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The Digene Hybrid Capture® CMV DNA Assay is a qualitative, in vitro, diagnostic assay intended for the detection of human cytomegalovirus (CMV) DNA in human peripheral white blood cells isolated from whole blood specimens collected in EDTA. It is indicated for use as an aid in diagnosing CMV infection in solid organ transplant, bone marrow transplant and HIV/AIDS patients. This assay has not been cleared by the FDA for blood/plasma donor screening.

The Hybrid Capture® CMV DNA Assay is a qualitative in vitro diagnostic assay. It is a nucleic acid, signal enhanced, solution hybridization, antibody capture assay that uses chemiluminescent signaling to detect CMV DNA. The assay kit consists of 13 reagents and two accessories.

Whole blood specimens are treated with an agent that lyses red blood cells, and the specimen is centrifuged, resulting in a pellet of white blood cells. The white blood cell pellet is then used in the Hybrid Capture CMV DNA Assay.

Specimens potentially containing CMV DNA are denatured and then hybridized with a specific CMV RNA probe cocktail. This cocktail contains a probe mixture chosen to eliminate cross-reactivity with human or other herpesvirus sequences. The CMV probe supplied with the Hybrid Capture CMV DNA Assay is complementary to approximately 40,000 base pairs or 17% of the CMV genome (230,000 base pairs).

The RNA:DNA hybrids resulting from hybridization are captured on the surface of a tube coated with affinity-purified polyclonal caprine antibodies specific for RNA:DNA hybrids. The immobilized hybrids are then reacted with alkaline phosphatase-conjugated, murine monoclonal antibody to RNA:DNA hybrids, and are detected with a chemiluminescent substrate. Several alkaline phosphatase molecules are conjugated to each antibody. Multiple conjugated antibodies bind to each captured hybrid, resulting in signal enhancement. As the substrate is cleaved by the bound alkaline phosphatase, light is emitted and is measured in Relative Light Units (RLUs) on a standard commercial luminometer. The RLU value of a specimen is compared to a Positive Cutoff Value and to an Equivocal Cutoff Value to determine if the specimen is positive, equivocal, or negative for the presence of CMV DNA.

Here's a summary of the acceptance criteria and the study details for the Digene Hybrid Capture® System CMV DNA Assay, based on the provided 510(k) summary:

Acceptance Criteria and Device Performance

The provided document does not explicitly present a table of acceptance criteria with corresponding performance metrics like sensitivity, specificity, or accuracy derived from a pre-defined threshold. Instead, it describes analytical sensitivity and clinical performance relative to predicate devices and established methods.

The key performance metrics and their reported values are:

Study Details

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

   • Clinical Testing: The summary mentions "clinical testing in HIV/AIDS patients and patients who had undergone a solid-organ or bone marrow transplants" and "parallel testing of specimens from solid organ transplant, bone marrow transplant and HIV/AIDS patients." It also states testing in "a population comprised of approximately equal numbers of CMV seropositive and seronegative individuals."
   • Sample Size: The exact number of patients or specimens in these clinical test sets is not specified in the provided document.
   • Data Provenance: The document does not specify the country of origin of the data. The studies appear to be prospective clinical studies, as indicated by "clinical testing" and "parallel testing of specimens."

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

   • The document implies that the ground truth for clinical performance was established by comparing the device's results to "shell vial culture and cell culture" and "expected results based on a combination of the cell culture result, the shell vial culture result, and clinical information."
   • It does not specify the number of individual experts (e.g., clinicians, microbiologists) involved in establishing the "clinical information" component of the ground truth or their specific qualifications (e.g., years of experience). The reference methods (cell culture, shell vial culture) are laboratory-based and generally performed by trained laboratory personnel.

3. Adjudication method for the test set:

   • The primary adjudication method for clinical performance appears to be a composite reference standard: "expected results based on a combination of the cell culture result, the shell vial culture result, and clinical information."
   • The specific method of combining these different results (e.g., how conflicts were resolved, if a 2+1 or 3+1 rule was used) is not detailed in the summary.

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 device is an in vitro diagnostic (IVD) assay for detecting CMV DNA, not an imaging device or an AI-assisted diagnostic system where "human readers" would be involved in interpreting images or other complex data. Therefore, an MRMC study related to human reader improvement with AI assistance is not applicable and was not performed. The assay generates a quantitative RLU value that is compared to predefined cutoffs.

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

   • Yes, this is a standalone assay. The entire evaluation described is of the assay itself (Hybrid Capture® System CMV DNA Assay) without human interpretation steps that would be "in-the-loop." The luminometer measures RLU values, and the comparison to cutoff values for positive, equivocal, or negative results is algorithm-driven (or rule-based), not requiring human reader judgment for the final diagnostic outcome from the assay itself.

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

   • For analytical performance, the ground truth was derived from known dilutions of plasmid CMV DNA.
   • For clinical performance, the ground truth was a composite reference standard using traditional laboratory methods (shell vial culture, cell culture) combined with "clinical information." This clinical information could encompass patient symptoms, serology, treatment response, and other relevant medical data, potentially involving physician adjudication or consensus, though specific details are not provided.

7. The sample size for the training set:

   • The document does not explicitly refer to a "training set" in the context of machine learning or AI. This is a traditional IVD assay. The development of the assay (e.g., defining the probe cocktail, optimizing reaction conditions, establishing cutoff values) would involve empirical studies and iterative testing/optimization, but these are not typically referred to as "training sets" in the same way as in AI/ML validation studies. The analytical sensitivity studies on known concentrations of CMV DNA would contribute to establishing cutoff values but aren't described as a "training set."

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

   • As there is no explicitly defined "training set" in the AI/ML sense, this question is not directly applicable. The establishment of assay parameters (like cutoff values for positive/equivocal results) would be based on studies using known CMV DNA concentrations (as mentioned for analytical sensitivity) and potentially retrospective clinical samples alongside the predicate methods.

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