf  [( SNPS and haplotypes did not further improve warfarin dose prediction.)] TJ ET
0.39 w 1 J 1 j
59.837 145.911 m 
59.837 146.358 59.654 146.802 59.338 147.118 c
59.022 147.434 58.578 147.617 58.131 147.617 c
57.685 147.617 57.241 147.434 56.925 147.118 c
56.609 146.802 56.425 146.358 56.425 145.911 c
56.425 145.465 56.609 145.021 56.925 144.705 c
57.241 144.389 57.685 144.205 58.131 144.205 c
58.578 144.205 59.022 144.389 59.338 144.705 c
59.654 145.021 59.837 145.465 59.837 145.911 c s
BT 65.250 142.944 Td /F5 9.8 Tf  [(VKORC1 )] TJ ET
BT 108.053 142.944 Td /F1 9.8 Tf  [(explained greater variability in warfarin dose among whites than in Asians or blacks, a finding explained )] TJ ET
BT 65.250 131.039 Td /F1 9.8 Tf  [(largely by race-specific differences in the frequency of the -1639 A and 1173T alleles.)] TJ ET
40.337 107.102 m 
40.337 107.548 40.154 107.992 39.838 108.308 c
39.522 108.624 39.078 108.808 38.631 108.808 c
38.185 108.808 37.741 108.624 37.425 108.308 c
37.109 107.992 36.925 107.548 36.925 107.102 c
36.925 106.655 37.109 106.211 37.425 105.895 c
37.741 105.579 38.185 105.395 38.631 105.395 c
39.078 105.395 39.522 105.579 39.838 105.895 c
40.154 106.211 40.337 106.655 40.337 107.102 c f
BT 45.750 104.134 Td /F1 9.8 Tf  [(A study designed to examine the effect of)] TJ ET
BT 224.604 104.134 Td /F5 9.8 Tf  [( CYP2C9)] TJ ET
BT 265.242 104.134 Td /F1 9.8 Tf  [( and )] TJ ET
BT 286.926 104.134 Td /F5 9.8 Tf  [(VKORC1 )] TJ ET
BT 329.728 104.134 Td /F1 9.8 Tf  [(genotypes on rate of International Normalized Ratio \(INR\) )] TJ ET
BT 45.750 92.229 Td /F1 9.8 Tf  [(increase, anticoagulation maintenance, risk of over anticoagulation, and change in dose over 30 days. )] TJ ET
0.267 0.267 0.267 rg
BT 487.981 92.229 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 79.542 m 
59.837 79.989 59.654 80.433 59.338 80.749 c
59.022 81.065 58.578 81.248 58.131 81.248 c
57.685 81.248 57.241 81.065 56.925 80.749 c
56.609 80.433 56.425 79.989 56.425 79.542 c
56.425 79.096 56.609 78.652 56.925 78.336 c
57.241 78.020 57.685 77.836 58.131 77.836 c
58.578 77.836 59.022 78.020 59.338 78.336 c
59.654 78.652 59.837 79.096 59.837 79.542 c s
BT 65.250 76.575 Td /F1 9.8 Tf  [(The )] TJ ET
BT 84.760 76.575 Td /F5 9.8 Tf  [(VKORC1 )] TJ ET
BT 127.562 76.575 Td /F1 9.8 Tf  [(variant genotype \(with/without the )] TJ ET
BT 275.509 76.575 Td /F5 9.8 Tf  [(CYP2C9 )] TJ ET
BT 316.147 76.575 Td /F1 9.8 Tf  [(variant genotype\) was associated with higher risk of over )] TJ ET
BT 65.250 64.670 Td /F1 9.8 Tf  [(anti-coagulation in European Americans but not African Americans.)] TJ ET
0.39 w 1 J 1 j
59.837 51.983 m 
59.837 52.429 59.654 52.873 59.338 53.189 c
59.022 53.505 58.578 53.689 58.131 53.689 c
57.685 53.689 57.241 53.505 56.925 53.189 c
56.609 52.873 56.425 52.429 56.425 51.983 c
56.425 51.536 56.609 51.092 56.925 50.776 c
57.241 50.460 57.685 50.276 58.131 50.276 c
58.578 50.276 59.022 50.460 59.338 50.776 c
59.654 51.092 59.837 51.536 59.837 51.983 c s
BT 65.250 49.015 Td /F1 9.8 Tf  [(The risk of minor hemorrhage was not influenced by either)] TJ ET
BT 316.683 49.015 Td /F5 9.8 Tf  [( CYP2C9)] TJ ET
BT 357.321 49.015 Td /F1 9.8 Tf  [( or )] TJ ET
BT 371.410 49.015 Td /F5 9.8 Tf  [(VKORC1 )] TJ ET
BT 414.212 49.015 Td /F1 9.8 Tf  [(genotype.)] TJ ET
Q
q
15.000 42.884 577.500 734.116 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F5 9.8 Tf  [(* independent groups include the US Preventive Services Task Force \(USPSTF\) and Evaluation of Genomic)] TJ ET
BT 492.817 767.476 Td /F5 9.8 Tf  [(Applications in )] TJ ET
BT 26.250 755.571 Td /F5 9.8 Tf  [(Practice and Prevention \(EGAPP\) Working Group.)] TJ ET
BT 26.250 718.969 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 699.015 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 699.015 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 699.015 Td /F1 9.8 Tf  [(Test accuracy and reliability in identifying alleles at multiple SNPs \(analytic sensitivity and specificity\).)] TJ ET
0.271 0.267 0.267 RG
40.337 682.577 m 
40.337 683.024 40.154 683.468 39.838 683.784 c
39.522 684.100 39.078 684.284 38.631 684.284 c
38.185 684.284 37.741 684.100 37.425 683.784 c
37.109 683.468 36.925 683.024 36.925 682.577 c
36.925 682.131 37.109 681.687 37.425 681.371 c
37.741 681.055 38.185 680.871 38.631 680.871 c
39.078 680.871 39.522 681.055 39.838 681.371 c
40.154 681.687 40.337 682.131 40.337 682.577 c f
BT 45.750 679.610 Td /F1 9.8 Tf  [(Based on findings from a ACCE evidence review and ACMG policy statement: )] TJ ET
0.39 w 1 J 1 j
59.837 666.923 m 
59.837 667.369 59.654 667.813 59.338 668.129 c
59.022 668.445 58.578 668.629 58.131 668.629 c
57.685 668.629 57.241 668.445 56.925 668.129 c
56.609 667.813 56.425 667.369 56.425 666.923 c
56.425 666.476 56.609 666.032 56.925 665.716 c
57.241 665.400 57.685 665.216 58.131 665.216 c
58.578 665.216 59.022 665.400 59.338 665.716 c
59.654 666.032 59.837 666.476 59.837 666.923 c s
BT 65.250 663.955 Td /F1 9.8 Tf  [(Limited data on analytic validity are available from laboratories performing these tests. )] TJ ET
0.267 0.267 0.267 rg
BT 438.607 663.955 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 651.268 m 
59.837 651.715 59.654 652.159 59.338 652.475 c
59.022 652.790 58.578 652.974 58.131 652.974 c
57.685 652.974 57.241 652.790 56.925 652.475 c
56.609 652.159 56.425 651.715 56.425 651.268 c
56.425 650.821 56.609 650.377 56.925 650.061 c
57.241 649.746 57.685 649.562 58.131 649.562 c
58.578 649.562 59.022 649.746 59.338 650.061 c
59.654 650.377 59.837 650.821 59.837 651.268 c s
