Table 4 Cost-effectiveness results of included studies

1

Kim,DJ et al., 2017 [16]

Korea

mechanical heart valve replacement (MHVR)

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

$50,000 per QALY gained

• ICER (b) vs (a): $13,562 per QALY gained

2

Verhoef et al., 2016 [17]

UK and Sweden

Atrial Fibrillation (AF)

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

UK £20,000 per QALY gained, Sweden500,000 SEK

• In UK: ICER (b) vs (a): £6702 per QALY gained

• In Sweden: ICER (b) vs (a): 253,848 SEK per QALY gained

3

Mitropoulou et al., 2015 [18]

Croatia

ischemic stroke patients with AF

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

€40,000 to €50,000 per QALY gained

• ICER (b) vs (a): €31,225 per QALY gained

4

Chong, HYet al, 2014 [21]

Thailand

newly initiated warfarin therapy

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

160,000 THB or $5333 per QALY gained

• Healthcare system perspective:

ICER (b) vs (a):1,477,042 THB ($49,234) per QALY gained

• Societal perspective

ICER (b) vs (a): 1,473,852 THB ($49,128) per QALY gained

5

You, et al., 2014 [19]

USA

AF

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided treatment

$50,000 per QALY gained

• ICER (b) vs (a): $ 2843 per QALY gained

6

Pink et al., 2014 [20]

Sweden

Non-valvular AF

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided treatment

(c) dabigatran

(d) rivaroxaban

(e) apixaban

£20,000–30,000 per QALY gained

• ICER (b) vs (a): £ 13,226 per QALY gained

• ICER (e) vs (b): £20,671 per QALY gained

• (d) is dominated by (c) and (e), high cost and lower QALYs than (c) and (e)

• (c) is dominated by (e), high cost and lower QALYs than (e)

7

You et al., 2012 [22]

USA

newly diagnosed AF

(a) warfarin

(b) CYP2C19and VKORC1genotyping-guided treatment

(c) dabigatran 110 mg twice daily

(d) dabigatran 150 mg twice daily

$50,000 per QALY gained

• (a) is dominated by (b), high cost and lower QALYs than (b)

• ICER (d) vs (b): $13,810 per QALY gained

• (c) is dominated by (d), (d) lower cost and more effective than (c)

8

Meckley et al., 2010 [23]

USA

newly initiated warfarin therapy

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

$50,000 per QALY gained

• ICER (b) vs (a): $ 60,725 per QALY gained

9

Eckman et al., 2009 [26]

USA

Non-valvular AF

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

$50,000 per QALY gained

• ICER (b) vs (a): $171,750 per QALY gained

10

Patrick et al., 2009 [25]

USA

newly diagnosed AF

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

$50,000 per QALY gained

• ICER (b) vs (a): ICER< 50,000 per QALY gained if it increased the time spent in the target INR range during the first 3 months of treatment by 5 to 9 percentage points

11

You et al., 2009 [24]

USA

newly initiated warfarin therapy

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

$50,000 per QALY gained

• ICER (b) vs (a): $ 347,059 per QALY gained

12

McWilliam et al., 2008 [27]

USA

newly initiated warfarin therapy

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

N/A

• Low baseline bleeding: ICER (b) vs (a): $82,890 per bleeding averted

• Medium baseline bleeding: ICER (b) vs (a): $13,589 per bleeding averted

• High baseline bleeding: (b) is dominated by (a) lower cost than (a)

13

Schalekamp et al., 2006 [28]

The Netherlands

newly initiated warfarin therapy

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

€20,000

• ICER (b) vs (a): € 4233 per bleeding averted

14

You et al., 2004 [29]

USA

newly initiated warfarin therapy

(a) warfarin

(b) CYP2C19 and VKORC1 genotyping-guided dosing of warfarin

N/A

• ICER (b) vs (a): $5778 per bleeding averted

1

Wang Y et al., 2018 [30]

Hong Kong

ACS undergoing PCI

(a) clopidogrel

(b) ticagrelor

(c) CYP2C19 testing guided therapy

Test: positive: ticagrelor;

