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The Alinity m HSV 1 & 2 / VZV assay is an in vitro real-time polymerase chain reaction (PCR) assay for the qualitative detection and differentiation of Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2) and Varicella Zoster Virus (VZV) DNA from clinician-collected cutaneous or mucocutaneous lesion swab specimens from symptomatic patients suspected of active herpes simplex virus 2 and/or varicella-zoster infection. The Alinity m HSV 1 & 2 / VZV assay is intended to aid in the diagnosis of herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster active cutaneous or mucocutaneous infections. Negative results do not preclude herpes virus type 1, herpes simplex virus type 2 or varicella-zoster virus infections and should not be used as the sole basis for diagnosis, treatment or other management decisions.

The Alinity m HSV 1 & 2 / VZV assay is not intended for use with cerebrospinal fluid (CSF) or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS). The Alinity m HSV 1 & 2 / VZV assay is not intended for use in prenatal screening.

The Alinity m HSV 1 & 2 / VZV assay is an in vitro real-time polymerase chain reaction (PCR) assay for the qualitative detection and differentiation of Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2) and Varicella Zoster Virus (VZV) DNA from clinician--collected cutaneous or mucocutaneous lesion swab specimens from symptomatic patients suspected of active herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster infection. This assay is intended for use with the automated Alinity m System.

The steps of the Alinity m HSV 1 & 2 / VZV assay consist of sample preparation, PCR assembly, amplification/detection, and result calculation and reporting. The steps involved in all stages of the Alinity m HSV 1 & 2 / VZV assay procedure are executed automatically by the Alinity m System. No intermediate processing or transfer steps are performed by the user. The Alinity m System is designed to be a random access analyzer that can perform the Alinity m HSV 1 & 2 / VZV assay in parallel with other Alinity assays on the same instrument.

The Alinity m HSV 1 & 2 / VZV assay requires two separate assay specific kits as follows:

1. The Alinity m HSV 1 & 2 / VZV AMP Kit (List No. 09N61-095) is comprised of 2 types of multi-well trays:

TRAY 1: Alinity m HSV 1 & 2 / VZV AMP TRAY 1 TRAY 2: Alinity m HSV 1 & 2 / VZV ACT TRAY 2.

TRAY 1 - Alinity m HSV 1 & 2 / VZV AMP is individually packed in a foil pouch and contains 48 unit-dose liquid amplification reagent wells and 48 unitdose liquid IC wells. One well of each is used per test.

· Amplification reagent wells consist of synthetic oligonucleotides, DNA Polymerase, dNTPs, and 0.15% ProClin® 950 in a buffered solution with a reference dye. IC wells consist of plasmid DNA with unrelated IC sequences and poly dA:dT in a TE buffer containing 0.15% ProClin 950 as a preservative.

TRAY 2 - Alinity m HSV 1 & 2 / VZV ACT is individually packed in a foil pouch and contains 48 unit-dose liquid activation reagent wells. One reagent well is used per test.

· Activation reagent wells consist of magnesium chloride, potassium chloride, and tetramethylammonium chloride. Preservative: 0.15% ProClin 950.

2. The Alinity m HSV 1 & 2 / VZV CTRL Kit (09N61-085) consists of negative controls and positive controls, each supplied as liquid in single-use tubes.

Alinity m HSV 1 & 2 / VZV Negative CTRL (List No. 9N61Z) consists of Negative Diluent / TE buffer (containing 0.085% Sodium Azide and 0.087% ProClin 950).

Alinity m HSV 1 & 2 / VZV Positive CTRL (List No. 9N61W) consists of linearized plasmid DNA containing HSV-1, HSV-2 and VZV DNA sequences in Negative Diluent / TE buffer (containing 0.085% Sodium Azide and 0.087% ProClin 950).

The Alinity m HSV 1 & 2 / VZV assay is to be run on the Alinity m System which is a fully integrated, sample to result automated system that performs real-time PCR test using the Alinity m HSV 1 & 2 / VZV AMP Kit along with the Alinity m HSV 1 & 2 / VZV CTRL Kit.

The provided text describes the performance of the "Alinity m HSV 1 & 2 / VZV" assay, which is an in vitro real-time PCR assay for detecting and differentiating Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2), and Varicella Zoster Virus (VZV) DNA.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the clinical agreement and analytical performance values demonstrated to establish substantial equivalence to a predicate device. For clinical agreement, the performance is measured by Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to a commercially available NAAT comparator method.

The acceptance criteria typically would be pre-defined statistical thresholds for PPA and NPA (e.g., PPA ≥ 95% and NPA ≥ 95%). Based on the reported results, the device successfully meets high performance metrics, suggesting that the implicit acceptance criteria were met for substantial equivalence.

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

• Prospective Study Test Set:
  • Sample Size: 1,258 results (1,257 for HSV-1, 1,257 for HSV-2, and 1,257 for VZV) from unique specimens.
  • Data Provenance: Multicenter, prospective clinical study conducted in the United States. Specimens were clinician-collected from symptomatic individuals.
• Retrospective Study Test Set:
  • Sample Size: 411 specimens (410 for HSV-1, 410 for HSV-2, and 411 for VZV).
  • Data Provenance: Retrospective study using archived, leftover lesion swab specimens from routine clinical testing. The location is not explicitly stated, but given it follows a prospective US study and is for US FDA clearance, it is highly likely to be from the US.

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

• The document does not specify the number or qualifications of experts used to establish the ground truth.
• The ground truth was established by comparison to a "commercially available NAAT comparator method (NAAT 1)". For discordant results, a "second commercially available RT-PCR comparator method (NAAT 2)" was used for informational purposes only (not for the primary analysis of device performance). This means the ground truth is essentially defined by the predicate/comparator device(s).

4. Adjudication Method for the Test Set

• The primary ground truth was established by a single comparator method (NAAT 1).
• For specimens with discordant results between the Alinity m assay and NAAT 1, a second NAAT method (NAAT 2) was used. However, the results of this second test were "not included in the analysis of device performance and are considered for information purposes only." This implies that the primary PPA/NPA calculations are based solely on the agreement with NAAT 1, and there was no formal 2+1 or 3+1 adjudication to establish a "resolved" ground truth for discordant cases that would then be used in the performance calculations.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and what was the effect size of how much human readers improve with AI vs without AI assistance

• This is not applicable as the device is an in vitro diagnostic (IVD) assay detecting viral DNA, not an AI-assisted diagnostic imaging device requiring human reader interpretation. There are no "human readers" in the context of this device.

