DOH99-HP-1205
99
6
... 7
... 7 ( ) 6 ... 7 1. (CAH) ... 7 2. (MSUD) ... 7 3. A (MCAD) ... 8 4. (GA I) ... 8 5. (IVA) ... 8 6. (MMA) ... 9 ( ) 6 ... 9 1. 6 ... 9 2. 6 ... 10 ( ) ... 10 ... 12... 13
... 13 (meta-analysis) ... 15 ( ) ... 15 ( ) ... 16 ... 17 ( ) ... 18 ( ) ... 18 ( ) ... 20 1. ... 21 2. ... 22 3. ... 23... 28 ... 28 ( ) ... 28 ( ) ... 28 ( ) ... 29 (meta-analysis) ... 29 ( ) ... 29 ( ) 6 ... 30 ( ) (meta-analysis) ... 30 1.sROC ... 30 2. ... 33 ( ) ... 34 1.
... 35
2.... 35
3.... 35
4.... 36
5.... 36
6.... 37
... 38 ( ) ... 38 ( ) ... 39 1.... 39
2.... 39
3.... 39
4.... 39
5.... 40
6.... 40
( ) 6 ... 41 ( ) 6 ... 42 ( ) 6 QALY ... 42 ( ) 6 ... 43 ( ) 6 ... 44 ( ) ... 45 1.
... 45
2.... 45
... 48
... 48 ( )... 49
( )... 49
( )... 49
6 ... 50 ( )... 50
( ) 6... 51
1.... 51
2.... 51
6 ... 52 ( ) 6 ... 52 1. ... 52 2. ... 52 3. ... 53 4. ... 53 5. ... 53 6. A ... 54( ) 6 ... 54 1. ... 54 2. ... 55 3. ... 57 4. ... 57 5. ... 57 ( ) ... 58 1. ... 59 2. ... 59
... 60
... 60
... 62
... 64
... 68
1 6 ... 69 2 2008 196,234 ... 71 3 6 ... 75 4 ... 81 5 ... 82 6 sROC ... 91 7 ... 92 8 - ... 93 9 ... 94 10 ... 100 11 ... 102 12 6 ... 103 13 6 ... 104 14 QALY ... 105 15 6 ... 10616 6 ... 107 17 6 ... 108 18 - ... 110 19 6 QALY ... 114 20 ... 115 21 ... 117 1 ... 72 2 6 (A) 6 (B) ... 73 3 ... 74 4 6 ... 80 5 (meta-analysis) ... 85 6 6 ... 86 7 (CAH) ... 87 8 (MSUD) ... 87 9 (GA I) ... 88 10 ( IVA) ... 88 11 (MMA) ... 89 12 A (MCAD) ... 90 13 1- ... 91 14 - QALY ... 110 15 - CAH ... 111 16 - MSUD ... 111 17 - IVA ... 112 18 - MMA ... 112 19 - GAI ... 113 20 - MCAD ... 113 6 6 6
6
(
A
)
6
6
6
?
6
(
)
(
)
(quality-adjusted life years,
QALYs)
(discount rate)
6
(
)
6
74
7
95
7
-6-
5
(Congenital Adrenal Hyperplasia, CAH)
(Maple Syrup
Urine Disease, MSUD)
A
(Medium Chain Acyl-CoA
Dehydrogenase Deficiency, MCADD)
(Glutaric Acidemia
Type I, GA I)
(Isovaleric Acidemia, IVA)
(Methylmalonic Acidemia, MMA)6
6
6
1
1.
(CAH)
6
(cortisol)
(Adrenocorticotropic hormone, ACTH)
(
,
2008)
Branched chain x-keto
aciddehydrogenase
Leucine
Isoleucine
Valine
Branched chain
amino acid
20-40
5-10
(
)
3.
A
(MCAD)
25
4.
(GA I)
A
(glutaryl CoA dehydrogenase)
(lysine)
(tryptophan)
(hydroxylysine)
5.
(IVA)
leucine
A
( Isovaleryl
Co-A dehydrogenase
IVD )
ataxia
6.
(MMA)
A
(methylmalonyl-CoA mutase)
(mut-)
B12
(mut
0 )
B12
(mut )
13
(
)
6
1.
6
CAH
89
3
~92
10
599,650
40
CAH
1/15,000 MSUD
74
7
76
8
76
9
G6PD
MSUD
GA I
IVA
MMA
MCAD
6
[1]
(Tandem Mass
Spectrometry; MS/MS)
CAH
MSUD
MCAD
GA I
IVA
MMA
95
7
6
2009
[2]
2008
196,234
98.7
(CAH)34
(MSUD)0
(GA I)13
(IVA)1
(MMA)4
A
9
2
2.
6
CAH
[3]
MSUD
[3]
MCAD GA I IVA
MMA
[4]
[5]
[6]
[3]
(quality-adjusted life years, QALYs)
(disability-adjusted life years, DALYs)
1
1
0
QALY
(burden
of disease)
-QALY
DALY
QALY
DALY
(
)
(
)
6
(
A
)
(
)
(
)
6
(
A
)
6
(
)
6
…
(
)
(discount rate)
6
?
?
(meta-analysis)
6
(beneficience)
(not
doing harm
non-maleficience)
(autonomy)
(justice)
(
)
(
)
2.
3.
4.
5.
6.
(
)
(Hart, 1971)
Hall[7]
(
)
(meta-analysis)
6
(
)
(pooled estimate)
(
)
(
)
(
)
(
)
1.
2.
:
3.
4.
5.
(
)
6.
(forest plot)
7.
(funnel plot)
(publication bias)
(
)
Q
(summary results)
(test overall significance)
Q
Σw
i(
–
)
2w
i:
Q
-1
I
2= 100 { 1 –( 1 /
H
2) }
H = SQRT { Q / (k-1) }
k
I
225%
(
)
iw
i:
) * (∑
∑
= i i i w w(societal perspective)
6
(incremental cost-effectiveness analysis)
1
(
)
(
)
(
)
(
)
2
(A)
(B)
6
(
0.25 [8, 9])
3
6
6
6
6
(
1
)
(
1
)
(
2 B
)
1
(
)
1
(
)
1
(
)
3
1.
4,000
[10]
2.
(1)
(2)
(3)
(4)
(5)
(
)
1.
(
6
[10]
)
2.
3.
4.
=
) ( × −3
58.6
[11]
2009
78.97
98
(incremental cost-effectiveness ratio, C/E ratio)
98
$507,135
[12]
(
)
1.
2.
(
)
3.
4.
5.
(
)
6.
(
)
(
)
99
4
9
(
)
5
1.
