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The Cancer Genetics 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 acording 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 Cancer Genetics 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 Cancer Genetics 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 modified and the predicate devices (K092967 and K120489) are all in vitro diagnostic product consisting of a reagent kit and instructions, plus a microchip and software, for the comparison of the RNA expression pattern of a patient's tumor sample to a database of expression patterns of 15 known tumor tissues. Equipment required but not provided are an Affymetrix GeneChip Fluidics Station FS450Dx v2 and an Affymetrix GeneChip Scanner GCS3000Dx, attached to an Affymetrix Workstation with GeneChip Operating System (GCOS). Additional equipment required but not provided is commonly available laboratory equipment.

Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text.

It's important to note that this document is a 510(k) summary, which often focuses on demonstrating substantial equivalence to an existing device rather than presenting a full, de novo validation study. Therefore, some of the requested information, particularly regarding initial clinical validation or ground truth establishment for the original device, might not be explicitly detailed. The acceptance criteria described here pertain to demonstrating performance after modifications to an already cleared device.

Acceptance Criteria and Device Performance for Modified Tissue of Origin Test Kit-FFPE

The acceptance criteria here refer to the demonstration that two specific modifications (reagent change and software update) to an already cleared device (Pathwork Tissue of Origin Test Kit FFPE, K120489) did not negatively impact its performance. The primary metric used is concordance with the previous, validated method.

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample Size Used for the Test Set and Data Provenance

• Test Set Sample Size:
  • Reagent Comparison: 142 specimens
  • Software Comparison: 20 specimens
• Data Provenance: The specimens were "randomly selected from FFPE tumor specimens employed for assessment of performance during development of the original TOO-FFPE kit." This indicates the data is retrospective, using archived samples. The country of origin is not specified, but the context of an FDA submission implies commercial use in the US, suggesting data likely from US/North American sources, though not explicitly stated.

3. Number of Experts Used to Establish Ground Truth for the Test Set and Their Qualifications

• This information is not provided in the document. The studies assess concordance between the modified and original methods, implying the "truth" is established by the original method's result for the sample. The original device's clearance (K092967, K120489) would have involved establishing its ground truth based on clinical and pathological practice, but the details are not replicated here for this 510(k) summary focused on modifications.

4. Adjudication Method for the Test Set

• This information is not applicable in the context of these specific studies. The studies are comparing the output of a modified process against the output of the original, previously cleared process for the same samples. Discrepancies are noted as "discordance" rather than requiring expert adjudication of a "ground truth" difference, as the reference is the prior method's output.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size

• No, an MRMC comparative effectiveness study was not conducted. This device is an in vitro diagnostic (IVD) test measuring molecular expression patterns, not an imaging AI designed to assist human readers. The outputs are numerical similarities to pre-defined tumor types, not interpretations for human review.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

• Yes, the performance described is standalone (algorithm only). The device, the "Tissue of Origin Test Kit-FFPE," measures RNA expression patterns and provides a similarity score. The studies assess the consistency of these scores between modified and original methods, which is a direct output of the algorithm and associated lab processes without human interpretation as part of the core performance evaluation.

7. The Type of Ground Truth Used

• For the purpose of these modification studies, the "ground truth" for each sample's classification is implicitly the result obtained from the original, previously cleared and validated method. The studies aim to show that the new modifications yield the same result as the established method. The ultimate ground truth for the original validation of the TOO-FFPE test, as stated in its Indications for Use, was based on "diagnosed according to then current clinical and pathological practice" for the 15 tumor types in its database. This would typically involve expert consensus diagnostics (e.g., pathology reports, clinical history).

8. The Sample Size for the Training Set

• The sample size for the training set is not specified in this document. This 510(k) summary pertains to modifications of an already developed and trained device. The original development and validation of the "Tissue of Origin Test Kit-FFPE" (K092967 / K120489) would have involved a training set, but its details are not part of this summary for a modified device. The document mentions the "database of fifteen tumor types" against which patient samples are compared, which serves as the trained model/reference.

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

• How the ground truth for the original training set was established is not detailed in this document.
  • However, the Indications for Use states that the database samples were "diagnosed according to then current clinical and pathological practice." This typically means that the ground truth for the 15 tumor types in the database was established by expert consensus diagnoses based on a combination of clinical history, pathological findings (histology, immunohistochemistry), and potentially other diagnostic tests. This implies a rigorous, multi-modal diagnostic approach by qualified medical professionals (e.g., pathologists, oncologists).

