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Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28
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Personalized Medicine in Transplantation by Maarten Naesens - at Université Libre de Bruxelles - 2014-01-28

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  • 1. MAARTEN NAESENS, MD, PHD MAARTEN NAESENS DEPARTMENT OF NEPHROLOGY AND RENAL TRANSPLANTATION DEPARTMENT OF N UNIVERSITY HOSPITALS LEUVEN, BELGIUM, EU EPHROLOGY AND RENAL TRANSPLANTATION UNIVERSITY HOSPITALS LEUVEN, BELGIUM, EU LABORATORY OF NEPHROLOGY DEPARTMENT OF PEDIATRICS DEPARTMENT OF MICROBIOLOGY AND IMMUNOLOGY STANFORD UNIVERSITY, CALIFORNIA, USA KU LEUVEN, BELGIUM, EU BRUSSELS, JANUARY 28, 2013 TTS – 2ND TRANSPLANTOMICS AND BIOMARKERS MEETING BARCELONA, MARCH 2011
  • 2. Personalized Medicine and Organ Transplantation •  General: Personalized Medicine and Systems Medicine •  Kidney Transplantation: o  o  o  Current Tools for Personalized Medicine Novel Tools for Personalized Medicine The BioMargin Project •  Evidence-Based Medicine vs. Personalized Medicine
  • 3. What is “Personalized Medicine?” “Although personalized medicine has many definitions, most share the core idea that any one patient’s health is best managed by tailoring preventive measures and treatment to personal preferences as well as to the patient’s particular environmental and biologic … attributes.” Feero, Guttmacher and Collins Feero, Guttmacher and Collins New Engl J Med 2010
  • 4. What is “Personalized Medicine?” Traditional clinical diagnosis and management focuses on the individual patient's clinical signs and symptoms, medical and family history, and data from laboratory and imaging evaluation to diagnose and treat illnesses. This is often a reactive approach to treatment, i.e., treatment/medication starts after the signs and symptoms appear. Personalized medicine is a medical model that proposes the customization of healthcare - with medical decisions, practices, and/or products being tailored to the individual patient. In this model, diagnostic testing* is essential for selecting appropriate therapies. *Companion diagnostics; theranostics From Wikipedia
  • 5. Personalized Medicine Which molecules are involved? BIOMARKERS Slideadapted from Atul Butte
  • 6. Which molecules? Evolving paradigms Feero et al New Engl J Med 2010
  • 7. Which molecules? Evolving paradigms Naesens and Sarwal, Nature Rev. Nephrol. 2010
  • 8. Which molecules? Evolving paradigms Naesens and Sarwal, Nature Rev. Nephrol. 2010
  • 9. Systems Medicine Systems medicine is an interdisciplinary field of study that looks at the dynamic systems of the human body as part of an integrated whole, incorporating biochemical, physiological, and environment interactions that sustain life. From Wikipedia
  • 10. The need for a holistic approach Hokusai 1818
  • 11. Systems Medicine Etiome (environment) Metabolome Proteome Transcriptome (Epi)Genome
  • 12. Systems Medicine Oksenberg et al Nat Rev Genet 2008
  • 13. Omics: new research paradigms Hypothesis-driven research Hypothesis-generating / data-driven research Holistic Reductionistic Holistic
  • 14. Omics: new research paradigms Hypothesis-driven research Hypothesis-generating / data-driven research Reductionistic Holistic Hypothesis/Theory Samples Falsification Unbiased omics strategies New hypothesis 1 New hypothesis 2 Falsification Falsification Unbiased omics strategies Data-driven results NH3 NH4 NH5 NH6 NH7 NH8 Data-driven hypothesis/theory F F F F F F
  • 15. Personal “Omics” Profiling (POP) Genome Epigenome Transcriptome (mRNA, miRNA, isoforms, edits) Proteome/peptidome Cytokines Metabolome Autoantibody-ome Microbiome From: Michael Snyder; see also Chen R et al Cell 2012 Personal Omics Profile
  • 16. Personal “Omics” Profiling (POP) Genome (1TB) Epigenome (2TB) Transcriptome (0.7TB) (mRNA, miRNA, isoforms, edits) Proteome/peptidome (0.02 TB) Cytokines Metabolome (0.02 TB) Autoantibody-ome Microbiome (3TB) From: Michael Snyder; see also Chen R et al Cell 2012 Personal Omics Profile Total = 5.74TB/Sample + 1 TB Genome