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

• Yes, this is a standalone device performance study. The Alinity m HSV 1 & 2 / VZV assay is an automated system described as "fully integrated, sample to result." The performance data presented (clinical agreement, analytical sensitivity, specificity, precision, reproducibility, carryover) represent the performance of the algorithm/assay system without direct human interpretation of raw data being a variable. The "results are calculated and reported" automatically by the Alinity m System.

7. The Type of Ground Truth Used

• The ground truth was established by comparison to a "commercially available NAAT comparator method (NAAT 1)." For discordant cases, a second NAAT (NAAT 2) was used, but its results were for informational purposes only. This is a form of clinical surrogate ground truth, relying on an established and legally marketed diagnostic method. It is not pathology, expert consensus (in the traditional sense of multiple human interpretations), or outcomes data.

8. The Sample Size for the Training Set

• The document does not provide information regarding a specific training set size or how the device's algorithms (if any, beyond PCR signal processing) were trained. Regulatory submissions for IVD assays primarily focus on analytical and clinical validation of the final, locked-down device performance, rather than algorithm development specifics. The device seems to be a PCR assay, where the "training" would be more akin to assay design and optimization, not machine learning model training on large datasets in the way an AI imaging model is.

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

• As the document does not mention a training set in the context of machine learning, there is no information on how a ground truth for such a set would have been established. For a PCR assay, the development process involves extensive analytical characterization, optimization, and verification using characterized samples (e.g., known positive/negative samples, spiked samples, reference strains) to establish assay parameters and thresholds. This is distinct from establishing ground truth for a machine learning training dataset.

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The Savanna HSV 1+2/VZV Assay is an automated, rapid multianalyte real-time PCR test for the simultaneous qualitative detection and differentiation of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus DNA isolated from human cutaneous or mucocutaneous lesion samples obtained from symptomatic patients suspected of active herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster infection. This in vitro diagnostic test is intended to aid in the diagnosis of patients with signs or symptoms of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus infection.

The Savanna HSV 1+2/VZV Assay is intended to aid in the diagnosis of herpes simplex virus 1, herpes simplex virus 2 and varicella-zoster virus active infections. The results of this test should not be used as the sole basis for diagnosis, treatment or other management decisions and must be combined with clinical observations, patient history and/or epidemiological information. Negative results do not preclude herpes simplex virus type 1, herpes simplex virus type 2, or varicella-zoster virus infection that is not detected by a cutaneous or mucocutaneous lesion swab specimen. Positive results do not rule out co-infection with other organisms. Additional laboratory testing (e.g., viral culture, immunoassay, serology) may be necessary for patient evaluation. Savanna HSV 1+2/VZV Assay is for professional use. The Savanna HSV 1+2/VZV Assay is intended for use only with the Savanna instrument.

Warning: The Savanna HSV 1+2/VZV Assay is not intended for use with the cerebrospinal fluid (CSF) or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS). The Savanna HSV 1+2/VZV Assay is not intended for use in prenatal screening.

The Savanna HSV 1+2/VZV Assay consists of a single, self-contained assay cartridge employing real-time PCR technology for use with the Savanna instrument to detect and differentiate DNA from herpes simplex virus type 1, herpes simplex virus type 2 and varicella-zoster virus. In approximately 24 minutes, this platform extracts, amplifies and detects DNA present in cutaneous or mucocutaneous lesion swab specimens obtained from symptomatic patients and placed in transport media.

To initiate the assay, a patient cutaneous or mucocutaneous lesion swab specimen in transport medium is transferred via the supplied transfer pipette to the Liguid Sample Port of the Test Cartridge. The user closes the Sample Port and inserts the Test Cartridge into the Savanna instrument, initiating sample processing. The sample containing human DNA is pushed out of the Sample Port by lysis buffer, which then rehydrates the Process Internal Control (IC), and together with the paramagnetic nucleic acid binding particles, are pumped into the extraction chamber. The solution is mixed, and virus and/ or bacteria are further lysed by sonication within the extraction chamber. Specimen and IC DNA are bound to, washed and then eluted off the paramagnetic particles. The purified specimen DNA and IC solution is used to rehydrate four individual lyophilized master mixes. Each master mix is pumped into a PCR chamber and Taq-man® multiplex real-time PCR reactions are carried out under optimized conditions, generating amplicons for the targeted pathogen (if present) and the Process Internal Control (IC).

Each master mix contains primers and dual-labeled probes unique for the pathogen targets and the IC. The probes are labeled with a fluorophore on one end and a quencher on the other end. Target DNA sequences are amplified by pathogen-specific primers and detected by correspondingly specific fluorescence probes. The IC targets are also amplified by specific primers and detected by an IC-specific fluorescence probe. A polymerase included in the master mix cleaves the probes bound to complementary DNA sequences, separating the fluorophore from the quencher. This step generates a signal and if it surpasses multiple defined thresholds, the sample is reported as positive for the detected target sequence.

The Savanna instrument will display the test results (Positive or Invalid) on the main bay screen.

The provided text describes the performance characteristics and clinical studies of the Savanna HSV 1+2/VZV Assay, which is an in vitro diagnostic (IVD) device for the detection and differentiation of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus DNA. It is not an AI/ML device in the context of typical FDA AI/ML medical device submissions, as it is a molecular diagnostic test. Therefore, many of the requested points regarding AI/ML device evaluation (like human-in-the-loop, expert consensus for ground truth, MRMC studies, number of experts for ground truth, adjudication methods, and sample size for training set) are not applicable to this type of device.

However, I can extract the acceptance criteria and performance data for this diagnostic assay as presented. The study aims to demonstrate substantial equivalence to a predicate device, the Solana HSV 1+2/VZV Assay (K162451), not to prove performance of an AI model.

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

The document does not explicitly state "acceptance criteria" in a tabulated format for the clinical performance. Instead, it presents the results of the clinical studies with Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) values with their confidence intervals, comparing the Savanna Assay to a commercially available RT-PCR comparator method. For laboratory studies, the acceptance criteria are implied by the results (e.g., >95% positivity for LoD, 100% detection for inclusivity, no interference/cross-reactivity).

I will present the clinical performance results as the "reported device performance" against an implied high standard of agreement with the comparator method.

Table: Reported Device Performance (Clinical Study 1 & 2)

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

• Clinical Study 1 (Fresh Samples):

  • Sample Size: 590 residual specimens (207 cutaneous, 383 mucocutaneous).
  • Data Provenance: United States, from symptomatic patients suspected of HSV-1, HSV-2, or VZV infection. Retrospective (residual specimens).