BT 65.250 648.300 Td /F1 9.8 Tf  [(High analytic sensitivity and specificity is expected for testing of common CYP2C9 alleles. )] TJ ET
0.267 0.267 0.267 rg
BT 454.850 648.300 Td /F1 9.8 Tf  [([3] [4])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 635.613 m 
59.837 636.060 59.654 636.504 59.338 636.820 c
59.022 637.136 58.578 637.319 58.131 637.319 c
57.685 637.319 57.241 637.136 56.925 636.820 c
56.609 636.504 56.425 636.060 56.425 635.613 c
56.425 635.167 56.609 634.723 56.925 634.407 c
57.241 634.091 57.685 633.907 58.131 633.907 c
58.578 633.907 59.022 634.091 59.338 634.407 c
59.654 634.723 59.837 635.167 59.837 635.613 c s
BT 65.250 632.646 Td /F1 9.8 Tf  [(Few data are available for evaluation on analytic sensitivity and specificity of testing for VKORC1alleles. )] TJ ET
0.267 0.267 0.267 rg
BT 515.017 632.646 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
40.337 608.708 m 
40.337 609.155 40.154 609.599 39.838 609.915 c
39.522 610.231 39.078 610.415 38.631 610.415 c
38.185 610.415 37.741 610.231 37.425 609.915 c
37.109 609.599 36.925 609.155 36.925 608.708 c
36.925 608.262 37.109 607.818 37.425 607.502 c
37.741 607.186 38.185 607.002 38.631 607.002 c
39.078 607.002 39.522 607.186 39.838 607.502 c
40.154 607.818 40.337 608.262 40.337 608.708 c f
BT 45.750 605.741 Td /F1 9.8 Tf  [(College of American Pathology \(CAP\)/American College of Medical Genetics proficiency testing program for warfarin )] TJ ET
BT 45.750 593.836 Td /F1 9.8 Tf  [(pharmacogenetic testing may improve access to analytic validity data. )] TJ ET
0.267 0.267 0.267 rg
BT 349.745 593.836 Td /F1 9.8 Tf  [([3][4])] TJ ET
BT 45.750 581.931 Td /F1 9.8 Tf  [(https://www.cap.org/apps/docs/proficiency_testing/surveys_catalog/2010_surveys_catalog.pdf#page=214)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 558.777 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 558.777 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 558.777 Td /F1 9.8 Tf  [( Test accuracy and reliability in predicting appropriate warfarin dose \(predictive value\).)] TJ ET
40.337 542.339 m 
40.337 542.786 40.154 543.230 39.838 543.546 c
39.522 543.862 39.078 544.046 38.631 544.046 c
38.185 544.046 37.741 543.862 37.425 543.546 c
37.109 543.230 36.925 542.786 36.925 542.339 c
36.925 541.893 37.109 541.449 37.425 541.133 c
37.741 540.817 38.185 540.633 38.631 540.633 c
39.078 540.633 39.522 540.817 39.838 541.133 c
40.154 541.449 40.337 541.893 40.337 542.339 c f
BT 45.750 539.372 Td /F1 9.8 Tf  [(Published studies have examined the relationship of CYP2C9 alleles to warfarin dose. )] TJ ET
0.267 0.267 0.267 rg
BT 419.126 539.372 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 526.685 m 
59.837 527.131 59.654 527.575 59.338 527.891 c
59.022 528.207 58.578 528.391 58.131 528.391 c
57.685 528.391 57.241 528.207 56.925 527.891 c
56.609 527.575 56.425 527.131 56.425 526.685 c
56.425 526.238 56.609 525.794 56.925 525.478 c
57.241 525.162 57.685 524.978 58.131 524.978 c
58.578 524.978 59.022 525.162 59.338 525.478 c
59.654 525.794 59.837 526.238 59.837 526.685 c s
0.267 0.267 0.267 rg
BT 65.250 523.717 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.271 0.267 0.267 rg
BT 136.230 523.717 Td /F1 9.8 Tf  [(: query �)] TJ ET
0.267 0.267 0.267 rg
BT 171.993 523.717 Td /F1 9.8 Tf  [(warfarin and CYP2C9)] TJ ET
0.271 0.267 0.267 rg
BT 266.275 523.717 Td /F1 9.8 Tf  [(�)] TJ ET
40.337 499.780 m 
40.337 500.227 40.154 500.671 39.838 500.987 c
39.522 501.302 39.078 501.486 38.631 501.486 c
38.185 501.486 37.741 501.302 37.425 500.987 c
37.109 500.671 36.925 500.227 36.925 499.780 c
36.925 499.333 37.109 498.889 37.425 498.573 c
37.741 498.258 38.185 498.074 38.631 498.074 c
39.078 498.074 39.522 498.258 39.838 498.573 c
40.154 498.889 40.337 499.333 40.337 499.780 c f
BT 45.750 496.812 Td /F1 9.8 Tf  [(Published studies have examined the relationship of VKORC1 alleles to warfarin dose. )] TJ ET
0.267 0.267 0.267 rg
BT 421.291 496.812 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 484.125 m 
59.837 484.572 59.654 485.016 59.338 485.332 c
59.022 485.648 58.578 485.831 58.131 485.831 c
57.685 485.831 57.241 485.648 56.925 485.332 c
56.609 485.016 56.425 484.572 56.425 484.125 c
56.425 483.679 56.609 483.235 56.925 482.919 c
57.241 482.603 57.685 482.419 58.131 482.419 c
58.578 482.419 59.022 482.603 59.338 482.919 c
59.654 483.235 59.837 483.679 59.837 484.125 c s
0.267 0.267 0.267 rg
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0.271 0.267 0.267 rg
BT 136.230 481.158 Td /F1 9.8 Tf  [(: query �)] TJ ET
0.267 0.267 0.267 rg
BT 171.993 481.158 Td /F1 9.8 Tf  [(warfarin and VKORC1)] TJ ET
0.271 0.267 0.267 rg
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40.337 457.220 m 
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BT 45.750 442.348 Td /F1 9.8 Tf  [(with the stable warfarin dose. There is limited evidence for an association between CYP2C9 and severe bleeding events, )] TJ ET
BT 45.750 430.443 Td /F1 9.8 Tf  [(and an absence of evidence for bleeding events associated with VKORC1. )] TJ ET
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BT 370.376 430.443 Td /F1 9.8 Tf  [([3][4])] TJ ET
0.271 0.267 0.267 rg
BT 45.750 407.289 Td /F1 9.8 Tf  [(Recent additions to the literature:)] TJ ET
40.337 390.851 m 
40.337 391.298 40.154 391.742 39.838 392.058 c
39.522 392.374 39.078 392.558 38.631 392.558 c
38.185 392.558 37.741 392.374 37.425 392.058 c
37.109 391.742 36.925 391.298 36.925 390.851 c
36.925 390.405 37.109 389.961 37.425 389.645 c