Test negative: clopidogrel

$42,423 per QALY gained

• ICER (c) vs (a): $2560 per QALY gained

• (b) is dominated by (c), high cost and lower QALYs than (c)

2

Jiang, M et al., 2017 [31]

USA

ACS undergoing PCI

(a) clopidogrel

(b) prasugrel or ticagrelor

(c) CYP2C19 testing guided therapy

Test: positive: prasugrel or ticagrelor;

Test negative: clopidogrel

$50,000 per QALY gained

• (a) is dominated by (c), high cost and lower QALYs than (c)

• (b) is dominated by (c), high cost and lower QALYs than (c)

3

Deiman BA et al., 2016 [32]

the Netherlands

ACS undergoing PCI

(a) clopidogrel

(b) prasugrel

(c) ticagrelor

(d) CYP2C19 testing guided therapy

Test: positive: prasugrel or ticagrelor;

Test negative: clopidogrel

€65,000 per QALY gained

• ICER (d) vs (a): €81,500 per QALY gained

• ICER (d) vs (b): €9111 per QALY gained

• ICER (d) vs (c): €5972 per QALY gained

4

Kazi DS et al., 2014 [34]

USA

ACS undergoing PCI

(a) clopidogrel

(b) prasugrel

(c) ticagrelor

(d) CYP2C19 testing guided therapy

Test: positive: prasugrel or ticagrelor;

Test negative: clopidogrel

$50,000 per QALY gained

• Genotyping with prasugrel vs (a): $35,800 per QALY gained

• Genotyping with ticagrelor vs (a): $30,200 per QALY gained

5

Patel et al., 2014 [33]

USA

ACS undergoing PCI

(a) clopidogrel+asprin

(b) prasugrel+aspirin

(c) CYP2C19 testing guided therapy

Test: positive: prasugrel+asprin;

Test negative: clopidogrel+asprin

$50,000 per QALY gained

• ICER (c) vs (a): $4200 per QALY gained

• (b) is dominated by (c), high cost and lower QALYs than (c)

6

LALA A et al., 2013 [36]

USA

ACS undergoing PCI

(a) clopidogrel

(b) prasugrel

(c) CYP2C19 testing guided therapy

Test: positive: prasugrel;

Test negative: clopidogrel

$50,000 per QALY gained

• (a) is dominated by (c), (c) lower cost and more effective than (a)

• (b) is dominated by (c), (c) lower cost and more effective than (b)

7

Sorich et al., 2013 [35]

Australia

ACS undergoing PCI

(a) clopidogrel

(b) ticagrelor

(c) CYP2C19 testing guided therapy

Test: positive: ticagrelor;

Test negative: clopidogrel

AUS$

50,000 per QALY gained

• ICER (c) vs (a): $AUS 6346 per QALY gained

• ICER (b) vs (c): $AUS 22,821 per QALY gained

8

Panattoni L et al., 2012 [38]

New Zealand

ACS (included the four largest ethnic groups)

(a) clopidogrel

(b) prasugrel

(c) CYP2C19 testing guided therapy

Test: positive: prasugrel;

Test negative: clopidogrel

$NZ50000 per QALY gained

• (b) is dominated by (a), high cost and lower QALYs than (a)

• ICER (c) vs (a): $NZ 24,617 per QALY gained

• (b) is dominated by (c), (c) lower cost and more effective than (b)

9

Reese E S et al., 2012 [37]

USA

ACS, recent MI or stroke undergoing PCI

(a) clopidogrel

(b) prasugrel

(c) CYP2C19 testing guided therapy

Test: positive prasugrel;

Test negative clopidogrel

N/A

• (a) is dominated by (c), (c) lower cost and more effective than (a)

• (b) is dominated by (c), (c) lower cost and more effective than (b)

1

Mitchel et al., 2017 [39]

Canada

cardiovascular patients

(a) statin

(b) genotyping-guided treatment with statin (only patients experiencing musculoskeletal pain are being tested)

CAN

$6150 per QALY gained

• (a) is dominated by (b), high cost and lower QALYs than (b)

