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The Liat™ Strep A Assay, performed on the Liat™ Analyzer, is a qualitative in vitro diagnostic test for the detection of Streptococus pyogenes (Group A 8-hemolytic Streptococcus, Strep A) in throat swab specimens from patients with signs and symptoms of pharyngitis.

The Liat™ Strep A Assay utilizes nucleic acid purification and polymerase chain reaction (PCR) technology to detect Streptococcus pyogenes by targeting a segment of the Streptococcus pyogenes genome.

The Liat™ Strep A Assay, performed on the Liat™ Analyzer, is a rapid, automated in vitro diagnostic test for the qualitative detection of Streptococcus pyogenes (Group A B-hemolytic Streptococcus, Strep A) DNA in throat swab specimens in Amies medium.

The Liat™ Strep A Assay targets a well-conserved region of Strep A genome. An Internal Process Control (IPC) is also included. The IPC is present to control for adequate processing of the target bacteria through all steps of the assay process and to monitor the presence of inhibitors in the sample preparation and PCR. The sample-to-result time is ~15 minutes.

The assay utilizes a single-use disposable Liat™ Tube that holds the sample purification and PCR reagents, and hosts the sample preparation and PCR processes. The Liat™ Tube contains all required unit dose reagents pre-packed in tube segments, separated by peelable seals, in the order of reagent use.

The Liat™ Analyzer automates and integrates sample purification, nucleic acid amplification, and detection of the target sequence in biological samples. The Liat™ Analyzer performs all assay steps from clinical sample and reports assay result automatically. During the testing process, multiple sample processing actuators of the analyzer compress the Liat™ Tube to selectively release reagents from tube segments, move the sample from one segment to another, and control reaction volume, temperature, and time to conduct sample preparation, nucleic acid extraction, target enrichment, inhibitor removal, nucleic acid elution and real-time PCR. An embedded microprocessor controls and coordinates the actions of these sample processors to perform all required assay processes within the closed Liat™ Tube.

Positive and negative controls are provided in the Liat™ Strep A Assay Quality Control Kit. The positive control comprises inactivated Strep A bacteria in a dried format. The negative control comprises Amies medium.

To perform the Liat™ Strep A Assay, an operator first collects a throat swab and places the swab into Amies transport medium. The operator transfers the sample into the Liat™ Strep A Assay tube using a transfer pipette, and scans the tube barcode to identify the test and the sample barcode to code the sample ID with the assay run on the Liat™ Analyzer. The Liat™ Tube is then inserted into the Liat™ Analyzer. The analyzer performs all the test steps and outputs interpreted results (e.g. Strep A Detected, Strep A Not Detected) in ~15 minutes. A report of the interpreted results can be viewed on the Liat™ Analyzer's LCD screen, and printed directly through a USB or network connected printer. No reagent preparation or additional steps are required other than adding the sample to the Liat™ Tube. Because all the reagents are contained within the Liat™ assay tube and no sample or reagent needs to be removed from the tube, crosscontamination between samples is minimized.

The results are interpreted by the Liat™ Analyzer software from measured fluorescent signals and real time curve recognition algorithm.

Here's a breakdown of the acceptance criteria and study information for the Liat™ Strep A Assay, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for clinical performance, but rather presents the computed clinical performance metrics. For analytical performance, criteria are implied by the results (e.g., 95% detection for LOD, absence of cross-reactivity).

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

• Clinical Test Set Sample Size: 570 throat swab specimens were analyzed for clinical performance. An additional 7 specimens initially yielded invalid/indeterminate/aborted results, bringing the total to 577 specimens processed.
• Data Provenance: The clinical study was conducted at six clinical sites in the United States (geographically distinct regions) between December 2013 and April 2014. This indicates a prospective collection of real-world clinical samples.

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. It states that "Performance characteristics of the assay were determined by comparison to culture and latex agglutination for Strep A typing. Discordant results were investigated using PCR and bi-directional sequencing based on published methods." This implies laboratory personnel with expertise in microbiology, culture techniques, latex agglutination, PCR, and sequencing.

4. Adjudication Method for the Test Set

The adjudication method for the clinical test set was:

• Initial comparison: Liat™ Strep A Assay results vs. culture and latex agglutination.
• Discordant results investigation: PCR and bi-directional sequencing.
  • For the 23 Liat positive, culture negative specimens, all 23 were confirmed Strep A positive by PCR/sequencing.
  • For the 3 Liat negative, culture positive specimens, all 3 were confirmed Strep A positive by PCR/sequencing. (Re-testing with Liat also yielded positive results for these 3).

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done for this device. The Liat™ Strep A Assay is an automated in vitro diagnostic test for the qualitative detection of DNA, not an imaging device requiring human interpretation, so MRMC studies are not applicable in this context. It's a standalone device that provides an automated result.

