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The Accula™ Strep A Test performed on the Accula Dock is a molecular in vitro diagnostic test utilizing polymerase chain reaction (PCR) and lateral flow technologies for the qualitative, visual detection of Streptococcus pyogenes (Group A B-hemolytic Streptococcus, Strep A) bacterial nucleic acid. It is intended to aid in the rapid diagnosis of Group A Streptococcus bacterial infections from throat swabs of patients with signs and symptoms of pharyngitis.

All negative test results should be confirmed by bacterial culture because negative results do not preclude infection with Group A Streptococcus and should not be used as the sole basis for treatment.

The Accula™ Strep A Test is a semi-automated, colorimetric polymerase chain reaction (PCR) nucleic acid amplification test to qualitatively detect Streptococcus pyogenes (Group A Bhemolytic Streptococcus, Strep A) bacterial nucleic acid from unprocessed throat swabs that have not undergone prior nucleic acid extraction. The system integrates nucleic acid extraction, a novel Mesa Biotech PCR nucleic acid amplification technology named OscAR™, and hybridization-based visual detection into a completely self-contained and automated system. The Accula Strep A system consists of a small reusable Dock to drive the automated testing process, and a single-use disposable test cassette that contains all the enzymes and reagents.

The Mesa Biotech Accula Strep A Test is an in vitro diagnostic test for the qualitative, visual detection of Streptococcus pyogenes (Group A B-hemolytic Streptococcus, Strep A) bacterial nucleic acid from throat swabs. The device integrates nucleic acid extraction, OscAR™ PCR amplification technology, and hybridization-based visual detection.

Acceptance Criteria and Device Performance:

The primary performance metrics for the Accula Strep A Test were Sensitivity, Specificity, Positive Percent Agreement (PPA), and Negative Percent Agreement (NPA). These were evaluated against a reference bacterial culture and an FDA-cleared molecular comparator.

Study Details:

1. Sample Size and Data Provenance:

   • Test Set (Clinical Study):
     • Evaluable for Accula vs. Culture: 654 samples from 669 enrolled subjects.
     • Evaluable for Accula vs. Molecular Comparator: 648 samples from 669 enrolled subjects.
     • Provenance: Prospective clinical study conducted at nine U.S. sites from May 2019 to January 2020.
   • Reproducibility/Near-Cutoff Study: 90 samples per condition (Low Positive, Moderate Positive, Negative) tested across three CLIA-waived sites. These were contrived throat swabs.
   • Limit of Detection (LoD): Replicates of 20 for confirmatory testing of two Strep A strains.
   • Analytical Reactivity: 3 replicates per strain (4 strains total) at two concentrations.
   • Analytical Specificity (Cross-Reactivity): 3 replicates per organism (47 organisms total), both in presence and absence of Strep A.
   • Interfering Substances: 3 replicates per substance, positive and negative Strep A samples.

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

   • The document does not explicitly state the "number of experts" used to establish the ground truth for the clinical test set. However, for the reference methods:
     • Bacterial Culture (Blood Agar Culture): Performed at a "central laboratory" according to "instructions from the reference laboratory." This implies trained laboratory personnel, but specific qualifications are not detailed.
     • FDA-cleared molecular test (comparator): Performed at the central laboratory.
     • Second FDA-cleared molecular test (discrepant analysis): Used for all discrepant results.

3. Adjudication Method for the Test Set:

   • For the clinical study, a discrepant analysis method was used. "All specimens generating discrepant results between the Accula Strep A Test and Blood Agar Culture, or between Accula and the molecular comparator test, were tested with a second FDA-cleared molecular test." This effectively acts as a "tie-breaker" or confirmatory method for unusual results.

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

   • No MRMC comparative effectiveness study was specifically described in terms of human readers' improvement with AI vs. without AI assistance.
   • However, the Reproducibility/Near-Cutoff Study and the CLIA Waiver Studies involved "non-laboratory personnel" at "CLIA-waived sites" (Point of Care sites) to demonstrate that the device could be accurately used by intended users in the intended environment. This indirectly assesses the effectiveness of the device in the hands of typical users, rather than an AI assistance to human readers.