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39.078 389.145 39.522 389.329 39.838 389.645 c
40.154 389.961 40.337 390.405 40.337 390.851 c f
BT 45.750 387.884 Td /F1 9.8 Tf  [(A study designed to compare a clinical algorithm versus a pharmacogenetic algorithm using INR values \(day 4 or 5 of )] TJ ET
BT 45.750 375.979 Td /F1 9.8 Tf  [(treatment\), clinical factors and genotype to predict warfarin dose. In the derivation set \(N=969\), the clinical algorithm had an )] TJ ET
BT 45.750 364.074 Td /F1 9.8 Tf  [(coefficient of determination R\(2\) of 48% and the pharmacogenetic algorithm had an R\(2\) of 63% in predicting warfarin )] TJ ET
BT 45.750 352.170 Td /F1 9.8 Tf  [(dose. In independent validation sets, the clinical algorithm had an R\(2\) of 26-43% and the pharmacogenetic algorithm had )] TJ ET
BT 45.750 340.265 Td /F1 9.8 Tf  [(an R\(2\) of 42-58% in predicting warfarin dose. )] TJ ET
0.267 0.267 0.267 rg
BT 247.331 340.265 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
40.337 327.578 m 
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39.522 329.100 39.078 329.284 38.631 329.284 c
38.185 329.284 37.741 329.100 37.425 328.784 c
37.109 328.468 36.925 328.024 36.925 327.578 c
36.925 327.131 37.109 326.687 37.425 326.371 c
37.741 326.055 38.185 325.872 38.631 325.872 c
39.078 325.872 39.522 326.055 39.838 326.371 c
40.154 326.687 40.337 327.131 40.337 327.578 c f
BT 45.750 324.610 Td /F1 9.8 Tf  [(A retrospective cohort study designed to examine the accuracy of pharmacogenetic warfarin dosing algorithms in predicting )] TJ ET
BT 45.750 312.705 Td /F1 9.8 Tf  [(warfarin dose. Data from 71 adult patients at an outpatient anticoagulation clinic on a stable, therapeutic warfarin dose were )] TJ ET
BT 45.750 300.801 Td /F1 9.8 Tf  [(included in the analysis. Six pharmacogenetic warfarin dosing algorithms and a 5 mg fixed dose approach were evaluated. )] TJ ET
BT 45.750 288.896 Td /F1 9.8 Tf  [(The algorithms published by Gage et al. 2008 and the IWPC 2009 were the most accurate in predicting warfarin dose in the )] TJ ET
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0.271 0.267 0.267 rg
40.337 264.304 m 
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39.522 265.826 39.078 266.010 38.631 266.010 c
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37.109 265.195 36.925 264.751 36.925 264.304 c
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37.741 262.782 38.185 262.598 38.631 262.598 c
39.078 262.598 39.522 262.782 39.838 263.097 c
40.154 263.413 40.337 263.857 40.337 264.304 c f
BT 45.750 261.336 Td /F1 9.8 Tf  [(A study designed to compare the International Warfarin Pharmacogenetics Consoritum \(IWPC\) algorithm versus a clinical )] TJ ET
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BT 45.750 225.622 Td /F1 9.8 Tf  [(percentage of patients to achieve the target INR than did the clinical algorithm. )] TJ ET
0.267 0.267 0.267 rg
BT 386.630 225.622 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
40.337 212.935 m 
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39.522 214.457 39.078 214.641 38.631 214.641 c
38.185 214.641 37.741 214.457 37.425 214.142 c
37.109 213.826 36.925 213.382 36.925 212.935 c
36.925 212.488 37.109 212.044 37.425 211.728 c
37.741 211.413 38.185 211.229 38.631 211.229 c
39.078 211.229 39.522 211.413 39.838 211.728 c
40.154 212.044 40.337 212.488 40.337 212.935 c f
BT 45.750 209.967 Td /F1 9.8 Tf  [(A study by the International Warfarin Pharmacogenetics Consortium reported a comprehensive assessment of the )] TJ ET
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0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 173.471 m 
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BT 65.250 170.503 Td /F1 9.8 Tf  [(VKORC1-1639G>A and 1173C>T individually explained the greatest variance in warfarin dose across the three racial )] TJ ET
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0.39 w 1 J 1 j
59.837 145.911 m 
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BT 65.250 142.944 Td /F5 9.8 Tf  [(VKORC1 )] TJ ET
BT 108.053 142.944 Td /F1 9.8 Tf  [(explained greater variability in warfarin dose among whites than in Asians or blacks, a finding explained )] TJ ET
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59.837 79.542 m 
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0.39 w 1 J 1 j
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40.337 751.039 m 
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40.154 710.684 40.337 711.128 40.337 711.575 c f
BT 45.750 708.607 Td /F1 9.8 Tf  [(Results of a randomized clinical trial suggested that an algorithm including )] TJ ET
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BT 408.811 708.607 Td /F1 9.8 Tf  [(and)] TJ ET
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BT 470.587 708.607 Td /F1 9.8 Tf  [(along with clinical factors )] TJ ET
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BT 428.350 642.238 Td /F1 9.8 Tf  [(and )] TJ ET
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BT 487.415 642.238 Td /F1 9.8 Tf  [( alleles on health )] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(outcomes in persons treated with warfarin have not been conducted. )] TJ ET
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BT 45.750 591.524 Td /F1 9.8 Tf  [(A national, prospective comparative effectiveness study was designed to examine the 6-month incidence of hospitalization )] TJ ET
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59.654 542.232 59.837 542.676 59.837 543.122 c s
