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The AneuVysion™ (CEP 18, X, Y-alpha satellite, LSI 13 and 21) Multicolor Probe Panel is intended to use CEP 18/X/Y probe to detect alpha satellite sequences in the centromere regions of chromosomes 18, X, and Y, and LSI 13/21 probe to detect the 13q14 region and the 21q22.13 to 21q22.2 region. The AneuVysion™ kit is indicated for use as an adjunct to standard cytogenetic metaphase analysis for identifying and enumerating chromosomes 13, 18, 21, X, and Y via fluorescence in situ hybridization (FISH) in metaphase cells and interphase nuclei obtained from amniotic fluid in subjects with presumed high risk pregnancies. It is not intended to be used as a stand alone assay for test reporting. FISH results are intended to be reported and interpreted only in conjunction with results of standard cytogenetic analysis, performed concurrently, utilizing the same patient specimen. FISH results should not be reported prior to standard cytogenetic results except in instances where reporting of FISH results alone is medically indicated or standard cytogenetic results are not available, e.g., culture failure. Reporting and interpretation of FISH should be consistent with professional standards of practice! This device is intended for use only with amniocyte cells; it is not intended for and has not been validated for use with other test matrices. This FISH assay will not detect the presence of structural chromosome abnormalities frequently associated with birth defects. This FISH assay will be performed in cytogenetics laboratories.

The AneuVysion™ kit is a combination of two DNA probe mixtures; CEP 18/X/Y and LSI 13/21. The CEP 18/X/Y probe is a mixture of directly labeled fluorescent DNA probes specific for the D18Z1, DXZ1 and DYZ3 regions of chromosomes 18, X, and Y respectively. The LSI 13/21 probe contains a mixture of unique DNA sequences that hybridize in the 13q14 region of chromosome 13, and unique DNA sequences complementary to the D21S259, D21S341, and D21S342 loci contained within the 21q22.13 to 21q22.2 region on the long arm of chromosome 21. The LSI 13 probe was created from a set of overlapping clones which contain the entire RB-1 gene as well as regions extending beyond the gene on both sides. The probe extends beyond the 180 kb RB-1 gene for 110-170 kb in the 5' direction and approximately 120 kb in the 3' direction; the entire probe is 410-470 kb. CEP 18/X/Y is an aqua, green, and orange tri-color probe mixture and LSI 13/21 is a green and orange dual-color probe mixture.

Table of Acceptance Criteria and Reported Device Performance

Study Details Proving Device Meets Acceptance Criteria:

The information provided describes several studies that collectively demonstrate the performance of the AneuVysion™ kit.

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

   • Analytical Specificity: 705 metaphase spreads.
   • Reproducibility (Pivotal Study): Not explicitly stated how many individual specimens, but 24 measurements were taken for each of the four specimen types (100% XY, 10% X/90% XX, 17% X/47% XX/36% XXX, 50% XY+21/50% XY). The specimens were "cultured human amniocyte specimens."
   • Methods Comparison / Clinical Specimens (Pivotal Multi-center Study):
     • Total Patients: 1516 patients.
     • Total Amniocyte Specimens: 2,238 specimens.
     • Aneuploid Cases: 861 cases.
     • Mosaic Cases: 62 cases.
     • Pseudomosaic Cases: 76 cases.
     • Euploid Cases: 504 cases.
     • Pairwise Comparison (Cultured vs. Uncultured): 722 patients.
   • Data Provenance: The studies were conducted at "Thirty one investigation sites" in a "multi-center, blinded, controlled, comparative study." The specimens were "human amniotic fluid specimens obtained from a total of 1516 patients." The origin seems to be implicitly from the countries where these investigation sites are located, likely including the USA given the FDA submission. The study is prospective in nature as it involved collecting and analyzing patient samples for the purpose of the study.

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

   • The ground truth for the clinical specimens was established by "standard cytogenetic analysis." While the document doesn't explicitly state the number of experts, cytogenetic analysis is a specialized field, and it's implied that qualified cytogeneticists performed this analysis at each of the "Thirty one investigation sites." The qualifications would inherently be those required to perform and interpret standard cytogenetic metaphase analysis.

3. Adjudication method for the test set:

   • The document states that the "results of interphase FISH analysis were compared to standard cytogenetics." Standard cytogenetic analysis served as the gold standard. There is no mention of a specific adjudication method (like 2+1 or 3+1 consensus) for discrepancies between FISH and cytogenetics; rather, standard cytogenetics was the reference.

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:

   • This is not an AI-based device. It is a DNA probe kit (FISH assay) for manual interpretation by human cytogeneticists. Therefore, an MRMC study comparing human readers with and without AI assistance is not applicable and was not performed.

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

   • No. The AneuVysion™ kit "is not intended to be used as a stand alone assay for test reporting." FISH results are "intended to be reported and interpreted only in conjunction with results of standard cytogenetic analysis, performed concurrently, utilizing the same patient specimen." The device is a diagnostic reagent, requiring human interpretation of the hybridization signals on cells.

6. The type of ground truth used:

   • The primary ground truth used for the clinical validation was standard cytogenetic analysis (karyotyping of metaphase spreads). This is widely considered the gold standard for detecting chromosomal abnormalities.

7. The sample size for the training set:

   • The document does not explicitly describe a separate "training set" for the AneuVysion™ kit. As this is a probe-based assay that relies on established biological principles of hybridization and is interpreted by human experts, there isn't a machine learning algorithm that requires a traditional training set. The various studies on hybridization efficiency, analytical sensitivity/specificity, and reproducibility likely served to establish and refine the assay's performance characteristics rather than "train" an algorithm.