(1)
A.
(A)
74
7
6
99
4
9
6
6
6
(B)
/
[13]
7
(3
6
1
1.5
2
2.5
3
)
B.
(A)
2004
2008
6
2006
7
6
(B)
2004
2008
6
2006
7
6
C.
6
(
)
18
[9]
(2)
2004-2008
6
2.
(1)
A.
(
)
B.
C.
D.
(2)
A.
6
3
B.
2004
2008
2006
7
1
6
C.
3.
(1)
4
6
6
6
(
)
(
)
(QALY
)
6
(
)
(2)
4
3
A.
6
2009
噁
1:9,400
1:302,091
1:67,131
1:151,046
1:33,566
1:67,131)
(98.7%)
(196,234)
[2]
B.
Carroll
[9]
(
k)
78.97
67.6
65
58.6
(
3)
C.
(
3)
[9]
D.
[9]
= ( × × ) + 1 − ×E.
(A) = × 6 + × 6 + 6 (B) = × 6 + 6 (C) = × 6 + ×6 + 6 (D) = (A) + (B) + (C)
F.
(
)
= { × 6 ) + 6 }G.
2004
2008
6
ID
0
(C
0)
(C
0)
(i
2.51%)
(r
3%)
6
(A) k : C =∑ C =∑ ( ) ( ) ( ) C =∑ ( ) ( ) ( ) (B) = +H.
2009
18
[9]
(p 0.89%)[12]
(r
3%)
6
18
C =∑ C =∑ ( ) ( ) ( )I.
QALY
QALY
4
1
QALY
0
QALY
0.5625
0.3909
0.5625
0.3909[14]
(3)
(1)
(2)
1%
9%
1981
3.1%
2007
2.9%
98.7%
PubMed
(Neonatal Screening newborn screening)
(ethical
considerations)
5
(
)
1976
[15]
(
)
[16]
[17]
。(
)
[18]
[15]
[16, 19]
(meta-analysis)
(
)
PubMed
’sensitivity’
”specificity”
”Congenital Adrenal
Hyperplasia ” ” Maple Syrup Urine Disease” ” Medium Chain Acyl-CoA
Dehydrogenase Deficiency”
” Glutaric Acidemia Type I”
” Isovaleric
Acidemia”
” Methylmalonic Acidemia”
(
12
9
A
15
6
5
5
1978
2009
(
)
6
6
6
(CAH)
(MSUD)
(GA I)
(IVA)
(MMA)
A
(MCAD)
(
7-12)
(
)
(meta-analysis)
(meta-analysis)
(pooling)
(summary
Receiver Operating Characteristic
sROC)
sROC
—
(
)
(
)
sROC
(bivariate model)
1.
sROC
sROC
Moses[20]
Littenberg[21]
“
”
(
7)
sROC
(TPR)
1
(FPR)
ROC
(fitness)
TPR
FPR
D
TPR
FPR
(logit)
S
! = ln $
(%&'%&') − ln $
(*&'*&') = ln(DOR)
(1)
. = ln $
(%&'%&') + ln(
(*&'*&')
(2)
D
(DOR)
DOR
S
0
S
S
ROC
log
(DOR)
! = / + 0.
(3)
[21]
(Congenital Adrenal Hyperplasia, CAH)
A
(Medium Chain Acyl-CoA Dehydrogenase Deficiency,
MCAD)
(Methylmalonic Acidemia, MMA)
(ACTH)
21-17-hydroxyprogesterone
(2)
A
A
(C8)
(C6)
(C10)
C8/C10
(3)
11
4
2
A
(
8)
1-
13
(3)
(DOR)
S(
β≈0)
DOR
DOR
S
β
sROC
[22]
Q
sROC
Q
sROC
sROC
Q
Q
S
S
2.
[23, 24]
random effect
[25, 26]
(precision)
K
(I=1,2,3…,K)
N
2(
p
2,5)
N
6(
p
6,5)
θ
2,55
θ
2,5θ
2σ
29θ
6σ
69(
)
:
θ
θ
2,5 6,5; ~= :>
?
@?
AB , Σ; DEFℎ Σ = : H
@9H
@IH
@IH
I9;
σ
26N
2N
60
p
2,5,
p
6,51
S
2,K9=
L,5 ∙ NL,5 ∙ ((NL,5)S
6,59=
O,5 ∙ NO,5 ∙ ((NO,5) $PQL,5 PQO,5) ~= :$ PL,5 PO,5) , 5; with 5= : .2,59 0 0 .6,59 ; :θWθW2,5 6,5; ~= :> θ2 θ6B , X + 5;(likelihood-based method)
(fitted)
SAS
Mixed
7
1.
15
25
19
[27]
1,000
40
30
25
100
[28]
2.
1970
Department
of Health
phenylketonuria(PKU)
maple syrup urine
disease(MSUD)
homocystinuria (HCU),galactosemia (GE)
hypothyroidism
21-hydroxyase deficiency
[29]
3.
60
99
[30]
2004
Disorders
Cystic Fibrosis
UK
Wales
[31]
2004
Medium-chain acyl-CoA dehydrogenase
deficiency
MCAD
4.
Congenital Hypothyreosis
(CH)
Congenital Adrenal Hyerplasia
CAH
Deficiency of
Biotinidase Classical form of Galacosemia Deficiency of GALT
11
Nennstiel-Ratzel U
[32]
1999
2001
35
80
98
217
5.
Yoo[33]
255,700
292,000
Insinga[34]
A
(MCAD)
41,862
(
9)
6.
Thil'en
[35]
26,700
53,400
Tran[36]
A
A
450,521
934,923
2,676
Autti-Ramo[10]
5,500
25,500
5
10
1
3
1
5
Venditti[8]
Markov
(
9)
(
)
(
)
(99)
4
9
(
)
(99)
12
3
1.
(1)
(2)
(3)
2.
(
)
40
2
4
5
16
67
(
10)
1.
(47.5%)
(40%)
(7.5)
(5%)
32.5%
(22.5%)
(15%)
(15%)
(7.5%)
(7.5%)
2.
84.6
220.6
3.
6
1527.78
3421.88
4.
6
5
2083.33
5.
16
7
(43.75%)
4
(25%)
2
(12.5%)
2
(12.5%)
1
(6.25%)
85.42
348.33
178.75
58.67
1239.57
6.
