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The Pathwork® Tissue of Origin Test is an in vitro diagnostic intended to measure the degree of similarity between the RNA expression patterns in a patient's formalin-fixed, paraffin-embedded (FFPE) tumor and the RNA expression patterns in a database of fifteen tumor types (poorly differentiated, undifferentiated and metastatic cases) that were diagnosed according to then current clinical and pathological practice. This test should be evaluated by a qualified physician in the context of the patient's clinical history and other diagnostic test results.

Limitations: The Pathwork Tissue of Origin Test is not intended to establish the origin of tumors (e.g. cancer of unknown primary) that cannot be diagnosed according to current clinical and pathological practice. It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathological practice, nor to predict disease course or survival or treatment efficacy, nor to distinguish primary from metastatic tumor. Tumor types not in the Pathwork Tissue of Origin Test database may have RNA expression patterns that are similar to patterns in the database; therefore, results cannot be used to distinguish tumor types in the database from tumor types not in the database.

The Pathwork® Tissue of Origin Test Kit-FFPE is a test kit consisting of the Pathchip microarray, reagents, software, and labeling. The Pathchip is a custom-designed microarray manufactured by Affymetrix, Inc. (Santa Clara, CA) per Pathwork design requirements and functions in a manner similar to GeneChip HG-U133A. The Pathchip has over 500,000 unique oligonucleotide features (18-micron in size), covering over 18,400 transcript variants (across 22.300 probesets) which in turn represent 14,500 of the best characterized human genes. Each transcript is represented by a probeset, comprised of 11-16 pairs of oligonucleotide probes. The probesets are spatially distributed over the arrav and are used to measure the level of transcription of each sequence represented on the array. For each array, there are 2000 probesets representing 2000 human genes which are used by the Tissue of Origin Test Kit - FFPE algorithm as markers to identify the tissue of origin of the specimen being tested. These probesets were selected using machine learning methods and each set has between 11 and 16 probe pairs of 25 bases whose sequences are matched to mRNA species that are found in human tissue. In addition, the array has 29 probesets that are used for normalization and data verification.

The algorithm of the Pathwork® Tissue of Origin Test was developed using a database of 2196 specimens, divided into independent training and test datasets. The test development used a machine learning approach based on marker selection to build a predictive model. The model consists of a list of markers, a set of reference (support) samples and a set of coefficients. These components are combined to produce 15 Similarity Scores, one for each of the possible tissues on the test panel. Each similarity score ranges from 0 to 100, with a higher score being associated with a higher likelihood that the input specimen has a molecular signature of the corresponding tissue of origin. The 15 similarity scores are scaled to sum up to 100. Each is based on the microarray standardized expression (SE) values of selected biomarkers. The process consists of the following steps:

• Read SE values for the biomarkers used in the Tissue of Origin Test from 1. the input file.
• Compute a decision function ("score") for each of 105 possible pairings of 2. the 15 tissues on the test panel with respect to the sample described by the input SE values.
• Convert the 105 pairwise scores into pairwise probabilities. 3.
• Reduce the 105 pairwise probabilities to 15 Similarity Scores, one for each 4. Tissue of Origin. These are the final 15 Similarity Scores presented in the Tissue of Origin Test Report.

Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:

Acceptance Criteria and Device Performance

Study Details

1. Sample Size and Data Provenance:

   • Test Set Sample Size: 43 tumor specimens were actually analyzed for comparison. The study aimed for 45 tumors (3 of each of the 15 tumor types).
   • Data Provenance: The specimens were "reserves of FFPE tumor specimens employed for assessment of performance during development of the TOO-FFPE Test." These pre-existing specimens had prior results obtained using the 510(k) cleared method. The text does not specify the country of origin, but the company is based in Redwood City, CA, USA. The data is retrospective, as it used pre-existing specimens with "extant results."

2. Number of Experts and Qualifications for Ground Truth:

   • The primary ground truth for this modification study was the result obtained from the original 510(k) cleared method using ≥150 ng of RNA without ethanol. The text states these original results "all agreed with their available diagnosis."
   • The ground truth for the original validation of the device (K092967) was established by "then current clinical and pathological practice." The text does not specify the number or qualifications of experts involved in establishing these diagnoses for the original specimens.

3. Adjudication Method for Test Set: Not applicable. The study was a comparison of results from two different processing methods on the same specimens against a pre-established "available diagnosis." There wasn't an expert adjudication process described for new interpretations in this specific modification study.

4. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study: No. This study focused on the technical performance equivalence of a modified RNA extraction and purification protocol, not on human reader performance with or without AI assistance.

5. Standalone Performance (Algorithm Only without Human-in-the-loop): Yes, the study evaluated the performance of the algorithm with different input RNA quantities and processing steps. The output (Similarity Scores) is generated by the algorithm and then compared. While the ultimate intended use involves a physician's interpretation, this particular study focused on the analytical performance of the modified test.

6. Type of Ground Truth Used:

   • For the modification study, the ground truth was the result obtained from the original 510(k) cleared method for the same specimen, which "agreed with their available diagnosis."
   • For the original establishment of the device's accuracy (referenced as the predicate device), the ground truth was established by "available diagnosis" or "current clinical and pathological practice."

