SUPPLEMENTARY DATA Supplementary Figure 1

SUPPLEMENTARY DATA Supplementary Figure 1. Flowchart of study population. IA Negative: individuals who were never persistently positive for any islet autoantibody; IA Positive: individuals who had one or more persistently positive islet autoantibodies; Type 1 diabetes: diagnosed by ADA criteria between 1994 and 2011; AbPos: Antibody positive group; T1D: type 1 diabetes group.

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Figure 2. Description of Repeated Optimization for Feature Interpretation with Posterior Probability Product (ROFI-P3) Algorithm.

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Figure 3. Average Area Under the Receiver Operating Characteristic Curve (AUC) based on 5-fold cross-validation repeated 100 times for each data source and machine learning classification method.

Outlined by a box are the maximum average AUC values selected for each of the six datasets across seven machine learning algorithms for two disease stages: (A) seroconversion and (B) progression to diabetes. This was the optimal machine learning algorithm.

Methods used: RF: Random Forest; KNN: K-Nearest Neighbors; LDA: Linear Discriminant Analysis; LR: Logistic Regression; SVM (RBF): Support Vector Machine with a radial basis function kernel, SVM (LIN): SVM with a linear kernel; and NB: Naïve Bayes.

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Figure 4. Number of features from each data stream retained at 50% selection for (A) Development of IA and (B) Progression from IA to diabetes

Data Stream Data Data Stream Data

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Table 1. Raw data for age and islet autoantibody status for control, islet autoantibody positive (AbPos) and type 1 diabetes (T1D) groups. Age and islet autoantibody status (1=positive, 0=negative) are given for each time point. Serum autoantibodies were measured for insulin (IAA), glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A) and zinc transporter 8 (ZnT8A).