(precision)
11
3
(16.67%)
19
(31.67%)
3
(3.49%)
15(4.44%)
(
5%)
10%
8.26%
50%
(7
)
2004~2008
(
)
6
2009
198,819
(
12
A)
6
6
(
12)
(CAH)
21.16
Carroll[9]
10%
2.12
(GA I)
1
33,566
5.92
5%
20%
4.44
0.30
1.18
2.96
(95%
2.81
)
(5%
0.15
)
A
(75% 2.22
)
(5% 0.15
)
(20% 2.22
)[34]
1.56
(28%
0.44
)
(22%
0.34
)
(50%
0.78
)[37]
1:151,046
1.31
(
1.05
)
(0.26
)(
12)
(D)
††††=
(A)
††††×
(B)
††††×
(C)
†††† † (A) (B) (C) (D) 12(
)
6
6
6
6
(
13)
20.63
(97.52%)
0.52
(2.48%)
1.13
(71.96%)
0.02
(1.54%)
0.41
(26.5%)
2.96
5.92
8%(
0.11
)
18.4%(
0.24
)
73.6%(
0.97
)
A
94.6%(2.80
)
0.40%(0.01
)
5%(0.15
) (
13)
(
)
6
QALY
Bennett[14]
QALY
1
0
1.
(E)
††††=
×
(C)
††††×
+(1-
)
×
(C)
†††† 2.(D’)
††††=
(A)
††††×
(B)
††††×
(C)
††††×
† (A) (B) (C) (E) (D’) (E’) 13
∆QALY(I)
††††=
QALY(G)
††††癇
癇癇
癇
QALY(F)
††††0.5625
0.3909
0.5625
QALY
(
13)
QALY
QALY
3.92
(-0.03)
(-0.08)
(-0.17)
(-0.18)
(-0.21)
QALY
QALY
(1.59)
(1.48)
QALY
(
14)
6
QALY
1.59QALY
0.30QALY
0.06
QALY
0.07QALY
1.31QALY
A
0.58
QALY
(
)
6
2004
2008
6
1.
(J)
†=
∑ ( (K) (K) ) (Y%) ( )2.
(K)
†=
=∑ ( ) (Y%) ( )3.
(L)
†=
(J)
†+
(K)
†4.
(L’)
†=
(M)
†+
(N)
†+
(J’)
†+
(K’)
† † (J) (K) (L) (M) (N) (L’) (J’) (K’) 15 162009
3%
(
15)
(11,806,590
)
(11,787,898
)
(8,975,883
)
(7,903,600
)
A
(6,610,881
)
(6,099,283
)
(1,762,955
)(
15)
(
16)
2,941.45
3,077.45
14,583
(1,755,084
1,731,393
)
(
)
6
(
17)
(33,559,377
)
(9,237,558
)
1.
(Q)
†=
(O)
†×
(P)
†2.
(Q’)
†=
(O’)
†×
(P’)
†+
(R)
†×
(S)
† † (O) (P) (Q) (R) (S) (O’) (P’) (Q’) 17(8,322,688
)
(
17)
(36,201,140
)
(7,399,069
)
(6,330,938
)
(6,330,938
)
13,252,714
(
6,612,272
3,879,787
)
(2,658,309
)(
17)
(
)
1.
1%
9%
13
1%
9%
QALY
(
14)
2.
(1)
6
(
QALY
)
(
15)
(2)
1:302,091
(
16)
QALY
(3)
(
17)
2009
1:67,131
(4)
(
18)
QALY
(5)
1:33,566
QALY
(
19)
(6)
A
A
1:67,131
QALY
A
QALY
99%
[2]
2006
6
(
A
)
6
1
9,400
2006
6
6
[38]
(
)
(
)
(
)
6
(
)
(meta-analysis)
(pooling)
(bivariate model)
sROC
1.
2.
(summary
estimate)
95%
(
)
3.
4.
sROC
sROC
sROC
sROC
5.
6.
(
)
6
1.
Yoo[33]
255,700
292,000
(
3%)
141,894
(
4,577
)
Insinga[34]
A
(MCAD)
41,862
A
(MCAD)
66,374
(2,141
)
2.
Thil'en[35]
Tran[36]
Autti-Ramo[10]
6
(
)
6
1.
Carrol
80%
[9]
97.52%(20.63
)
2.48%(0.52
)
2.
Naughten
Scriver
93%[37]
53%[39]
71.96%(
1.13
)
1.54%(0.02
)
26.5%(0.41
)
3.
[1]
[40]
Tandem mass
5%
(
2.96
)
4.
[40]
8%
8%
8%(
0.11
)
18.4%(
0.24
)
73.6%(
0.97
)
5.
[40]
8%
6.
A
Washington
[41]
A
98%
[40]
A
A
A
98%
94.6%(2.80
)
0.40%(0.01
)
5%(0.15
)
(
)
6
(
3)
1.
6
5
(
-6-
)
(
)
6
(
)
(2,941.45
)
(14,583
)
2.
2004
2008
2006
9
1
(1)
1.59
QALY
2,651,000
QALY
1,666,717
(2)
0.30QALY
10,472,172
QALY
34,796,722
(3)
0.06QALY
850,867
QALY
13,133,449
(4)
0.08
0.07
QALY
2,193,394
QALY
30,307,089
(5)
6
QALY
1.31
QALY
2,553,700
QALY
1,943,136
(6)
A
A
0.58QALY
166,420
QALY
286,691
6
QALY
(1.59 QALY)
(1.31QALY)
A
(0.58 QALY)
(0.30 QALY)
QALY
(0.06 QALY)
(0.07QALY)
QALY
A
18
3.
2009
Insinga[34]
18
18
9,648,839
9,648,839
4.
A
(
13,252,714
3.92QALY)
25
(
2010
507,135
3%)
6,808,395
5.
(1)
1%
10%
13
14
3%
18%
(2)
A
(
)
(
)
(Pompe disease)
(Fabry disease)
1
400,000
2004
2008
Pompe disease
Fabry
disease
2
Merta[42] Chien[43]
1.
15,158,305
6.8
QALY
3.19
25
(
2010
507,135
3%)
6,560,475
(
20)
2.
13,574,105
6.5
QALY
2.95
6,510,660
(
21)
(
6.8QALY
6.5QALY)
6
20
60
1/3
(
)
99
(
)
5
20
(
)
(
)
(
)
6
(
2,651,000
)
A
(
166,420
)
(
10,472,172
)
(
2,553,700
)
(
2,193,394
(
850,867
)
(
)
6
(
)
6
6
(
)
11
(
)
1:500,000
1:200,000
1:10
1:200
1. , et al., . 2004: .
2. , 2009 . 2009,
.
3. website, M.o.D.B.D.F. 2004; Available from:
http://www.marchofdimes.com/home.asp.
