Table 1 Summary statistics of individual studies for non-replicated alleles.

From: Pharmacogenomics of Clozapine-induced agranulocytosis: a systematic review and meta-analysis

Author

Ethnicity

Allele

CIA + 

CIA−

Control + 

Control−

Sensitivity

Specificity

NPVa

PPVa

NNG

OR [95% CI]

 | Z | 

p value

pb,a

Turbay 1997c

European

TNFb5

9

57

43

23

14%

35%

97.8%

0.2%

−2

0.08 [0.04, 0.20]

5.6

2.25E–08

1.64E–06

Saito 2016

Japanese

HLA-B*59:01

19

53

18

362

26%

95%

99.3%

4.9%

3

7.21 [3.56, 14.61]

5.5

4.19E–08

3.06E–06

Turbay 1997c

European

TNFb4

48

18

17

49

73%

74%

99.7%

2.5%

3

7.69 [3.55, 16.65]

5.2

2.34E–07

1.71E–05

Turbay 1997c

European

TNFd3

51

15

28

38

77%

58%

99.6%

1.6%

3

4.61 [2.17, 9.82]

4.0

7.16E–05

5.23E–03

Lahdelma 2001

Caucasian

HLA-A1

3

23

11

8

12%

42%

98.1%

0.2%

−2

0.09 [0.02, 0.43]

3.1

2.22E–03

0.16

Yunis 1995

Non-Jewish

HLA-DQA1*01:02

15

27

3

29

36%

91%

99.4%

3.4%

3

5.37 [1.40, 20.63]

2.4

0.01

1

Yunis 1995

Ashkenazi Jewish

HLA-DR4

9

1

12

20

90%

63%

99.9%

2.2%

3

15.00 [1.68, 133.56]

2.4

0.02

1

Turbay 1997c

Ashkenazi Jewish

HLA-DQA1*03:01

12

12

13

41

50%

76%

99.4%

1.9%

4

3.15 [1.14, 8.70]

2.2

0.03

1

Yunis 1995

Non-Jewish

HLA-DR2

13

8

5

14

62%

74%

99.5%

2.1%

3

4.55 [1.18, 17.52]

2.2

0.03

1

Turbay 1997c

Non-Jewish

HLA-DRB1*02

14

26

4

28

35%

88%

99.3%

2.5%

4

3.77 [1.10, 12.93]

2.1

0.03

1

Ostrousky 2003

Jewish

NQO2 372 T > C

14

4

40

40

78%

50%

99.6%

1.4%

6

3.50 [1.06, 11.56]

2.1

0.04

1

Ostrousky 2003

Jewish

NQO2 202 G > A

17

1

54

26

94%

33%

99.8%

1.3%

5

8.19 [1.03, 64.89]

2.0

0.05

1

van der Weide 2017

Dutch

ABCB1 2677 G > T

16

15

167

73

52%

30%

98.6%

0.7%

−13

0.47 [0.22, 0.99]

2.0

0.05

1

Lahdelma 2001

Caucasian

HLA-A28

8

18

1

18

31%

95%

99.3%

5.1%

3

8.00 [0.91, 70.71]

1.9

0.06

1

Dettling 2001

German

HLA-DQB1*02:01

13

17

20

57

43%

74%

99.3%

1.5%

7

2.18 [0.90, 5.27]

1.7

0.08

1

van der Weide 2017

Dutch

ABCB1 3435 C > T

26

5

166

75

84%

31%

99.5%

1.1%

14

2.35 [0.87, 6.36]

1.7

0.09

1

Lahdelma 2001

Caucasian

HLA-A9

6

20

1

18

23%

95%

99.3%

3.9%

4

5.40 [0.59, 49.26]

1.5

0.13

1

van der Weide 2017

Dutch

TNFa -308 G > A

12

19

63

178

39%

74%

99.2%

1.3%

16

1.78 [0.82, 3.88]

1.5

0.14

1

van der Weide 2017

Dutch

Hsp70-2 1267 G > A

22

9

195

43

71%

18%

98.5%

0.8%

−14

0.54 [0.23, 1.25]

1.4

0.15

1

Lahdelma 2001

Caucasian

HLA-B16

6

16

2

17

27%

89%

99.3%

2.3%

4

3.19 [0.56, 18.16]

1.3

0.19

1

Lahdelma 2001

Caucasian

HLA-A11

5

21

1

18

19%

95%

99.2%

3.2%

4

4.29 [0.46, 40.16]

1.3

0.20

1

Lahdelma 2001

Caucasian

HLA-B27

1

21

3

16

5%

84%

99.0%

0.3%

−4

0.25 [0.02, 2.68]

1.1

0.25

1

Yunis 1995

Ashkenazi Jewish

HLA-DQ3

9

1

23

9

90%

28%

99.7%

1.1%

6

3.52 [0.39, 31.95]

1.1

0.26

1

Mosyagin 2005

Caucasian

FcγRIIa R/H

41

7

59

16

85%

21%

99.4%

1.0%

10

1.59 [0.60, 4.20]

0.9

0.35

1

Yunis 1995

Non-Jewish

HLA-DQ1

13

8

14

5

62%

26%

98.7%

0.8%

−8

0.58 [0.15, 2.24]

0.8

0.43

1

Mosyagin 2005

Caucasian

FcγRIIIb NA2/NA1

25

23

44

31

52%

41%

98.9%

0.8%

−16

0.77 [0.37, 1.59]

0.7

0.47

1

Lahdelma 2001

Caucasian

HLA-B18

1

21

2

17

5%

89%

99.0%

0.4%

−5

0.40 [0.03, 4.85]

