(94 days)
The ADVIA Centaur® Herpes-1 IgG (HSV1) assay is for in vitro diagnostic use in the qualitative determination of IgG antibodies to herpes simplex virus type 1 (HSV-1) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur systems. The test is indicated for testing sexually active adults or expectant mothers for aiding in the presumptive diagnosis of HSV infection. The predictive or negative result depends on the prevalence of HSV-1 infection in the population and the pre-test likelihood of HSV-1 infection.
The test is not FDA cleared for screening blood or plasma donors. The performance of this assay has not been established for immunocompromised patients, pediatic patients or matrices other than human serum and plasma (EDTA and lithium heparin).
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The provided text describes the performance study for the ADVIA Centaur Herpes-1 IgG (HSV1) assay, an in vitro diagnostic device. This device is intended for the qualitative determination of IgG antibodies to HSV-1 in human serum and plasma, aiding in the presumptive diagnosis of HSV infection and serological status determination.
The study aims to demonstrate that the device meets its performance requirements, which can be interpreted as acceptance criteria for precision, matrix equivalency, panel agreement, interference, cross-reactivity, and clinical accuracy (sensitivity and specificity).
Here is a breakdown of the requested information:
1. A table of acceptance criteria and the reported device performance
The document implicitly defines acceptance criteria through its "Design Requirement" for precision and agreement percentages for panels, interference, cross-reactivity, and clinical studies.
| Performance Characteristic | Acceptance Criteria (Design Requirement) | Reported Device Performance |
|---|---|---|
| Precision | ||
| Repeatability (%CV) | ||
| Index 6.00 | ≤ 5.0% | 4.0% for Serum 6 (13.37 Index) |
| Within-Lab (%CV) | ||
| Index 6.00 | ≤ 10.0% | 7.7% for Serum 6 (13.37 Index) |
| Sample Matrix Equivalence | Demonstrated equivalency with Serum | Correlations from Deming regression: |
- Serum Separator Tube vs Serum: r=0.996
- EDTA Plasma vs Serum: r=0.998
- Lithium Heparin Plasma vs Serum: r=0.998 |
| Commercial Panel Agreement | Not explicitly stated as a numerical criterion, but high agreement expected. | - Seracare Diagnostics: 92% total agreement with reference assay 1 (25 samples) - ToRCH-mixed Zeptometrix: 96% total agreement with reference assay 1 (24 samples)
- CDC panel: 100% total agreement with CDC results (100 samples) |
| Interferences | ≤ 10% change in results with interfering substances | Confirmed ≤ 10% change for various substances up to specified concentrations (e.g., Biotin 3500 ng/mL, Hemoglobin 500 mg/dL) |
| Cross-reactivity | Not explicitly stated as a numerical criterion, but high agreement expected. | 95.8% total agreement (413/431) against Comparative Assay/Western Blot across various clinical categories. |
| Clinical Sensitivity (Overall) | Not explicitly stated, but common for diagnostic tests to aim for high sensitivity/specificity. | 97.5% (507/520) with 95% CI of 95.8%-98.5% |
| Clinical Specificity (Overall) | Not explicitly stated. | 96.2% (331/344) with 95% CI of 93.6%-97.8% |
| Clinical Sensitivity (Pregnant Women) | Not explicitly stated. | 98.7% (155/157) with 95% CI of 95.5%-99.7% |
| Clinical Specificity (Pregnant Women) | Not explicitly stated. | 98.3% (115/117) with 95% CI of 94.0%-99.5% |
2. Sample sizes used for the test set and the data provenance
- Precision Study: 80 replicates per level (for 2 controls and 6 samples). The data provenance is not explicitly stated beyond "performed according to CLSI EP05-A3," suggesting controlled laboratory conditions.
- Sample Matrix Study: 68 sets of matched samples (serum, SST, EDTA plasma, lithium heparin plasma) from "commercial sources." Provenance not explicitly country-specific, but generally implies a controlled study.
- Panels Study:
- Seracare Diagnostics panel: 25 characterized HSV samples.
- ToRCH-mixed Zeptometrix panel: 24 characterized HSV samples.
- CDC panel: 100 blind characterized HSV samples.
- Provenance: Commercial sources and CDC (likely US-based).
- Interferences Study: Not specified, but involved testing at three levels of samples for each interfering substance.
- Cross-reactivity Study: 431 specimens across various clinical categories. Provenance not specified.