  • 17. Personalized Medicine and Organ Transplantation •  General: Personalized Medicine and Systems Medicine •  Kidney Transplantation: o  o  o  Current Tools for Personalized Medicine Novel Tools for Personalized Medicine The BioMargin Project •  Evidence-Based Medicine vs. Personalized Medicine
  • 18. Personalized Medicine and Organ Transplantation •  General: Personalized Medicine and Systems Medicine •  Kidney Transplantation: o  o  o  Current Tools for Personalized Medicine Novel Tools for Personalized Medicine The BioMargin Project •  Evidence-Based Medicine vs. Personalized Medicine
  • 19. Kidney Transplantation Outcome
  • 20. Time after last biopsy (years) Time after last biopsy (years) Why do kidney transplants fail? B Last histological diagnosis within 2 years prior to graft loss 8.3% 8.3% 7.6% 6.2% IF/TA 2-3 or glomerulosclerosis > 50% / prior specific disease IF/TA 2-3 or glomerulosclerosis > 50% / never specific disease IF/TA < 2 and glomerulosclerosis < 50% / prior specific disease IF/TA < 2 and glomerulosclerosis < 50% / never specific disease 30.6% 23.6% 10.4% 2.08% 16.7% 11.8% 4.86% No specific disease T-cell mediated rejection (including borderline) Mixed T-cell and antibody-mediated rejection Antibody-mediated rejection Transplant glomerulopathy^ De novo/recurrent glomerular disease Polyomavirus nephropathy All renal allograft recipients transplanted between 01/01/1991 – 31/01/2001 (N=1197) N=144 All renal allograft biopsies performed between 01/01/1991 and 14/04/2011 (N=1365) Naesens et al. submitted
  • 21. The histology of indication biopsies Prevalence (%) 60% 40% IF/TA 2-3 Transplant glomerulopathy TCMR Glom. dis. 20% aABMR 0% Normal PVAN 0.5 1 2 4 6 8 Time after transplantation (years) All renal allograft recipients transplanted between 01/01/1991 – 31/01/2001 (N=1197) All renal allograft biopsies performed between 01/01/1991 and 14/04/2011 (N=1365) Naesens et al. submitted >10
  • 22. Personalized medicine and transplantation “If we are to improve on the results that we are achieving today in adherent patients, then it will have to come from an earlier intervention to prevent irreversible damage in an individualized therapeutic approach – personalized medicine.” Jeremy Chapman Past-President of TTS Chapman J. Curr Opin Nephrol Hypertens 2012
  • 23. Current non-invasive diagnostics? TCMR eGFR aABMR proteinuria cABMR Glom. Dis. haematuria NSA/IFTA DSA testing RI index ATN PVAN BKV PCR None of these markers is a good biomarker for intragraft pathology: low sensitivity, low specificity, low NPPV, low PPV
  • 24. Graft dysfunction Transplant biopsy Nankivell and Kuypers Lancet 2011
  • 25. Personalized medicine in transplantation? Creatinine Proteinuria Diagnostic threshold Acute dysfunction Subclinical acute rejection Chronic dysfunction Time I-BX I-BX BX for cause Nankivell et al. NEJM 2003 Lerut et al. Transplantation 2007 Naesens et al. JASN 2009 Ters et al. AJT 2013
  • 26. Personalized medicine in transplantation? Creatinine Proteinuria Treatment Diagnostic threshold Acute dysfunction Subclinical acute rejection Chronic dysfunction Acute pathology I-BX I-BX BX for cause Time Nankivell et al. NEJM 2003 Lerut et al. Transplantation 2007 Naesens et al. JASN 2009 Ters et al. AJT 2013
  • 27. Personalized medicine in transplantation? Creatinine Treatment Proteinuria Diagnostic threshold Acute dysfunction Subclinical acute rejection Chronic dysfunction Acute pathology I-BX I-BX BX for cause I-BX Chronic pathology Chronic pathology Time Protocol BX P-BX P-BX P-BX P-BX Nankivell et al. NEJM 2003 Lerut et al. Transplantation 2007 Naesens et al. JASN 2009 Ters et al. AJT 2013