BT 65.250 540.155 Td /F1 9.8 Tf  [(Adjusted hospitalization rates based on the intention-to-treat analysis showed that the genotyped group had a 31% )] TJ ET
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39.078 423.024 39.522 423.207 39.838 423.523 c
40.154 423.839 40.337 424.283 40.337 424.730 c f
BT 45.750 421.762 Td /F1 9.8 Tf  [(A study designed to compare gene based warfarin dosing versus standard of care practices in an orthopedic surgery )] TJ ET
BT 45.750 409.857 Td /F1 9.8 Tf  [(population. Adults \(n=229\) undergoing elective total hip and knee arthroplasty and receiving warfarin under the direction of )] TJ ET
BT 45.750 397.953 Td /F1 9.8 Tf  [(a dedicated anticoagulation services team were enrolled. The primary endpoint was the reduction in the incidence of )] TJ ET
BT 45.750 386.048 Td /F1 9.8 Tf  [(adverse events; additional endpoints included time to first therapeutic International Normalized Ratio \(INR\), time to first )] TJ ET
BT 45.750 374.143 Td /F1 9.8 Tf  [(supratherapeutic INR; and the percent of INR determinations that fell below, within or above the therapeutic range. )] TJ ET
BT 45.750 362.238 Td /F1 9.8 Tf  [(Endpoints did not achieve statistical significance. )] TJ ET
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40.337 349.551 m 
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39.078 347.845 39.522 348.029 39.838 348.345 c
40.154 348.661 40.337 349.105 40.337 349.551 c f
BT 45.750 346.584 Td /F1 9.8 Tf  [(Four published dosing algorithms and a prediction model incorporating the )] TJ ET
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59.837 321.992 m 
59.837 322.438 59.654 322.882 59.338 323.198 c
59.022 323.514 58.578 323.698 58.131 323.698 c
57.685 323.698 57.241 323.514 56.925 323.198 c
56.609 322.882 56.425 322.438 56.425 321.992 c
56.425 321.545 56.609 321.101 56.925 320.785 c
57.241 320.469 57.685 320.286 58.131 320.286 c
58.578 320.286 59.022 320.469 59.338 320.785 c
59.654 321.101 59.837 321.545 59.837 321.992 c s
BT 65.250 319.024 Td /F1 9.8 Tf  [(The four pharmacogenetic-based dosing algorithms performed similarly in the small, white-only dataset and the large, )] TJ ET
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0.39 w 1 J 1 j
59.837 294.432 m 
59.837 294.879 59.654 295.323 59.338 295.639 c
59.022 295.955 58.578 296.139 58.131 296.139 c
57.685 296.139 57.241 295.955 56.925 295.639 c
56.609 295.323 56.425 294.879 56.425 294.432 c
56.425 293.986 56.609 293.542 56.925 293.226 c
57.241 292.910 57.685 292.726 58.131 292.726 c
58.578 292.726 59.022 292.910 59.338 293.226 c
59.654 293.542 59.837 293.986 59.837 294.432 c s
BT 65.250 291.465 Td /F1 9.8 Tf  [(The International Warfarin Pharmacogenetics Consortium algorithm performed best overall for the two datasets )] TJ ET
BT 65.250 279.560 Td /F1 9.8 Tf  [(combined when comparing the percent of patients whose predicted dose was within 20% of the actual dose.)] TJ ET
40.337 263.123 m 
40.337 263.569 40.154 264.013 39.838 264.329 c
39.522 264.645 39.078 264.829 38.631 264.829 c
38.185 264.829 37.741 264.645 37.425 264.329 c
37.109 264.013 36.925 263.569 36.925 263.123 c
36.925 262.676 37.109 262.232 37.425 261.916 c
37.741 261.600 38.185 261.417 38.631 261.417 c
39.078 261.417 39.522 261.600 39.838 261.916 c
40.154 262.232 40.337 262.676 40.337 263.123 c f
BT 45.750 260.155 Td /F1 9.8 Tf  [(A study of patients with nonvalvular atrial fibrillation examining the cost-effectiveness of genotype guided dosing compared )] TJ ET
BT 45.750 248.250 Td /F1 9.8 Tf  [(to standard of care for initiating warfarin treatment. Study design was Markov state transition decision model, and data )] TJ ET
BT 45.750 236.346 Td /F1 9.8 Tf  [(sources included MEDLINE searches and bibliographies from relevant articles. The outcome measures were quality-)] TJ ET
BT 45.750 224.441 Td /F1 9.8 Tf  [(adjusted life years \(QALYs\) and costs in US dollars. The authors concluded that based on current data and cost of testing, )] TJ ET
BT 45.750 212.536 Td /F1 9.8 Tf  [(there is a 10% chance that genotype guided dosing is likely to be cost effective for nonvalvular artial fibrillation patients. )] TJ ET
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BT 562.207 212.536 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 189.381 Td /F1 9.8 Tf  [(The Center for Medicare and Medicaid Services \(CMS\) does not generally reimburse costs, but it does provide coverage for )] TJ ET
BT 26.250 177.477 Td /F1 9.8 Tf  [(individuals enrolled in appropriate clinical trials designed to examine clinical utility of genetic testing for Warfarin dosing. )] TJ ET
0.267 0.267 0.267 rg
BT 543.195 177.477 Td /F1 9.8 Tf  [(See )] TJ ET
BT 26.250 165.572 Td /F1 9.8 Tf  [(CMS decision memo.)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 128.969 Td /F4 12.0 Tf  [(Links)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 109.015 Td /F4 9.8 Tf  [(U.S, Food and Drug Administration:)] TJ ET
BT 192.010 109.015 Td /F1 9.8 Tf  [(Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels)] TJ ET
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BT 518.771 109.015 Td /F1 9.8 Tf  [( ; )] TJ ET
0.267 0.267 0.267 rg
BT 526.903 109.015 Td /F1 9.8 Tf  [(Search )] TJ ET
BT 26.250 97.110 Td /F1 9.8 Tf  [(FDA 510\(k\) database)] TJ ET
BT 26.250 77.706 Td /F4 9.8 Tf  [(ClinicalTrials.gov:)] TJ ET
BT 110.237 77.706 Td /F1 9.8 Tf  [(Warfarin and CYP2C9)] TJ ET
0.271 0.267 0.267 rg
BT 206.684 77.706 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 212.105 77.706 Td /F1 9.8 Tf  [(Warfarin and VKCORC1)] TJ ET