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

   • See point 7. Since a traditional training set for an algorithm is not applicable, the concept of establishing ground truth for it is also not applicable in the context of this device. The performance characteristics were established via validation studies using reference methods (like G-banding for specificity and standard cytogenetics for clinical concordance).

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This assay is designed to provide a method for the detection and quantification of chromosome 8 in both interphase nuclei and metaphase spreads by fluorescence in situ hybridization (FISH).

The CEP 8 SpectrumOrange DNA Probe is a SpectrumOrange fluorescent labeled DNA probe specific for the centromeric region of chromosome 8.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Acceptance Criteria and Device Performance for CEP 8 SpectrumOrange DNA Probe Kit

1. Table of Acceptance Criteria and Reported Device Performance

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

• Analytical Sensitivity & Specificity:
  • Hybridization Efficiency: Pilot study had 35 bone marrow (BM) specimens. Pivotal study had 60 BM specimens.
  • Analytical Specificity: 62 metaphase spreads.
  • Data Provenance: Not explicitly stated (e.g., country of origin), assumed to be within the US given FDA submission. It's retrospective for analytical specificity (archived metaphase spreads).
• Reproducibility:
  • Pilot Study: One normal bone marrow specimen. N=24 observations/measurements.
  • Pivotal Study: One low-level (approximately 7%) trisomy 8 bone marrow specimen. N=24 observations/measurements.
  • Data Provenance: Not explicitly stated, likely multi-site within the US. Retrospective (single specimens used for repeated testing).
• Clinical Performance (Methods Comparison):
  • Test Set Size: 368 archived bone marrow specimens.
  • Data Provenance: Multi-center study involving four laboratories providing specimens (Site 1: 101, Site 2: 57, Site 3: 130, Site 4: 80, with Site 4 specimens analyzed at Site 3). The source of the specimens is described by the diseases: Acute myeloid leukemia (AML), Myeloproliferative disorder (MPD), Myelodysplastic syndrome (MDS), Chronic myelogenous leukemia (CML), Hematological disorder, not otherwise specified (HIDNOS). The data is retrospective as it used "archived bone marrow specimens." The country of origin is not specified but the study was submitted to the FDA.

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

• The ground truth for the clinical studies (Methods Comparison) was established by "standard cytogenetic analysis" performed by the participating laboratories.
• The text does not specify the number of individual experts per lab or their specific qualifications (e.g., "radiologist with 10 years of experience"). However, "standard cytogenetic analysis" implies trained and qualified cytogeneticists or laboratory personnel are performing the traditional karyotyping and interpretation.

4. Adjudication Method for the Test Set

• The text does not explicitly describe an adjudication method for the ground truth (standard cytogenetics) in the methods comparison study. It implies that the "standard cytogenetic analysis" results from each participating laboratory were accepted as the ground truth.
• For the device's own FISH analysis, inter-observer and inter-site variability were assessed in the reproducibility studies, suggesting that multiple observers/sites independently evaluated the samples, but it doesn't detail a formal adjudication process for discordant results.

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

• No, a MRMC comparative effectiveness study was not explicitly conducted to assess human readers' improvement with AI vs. without AI assistance.
• This device is a DNA probe kit for Fluorescence In Situ Hybridization (FISH), which is a laboratory assay where trained personnel visually count signals or use automated enumeration systems. It is not an "AI" device as described in modern AI/ML contexts that would assist radiologists or other human readers. The study compares the performance of the FISH assay (both interphase and metaphase interpretation) against the standard cytogenetic analysis.
• The reproducibility studies assessed inter-observer variability for the FISH assay itself, reflecting the inherent subjectivity of visual enumeration, but not the impact of an AI assistance tool on human performance.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

• Yes, standalone performance was assessed. The CEP 8 SpectrumOrange DNA Probe Kit is the "algorithm" in this context (or more accurately, the assay and its interpretation guidelines).
• The entire clinical methods comparison study (comparing FISH interphase and metaphase analysis to standard cytogenetics) represents the standalone performance of the assay and its associated interpretation criteria (e.g., 2.2% cutoff for interphase, >=2 tri-signaled metaphases for metaphase). The sensitivity, specificity, and correlation coefficients reported are for the device's performance when applied according to its instructions.

7. Type of Ground Truth Used

• For the clinical methods comparison study, the ground truth was expert consensus / established diagnostic method: Standard Cytogenetic Analysis. This method is referred to as "the standard of care."

8. Sample Size for the Training Set

• The text does not explicitly describe a separate training set in the way modern machine learning models would have one.
• The "pilot study" and "pivotal study" results for hybridization efficiency and reproducibility involve smaller numbers of specimens (35 BM, 60 BM, single normal and single trisomy 8 specimens) that could be considered part of the development and refinement of the assay and its interpretation rules, but not a formal "training set" for an algorithm. The 2.2% cutoff for interphase analysis appears to have been 'validated by the same pivotal clinical study,' suggesting it was developed and then verified within the context of the overall validation.

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

• Since there's no explicitly defined "training set" for an algorithm in the modern sense, the concept of establishing ground truth for it doesn't directly apply here.
• However, the underlying biological understanding and the methodology of interpreting FISH signals (e.g., what constitutes a "tri-signaled nuclei") would be based on established cytogenetic principles and likely refined through internal studies during the probe's development, informed by standard cytogenetic analysis, which is the gold standard for chromosomal abnormalities. The cutoff values (like 2.2%) were likely empirically determined and then validated against the clinical performance.

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