• Clinical Study 2 (Frozen Residual Samples):

  • Sample Size: 154 evaluable samples.
  • Data Provenance: Not explicitly stated but implies U.S. as it's a supplement to Clinical Study #1. Retrospective (residual frozen samples).

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

This is not applicable as this is an IVD device, not an AI/ML device relying on human expert labels for ground truth. The ground truth is established by a comparator FDA-cleared nucleic acid amplification test.

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

Not applicable. The ground truth is determined by the results of an FDA-cleared comparator nucleic acid amplification test, not by human adjudication of images.

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

Not applicable. This is an IVD device, not an AI/ML device intended to assist human readers.

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

The device is a standalone diagnostic assay (real-time PCR test on the Savanna instrument). Its performance is evaluated independently against a comparator method. The results presented (PPA, NPA) represent this standalone performance.

7. The type of ground truth used

The ground truth for the clinical studies was established by comparison to FDA-cleared nucleic acid amplification tests (comparator method).

8. The sample size for the training set

Not applicable. This is not an AI/ML device that requires a "training set" in the context of machine learning model development. The robust performance of an IVD often relies on extensive analytical studies (LoD, inclusivity, cross-reactivity, precision, etc.) and clinical validation.

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

Not applicable, as there is no "training set" in the AI/ML sense. The analytical performance was established through various laboratory studies (e.g., Limit of Detection, Inclusivity, Cross-Reactivity, Precision) using well-characterized viral strains and matrices.

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The ARCHITECT HSV-1 IgG assay is a chemiluminescent microparticle immunoassay (CMIA) used for the qualitative detection of specific IgG antibodies to herpes simplex virus type 1 (HSV-1) in human serum (collected in serum and serum separator tubes) and plasma (collected in dipotassium EDTA, lithium heparin plasma separator tubes) on the ARCHITECT i System.

The ARCHITECT HSV-1 IgG assay is to be used for testing sexually active adults or expectant mothers to aid in the presumptive diagnosis of HSV-1 infection. The test results may not determine the state of active lessociated disease manifestations, particularly for primary infection. The predictive value of a reactive or nonreactive result depends on the prevalence of HSV-1 infection in the population and the pre-test likelihood of HSV-1 infection.

NOTE: The performance of the ARCHITECT HSV-1 IgG assay has not been established for use in the pediatric population, for neonatal screening, or for testing immunosompromised or immunosuppressed patients. The assay has not been FDA cleared or approved for screening blood or plasma donors.

This assay is an automated, two-step immunoassay for the qualitative detection of specific IgG antibodies to HSV-1 in human serum and plasma using chemiluminescent microparticle immunoassay (CMIA) technology. Sample, HSV-1 specific recombinant gG1 antigen coated paramagnetic microparticles, and assay diluent are combined and incubated. The IgG antibodies to HSV-1 (HSV-1 IgG) present in the sample bind to the HSV-1 specific recombinant gG1 antigen coated microparticles. The mixture is washed. Anti-human IgG acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle, Pre-Trigger and Trigger Solutions are added. The resulting chemiluminescent reaction is measured as a relative light unit (RLU). There is a relationship between the amount of HSV-1 IgG in the sample and the RLU detected by the system optics. The presence or absence of HSV-1 IgG in the sample is determined by comparing the chemiluminescent RLU in the reaction to the cutoff RLU determined from an active calibration.

Here's a breakdown of the acceptance criteria and the studies performed for the ARCHITECT HSV-1 IgG assay, based on the provided document:

Acceptance Criteria and Device Performance

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Immunoassay for the in vitro qualitative determination of IgG class antibodies to HSV-1 in human serum and lithium-heparin plasma, K2-EDTA plasma, and K3-EDTA plasma. The test is intended for sexually active individuals and expectant mothers as an aid in the presumptive diagnosis of HSV-1 infection. The test results may not determine the state of active lesions or associated disease manifestations, particularly for primary infection. The predictive value of positive and negative results depends on the population's prevalence and the pretest likelihood of HSV-1.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

This 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, immunocompromised patients, or for use at point-of-care facilities.

The Elecsys HSV-1 IgG immunoassay makes use of a sandwich test principle using biotinylated recombinant HSV-1-specific antigens and HSV-1-specific recombinant antigens labeled with a ruthenium complex. The Elecsys HSV-1 IgG immunoassay is intended for the qualitative determination of IgG class antibodies to HSV-1 in human serum and in the presumptive diagnosis of HSV-1 infection. It is intended for use on the cobas e immunoassay analyzers. Results are determined automatically by the software by comparing the electrochemiluminescence signal obtained from the reaction product of the sample with the signal of the cutoff value previously obtained by calibration.

The provided text describes the Elecsys HSV-1 IgG immunoassay (08948844160) and its substantial equivalence to a legally marketed predicate device (Elecsys HSV-1 IgG, K120625). However, the document does not contain specific acceptance criteria, reported device performance figures, or detailed study information such as sample sizes, data provenance, ground truth establishment methods, or the results of comparative effectiveness studies.

The document primarily focuses on the regulatory aspects of the device, its intended use, and the technological updates made to improve biotin and streptavidin tolerance.

Therefore, many of the requested fields cannot be filled from the provided text.

Here's a breakdown of what can be extracted and what cannot:

1. Table of Acceptance Criteria and Reported Device Performance:

• Acceptance Criteria: Not explicitly stated in the document.
• Reported Device Performance: Not provided in the document.

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

• Sample Size (Test Set): Not provided.
• Data Provenance: Not provided.

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

• Not provided.

4. Adjudication method for the test set:

• Not provided.

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 is an immunoassay, not an AI-assisted diagnostic imaging or interpretation device. Therefore, an MRMC study as typically understood for AI in medical imaging would not be applicable, and no such study is mentioned.

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

• This is a standalone immunoassay device. The document mentions: "Results are determined automatically by the software by comparing the electrochemiluminescence signal obtained from the reaction product of the sample with the signal of the cutoff value previously obtained by calibration." This suggests standalone performance, but no specific study or performance metrics are detailed in this document.

7. The type of ground truth used:

• Not explicitly stated for performance evaluation. For HSV-1 serological assays, ground truth is typically established through a combination of confirmatory methods (e.g., Western blot, PCR, or clinical diagnosis based on symptoms and other tests), but the document does not specify this for its validation.

8. The sample size for the training set:

• Not provided.

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

• Not provided.

