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The Theranos™ HSV-1 IgG Assay is a chemiluminescent immunoassay intended for the qualitative detection of IgG antibodies to herpes simplex virus type 1 (HSV-1) in human serum, in K2-EDTA anticoagulated human plasma from venous blood, and in human fingerstick K2-EDTA anticoagulated whole blood obtained with the Theranos Capillary Tubes and Nanotainer Tubes. The test is indicated for sexually active individuals and expectant mothers as an aid in the presumptive diagnosis of HSV-1 infection. The predictive value of positive and negative results depends on the population's prevalence and the pretest likelihood of HSV-1.

The test is not FDA cleared for screening blood or plasma donors. The performance of this assay has not been established for use in a pediatric population, neonates and immunocompromised patients.

The Theranos HSV-1 IgG Assay is for use with the Theranos System which performs automated sample processing steps and result analysis.

The Theranos HSV-1 IgG Assay is for use with the Theranos System. The Theranos System performs automated sample processing steps and analysis to produce the test results.

The Theranos HSV-1 IgG Assay is a three-step sandwich immunoassav with an HSV-1 glycoprotein G (gG) recombinant antigen coated surface, an anti-human IgG detection reagent conjugated to alkaline phosphatase (AP) and chemiluminescent substrate. During the first incubation step, the HSV-1 IgG antibodies present in the positive control and sample bind to the gG recombinant antigen on the coated surface. Following the first incubation step, unbound materials are removed with a wash cycle. Then the detection reagent-AP conjugate is added and during the second incubation step, the detection reagent-AP conjugate reacts with the HSV-1 IgG antibodies already bound to the capture surface. Following the second incubation, unbound materials are removed with a wash cycle. The chemiluminescent substrate is added to the capture-analyte-detection complex during the third incubation step to initiate the chemiluminescence reaction. Light generated by this reaction is detected and analyzed by the Theranos System using a calibration function to determine the cut-off index (COI) values for the sample and controls. The results for the Positive and Negative controls must be within specified limits for a run to be considered valid.

The Theranos Herpes Simplex Virus-1 (HSV-1) IgG Assay is a chemiluminescent immunoassay for the qualitative detection of IgG antibodies to HSV-1 in human serum, K2-EDTA anticoagulated human plasma from venous blood, and human fingerstick K2-EDTA anticoagulated whole blood. It is intended to aid in the presumptive diagnosis of HSV-1 infection in sexually active individuals and expectant mothers.

Here's an analysis of the acceptance criteria and supporting study details:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state a consolidated table of acceptance criteria for all performance aspects. However, based on the studies described, we can infer some key criteria and the reported performance. The most critical performance metrics for a diagnostic assay like this are Sensitivity and Specificity in the intended use populations.

2. Sample Sizes and Data Provenance:

• Clinical Performance Study (Sexually Active Adults): 260 retrospectively collected, archived venous serum samples. Samples obtained from multiple specimen sources covering 10 US states and Mexico.
• Clinical Performance Study (Pregnant Women): 298 retrospectively collected, archived venous serum samples. Samples obtained from multiple specimen sources covering 10 US states and Mexico.
• Low Prevalence Population Study: 82 samples. Samples obtained from multiple specimen sources covering 10 US states and Mexico.
• CDC Panel Testing: 100 well-characterized serum samples. Origin: U.S. Centers for Disease Control and Prevention (CDC).
• Precision (Venous Serum): 6 serum samples, with varying replicates (72-94 total replicates per panel member). One site (CLIA Laboratory model).
• Precision (Fingerstick Whole Blood): 3 fingerstick plasma samples, with 170-171 total replicates per panel member. One site (CLIA Laboratory model).
• Reproducibility (Fingerstick Whole Blood): 30 subjects (10 subjects at each of 3 collection sites). From each subject, 9 Capillary Tubes and Nanotainer Tubes and 2 serum separator tubes (SSTs) were collected.
• Analyte Stability: Not explicitly stated but implied sufficient samples to represent different baseline COI values and matrices.
• Interfering Substances: 3 serum samples (negative, high negative, low positive) contrived from a high positive sample and pooled negative serum. Each pool tested in duplicate.
• Cross-reactivity: 21 different infectious agents/conditions, with at least 3 samples per agent (total of 139 samples). Samples acquired from commercial vendors.
• Assay Cut-off Establishment/Validation: 192 serum samples to establish, then 120 independent serum samples to validate.

3. Number of Experts and Qualifications for Ground Truth:

The document primarily relies on reference methods for ground truth, rather than independent experts for adjudication of individual cases.

• Clinical Performance (Sexually Active Adults & Pregnant Women): The FOCUS HerpeSelect Immunoblot was used as the reference method. When initial results were equivocal on the Focus HerpeSelect Immunoblot, a validated western blot reference test (University of Washington, Seattle) was used for resolution.
• CDC Panel Testing: The CDC itself provided a panel of "well characterized serum samples" (implies expert characterization and consensus by the CDC).
• Cross-reactivity: Banked serum samples "confirmed positive for IgG against the infectious agents of interest" and "negative for HSV-1 IgG on the reference method" were acquired from commercial vendors. The implicit experts are those who characterized these commercial samples and the reference method used.

No specific number or qualifications of experts are given beyond the implicit expertise associated with the CDC and the University of Washington laboratory performing the western blot.

4. Adjudication Method:

• Clinical Performance Studies: For equivocal results on the primary reference method (Focus HerpeSelect Immunoblot), a secondary reference method (University of Washington western blot) was used. This acts as a 2+1 adjudication method, where the primary reference method's equivocal cases are resolved by a more definitive test. Specifically, for sexually active adults, 10 samples were initially equivocal, and a western blot resolved 9 (2 negative, 7 positive), with 1 unresolved. For pregnant women, 8 samples were initially equivocal, with 4 resolved by western blot (1 negative, 3 positive) and 4 unresolved due to insufficient volume.

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

• No MRMC study was done. This device is an automated, standalone diagnostic assay (algorithm only) that provides a qualitative result (positive, negative, equivocal). It does not involve human readers interpreting results in the loop, or any comparison of human readers with vs. without AI assistance.

6. Standalone Performance:

• Yes, a standalone (algorithm only) performance study was done. The entire submission describes the performance of the Theranos HSV-1 IgG Assay and the Theranos System (which performs automated sample processing and result analysis) as a standalone device. The device itself generates the final qualitative result (positive, negative, equivocal) without human interpretation of the assay signal.

7. Type of Ground Truth Used:

• The ground truth for the clinical performance studies (Sexually Active Adults, Pregnant Women, Low Prevalence Population) was established by a reference method, specifically the FOCUS HerpeSelect Immunoblot, with equivocal results resolved by a validated western blot reference test (from the University of Washington, Seattle).
• For the CDC panel testing, the ground truth was based on the CDC's characterization of the serum samples.
• For cross-reactivity, ground truth was based on third-party validated positive samples for other infectious agents and negative for HSV-1.

8. Sample Size for the Training Set:

The document does not explicitly state the sample size for a "training set." This type of regulatory submission (510(k)) focuses on validation rather than the development and training phases of an algorithm. Therefore, details about the internal development (training and internal validation) of the device's algorithm are typically not included or required in this format. The performance studies discussed are considered validation studies.

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

As no "training set" details are provided in this document, the method for establishing its ground truth is also not described. The document focuses on the validation of the device's performance against established reference methods.

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