• (b) would be cost-effective as long as the test costs less than CAN$906

1

Cheng H et al., 2018 [41]

China (Han population)

Hyperuricemia and gout

(a) allopurinol 100 mg and 600 mg per day

(b) febuxostat 40mgand 80 mg per day

(c) HLA-B5801 testing prior to treatment

Test positive: febuxostat

Test negative: allopurinol

N/A

• In all 253 patients

• (c) saved 1,384,040 yuan for allopurinol and febuxostat at the lowest dosages

• (c) saved 2,807,770 yuan for allopurinol and febuxostat at the highest dosages

2

Chong et al., 2018 [40]

Malaysia

gout

(a) allopurinol starting dose 300 mg, target dose 600 mg per day (current practice)

(b) probenecid target dose 2 g per day

(c) HLA-B5801 testing prior to treatment

Test positive: probenecid

Test negative: allopurinol

MYR 39,000 or $8695 per QALY gained

• (b) is dominated by (a), high cost and lower QALYs than (a)

• (c) is dominated by (a), high cost and lower QALYs than (a)

3

Jutkowitz et al., 2017 [44]

USA

gout

(a) allopurinol-febuxostat sequential therapy: allopurinol:target dose 300 mg/day and febuxostat: 80 mg/day, (current practice)

(b) HLA-B5801 testing prior to treatment

Test positive: febuxostat

Test negative:allopurinol

$109,000 per QALY gained

• ICER (b) vs (a): for

-Asians $64,190,

-African Americans $83,450,

-Caucasians or Hispanics $183,720 per QALY gained

4

Ke CH et al., 2017 [43]

Taiwan

gout with chronic kidney disease

(a) benzbromarone 100 mg/day (current practice)

(b) allopurinol target dose 100 mg/ day

(c) febuxostat 80 mg/day

(d) HLA-B5801 testing prior to treatment

Test positive: febuxostat or benzbromarone

Test negative: allopurinol

NT

$800,000 or US

$25,600 per QALY gainedin 2015

• (b) is dominated by (a), high cost and lower QALYs than (a) current practice)

• (c) is dominated by (d), high cost and lower QALYs than (d) current practice)

• ICER (d) vs (a): NT$ 234,610 per QALY gained in the base-case and NT$ 230,925 per QALY gained in patients with chronic kidney disease

5

Plumpton CO et al., 2017 [42]

UK

gout

(a) allopurinol target dose 300 mg per day add prophylactic treatment with colchicine

(b) HLA-B5801 testing prior to treatment

Test positive: febuxostat: target dose 80 mg per day

Test negative: allopurinol

£30,000 per QALY gained

• ICER (d) vs (a): £44,954 in the base case and £38,478 per QALY in patients with chronic renal insufficiency

6

Dong D et al., 2015 [46]

Singapore

gout

(a) allopurinol starting dose 300 mg, target dose 600 mg per day

(b) allopurinol +safety program (SP)

(c) HLA-B5801 testing prior to treatment + SP

(d) HLA-B5801 testing prior to treatment + SP

Test positive: probenecid target dose 2 g per day

Test negative: allopurinol

(e) HLA-B5801 testing prior to treatment

Test positive: probenecid target dose 2 g per day

Test negative: allopurinol

(f) no allopurinol (treatment of acute flares only)

$50,000 per QALY gained

• -ICER (b) vs (a): $79,140 per QALY

• (c) is dominated by (b), high cost and lower QALYs than (b) current practice)

• ICER (d) vs (b): $85,630 per QALY

• (e) is dominated by (d), high cost and lower QALYs than (d) current practice)

• (f) is dominated by (d), high cost and lower QALYs than (d) current practice)

7

Park DJ et al., 2015 [45]

Korea

gout with chronic renal insufficiency

(a) allopurinol starting dose 100 mg, target dose 300 mg per day

(b) HLA-B5801 testing prior to treatment

Test positive: febuxostat starting dose 40 mg, target dose 80 mg) per day

Test negative: allopurinol

N/A

• Costs of (a) $1193 and (b) $1055

(b) is less costly and more effective than (a)

8

Saokaew et al., 2014 [47]

