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Focus Technologies' HerpeSelect® 1 ELISA IgG test is intended for qualitatively detecting the presence or absence of human IgG class antibodies to HSV-1 in human sera. In conjunction with the Focus HerpeSelect® 2 ELISA IgG, the test is indicated for testing sexually active adults or expectant mothers for aiding in the presumptive diagnosis of HSV infection. The assay can be used manually or in conjunction with an automated system as outlined in the package insert. The user is responsible for assay performance characteristics when an automated system is used. The performance of this assay has not been established for use in a pediatric population, for neonatal screening, or for testing of immunocompromised patients.

In the HerpeSelect® I ELISA IgG IgG assay, the polystyrene microwells are coated with recombinant gG-1 antigen. Diluted serum samples and controls are incubated in the wells to allow specific antibody present in the samples to react with the antigen. Nonspecific reactants are removed by washing, and peroxidase-conjugated anti-human IgG is added and reacts with specific IgG. Excess conjugate is removed by washing. Enzyme substrate and chromogen are added, and the color is allowed to develop. After adding the Stop Reagent, the resultant color change is quantified by a spectrophotometric reading of optical density (OD). Sample optical density readings are compared with reference cut-off OD readings to determine results.

Here's an analysis of the provided text regarding the HerpeSelect® 1 ELISA IgG device, broken down by your requested criteria:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in terms of specific thresholds the device needed to meet for regulatory approval. Instead, it presents various "performance characteristics" studies. However, we can infer performance goals based on the reported results within the different populations. The primary comparative method used is the HSV-1 Western blot (WB).

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

• Sexually Active Adults: n = 246 (archived, unselected sera)
• Expectant Mothers: n = 241 (archived, unselected sera)
• Culture Positives: n = 38 (sera from culture positive patients)
• Low Prevalence Population: n = 81 (sera from college students claiming to lack sexual experience)
• Type Specificity (HSV-2 Western blot positives / HSV-1 negatives): n = 90 (combined from expectant mothers, sexually active adults, low prevalence persons, and HSV-2 culture positives)
• Cross-reactivity (Taxonomically Related Viruses): n = 26 (HSV sero-negative by other FDA cleared ELISAs, IFA IgG positive for CMV, EBV VCA, HHV6, VZV)
• CDC Panel: Panel of unstated size (59% positive, 41% negative samples)
• Manual vs. Automated Methods Agreement: n = 248 (adult samples from US and 2 outside US, submitted for HSV testing)

Data Provenance:

• Most studies were conducted by an "outside investigator."
• The reference method for most studies (excluding cross-reactivity and agreement with CDC) was an HSV-1 Western blot from a Pacific Northwest university.
• The sera were "archived" and "masked" for several studies, indicating a retrospective design.
• The "outside investigator" for the manual vs. automated method comparison was part of a CLIA validation for a major clinical laboratory in Southern California.
• The CDC panel was obtained from the CDC.

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 used or their qualifications for establishing the ground truth. The ground truth for most studies was established using a "HSV-1 Western blot from a Pacific Northwest university" or "culture" results. Western blot interpretation is typically done by trained laboratory personnel or experts in serology, but specific details on the number and qualifications are not provided here. For the CDC panel, it states the panel was "characterized," implying expert review and consensus, but again, no specifics are given.

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method for the test set. It reports concordance with the reference methods (Western blot, culture, or CDC panel) and notes "equivocals" and "atypical Western blots" that were excluded from calculations, but it doesn't detail a process for resolving discrepancies.

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

This device is an ELISA (Enzyme-linked Immunosorbent Assay), which is a laboratory test for detecting antibodies. It's not an imaging or diagnostic device that involves human "readers" in the context of interpreting complex medical images like radiology or pathology. Therefore, an MRMC comparative effectiveness study comparing human reader performance with and without AI assistance is not applicable to this type of device and was not performed.

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

Yes, the studies evaluating "Relative Sensitivity and Relative Specificity" with various populations (sexually active adults, expectant mothers, culture positives, low prevalence, type specificity) demonstrate the standalone performance of the HerpeSelect® 1 ELISA IgG device. The results (optical density readings) are automatically compared to reference cut-off OD readings to determine results, implying an algorithmic determination. The device's performance is compared directly against the reference standard (Western blot or culture), indicating a standalone assessment.

The document also describes "Reproducibility Using an Automated Instrument" and "% Agreement between the Manual and Automated Methods," which further supports assessment of the device's automated, standalone capabilities.

7. The Type of Ground Truth Used

The primary type of ground truth used was:

• Reference Method: HSV-1 Western blot from a Pacific Northwest university.
• Culture: For the "Relative Sensitivity with Culture Positives" study.
• CDC Panel Characterization: For the "Agreement with CDC Panel" study, indicating a highly characterized set of samples.
• Other FDA cleared HSV ELISAs and IFA IgG positive for taxonomically similar viruses: For the "Cross-reactivity with Taxonomically Related Viruses" study.

8. The Sample Size for the Training Set

The document describes performance characteristics using various test sets (as detailed in point 2). It does not explicitly mention a "training set" or a separate process for training the device. For ELISA tests, the "training" equivalent would typically involve the development and validation of the assay's reagents and cut-off values using known positive and negative samples during the assay development phase. This document focuses on the validation of the finalized device.

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

Since an explicit "training set" is not detailed, the method for establishing its ground truth is also not provided. However, the general principle for establishing ground truth during the development of an ELISA (which constitutes the implicit "training" for the assay's cut-offs and performance characteristics) would typically involve:

• Well-characterized clinical samples: Samples from individuals with confirmed HSV-1 infection (via culture or strong clinical evidence) and confirmed non-infected individuals.
• Comparative methods: Using established gold standard tests like Western blot, PCR, or viral culture to classify these samples.
• Expert Consensus: Review by infectious disease specialists or laboratory experts to ensure accurate classification of reference samples.

The studies presented here are mainly for the validation of the device rather than its initial development or training.

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