4. Wiley, V., K. Carpenter, and B. Wilcken, Newborn screening with tandem
mass spectrometry: 12 months' experience in NSW Australia. Acta Paediatr
Suppl, 1999. 88(432): p. 48-51.
5. Schulze, A., et al., Expanded newborn screening for inborn errors of
metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics, 2003. 111(6 Pt 1): p. 1399-406.
6. Pollitt, R.J., et al., Neonatal screening for inborn errors of metabolism: cost,
yield and outcome. Health Technol Assess, 1997. 1(7): p. i-iv, 1-202.
7. Hall, A.J., Public health trials in West Africa: logistics and ethics. IRB, 1989.
11(5): p. 8-10.
8. Venditti, L.N., et al., Newborn screening by tandem mass spectrometry for
medium-chain Acyl-CoA dehydrogenase deficiency: a cost-effectiveness analysis. Pediatrics, 2003. 112(5): p. 1005-15.
9. Carroll, A.E. and S.M. Downs, Comprehensive cost-utility analysis of newborn
screening strategies. Pediatrics, 2006. 117(5 Pt 2): p. S287-95.
10. Autti-Ramo, I., et al., Expanding screening for rare metabolic disease in the
newborn: an analysis of costs, effect and ethical consequences for decision-making in Finland. Acta Paediatr, 2005. 94(8): p. 1126-36.
11. Bittles, A.H., et al., The influence of intellectual disability on life expectancy. J Gerontol A Biol Sci Med Sci, 2002. 57(7): p. M470-2.
12. . . Available from:
http://www.dgbas.gov.tw/mp.asp?mp=1.
13. ,
, , Editor. 2009,
.
14. Bennett, J.E., et al., Parents' utilities for outcomes of occult bacteremia. Arch Pediatr Adolesc Med, 2000. 154(1): p. 43-8.
15. Faden, R., et al., A survey to evaluate parental consent as public policy for
neonatal screening. Am J Public Health, 1982. 72(12): p. 1347-52.
16. Huang, M.C., et al., Parental consent for newborn screening in southern
17. , , and , .
Formosan J Med, 2003. 7(5): p. 774-779.
18. Edwards, A., Neonatal screening. Pretest counselling and informed consent
should be prerequisites. BMJ, 1996. 312(7024): p. 182-3.
19. , , and ,
. , 2004. 16(1): p. 43-50.
20. Moses, L.E., D. Shapiro, and B. Littenberg, Combining independent studies of
a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med, 1993. 12(14): p. 1293-316.
21. Littenberg, B. and L.E. Moses, Estimating diagnostic accuracy from multiple
conflicting reports: a new meta-analytic method. Med Decis Making, 1993.
13(4): p. 313-21.
22. Walter, S.D., Properties of the summary receiver operating characteristic
(SROC) curve for diagnostic test data. Stat Med, 2002. 21(9): p. 1237-56.
23. Kardaun, J.W. and O.J. Kardaun, Comparative diagnostic performance of
three radiological procedures for the detection of lumbar disk herniation.
Methods Inf Med, 1990. 29(1): p. 12-22.
24. van Houwelingen, H.C., L.R. Arends, and T. Stijnen, Advanced methods in
meta-analysis: multivariate approach and meta-regression. Stat Med, 2002.
21(4): p. 589-624.
25. Van Houwelingen, H.C., K.H. Zwinderman, and T. Stijnen, A bivariate
approach to meta-analysis. Stat Med, 1993. 12(24): p. 2273-84.
26. S, K., B. N, and J. NL, Bivariate and trivariate normal distributions In
Continuous multivariate distributions. 2000, New York. 251-348.
27. Center, N.N.S.G.R. International NBS Programs. International NBS Programs 2010; Available from:
http://genes-r-us.uthscsa.edu/resources/newborn/international.htm.
28. Herald-Dispatch, T. Newborn Testing Varies By State. 2004; Available from:
http://www.herald-dispatch.com/2004/September/22/LNspot.htm. 29. Department of Health, J. Sapporo City Japan. 2010; Available from:
http://www.city.sapporo.jp/eiken/screen/index-e.htm.
30. Committee, U.N.S. United Kingdom National Screening Committee. Available from: http://www.screening.nhs.uk/.
31. Westmead, T.C.s.H.a. The NSW Newborn Screening Programme. 2010; Available from: http://www.chw.edu.au/prof/services/newborn/.
32. Nennstiel-Ratzel, U., B. Liebl, and A. Zapf, [Model project for reorganising of
newborn screening]. Gesundheitswesen, 2003. 65 Suppl 1: p. S31-5.
congenital adrenal hyperplasia. Public Health Genomics, 2009. 12(2): p.
67-72.
34. Insinga, R.P., R.H. Laessig, and G.L. Hoffman, Newborn screening with
tandem mass spectrometry: examining its cost-effectiveness in the Wisconsin Newborn Screening Panel. J Pediatr, 2002. 141(4): p. 524-31.
35. Thil'en, A., et al., Benefits of neonatal screening for congenital adrenal
hyperplasia (21-hydroxylase deficiency) in Sweden. Pediatrics, 1998. 101(4): p.
E11.
36. Tran, K., et al., Clinical efficacy and cost-effectiveness of newborn screening
for medium chain acyl-CoA dehydrogenase deficiency using tandem mass spectrometry. Clin Biochem, 2007. 40(3-4): p. 235-41.
37. Naughten, E.R., et al., Outcome of maple syrup urine disease. Arch Dis Child, 1982. 57(12): p. 918-21.
38. Walsh-Vockley, C., Counseling issues in genetic screening. Yale J Biol Med, 1991. 64(3): p. 255-7.
39. Newborn screening fact sheets. American Academy of Pediatrics. Committee on Genetics. Pediatrics, 1996. 98(3 Pt 1): p. 473-501.
40. Niu, D.M., et al., Nationwide survey of extended newborn screening by tandem
mass spectrometry in Taiwan. J Inherit Metab Dis, 2010. 33(Suppl 2): p.
S295-305.
41. Health, w.s.d.o. least burden and cost benefit analysis, newborn screening for
metabolic disease. 2003.
42. Merta, M., et al., A nationwide blood spot screening study for Fabry disease in
the Czech Republic haemodialysis patient population. Nephrol Dial Transplant,
2007. 22(1): p. 179-86.
43. Chien, Y.H., et al., Early detection of Pompe disease by newborn screening is
feasible: results from the Taiwan screening program. Pediatrics, 2008. 122(1):
p. e39-45.
44. Balsamo, A., et al., Congenital adrenal hyperplasia: neonatal mass screening
compared with clinical diagnosis only in the Emilia-Romagna region of Italy, 1980-1995. Pediatrics, 1996. 98(3 Pt 1): p. 362-7.
