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The ADVIA Centaur® Herpes-2 IgG (HSV2) assay is for in vitro diagnostic use in the qualitative determination of IgG antibodies to herpes simplex virus type 2 (HSV-2) 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 value of a positive or negative result depends on the prevalence of HSV-2 infection in the population and the pre-test likelihood of HSV-2 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, pediatric patients or matrices other than human serum and plasma (EDTA and lithium heparin).

The ADVIA Centaur Herpes-2 IgG (HSV2) assay is a fully automated two-step sandwich immunoassay using indirect chemiluminometric technology. The specimen is incubated with the Solid Phase, which contains HSV-2-specific recombinant-gG2 antigen. Antigen-antibody complexes will form if anti-HSV-2 antibody is present in the specimen. The Lite Reagent contains monoclonal anti-human IgG labeled with acridinium ester, and is used to detect HSV-2 IgG in the specimen.

The provided document describes the performance of the ADVIA Centaur Herpes-2 IgG (HSV2) assay, which is an in vitro diagnostic device. The study aims to demonstrate that the device meets acceptance criteria for substantial equivalence to a predicate device.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document presents performance characteristics and compares them against design requirements or expected outcomes.

2. Sample Size and Data Provenance

• Precision Study: 6 samples and Negative/Positive Controls. Each material tested in duplicate, twice a day for 20 days.
  • N = 80 replicates per level for within-lab precision.
• Sample Matrix Study: 68 sets of matched samples (serum, serum separator tube, EDTA plasma, lithium heparin plasma).
• Panel Testing:
  • ToRCH-mixed Zeptometrix panel: 24 characterized HSV samples.
  • CDC panel: 100 blind characterized HSV samples.
• Cross-Reactivity Study: 522 specimens across various clinical categories.
• Multi-site Reproducibility: 6 samples and Negative/Positive Controls.
  • N = 90 replicates per level (from 3 external sites, 5 days, 2 runs/day, 3 replicates/run).
• Clinical Study:
  • Total: 864 specimens (≥ 18 years of age), including 274 pregnant women.
  • Data Provenance: Specimens collected within the United States. The study was conducted at 3 independent external laboratories. The nature of the specimen collection implies it was prospective for the purpose of this study, although the individual samples may have been sourced retrospectively from biobanks or collected prospectively for the study itself. The document does not explicitly state "retrospective" or "prospective" for the clinical sample collection, but "collected within the United States" and tested at external labs suggests purpose-collected samples for the study.

3. Number of Experts and Qualifications for Ground Truth

• The document implies the use of "reference assay 1" for the ToRCH-mixed Zeptometrix panel and "results provided by the CDC" for the CDC panel, as well as a "Comparative Assay" and "validated Western Blot reference confirmatory test (University of Washington, Seattle)" for the clinical study and cross-reactivity assessment.
• Number of Experts: Not explicitly stated how many individual experts established the ground truth for these reference methods. The description refers to "characterized HSV samples" for panels and "validated Western Blot" from a university, which implies expert consensus or highly standardized laboratory procedures.
• Qualifications of Experts: Not explicitly stated (e.g., "radiologist with 10 years of experience" is not applicable here as it's an in vitro diagnostic test for antibodies). However, the use of "validated Western Blot" from a reputable institution (University of Washington, Seattle) and "CDC" as sources for ground truth implies the highest level of expertise and validated methodologies in serological testing.

4. Adjudication Method for the Test Set

• For the clinical study: Of the 864 specimens, 22 were equivocal with the Comparative Assay. These 22 samples were resolved by Western Blot testing. 20 were resolved to be negative, and 2 remained equivocal. This describes a form of adjudication where an equivocal result from one reference method is adjudicated by a more definitive reference method (Western Blot).
• No multi-reader consensus (e.g., 2+1, 3+1) is mentioned, as this is an in vitro diagnostic assay, not an image-reading task.