6. Standalone (Algorithm Only) Performance

Yes, the study presents standalone performance. The Liat™ Strep A Assay is an automated system where the analyzer performs all test steps and outputs interpreted results (e.g., "Strep A Detected," "Strep A Not Detected") directly. The results are interpreted by the Liat™ Analyzer software using measured fluorescent signals and a real-time curve recognition algorithm.

7. Type of Ground Truth Used

The ground truth for the clinical study was established using a combination of methods:

• Microbial Culture: The primary comparative method for detecting Streptococcus pyogenes (Group A ß-hemolytic Streptococcus) in throat swab specimens.
• Latex Agglutination: Used for Strep A typing in conjunction with culture.
• PCR and Bi-directional Sequencing: Used as a reference method to resolve discordant results between the Liat™ assay and the primary culture/latex agglutination method. This serves as a highly specific molecular confirmation.

8. Sample Size for the Training Set

The document does not explicitly mention a separate "training set" or its size. For in vitro diagnostic devices like the Liat™ Strep A Assay, method development and initial algorithm design would typically involve a range of known positive and negative samples, and potentially spiked samples, to establish parameters like cut-offs and curve recognition algorithms.

The analytical performance studies (LOD, reactivity, cross-reactivity, interfering substances, etc.) used various biological and chemical samples to characterize the assay's behavior. For instance, the assay cut-offs were determined through "analysis of a combination of negative clinical samples that were spiked with different strains of S. pyogenes at the LOD target level." This could be considered part of the internal development and tuning process, which might be analogous to a training or development dataset in some contexts, but not typically reported as a formalized "training set" in the same way as machine learning models.

9. How the Ground Truth for the Training Set (or assay development) Was Established

As noted above, a formal "training set" with ground truth establishment is not detailed. However, for the development of cut-offs and algorithms, the ground truth was established by:

• Spiking studies: Negative clinical samples were spiked with known concentrations of different strains of S. pyogenes at target LOD levels. This engineered ground truth allows the system to learn to differentiate true positives from negatives and establish appropriate thresholds (Ct value and endpoint amplitude cut-offs) and curve recognition algorithms using known concentrations of bacteria.
• Controlled experiments: Analytical studies like LOD, reactivity, and cross-reactivity used pre-characterized strains and samples, where the presence or absence of specific microbes and their concentrations were known.

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The IQuum Liat™ Influenza A/B Assay performed on the Liat™ Analyzer is an automated multiplex real-time RT-PCR assay for the rapid in vitro qualitative detection and discrimination of influenza A virus and influenza B virus RNA in nasopharyngeal swab specimens from patients with signs and symptoms of respiratory infection in conjunction with clinical and epidemiological risk factors. The test is intended for use as an aid in the differential diagnosis of influenza A and influenza B in humans and is not intended to detect influenza C.

Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other patient management decisions. Conversely, positive results do not rule-out bacterial infection or co-infection with other viruses. The agent detected may not be the definite cause of disease.

Performance characteristics for influenza A were established when influenza A/H1 and A/H3 were the predominant influenza A viruses in circulation. When other influenza A viruses are emerging, performance characteristics may vary.

If infection with a novel influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent Influenza viruses and sent to state or local health department for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

The Liat™ Influenza A/B Assay is a rapid, automated in vitro diagnostic test for the detection and differentiation of Influenza type A and type B viral RNA in nasopharyngeal swab (NPS) specimens in universal transport media (UTM) from patients signs and symptoms of respiratory infection. The assay targets a well-conserved region of the matrix gene of Influenza A viral RNA (Inf A target) and non-structural protein (NS) gene of Influenza B (Inf B target). An Internal Process Control (IPC) is also included. The IPC is present to control for adequate processing of the target viruses and to monitor the presence of inhibitors in the RT-PCR reactions.

The Liat Influenza A/B Assay is performed on the lab-in-a-tube technology platform. The system consists of a disposable Liat Influenza A/B Assay Tube and the Liat™ Analyzer. The Liat™ Tube uses a flexible tube as a sample vessel. It contains all required unit dose reagents prepacked in tube segments, separated by peelable seals, in the order of reagent use. Manipulating a Liat Tube, the Liat Analyzer performs all assay steps from raw sample and report assay result automatically, During the testing process, multiple sample processing actuators of the analyzer compress the Liat Tube to selectively release reagents from tube segments, move the sample from one segment to another, and control reaction volume, temperature and time to conduct sample preparation, nucleic acid extraction, target enrichment, inhibitor removal, nucleic acid elution and real-time RT-PCR. An embedded microprocessor controls and coordinates the actions of these sample processors to perform all required assay processes within the closed Liat Tube. Turnaround time from sample input to result is ~20 minutes.

1. Table of Acceptance Criteria and Reported Device Performance:

The document provided is a 510(k) Summary for the IQuum Liat™ Influenza A/B Assay and Liat™ Analyzer, a diagnostic device. For diagnostic devices like this, "acceptance criteria" are typically defined by performance metrics (e.g., sensitivity, specificity, accuracy) that demonstrate the new device is "substantially equivalent" to a legally marketed predicate device. While explicit numerical acceptance criteria are not always stated directly in the summary, the study's results (performance) serve to demonstrate this equivalence. The key performance indicators presented are clinical agreement (sensitivity and specificity) and analytical performance (limit of detection, reactivity, cross-reactivity, interference, precision, reproducibility).