45. Cartigny-Maciejewski, M., et al., Neonatal screening of congenital adrenal
hyperplasia due to 21-hydroxylase deficiency: Lille experience 1980–1996
Archives de Pédiatrie, 1999. 6(2): p. 151-158.
46. Kwon, C. and P.M. Farrell, The magnitude and challenge of false-positive
newborn screening test results. Arch Pediatr Adolesc Med, 2000. 154(7): p.
714-8.
hyperplasia. Eur J Endocrinol, 2004. 151 Suppl 3: p. U71-5.
48. Steigert, M., et al., High reliability of neonatal screening for congenital
adrenal hyperplasia in Switzerland. J Clin Endocrinol Metab, 2002. 87(9): p.
4106-10.
49. Varness, T.S., D.B. Allen, and G.L. Hoffman, Newborn screening for
congenital adrenal hyperplasia has reduced sensitivity in girls. J Pediatr, 2005.
147(4): p. 493-8.
50. Matern, D., et al., Reduction of the false-positive rate in newborn screening by
implementation of MS/MS-based second-tier tests: the Mayo Clinic experience (2004-2007). J Inherit Metab Dis, 2007. 30(4): p. 585-92.
51. Gleeson, H.K., et al., Two-year pilot study of newborn screening for
congenital adrenal hyperplasia in New South Wales compared with nationwide case surveillance in Australia. J Paediatr Child Health, 2008. 44(10): p. 554-9.
52. Larsson, A., et al., Screening of half a million Swedish newborn infants for
congenital adrenal hyperplasia Screening, 1992. 1(3): p. 159-166.
53. Pourfarzam, M., et al., Neonatal screening for medium-chain acyl-CoA
dehydrogenase deficiency. Lancet, 2001. 358(9287): p. 1063-4.
54. Van der Kamp, H.J., et al., Newborn screening for congenital adrenal
1 6 a 1:5,000 (1) (2) (3) 1:100,000 (1) (2) A 1:15,000( ) 1:9,733( ) 1:9,091~1:20,000( ) 1:16,000( )
1 6 ( ) a 1:20,000~15,000 ( ) (1) (2) (riboflavin) (carnitine) (3) 1:14,000~50,000 ( ) (1) (2) 1 15,000~61,000 ( ) VitB12 B12 VitB12 (http://www.tfrd.org.tw/rare/typekind.php?kind_id=3) (http://www.bhp-gc.tw/main.php/02about/01object)
a:Patricia M. Jones, Michael J. Bennett. The changing face of newborn screening: diagnosis of inborn errors of metabolism by tandem mass spectrometry. Clinica Chimica Acta 2002; 324:121-8.
2 2008 196,234 (CAH) 1 9,440 34 (MSUD) 1 302,091 0 A (MCAD) 1 67,131 9 (GA I) 1 33,566 13 (IVA) 1 67,131 1 (MMA) 1 151,046 4
噁1) 噁1)噁1) 噁1) 噁饋) 噁饋) 噁饋) 噁饋) 噁3) 噁3) 噁3) 噁3) 噁4) 噁4) 噁4) 噁4)
1
6 6 6 A B 6 6 6 6 6 B 2 6 (A) 6 (B)
3 6 196,234 2009 [2] 98.70% 2009 [2] 198,819 2009 $507,135 2010 [12] 0.89% 2005~2009 [12] 2.51% 2005~2009 [12] 3% (CAH) 1 : 9,400 2009 [2] (MSUD) 1 :127,056 2009 [2] (IVA) 1:67,131 2009 [2] (MMA) 1:151,046 2009 [2] (GA I) 1:33,566 2009 [2] A (MCAD) 1:67,131 2009 [2] 94% [44-51] 100% [5] 74% [5] 100% [5, 50] 100% [5] A 92% [5, 8, 34, 36] 99.8% [45-52] 99.9% [5] 99.9% [5]
3 6 ( ) 99.9% [5, 50] 100.0% [5] A 99.9% [4, 5, 8, 34, 36, 53] 5 10% [9] 22% [37] 50% [37] 5% [1] 20% [40] 80% [40] 5% A 20% [41] A 5% [34] 78.97 2009 [12] 67.6 [11] ( ) 65 [11] 58.6 [11] 80% [9] 93% [37] 53% [39] 100%
3 6 ( ) 8% [40] 100% [40] A 98% [41] QALY 1 0 0.5625 [14] 0.3909 [14] 0.5625 [14] 0.3909 [14] $382.02 CAH $84.60 MSUD-MCAD-GAI-IVA-MMA $220.60 $2,475 $852 2004~2008 $70,625 2004~2008 $1,180 2004~2008 $25,665 2004~2008 $2,083.33 7
3 6 ( ) $492,251 2009 [12] 18 [34] $808 2004~2008 2004~2008 2004~2008 2004~2008 2004~2008 2004~2008 - - - - A - 2 2004~2008 - 2004~2008 - 2004~2008 - 2004~2008 - 2004~2008 A - 2004~2008 $70,576.83 2004~2008 - 2004~2008 - 2004~2008 $879,181.00 2004~2008 $23,373.00 2004~2008 A - 2004~2008 1 2004~2008 - 2004~2008 - 2004~2008 0.86 2004~2008 0.64 2004~2008 A - 2004~2008
3 6 ( ) $982.91 2004~2008 $304.50 2004~2008 - 2004~2008 $1,622.00 2004~2008 $508.00 2004~2008 A - 2004~2008 2.00 2004~2008 0.86 2004~2008 - 2004~2008 1.29 2004~2008 0.43 2004~2008 A - 2004~2008 $71,282.17 2004~2008 $100,001.41 2004~2008 $11,406.00 2004~2008 $36,386.12 2004~2008 $59,637.33 2004~2008 A $11,220.86 2004~2008 1 2004~2008 2.55 2004~2008 1.47 2004~2008 2.54 2004~2008 2.31 2004~2008 A 3.43 2004~2008
6 6
(1)
(2)