Group randomID Timepoint Age (years) GADA IA-2A IAA ZnT8A

Control 11010

T1 0.8 0 0 0

T2 3.0 0 0 0

T3 6.0 0 0 0

T4 12.0 0 0 0

Last 19.0 0 0 0

Control 13063

T1 0.8 0 0 0

T2 2.3 0 0 0

T3 4.3 0 0 0

T4/Last 6.8 0 0 0 0

Control 21580

T1 0.7 0 0 0

T2 7.5 0 0 0

T3 9.3 0 0 0

T4/Last 13.4 0 0 0

Control 21645

T1 0.7 0 0 0

T2 3.0 0 0 0

T3 5.2 0 0 0

T4/Last 8.2 0 0 0 0

T1 0.8 0 0 0

T2 2.1 0 0 0

T3 9.1 0 0 0

T4 12.1 0 0 0

Last 18.8 0 0 0

Control 28102

T1 0.7 0 0 0

T2 4.2 0 0 0

T3 7.6 0 0 0

T4/Last 16.1 0 0 0

Control 28410

T1 1.9 0 0 0

T2 5.1 0 0 0

T3 6.1 0 0 0

T4 7.2 0 0 0 0

Last 14.0 0 0 0

Control 31888

T1 0.7 0 0 0

T2 4.3 0 0 0

T3 6.3 0 0 0

T4 11.8 0 0 0

Last 19.2 0 0 0

Control 35055

T1 0.7 0 0 0

T2 3.0 0 0 0

T4 16.0 0 0 0

Last 18.9 0 0 0

Control 38964

T1 0.8 0 0 0

T2 1.3 0 0 0

T3 2.1 0 0 0

T4 11.1 0 0 0

Last 18.5 0 0 0

Control 44935

T1 0.8 0 0 0

T2 2.0 0 0 0

T3 4.2 0 0 0

T4 6.9 0 0 0

Last 12.8 0 0 0

Control 51884

T1 1.2 0 0 0

T2 2.0 0 0 0

T3 3.1 0 0 0

T4/Last 4.1 0 0 0 0

Control 54642

T1 0.7 0 0 0

T2 2.0 0 0 0

T3 4.0 0 0 0

T4/Last 8.8 0 0 0 0

Control 57003

T2 5.4 0 0 0

T3 11.5 0 0 0

T4 15.5 0 0 0

Last 17.5 0 0 0 0

Control 57732

T1 0.8 0 0 0

T2 1.3 0 0 0

T3 2.1 0 0 0

T4 3.1 0 0 0 0

Last 9.2 0 0 0

Control 61032

T1 0.9 0 0 0

T2 1.5 0 0 0

T3 2.0 0 0 0

T4 4.1 0 0 0 0

Last 16.3 0 0 0

Control 62568

T1 2.0 0 0 0

T2 4.5 0 0 0

T3 6.6 0 0 0

T4 7.6 0 0 0

Last 11.8 0 0 0 0

Control 66029

T1 1.2 0 0 0

T2 3.0 0 0 0

T4 16.1 0 0 0

Last 23.0 0 0 0

Control 74515

T1 0.8 0 0 0

T2 3.2 0 0 0

T3 6.5 0 0 0

T4 12.1 0 0 0

Last 17.4 0 0 0

Control 81324

T1 0.7 0 0 0

T2 2.0 0 0 0

T3 4.2 0 0 0 0

T4 6.5 0 0 0

Last 14.8 0 0 0

Control 90948

T1 0.8 0 0 0

T2 6.1 0 0 0

T3 9.1 0 0 0

T4 16.0 0 0 0

Last 21.5 0 0 0

Control 92568

T1 0.8 0 0 0

T2 5.4 0 0 0

T3 8.7 0 0 0

T4 13.9 0 0 0

Control 95491

T1 0.9 0 0 0

T2 6.0 0 0 0

T3 8.0 0 0 0

T4/Last 15.0 0 0 0

Control 98695

T1 0.7 0 0 0

T2 5.1 0 0 0

T3 9.4 0 0 0

T4 15.4 0 0 0

Last 22.5 0 0 0

Control 99949

T1 0.8 0 0 0

T2 5.2 0 0 0

T3 8.2 0 0 0

T4 14.1 0 0 0

Last 18.6 0 0 0

AbPos 10929

T1 0.8 0 0 0 0

T2 4.3 0 0 0 0

IA 5.3 1 0 0 0

T3 6.6 1 0 0 0

T4 17.0 1 1 0

Last 23.4 1 1 0 0

AbPos 12712

T2 3.8 0 0 0

IA 5.8 1 0 0

T3 6.0 1 0 1

T4 6.5 1 0 1

Last 10.0 1 1 1 0

AbPos 15560

T1 0.8 0 0 0

T2 5.0 0 0 0 0

IA 6.0 0 0 1

T3 6.7 0 0 0 1

T4 8.6 1 1 1

Last 14.9 1 1 0 1

AbPos 18895

T1 0.9 0 0 0

T2 5.5 0 0 0

IA 10.1 0 1 0 1

T3 10.2 0 1 0 1

T4 12.0 1 1 0

Last 18.1 0 1 0 1

AbPos 28916

T1 1.3 0 0 0 0

T2 7.3 0 0 0 0

IA 8.3 0 0 0 1

T3 9.3 0 0 0 1

T4 15.2 1 1 0

AbPos 33999

T1 0.7 0 0 0 0

T2 3.1 0 0 0 0

IA 7.9 1 0 1 0

T3 8.1 1 0 1 0

T4 15.7 1 0 0

Last 21.6 1 0 0 0

AbPos 44628

T1 0.8 0 0 0 0

T2 2.0 0 0 0 0

IA 3.0 1 0 1 1

T3 3.1 1 0 1 1

T4 9.1 1 1 1

Last 14.2 1 1 1 1

AbPos 54078

T1 3.5 0 0 0 0

T2 5.5 0 0 0 0

IA 7.4 0 0 0 1

T3 10.3 1 0 0 0

T4 14.1 1 1 0

Last 19.9 1 1 0 0

AbPos 66191

T1 2.1 0 0 0

T2 11.0 0 0 0 0

IA 12.0 1 0 1 0

T4 13.7 1 0 0

Last 20.0 1 0 0 1

AbPos 68942

T1 4.4 0 0 0 0

T2 6.5 0 0 0 0

IA 13.5 1 0 0 0

T3 13.5 1 0 0 0

T4/Last 18.3 1 1 0 0

AbPos 76157

T1 0.7 0 0 0

T2 5.1 0 0 0 0

IA 6.0 1 0 0 0

T3 6.2 1 0 0 0

T4 7.2 1 0 1 1

T1D 8.6

AbPos 77508

T1 0.8 0 0 0 0

T2 6.4 0 0 0 0

IA 7.4 1 1 0 0

T3 8.5 1 0 0 0

T4 15.2 1 0 0

Last 20.7 1 0 0 0

AbPos 78545

T1 0.8 0 0 0

T2 4.9 0 0 0 0

T3 5.6 1 0 0 0

T4 8.6 1 1 0

Last 14.6 1 1 0 1

AbPos 79070

T1 0.7 0 0 0

T2 8.5 0 0 0 0

IA 9.5 0 1 0 0

T3 10.3 1 1 1 1

T4 11.0 0 1 0

T1D 12.6

AbPos 81198

T1 0.9 0 0 0 0

T2 2.0 0 0 0 0

IA 3.1 1 0 1 0

T3 3.4 1 0 1 0

T4 7.5 1 0 0

Last 13.4 1 0 1 0

AbPos 84814

T1 0.8 0 0 0 0

T2 1.3 0 0 0 0

IA 3.0 0 0 0 1

T3 4.2 1 1 1 1

T4 10.5 1 1 1

T1D 12.4 1 1 1 1

AbPos 92799

T2 10.7 0 0 0 0

IA 11.8 1 0 0 0

T3 11.9 1 0 0 0

T4 20.2 1 0 0

Last 26.5 1 0 0 0

AbPos 97632

T1 0.8 0 0 0 0

T2 3.1 0 0 0 0

IA 4.2 0 0 0 1

T3 5.4 1 0 1 0

T4 10.0 1 1 1

Last 16.2 1 1 0 1

AbPos 98530

T1 0.7 0 0 0

T2 8.8 0 0 0 0

IA 9.8 1 0 0

T3 10.0 1 0 0

T4 12.3 1 0 0

