Download Supplementary Figures 1-4 (ppt 238K)

Supplementary Figure 1
100
12-15 alleles
Sens: 54%
1-Spec: 66%
Sensitivity (%)
80
60
<12 alleles
Sens: 2%
1-Spec: 15%
>15 alleles
Sens: 44%
1-Spec: 19%
40
AUC: 0.61
P=0.01
20
0
20
40
60
80
100
1-Specificity (%)
0.25
0.20
0.15
0.10
0.05
0.00
21
18
15
12
9
6
3
Sensitivity minus 1-specificity
0
Risk score threshold
Supplementary Figure 1: Receiver Operator Curve (sensitivity vs 1-specificity) for type 1
diabetes outcome using risk allele scores of all 12 gene SNPs (upper panel). The risk allele
scores for each child were calculated from the total sum of risk alleles at the 12 gene SNPs
(maximum possible score = 24, minimum possible score = 0). The area under the curve
(AUC) of the plot is 0.61 (P=0.01). The diagonal dotted line represents the curve if there
was not discrimination between children who did and did not develop diabetes (AUC = 0.5).
The vertical dashed lines represent thresholds used for categories representing low risk
(<12), moderate risk (12-15), and high risk (>15), and were selected by
sensitivity/specificity trade-off. The bottom panel plots the difference between sensitivity
and 1-specificity at risk score threshold and aids in identifying points of inflexion in the
ROC curve.
Supplementary Figure 2
0.75
0.70
AUC
0.65
0.60
0.55
0.50
0.45
T1D
in HLA risk
children
T1D
in all
children
AB
in HLA risk
children
AB
in all
children
Supplementary Figure 2: Box-plot for all area under the curve (AUC) calculated
from the receiver operator curve analysis (ROC) for all 4095 possible
combinations of the 12 SNPs using diabetes as outcome in children with HLA risk
genotypes, diabetes as outcome in all children, using islet autoimmunity as
outcome in children with the HLA risk genotypes and islet autoimmunity as
outcome in all children.
Supplementary Figure 3
INS (97%)
COBL (59%)
IL10 (19%)
IL18RAP (91%)
IL2 (4%)
SH2B3R (67%)
CTLA4 (99%)
KIAA0350 (68%)
CD25 (44%)
PTPN22 (97%)
IFIH1 (89%)
PTPN2 (37%)
ERBB3 (38%)
AUC
0
20
40
60
80
100
0.8
-5
0.75
-6
0.7
-7
0
20
40
60
80
100
Supplementary Figure 3: The combinations of the 12 genes plus INS genotype
which resulted in receiver operator curve AUCs with P-values <0.00001 when
diabetes was used as outcome in 291 genotyped HLA risk children are shown as
heat maps (n = 117 combinations). The heat maps represent the 116 combinations
horizontally for each of the 13 genes listed vertically. Combinations are arranged
from highest (left) to lowest (right) AUC, and the corresponding AUC and -log10 p
values are provided in the lower panel. The presence of the gene in a combination is
indicated as a black bar. The frequency of the gene in the 117 combinations is
indicated.
Supplementary Figure 4
100
5-9 alleles
Sens: 44%
1-Spec: 60%
Sensitivity
80
60
<5alleles
Sens: 3%
1-Spec: 21%
>9 alleles
Sens: 53%
1-Spec: 19%
40
AUC: 0.73
P<0.00001
20
0
0
20
40
60
80
100
1-Specificity
Supplementary Figure 4: Receiver Operator Curve (sensitivity vs 1-specificity) for
type 1 diabetes outcome using risk allele scores of 8 gene SNPs in all genotyped
children. The 8 genes used to calculate scores were those that provided the highest
receiver operator curve AUC for diabetes outcome in the HLA risk children (IFIH1,
CTLA4, PTPN22, IL18RAP, SH2B3, KIAA0350, COBL, ERBB3). The risk allele
scores for each child were calculated from the total sum of risk alleles at the 8 gene
SNPs (maximum possible score = 16, minimum possible score = 0). The area under
the curve (AUC) of the plot is 0.73 (P<0.00001). The diagonal dotted line represents
the curve if there was no discrimination between children who did and did not
develop diabetes (AUC = 0.5). The vertical dashed lines represent thresholds used
for categories representing low risk (<6), moderate risk (6-9), and high risk (>9), and
were selected by sensitivity/specificity trade-off.