4
5
Ruth F. [15]
A Survey To Evaluate Parental Consent As Public Policy for Neonatal Screening 1982 1976 Walsh-Vockley, C.[38] Counseling Issues in Genetic Screening 1991
5 ( )
A Edwards[18]
Pretest counseling and informed consent should be prerequisites
1996
( )
5 ( )
[19] 2004
15 22
Huang, M. C. [16]
Parental consent for newborn screening in southern Taiwan 2005 23 15 8 /
5 (meta-analysis)
(systematic review)
PubMed
sensitivity
specificity
Congenital Adrenal Hyperplasia
Maple Syrup Urine Disease
Medium Chain Acyl-CoA Dehydrogenase
Deficiency
Glutaric Acidemia Type I
Isovaleric Acidemia
Methylmalonic Acidemia
噁1饋8
)
噁18 )
A
噁41 )
噁6 )
噁5 )
噁6 )
+ Sensitivity 1癇Sensitivtiy CAH CAH CAH CAH 1癇Specificity Specificity 噁 ) 噁 ) 6 6 噁 CHA )
7 (CAH) 8 (MSUD) CAH (97.52%) (2.48%) (90%)
(10%)
MSUD (71.96%) (1.54%) (26.5%) (28%) (22%) (50%)9 (GA I) 10 ( IVA) GAⅠ (100%) (0%) (0%) (75%) (5%) (20%) IVA (100%) (0%) (95%) (5%)
11 (MMA) MMA (8%) (73.6%) (18.4%) (0%) (20%) (80%)
12 A (MCAD) MCAD (94.6%) (5%) (0.40%) (75%) (5%) (20%)
13 6 sROC α ( ) β ( ) S (95% ) Q CAH 0.64 (3.59) -0.40 (0.37) 0.0398 (-2.2590 to 2.3387) 0.5793 MCAD -5.53 (1.71) 0.02 (0.16) 0.0049 (-0.2118 to 0.2167) 0.0592 MMA 24.68 (-) -3.35 (-) 0.0005 (-) 0.9999 70.0% 71.0% 72.0% 73.0% 74.0% 75.0% 76.0% 77.0% 78.0% 79.0% 80.0% 81.0% 82.0% 83.0% 84.0% 85.0% 86.0% 87.0% 88.0% 89.0% 90.0% 91.0% 92.0% 93.0% 94.0% 95.0% 96.0% 97.0% 98.0% 99.0% 100.0% 0.00% 0.20% 0.40% 0.60% 0.80% 1.00% 1.20% 1.40% S e n si ti v it y 1-Specificity CAH MCAD MMA
7
(95% ) (95% )
CAH 0.94(0.91-0.97) 0.998(0.996-0.999)
MCAD 0.92(0.76-0.98) 0.999(0.998-0.999)
MMA 0.74(0.49-0.89) 0.999(0.998-0.999_
P-value CAH vs. MCAD 0.600 0.060
P-value CAH vs. MMA 0.004 0.037
8
-CAH Larsson [43] 1992 Swden 557410 1/11612 92.00% 99.96%
CAH Balsamo [44] 1996 Italy Mar, 1991~ Aug, 1995 128,330 10 1/11661 91.00% 99.66%
CAH Cartigny-Maciejewski [45] 1999 France 1980~1996 408,138 49 1/11661 97.00% 99.62%
CAH Kwon [46] 2000 USA 1993 60 1/19200 100.00% 99.00%
CAH Kwon [46] 2000 USA 1994 51 1/25100 100.00% 99.20%
CAH van der Kamp [54] 2001 Netherlands 1998~1999 176,684 1/11778 100.00% 99.86%
CAH Steigert [48] 2002 Switzerland Jan, 1993~ May, 2001 333,221 30 1/10749 97.00% 99.99%
CAH van der Kamp [47] 2004 Netherlands 1998-2001 647,674 1/14700 100.00% 99.95%
CAH Varness [49] 2005 Wisconsin, American Jan, 2000~ Jun, 2003 239,879 1/21345 0.0047 86.00% 99.65%
CAH Matern [50] 2007 USA Jun, 2004~ Mar, 2007 204281 9 1/22698 92.70% 99.94%
CAH Gleeson [51] 2008 Australia Apr, 1995~Dec, 1997 185,854 12 1/15488 90.90% 99.60%
MACD Insinga [34] 2002 Wisconsin, USA 155,500 7 4.5/100000 90.00% 99.90%
MACD Schulze [5] 2003 Germany Apr, 1998~Sep, 2001 250,000 16 1/20800 1/2400 100.00% 99.98%
MACD Venditti [8] 2003 USA 930,078 13 1/71544 1/15000 100.00% 99.99%
MACD Tran [36] 2007 Canada 2003-2004 330803 20 1/160000 100.00% 99.99%
MMA Schulze [5] 2003 Germany Apr, 1998~Sep, 2001 250,000 1 1/250000 100.00% 99.92%
9 Yoo [33] SW* SW* SW* CAH 50,000 300,000 CAH 2,800,000 CAH 255,700~292,000 SW* SW* 2% 9% 613,200 136,300
9 ( ) Autti-Ramo [10] ( ) ( ) ( ) CAH MCAD LCHADD PKU GA I 2,500,000 45 5 10 1 3 1 5 5500 25500 - Carroll [9] ( ) CAH GAL 4838.71
9 ( ) Insinga [34] MCAD 41,862 150 300 MCAD 20 30
9 ( ) Tran [36] MCAD ( ) ( ) MCAD 1:160000 100% 99% 934,923 450,521 2,676 MCAD 2 -756 7,875 -860 7,363
9 ( ) Venditti [8] MCAD MCAD MCAD MCAD 11,000 5,600 Markov 70 300 100 MCAD 70 MCAD 97.5% 99.5% 20 50,000
9 ( ) Thil'en [35] 2.6 150 2.6 CAH 26,700 53,400 - *SW:
10 / // / 噁噁噁噁 )))) 40(59.70%) 2(2.99%) 4(5.97%) 5(7.46%) 13(23.88%) 2(5%) 19(47.5%) 3(7.5%) 16(40%) 9(22.5%) 3(7.5%) 13(32.5%) 6(15%) 6(15%) 3(7.5%) 2941.45 $305.68 $2,504.92 $709.86 $6,918.91 $2,083.33 $2,474.83
10 ( ) / // / 噁噁噁噁 ))) ) 2(12.5%) 4(25%) 2(12.5%) 1(6.25%) 7(43.75%) A 0(0%) $85.42 $348.33 $6.21 ( ) 178.75 $858.18 ( ) 58.67 $1,239.57
