Addressing The Unmet Need For Precision Diagnosis: Potential Impact of Molecular Assessments On Conventional Biopsy Diagnostics in 41% of 700 Indication Biopsies.

When transplants develop problems, treatment depends critically on accurate assessment of antibody-mediated and T cell-mediated rejection (ABMR, TCMR). But conventional assessments have problems, including the poor reproducibility of pathologist opinions e.g. 50% sensitivity for TCMR diagnoses in rejecting biopsies, and variability in DSA measurement. The addition of objective molecular measurements could add precision and guide therapy. We compared conventional and molecular assessments in 700 indication biopsies, prospectively collected 3 days to 31 years post transplant between 2004-13, including 291 from INTERCOM, 242 from Genome Canada, 81 from Hopital St Louis, Paris, and 86 new biopsies from INTERCOM centers. All were diagnosed conventionally and by the Molecular Microscope (MM) system using new Affymetrix U219 microarrays. The U219 classifiers were built using Genome Canada and INTERCOM samples with published methods. MM diagnoses strongly correlated with conventional diagnoses (table 1) but offered many new insights.Table: No Caption available.In 104 conventional ABMR, MM found 58 ABMR, 5 TCMR, 6 mixed, and 35 with no rejection (accuracy 82%). In 25 called TG but not ABMR, MM found 9 ABMR and 1 TCMR. In 77 conventional TCMR, MM found 37 TCMR, 8 mixed, 6 ABMR, and 9 with no rejection (accuracy 84%). In 32 with conventional mixed, MM found 24 (75%) were not mixed. MM assigned categories to 104 biopsies where conventional assessment was explicitly indeterminate, including 35 called suspicious for ABMR and all 79 Borderline. Moreover, in 20 with BK, MM found TCMR in 11. In 306 conventionally assessed as no rejection or BK, the MM found 26 ABMR, 12 TCMR, and 2 mixed. Thus in 285 (41%) of 700 biopsies, the addition of MM scores for ABMR and TCMR had potential to change management e.g. finding TCMR in BK cases, making diagnoses in “borderline” and “suspicious” cases, and suggesting that most “mixed” is not mixed. Thus molecular diagnosis, while not necessarily always correct, adds a new dimension to the understanding of troubled transplants in critical situations, addressing a major unmet need. DISCLOSURE:Halloran, P.: Other, Astellas, Lecturing, One Lambda, Lecturing, Novartis, Lecturing.

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