BT 26.250 58.301 Td /F4 9.8 Tf  [(PharmGKB)] TJ ET
BT 78.257 58.301 Td /F4 9.8 Tf  [(:)] TJ ET
BT 81.503 58.301 Td /F1 9.8 Tf  [( warfarin)] TJ ET
0.271 0.267 0.267 rg
BT 118.885 58.301 Td /F1 9.8 Tf  [( , )] TJ ET
0.267 0.267 0.267 rg
BT 127.016 58.301 Td /F1 9.8 Tf  [(International Warfarin Pharmacogenetics Consortium)] TJ ET
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59.837 770.444 m 
59.837 770.890 59.654 771.334 59.338 771.650 c
59.022 771.966 58.578 772.150 58.131 772.150 c
57.685 772.150 57.241 771.966 56.925 771.650 c
56.609 771.334 56.425 770.890 56.425 770.444 c
56.425 769.997 56.609 769.553 56.925 769.237 c
57.241 768.921 57.685 768.738 58.131 768.738 c
58.578 768.738 59.022 768.921 59.338 769.237 c
59.654 769.553 59.837 769.997 59.837 770.444 c s
BT 65.250 767.476 Td /F1 9.8 Tf  [(Over the first 30 days of therapy, )] TJ ET
BT 209.404 767.476 Td /F5 9.8 Tf  [(CYP2C9)] TJ ET
BT 247.331 767.476 Td /F1 9.8 Tf  [( and )] TJ ET
BT 269.015 767.476 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 309.107 767.476 Td /F1 9.8 Tf  [( genotypes explained 6.3% of the variance in dose change.)] TJ ET
40.337 751.039 m 
40.337 751.486 40.154 751.930 39.838 752.246 c
39.522 752.561 39.078 752.745 38.631 752.745 c
38.185 752.745 37.741 752.561 37.425 752.246 c
37.109 751.930 36.925 751.486 36.925 751.039 c
36.925 750.592 37.109 750.148 37.425 749.832 c
37.741 749.517 38.185 749.333 38.631 749.333 c
39.078 749.333 39.522 749.517 39.838 749.832 c
40.154 750.148 40.337 750.592 40.337 751.039 c f
BT 45.750 748.071 Td /F1 9.8 Tf  [(The International Warfarin Pharmacogenetics Consortium reported that an algorithm based on genetic and clinical data )] TJ ET
BT 45.750 736.167 Td /F1 9.8 Tf  [(performed better than a purely clinical algorithm or a fixed-dose approach in estimating the appropriate initial dose of )] TJ ET
BT 45.750 724.262 Td /F1 9.8 Tf  [(warfarin. )] TJ ET
0.267 0.267 0.267 rg
BT 85.842 724.262 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
40.337 711.575 m 
40.337 712.021 40.154 712.465 39.838 712.781 c
39.522 713.097 39.078 713.281 38.631 713.281 c
38.185 713.281 37.741 713.097 37.425 712.781 c
37.109 712.465 36.925 712.021 36.925 711.575 c
36.925 711.128 37.109 710.684 37.425 710.368 c
37.741 710.052 38.185 709.869 38.631 709.869 c
39.078 709.869 39.522 710.052 39.838 710.368 c
40.154 710.684 40.337 711.128 40.337 711.575 c f
BT 45.750 708.607 Td /F1 9.8 Tf  [(Results of a randomized clinical trial suggested that an algorithm including )] TJ ET
BT 368.173 708.607 Td /F5 9.8 Tf  [(CYP2C9 )] TJ ET
BT 408.811 708.607 Td /F1 9.8 Tf  [(and)] TJ ET
BT 425.074 708.607 Td /F5 9.8 Tf  [( VKORC1 )] TJ ET
BT 470.587 708.607 Td /F1 9.8 Tf  [(along with clinical factors )] TJ ET
BT 45.750 696.702 Td /F1 9.8 Tf  [(improved accuracy and efficiency of warfarin dose when compared with an empirical protocol; however, there was no )] TJ ET
BT 45.750 684.798 Td /F1 9.8 Tf  [(difference in the primary endpoint, the proportion of out-of-range clotting times. )] TJ ET
0.267 0.267 0.267 rg
BT 387.702 684.798 Td /F1 9.8 Tf  [([12])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 661.643 Td /F6 9.8 Tf  [(Clinical Utility )] TJ ET
BT 93.437 661.643 Td /F4 9.8 Tf  [(: )] TJ ET
BT 99.395 661.643 Td /F1 9.8 Tf  [(Net benefit of test in improving health outcomes.)] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(The ACCE review reported controlled trials that evaluate the net effect of testing for)] TJ ET
BT 385.001 642.238 Td /F5 9.8 Tf  [( CYP2C9 )] TJ ET
BT 428.350 642.238 Td /F1 9.8 Tf  [(and )] TJ ET
BT 447.323 642.238 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 487.415 642.238 Td /F1 9.8 Tf  [( alleles on health )] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(outcomes in persons treated with warfarin have not been conducted. )] TJ ET
0.267 0.267 0.267 rg
BT 324.317 630.333 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 610.929 Td /F1 9.8 Tf  [(Recent additions to the literature:)] TJ ET
40.337 594.491 m 
40.337 594.938 40.154 595.382 39.838 595.698 c
39.522 596.014 39.078 596.198 38.631 596.198 c
38.185 596.198 37.741 596.014 37.425 595.698 c
37.109 595.382 36.925 594.938 36.925 594.491 c
36.925 594.045 37.109 593.601 37.425 593.285 c
37.741 592.969 38.185 592.785 38.631 592.785 c
39.078 592.785 39.522 592.969 39.838 593.285 c
40.154 593.601 40.337 594.045 40.337 594.491 c f
BT 45.750 591.524 Td /F1 9.8 Tf  [(A national, prospective comparative effectiveness study was designed to examine the 6-month incidence of hospitalization )] TJ ET
BT 45.750 579.619 Td /F1 9.8 Tf  [(\(event-free time\) in patients receiving warfarin genotyping \(n=896\) compared to a matched historical control group )] TJ ET
BT 45.750 567.714 Td /F1 9.8 Tf  [(\(n=2,688\). To evaluate possible temporal changes in general clinical practice, the researchers compared the hospitalization )] TJ ET
BT 45.750 555.810 Td /F1 9.8 Tf  [(rates for two external control groups \(an external concurrent control group and an external historical control group\). )] TJ ET
0.267 0.267 0.267 rg
BT 543.215 555.810 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 543.122 m 
59.837 543.569 59.654 544.013 59.338 544.329 c
59.022 544.645 58.578 544.829 58.131 544.829 c
57.685 544.829 57.241 544.645 56.925 544.329 c
56.609 544.013 56.425 543.569 56.425 543.122 c
56.425 542.676 56.609 542.232 56.925 541.916 c
57.241 541.600 57.685 541.416 58.131 541.416 c
58.578 541.416 59.022 541.600 59.338 541.916 c
59.654 542.232 59.837 542.676 59.837 543.122 c s