7. Sample Size for Training Set: The algorithm for the Pathwork® Tissue of Origin Test was developed using a database of 2196 specimens, divided into independent training and test datasets. The exact split between training and test sets from this 2196 is not provided, but the sample size for the overall algorithm development is stated.

8. How Ground Truth for Training Set was Established: The ground truth for the training set (part of the 2196 specimens) was established based on diagnoses "according to then current clinical and pathological practice."

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The Pathwork® Tissue of Origin Test is intended to measure the degree of similarity between the RNA expression pattern in a patient's fresh-frozen tumor and the RNA expression patterns in a database of tumor samples (poorly differentiated, undifferentiated and metastatic cases) that were diagnosed according to then current clinical and pathological practice. The database contains examples of RNA expression patterns for fifteen common malignant tumor types: bladder, breast, colorectal, gastric, hepatocellular, kidney, non-small cell lung, ovarian, pancreatic, prostate, and thyroid carcinomas, melanoma, testicular germ cell tumor, non-Hodgkins lymphoma (not otherwise specified), and soft tissue sarcoma (not otherwise specified). The Pathwork® Tissue of Origin Test result is intended for use in the context of the patient's clinical history and other diagnostic tests evaluated by a qualified clinician.

Limitations: The Pathwork Tissue of Origin Test is not intended to establish the origin of tumors that cannot be diagnosed according to current clinical and pathological practice. (e.g. carcinoma of unknown primary). It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathological practice, nor to predict disease course or survival or treatment efficacy, nor to distinguish primary from metastatic tumor. Tumor types not in the Pathwork Tissue of Origin Test database may have RNA expression patterns that are similar to RNA expression patterns in tumor types in the database, leading to indeterminate results or misclassifications,

The Pathwork® Tissue of Origin Test is a microarray and analytics "kit" that quantifies the similarity of tumor specimens to 15 cancer types representing 60 morphologies. Frozen biopsy specimens are processed by the clinical laboratory as described in the User Guide. In brief, mRNA is extracted, amplified, labeled and hybridized to the Pathchip® microarray, which is then scanned using one of the instrument systems validated for use with this test. The resulting data file is transmitted via secure internet transfer protocol to the Pathwork® System Software for data quality control and analysis. Test results are available for clinical interpretation via a secure password protected website.

Components included in the kit:
Microarray: Pathchip microarrays, packaged in boxes of 5 or 10.
Tissue of Origin Test Report produced by the Pathwork System Software (by licensed agreement): The Pathwork® System Software receives data from the scanned Pathchip™ microarray and performs data quality control and analysis. The System Software then generates a Pathwork® Tissue of Origin Test Report which provides a Similarity Score for each of the 15 tissues on the test panel. The test report is accessible for clinical interpretation via a secure password protected website.
Tissue of Origin Test Reagents: Reagents for specimen processing and RNA extraction.

Here's a breakdown of the acceptance criteria and study details for the Pathwork® Tissue of Origin Test, based on the provided document:

Acceptance Criteria and Reported Device Performance

Study Information

1. Sample size used for the test set and the data provenance:

   • Sample Size: 545 frozen specimens.
   • Data Provenance: Not explicitly stated, but the study was performed at "four laboratory sites," implying multi-center data collection. It is likely retrospective as the samples were "diagnosed according to then current clinical and pathological practice" and stored as "frozen specimens."

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • Number of Experts: Not specified.
   • Qualifications: Ground truth was established by "the available diagnosis" based on "current clinical and pathological practice." This suggests diagnosis by qualified pathologists and clinicians, but specific numbers and their years of experience are not detailed.

3. Adjudication method for the test set:

   • Not explicitly stated. The document refers to "the available diagnosis," indicating that the clinical diagnoses were used as the reference standard without mentioning an adjudication process for discrepancies in the test set.

4. 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:

   • No MRMC comparative effectiveness study was done or reported in this document. The study focuses purely on the device's standalone performance against a diagnostic ground truth.

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

   • Yes, a standalone study was performed. The reported accuracy (positive and negative percent agreement) refers to the performance of the Pathwork® Tissue of Origin Test itself in identifying the tissue of origin. The device generates "Similarity Scores" and a "Test Report" for clinical interpretation, but the performance metrics provided are for the algorithm's output.

6. The type of ground truth used:

   • Clinical and Pathological Diagnosis: The ground truth for the test set was established based on "the available diagnosis" from "current clinical and pathological practice." This refers to established clinical and histopathological diagnoses for the tumor samples.

7. The sample size for the training set:

   • The document states that the test "quantifies the similarity of tumor specimens to 15 cancer types representing 60 morphologies" against "RNA expression patterns in a database of tumor samples." However, it does not explicitly state the sample size of this database used for training the algorithm. It only mentions the database contains examples of RNA expression patterns.

8. How the ground truth for the training set was established:

   • The ground truth for the samples in the database (which would have been used for training) was established by samples "diagnosed according to then current clinical and pathological practice." This implies standard clinical and pathological evaluations of the source tumor samples in the database.

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