5. Standalone (Algorithm Only) Performance:

   • Yes, the clinical performance described (Sensitivity, Specificity, PPA, NPA) represents the standalone performance of the Accula Strep A Test against established reference methods (Blood Agar Culture and FDA-cleared molecular tests). The device itself is a semi-automated system; these metrics evaluate its diagnostic accuracy independent of a human interpretation layer (beyond reading the visual result in the lateral flow).

6. Type of Ground Truth Used:

   • For the clinical study, the primary ground truth was bacterial culture (Blood Agar Culture) for Streptococcus pyogenes.
   • A second FDA-cleared molecular test was used as a confirmatory ground truth for discrepant results.
   • Additionally, an FDA-cleared molecular comparator method served as another reference standard for direct comparison.
   • For analytical studies (LoD, Reactivity, Specificity, Interfering Substances), the ground truth was established by contriving samples with known concentrations of specific organisms or substances.

7. Sample Size for the Training Set:

   • The document describes performance studies (validation). It does not provide information on a "training set" in the context of machine learning, as this is a nucleic acid amplification test, not an AI-driven image analysis or algorithm that would typically require a training set. The device's components (enzymes, reagents, PCR technology) are developed and optimized rather than "trained."

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

   • Not applicable as described in item 7. The device operates on molecular principles and does not involve a machine learning training phase with a labeled dataset in the traditional sense.

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The GenePOC"M Strep A assay, performed on the revogene"14 instrument, is an automated, qualitative in vitro diagnostic test that utilizes real-time polymerase chain reaction (PCR) for the direct detection of Streptococcus pyogenes (Group A B-hemolytic Streptococcus) nucleic acids from throat swab specimens obtained from patients with signs and symptoms of pharyngitis. The GenePOC™ Strep A assay is intended for use as an aid in the diagnosis of Group A Streptococcus infection.

The GenePOC™ Strep A assay is a single-use test for qualitative detection of Streptococcus pyogenes (group A Streptococcus - GAS) nucleic acids from throat swab specimens obtained from patients with signs and symptoms of pharyngitis. The GenePOCTM Strep A assay kit is comprised of the disposable Strep A microfluidic cartridge (PIE), Sample Buffer Tube (SBT), and Disposable Transfer Tool (DTT). These components are used to suspend the sample, extract, amplify, and detect Streptococcus pyogenes (S. pyogenes) nucleic acid.

A Process Control (PrC) is also incorporated into each PIE to verify sample processing and amplification steps. The PrC allows for the verification of potential inhibitor substances as well as microfluidic, instrument or reagent failure. The GenePOC™ Strep A assay is designed to be used on the revogene™. The revogene™ is an instrument that automates sample homogenization, sample dilution, cell lysis, DNA amplification and detection of the amplified PCR products.

Each GenePOC™ Strep A assay kit provides components for twenty-four (24) tests. User intervention is required for sample preparation, transferring throat swab specimen into the SBT, using the DTT to transfer the sample into the PIE, and loading the PIE into the revogene™ carousel. Each PIE is a completely integrated closed device in which a sample is dispensed and processed through different microfluidic chambers and channels that allow for the sample processing and subsequent real-time PCR steps.

During the run and at run completion, the results are computed by the revogene™ from measured fluorescent signals and embedded calculation algorithms. The output results include positive, negative, indeterminate, and unresolved. An Early Positive Result Outcome (E-PRO) feature provides positive result if the signal from the target DNA reaches a predetermined threshold before the full PCR cycles have been completion of a run, the user removes the used cartridges and disposes of them in normal biological waste. Results may be viewed, printed, transferred, and/or stored by the user.