BT 65.250 540.155 Td /F1 9.8 Tf  [(Adjusted hospitalization rates based on the intention-to-treat analysis showed that the genotyped group had a 31% )] TJ ET
BT 65.250 528.250 Td /F1 9.8 Tf  [(lower rate of all-cause hospitalizations and a 28% lower rate of hospitalizations for bleeding or thromboembolism )] TJ ET
BT 65.250 516.345 Td /F1 9.8 Tf  [(compared to the matched historical control group during the 6 month follow up period. There were no significant )] TJ ET
BT 65.250 504.441 Td /F1 9.8 Tf  [(differences in the adjusted hospitalization rates between the two external control groups. )] TJ ET
0.267 0.267 0.267 rg
BT 448.942 504.441 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 491.753 m 
59.837 492.200 59.654 492.644 59.338 492.960 c
59.022 493.276 58.578 493.460 58.131 493.460 c
57.685 493.460 57.241 493.276 56.925 492.960 c
56.609 492.644 56.425 492.200 56.425 491.753 c
56.425 491.307 56.609 490.863 56.925 490.547 c
57.241 490.231 57.685 490.047 58.131 490.047 c
58.578 490.047 59.022 490.231 59.338 490.547 c
59.654 490.863 59.837 491.307 59.837 491.753 c s
BT 65.250 488.786 Td /F1 9.8 Tf  [(A per-protocol analysis was conducted in which only events occurring after genotyping were counted for patients in the )] TJ ET
BT 65.250 476.881 Td /F1 9.8 Tf  [(genotyped group. Adjusted hospitalization rates based on the per-protocol analysis showed that the genotyped group )] TJ ET
BT 65.250 464.976 Td /F1 9.8 Tf  [(had a 33% lower rate of all-cause hospitalizations and a 43% lower rate of hospitalizations for bleeding or )] TJ ET
BT 65.250 453.072 Td /F1 9.8 Tf  [(thromboembolism compared to the matched historical control group during the 6 month follow up period. There were )] TJ ET
BT 65.250 441.167 Td /F1 9.8 Tf  [(no significant differences in the adjusted hospitalization rates between the two external control groups. )] TJ ET
0.267 0.267 0.267 rg
BT 508.553 441.167 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
40.337 424.730 m 
40.337 425.176 40.154 425.620 39.838 425.936 c
39.522 426.252 39.078 426.436 38.631 426.436 c
38.185 426.436 37.741 426.252 37.425 425.936 c
37.109 425.620 36.925 425.176 36.925 424.730 c
36.925 424.283 37.109 423.839 37.425 423.523 c
37.741 423.207 38.185 423.024 38.631 423.024 c
39.078 423.024 39.522 423.207 39.838 423.523 c
40.154 423.839 40.337 424.283 40.337 424.730 c f
BT 45.750 421.762 Td /F1 9.8 Tf  [(A study designed to compare gene based warfarin dosing versus standard of care practices in an orthopedic surgery )] TJ ET
BT 45.750 409.857 Td /F1 9.8 Tf  [(population. Adults \(n=229\) undergoing elective total hip and knee arthroplasty and receiving warfarin under the direction of )] TJ ET
BT 45.750 397.953 Td /F1 9.8 Tf  [(a dedicated anticoagulation services team were enrolled. The primary endpoint was the reduction in the incidence of )] TJ ET
BT 45.750 386.048 Td /F1 9.8 Tf  [(adverse events; additional endpoints included time to first therapeutic International Normalized Ratio \(INR\), time to first )] TJ ET
BT 45.750 374.143 Td /F1 9.8 Tf  [(supratherapeutic INR; and the percent of INR determinations that fell below, within or above the therapeutic range. )] TJ ET
BT 45.750 362.238 Td /F1 9.8 Tf  [(Endpoints did not achieve statistical significance. )] TJ ET
0.267 0.267 0.267 rg
BT 259.265 362.238 Td /F1 9.8 Tf  [([14])] TJ ET
0.271 0.267 0.267 rg
40.337 349.551 m 
40.337 349.998 40.154 350.442 39.838 350.758 c
39.522 351.074 39.078 351.258 38.631 351.258 c
38.185 351.258 37.741 351.074 37.425 350.758 c
37.109 350.442 36.925 349.998 36.925 349.551 c
36.925 349.105 37.109 348.661 37.425 348.345 c
37.741 348.029 38.185 347.845 38.631 347.845 c
39.078 347.845 39.522 348.029 39.838 348.345 c
40.154 348.661 40.337 349.105 40.337 349.551 c f
BT 45.750 346.584 Td /F1 9.8 Tf  [(Four published dosing algorithms and a prediction model incorporating the )] TJ ET
BT 368.728 346.584 Td /F5 9.8 Tf  [(CYP2C9*2, CYP2C9*3)] TJ ET
BT 468.432 346.584 Td /F1 9.8 Tf  [(, and )] TJ ET
BT 492.827 346.584 Td /F5 9.8 Tf  [(VKORC1-1639)] TJ ET
BT 45.750 334.679 Td /F1 9.8 Tf  [(polymorphisms were evaluated in two independent datasets \(total n=1095\). )] TJ ET
0.267 0.267 0.267 rg
BT 372.804 334.679 Td /F1 9.8 Tf  [([15])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 321.992 m 
59.837 322.438 59.654 322.882 59.338 323.198 c
59.022 323.514 58.578 323.698 58.131 323.698 c
57.685 323.698 57.241 323.514 56.925 323.198 c
56.609 322.882 56.425 322.438 56.425 321.992 c
56.425 321.545 56.609 321.101 56.925 320.785 c
57.241 320.469 57.685 320.286 58.131 320.286 c
58.578 320.286 59.022 320.469 59.338 320.785 c
59.654 321.101 59.837 321.545 59.837 321.992 c s
BT 65.250 319.024 Td /F1 9.8 Tf  [(The four pharmacogenetic-based dosing algorithms performed similarly in the small, white-only dataset and the large, )] TJ ET
BT 65.250 307.119 Td /F1 9.8 Tf  [(ethnically diverse dataset.)] TJ ET
0.39 w 1 J 1 j
59.837 294.432 m 
59.837 294.879 59.654 295.323 59.338 295.639 c
59.022 295.955 58.578 296.139 58.131 296.139 c
57.685 296.139 57.241 295.955 56.925 295.639 c
56.609 295.323 56.425 294.879 56.425 294.432 c
56.425 293.986 56.609 293.542 56.925 293.226 c
57.241 292.910 57.685 292.726 58.131 292.726 c
58.578 292.726 59.022 292.910 59.338 293.226 c
59.654 293.542 59.837 293.986 59.837 294.432 c s
BT 65.250 291.465 Td /F1 9.8 Tf  [(The International Warfarin Pharmacogenetics Consortium algorithm performed best overall for the two datasets )] TJ ET
BT 65.250 279.560 Td /F1 9.8 Tf  [(combined when comparing the percent of patients whose predicted dose was within 20% of the actual dose.)] TJ ET