Summary of Available Information (with placeholders for missing data):

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The HSV 1&2 ELITe MGB® Assay is a real-time polymerase chain reaction (PCR) based qualitative in vitro diagnostic test for the direct detection and differentiation of Herpes Simplex Virus 1 and 2 (HSV-2) DNA in cutaneous or mucocutaneous lesion swab specimens from patients with signs and symptoms of HSV-2 infection. This test is an aid in the differential diagnosis of HSV-1 and HSV-2 infections.

The HSV 1&2 ELITe MGB Assay is not FDA cleared for use with cerebrospinal fluid (CSF) specimens. The assay is not intended to be used for prenatal screening or for screening blood or blood products.

The HSV 1&2 ELITe MGB Assay is a qualitative in vitro diagnostic Real-Time PCR Assay for the direct detection of Herpes Simplex Virus (HSV) DNA (glycoprotein D gene for HSV-1 and glycoprotein G gene for HSV-2) in symptomatic male and female patients using DNA purified from swab specimens collected from individuals with cutaneous or mucocutaneous herpetic lesions.

The HSV 1&2 ELITe MGB Assay system is comprised of three major processes: (1) automated preparation of unprocessed sample to extract nucleic acids from primary swab specimens using the ELITe InGenius SP 200 Extraction Cartridge, (2) PCR amplification of target DNA sequences using HSV-1 and HSV-2 specific primers, and (3) real-time detection of fluorescent-labeled HSV-1 and HSV-2 specific oligonucleotide detection probes.

An Internal Control (IC), containing unrelated randomized DNA sequence, is added to all samples prior to extraction and monitors the integrity of the reagents, equipment function, and the presence of inhibitors in the samples. A positive signal in the Internal Control channel in the absence of HSV DNA indicates that the PCR has not been inhibited.

The amplification reagents, Positive Control and Internal Control are packaged as part of the HSV 1&2 ELITe MGB Assay.

Here's a breakdown of the acceptance criteria and study information for the HSV 1&2 ELITe MGB Assay, based on the provided text:

Acceptance Criteria and Reported Device Performance

The acceptance criteria for the HSV 1&2 ELITe MGB Assay are presented in terms of Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) against a composite reference method.

Study Information

1. Sample Size Used for the Test Set and Data Provenance:

   • Test Set Sample Size: 1,174 prospectively collected archived swab samples were initially collected. After exclusions:
     • 1,171 samples were analyzed for HSV-1.
     • 1,170 samples were analyzed for HSV-2.
     • A separate contrived oral panel study involved 75 individual negative cheek swab samples spiked with HSV-2, plus 10 HSV-1 positive samples and 15 HSV-1/HSV-2 negative oral samples.
   • Data Provenance: The samples were "left-over prospectively collected archived swab samples" from symptomatic patients. The country of origin is not explicitly stated, but the context of an FDA submission generally implies US-based data.

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

   • The document does not explicitly state the number of experts or their qualifications for establishing the ground truth. The ground truth was established using a composite reference method.

3. Adjudication Method for the Test Set:

   • The adjudication method for the test set was a "composite reference method" defined as: "an FDA cleared assay and a validated HSV 1&2 PCR followed by bi-directional sequencing of gel electrophoresis-positive samples."
   • "A positive result by the composite reference method is defined as a positive by the FDA cleared PCR or the validated sequencing. Two negative results are needed to confirm a negative." This implies a type of adjudicted consensus, where the "truth" is determined by agreement or hierarchical resolution between different methods, rather than human experts per se.

4. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done:

   • No. This document describes the analytical and clinical performance of an in vitro diagnostic (IVD) assay, which is an algorithm-only (standalone) test. It does not involve human readers in the primary diagnostic decision-making process that would warrant an MRMC study comparing human performance with and without AI assistance.

5. If a Standalone Performance Study Was Done:

   • Yes. The entire clinical performance section (Section 11.b) is a standalone performance study where the HSV 1&2 ELITe MGB Assay's performance is compared directly against a composite reference method. The assay operates without human intervention in the interpretation of results.

6. The Type of Ground Truth Used:

   • Composite Reference Method: This ground truth combined an FDA-cleared PCR assay and a validated HSV 1&2 PCR followed by bi-directional sequencing. This type of ground truth integrates highly sensitive and specific molecular methods, reflecting a robust laboratory-based gold standard.

7. The Sample Size for the Training Set:

   • The document does not explicitly mention a "training set" in the context of an AI/ML algorithm. This device is a real-time PCR assay, which is a chemical and enzymatic reaction rather than a machine learning model that would typically require a separate training set. The various analytical performance studies (Limit of Detection, Analytical Reactivity, Specificity, etc.) serve to characterize the assay's performance across different conditions, which is analogous to how a system is "trained" or refined during development, but not in the sense of a distinct machine learning training set. The "assay cut-off" was established using a separate set of 141 clinical samples, which could be considered a form of calibration/training for the threshold of positivity.

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

   • As noted above, a traditional "training set" for an AI model is not applicable here. For the establishment of the assay cut-off (using 141 clinical samples), the ground truth was established using the same "composite reference method" (FDA-cleared real-time PCR assay combined with PCR amplification and bidirectional sequencing). For other analytical studies (like LoD, inclusivity, cross-reactivity), quantitated viral strains or characterized organisms were used as the reference.

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The DiaSorin Molecular Simplexa™ HSV 1 & 2 Direct assay is intended for use on the LIAISON® MDX instrument for the qualitative detection and differentiation of herpes simplex virus (HSV-2) DNA present in mucocutaneous and cutaneous lesion swabs from patients with signs and symptoms of HSV-1 or HSV-2 infection. This test is an aid in the differential diagnosis of HSV-1 and HSV-2 infections.

The assay is not intended for use as a screening test for the presence of HSV-2 in blood or blood products. The assay is for professional use only.

Simplexa™ HSV 1 & 2 Positive Control Pack MOL2160

The Simplexa™ HSV 1 & 2 Positive Control Pack is intended to be used as a control with the Simplexa™HSV 1 & 2 Direct kit.

This control is not intended for use with other assays or systems.

The Simplexa™ HSV 1 & 2 Direct assay system is a real-time PCR that enables the direct amplification, detection and differentiation of HSV-1 and/or HSV-2 DNA from unprocessed cutaneous and mucocutaneous lesion swab specimens without nucleic acid extraction. The system consists of the Simplexa™ HSV 1 & 2 Direct assay, the LIAISON® MDX (with LIAISON® MDX Studio Software), the Direct Amplification Disc and associated accessories.