11 † †† † 18 3 16.67% 60 19 31.67% 86 3 3.49% 338 15 4.44% 3 2 66.67% 6 4 66.67% 10 5 50.00% 34 2 5.88% 13 4 30.77% 1 2 - 4 1 25.00% 3 7 - A 1 0 0.00% 577 67 11.61% †
12 6 (A) (B) (C) (D) 198,819 1 : 9,400 90% 19.04 10% 2.12 1 :127,056 28% 0.44 22% 0.34 50% 0.78 1:67,131 95% 2.81 5% 0.15 1:151,046 0% 0.00 20% 0.26 80% 1.05 1:33,566 75% 4.44 20% 1.18 5% 0.30 A 1:67,131 75% 2.22 20% 0.59 5% 0.15
13 6 (A) (B) (C) (E) (D’) 198,819 1 : 9,400 94% 99.8% 97.52% 20.63 10% 80% 2.48% 0.52 1 :127,056 100% 99.9% 71.96% 1.13 22% 93% 1.54% 0.02 50% 53% 26.50% 0.41 1:67,131 74% 99.9% 95% 100.00% 2.96 5% 100% 0.00% 0.00 1:151,046 100% 99.9% 8.00% 0.11 20% 8% 18.40% 0.24 80% 8% 73.60% 0.97 1:33,566 100% 100.0% 75% 100.00% 5.92 20% 100% 0.00% 0.00 5% 100% 0.00% 0.00 A 1:67,131 92% 99.9% 75% 94.60% 2.80 20% 98% 0.40% 0.01 5% 5.00% 0.15
14 QALY (F) (G) ∆QALY(I) 19.04 20.63 1.59 0.00 0.00 0.00 0.44 1.13 0.69 0.19 0.01 -0.18 0.44 0.23 -0.21 2.81 2.96 0.15 0.08 0.00 -0.08 0.00 0.11 0.11 0.00 0.00 0.00 0.41 0.38 -0.03 4.44 5.92 1.48 0.00 0.00 0.00 0.17 0.00 -0.17 A 2.22 2.80 0.58 0.00 0.00 0.00 0.08 0.08 0.00 30.33 20.63 3.92
15 6 (K) (L)†††† (J) $1,966 $71,282 $1,762,955 - - $1,762,955 - - - $0 - - - $0 $261 $255,004 $6,120,222 $492,251 $5,667,676 $11,787,898 $261 $255,004 $6,138,914 $492,251 $5,667,676 $11,806,590 - - - $0 $1,180 $16,767 $431,607 $492,251 $5,667,676 $6,099,283 - - - $0 - - - $0 $2,085 $92,421 $2,235,924 $492,251 $5,667,676 $7,903,600 - - - $0 - - - $0 $218 $137,762 $3,308,207 $492,251 $5,667,676 $8,975,883 A - - - $0 - - - $0 $852 $38,488 $943,205 $492,251 $5,667,676 $6,610,881 †
16 6 (K’) (L’)†††† (M) (N) (J’) $2,941.45 $14,583 $1,616 $70,577 $1,737,560 - - $1,755,084 $2,941.45 $14,583 - - - $17,525 $3,077.45 $14,583 - - - $17,661 $3,077.45 $14,583 $852 $70,625 $1,713,732 $492,251 $5,667,676 $7,399,069 $3,077.45 $14,583 $1,180 $25,665 $645,601 $492,251 $5,667,676 $6,330,938 $3,077.45 $14,583 - - - $17,661 $3,077.45 $14,583 $1,180 $25,665 $645,601 $492,251 $5,667,676 $6,330,938 $3,077.45 $14,583 - - - $17,661 $3,077.45 $14,583 - - - $17,661 $3,077.45 $14,583 $1,180 $25,665 $635,127 $492,251 $5,667,676 $6,320,463 $3,077.45 $14,583 - - - $17,661 $3,077.45 $14,583 - - - $17,661 $3,077.45 $14,583 $852 $14,959 $379,078 $492,251 $5,667,676 $6,064,414 A $3,077.45 $14,583 - - - $17,661 $3,077.45 $14,583 - - - $17,661 $3,077.45 $14,583 $852 $70,625 $1,713,732 $492,251 $5,667,676 $7,399,069 †
17 6 (O) (P) QALY (T) (Q) (O’) (P’) QALY (T’) (R) (S) (Q’) $1,762,955 19.04 19.04 33,559,377 $1,755,084 20.63 20.63 $17,525 0.0025 $36,201,140 $0 2.12 0.00 0 $17,525 0.52 0.00 $17,525 0.0025 $9,237 $1,762,955 21.15 19.04 33,559,377 $1,772,609 21.15 20.63 $35,050 0.0051 $36,210,377 $0 0.44 0.44 0 $17,661 1.13 1.13 $17,661 0.0000 $19,887 $11,787,898 0.34 0.19 4,058,091 $7,399,069 0.02 0.01 $17,661 0.0000 $178,304 $11,806,590 0.78 0.44 9,237,558 $6,330,938 0.41 0.23 $17,661 0.0000 $2,625,286 $23,594,488 1.56 1.07 13,295,649 $13,747,668 1.56 1.37 0.0000 $2,823,477 $0 2.81 2.81 0 $17,661 2.96 2.96 $17,661 0.0008 $52,319 $6,099,283 0.15 0.08 903,199 $6,330,938 0.00 0.00 $17,661 0.0008 $14 $6,099,283 2.96 2.90 903,199 $6,348,599 2.96 2.96 0.0015 $52,332 $0 0.00 0.00 0 $17,661 0.11 0.11 $17,661 0.0000 $1,860 $0 0.26 0.00 0 $17,661 0.24 0.00 $17,661 0.0000 $4,277 $7,903,600 1.05 0.41 8,322,688 $6,320,463 0.97 0.38 $17,661 0.0000 $6,123,157 $7,903,600 1.32 0.41 8,322,688 $6,355,785 1.32 0.48 0.0000 $6,129,294 $0 4.44 4.44 0 $17,661 5.92 5.92 $17,661 0.0000 $104,609 $0 1.18 0.00 0 $17,661 0.00 0.00 $17,661 0.0000 $0 $8,975,883 0.30 0.17 2,658,309 $6,064,414 0.00 0.00 $17,661 0.0000 $0 $8,975,883 5.92 4.61 2,658,309 $6,099,736 5.92 5.92 0.0000 $104,609
17 6 ( ) † (O) (P) QALY (T) (Q) (O’) (P’) QALY (T’) (R) (S) (Q’) A AA A $0 2.22 2.22 0 $17,661 2.80 2.80 $17,661 0.0002 $49,485 $0 0.59 0.00 0 $17,661 0.01 0.00 $17,661 0.0002 $213 $6,610,881 0.15 0.08 978,958 $7,399,069 0.15 0.08 $17,661 0.0002 $1,095,679 $6,610,881 2.96 2.30 978,958 $7,434,390 2.96 2.89 0.0007 $1,145,378 $54,947,090 35.88 30.33 $59,718,180 $41,758,787 35.88 34.25 $282,300 0.0073 $46,465,466