Last 17.4 1 0 0 0

AbPos 99827

T1 3.5 0 0 0 0

T2 9.1 0 0 0 0

IA 10.1 1 0 0 0

T3 10.6 1 0 0 0

T4 19.1 1 0 0

T1D 10030

T1 7.9 0 0 0 0

T2 9.0 0 0 0 0

IA 10.1 1 0 0 0

T3 10.9 1 1 0 0

T4/T1D 13.7 1 1 0 1

T1D 16375

T1 1.3 0 0 0 0

T2 2.0 0 0 0 0

IA 3.1 1 1 0 1

T3 3.3 1 1 0 1

T4 14.0 1 1 1 1

T1D 14.4

T1D 18431

T1 1.3 0 0 0 0

T2 9.0 0 0 0 0

IA 10.0 1 0 0 0

T3 10.2 1 0 0 0

T4/T1D 13.7 1 0 1 0

T1D 21270

T1 2.1 0 0 0 0

T2 7.0 0 0 0 0

IA 7.9 0 1 1 0

T3 8.2 1 1 1 1

T4 13.6 0 1 0 1

T1D 34040

T1 0.8 0 0 0 0

T2 4.9 0 0 0 0

IA 6.9 1 0 0 1

T3 7.3 1 0 0 1

T4 11.0 1 1 0 1

T1D 11.2 1 1 0 1

T1D 39171

T1 0.8 0 0 0 0

IA 1.6 1 1 0 0

T3 3.9 0 1 0 0

T4 4.9 1 1 0 0

T1D 7.0

T1D 41850

T1 3.8 0 0 0 0

T2 7.0 0 0 0 0

IA 7.9 0 0 1 0

T3 9.0 1 0 1 0

T4 11.3 1 0 1 0

T1D 11.3

T1D 42578

T1 1.3 0 0 0 0

T2 6.4 0 0 0 0

IA 7.6 0 0 0 1

T3 8.9 1 1 1 1

T1D 44461

T1 1.1 0 0 0 0

T2 4.0 0 0 0 0

IA 4.6 0 0 1 0

T3 4.9 0 0 1 0

T4 11.7 0 0 0 0

T1D 11.7

T1D 45654

T1 0.7 0 0 0 0

T2 1.8 0 0 0 0

IA 5.8 1 0 0 0

T3 7.1 1 0 1 1

T4 9.6 0 1 1 1

T1D 10.0

T1D 48987

T1 2.1 0 0 0 0

T2 3.1 0 0 0 0

IA 4.1 0 0 1 1

T3 5.8 0 0 0 1

T4 9.8 0 0 0 1

T1D 10.9 0 0 0 1

T1D 55932

T1 1.0 0 0 0 0

T2 1.2 0 0 0 0

IA 2.2 0 1 0 0

T4 7.9 1 1 0 1

T1D 8.3 0 1 0 1

T1D 58044

T2 2.0 0 0 0 0

IA 3.0 0 0 0 1

T3 4.1 1 0 1 1

T4 8.9 1 1 0

T1D 9.4

T1D 58364

T1 1.2 0 0 0 0

IA 2.0 1 1 1 1

T3 2.2 1 1 1 1

T4 5.0 1 1 1 1

T1D 6.2 1 1 1 1

T1D 69161

T1 1.2 0 0 0 0

T2 2.0 0 0 0 0

IA 6.0 1 0 0 1

T3 8.4 0 0 0 1

T4/T1D 10.0 0 0 0 1

T1D 72005

T1 1.3 0 0 0 0

T2 5.2 0 0 0 0

IA 6.4 1 0 0 0

T3 6.9 1 0 0 0

T1D 13.1 0 1 0 1

T1D 78552

T1 3.0 0 0 0 0

T2 9.4 0 0 0 0

IA 12.6 0 1 0 0

T3 12.8 0 1 0 0

T4 14.7 0 1 0 0

T1D 15.0

T1D 79606

T1 1.2 0 0 0 0

IA 4.0 1 0 1 0

T3 4.1 1 1 0 0

T4/T1D 9.6 0 1 1 0

T1D 91993

T1 0.8 0 0 0 0

T2 1.3 0 0 0 0

IA 2.2 1 0 1 0

T3 3.1 1 1 0 1

T4 6.7 1 0 0 1

T1D 6.9

T1D 95373

T1 0.9 0 0 0 0

IA 2.9 1 1 0 1

T3 3.1 1 1 1 0

T4 10.4 0 1 0 1

T1D 95696

T1 2.0 0 0 0 0

T2 6.0 0 0 0 0

IA 9.0 1 0 0

T3 12.0 1 0 0 0

T4 14.0 1 0 0

T1D 14.0

T1D 98856

T1 0.9 0 0 0 0

IA 2.2 1 0 1 0

T3 2.9 1 1 0 1

T4/T1D 6.7 1 0 0 1

SNP Locus Reference rs11712165 ARHGAP1 10 rs1038914 ARHGEF25 4 rs2241880 ATG16L1 4 rs10806425 BACH2 10 rs10509540 C10orf59 7 rs4900384 C14orf 8 rs1465788 C14orf181 4 rs229541 C1QTNF6 4 rs9388489 C6orf173 4 rs13098911 CCR1-3, LTF 10 rs13314993 CCR4, GLB1 10 microsatellite CCR5 9 rs11711054 CCR5 5 rs4763879 CD69 7 rs12708716 CLEC16A 8 rs231775 CTLA4 7 rs3087243 CTLA4 9 rs4675374 CTLA4, ICOS, CD28 10 rs7202877 CTRB 8 rs11254363 CUBN 4 rs6013897 CYP24A1 3 rs4646536 CYP27B1 3 rs10741657 CYP2R1 3 rs12794714 CYP2R1 3 rs12785878 DHCR7/NADSYN1 3 rs7454108 DR4-DQB1*0302 1 rs3798719 ELOVL2 6 rs7744440 ELOVL2 6 rs1570069 ELOVL2 6 rs953413 ELOVL2 6 rs11221332 ETS1 10 rs174556 FADS1 6 rs174537 FADS1/FADS2 6 rs174570 FADS1/FADS2 6 rs174583 FADS2 6 rs2664170 GAB3 7 rs2282679 GC [vitamin D binding protein] 3 rs3755967 GC [vitamin D binding protein] 3 rs4588 GC [vitamin D binding protein] 3 rs7041 GC [vitamin D binding protein] 3 rs7020673 GLIS3 7

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA rs2290400 GSDMB/ORMDL3 8 rs399604 HLA-DOA 4 rs1431403 HLA-DPA1 4 rs3135021 HLA-DPA1, HLA-DPB1 10 rs2064476 HLA-DPB1 4 rs9277554 HLA-DPB1 4 rs7775228 HLA-DQ2.2 5 rs4713586 HLA-DQ4 10 rs2187668 HLA-DQA1 10 rs2157678 HLA-DQB1 8.1 5 rs5753037 HORMAD2 8 rs16940765 HRH4 4 rs3024496 IL10 7 rs17810546 IL12A-AS1 10 rs1295686 IL13 9 rs20541 IL13 9 rs917997 IL18RAP, IL18R1 10 rs2069762 IL2 4 rs4505848 IL2 4 rs181206 IL27 8 rs4788084 IL27 8 rs12251307 IL2RA 7 rs12722563 IL2RA 4 rs2104286 IL2RA 4 rs1805010 IL4R 9 rs2107356 IL4R 9 rs6897932 IL7R 4 rs689 INS-23-Hph1 7 rs2825932 intergenic between C1QBPP and FDPSP6 4 rs4667121 ITGA4, UBE2E3 10 rs13151961 KIAA1109 10 rs1464510 LPP 10 rs2160322 MAGI2 10 rs6962966 MAGI2 10 rs3117103 MHC 5 rs2853977 MICA 4 rs2066844 NOD2 4 rs10763976 PARD3 4 rs4379776 PARD3 10 rs17035378 PLEK, FBX048 10 rs947474 PRKCQ 4 rs1893217 PTPN2 2 rs478582 PTPN2 2 rs2476601 PTPN22 5