In the Simplexa™ HSV 1 & 2 Direct assay, bi-functional fluorescent probe-primers are used together with corresponding reverse primers to amplify HSV-1, HSV-2 and internal control targets. Well conserved regions of the HSV-1 and HSV-2 DNA polymerase genes are targeted to identify HSV-1 and HSV-2 DNA respectively in the specimen. An internal control is used to detect PCR failure and/or inhibition.

Here's a breakdown of the acceptance criteria and study information for the Simplexa™ HSV 1 & 2 Direct device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria (e.g., "PPA must be ≥ 95%"). Instead, it presents the "Clinical Agreement" results from validation studies and implies that these figures demonstrate acceptable performance for clearance. Therefore, the "acceptance criteria" listed below are inferred from the reported performance, representing the observed outcomes deemed sufficient for the device to be considered substantially equivalent.

Note on "Acceptance Criteria": The document provides the study results directly. For diagnostics, these agreement percentages are typically compared against pre-specified acceptance criteria. The absence of explicit acceptance criteria in the provided text implies that the reported performance was considered adequate for FDA clearance.

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

• Prospective Study 1 (K150962 data, re-used):
  • Original Collected: 718 samples
  • Evaluated: 696 samples (after removals for various reasons like not tested, invalid results, internal control failure, wrong sample type, insufficient volume, control issues, non-enrollable)
  • Data Provenance: From 6 geographically diverse locations, prospectively collected from May 28, 2014, through December 4, 2014.
• Prospective Study 2 (K173798 data):
  • Original Collected: 514 samples
  • Evaluated:
    • 511 samples for Simplexa™ HSV 1 & 2 Direct
    • 512 samples for culture method
    • 510 samples for bi-directional sequencing method (after removals for EC505 codes, insufficient volume, daily control issues, non-enrollable)
  • Data Provenance: From 4 geographically diverse sites, prospectively collected from July 24, 2017, through October 11, 2017.
• Retrospective Study:
  • Evaluated: 174 Cutaneous HSV-1 swabs, 174 Mucocutaneous HSV-2 swabs, and 17 samples from unknown locations.
  • Data Provenance: Retrospectively collected from June 6, 2011, to May 17, 2014, and February 21, 2017, through July 17, 2017.

All clinical samples were cutaneous and mucocutaneous lesion swabs from patients with signs and symptoms of HSV-1 or HSV-2 infection.

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

The document does not specify the number or qualifications of experts for establishing ground truth. The ground truth was established using a "composite comparator algorithm" rather than expert opinion alone.

4. Adjudication Method for the Test Set

The ground truth was established using a composite comparator algorithm based on a "2 out of 3 rule":

• Components: Culture, bi-directional sequencing, and an FDA-cleared NAAT (Nucleic Acid Amplification Test).
• Method: Any sample yielding a positive result by either sequencing or culture was then tested on an FDA-cleared NAAT. A "2 out of 3 rule" (implying agreement between at least two of the three methods) was used to determine the final composite results.
• Note: For culture, HSV-2 was tested first. If positive for HSV-2, no further culture testing was done (meaning dual positives could not be identified by culture alone).

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not explicitly done. The study focuses on evaluating the device's performance against a composite reference method, not on human reader performance with or without AI assistance. The device is a molecular diagnostic assay, not an AI-assisted diagnostic tool for human readers.

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 Simplexa™ HSV 1 & 2 Direct assay, which is a real-time PCR system. This system performs direct amplification, detection, and differentiation of HSV-1 and HSV-2 DNA from unprocessed swab specimens, without requiring human interpretation of results beyond reading the instrument's output. The "algorithm" here refers to the PCR assay's mechanics and the LIAISON® MDX instrument's software for detection.

7. The Type of Ground Truth Used

The ground truth for the clinical studies was a composite comparator algorithm consisting of:

• Cell culture
• Bi-directional sequencing
• An FDA-cleared NAAT

This is considered a robust method for establishing ground truth in molecular diagnostics, combining phenotypic (culture) and genotypic (sequencing, NAAT) evidence.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning, as this is a molecular diagnostic assay cleared through substantial equivalence, not an AI/ML-based device requiring separate training and test sets in that sense. The analytical studies (reproducibility, LoD, cross-reactivity, interference) use contrived samples and defined panels. The "clinical agreement" uses the prospective and retrospective patient samples as the validation/test sets to demonstrate performance against the composite reference standard.

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

As stated above, no "training set" in the AI/ML context is described. For the analytical studies, the "ground truth" (e.g., presence/absence and concentration of a virus, presence of cross-reactants/interferents) was established by using:

• Quantified stocks of HSV-1 and HSV-2 (for Limit of Detection, Analytical Reactivity).
• Known concentrations of various microorganisms and substances (for Cross-Reactivity and Interference studies).
• Contrived sample pools with known viral loads (for Reproducibility and Competitive Interference).

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The Sentosa® SA201 HSV-1/2 PCR Test is a real-time PCR-based qualitative in vitro diagnostic test for detection and differentiation of Herpes Simplex Virus (HSV-1 and HSV-2) DNA from male and female skin lesions from anogenital or oral sites. The test is intended for use as an aid in diagnosis of herpes infection in symptomatic patients.

Warning: The Sentosa® SA201 HSV-1/2 PCR Test is not FDA cleared for use with cerebrospinal fluid (CSF). The test is not intended to be used for prenatal screening.

The Sentosa® SA201 HSV-1/2 PCR Test is a (4x24) configuration contains reagents and enzymes for specific amplification of a 104 bp (base-pair) fragment of the UL30 gene common to both HSV1 and HSV2, and specific probes for the direct detection and differentiation of HSV1 and HSV2 amplicons, respectively. Pathogen detection by PCR is based on the amplification of specific regions of the pathogen genome. In real-time PCR, the amplified product is detected via fluorescent dyes, which are usually linked to oligonucleotide probes that bind specifically to the target sequences. Real-time monitoring of the fluorescence intensities during a PCR run allows the detection of the accumulating product. Amplification of the targets occurs in three channels: green, orange and red on the Sentosa® SA201. Output is recorded as the increase of fluorescence over time in comparison to background signal. Monitoring the fluorescence intensities during the PCR run allows the detection of the accumulating product without having to re-open the reaction tubes after the PCR run.