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

• No MRMC comparative effectiveness study was done. This type of study is typically performed for AI/CAD systems that assist human readers in interpreting medical images, not for in vitro diagnostic assays like this one which provides a quantitative or qualitative result directly.

6. Standalone (Algorithm Only) Performance

• This device is an automated immunoassay (ADVIA Centaur HSV2 assay). Its performance is inherently "standalone" in the sense that it directly measures antibodies without human interpretation in the loop to generate the initial result. The reported sensitivity and specificity values are for the device (algorithm) itself against the established ground truth.

7. Type of Ground Truth Used

• Expert Consensus / Highly-validated Reference Methods:
  • For panels: "characterized HSV samples," "reference assay 1," and "results provided by the CDC."
  • For clinical and cross-reactivity studies: A Comparative Assay (likely another FDA-cleared or well-established commercial immunoassay) and a validated Western Blot reference confirmatory test (University of Washington, Seattle). Western Blot is generally considered a highly specific and confirmatory test for antibody presence in serology. The use of a confirmatory test like Western Blot for equivocal results strengthens the ground truth.

8. Sample Size for the Training Set

• The document describes a 510(k) submission for an in vitro diagnostic device (immunoassay). Immunoassays are based on biochemical reactions and established calibration curves, not typically on machine learning models requiring large "training sets" in the same sense as AI/ML software. Therefore, a "training set" for an algorithm, as understood in AI/ML, isn't applicable or mentioned for this device. The development process would involve characterization, optimization, and validation using various samples, but not "training data" for a learnable algorithm.

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

• As explained in point 8, the concept of a "training set" with ground truth establishment in the AI/ML sense does not apply to this immunoassay. The device's performance is driven by its reagent chemistry and instrumentation, not by a trained algorithm.

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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.

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The LIAISON® HSV-1 Type Specific IgG assay is a chemiluminescent immunoassay (CLIA) to be used with the LIAISON® Analyzer for the qualitative determination of type specific IgG antibodies to Herpes Simplex Virus Type 1 (HSV-1) in human serum, The assay is indicated for testing sexually active adults or expectant mothers to aid in the presumptive diagnosis of HSV-1 infection.

The LIAISON® HSV-1 Type Specific IgG assay has not been established for use in the pediatrics population, for neonatal screening, or for testing immunocompromised patients. The assay is neither FDA cleared nor approved for testing blood or plasma donors.

The LIAISON® Control HSV-1 (negative and positive) are intended for use as assayed quality control samples to monitor the performance of the LIAISON® HSV-1 Type Specific IgG assay.

The method for qualitative determination of specific IgG to HSV-1 is an indirect chemiluminescence immunoassay (CLIA). HSV-1 gG1recombinant antigen is used for coating magnetic particles (solid phase) and a mouse monoclonal antibody is linked to an isoluminol derivative (isoluminol-antibody conjugate). During the first incubation. HSV-1 antibodies present in calibrators, samples or controls bind to the solid phase. During the second incubation, the antibody conjugate reacts with HSV-1 IgG already bound to the solid phase. After each incubation the unbound material is removed with a wash cycle. Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminol-antibody conjugate, is measured by a photomultiplier as relative light units (RLU) and is indicative of HSV-1 IgG present in calibrators, samples or controls.

Here's a summary of the acceptance criteria and study details for the DiaSorin LIAISON® HSV-1 Type Specific IgG assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the comparison to the predicate device and the desired performance characteristics for diagnostic assays. While explicit acceptance thresholds (e.g., "sensitivity must be > X%") are not stated, the study aims to demonstrate equivalent performance to the FDA-cleared predicate device across various populations.

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

• Total Sample Size for Comparative Clinical Trials: 951 samples
  • "At risk" samples (Sexually Active Adults): 401
  • Expectant Mothers: 430
  • Low Prevalence population: 120
• Data Provenance: Samples were collected in the Northeastern United States. The study was retrospective, using collected samples.