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA rs2476601 PTPN22 7 rs802734 PTPRK 10 rs7738609 PTPRK 5 rs13003464 PUS10 10 rs9792269 PVT1 10 rs842647 REL 5 rs10903122 RUNX3 10 rs9811792 SCHIP1, IL12A 10 rs2281808 SIRPG 7 rs7804356 SKAP2 4 rs7221109 SMARCE1 4 rs12928822 SOCS1, PRM1, PRM2 10 rs17718324 SPARC 4 rs1738074 TAGAP 10 rs5979785 TLR8 4 rs10517086 TNFAIP3 4 rs11203203 UBASH3A 7 rs3788013 UBASH3A 4 rs9976767 UBASH3A 8 rs11568820 VDR 2 rs1544410 VDR 2 rs2228570 VDR 2 rs1250552 ZMIZ1 10

1. Barker JM, Triolo TM, Aly TA, Baschal EE, Babu SR, Kretowski A, et al. Two single nucleotide polymorphisms identify the highest-risk diabetes HLA genotype. Diabetes. 2008 Nov;57(1939–327X (Electronic)):3152–5. 2. Frederiksen B, Liu E, Romanos J, Steck AK, Yin X, Kroehl M, et al. Investigation of the vitamin D receptor gene (VDR) and its interaction with protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2) on risk of islet autoimmunity and type 1 diabetes: The Diabetes Autoimmunity Study in the Young (DAISY). J Steroid Biochem Mol Biol. 2013 Jan;133:51–7. 3. Frederiksen BN, Kroehl M, Fingerlin TE, Wong R, Steck AK, Rewers M, et al. Association Between Vitamin D Metabolism Gene Polymorphisms and Risk of Islet Autoimmunity and Progression to Type 1 Diabetes: The Diabetes Autoimmunity Study in the Young (DAISY). The Journal of Clinical Endocrinology & Metabolism. 2013 Aug 26;98(11):E1845–51. 4. Frederiksen BN, Steck AK, Kroehl M, Lamb MM, Wong R, Rewers M, et al. Evidence of Stage- and Age- Related Heterogeneity of Non-HLA SNPs and Risk of Islet Autoimmunity and Type 1 Diabetes: The Diabetes Autoimmunity Study in the Young. Clin Dev Immunol [Internet]. 2013 [cited 2015 Sep 18];2013. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866813/ 5. Romanos J, Rosen A, Kumar V, Trynka G, Franke L, Szperl A, et al. Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants. Gut. 2014 Mar;63(1468–3288 (Electronic)):415–22. 6. Norris JM, Kroehl M, Fingerlin TE, Frederiksen BN, Seifert J, Wong R, et al. Erythrocyte membrane docosapentaenoic acid levels are associated with islet autoimmunity: the Diabetes Autoimmunity Study in the Young. Diabetologia. 2014 Feb;57(2):295–304. 7. Steck AK, Wong R, Wagner B, Johnson K, Liu E, Romanos J, et al. Effects of non-HLA gene polymorphisms on development of islet autoimmunity and type 1 diabetes in a population with high-risk HLA-DR,DQ genotypes. Diabetes. 2012 Mar;61(3):753–8. 8. Steck AK, Dong F, Wong R, Fouts A, Liu E, Romanos J, et al. Improving prediction of type 1 diabetes by

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA testing non-HLA genetic variants in addition to HLA markers. Pediatr Diabetes. 2014 Aug;15(5):355–62. 9. Steck AK, Bugawan TL, Valdes AM, Emery LM, Blair A, Norris JM, et al. Association of Non-HLA Genes With Type 1 Diabetes Autoimmunity. Diabetes. 2005 Aug 1;54(8):2482–6. 10. Gutierrez-Achury J, Romanos J, Bakker SF, Kumar V, Haas EC de, Trynka G, et al. Contrasting the Genetic Background of Type 1 Diabetes and Celiac Disease Autoimmunity. Dia Care. 2015 Oct 1;38(Supplement 2):S37– 44.

Clinical Age at Sampling Event Group Gender N Time 1 Time 2 Time3 Time 4 Age (y) Age Age Age (min/max) (min/max) (min/max) (min/max) Control F 13 1.0 ± 0.5 3.6 ± 1.7 6.4 ± 2.3 10.9 ± 3.9 (0.7 / 2.0) (1.3/ 7.5) (2.1 / 9.4) (4.1 / 16.1) M 12 0.9 ± 0.2 3.6 ± 1.9 6.3 ± 3.0 11.0 ± 4.9 (0.7 / 1.3) (1.3 / 6.1) (2.0 / 11.5) (3.1 / 16.1)

AbPos F 8 1.8 ± 1.6 6.1 ± 3.8 8.2 ± 3.5 12.9 ± 3.9 (0.7 / 5.0) (1.3 / 11.0) (3.4 / 12.2) (7.5 / 20.2) M 12 1.4 ± 1.2 5.4 ± 2.1 8.0 ± 2.8 12.3 ± 4.5 (0.7 / 4.4) (2.0 / 9.1) (3.1 / 13.5) (6.5 / 19.1)

T1D F 10 1.6 ± 0.7 *5.1 ± 2.7 6.7 ± 3.8 10.8 ± 3.1 (0.8 / 3.0) (1.3 / 9.4) (2.2 / 12.8) (5.0 / 14.7) M 12 1.8 ± 2.1 *4.6 ± 3.1 6.2 ± 2.9 10.2 ± 3.0 (0.7 / 7.9) (1.3 / 9.0) (2.9 / 10.9) (4.9 / 14.0)

*T1D group is missing samples for 2 females and 3 males at Time 2

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Table 4. The top features in development of islet autoimmunity (IA). Analysis by ROFI-P3 comparing controls to pooled islet autoantibody positive (AbPos) and type 1 diabetes (T1D) subjects from T1 to T2 for metadata, cytokines, metabolites and proteins and SNPs. Ranking by selection frequency, reporting features selected at least 50% of the time. (See supplemental tables 5-9 for comparison of each feature for case vs. control.)

