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The Alethia CMV Assay Test System includes separately provided test kits for the Alethia CMV DNA Amplification Assay and the Alethia CMV External Control Reagents.

The Alethia CMV DNA Amplification Assay, performed on the Alethia instrument, is a qualitative, in vitro diagnostic test system for the direct detection of Cytomegalovirus (CMV) DNA in saliva samples from neonates younger than 21 days of age. The test is used as an aid in the diagnosis of congenital CMV infection. The results of this test should be used in conjunction with the results of other clinical findings.

Flocked swabs should be used to collect saliva from neonates. The swab can be collected dry, without viral transport media (VTM), or placed in no more than 1 mL VTM.

The Alethia CMV External Control Reagents are used as part of a routine quality control program to aid the user in detection of unexpected conditions that may lead to test errors. The external controls are intended for use with the Alethia CMV DNA Amplification Assay; the controls are not intended for use with other assays or systems.

The Alethia CMV Assay Test System, including the Alethia CMV DNA Amplification Assay and the Alethia CMV External Controls, is based on loopmediated amplification (LAMP) technology. The assay targets a region of the Cytomegalovirus genome that is conserved across multiple CMV strains. The Alethia CMV target is a 194 base pair (bp) sequence of the Human herpesvirus 5 genome.

LAMP uses specially designed primers to provide for specific and continuous isothermal DNA amplification. A bv-product of amplification is magnesium pyrophosphate, which forms a white precipitate leading to a turbid solution. Reaction solution absorbance characteristics are monitored by the Alethia™ instrument.

Changes in reaction solution turbidity created by precipitation of magnesium pyrophosphate indicate the presence of target DNA. The absence of target DNA results in no significant change in sample absorbance.

The Alethia CMV DNA Amplification Assay is a qualitative in vitro diagnostic test for the direct detection of Cytomegalovirus (CMV) DNA in saliva samples from neonates younger than 21 days of age. It aids in the diagnosis of congenital CMV infection.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance:

2. Sample Sizes Used for the Test Set and Data Provenance:

• Prospective Test Set:
  • Sample Size: 1,514 specimens.
  • Data Provenance: Prospectively collected from August 2017 to March 2018 at seven clinical study sites representing geographically distinct regions throughout the United States, Canada, Europe, and Australia.
• Archived Preselected Positive Samples:
  • Sample Size: 34 specimens.
  • Data Provenance: De-identified samples previously evaluated from prospective clinical studies and found to have CMV infection. Collected from infants less than 21 days of age and stored at -80 ℃. The provenance is retrospective, as they were existing samples used to supplement positive cases.

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

The document does not explicitly state the number of experts or their specific qualifications (e.g., radiologist with X years of experience) used to establish the ground truth.

Instead, the ground truth (Composite Reference Method - CRM) was established by a technical algorithm:

• Two manufacturer-developed and validated PCR assays were used.
• Samples positive by either PCR assay were further tested by bidirectional sequencing (BDS).
• Ground Truth: Samples were considered positive when BDS confirmed the presence of CMV DNA, and negative when neither PCR assay produced amplicon after 40 cycles or BDS was negative.

4. Adjudication Method for the Test Set:

The adjudication method for the test set relied on a defined algorithm using two PCR assays and bidirectional sequencing.

• If both PCRs were positive and BDS was positive, it was CRM positive.
• If both PCRs were positive and BDS was negative, it was CRM negative.
• If one PCR was positive and BDS was positive, it was CRM positive.
• If one PCR was positive and BDS was negative, it was CRM negative.
• If both PCRs were negative, it was CRM negative (BDS not applicable).

This is a rule-based algorithmic adjudication, not human consensus-based.

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:

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed. This device is an automated in vitro diagnostic test (qualitative LAMP technology) for direct detection of CMV DNA, not an AI-powered image analysis or diagnostic support tool intended to improve human reader performance. Therefore, the concept of human readers improving with AI assistance is not applicable here.

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

Yes, the studies presented are for the standalone performance of the Alethia CMV Assay Test System. The device is a qualitative, automated system that detects CMV DNA, providing a POSITIVE, NEGATIVE, or INVALID result based on its internal algorithms and measured absorbance characteristics. Human intervention is limited to sample preparation and operating the instrument, not interpretation of raw signals to determine positivity or negativity. The clinical performance (PPA, NPA) directly reflects the algorithm's accuracy against a molecular ground truth.

7. The Type of Ground Truth Used:

The ground truth used was a Composite Reference Method (CRM) based on molecular testing results (two PCR assays and bidirectional sequencing). This is a type of technical/laboratory ground truth, not expert consensus, pathology, or direct outcomes data.

8. The Sample Size for the Training Set:

The document does not explicitly state the sample size for a training set. This type of in vitro diagnostic assay, based on LAMP technology, would typically be developed and optimized using analytical studies (determining LoD, inclusivity, specificity, precision, etc.) and then validated in clinical studies, rather than relying on a separate "training set" in the machine learning sense. The performance characteristics represent the validation of the assay's design.

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

As no explicit training set is detailed for an algorithm in the machine learning sense, the method for establishing its ground truth is not described. The analytical performance evaluations (LoD, inclusivity, specificity) are based on contrived samples with known CMV status and concentration, which serve as the "ground truth" for evaluating those specific analytical characteristics.

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