Thailand

gout

(a) allopurinol starting dose 300 mg per day

(b) HLA-B5801 testing prior to treatment

Test positive: probenecid target dose 1 mg target to 2 g per day

Test negative: allopurinol

160,000 THB per QALY gained

• ICER (b) vs (a): 156,937 THB per QALY

1

Kubaeva et al., 2018 [48]

Russia

HIV

(a) abacavir regimen

(b) HLA-B* 5701 testing prior to treatment

Test positive: alternative regimens without abacavir

Test negative: abacavir regimen

N/A

• (b) vs (a): was cost-saving 54,1646 rubles

2

Kapoor R et al., 2015 [49]

3 ethnic groups in Singapore

HIV

(a) abacavir-based ART

(b) tenofovir-based ART

(c) HLA-B:5701 testing prior to treatment

Test positive: tenofovir-based ART

Test negative: abacavir-based ART

$50,000 per QALY gained

• Early stage: ICER (c) vs (a):

Chinese $415,845 per QALY gained,

Malay $318,029 per QALY gained,

Indian $208,231 per QALY gained

• Late stage: ICER (c) vs (a):

Chinese $926,938 per QALY gained, Malay $624,297 per QALY gained, Indian $284,598 per QALY gained

• HIV who are contraindicated to tenofovir

ICER (b) vs (a): all ethnicity was not cost-effective, except for Indian patients with early-stage ICER (c) vs (a): $44,649 per QALY gained

3

Nieves Calatrava et al., 2010 [51]

Spain

HIV

(a) abacavir regimen

(b) HLA-B:5701 testing prior to treatment

Test positive: alternative HAART regimen without ABC

Test negative: abacavir regimen

N/A

• cost per HSR avoided of €630

4

Kauf TL et al., 2010 [52]

USA

HIV

(a) short-term: abacavir+ lamivudine+efavirenz

(b) long-term: tenofovir+emtricitabine+efavirenz

(c) HLA-B:5701 testing prior to treatment

Test positive: tenofovir+emtricitabine+efavirenz

Test negative: abacavir+lamivudine+efavirenz;

$50,000 per QALY gained

• Short-term: (c) is dominated by (a), high cost and lower QALYs than (a)

• Long-term: (b) is dominated by (c), high cost and lower QALYs than (c)

5

Wolf et al., 2010 [50]

Germany

HIV

(a) combination of abacavir+ lamivudine

(b) HLA-B:5701 testing prior to treatment

Test positive combination of tenofovir, emtricitabine

Test negative combination of abacavir+ lamivudine

N/A

• (b) vs (a): (b) cost-saving €44 and 127 per screened patient from healthcare payer and societal perspective

6

Schackman BR et al., 2008 [53]

USA

HIV

(a) abacavir-based regimen

(b) tenofovir-based regimen

(c) HLA-B:5701 testing prior to treatment

Test positive: tenofovir or AZT-based regimen

Test negative: abacavir-based regimen

$50,000 per QALY gained

• ICER (c) vs (a): $36,700 per QALY gained

• (b) is dominated by (a),high cost and lower QALYs than (a)

7

Hughes DA et al., 2004 [54]

UK

HIV

(a) Trizivir (AZT/3TC/ABC)

(b) HLA-B:5701 testing prior to treatment

Test positive: HAART regimen without abacavir

Test negative: Trizivir (AZT/3TC/ABC)

(HAART: highly active antiretroviral therapy)

N/A

• (a) is dominated by (b), high cost and lower benefit than (b), except for Trizivir is substituted with ritonavir+indinavir+combivir

• ICER (b) vs (a): € 22,811 per hypersensitivity reaction avoided

1

Schackman et al., 2015 [55]

USA

HIV

(a) efavirenz 600 mg + tenofovir+ emtricitabine

(b) CYP 2B6 testing prior to treatment

Test positive: decrease dose to 200,400 mg

Test negative: efavirenz 600 mg

(c) Universal low dose efavirenz 400 mg + tenofovir+ emtricitabine

$ < 100,000 per QALY gained

• (a) is dominated by (b), high cost and lower benefit than (b)