- Clinical Study:
- Sample Size: 864 specimens (total enrollment)
- Provenance: "Collected within the United States" and tested at "3 independent external laboratories." This indicates a prospective collection for the clinical study.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
The document does not specify the number of experts or their qualifications for establishing ground truth.
- For the panel studies, "characterized HSV samples" from commercial sources and "blind characterized HSV samples" from the CDC were used. This implies that the ground truth for these samples was established by the respective commercial supplier or the CDC, likely through a validated reference method, but the specific expertise of those who characterized them is not detailed.
- For the cross-reactivity study, the HSV-1 IgG status of specimens was verified using a "Comparative Assay" (a commercially available anti-HSV-1 IgG immunoblot method) and, for equivocal cases, a "validated Western Blot reference confirmatory test (University of Washington, Seattle)." This points to a recognized reference laboratory (University of Washington) for confirmatory testing, but the specific experts (e.g., medical technologists, scientists, physicians) and their qualifications involved in interpreting these reference methods are not stated.
- For the clinical study, the ground truth was established by comparing the device's performance to a "commercially available anti-HSV-1 IgG immunoblot method (Comparative Assay)" and a "validated Western Blot reference confirmatory test (University of Washington, Seattle)" for equivocal results. Again, the specific experts involved in the interpretation of these reference methods are not detailed.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
The document states that for the clinical study, 22 "equivocal" results from the Comparative Assay were "further tested by the Western Blot test." This serves as a form of adjudication, where a higher-level, confirmed reference method (Western Blot) resolves uncertain or equivocal results from the primary comparative method. It's not a multi-reader, consensus-based adjudication, but rather a hierarchical resolution using a more definitive test.
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, this is not a multi-reader multi-case (MRMC) comparative effectiveness study. The device reviewed is an in vitro diagnostic assay (HSV-1 IgG antibody test), not an AI-based imaging or interpretive software that would be used by human readers. Therefore, the concept of human readers improving with AI assistance is not applicable to this device.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the studies presented (precision, matrix, panels, interference, cross-reactivity, and clinical sensitivity/specificity) reflect the standalone performance of the ADVIA Centaur HSV1 assay as an automated in vitro diagnostic device. Its output (qualitative determination of IgG antibodies) is directly provided by the instrument based on its chemical reactions and detector, without a human-in-the-loop directly influencing the test result. Human intervention would be for specimen handling, loading, and result review, but not for the determination of the assay's output itself.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth for this in vitro diagnostic device was established primarily through:
- Reference Assays/Methods:
- A "reference assay 1" for commercial panels.
- "Results provided by the CDC" for the CDC panel.
- A "commercially available anti-HSV-1 IgG immunoblot method (Comparative Assay)" and a "validated Western Blot reference confirmatory test (University of Washington, Seattle)" for the clinical and cross-reactivity studies.
- This falls under the category of reference standard comparison using established laboratory methods believed to be highly accurate.
8. The sample size for the training set
The document describes performance studies for regulatory submission (510(k)). It does not provide information about a "training set" in the context of machine learning, as this is an immunoassay, not an AI/ML-based device. If "training set" refers to samples used during the assay's development or optimization prior to these validation studies, that information is not provided in this regulatory summary. The presented data represents the validation/test set.
9. How the ground truth for the training set was established
As there is no mention of a "training set" in the context of an AI/ML device, this question is not applicable. The assay's performance relies on its biochemical design and manufacturing controls, not on a machine learning model that requires a ground-truth-labeled training set.
§ 866.3305 Herpes simplex virus serological assays.
(a)
Identification. Herpes simplex virus serological assays are devices that consist of antigens and antisera used in various serological tests to identify antibodies to herpes simplex virus in serum. Additionally, some of the assays consist of herpes simplex virus antisera conjugated with a fluorescent dye (immunofluorescent assays) used to identify herpes simplex virus directly from clinical specimens or tissue culture isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by herpes simplex viruses and provides epidemiological information on these diseases. Herpes simplex viral infections range from common and mild lesions of the skin and mucous membranes to a severe form of encephalitis (inflammation of the brain). Neonatal herpes virus infections range from a mild infection to a severe generalized disease with a fatal outcome.(b)
Classification. Class II (special controls). The device is classified as class II (special controls). The special control for the device is FDA's revised guidance document entitled “Class II Special Controls Guidance Document: Herpes Simplex Virus Types 1 and 2 Serological Assays.” For availability of the guidance revised document, see § 866.1(e).