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AlloMap Heart Molecular Expression Testing is an In Vitro Diagnostic Multivariate Index assay (IVDMIA) test service, performed in a single laboratory, assessing the gene expression profile of RNA isolated from peripheral blood mononuclear cells (PBMC). AlloMap Heart Testing is intended to aid in the identification of heart transplant recipients with stable allograft function who have a low probability of moderate/severe acute cellular rejection (ACR) at the of testing in conjunction with standard clinical assessment.

Indicated for use in heart transplant recipients:

· 15 years of age or older

· At least 2 months (>55 days) post-transplant

AlloMap Heart Molecular Expression Testing is an In Vitro Diagnostic Multivariate Index Assay (IVDMIA) test service performed in a single laboratory, assessing the gene expression profile of RNA isolated from peripheral blood mononuclear cells (PBMC). AlloMap Heart Testing is a non-invasive blood test that uses genomic technologies to identify the absence of cardiac rejection. When used in conjunction with standard clinical assessments, AlloMap Heart Testing may help identify patients with stable allograft function who have a low probability of moderate to severe acute cellular rejection (ACR) at the time of Testing.

AlloMap is a panel of 20 gene assays, 11 informative and 9 used for normalization and quality control, which produces gene expression data used to calculate a reported AlloMap test score - an integer ranging from 0 to 40. The Score is an algorithmic composite of the expression of 11 differentially weighted informative genes that have a role in rejection and reflect host immune response, representing multiple diverse molecular pathways. The clinician uses the AlloMap Score and other standard clinical assessments to evaluate the patient's probability of rejection and the need for additional diagnostic evaluations. Compared with patients in the same post-transplant period, the lower the Score, the lower the probability of acute cellular rejection at the time of Testing. AlloMap Heart Testing is only performed at the CLIA-certified and CAP-accredited clinical laboratory at CareDx in Brisbane, California.

The provided text describes the acceptance criteria and the study results for the AlloMap Heart Molecular Expression Testing, specifically focusing on the performance of the Roche LightCycler 480 II (LC480) instrument compared to the predicate ABI 7900HT instrument.

Here's a breakdown of the requested information:

1. A table of acceptance criteria and the reported device performance

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Between Instrument Variability: Not explicitly stated, but implies multiple samples across low, medium, and high score ranges.
• Reproducibility:
  • Low Sample Pool: 88 samples
  • Medium Sample Pool: 90 samples
  • High Sample Pool: 90 samples
  • Total: 268 samples
• Linearity: Six different amounts of the same patient RNA sample.
• Method Comparison - Accuracy (Passing-Bablok and ATD Zones): 163 patient RNA samples.
• Method Comparison - Clinical Equivalence (Projected NPV/PPV): Based on the "300 samples in the original clinical validation study from the predicate device, K073482." No specific country of origin is mentioned, but the testing was done at CareDx in Brisbane, CA, USA, implying the samples were processed there. The samples were "previously tested heart transplant patient samples with clinical relevance to AlloMap score... after deidentification," suggesting a retrospective origin.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

The document does not describe the use of experts to establish a "ground truth" in the traditional sense of diagnostic interpretation. This is an analytical performance study comparing two instruements, where the ground truth is essentially the quantitative measurement produced by the predicate device (ABI 7900HT) and the clinical relevance (NPV/PPV) established in its original clinical validation. The "ground truth" for the patient samples' AlloMap scores were their scores obtained from the 7900HT.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

Not applicable. This was an analytical comparison study of test instrumentation, not a diagnostic interpretation study requiring expert adjudication of cases.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This is not an AI-assisted diagnostic device or a MRMC study. It is an analytical validation of an in vitro diagnostic (IVD) assay instrument change.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, in a sense. The study primarily evaluated the standalone performance of the new instrument (LC480) and its adapted software (SAX v1.2) against the predicate instrument (ABI 7900HT) to ensure equivalent analytical and clinical equivalency of the AlloMap score calculation. The AlloMap test itself is an algorithm-based test ("Multivariate Index Assay") performed in a lab environment. The "standalone" evaluation here refers to the instrument's ability to produce equivalent scores.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The primary ground truth for the analytical performance studies was the AlloMap scores generated by the predicate ABI 7900HT instrument. For the clinical equivalence projection (NPV/PPV), it refers back to the clinical outcomes data that supported the original clearance of the predicate device (K073482).

8. The sample size for the training set

The document does not explicitly describe a "training set" for the current submission, as it focuses on the analytical and clinical equivalency verification of an instrument change. The "Software Analyzer, SAX v1.2" was modified to support the LC480, and it applied "two gene-level correction factors" to map LC480 response to 7900HT response. The data used to derive these correction factors (which could be considered analogous to a training step for the software adaptation) is not specified in terms of sample size or methodology. However, the original AlloMap algorithm itself was likely developed and "trained" on a much larger dataset during its initial development and clearance (DEN080007 / K073482), but that information is not part of this specific submission's details.

9. How the ground truth for the training set was established

As mentioned above, the current submission focuses on instrument equivalency. For the underlying AlloMap algorithm, the ground truth for its initial development would have involved patient outcomes related to acute cellular rejection (ACR), likely correlated with biopsy results (pathology) which is the gold standard for ACR diagnosis, and potentially other clinical assessments in heart transplant recipients. This background is implied by the "Indications for Use" and the nature of the "Cardiac Allograft Gene Expression Profiling Test System." However, the specifics for the original training set's ground truth establishment are not provided in this document.