Selected (%) Source Feature 100 Metabolite Ascorbate (Vitamin C) 100 Metadata Age (years) 98 Metadata First-degree relative status 94 Metabolite 3-methyl-2-oxobutyrate 93 Protein FCRL3 (Fc receptor-like protein 3) 91 Metabolite 4-hydroxyhippurate 90 Metadata Hispanic 90 Protein NKG2-D type II integral membrane protein/ KLRK1 89 SNP PTPN22 (rs2476601) 89 Protein SSRP1 (FACT complex subunit) 89 Metabolite Pyroglutamine 87 Protein MMP-2 (Matrix Metallopeptidase 2) 86 Protein Activin A 85 SNP PTPN22 (rs2476601) 84 Protein CSK21 (Casein kinase II subunit alpha) 84 SNP CTLA4 ( rs3087243) 82 Protein HAI-1(Hepatocyte growth factor activator inhibitor type 1/Kunitz-type protease inhibitor 1) 82 Protein Macrophage scavenger receptor 79 Metadata HLA risk group 77 Metabolite Betaine 77 Protein CD22 (B-cell receptor CD22) 77 Peptide C6 (Complement component C6) 76 Metadata Sex 76 Protein CCL18 (C-C motif chemokine 18/PARC) 75 Protein CRIS3 (Cysteine-rich secretory protein 3) 75 Protein Hepcidin (Liver-expressed antimicrobial peptide 1/LEAP-1) 73 Metabolite 4-androsten-3b,17b-diol disulfate 1 73 Metabolite N-acetylornithine 73 Protein FSTL3 (Follistatin-related protein 3) 73 Protein Angiopoietin-2 72 SNP rs2290400 ( GSDMB/ORMDL3 )

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA 71 Metabolite Dihomo-linolenate (20:3n3 or n6) 71 Metabolite S-methylcysteine 71 Metabolite Xylitol 71 Protein MFRP (Membrane frizzled-related protein) 71 Protein FGFR-3 (Fibroblast growth factor receptor 3) 71 Protein BSSP4 (Brain-specific serine protease 4) 71 Protein SEPR (Seprase/Prolyl endopeptidase FAP) 70 Metabolite 7-hydroxyoctanoate 69 Protein Cathepsin 68 Protein C8 (Complement component 8) 67 Protein IGFBP-2 (Insulin-like growth factor-binding protein 2) 66 Metabolite Thymol sulfate 66 Protein Osteoblast-specific transcription factor 2 65 Metabolite Dodecanedioate 65 Protein Protein disulfide isomerase A3 65 Protein Coagulation Factor X 65 Protein Stanniocalcin-1 65 SNP rs2282679 ( GC [vitamin D binding protein]) 64 Metabolite 4-androsten-3b,17b-diol disulfate 2 64 Metabolite Sphingosine 64 Protein LKHA4 (Leukotriene A-4 hydrolase) 64 Protein LYVE1 (Lymphatic vessel endothelial hyaluronic acid receptor 1) 64 Protein Testican-2 64 Protein ROR1 (Inactive tyrosine-protein kinase transmembrane receptor ROR1) 63 Metabolite Phosphate 63 Protein TrATPase (Tartrate-resistant acid phosphatase type 5) 63 Protein Kininogen, HMW 62 Peptide CLU (Clusterin) 61 Protein Cystatin C 61 Protein VEGF sR2 (Vascular endothelial growth factor receptor 2) 61 Protein PSA6 (Proteasome subunit alpha type-6) 60 Protein Olfactomedin-4 60 Protein Thrombopoietin Receptor 60 Protein DPP2 (Dipeptidyl peptidase 2) 59 Metabolite Uridine 58 Metabolite 3-indoxyl sulfate

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA 58 Protein NKp30 (Natural killer cell p30-related protein/Natural cytotoxicity triggering receptor 3/ NCR3) 58 Protein CLF-1/CLC Complex (Cytokine receptor-like factor 1/ Cardiotrophin-like cytokine factor 1) 57 Protein MMP-3 (MMP-2 (Matrix Metallopeptidase 3) 57 Protein GFRa-2 (GDNF family receptor alpha-2) 57 SNP PRKCQ (rs947474) 57 SNP CTLA4 (rs231775) 56 Protein MAPK2 (MAP kinase-activated protein kinase 2/MAPKAPK2) 56 Protein MAPT (Microtubule-associated protein tau) 54 Metabolite Tryptophan 54 Protein C3d (Complement C3d fragment) 51 SNP PARD3 (rs10763976)

Control Case (AbPos/T1D) Selected (%) SNP Genotypes Genotypes 89 rs2476601 ( PTPN22 ) GG AG 85 rs2476601 ( PTPN22 ) GG AG 84 rs3087243 ( CTLA4 ) AA AG or GG 72 rs2290400 ( GSDMB/ORMDL3 ) GG AA 65 rs2282679 ( GC [vitamin D binding protein]) AA AC 57 rs947474 ( PRKCQ ) AA AG or GG 57 rs231775 ( CTLA4 ) AA GG 51 rs10763976 ( PARD3 ) AG GG

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Table 6. Comparison of metabolomic features between cases (AbPos/T1D) and controls for development of islet autoimmunity (IA). Ranking by selection frequency, reporting features selected at least 50% of the time. Metabolites identified by ultrahigh performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS2) and gas chromatography/mass spectrometry (GS/MS). Mean Log 2(fold ∆) is the mean fold change from time 1 to time 2 for each group. Positive number indicates increase in the measure over time; negative number indicates decrease over time.