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

The ground truth was primarily established using an FDA-cleared Immunoblot (Focus Diagnostics HerpeSelect® 1 and 2 Immunoblot IgG) as the reference method. For samples that were "repeat Equivocal" on the predicate device, they were sent for Western Blot testing at a Reference Laboratory.

• No specific number of human experts for interpreting the Immunoblot or Western Blot is mentioned, nor are their qualifications. It's implied that these reference methods were performed and interpreted according to their standard operating procedures at designated facilities (a reference laboratory for Western Blot).

4. Adjudication Method for the Test Set

• The primary method of determining the true status of a sample (ground truth) was through an FDA-cleared Immunoblot.
• For equivocal results on the predicate Immunoblot, samples were repeat tested. If still equivocal, they were sent for Western Blot testing. This effectively acts as an adjudication step for indeterminate results from the primary reference method.

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 MRMC comparative effectiveness study was done. This study evaluates a laboratory assay (immunoassay) and not an imaging or interpretive AI device that assists human readers.

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

• Yes, a standalone study was done. The LIAISON® HSV-1 Type Specific IgG assay is an automated chemiluminescent immunoassay run on the LIAISON® Analyzer. Its performance (sensitivity, specificity, agreement) was determined directly by comparing its results to a reference method (Immunoblot/Western Blot) without human intervention in the interpretation of the LIAISON® device's raw output.

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

• The primary ground truth was established by an FDA-cleared Immunoblot.
• For equivocal cases from the Immunoblot, a Western Blot was used as the confirmatory ground truth. Both are laboratory-based diagnostic tests considered highly reliable for HSV-1 type-specific IgG detection.
• Additionally, a CDC panel of characterized serum samples was used to further evaluate agreement.

8. The Sample Size for the Training Set

• The document does not provide information regarding a distinct training set. This is a traditional in vitro diagnostic device, not typically a machine learning or AI-driven system that requires a separate "training set" in the same sense. The device's parameters would have been optimized during its development, likely using internal validation samples, but this information is not detailed in the 510(k) summary.

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

• As no specific training set for a machine learning model is described, the method for establishing its ground truth is not applicable or provided. For a traditional immunoassay, calibration and internal validation would involve characterized samples whose status is known through established reference methods, but specifics are not mentioned here.

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The LIAISON® HSV-2 Type Specific IgG assay is a chemiluminescent immunoassay to be used with the LIAISON® Analyzer for the qualitative determination of type specific IgG antibodies to Herpes simplex virus Type 2 (HSV-2) in human serum. The assay is indicated for testing sexually active adults or expectant mothers to aid in the presumptive diagnosis of HSV-2 infection.

The LIAISON® HSV-2 Type Specific IgG assay has not been established for use in the pediatrics population, for neonatal screening, or for testing immunocompromised patients. The assay is neither FDA cleared nor approved for testing blood or plasma donors.

The LIAISON® Control HSV-2 (negative and positive) are intended for use as assayed quality control samples to monitor the performance of the LIAISON® HSV-2 Type Specific IgG assay.

The method for qualitative determination of specific IgG to HSV-2 is an indirect chemiluminescence immunoassay (CLIA). HSV-2 gG2 recombinant antigen is used for coating magnetic particles (solid phase) and a mouse monoclonal antibody is linked to an isoluminol derivative (isoluminolantibody conjugate), During the first incubation, HSV-2 antibodies present in calibrators, samples or controls bind to the solid phase. During the second incubation, the antibody conjugate reacts with HSV-2 IgG already bound to the solid phase. After each incubation, the unbound material is removed with a wash cycle. Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminol-antibody conjugate, is measured by a photomultiplier as relative light units (RLU) and is indicative of HSV-2 IgG concentration present in calibrators, samples or controls.