Here's a table summarizing the reported device performance, which the FDA presumably found acceptable for clearance based on substantial equivalence.

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

• Clinical Test Set Sample Size: A total of 615 clinical specimens were tested.

  • Prospective Samples: 435 samples.
  • Retrospective Samples: 180 samples. (One retrospective sample was excluded from analysis due to being indeterminate by PCR/sequencing and retest, making the effective count 179 for that portion of the analysis).

• Data Provenance (Country of Origin and Retrospective/Prospective):

  • Prospective Samples: Collected from patients with signs and symptoms of influenza in the Eastern and Southwestern US from February 12, 2009, to March 26, 2009. These are prospective samples.
  • Retrospective Samples: Collected between 2008-2010, including 2009 H1N1 samples from the 2009-2010 flu season. These are retrospective samples.

3. Number of Experts and Qualifications for Ground Truth of the Test Set:

For this type of in vitro diagnostic device (IVD), ground truth is established by reference laboratory methods, not by human experts in the sense of radiologists.

• For prospective samples (435 samples): The reference method (ground truth) was Viral Culture and IFA staining. These are standard laboratory techniques for influenza detection, typically performed by trained clinical laboratory personnel. The document does not specify the number of individual experts or their specific qualifications beyond the method itself.
• For retrospective samples (179 samples): The reference method (ground truth) was PCR and bi-directional sequencing based on published methods (Ghedin et al. 2005; Ghedin et al. 2009; World Health Organization Sequencing Primers and Protocols, 2009). Again, this refers to established molecular diagnostic techniques performed by qualified laboratory personnel, rather than a panel of clinical experts adjudicating images or reports.

4. Adjudication Method for the Test Set:

The document describes discordant results investigation for the prospective samples:

• "Discordance results were investigated using PCR and bi-directional sequencing."

This implies that if the Liat™ Assay result differed from the initial Viral Culture/IFA staining result, a third, more definitive molecular method (PCR/sequencing) was used to resolve the discrepancy and establish the "true" status of the sample. This is a common practice in IVD studies and functions as an adjudication method for discordant results.

For the retrospective samples, PCR/sequencing itself served as the primary reference method.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done:

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done.

MRMC studies typically evaluate human reader performance (e.g., radiologists interpreting images) with and without the assistance of an AI algorithm. The IQuum Liat™ Influenza A/B Assay is an automated real-time RT-PCR assay performed on an analyzer. It is an in vitro diagnostic device, not an imaging AI or a decision support system for human readers. Therefore, the concept of human readers improving with AI assistance does not apply in this context.

6. If a Standalone (Algorithm Only without Human-in-the-Loop Performance) was done:

Yes, the performance presented for the Liat™ Influenza A/B Assay is essentially standalone (algorithm only without human-in-the-loop performance).

The device is an automated in vitro diagnostic test. The Liat™ Analyzer performs all assay steps from raw sample and automatically reports results. The user adds the sample, scans barcodes, and inserts the tube, but the detection, amplification, and interpretation are done by the instrument system, not by human interpretation of raw signals. The clinical agreement section evaluates the performance of this automated system directly against the reference methods (viral culture/IFA, PCR/sequencing).

7. The Type of Ground Truth Used:

The types of ground truth used were:

• Viral Culture and IFA staining: For prospective clinical samples.
• PCR and bi-directional sequencing: For retrospective clinical samples, and for resolving discrepancies in prospective samples.

These are established laboratory diagnostic methods considered to be definitive for the presence of influenza viruses.

8. The Sample Size for the Training Set:

The document does not explicitly mention a "training set" size for the Liat™ Influenza A/B Assay. This is common for IVD devices based on RT-PCR; their design is based on known genetic targets, and analytical validation (LOD, reactivity, specificity) uses characterized strains and samples. "Training" in the machine learning sense is not typically applicable or detailed in such 510(k) summaries for IVD assays. The studies described are primarily for analytical and clinical validation of the final device.

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

As no "training set" in the machine learning sense is described for the Liat™ Assay, the establishment of ground truth for such a set is not detailed. However, the ground truth for all samples used in the analytical and clinical performance studies (which would serve a similar purpose of verifying performance) was established using:

• Titered viruses: For Limit of Detection and Reactivity studies, the concentration of viral strains was precisely known (TCID50/mL).
• Characterized pathogens/microorganisms: For Cross-Reactivity and Interference studies, specific strains/species of bacteria and viruses were used at known concentrations (CFU/mL or TCID50/mL).
• Viral culture and IFA staining: For prospective human clinical samples.
• PCR and bi-directional sequencing: For retrospective human clinical samples and for resolving discordant results in prospective samples.

These are all well-established, objective laboratory methods for determining the presence and type of influenza virus or other microorganisms.

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