*Purpose: Unsuspected subclinical acute rejection (subAR) is currently only detectable in 15-25% of invasive surveillance biopsies (SB) and can lead to chronic rejection and poor graft function. TruGraf v1, a CLIA-approved microarray-based blood gene expression minimally-invasive laboratory developed test provides accurate information on potential association with a normal surveillance biopsy (TX) reflecting immune quiescence and adequacy of (IS) in kidney transplant recipients (KTR). A negative test connotes a high probability of a ‘TX’ phenotype, whereas a positive test (non-TX) suggests a possibility of immune activation associated with rejection on a SB. We have recently discovered and validated a new gene expression classifier test (TruGraf v2) that correlates with subAR vs no subAR (TX) in KTR with stable renal function (sKTR). Here, we compare the performance of TruGraf v1 and v2 classifiers vs histology in SB in sKTR at 9 clinical sites.

*Methods: 166 blood samples paired with SB (TX=37; non-TX/subAR=129) were collected in PAXgene tubes and run on Affymetrix HG‐U133+PM Array plates. Gene expression data were analyzed using locked thresholds for each classifier.

*Results: Overall accuracy: 68%, 74%; sensitivity: 57%, 32%; specificity: 71%, 86%; PPV 39%, 43%; NPV 84%, 74% for TruGraf v1 vs v2. Both classifiers called 82 results correctly and 18 results incorrectly. Importantly, TruGraf v2 called 41 phenotypes correctly that were miscalled by TruGraf v1, whereas TruGraf v1 called only 25 phenotypes correctly that were miscalled by TruGraf v2. A McNemar’s test for two outcome variables from a single population had a p-value 0.06, showing the difference in proportions of correct/incorrect calls by the two test versions, with v2 being more accurate.

*Conclusions: A multi-center validation of TruGraf v2 from 9 clinical sites shows similar performance compared with our initial validation cohort. In addition, when compared to an earlier classifier (v1), TruGraf v2 demonstrates better specificity and accuracy compared to v1. This could be attributed to a rigorous discovery and validation based on a cohort consisting exclusively of patients with biopsy-confirmed subAR. TruGraf v2, optimized for ruling out subAR is an improved version of the original v1, providing the ability to use a minimally-invasive blood test as an alternative approach to routinely scheduled SB in sKTR.

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