The information provided details the performance study for the LIAISON® HSV-2 Type Specific IgG assay, but it does not explicitly state pre-defined acceptance criteria for sensitivity and specificity that the device must meet. Instead, it presents the performance data and then concludes that the device performed equivalently to an FDA-cleared comparison method.

However, based on the provided data, we can infer the reported performance metrics.

Here's a breakdown of the requested information:

1. A table of acceptance criteria and the reported device performance:

As mentioned, no explicit "acceptance criteria" are given in terms of numerical thresholds for sensitivity and specificity. The study aims to demonstrate "equivalent performance" to the predicate device. Therefore, the table below will list the reported performance values.

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

• Total Test Set Sample Size: 951 samples for comparison against the FDA-cleared Immunoblot.
  • 401 samples from Sexually Active Adults
  • 430 samples from Expectant Mothers
  • 120 samples from a "Low Prevalence" population
  • Additionally, a 100-sample CDC panel (52% positive, 48% negative) was used for further performance assessment.
• Data Provenance:
  • Country of Origin: Northeastern United States for the 951 samples. The CDC panel provenance is not specified beyond being from the Centers for Disease Control and Prevention.
  • Retrospective or Prospective: Not explicitly stated, but the description "samples collected" and "samples obtained" suggests a retrospective collection of existing samples, rather than prospective enrollment for the purpose of this study.

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

The ground truth was primarily established using an FDA-cleared Immunoblot (Predicate Device: Focus Diagnostics HerpeSelect® 1 and 2 Immunoblot IgG, K000238). For equivocal samples on the predicate device, Western Blot testing was performed by a Reference Laboratory in the Pacific Northwest.

• Number of Experts: Not applicable in the context of human expert review for independent ground truth. The initial ground truth was established by another diagnostic device (the predicate Immunoblot).
• Qualifications of Experts: Not applicable, as the primary ground truth was instrument-based. The "Reference Laboratory" for Western Blotting implies trained laboratory personnel, but specific qualifications are not mentioned.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

• Adjudication Method: Not applicable in the traditional sense of multiple human readers adjudicating results. The ground truth was established by a predicate device, and for equivocal results from the predicate, a Western Blot was used for resolution. This acts as a form of reference method adjudication for indeterminate cases from the predicate.

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:

• MRMC Study: No, this was not a multi-reader multi-case comparative effectiveness study. This study compares the performance of a new in vitro diagnostic device (LIAISON® HSV-2 Type Specific IgG assay) against a legally marketed predicate device (FDA cleared Immunoblot). It does not involve human readers' interpretation of results that are enhanced or assisted by AI.

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

• Standalone Performance: Yes, the study evaluated the LIAISON® HSV-2 Type Specific IgG assay as a standalone diagnostic device. It is an automated chemiluminescent immunoassay (CLIA) and its performance is measured independently against the predicate device and Western Blot as reference methods. It does not involve a human in the loop for interpreting the assay's primary output.

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

• Ground Truth Type: A combination of a legally marketed predicate device (FDA-cleared Immunoblot) and a reference laboratory method (Western Blot) for resolving equivocal results from the predicate device. This is a common approach for establishing ground truth in diagnostic device comparisons. The CDC panel serves as an external, well-characterized control for further validation.

8. The sample size for the training set:

• Training Set Sample Size: Not explicitly stated or provided in the document. The document describes a "comparative clinical trial" and "reproducibility study" for performance validation, not the development or training of the assay itself. The LIAISON® HSV-2 Type Specific IgG assay is an immunoassay, the "training" aspect is related to the assay's development and optimization, for which specific sample sizes are not typically released in 510(k) summaries for such devices.

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

• Ground Truth for Training Set: Not specified. As an immunoassay, its "training" involves optimizing reagents, concentrations, and reaction conditions during its development phase. The ground truth for this optimization would typically involve well-characterized positive and negative serum samples, likely confirmed by established reference methods (e.g., Western Blot, clinical diagnosis, culture), but these details are not part of the provided 510(k) summary focused on validation.

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