  • 28. Personalized medicine in transplantation? Creatinine Treatment Proteinuria Diagnostic threshold Acute dysfunction Subclinical acute rejection Chronic dysfunction Acute pathology I-BX I-BX BX for cause I-BX Chronic pathology Chronic pathology Time Protocol BX P-BX P-BX P-BX P-BX Nankivell et al. NEJM 2003 Lerut et al. Transplantation 2007 Naesens et al. JASN 2009 Ters et al. AJT 2013
  • 29. Personalized medicine in transplantation? Integration histology – genomics Traditional Changing Banff consensus on allograft pathology Dx Improving patient care Naesens and Sarwal, Nature Rev. Nephrol. 2010
  • 30. Personalized Medicine and Organ Transplantation •  General: Personalized Medicine and Systems Medicine •  Kidney Transplantation: o  o  o  Current Tools for Personalized Medicine Novel Tools for Personalized Medicine The BioMargin Project •  Evidence-Based Medicine vs. Personalized Medicine
  • 31. Personalized Medicine and Organ Transplantation •  General: Personalized Medicine and Systems Medicine •  Kidney Transplantation: o  o  o  Current Tools for Personalized Medicine Novel Tools for Personalized Medicine The BioMargin Project •  Evidence-Based Medicine vs. Personalized Medicine
  • 32. Omics and Kidney Transplantation Naesens and Sarwal, Nature Rev. Nephrol. 2010
  • 33. Omics and Kidney Transplantation Naesens and Sarwal, Nature Rev. Nephrol. 2010
  • 34. One step closer to “Rejectostix” In independent validation set: ROC AUC=0.74 (0.61-0.86; P<0.001) mRNA in urine 3 gene signature CD3ε, IP-10 and 18s Suthanthiran et al. NEJM 2013 Ingelfinger and Alexander NEJM 2013
  • 35. What about the peripheral blood? Recipient & and donor APCs move to lymphoid organs T cells stimulated in secondary lymphoid organs TISSUE SPECIFIC ALLOIMMUNE INJURY Alloreactive T cells to graft
  • 36. Peripheral blood “5-gene test” In independent validation set: ROC AUC=0.74 (0.61-0.86; P<0.001) mRNA in blood 5 gene signature DUSP1, PBEF1, PSEN1, MAPK9 and NKTR Li, Naesens, Sarwal et al. AJT 2012
  • 37. Peripheral blood “11-gene test” mRNA in blood 11 gene signature NPV = 99.6% PPV = 2.3% Pham et al. NEJM 2010
  • 38. Biopsy reclassification: TCMR score 77/300 (26%) biopsies reclassified Halloran et al. Am J Transplant 2013 mRNA in biopsy Whole genome expression “TCMR score”
  • 39. Cross-organ comparison of rejection? The common rejection module (11 genes) Khatri, Naesens, Sarwal et al. J Exp Med 2013
  • 40. Validation of biomarker candidates Prospec5ve* studies* Retrospec5ve* longitudinal* studies* Clinical*assay* development* and*valida5on* Exploratory* studies* Standardiza5on* (FDA*MAQC*project)* Partially based on Coyle and Johnston Nat Rev Clin Oncol 2010 Randomized** Controlled* Trials*
  • 41. Validation of biomarker candidates “Rejectostix”3 79% sensitivity 78% specificity Randomized** Controlled* Trials* Prospec5ve* studies* Peripheral blood 5-gene test2 91% sensitivity 94% specificity TCMR score1 Sensitivity? Specificity? Allomap4 NPV 99.6% PPV 2.3% Retrospec5ve* longitudinal* studies* Clinical*assay* development* and*valida5on* Exploratory* studies* 1Halloran Standardiza5on* (FDA*MAQC*project)* et al. AJT 2013 Naesens, Sarwal AJT 2012 3Suthanthiran et al NEJM 2013 4Pham et al NEJM 2010 2Li,
  • 42. Personalized Medicine and Organ Transplantation •  General: Personalized Medicine and Systems Medicine •  Kidney Transplantation: o  o  o  Current Tools for Personalized Medicine Novel Tools for Personalized Medicine The BioMargin Project •  Evidence-Based Medicine vs. Personalized Medicine
  • 43. Personalized Medicine and Organ Transplantation •  General: Personalized Medicine and Systems Medicine •  Kidney Transplantation: o  o  o  Current Tools for Personalized Medicine Novel Tools for Personalized Medicine The BioMargin Project •  Evidence-Based Medicine vs. Personalized Medicine
  • 44. Validation of biomarker candidates Prospec5ve* studies* Retrospec5ve* longitudinal* studies* Clinical*assay* development* and*valida5on* 1. Exploratory* studies* OMICS Standardiza5on* (FDA*MAQC*project)* Randomized** Controlled* Trials*
  • 45. Systems Medicine in Kidney Transplantation Naesens and Sarwal, Nature Rev. Nephrol. 2010