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AlloMap Molecular Expression Testing is an In Vitro Diagnostic Multivariate Index assay (IVDMIA) test service, performed in a single laboratory, assessing the gene expression profile of RNA isolated from peripheral blood mononuclear cells (PBMC). AlloMap Testing is intended to aid in the identification of heart transplant recipients with stable allograft function who have a low probability of moderate/severe acute cellular rejection (ACR) at the time of testing in conjunction with standard clinical assessment.

Indicated for use in heart transplant recipients:

• l 15 years of age or older
• I At least 2 months (>55 days) post-transplant

AlloMap Molecular Expression Testing is performed in a single laboratory (XDx Laboratories). Blood is drawn from the patient and subsequently processed, packaged and shipped frozen to the XDx Laboratory. At the XDx Laboratory, gene expression levels are determined via real time PCR for each of the test and control genes and converted to the AlloMap Test Score. The AlloMap Test Score is then reported to the physician.

Here's a breakdown of the acceptance criteria and study information for the AlloMap® Molecular Expression Testing device, based on the provided document:

Description of Acceptance Criteria and the Study that Proves the Device Meets the Acceptance Criteria

The AlloMap® Molecular Expression Testing is an In Vitro Diagnostic Multivariate Index assay (IVDMIA) intended to aid in identifying heart transplant recipients with stable allograft function who have a low probability of moderate/severe acute cellular rejection (ACR). The device performance was evaluated through analytical and clinical studies.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied through the presented experimental findings and the successful classification as a Class II device. The precision/reproducibility and various analytical specificity studies demonstrate the robustness and reliability of the assay. The clinical study established the predictive values for the assay.

2. Sample Size for the Test Set and Data Provenance

• Precision Study (Analytical Performance):

  • Healthy Donor Samples: Four healthy donor samples (D1-D4) evaluated in Arm A (RNA->cDNA->Assay). One healthy donor sample evaluated in Arm C (reagent lot-to-lot, plate-to-plate, section-to-section).
  • Patient Samples: Six individual cardiac transplant recipients (P1-P6 from two CARGO centers: 3 per center). Three samples per patient from one center, and four samples per patient from the second center. One pooled patient sample evaluated in Arm C.
  • Data Provenance: Not explicitly stated for healthy donors, but patient samples are from "CARGO centers," implying data from the Cardiac Allograft Rejection Gene Expression Observational (CARGO) study. The study appears to be prospective in nature for data collection used in precision.

• Analytical Specificity (Interference Studies):

  • Immunosuppression Therapy: 700 CARGO samples (from the XDx Population study).
  • CMV Interference: 61 samples from CARGO (11 CMV+, 50 CMV-).
  • Other Compound Interference: 5 donors for acetaminophen, acetylsalicylic acid, bilirubin, triglycerides; 1 donor for hemoglobin; CPT tubes from volunteer XDx donors and same donors for citrate controls for heparin.
  • Genomic DNA Interference: Not explicitly specified, but appears to be conducted on samples where gDNA was manipulated.
  • Data Provenance: Primarily from the CARGO study (retrospective use of collected samples for specificity analysis) and internal XDx donor/volunteer samples.

• Clinical Study (Clinical Validation):

  • Sample Size: 300 samples from 154 patients.
  • Data Provenance: Derived from the prospective, observational multi-center Cardiac Allograft Rejection Gene Expression Observational (CARGO) study. These samples were explicitly "not used to develop the AlloMap Test algorithm."

3. Number of Experts and Qualifications for Ground Truth (Clinical Test Set)

• Number of Experts: Three panel pathologists.
• Qualifications of Experts: Not specified beyond "panel pathologists." They were responsible for grading local biopsies and confirming rejection diagnoses.

4. Adjudication Method (Clinical Test Set)

• The definition for rejection was "a local biopsy grade ≥3A that was also assigned grade ≥3A by at least one of the three panel pathologists ("confirmed rejection")."
• The "no rejection class" included all samples that did not qualify as rejection.
• This suggests a form of majority or consensus-based adjudication, specifically "local ≥3A confirmed by at least one of three central pathologists."

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• No, a MRMC comparative effectiveness study involving human readers and AI assistance was not explicitly described in this document. The AlloMap test is presented as a standalone diagnostic aid, not an AI-assisted interpretation tool for human readers.

6. Standalone (Algorithm Only) Performance

• Yes, a standalone performance evaluation was the primary focus of the clinical validation. The "AlloMap Test" (algorithm) generated a score, and its performance (AUC, PPV, NPV) was assessed against the biopsy-confirmed ground truth, without human expert-in-the-loop directly interpreting AlloMap scores to classify cases for the study's primary clinical endpoints. Physicians interpret the final AlloMap score along with other clinical assessments, but the study evaluates the algorithm's performance itself.

7. Type of Ground Truth Used (Clinical Test Set)

• Expert Consensus Pathology: The ground truth for acute cellular rejection (ACR) was defined as a "local biopsy grade ≥3A that was also assigned grade ≥3A by at least one of the three panel pathologists ('confirmed rejection')." This relies on histopathological examination and a form of expert consensus.

8. Sample Size for the Training Set

• The document states that the 300 samples from 154 patients used in the clinical validation study were "not used to develop the AlloMap Test algorithm." This implies there was a separate training set, but the sample size for the training set is not provided in this document.

9. How the Ground Truth for the Training Set was Established

• Since the training set size and specific details are not provided, the method for establishing ground truth for the training set is not explicitly described in this document. However, given the nature of the device and the clinical validation methods, it can be inferred that the training set ground truth would also have been established based on similar histopathological assessments of biopsy samples for acute cellular rejection.

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