40.337 263.123 m 
40.337 263.569 40.154 264.013 39.838 264.329 c
39.522 264.645 39.078 264.829 38.631 264.829 c
38.185 264.829 37.741 264.645 37.425 264.329 c
37.109 264.013 36.925 263.569 36.925 263.123 c
36.925 262.676 37.109 262.232 37.425 261.916 c
37.741 261.600 38.185 261.417 38.631 261.417 c
39.078 261.417 39.522 261.600 39.838 261.916 c
40.154 262.232 40.337 262.676 40.337 263.123 c f
BT 45.750 260.155 Td /F1 9.8 Tf  [(A study of patients with nonvalvular atrial fibrillation examining the cost-effectiveness of genotype guided dosing compared )] TJ ET
BT 45.750 248.250 Td /F1 9.8 Tf  [(to standard of care for initiating warfarin treatment. Study design was Markov state transition decision model, and data )] TJ ET
BT 45.750 236.346 Td /F1 9.8 Tf  [(sources included MEDLINE searches and bibliographies from relevant articles. The outcome measures were quality-)] TJ ET
BT 45.750 224.441 Td /F1 9.8 Tf  [(adjusted life years \(QALYs\) and costs in US dollars. The authors concluded that based on current data and cost of testing, )] TJ ET
BT 45.750 212.536 Td /F1 9.8 Tf  [(there is a 10% chance that genotype guided dosing is likely to be cost effective for nonvalvular artial fibrillation patients. )] TJ ET
0.267 0.267 0.267 rg
BT 562.207 212.536 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 189.381 Td /F1 9.8 Tf  [(The Center for Medicare and Medicaid Services \(CMS\) does not generally reimburse costs, but it does provide coverage for )] TJ ET
BT 26.250 177.477 Td /F1 9.8 Tf  [(individuals enrolled in appropriate clinical trials designed to examine clinical utility of genetic testing for Warfarin dosing. )] TJ ET
0.267 0.267 0.267 rg
BT 543.195 177.477 Td /F1 9.8 Tf  [(See )] TJ ET
BT 26.250 165.572 Td /F1 9.8 Tf  [(CMS decision memo.)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 128.969 Td /F4 12.0 Tf  [(Links)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 109.015 Td /F4 9.8 Tf  [(U.S, Food and Drug Administration:)] TJ ET
BT 192.010 109.015 Td /F1 9.8 Tf  [(Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels)] TJ ET
0.271 0.267 0.267 rg
BT 518.771 109.015 Td /F1 9.8 Tf  [( ; )] TJ ET
0.267 0.267 0.267 rg
BT 526.903 109.015 Td /F1 9.8 Tf  [(Search )] TJ ET
BT 26.250 97.110 Td /F1 9.8 Tf  [(FDA 510\(k\) database)] TJ ET
BT 26.250 77.706 Td /F4 9.8 Tf  [(ClinicalTrials.gov:)] TJ ET
BT 110.237 77.706 Td /F1 9.8 Tf  [(Warfarin and CYP2C9)] TJ ET
0.271 0.267 0.267 rg
BT 206.684 77.706 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 212.105 77.706 Td /F1 9.8 Tf  [(Warfarin and VKCORC1)] TJ ET
BT 26.250 58.301 Td /F4 9.8 Tf  [(PharmGKB)] TJ ET
BT 78.257 58.301 Td /F4 9.8 Tf  [(:)] TJ ET
BT 81.503 58.301 Td /F1 9.8 Tf  [( warfarin)] TJ ET
0.271 0.267 0.267 rg
BT 118.885 58.301 Td /F1 9.8 Tf  [( , )] TJ ET
0.267 0.267 0.267 rg
BT 127.016 58.301 Td /F1 9.8 Tf  [(International Warfarin Pharmacogenetics Consortium)] TJ ET
Q
q
15.000 29.015 577.500 747.985 re W n
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
0.39 w 1 J 1 j
59.837 770.444 m 
59.837 770.890 59.654 771.334 59.338 771.650 c
59.022 771.966 58.578 772.150 58.131 772.150 c
57.685 772.150 57.241 771.966 56.925 771.650 c
56.609 771.334 56.425 770.890 56.425 770.444 c
56.425 769.997 56.609 769.553 56.925 769.237 c
57.241 768.921 57.685 768.738 58.131 768.738 c
58.578 768.738 59.022 768.921 59.338 769.237 c
59.654 769.553 59.837 769.997 59.837 770.444 c s
BT 65.250 767.476 Td /F1 9.8 Tf  [(Over the first 30 days of therapy, )] TJ ET
BT 209.404 767.476 Td /F5 9.8 Tf  [(CYP2C9)] TJ ET
BT 247.331 767.476 Td /F1 9.8 Tf  [( and )] TJ ET
BT 269.015 767.476 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 309.107 767.476 Td /F1 9.8 Tf  [( genotypes explained 6.3% of the variance in dose change.)] TJ ET
40.337 751.039 m 
40.337 751.486 40.154 751.930 39.838 752.246 c
39.522 752.561 39.078 752.745 38.631 752.745 c
38.185 752.745 37.741 752.561 37.425 752.246 c
37.109 751.930 36.925 751.486 36.925 751.039 c
36.925 750.592 37.109 750.148 37.425 749.832 c
37.741 749.517 38.185 749.333 38.631 749.333 c
39.078 749.333 39.522 749.517 39.838 749.832 c
40.154 750.148 40.337 750.592 40.337 751.039 c f
BT 45.750 748.071 Td /F1 9.8 Tf  [(The International Warfarin Pharmacogenetics Consortium reported that an algorithm based on genetic and clinical data )] TJ ET
BT 45.750 736.167 Td /F1 9.8 Tf  [(performed better than a purely clinical algorithm or a fixed-dose approach in estimating the appropriate initial dose of )] TJ ET
BT 45.750 724.262 Td /F1 9.8 Tf  [(warfarin. )] TJ ET
0.267 0.267 0.267 rg
BT 85.842 724.262 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
40.337 711.575 m 
40.337 712.021 40.154 712.465 39.838 712.781 c
39.522 713.097 39.078 713.281 38.631 713.281 c
38.185 713.281 37.741 713.097 37.425 712.781 c
37.109 712.465 36.925 712.021 36.925 711.575 c
36.925 711.128 37.109 710.684 37.425 710.368 c
37.741 710.052 38.185 709.869 38.631 709.869 c
39.078 709.869 39.522 710.052 39.838 710.368 c
40.154 710.684 40.337 711.128 40.337 711.575 c f
BT 45.750 708.607 Td /F1 9.8 Tf  [(Results of a randomized clinical trial suggested that an algorithm including )] TJ ET
BT 368.173 708.607 Td /F5 9.8 Tf  [(CYP2C9 )] TJ ET
BT 408.811 708.607 Td /F1 9.8 Tf  [(and)] TJ ET
BT 425.074 708.607 Td /F5 9.8 Tf  [( VKORC1 )] TJ ET
BT 470.587 708.607 Td /F1 9.8 Tf  [(along with clinical factors )] TJ ET
BT 45.750 696.702 Td /F1 9.8 Tf  [(improved accuracy and efficiency of warfarin dose when compared with an empirical protocol; however, there was no )] TJ ET