The Sentosa® SA201 HSV-1/2 PCR Test workflow starts with extraction of nucleic acids from samples (anogenital or oral swabs) using the Sentosa® SX Virus Total Nucleic Acid Kit on the Sentosa SX101 instrument. Following extraction, the instrument will automatically set up the PCR with the extracted nucleic acids in a 96-well PCR plate. Subsequently, the 96-well PCR plate is sealed and transferred to the Sentosa® SA201 for PCR amplification, followed by data analysis.

The Sentosa® Link facilitates data transfer between the Sentosa® SX101, the Sentosa® SA201 Reporter and existing LIS/LIMS (laboratory information systems) in the clinical lab. The Sentosa SX101 instrument communicates with Sentosa® SA201 thermocycler. This creates a user environment that links the SX101 and the Sentosa® SA201 to facilitate automated workflow to export results in a LIS/LIMS-compatible format.

The provided document describes the analytical and clinical performance of the Sentosa SA201 HSV-1/2 PCR Test, a qualitative in vitro diagnostic test for the detection and differentiation of Herpes Simplex Virus (HSV-1 and HSV-2) DNA. It is not an AI/ML-based device. Therefore, the questions related to AI/ML specific aspects (e.g., number of experts, adjudication, MRMC study, training set, ground truth for training set) are not applicable. The information focuses on the device's ability to accurately detect and differentiate HSV-1 and HSV-2 DNA in patient samples.

Here's an analysis of the provided information, focusing on the device's acceptance criteria and the studies proving it meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in a single table, but the performance studies demonstrate implied criteria. For diagnostic devices like this, the key performance metrics are sensitivity, specificity, limit of detection (LoD), precision, and freedom from interference.

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The Solana® HSV 1+2/VZV Assay is an in vitro diagnostic test, using isothermal amplification technology (helicase-dependent amplification, HDA), for the qualitative detection and differentiation of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus DNA isolated and purified from cutaneous or mucocutaneous lesion samples obtained from symptomatic patients suspected of active herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster infection. The Solana® HSV 1+2/VZV Assay is intended to aid in the diagnosis of herpes simplex virus 1, herpes simplex virus 2 and varicella-zoster virus active cutaneous or mucocutaneous infections. Negative results do not preclude herpes simplex virus 1, herpes simplex virus 2 and varicella-zoster virus infections and should not be used as the sole basis for diagnosis, treatment or other management decisions. The Solana® HSV 1+2/VZV Assay is intended for use only with the Solana® instrument.

Warning: The Solana® HSV 1 + 2/VZV Assay is not intended for use with cerebrospinal fluid or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS). The Solana® HSV 1 + 2/VZV Assay is not intended for use in prenatal screening.

The Solana® HSV 1+2/VZV Assay amplifies and detects viral DNA isolated from cutaneous or mucocutaneous lesion samples obtained from symptomatic patients suspected of active herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster infection.

The assay consists of two (2) major steps: 1) specimen preparation, and 2) amplification and detection of target sequence specific to HSV-1, HSV-2 and/or VZV using isothermal Helicase-Dependent Amplification (HDA) in the presence of target-specific fluorescence probe.

Patient specimen is transferred to a Process Tube, subjected to heat treatment at 95°C for 5 minutes and mixed and vortexed. The processed sample is transferred to a Reaction Tube and mixed. The Reaction Tube contains lyophilized HDA reagents, dNTPs, primers and probes. Once rehydrated with the diluted sample, the Reaction Tube is placed in Solana for amplification and detection of specific target sequence. In Solana, the target sequences are amplified by HSV-1, HSV-2 and/or VZV specific primers and detected by HSV-1, HSV-2 and/or VZV specific fluorescence probes included in the Reaction Tube. A competitive process control (PRC) is included in the Process Tube to monitor sample processing, inhibitory substances in clinical samples, reagent failure or device failure. The PRC target is amplified by specific primers and detected by a PRC specific fluorescence probe.

The target and PRC probes are labeled with a quencher on one end and a fluorophore on the other end. In addition, the target and PRC probes carry a ribonucleic acid. Upon annealing to HSV-1, HSV-2, VZV or PRC amplicons, the fluorescence probes are cleaved by RNaseH2 and the fluorescence signal increases due to physical separation of fluorophore from quencher. Solana measures and interprets the fluorescent signal, using on-board method-specific algorithms. Solana will then report the test results to the user on its display screen, and the results can be printed via an attached printer.