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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 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 (Origin Test Kit-FFPE) is a test kit consisting of the Pathchip microarray, reagents, software, Pathwork Specimen Processing Guide and Guide to Report Interpretation (GRI). The Pathchip is a custom-designed microarray that functions in a manner similar to GeneChip HG-U133A. The Pathchip has over 500,000 unique oligonucleotide features covering over 18,400 transcript variants (across 22,300 probesets) which in turn represent 14,500 of the best characterized human genes. For each array, there are 2000 probesets representing 2000 human genes which are used by the 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. The algorithm of the Origin Test Kit-FFPE 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 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 reading SE values, computing a decision function for pairwise tissue pairings, converting pairwise scores to probabilities, and reducing pairwise probabilities to 15 Similarity Scores. The Pathwork Specimen Processing Guide (SPG) contains instructions for processing tissue specimens. The specimen used is a formalin-fixed, paraffin-embedded (FFPE) specimen containing at least 60% viable tumor. Total RNA is isolated and processed through a two-cycle RNA amplification, hybridization to the Pathchip microarray, washing and scanning, data acquisition, data verification, standardization of signal intensities, determination of similarity to 15 tissues of origin, and generation of a Report. The CEL file from each laboratory is transported to Pathwork Diagnostics for analysis using the Pathwork System Software (PSS). The PSS converts the CEL file to gene expression measurements, performs data verification, normalizes the data, performs statistical tests, and produces a report summarizing the 15 Similarity Scores. The report quantifies the similarity of the RNA expression pattern in a tumor specimen to expression patterns found in tumor specimens from 15 known tissues of origin and is provided back to the laboratory over a secure internet connection in pdf format. Clinical laboratory customers use the report for incorporation into the surgical pathology report delivered to the requesting physician. The report presents the 15 computed Similarity Scores in a graphical format. The ordering physician interprets the report using the Guide to Report Interpretation (GRI).

Acceptance Criteria and Study Details for Pathwork® Tissue of Origin Test Kit-FFPE

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document explicitly states "Each laboratory was expected to achieve the overall acceptance criteria of at least 80% agreement with the available diagnosis, with no more than 20% non-agreement." This was met by all three labs in the reproducibility study (Table 6.4) and the overall clinical validation (Table 6.5). Other criteria are inferred from the reported performance, implying they met the implicit expectations for a successful validation.

2. Sample Size Used for the Test Set and Data Provenance

• Sample Size: 462 specimens (from an initial 598 tumor specimens processed) met the labeling limitations for tumor grade and available diagnosis and passed data verification quality tests.
• Data Provenance: The document does not explicitly state the country of origin. However, the study involved "three different processing laboratories," implying a multi-site clinical validation. The data is retrospective, as it utilizes existing formalin-fixed, paraffin-embedded (FFPE) tumor specimens with previously established "available diagnoses."

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

• The document refers to "available diagnosis established for each specimen" as the ground truth. It is stated that these diagnoses were made "according to then current clinical and pathological practice."
• Number of Experts: Not specified.
• Qualifications of Experts: Not specified beyond the implication of being experts in "clinical and pathological practice."

4. Adjudication Method for the Test Set

• The document does not describe a formal adjudication method for establishing the ground truth (available diagnosis). It states the device results were "compared to available diagnosis established for each specimen." This suggests that the existing clinical and pathological diagnoses were accepted as the ground truth without further expert review or adjudication for the study.

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

• No, an MRMC comparative effectiveness study was not explicitly described. The study focused on the standalone performance of the device against established diagnoses. While the device is intended for interpretation by a qualified physician, the study does not compare human reader performance with and without AI assistance to determine an effect size.

6. Standalone Performance Study

• Yes, a standalone performance study was done. The entire clinical validation described in Section 807.92 (b)(2) is a standalone study, evaluating the algorithm's performance (Pathwork® Tissue of Origin Test Kit-FFPE) in identifying the tissue of origin by comparing its results directly against the "available diagnosis" for each specimen.

7. Type of Ground Truth Used

• Expert Consensus / Pathology / Outcomes Data: The ground truth used was the "available diagnosis established for each specimen," which was based on "current clinical and pathological practice." This strongly implies a combination of morphological pathology (histopathology) and clinical assessment, likely representing an expert consensus or standard clinical diagnosis process. It is not outcomes data.

8. Sample Size for the Training Set

• The algorithm was developed using a database of 2196 specimens, which was "divided into independent training and test datasets." The exact split between training and the developmental test set (different from the clinical validation test set mentioned above) is not precisely specified for the training set alone, but the 2196 specimens were used for algorithm development.

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

• The ground truth for the specimens within the 2196-specimen database used for algorithm development was "diagnosed according to then current clinical and pathological practice." This is consistent with the method for the clinical validation test set, implying clinical and pathological diagnoses.

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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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