BT 45.750 684.798 Td /F1 9.8 Tf  [(difference in the primary endpoint, the proportion of out-of-range clotting times. )] TJ ET
0.267 0.267 0.267 rg
BT 387.702 684.798 Td /F1 9.8 Tf  [([12])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 661.643 Td /F6 9.8 Tf  [(Clinical Utility )] TJ ET
BT 93.437 661.643 Td /F4 9.8 Tf  [(: )] TJ ET
BT 99.395 661.643 Td /F1 9.8 Tf  [(Net benefit of test in improving health outcomes.)] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(The ACCE review reported controlled trials that evaluate the net effect of testing for)] TJ ET
BT 385.001 642.238 Td /F5 9.8 Tf  [( CYP2C9 )] TJ ET
BT 428.350 642.238 Td /F1 9.8 Tf  [(and )] TJ ET
BT 447.323 642.238 Td /F5 9.8 Tf  [(VKORC1)] TJ ET
BT 487.415 642.238 Td /F1 9.8 Tf  [( alleles on health )] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(outcomes in persons treated with warfarin have not been conducted. )] TJ ET
0.267 0.267 0.267 rg
BT 324.317 630.333 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 610.929 Td /F1 9.8 Tf  [(Recent additions to the literature:)] TJ ET
40.337 594.491 m 
40.337 594.938 40.154 595.382 39.838 595.698 c
39.522 596.014 39.078 596.198 38.631 596.198 c
38.185 596.198 37.741 596.014 37.425 595.698 c
37.109 595.382 36.925 594.938 36.925 594.491 c
36.925 594.045 37.109 593.601 37.425 593.285 c
37.741 592.969 38.185 592.785 38.631 592.785 c
39.078 592.785 39.522 592.969 39.838 593.285 c
40.154 593.601 40.337 594.045 40.337 594.491 c f
BT 45.750 591.524 Td /F1 9.8 Tf  [(A national, prospective comparative effectiveness study was designed to examine the 6-month incidence of hospitalization )] TJ ET
BT 45.750 579.619 Td /F1 9.8 Tf  [(\(event-free time\) in patients receiving warfarin genotyping \(n=896\) compared to a matched historical control group )] TJ ET
BT 45.750 567.714 Td /F1 9.8 Tf  [(\(n=2,688\). To evaluate possible temporal changes in general clinical practice, the researchers compared the hospitalization )] TJ ET
BT 45.750 555.810 Td /F1 9.8 Tf  [(rates for two external control groups \(an external concurrent control group and an external historical control group\). )] TJ ET
0.267 0.267 0.267 rg
BT 543.215 555.810 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 543.122 m 
59.837 543.569 59.654 544.013 59.338 544.329 c
59.022 544.645 58.578 544.829 58.131 544.829 c
57.685 544.829 57.241 544.645 56.925 544.329 c
56.609 544.013 56.425 543.569 56.425 543.122 c
56.425 542.676 56.609 542.232 56.925 541.916 c
57.241 541.600 57.685 541.416 58.131 541.416 c
58.578 541.416 59.022 541.600 59.338 541.916 c
59.654 542.232 59.837 542.676 59.837 543.122 c s
BT 65.250 540.155 Td /F1 9.8 Tf  [(Adjusted hospitalization rates based on the intention-to-treat analysis showed that the genotyped group had a 31% )] TJ ET
BT 65.250 528.250 Td /F1 9.8 Tf  [(lower rate of all-cause hospitalizations and a 28% lower rate of hospitalizations for bleeding or thromboembolism )] TJ ET
BT 65.250 516.345 Td /F1 9.8 Tf  [(compared to the matched historical control group during the 6 month follow up period. There were no significant )] TJ ET
BT 65.250 504.441 Td /F1 9.8 Tf  [(differences in the adjusted hospitalization rates between the two external control groups. )] TJ ET
0.267 0.267 0.267 rg
BT 448.942 504.441 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
0.39 w 1 J 1 j
59.837 491.753 m 
59.837 492.200 59.654 492.644 59.338 492.960 c
59.022 493.276 58.578 493.460 58.131 493.460 c
57.685 493.460 57.241 493.276 56.925 492.960 c
56.609 492.644 56.425 492.200 56.425 491.753 c
56.425 491.307 56.609 490.863 56.925 490.547 c
57.241 490.231 57.685 490.047 58.131 490.047 c
58.578 490.047 59.022 490.231 59.338 490.547 c
59.654 490.863 59.837 491.307 59.837 491.753 c s
BT 65.250 488.786 Td /F1 9.8 Tf  [(A per-protocol analysis was conducted in which only events occurring after genotyping were counted for patients in the )] TJ ET
BT 65.250 476.881 Td /F1 9.8 Tf  [(genotyped group. Adjusted hospitalization rates based on the per-protocol analysis showed that the genotyped group )] TJ ET
BT 65.250 464.976 Td /F1 9.8 Tf  [(had a 33% lower rate of all-cause hospitalizations and a 43% lower rate of hospitalizations for bleeding or )] TJ ET
BT 65.250 453.072 Td /F1 9.8 Tf  [(thromboembolism compared to the matched historical control group during the 6 month follow up period. There were )] TJ ET
BT 65.250 441.167 Td /F1 9.8 Tf  [(no significant differences in the adjusted hospitalization rates between the two external control groups. )] TJ ET
0.267 0.267 0.267 rg
BT 508.553 441.167 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
40.337 424.730 m 
40.337 425.176 40.154 425.620 39.838 425.936 c
39.522 426.252 39.078 426.436 38.631 426.436 c
38.185 426.436 37.741 426.252 37.425 425.936 c
37.109 425.620 36.925 425.176 36.925 424.730 c
36.925 424.283 37.109 423.839 37.425 423.523 c
37.741 423.207 38.185 423.024 38.631 423.024 c
39.078 423.024 39.522 423.207 39.838 423.523 c
40.154 423.839 40.337 424.283 40.337 424.730 c f
BT 45.750 421.762 Td /F1 9.8 Tf  [(A study designed to compare gene based warfarin dosing versus standard of care practices in an orthopedic surgery )] TJ ET
BT 45.750 409.857 Td /F1 9.8 Tf  [(population. Adults \(n=229\) undergoing elective total hip and knee arthroplasty and receiving warfarin under the direction of )] TJ ET
BT 45.750 397.953 Td /F1 9.8 Tf  [(a dedicated anticoagulation services team were enrolled. The primary endpoint was the reduction in the incidence of )] TJ ET
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