{
  "1. A table of acceptance criteria and the reported device performance": {
    "HSV-1 Cutaneous Lesions": {
      "Acceptance Criteria": {
        "Sensitivity": "≥ 85%",
        "Specificity": "≥ 95%"
      },
      "Reported Device Performance": {
        "Sensitivity": "100% (95% CI: 85.1% to 100%)",
        "Specificity": "97.8% (95% CI: 95.0% to 99.1%)"
      }
    },
    "HSV-2 Cutaneous Lesions": {
      "Acceptance Criteria": {
        "Sensitivity": "≥ 85%",
        "Specificity": "≥ 95%"
      },
      "Reported Device Performance": {
        "Sensitivity": "92.3% (95% CI: 75.9% to 97.9%)",
        "Specificity": "94.4% (95% CI: 90.8% to 96.6%)"
      }
    },
    "VZV Cutaneous Lesions": {
      "Acceptance Criteria": {
        "Sensitivity": "≥ 85%",
        "Specificity": "≥ 95%"
      },
      "Reported Device Performance": {
        "Sensitivity": "100% (95% CI: 85.1% to 100%)",
        "Specificity": "96.5% (95% CI: 93.0% to 98.3%)"
      }
    },
    "HSV-1 Mucocutaneous Lesions": {
      "Acceptance Criteria": {
        "Sensitivity": "≥ 85%",
        "Specificity": "≥ 95%"
      },
      "Reported Device Performance": {
        "Sensitivity": "100% (95% CI: 96.7% to 100%)",
        "Specificity": "96.4% (95% CI: 94.0% to 97.8%)"
      }
    },
    "HSV-2 Mucocutaneous Lesions": {
      "Acceptance Criteria": {
        "Sensitivity": "≥ 85%",
        "Specificity": "≥ 95%"
      },
      "Reported Device Performance": {
        "Sensitivity": "99.1% (95% CI: 95.0% to 99.8%)",
        "Specificity": "97.2% (95% CI: 95.4% to 98.3%)"
      }
    },
    "VZV Mucocutaneous Lesions": {
      "Acceptance Criteria": {
        "Sensitivity": "≥ 85%",
        "Specificity": "≥ 95%"
      },
      "Reported Device Performance": {
        "Sensitivity": "100% (95% CI: 51.0% to 100%)",
        "Specificity": "98.6% (95% CI: 96.9% to 99.4%)"
      }
    },
    "HSV-1 Uncategorized Lesions": {
      "Acceptance Criteria": {
        "Sensitivity": "≥ 85%",
        "Specificity": "≥ 95%"
      },
      "Reported Device Performance": {
        "Sensitivity": "100% (95% CI: 86.7% to 100%)",
        "Specificity": "97.6% (95% CI: 93.1% to 99.2%)"
      }
    },
    "HSV-2 Uncategorized Lesions": {
      "Acceptance Criteria": {
        "Sensitivity": "≥ 85%",
        "Specificity": "≥ 95%"
      },
      "Reported Device Performance": {
        "Sensitivity": "100% (95% CI: 82.4% to 100%)",
        "Specificity": "96.6% (95% CI: 92.3% to 98.6%)"
      }
    },
    "VZV Uncategorized Lesions": {
      "Acceptance Criteria": {
        "Sensitivity": "≥ 85%",
        "Specificity": "≥ 95%"
      },
      "Reported Device Performance": {
        "Sensitivity": "100% (95% CI: 81.6% to 100%)",
        "Specificity": "94.1% (95% CI: 87.8% to 97.3%)"
      }
    }
  },
  "2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)": {
    "Total Sample Size": "1062 fresh lesion specimens (combined Cutaneous, Mucocutaneous, and Uncategorized)",
    "Data Type": "Prospective study",
    "Country of Origin": "United States (three sites across the United States)",
    "Specific Sample Sizes by Lesion Type for Clinical Performance": {
      "Cutaneous Lesions (HSV-1)": "249 specimens",
      "Cutaneous Lesions (HSV-2)": "275 specimens",
      "Cutaneous Lesions (VZV)": "222 specimens",
      "Mucocutaneous Lesions (HSV-1)": "501 specimens",
      "Mucocutaneous Lesions (HSV-2)": "610 specimens",
      "Mucocutaneous Lesions (VZV)": "372 specimens",
      "Uncategorized Lesions (HSV-1)": "148 specimens",
      "Uncategorized Lesions (HSV-2)": "166 specimens",
      "Uncategorized Lesions (VZV)": "119 specimens"
    }
  },
  "3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)": "Not specified. The ground truth was established by comparator methods (ELVIS cell culture system for HSV-1/2 and H&V mixed cells with DFA for VZV), which are FDA-cleared laboratory methods, rather than expert consensus on images or other forms of data typically requiring expert review.",
  "4. Adjudication method (e.g. 2+1, 3+1, none)  for the test set": "For discrepant results between the Solana assay and the primary comparator method, an additional RT-PCR assay was used for secondary adjudication. The document notes how many of the discrepant cases were resolved by this additional RT-PCR assay (e.g., 'Three (3) of the five (5) positives was positive by an additional RT-PCR assay' for HSV-1 cutaneous lesions). This indicates a form of adjudication involving a third, independent 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": "Not applicable. This is a molecular diagnostic assay, not an imaging device that uses AI for interpretation by human readers. The clinical study compares the device's performance against established laboratory methods.",
  "6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done": "Yes, a standalone study was conducted. The Solana® HSV 1+2/VZV Assay is an in vitro diagnostic test that processes specimens and provides results using on-board method-specific algorithms on the Solana® instrument. The reported performance characteristics (clinical sensitivity and specificity) are for the device operating as a standalone system against the comparator methods.",
  "7. The type of ground truth used (expert concensus, pathology, outcomes data, etc)": "Laboratory comparator methods: ELVIS cell culture system for HSV-1 and HSV-2, and H&V mixed cells with DFA cell culture systems for VZV. Discrepancies were resolved using an additional RT-PCR assay.",
  "8. The sample size for the training set": "Not explicitly stated for a distinct training set. The descriptions focus on the performance evaluation of the final device. For analytical performance (e.g., LOD, cross-reactivity, interference), contrived samples and specific strains were used for testing, but these are not referred to as a 'training set' in the context of machine learning. Clinical studies used fresh lesion specimens as described in section 2.",
  "9. How the ground truth for the training set was established": "Not applicable, as a distinct training set (in the machine learning sense) with established ground truth is not described for this diagnostic device. Analytical sensitivities (LOD) were determined using quantified viral cultures (TCID50/mL), which would serve as a 'truth' for analytical performance testing."
}

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The Luminex® ARIES® M1 System is an in vitro diagnostic (IVD) platform that performs nucleic acid based tests in clinical laboratories. The Luminex ARIES® M1 System is capable of automated extraction and purification of nucleic acids from multiple sample types as well as the automated amplification of target nucleic acid sequences by fluorescence-based PCR.

Not Found

This document is a FDA clearance letter for the Luminex ARIES® M1 System, an in vitro diagnostic (IVD) platform. It primarily describes the regulatory approval rather than a detailed study proving the device meets specific acceptance criteria with performance metrics.

Therefore, the requested information about acceptance criteria, device performance, sample sizes, ground truth establishment, expert qualifications, and specific study designs (like MRMC or standalone performance) is not available within the provided text.

The document states the "ARIES® M1 System is an in vitro diagnostic (IVD) platform that performs nucleic acid based tests in clinical laboratories" and that it "is capable of automated extraction and purification of nucleic acids from multiple sample types as well as the automated amplification of target nucleic acid sequences by fluorescence-based PCR." This is a description of its capabilities rather than performance statistics.

To answer your request, a detailed performance study report from Luminex Corporation would be required, which is typically a separate document submitted to the FDA as part of the 510(k) application, but not included in this clearance letter.

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The ARIES® HSV 1&2 Assay is a real-time polymerase chain reaction (PCR) based qualitative in vitro diagnostic test for the direct detection and differentiation of Herpes Simplex Virus 1 and HSV 2) DNA in cutaneous or mucocutaneous lesion specimens from symptomatic patients. The test is indicated for use as an aid in diagnosis of HSV infection in symptomatic patients. The ARIES® HSV 1&2 Assay is indicated for use on the ARIES® System.

WARNING: The ARIES® HSV 1&2 Assay is not FDA cleared for use with cerebrospinal fluid (CSF). The assay is not intended to be used for prenatal screening.