  • 46. Systems Medicine in Kidney Transplantation Naesens and Sarwal, Nature Rev. Nephrol. 2010
  • 47. BioMargin partners Analytical Centers (-omics data) Clinical Centers Acureomics MHH Hannover Urinary + plasma metabolomics Mosaiques Diagnostic GmbH UZ Leuven VITO AP-HP Paris Urinary proteomics and peptidomics Blood + biopsy miRNA KU Leuven Urinary mRNA Blood + biopsy miRNA UnivPDes Cardinal Systems Blood + biopsy mRNA AP-HP Paris CHU Limoges Urinary lipidomics CNRS Inserm-Transfert Biopsy lipidomics, peptidomics, proteomics INSERM Limoges Coordination CEA Urinary proteomics + peptidomics INSERM Toulouse Urinary proteomics + peptidomics Urinary miRNA Bio-informatics Center www.biomargin.eu
  • 48. Validation of biomarker candidates STEP 4 STEP 3 Retrospec5ve* longitudinal* studies* STEP 2 STEP 1 Clinical*assay* development* and*valida5on* Exploratory* studies* Standardiza5on* (FDA*MAQC*project)* Prospec5ve* studies* Randomized** Controlled* Trials*
  • 49. Study Outline Step 1-3 Step 4 Biobank Hannover Biobank Leuven Biopsies 3XBIOS2 BECS Biobank Paris Biobank Limoges 3ÐBIOS2 = 3-step BIOmargin Study on BIObanked Samples BECS = Biomargin European Cohort Study
  • 50. Study Outline Time post-TX 0m Histology Biopsy RNA Plasma Serum Blood RNA Urine 3m 6m 1y 2y 5y
  • 51. Study Outline Time post-TX 0m 3m Time post-TX Ind 6m Ind 1y 0m 2y Histology Histology Biopsy RNA Biopsy RNA Plasma Serum Plasma Serum Blood RNA Blood RNA Urine Urine 3m Ind 6m Ind 1y 5y
  • 52. 3 x BIOS2 BECS Number of samples Number of molecules
  • 53. 3 x BIOS2 BECS Number of samples Number of molecules
  • 54. Personalized Medicine and Organ Transplantation •  General: Personalized Medicine and Systems Medicine •  Kidney Transplantation: o  o  o  Current Tools for Personalized Medicine Novel Tools for Personalized Medicine The BioMargin Project •  Evidence-Based Medicine vs. Personalized Medicine
  • 55. Personalized Medicine and Organ Transplantation •  General: Personalized Medicine and Systems Medicine •  Kidney Transplantation: o  o  o  Current Tools for Personalized Medicine Novel Tools for Personalized Medicine The BioMargin Project •  Evidence-Based Medicine vs. Personalized Medicine
  • 56. Evidence based medicine Evidence-Based Medicine (RCT) = commonality* Treatment * Homogenous cohort A Treatment * B * the fact of being common to more than one individual Outcome A Comparison = evidence Outcome B
  • 57. Biomarker discovery Personal Medicine = individuality^ Donor  at  time  of  transplantation DNA Test set mRNA Heterogenous cohort Patient C mRNA Sequence Expression Outcome 1 Donor  at  time  of  transplantation DNA Recipient  at  time  of  transplantation mRNA Donor  RNA  seq (biopsy) DNA mRNA Expression Sequence Patient B DNA Expression Sequence Patient A Recipient  at  time  of  transplantation ^ the qualities that distinguish one person or thing from another Sequence Expression Outcome 1 DNA mRNA DNA mRNA Donor-­‐recipient  specific Sequence Sequence Expression antigenic  capacity Expression Integration: Donor  RNA  seq Recipient  ecipient   specific donor-­‐r RNA  seq (biopsy) (blood) Recipient  antibodyome antibody  responses Donor  at  time  of  transplantation Recipient  at  time  of  transplantation by  protein  arrays Outcome 2 DNA mRNA DNA mRNA Donor-­‐recipient  specific Sequence Sequence Expression antigenic  capacity Expression Integration: Donor  RNA  seq donor-­‐recipient   specific Recipient  RNA  seq Recipient  antibodyome (biopsy) (blood) antibody  responses at  time  of  transplantation Donor  at  time  of  transplantation Recipient   by  protein  arrays DNA mRNA DNA mRNA Donor-­‐recipient  sSequence pecific Sequence Expression Expression antigenic  capacity Integration: Donor  RNA  seq Recipient  ecipient   specific donor-­‐r RNA  seq (biopsy) (blood) Recipient  antibodyome antibody  responses by  protein  arrays Patient D Expression Donor  at  time  of  transplantation Donor  at  time  