1

Thompson AJ et al., 2014 [56]

UK

autoimmune diseases

(a) azathioprine therapy

(b) TPMT testing prior to treatment

Test positive: alternative treatment

Test negative: azathioprine

£20,000 per QALY gained

• (b) is dominated by (a) lower cost and lower QALYs than (a)

2

Priest VLet al, 2006 [58]

New Zealand

inflammatory bowel disease (IBD)

(a) azathioprine

(b) TPMT testing prior to treatment (Phenotype and genotype)

N/A

• Phenotype and genotype testing dominated by (a), high cost and lower QALYs than (a) There are cost-savings (vs no testing) of $NZ120,000 and 71 neutropenias avoided;-034QALYs and $NZ11,000 and 40 neutropenias avoided, −058QALYs)

3

Hagaman JTet al, 2010 [57]

USA

Idiopathic Pulmonary Fibrosis (IPF)

(a) conservative therapy which no specific therapy

(b) azathioprine+N-acetylcysteine and steroids (no testing)

(c) TPMT testing prior to treatment

Test positive: conservative therapy

Test negative: azathioprine+N-acetylcysteine and steroid

$50,000 per QALY gained

• ICER (b) vs (a): $49,245 per QALY

*ICER (c) vs (b): $29,663 per QALY gained

4

Dubinsky MC et al., 2005 [60]

USA

Crohn’s disease

(a) TPMT testing prior to treatment

Test positive: metrotrexate

Test negative: azathioprine

(b) metabolite monitoring (MM) prior to treatment with azathioprin

(c) TPMT testing +MM prior to treatment with azathioprine

(d) community care (CC)

N/A

• (d) is dominated by (a), (b),and (c), (d) less costs and faster time to response or sustained response

5

Winter J et al., 2004 [61]

Scotland

IBD

(a) azathioprine

(b) TPMT testing prior to treatment

N/A

• for a 30 year old: ICER (b) vs (a): £347 per life-year saved and

• for a 60 year old: ICER (b) vs (a): £817 per life-year saved

6

Sayani FA et al., 2005 [59]

Canada

Crohn’s disease and IBD

(a) azathioprine

(b) TPMT testing prior to treatment

N/A

• The direct health care costs for (a) $30,011 per patient and (b) $34,887 per patient

7

Oh KT et al., 2004 [62]

Korea

rheumatoid arthritis and systemic lupus erythematosus

(a) azathioprine

(b) TPMT testing prior to treatment

N/A

• (a) is dominated by (b), (b) lower cost and more effective than (a)

8

Marra CA et al., 2002 [63]

Canada

rheumatoid arthritis and systemic lupus erythematosus

(a) azathioprine

(b) TPMT testing prior to treatment

N/A

• (a) cost $677 Cdn per patient, (b) cost $663 Cdn per patient

1

Chong et al., 2017 [64]

Malaysia

Epilepsy

(a) carbamazepine (current practice)

(b) sodium valproate (VPA)

(c) HLA-B*15:02 testing prior to treatment

Test positive: VPA

Test negative: carbamazepine

MYR 37,000 ($ 8982) per QALY gained

• (b) is dominated by (a), high cost and lower QALYs than (a) current practice)

• (c) is dominated by (a), high cost and lower QALYs than (a) current practice)

2

Chen et al., 2016 [65]

Hong Kong

Epilepsy

(a) current situation, using antiepileptic drug (pre-policy period)

(b) current situation, using antiepileptic drug (post-policy period)

(c) HLA-B*15:02 testing prior to treatment (the ideal situation) (ideal situation)

Test positive: alternative anti-epileptic drug

Test negative: carbamazepine or phenytoin

(d) HLA-B*15:02 testing prior to either carbamazepine or phenytoin (extended situation)

$50,000 per QALY gained

• ICER (b) vs (a): $85,697 per QALY gained

• ICER (c) vs (a): $11,090 per QALY gained

• ICER (d) vs (a): $197,158 per QALY gained

3

Rattanavipapong W et al., 2013 [67]