The Luminex ARIES® HSV 1 & 2 Kit is a polymerase chain reaction (PCR)-based qualitative in vitro diagnostic test for the direct detection and differentiation of herpes simplex virus (HSV) DNA using cutaneous and mucocutaneous lesion swab specimens. Patient lesion swab specimens are collected in Copan Universal Transport Medium, or identical Copan manufactured media formulations (Becton Dickinson Universal Viral Transport Media, Copan branded Universal Transport Medium for LabCorp, and the Quest Viral Culture Media) and transported to the laboratory. The specimen is pipetted into a cassette specific to the ARIES® HSV 1&2 Assay. In the cassette the specimen is lysed and nucleic acid is extracted using the ARIES® System and an extraction/ PCR cassette specific to the ARIES® HSV 1&2 Kit. An extractable sample processing control (SPC) target is present in the ARIES® HSV 1&2 assay cassette and is processed with the specimen. The Ct value of the SPC is designed to verify proper specimen lysis and nucleic acid extraction, to identify PCR inhibition, if any, and verify proper function of the extraction system and real-time instrument. The Tm value of the SPC is used as a reference for determining the target Tm.

The extracted nucleic acid is transferred via magnetic beads to the ARIES® HSV 1 & 2 Kit lyophilized PCR reagents in the cassette that contain a primer pair specific to HSV 1 and a primer pair specific to the SPC sequence. The specific primer pairs are labeled with distinct fluorophore labels. PCR amplification is performed and assay fluorescence is monitored on the Luminex ARIES® System. Incorporation of the quencher-labeled nucleotide causes a decrease in assay fluorescence. Following amplification, the reaction is slowly heated and fluorescence is monitored. The strands of the amplification products will separate at a specific melting temperature (Tm) that is determined by an increase in fluorescence as the strands are separated. The sequences between the PCR primer binding sites of the HSV 1 and HSV 2 amplicons have different base compositions that are distinguished by their different Tm. The instrument fluorescence output is analyzed and test results are determined using the ARIES® HSV 1 & 2 Kit assay protocol file. A printed results report is generated.

The Luminex ARIES® HSV 1&2 Assay chemistry is based on an expanded genetic alphabet technology, consisting of synthetic DNA base pair 2'-deoxy-5-methyl-isocytidine (iC): 2'deoxyisoguanosine (iG). The isobases ( iC and iG) pair specifically with each other and not with natural nucleotides. In addition isobases are efficiently incorporated during PCR. During PCR amplification, a quencher-modified iGTP is incorporated by the polymerase opposite an iC and a fluorophore reporter attached to a PCR primer. If the target is present and is amplified, assay fluorescence decreases with every cycle as amplification product accumulates. The decrease in assay fluorescence is monitored in real time using the Luminex ARIES® Instrument. Following PCR, the amplification products are thermally denatured and assay fluorescence is monitored. The strands of the amplification products are separated and assay fluorescence increases, thus enabling determination of the melting temperature (Tm) of the amplicon.

Here's an analysis of the acceptance criteria and study details for the ARIES® HSV 1&2 Assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in a single, defined table. However, analytical and clinical performance metrics are provided and can be inferred as the criteria against which the device's performance was judged.

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

• Clinical Test Set: A total of 1963 left-over clinical specimens were initially included.
  • 1500 specimens were prospectively collected ("all comers").
  • 463 specimens were pre-selected (also prospectively collected) to ensure representation of under-represented lesion types.
  • 62 specimens were excluded from accuracy determinations (55 undeclared anatomical sites, 4 invalid upon re-testing, 3 unavailable for re-testing).
  • Actual N values for clinical performance tables vary (e.g., N=347 for HSV-1 Cutaneous, N=1190 for HSV-1 Mucocutaneous, N=448 for HSV-2 Cutaneous, N=1453 for HSV-2 Mucocutaneous), reflecting subsets analyzed.
• Data Provenance: The clinical study was conducted at three (3) geographically diverse clinical sites in the United States. The data were collected prospectively.

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

The document does not specify the number or qualifications of experts used to establish the ground truth. The "reference/comparative method" used was the ELVIS HSV ID and D3 Typing Test System (a viral culture-based method). For discrepant results, bi-directional sequencing analysis using analytically validated primers was used as a supplemental reference. This implies that the ground truth was established by laboratory testing methods rather than by expert clinical consensus from a panel.

4. Adjudication Method for the Test Set

The primary reference method was the ELVIS viral culture. When the ARIES® HSV 1&2 Assay results differed from the ELVIS method, bi-directional sequencing analysis was performed as a confirmatory method for discrepancy resolution. This acts as a form of "adjudication" where a third, presumably more definitive, method is used to resolve conflicts between the index test and the primary reference.

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 study was described. This device is a fully automated in vitro diagnostic test for direct detection of viral DNA, not an imaging or diagnostic aid that requires human interpretation. Therefore, the concept of "human readers improving with AI" is not applicable here.

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

Yes, the clinical performance study describes the standalone performance of the ARIES® HSV 1&2 Assay, comparing its results directly against the reference method (ELVIS viral culture, with sequencing for discrepancy resolution). The device itself is an automated system (ARIES® System) that performs nucleic acid extraction, amplification, and detection without human intervention in the result generation process.

7. The Type of Ground Truth Used

The ground truth for the clinical study was established using a reference laboratory method:

• Primary Reference: ELVIS HSV ID and D3 Typing Test System (viral culture).
• Discrepancy Resolution/Confirmatory: Bi-directional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARIES® HSV 1&2 Assay. This can be considered a highly accurate laboratory-based ground truth.

8. The Sample Size for the Training Set

The document provided is a 510(k) summary for a diagnostic assay, which typically doesn't involve "training sets" in the same way machine learning algorithms do. The "assay" defines the biochemical and molecular components (primers, probes, reagents, protocol file) and the "system" (ARIES® System) is the instrument. These are developed and validated through analytical studies (LoD, specificity, reproducibility, etc.) and then clinically evaluated.

Therefore, there is no explicit "training set" sample size mentioned for a machine learning model, as this is a traditional in vitro diagnostic device, not an AI/ML-based one. The development of such assays involves extensive analytical testing of reagents and instrument parameters, which could be seen as an iterative "training" process for the assay design, but this is not reported in terms of "training set" sample sizes in the context of typical AI device submissions.

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

Since there is no "training set" in the AI/ML sense, this question is not directly applicable. The assay's performance characteristics (e.g., optimal primer design, reaction conditions, melting temperature thresholds) would have been established during the development and optimization phases before the formal validation studies, using internal R&D samples and controls. The specifics of how these internal "ground truths" were established for assay development are not detailed in this regulatory submission.

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