Control Case (AbPos/T1D)

Selected (%) Metabolite Mean Log 2(fold Δ) Mean Log 2(fold Δ) 100 Ascorbate (Vitamin C) -1.843 0.718 94 3-methyl-2-oxobutyrate 0.420 -0.357 91 4-hydroxyhippurate -0.590 0.133 89 Pyroglutamine -0.034 0.376 77 Betaine -0.288 0.034 73 4-androsten-3b,17b-diol disulfate 1 -0.209 0.904 73 N-acetylornithine -0.405 0.064 71 Dihomo-linolenate (20:3n3 or n6) 0.123 -0.214 71 S-methylcysteine -0.423 -0.066 71 Xylitol -0.231 0.158 70 7-hydroxyoctanoate -0.729 -0.145 66 Thymol sulfate 0.063 1.554 65 Dodecanedioate -1.372 -0.744 64 4-androsten-3b,17b-diol disulfate 2 -0.942 -0.199 64 Sphingosine -0.770 -0.142 63 Phosphate 0.008 -0.086 59 Uridine -0.047 -0.351 58 3-indoxyl sulfate 1.264 0.602 54 Tryptophan 0.035 -0.033

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Table 7. Comparison of protein features between cases (AbPos/T1D) and controls for development of islet autoimmunity (IA). Ranking by selection frequency, reporting features selected at least 50% of the time. Proteins identified by aptamer (Somalogic). Mean Log 2(fold ∆) is the mean fold change from time 1 to time 2 for each group. Positive number indicates increase in the measure over time; negative number indicates decrease over time.

Selected Control Case (AbPos/T1D)

(%) Mean Log 2(fold Δ) Mean Log 2(fold Δ) 93 FCRL3 (Fc receptor-like protein 3) 0.008 -0.034 90 NKG2-D type II integral membrane protein/ KLRK1 0.178 0.064 89 SSRP1 (FACT complex subunit) 0.006 -0.137 87 MMP-2 (Matrix Metallopeptidase 2) -0.075 0.006 86 Activin A -0.046 -0.040 84 CSK21 (Casein kinase II subunit alpha) -0.223 -0.066 82 HAI-1(Hepatocyte growth factor activator inhibitor type -0.002 0.038 1/Kunitz-type protease inhibitor 1) 82 Macrophage scavenger receptor 0.160 0.018 77 CD22 (B-cell receptor CD22) 0.100 0.020 76 CCL18 (C-C motif chemokine 18/PARC) -0.314 -0.238 75 CRIS3 (Cysteine-rich secretory protein 3) 0.145 0.067 75 Hepcidin (Liver-expressed antimicrobial -0.031 0.000 peptide 1/LEAP-1) 73 FSTL3 (Follistatin-related protein 3) 0.053 0.005 73 Angiopoietin-2 -0.045 -0.024 71 MFRP (Membrane frizzled-related protein) 0.126 0.077 71 FGFR-3 (Fibroblast growth factor receptor 3) -0.044 -0.100 71 BSSP4 (Brain-specific serine protease 4) 0.027 0.049 71 SEPR (Seprase/Prolyl endopeptidase FAP) -0.170 -0.155 69 Cathepsin H 0.337 0.252 68 C8 (Complement component 8) 0.070 0.013 67 IGFBP-2 (Insulin-like growth factor-binding 0.253 0.263 protein 2) 66 Osteoblast-specific transcription factor 2 0.084 -0.161 65 Protein disulfide isomerase A3 -0.270 -0.172 65 Coagulation Factor X -0.101 -0.220 65 Stanniocalcin-1 -0.040 0.052 64 LYVE1 (Lymphatic vessel endothelial hyaluronic acid receptor -0.050 -0.072 1) 64 Testican-2 -0.088 -0.099 64 ROR1 (Inactive tyrosine-protein kinase transmembrane -0.032 -0.051 receptor ROR1) 63 TrATPase (Tartrate-resistant acid phosphatase -0.336 -0.240 type 5) 63 Kininogen, HMW -0.013 -0.005 61 Cystatin C -0.068 0.021 61 VEGF sR2 (Vascular endothelial growth factor receptor 2) -0.126 0.034

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA 61 PSA6 (Proteasome subunit alpha type-6) -0.035 0.049 60 Thrombopoietin Receptor -0.274 -0.293 60 DPP2 (Dipeptidyl peptidase 2) 0.177 0.242 60 Olfactomedin-4 0.067 0.038 58 NKp30 (Natural killer cell p30-related protein/Natural -0.065 -0.052 cytotoxicity triggering receptor 3/ NCR3) 58 CLF-1/CLC Complex (Cytokine receptor-like factor 1/ -0.121 -0.030 Cardiotrophin-like cytokine factor 1) 57 MMP-3 (Matrix Metallopeptidase 3) -0.285 -0.211 57 GFRa-2 (GDNF family receptor alpha-2) -0.216 -0.127 56 MAPK2 (MAP kinase-activated protein kinase 2/ MAPKAPK2) 0.082 0.078 56 MAPT (Microtubule-associated protein tau) 0.012 -0.007 54 C3d (Complement C3d fragment) 0.238 0.182

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Table 8. Comparison of peptide features between cases (AbPos/T1D) and controls for development of islet autoimmunity (IA). Ranking by selection frequency, reporting features selected at least 50% of the time. Peptides identified by LC-MRM/MS. Mean Log 2(fold ∆) is the mean fold change from time 1 to time 2 for each group. Positive number indicates increase in the measure over time; negative number indicates decrease over time.

Control Case (AbPos/T1D)

Selected (%) Peptide Mean Log 2(fold Δ) Mean Log 2(fold Δ) 77 C6 (Complement component C6) 0.139 0.031 64 KNG1 (Kininogen-1) -0.008 -0.012 62 CLU (Clusterin) 0.073 0.084

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Table 9. The top features in progression from islet autoimmunity (IA) to type 1 diabetes. Analysis by ROFI-P3 comparing islet autoantibody positive subjects (controls) to T1D subjects (Cases) from T3 to T4 for metadata, cytokines, metabolites and proteins and SNPs. Ranking by selection frequency, reporting features selected at least 50% of the time. (See supplemental tables 11 – 15 for comparison of each feature for case vs. control.)

