Overview for Researchers

iGeneTRAIN is currently progressing through three phases shown below.The ultimate goal of iGeneTRAiN is the establishment a massive multi-site network with integrates deeply-characterized transplantation (phenotypes) and DNA data, and transitions to translational research for early detection of rejection.

Phase 1, which began in early 2013, focused on organizing existing projects to optimize the availability of data transplant and DNA data. and while most of the studies have now completed primary GWAS analyses, additional recruitment and engagement with new transplantation studies is still ongoing. Phase 2 is now well underway and entails coordination of large-scale meta-analyses across iGeneTRAIN sites. In Phase 3, entails deeper harmonization the consortium’s activities (once the majority of the single site publications have been completed) and establishing long-term sustainability through large national and international grants. Further details on respective phases is outlined below.

Phase 1: Phase 1 has largely been organizational, focusing on maximizing the data available to consortium members. Under Phase 1, we have, and continue to, assemble phenotypic and genetic data from existing solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) studies,. For clinical data, we have been defining and structure those pharmacological, and phenotype measures that will be used in analyses (Phase 2). An important component of this effort has been to harmonize data collected from different iGeneTRAIN sites. Ultimately, this will greatly facilitate data integration efforts and facilitate meta-analyses and replication studies across the consortium.

For DNA data, we have collated information from different genetic datasets, creating a comprehensive catalog of biomarkers derived from 1) second generation sequencing (SGS), 2) genome-wide association study GWAS) and 3) candidate gene studies.

Phase 1a (completed for the majority of existing studies): Surveying and collating the relevant covariate, phenotypic and outcome data information among existing and pending studies across all major University hospitals as well national and regional transplantation organizations. Phase I studies can also include DNA-only studies which can be leveraged as replication studies

Phase 1b (formed and ongoing): Formed phenotype-specific working groups. These include four groups focused on solid organ transplant (heart, kidney, liver and lung) as well as a hematopoietic stem cell transplant group. Respective groups focus on collating and formatting appropriate covariates, intermediate phenotypes.

Existing genomics studies, HLA and New Onset of Diabetes after Transplant and Acute Rejection outcomes
Organ Study Genotyping/SGS Platform Number of Variants Directly Captured Current existing Imputation Data HLA Outcomes
2-Digit Resolution 4-Digit Resolution NODAT (%) AR (%)
Kidney Go-CAR HumanOmniExpress ~900K Imputed by IMPUTE2 and MACH at two independent sites using 1KGPv3 reference set Yes Yes NA 10
TRANSPLANT-LINES Axiom Tx SNP GWAS array ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 Yes No 21 34
Vanderbilt BioVU Infinium 660K, Omni1M ~660K to 1 Million Imputed by IMPUTE2 at Vanderbilt using 1KGPv3 Yes Yes, since 2006 15 17
CHOP-Kidney Tx Axiom Tx SNP GWAS array ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 Yes Yes 2 0.3
UPenn-Kidney Tx Axiom Tx SNP GWAS array ~780K Imputed by IMPUTE2 at Penn State using 1KGPv3 Yes No 10 25
WTCCC-3 Infinium 660K ~660K Imputed by IMPUTE2 at Sanger Institute using 1KGPv3 Yes (subset) Yes (subset) N/A 19
GEN-03 DeKAF Genomics Axiom Tx SNP GWAS array ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 Yes (from clinic & from GWAS) Yes (imputed from GWAS) 7 14
Heart CTOT-3 71Mb/96Mb Seq + MetaboChip ~200K to 71Mb (SGS) Imputed by IMPUTE2 at Penn State using 1KGPv3 Yes No NA 22
CTOT-5 Axiom Tx SNP GWAS array ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 Yes No N/A 43
Stanford/LPCH Axiom Tx array + Omni 1M/2.5M ~780K Imputed by IMPUTE2 at Penn State using 1KGPv3 Yes Ad-hoc when allele specific Abs are detected 11 30
CHOP-Heart Tx Axiom Tx array + Infinium660K ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 Yes Yes N/A 4.4
UPenn-Heart Tx Axiom Tx SNP GWAS array ~780K Imputed by IMPUTE2 at Penn State using 1KGPv3 Yes No N/A 35
UCOR Axiom Tx SNP GWAS array ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 Yes, from 1993 No N/A 10
Madrid Heart Tx Study Axiom Tx SNP GWAS array ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 Yes (subset) No N/A 74
Vanderbilt BioVU Infinium 660K and 1M ~660K to 1 Million Imputed by IMPUTE2 at Vanderbilt using 1KGPv3 Yes Yes, since 2006 N/A N/A
Rotterdam cohort Axiom Tx SNP GWAS array ~780K N/A Yes No N/A 62
Liver CTOT-3 71Mb + MetaboChip ~200K to 71Mb (SGS) Imputed by IMPUTE2 at Penn State using 1KGPv3 No No N/A 9
AWISH (CTOT-7) Axiom Tx SNP GWAS array ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 No No N/A 24
A2ALL Axiom Tx SNP GWAS array ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 No No N/A 16
CHOP-Liver Tx Axiom Tx array + Infinium660K ~780K Imputed by IMPUTE2 at Penn State using 1KGPv3 No No N/A 5
UPenn-Liver Tx Axiom Tx SNP GWAS array ~660K to 780K Imputed by IMPUTE2 at Penn State using 1KGPv3 No No N/A 11
Baylor-Liver Tx Axiom Tx SNP GWAS array ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 Yes No 28 40
Lung LTOG Axiom Tx SNP GWAS array ~780K Imputed by IMPUTE2 at Penn State using 1KGPv3 Yes Yes 30 40
ULTx Axiom Tx SNP GWAS array ~780K Imputed by Impute2 at UMCU and Penn state using 1KGv3 and GoNLv5 Yes, prior to 1993 No 44 14
CTOT-3 71Mb + MetaboChip ~200K to 71Mb (SGS) Imputed by IMPUTE2 at Penn State using 1KGPv3 Yes No N/A 19

Phase 1c: : Formation of four additional working groups whose interests intersect across different transplant phenotypes. These groups are:

    • HLA working group
    • Genomic and other omics groups (including genomic analysis of SGS/GWAS/other genetic data)
    • Pharmacogenomics
    • Steering committee (comprised of representatives other workgroups).

Phase 1d (ongoing): Phase 1d focuses on meta-analyzing existing datasets. Relevant studies have a defined a priori set of biomarkers and/or analyses for replication. This will allow us to validate the integrity of existing datasets and approaches, and serves an important role in ensuring quality control and data harmonization.

Phase 2 (2015 ): Phase 2 will build upon relevant results, and conduct broader meta-analyses and functional studies across iGeneTRAIN groups. We are embarking on additional RNA expression, proteomic, and functional studies using biological materials collected from the respective studies. This requires relevant stakeholders to agree upon predefined analysis pipelines, authorship within manuscripts, and cost breakdowns using standard genomic consortium rules (available on request).

Phase 3 (2016 -2017):Phase 3 will involve large-scale expansion of the consortium in terms of aims and infrastructure. Member sites with transplant GWAS data will continue with expanded meta-analyses, and consortium efforts will focus intensively on supporting national and international grant applications. This strategy is aimed at ensuring the long-term sustainability of iGeneTRAIN and will leverage the considerable breadth and variety of expertise across member sites.

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