0.7

0.48

1

Lahdelma 2001

Caucasian

HLA-B37

1

21

2

17

5%

89%

99.0%

0.4%

−5

0.40 [0.03, 4.85]

0.7

0.48

1

Lahdelma 2001

Caucasian

HLA-B12

4

18

2

17

18%

89%

99.2%

1.6%

7

1.89 [0.31, 11.68]

0.7

0.49

1

Lahdelma 2001

Caucasian

HLA-B8

5

17

6

13

23%

68%

99.0%

0.7%

−9

0.64 [0.16, 2.56]

0.6

0.52

1

Lahdelma 2001

Caucasian

HLA-A2

10

16

9

10

38%

53%

98.9%

0.7%

−12

0.69 [0.21, 2.30]

0.6

0.55

1

Lahdelma 2001

Caucasian

HLA-B5

5

17

3

16

23%

84%

99.2%

1.3%

10

1.57 [0.32, 7.66]

0.6

0.58

1

Ostrousky 2003

Jewish

NQO2 -394 G > C

16

1

63

2

94%

3%

98.3%

0.9%

−8

0.51 [0.04, 5.96]

0.5

0.59

1

Lahdelma 2001

Caucasian

HLA-A3

9

17

8

11

35%

58%

99.0%

0.7%

−13

0.73 [0.22, 2.46]

0.5

0.61

1

Lahdelma 2001

Caucasian

HLA-B13

2

20

1

18

9%

95%

99.1%

1.6%

8

1.80 [0.15, 21.57]

0.5

0.64

1

Lahdelma 2001

Caucasian

HLA-B22

2

20

1

18

9%

95%

99.1%

1.6%

8

1.80 [0.15, 21.57]

0.5

0.64

1

van der Weide 2017

Dutch

GSTM1null

16

15

113

125

52%

53%

99.2%

1.0%

60

1.18 [0.56, 2.50]

0.4

0.67

1

Mosyagin 2005

Caucasian

FcγRIIIa F/V

28

20

41

34

58%

45%

99.2%

1.0%

29

1.16 [0.56, 2.41]

0.4

0.69

1

Lahdelma 2001

Caucasian

HLA-A10

2

24

1

18

8%

95%

99.1%

1.3%

11

1.50 [0.13, 17.86]

0.3

0.75

1

Dettling 2001

German

HLA-DQB1*03

16

14

43

34

53%

44%

99.0%

0.9%

−49

0.90 [0.39, 2.11]

0.2

0.81

1

van der Weide 2017

Dutch

GSTT1null

27

4

204

34

87%

14%

99.2%

0.9%

87

1.13 [0.37, 3.42]

0.2

0.84

1

Lahdelma 2001

Caucasian

HLA-B15

4

18

3

16

18%

84%

99.1%

1.0%

24

1.19 [0.23, 6.12]

0.2

0.84

1

Mosyagin 2004

Caucasian

CYPBA C242T

42

38

39

37

53%

49%

99.1%

0.9%

85

1.05 [0.56, 1.97]

0.1

0.88

1

Ostrousky 2003

Jewish

NQO2 -367 A > G

15

2

65

8

88%

11%

99.0%

0.9%

−80

0.92 [0.18, 4.80]

0.1

0.92

1

van der Weide 2017

Dutch

GSTP1 313 A > G

28

3

211

24

90%

10%

99.1%

0.9%

166

1.06 [0.30, 3.76]

0.1

0.93

1

Lahdelma 2001

Caucasian

HLA-A19

4

22

3

16

15%

84%

99.1%

0.9%

−133

0.97 [0.19, 4.95]

0.0

0.97

1

van der Weide 2017

Dutch

GSTA1 -69 C > T

26

5

199

39

84%

16%

99.1%

0.9%

522

1.02 [0.37, 2.82]

0.0

0.97

1

Ostrousky 2003

Jewish

NQO2 1536 C > T

18

0

41

39

100%

49%

100.0%

1.8%

4

35.22 [2.05, 604.37]d

2.5d

0.01d

1d

Yunis 1995

Ashkenazi Jewish

HLA-DQB1*03:01

0

16

18

36

0%

67%

98.6%

0.0%

−4

0.06 [0.00, 1.05]d

1.9d

0.05d

1d

Lahdelma 2001

Caucasian

HLA-B40

5

17

0

19

23%

100%

99.3%

100.0%

2

12.26 [0.63, 238.00]d

1.7d

0.10d

1d

Yunis 1995

Ashkenazi Jewish

HLA-DRB1*11

0

16

13

41

0%

76%

98.8%

0.0%

−4

0.09 [0.01, 1.66]d

1.6d

0.11d

1d

Lahdelma 2001

Caucasian

HLA-B17

0

22

1

18

0%

95%

99.0%

0.0%

−2

0.27 [0.01, 7.13]d

0.8d

0.44d

1d

van der Weide 2017

Dutch

NQO1 609 C > T

31

0

234

7

100%

3%

100.0%

0.9%

9

2.01 [0.11, 36.14]d

0.5d

0.63d

1d

  1. CIA clozapine-induced agranulocytosis, CIA+, number of variant positive CIA subjects, CIA− number of variant negative CIA subjects, Control+ number of variant positive control subjects, Control− number of variant negative control subjects, NNG number needed to genotype, NPV negative predictive value, OR odds ratio, PPV positive predictive value.
  2. aNPV and PPV were corrected for the prevalence of CIA in the US.
  3. bBonferroni correction (m = 73) was applied based on the number of alleles/haplotypes analyzed in this review.
  4. cStudy included both Jewish and Non-Jewish individuals.
  5. dHaldane correction was applied for case-control pairings which had 0 subjects in at least one cell.
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