Selected Source Feature (%) 100 Metabolite Glucose 100 Metadata Age (years) 100 Metabolite ADP fibrinogen DRR1 (Down-regulated in renal cell carcinoma 1)/ 100 Protein Actin-associated protein FAM107A 99 Metabolite Mannose 98 Protein RAD51 (DNA repair protein RAD51 homolog 1) 98 Protein Cystatin-F (CYTF) 97 Protein MAPKAPK3 (MAP kinase-activated protein kinase 3) 92 SNP MHC (rs3117103) 91 SNP from GWAS for T1D (rs7221109) 90 Protein Plasminogen 89 Metabolite Ribose 89 Protein IL-11 RA (Interleukin-11 receptor subunit alpha) 89 SNP HLA-DQB1 8.1 (rs2157678) 87 Metabolite Butyrylcarnitine 86 Protein Spondin-1 85 Metabolite Gluconate 84 Protein Tropomyosin 2 82 SNP UBASH3A (rs11203203) 80 SNP GSDMB/ORMDL3 (rs2290400) 80 Protein Carbonic Anhydrase X 80 Protein FCG2A (Low affinity immunoglobulin gamma Fc region receptor II-a) 80 Protein TPSB2 (Tryptase beta-2) 80 Protein MED-1 (Mediator of RNA polymerase II transcription subunit 1) 79 Protein Calcineurin 78 Metadata First-degree relative status 75 SNP MAGI2 (rs2160322) 75 SNP from GWAS for celiac (rs10806425) 74 SNP HORMAD2 (rs5753037) 74 SNP MHC (rs2853977)

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA 74 SNP CTLA4 (rs231775) 74 Protein FCG2B (Low affinity immunoglobulin gamma Fc region receptor II-b) 73 Protein Desmoglein-1 73 Protein NET4 (Netrin-4) IGFBP-1 (Insulin-like growth factor-binding 72 Protein protein 1) 72 Metabolite 3-methylhistidine 71 Protein Haptoglobin, Mixed Type 71 Peptide SERPI 71 Protein uPA (Urokinase-type plasminogen activator) 70 Protein PAK3 (Serine/threonine-protein kinase PAK 3) 70 Protein Trypsin 2 69 Protein PTP-1B (Protein-tyrosine phosphatase 1B/Tyrosine-protein phosphatase non-receptor type 1) 69 Protein IF4A3 (Eukaryotic initiation factor 4A-III) 68 Protein CCL17 (C-C motif chemokine 17)/TARC 68 Protein Discoidin domain receptor 2 68 Protein PAFAH beta subunit (Platelet-activating factor acetylhydrolase IB subunit beta) 67 Protein Proteinase-3 67 Metabolite Bradykinin, des-arg(9) 67 Metabolite 7-methylguanine 65 Protein Kininogen,HMW 64 Protein Fractalkine/CX3CL-1 64 Protein ARP19 (cAMP-regulated phosphoprotein 19) 64 Metabolite 1,6-anhydroglucose 63 Protein Trypsin 63 Protein SLIK1 (SLIT and NTRK-like protein 1) 63 Protein SH21A (SH2 domain-containing protein 1A) 62 Protein α1 -Antichymotrypsin 62 Protein TrkC (NT-3 growth factor receptor) 62 Protein Mn SOD (Superoxide dismutase [Mn], mitochondrial) 61 Protein MBL (Mannose-binding protein C) 61 Protein Nucleoside diphosphate kinase A 60 Protein Mitogen-activated protein kinase 14 (MAPK14) 60 Metabolite 3-hydroxyisobutyrate 59 Metabolite Threonine 58 Peptide PPBP 58 Metabolite Phenyllactate (PLA)

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA 58 Protein EphB4 (Ephrin type-B receptor 4) 58 Metabolite Cortisone 58 Metabolite 1,5-anhydroglucitol (1,5-AG) 57 Protein CD109 antigen 56 Protein GPVI (Platelet glycoprotein VI) 55 Metabolite Isoleucylglycine 55 Metabolite Fucose 54 Metabolite 2-hydroxyglutarate 54 Metabolite 1-linoleoylglycerophosphocholine 53 Protein MCP-4 (Monocyte chemotactic protein 4) / C-C motif chemokine 13 53 Protein Caspase-2 53 Protein ARTS1 (Endoplasmic reticulum aminopeptidase 1) 52 Protein Cardiotrophin I 52 Protein Kallikrein-6 51 Protein SARP-2 (Secreted apoptosis-related protein 2)/ sFRP-1 (Secreted frizzled-related protein 1) NKp44 (Natural killer cell p44-related protein)/ Natural cytotoxicity triggering receptor 2 / 50 Protein CD336 50 Protein LAG-1 (Lymphocyte activation gene 1 protein)/ C-C motif chemokine 4-like

Control (AbPos) Case (T1D) Selected (%) SNP Genotypes Genotypes 92 MHC (rs3117103) TT AT 91 from GWAS for T1D (rs7221109) CT CC 89 HLA-DQB1 8.1 (rs2157678) CC AC 82 UBASH3A (rs11203203) GG AA or AG 80 GSDMB/ORMDL3 (rs2290400) AG AA 75 MAGI2 (rs2160322) CG CC 75 from GWAS for celiac (rs10806425) CC AC 74 HORMAD2 (rs5753037) CC CT 74 MHC (rs2853977) TT AT 74 CTLA4 (rs231775) AG AA

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Table 11. Comparison of metabolomics features between cases (T1D) and controls (AbPos) for progression from islet autoimmunity (IA) to T1D. Ranking by selection frequency, reporting features selected at least 50% of the time. Metabolites identified by ultrahigh performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS2) and gas chromatography/mass spectrometry (GS/MS). Mean Log 2(fold ∆) is the mean fold change from time 3 to time 4 for each group. Positive number indicates increase in the measure over time; negative number indicates decrease over time.