of  transplantation DNA mRNA DNA mRNA Sequence Expression Sequence Donor  RNA  seqExpression Outcome 2 Recipient  at  time  of  transplantation Recipient  at  time  of  transplantation DNA mRNA DNA mRNA Sequence Expression Validation set Sequence Outcome 2 Patient E Donor  at  time  of  transplantation Donor  at  time  of  transplantation DNA mRNA DNA mRNA Sequence Expression Sequence Group 1 Recipient  RNA  seq (blood) Donor  at  time  of  transplantation Recipient  at  time  of  transplantation Donor  RNA  seq (biopsy) Expression Recipient  at  time  of  transplantation Recipient  at  time  of  transplantation DNA mRNA DNA mRNA Sequence Expression Group 2 Donor-­‐recipient  specific antigenic  capacity Recipient  antibodyome by  protein  arrays Donor-­‐recipient  specific antigenic  capacity Outcome 1 SequenceRecipient  RNA  seq Expression (biopsy) (blood) Donor  RNA  seq Recipient  RNA  seq Donor  at  time  of  transplantation Recipient  at  time  of  transplantation (biopsy) (blood) Donor  at  time  of  transplantation Recipient  at  time  of  transplantation DNA mRNA DNA mRNA Donor-­‐recipient  specific mRNA DNA DNA mRNA Sequence Sequence Expression antigenic  capacity Expression Donor-­‐recipient  specific Integration: Sequence Expression Donor  RNA  seq Sequence Recipient  RNA  seq antigenic  capacity Expressionrecipient   specific donor-­‐ Integration: (biopsy) (blood) Donor  RNA  seq Recipient  antibodyome Recipient  ecipient   specific antibody  r seq donor-­‐r RNA  esponses at  time  of  transplantation Donor  at  time  of  transplantation(blood) Recipient   (biopsy) by  at  time  of  transplantation protein  arrays Recipient  antibodyome antibody  responses at  time  of  transplantation Donor   Recipient   by   DNA protein  arrays mRNA DNA mRNA Donor-­‐recipient  specific mRNA DNA DNA mRNA Sequence Sequence Expression antigenic  capacity Expression Donor-­‐recipient  specific Expression Integration: Sequence Sequence Expression Donor  RNA   Recipient  RNA  seq antigenic  capacityseq donor-­‐recipient   s Donor  at  time  of  transplantation Integration:pecific at  time  of  transplantation Recipient   Recipient  antibodyome (biopsy) (blood) antibody  responses at  time  o RNA  seq Donor  R ransplantation recipient   specific Recipient  f  transplantation Donor  at  time  of  tNA  seq Recipient   donor-­‐ by   Recipient  antibodyome mRNA (biopsy) (blood) antibody  responses DNA protein  arrays DNA mRNA DNA protein  arrays mRNA DNA mRNA by   Sequence Expression Sequence Expression Donor-­‐recipient  sSequence pecific Sequence Expression Expression antigenic  capacity Donor-­‐recipient  specific Integration: Donor  RNA  seq Recipient  ecipient   specific antigenic  capacity donor-­‐r RNA  seq Integration: Donor  RNA  seq Recipient  antibodyome Recipient  RNA  seq (biopsy) (blood) antibody  responses donor-­‐recipient   specific (biopsy) (blood) by  protein  arrays Recipient  antibodyome antibody  responses by  protein  arrays Donor-­‐recipient  specific Donor  RNA  seq Donor-­‐recipient  specific Recipient  RNA  seq antigenic  capacity Integration: Donor  RNA  seq Recipient  RNA  seq antigenic  capacity (biopsy) (blood) Integration: donor-­‐recipient   specific (biopsy) (blood) donor-­‐recipient   specific Recipient  antibodyome antibody  responses Recipient  antibodyome antibody  responses by  protein  arrays by  protein  arrays Heterogenous cohort Outcome 2 Recipient  antibodyome by  protein  arrays Integration: Recipient  RNA  seq donor-­‐recipient   specific (blood) antibody  responses Comparison = Biomarker for outcome? Integration: donor-­‐recipient   specific antibody  responses Comparison = validation of biomarker - retrospectively - prospectively
  • 58. Evidence based biomarkers ‘Marker  enrichment’  clinical  trial  design   ‘Planned  analysis’  clinical  trial  design   Coyle  and  Johnston  Nat  Rev  Clin  Oncol  2010  
  • 59. Thank you

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