18 -QALY 1% $39,743,565 1,107,724 10,129,972 2% $27,661,068 770,963 7,050,345 3% $18,563,368 517,394 4,731,493 4% $12,412,249 345,951 3,163,675 5% $8,420,073 234,682 2,146,136 6% $5,849,804 163,044 1,491,017 7% $4,173,961 116,336 1,063,873 8% $3,051,754 85,058 777,841 9% $2,273,312 63,361 579,429 14 - QALY
47,720
436,390
0 2,000,000 4,000,000 6,000,000 8,000,000 10,000,000 12,000,000 1% 2% 3% 4% 5% 6% 7% 8% 9% 10%-QALY
15 - CAH 16 - MSUD $375,528 $4,187,792 $0.00 $1,000,000.00 $2,000,000.00 $3,000,000.00 $4,000,000.00 $5,000,000.00 $6,000,000.00 $7,000,000.00 $8,000,000.00 QALY 1,297,339 12,275,922 0 2,000,000 4,000,000 6,000,000 8,000,000 10,000,000 12,000,000 14,000,000 1 /9 4 0 0 0 0 1 /8 2 2 6 9 1 1 /3 4 5 8 5 4 1 /3 4 0 0 0 0 1 /3 3 0 0 0 0 1 /3 2 0 0 0 0 1 /3 1 0 0 0 0 1 /3 0 2 0 9 1 1 /3 0 0 0 0 0 1 /2 9 0 0 0 0 1 /2 8 0 0 0 0 1 /2 7 0 0 0 0 1 /2 6 0 0 0 0 1 /2 5 0 0 0 0 1 /2 3 2 8 1 8 1 /1 9 0 6 3 0 1 /1 8 5 9 7 8 1 /1 6 8 6 3 0 1 /1 5 3 8 3 3 1 /1 1 9 8 1 1 1 /1 0 4 5 7 4 1 /1 0 2 0 8 5 1 /1 0 0 0 0 0 1 /4 9 7 4 4 1 /2 5 7 0 0 QALY
17 - IVA 18 - MMA 368,878 4,082,333 0 500,000 1,000,000 1,500,000 2,000,000 2,500,000 3,000,000 3,500,000 4,000,000 4,500,000 1/71000 1/70000 1/69000 1/68000 1/67131 1/67000 1/66000 1/65000 1/64000 1/62500 QALY $671,046 $8,138,581 $0 $1,000,000 $2,000,000 $3,000,000 $4,000,000 $5,000,000 $6,000,000 $7,000,000 $8,000,000 $9,000,000 QALY
19 - GAI 20 - MCAD $375,595.79 $4,053,870.84 $0.00 $500,000.00 $1,000,000.00 $1,500,000.00 $2,000,000.00 $2,500,000.00 $3,000,000.00 $3,500,000.00 $4,000,000.00 $4,500,000.00 QALY $151,569 842,092 $0 $500,000 $1,000,000 $1,500,000 $2,000,000 $2,500,000 $3,000,000 $3,500,000 QALY
19 6 QALY QALY QALY 1 1.59 1 $2,651,000 6 $1,666,717 5 2 0.30 4 -$10,472,172 1 $34,796,722 1 3 0.06 6 -$850,867 4 $13,133,449 3 4 0.07 5 -$2,193,394 3 $30,307,089 2 5 1.31 2 -$2,553,700 2 $1,943,136 4 6 A 0.58 3 $166,420 5 $286,691 6
20 $1,762,955 19.04 $33,623,503 $1,755,084 20.63 $36,201,095 $0 2.12 $0 $17,525 0.52 $9,193 $1,762,955 $21 $33,623,503 $1,772,609 $21 $36,210,288 $0 0.44 $0 $17,661 1.13 $19,887 $11,787,898 0.34 $2,274,619 $7,399,069 0.02 $178,304 $11,806,590 0.78 $5,169,588 $6,330,938 0.41 $2,625,286 $23,594,488 $2 $7,444,207 $13,747,668 $2 $2,823,477 $0 2.81 $0 $17,661 2.96 $52,305 $6,099,283 0.15 $130,985 $6,330,938 0.00 $0 $6,099,283 $3 $130,985 $6,348,599 $3 $52,305 $4,133,877 0.99 $0 $4,151,538 4.18 $17,333,496 $0 3.98 $0 $17,661 0.80 $14,045 $4,133,877 $5 $0 $4,169,199 $5 $17,347,542 $0 4.44 $0 $17,661 5.92 $104,609 $0 1.18 $0 $17,661 0.00 $0 $8,975,883 0.30 $1,119,209 $6,064,414 0.00 $0 $8,975,883 $6 $1,119,209 $6,099,736 $6 $104,609
20 ( ) $0 2.22 $0 $17,661 2.80 $49,481 $0 0.59 $0 $17,661 0.01 $209 $6,610,881 0.15 $207,376 $7,399,069 0.15 $1,095,675 $6,610,881 $3 $207,376 $7,434,390 $3 $1,145,365 $51,177,367 $40 $42,525,280 $39,572,200 $40 $57,683,585
21 $1,762,955 19.04 $33,623,503 $1,755,084 20.63 $36,201,095 $0 2.12 $0 $17,525 0.52 $9,193 $1,762,955 $21 $33,623,503 $1,772,609 $21 $36,210,288 $0 0.44 $0 $17,661 1.13 $19,887 $11,787,898 0.34 $2,274,619 $7,399,069 0.02 $178,304 $11,806,590 0.78 $5,169,588 $6,330,938 0.41 $2,625,286 $23,594,488 $2 $7,444,207 $13,747,668 $2 $2,823,477 $0 2.81 $0 $17,661 2.96 $52,305 $6,099,283 0.15 $130,985 $6,330,938 0.00 $0 $6,099,283 $3 $130,985 $6,348,599 $3 $52,305 $4,133,877 0.84 $0 $4,151,538 3.79 $15,742,529 $0 4.13 $0 $17,661 1.18 $20,813 $4,133,877 $5 $0 $4,169,199 $5 $15,763,342 $0 4.44 $0 $17,661 5.92 $104,609 $0 1.18 $0 $17,661 0.00 $0 $8,975,883 0.30 $1,119,209 $6,064,414 0.00 $0 $8,975,883 $6 $1,119,209 $6,099,736 $6 $104,609
21 ( ) $0 2.22 $0 $17,661 2.80 $49,481 $0 0.59 $0 $17,661 0.01 $209 $6,610,881 0.15 $207,376 $7,399,069 0.15 $1,095,675 $6,610,881 $3 $207,376 $7,434,390 $3 $1,145,365 $51,177,367 39.53 $42,525,280 $39,572,200 39.53 $56,099,385