Control (AbPos) Case (T1D)

Selected (%) Metabolite Mean Log 2(fold Δ) Mean Log 2(fold Δ) 100 Glucose -0.225 0.423 100 ADP fibrinogen 0.048 0.745 99 Mannose -0.023 1.000 89 Ribose -0.494 0.147 87 Butyrylcarnitine -0.247 0.092 85 Gluconate -0.218 0.442 72 3-methylhistidine 0.871 0.008 67 Bradykinin, des-arg(9) 0.541 0.306 67 7-methylguanine -0.252 0.273 64 1,6-anhydroglucose -0.086 0.896 60 3-hydroxyisobutyrate -0.339 -0.056 59 Threonine -0.075 0.100 58 Phenyllactate (PLA) 0.085 0.210 58 Cortisone 0.422 0.026 58 1,5-anhydroglucitol (1,5-AG) 0.026 -0.708 55 Isoleucylglycine -0.317 0.139 55 Fucose -0.027 0.276 54 2-hydroxyglutarate -0.910 -0.527 54 1-linoleoylglycerophosphocholine 0.013 0.230

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Table 12. Comparison of protein features between cases and controls for progression from islet autoimmunity (IA) to T1D. Ranking by selection frequency, reporting features selected at least 50% of the time. Proteins identified by aptamer (Somalogic). Mean Log 2(fold ∆) is the mean fold change from time 3 to time 4 for each group. Positive number indicates increase in the measure over time; negative number indicates decrease over time.

Selected Control (AbPos) Mean Case (T1D) (%) Log 2(fold Δ) Mean Log 2(fold Δ) DRR1 (Down-regulated in renal cell carcinoma 1)/Actin- 0.085 0.008 100 associated protein FAM107A 98 RAD51 (DNA repair protein RAD51 homolog 1) 0.273 -0.042 98 Cystatin-F (CYTF) -0.160 0.109 97 MAPKAPK3 (MAP kinase-activated protein kinase 3) -0.082 0.146 90 Plasminogen 0.096 -0.045 89 IL-11 RA -0.120 0.022 86 Spondin-1 -0.165 0.051 84 Tropomyosin 2 0.090 -0.038 80 Carbonic Anhydrase X 0.190 -0.008 FCG2A (Low affinity immunoglobulin gamma Fc region receptor -0.045 0.079 80 II-a) 80 TPSB2 (Tryptase beta-2) -0.120 -0.015 80 MED-1 (Mediator of RNA polymerase II transcription subunit 1) -0.017 0.077 79 Calcineurin -0.276 -0.040 FCG2B (Low affinity immunoglobulin gamma Fc region receptor -0.087 0.125 74 II-b) 73 Desmoglein-1 0.273 0.001 73 NET4 (Netrin-4) -0.159 0.032 IGFBP-1 (Insulin-like growth factor-binding -0.466 -1.237 72 protein 1) 71 Haptoglobin, Mixed Type 0.241 -0.211 71 uPA (Urokinase-type plasminogen activator) -0.194 -0.001 70 PAK3 (Serine/threonine-protein kinase PAK 3) 0.134 -0.062 70 Trypsin 2 0.005 -0.333 PTP-1B (Protein-tyrosine phosphatase 1B/Tyrosine-protein 0.171 -0.022 69 phosphatase non-receptor type 1) 69 IF4A3 (Eukaryotic initiation factor 4A-III) 0.023 -0.110 68 CCL17 (C-C motif chemokine 17)/TARC -0.035 -0.072 68 Discoidin domain receptor 2 -0.065 0.058 PAFAH beta subunit (Platelet-activating factor acetylhydrolase IB 0.035 0.107 68 subunit beta) 67 Proteinase-3 0.529 0.228 65 Kininogen, HMW 0.078 -0.042 64 Fractalkine/CX3CL-1 0.197 -0.015 64 ARP19 (cAMP-regulated phosphoprotein 19) -0.134 0.039 63 Trypsin -0.123 -0.463 63 SLIK1 (SLIT and NTRK-like protein 1) 0.186 0.042

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA 63 SH21A (SH2 domain-containing protein 1A) -0.164 -0.045 62 -Antichymotrypsin 0.075 -0.026 62 TrkC (NT-3 growth factor receptor) -0.093 0.002 62 Mn SOD (Superoxide dismutase [Mn], mitochondrial) -0.025 -0.177 61 MBL (Mannose-binding protein C) -0.134 0.153 61 Nucleoside diphosphate kinase A 0.360 0.150 60 Mitogen-activated protein kinase 14 (MAPK14) -0.167 0.023 58 EphB4 (Ephrin type-B receptor 4) -0.018 0.050 57 CD109 antigen -0.275 0.082 56 GPVI (Platelet glycoprotein VI) 0.253 0.096 MCP-4 (Monocyte chemotactic protein 4) / C-C motif chemokine -0.073 0.010 53 13 53 Caspase-2 -0.026 -0.071 53 ARTS1 (Endoplasmic reticulum aminopeptidase 1) 0.897 0.384 52 Cardiotrophin I 0.006 -0.033 52 Kallikrein-6 0.173 0.008 SARP-2 (Secreted apoptosis-related protein 2)/ sFRP-1 (Secreted -0.127 -0.001 51 frizzled-related protein 1) NKp44 (Natural killer cell p44-related protein)/ Natural 0.026 -0.016 50 cytotoxicity triggering receptor 2 / CD336 LAG-1 (Lymphocyte activation gene 1 protein)/ C-C motif 0.063 -0.001 50 chemokine 4-like

©2019 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1263/-/DC1 SUPPLEMENTARY DATA Supplementary Table 13. Comparison of peptide features between cases and controls for progression from islet autoimmunity (IA) to T1D. Ranking by selection frequency, reporting features selected at least 50% of the time. Peptides identified by LC-MRM/MS. Mean Log 2(fold ∆) is the mean fold change from time 3 to time 4 for each group. Positive number indicates increase in the measure over time; negative number indicates decrease over time.

Control (AbPos) Case (T1D)

Selected (%) Peptide Mean Log 2(fold Δ) Mean Log 2(fold Δ) 71 SERPIND1 (Heparin cofactor 2) 0.039 -0.001 58 PPBP (Platelet basic protein) 0.077 0.103