Thailand

Epilepsy or neuropathic pain

(a) carbamazepine (no HLA-B*15:02 testing)

(b) HLA-B*15:02 testing prior to treatment

Test positive:

for epilepsy: valproate, for neuropathic pain: gabapentin;

Test negative: carbamazepine

(c) all prescribed alternative (no HLA-B*15:02 testing) (epilepsy: valproate, neuropathic pain: gabapentin)

120,000 THB per QALY gained

• ICER (b) vs (a):

222,000 THB per QALY for epilepsy, 130,000 THB per QALY for neuropathic pain

• ICER (c) vs (a):

32,522,000 per QALY for epilepsy, (epilepsy), 35,877,000 per QALY for neuropathic pain

4

Tiamkao S et al., 2013 [66]

Thailand

Epilepsy or neuropathic pain and neurological diseases

(a) carbamazepine

(b) HLA-B*15:02 testing prior to treatment

Test positive: non-specified

Test negative: carbamazepine

N/A

• (b) vs (a): (b) was cost-saving 98,54,994 THB per 100 cases of carbamazepine users

5

Dong D et al., 2012 [68]

Singapore

Epilepsy

(a) carbamazepine or phenytoin

(b) HLA-B*15:02 testing prior to treatment

Test positive: valproate;

Test negative carbamazepine or phenytoin

(c) valproate (no screening)

$50,000 per QALY gained

ICER (b) vs (a):

Chinese patients $37,030 per QALY gained, Malay $7930 per QALY gained and Indians $136,630 per QALY gained

• (c) is dominated by (b), high cost and lower QALYs than (b)

1

Plumpton et al., 2015 [69]

UK

Epilepsy

(a) carbamazepine

(b) HLA-B*31:01 testing prior to treatment

Test positive: lamotrigine;

Test negative: carbamazepine

£20,000 per QALY gained

• ICER (b) vs (a): £ 12,808 per QALY gained

1

Deenen MJ et al., 2016 [70]

The Netherland

cancer

(a) fluoropyrimidines-based therapy

(b) DPYD*2A testing prior to treatment

Test positive: alternative regimen

Test negative: Fluoropyrimidines-based

N/A

• (b) vs (a): (b) cost-savings of €45 ($61) per patient

1

Pichereau S et al., 2010 [71]

France

metastatic colorectal cancer

(a) FOLFIRI regimen (5-fluorouracil, leucovorin and irinotecan)

(b) UGT1A1 testing prior to treatment with FOLFIRI

Test positive: FOLFOX regimen (oxaliplatine + 5-FU + folinic acid)

Test negative: FOLFIRI

N/A

• ICER (b) vs (a): to avoid one febrile neutropenia per 1000 patients treated was € 9428 to € 10,901

2

Gold HT et al., 2009 [72]

USA

metastatic colorectal cancer

(a) FOLFIRI regimen (5-fluorouracil, leucovorin and irinotecan)

(b) UGT1A1 testing prior to treatment with FOLFIRI

Test positive: reduce dose to intermediate dose

Test negative: FOLFIRI

$100,000 per QALY gained

• ICER (b) vs (a): was cost-effective if the treatment efficacy of irinotecan in homozygotes after dose reduction had to be ≥984% of full-dose efficacy for genetic testing to remain preferred

1

Bern EJ et al., 2016 [73]

The Netherland

major depressive disorder

(a) nortriptyline

(b) CYP2D6 genotyping-guided dosing of nortriptyline

€50,000 per QALY gained

• ICER (b) vs (a): €1,333,000 per QALY gained

1

Smith KJ, et al., 2008 [74]

USA

women who receiving oral contraceptives (OCPs)

(a) usual care

(b) genotyping

(c) genotyping with OCP counseling

(d) genotyping with OCP counseling and AC for high-risk events

(e) genotyping with OCP counseling and AC for long-term

$20,000 per QALY gained

• ICER (d) vs (c): $ 147 per QALY gained

• ICER (e) vs (d): $ 639,500 per QALY

• (a) is dominated by (d), high cost and lower QALYs than (d)

• (b) is dominated by (d), high cost and lower QALYs than (d))