The provided text describes the acceptance criteria and the study proving the GenePOC™ Strep A device meets these criteria. Since the document is a 510(k) summary for an in vitro diagnostic (IVD) assay, the acceptance criteria are generally related to analytical performance (e.g., precision, detection limit, inclusivity, specificity, interference) and clinical performance (sensitivity and specificity compared to a reference method). The study design is focused on demonstrating the reliability and accuracy of the diagnostic test in detecting Streptococcus pyogenes.

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

1. Table of Acceptance Criteria and Reported Device Performance

For an IVD such as this, the acceptance criteria are typically implicit in the "Performance Characteristics" section, where the manufacturer demonstrates that the device performs reliably and accurately for its intended use. There are no explicit pass/fail acceptance values stated for each measured characteristic, but the reported performance values are the data presented to demonstrate adequacy.

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

• Clinical Performance Test Set (Clinical Studies):

  • Sample Size: 604 fully compliant prospective specimens.
  • Data Provenance:
    • Country of Origin: Geographically diverse clinical trial sites; two (2) in Canada and six (6) in the United States.
    • Retrospective or Prospective: Prospective multicenter trial. Throat swab specimens were collected from patients with signs and symptoms of pharyngitis.

• Analytical Performance Test Sets (Examples):

  • Within-Laboratory Precision: 240 samples (80 low positive, 80 moderate positive, 80 negative samples) tested over 20 days.
  • Between-Laboratory Reproducibility: 300 samples (90 low positive, 90 moderate positive, 120 negative samples) tested across 3 sites over 5 days.
  • Between-Lot Reproducibility: 300 samples (90 low positive, 90 moderate positive, 120 negative samples) tested across 3 reagent lots over 15 days.
  • Limit of Detection: 24 replicates per concentration per strain (3 strains) with 3 kit lots; confirmation with 20 replicates per strain.
  • Analytical Reactivity/Inclusivity: 9 replicates per strain (12 strains total).
  • Analytical Specificity: 50 analytes, concentrations tested for each.
  • Carry-over and Cross-Contamination: 80 samples for cross-contamination, 80 samples for carry-over.

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

• Clinical Performance Test Set: The ground truth for the clinical study was established by a "Reference Method" which is explicitly stated as culture. The text does not mention the number or qualifications of human experts (e.g., microbiologists, lab technicians) involved in performing or interpreting the reference culture method, as culture is considered the gold standard and its results are objective.
  • For discrepancies in the clinical study, an "alternative PCR with bi-directional sequencing" was performed on the discordant samples. This suggests a secondary method for adjudication rather than expert consensus on the primary ground truth.

4. Adjudication Method for the Test Set

• Clinical Performance Test Set:
  • The primary ground truth was established by the Reference Method (culture).
  • For discordant results between the GenePOC™ Strep A assay and the culture, an alternative PCR with bi-directional sequencing was used for further investigation. This is a form of discrepancy resolution or adjudication for the clinical performance data. The results of this alternative PCR are footnoted in the clinical performance table (e.g., "17 of 24 were Strep A Positive" for samples positive by GenePOC but negative by culture).
  • The text does not indicate a system like 2+1 or 3+1 involving human experts directly adjudicating case outcomes for the primary study endpoint; rather, it uses a technical discrepancy resolution method.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done, What was the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

• Not applicable. This device is an automated, qualitative in vitro diagnostic test for direct detection of nucleic acids. It does not involve human "readers" or image interpretation tasks where AI assistance would directly improve human reader performance. The device provides a direct positive/negative/indeterminate result.

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

• Yes, implicitly. The device, the GenePOC™ Strep A assay on the revogene™ instrument, is described as an "automated, qualitative in vitro diagnostic test." Once the sample is loaded, "No operator intervention is necessary once the PIE is loaded onto the revogene™." The results are "computed by the revogene™ from measured fluorescent signals and embedded calculation algorithms."
• The clinical performance study directly evaluates this standalone performance (assay results vs. culture ground truth). The human element is in sample preparation and loading, but the detection and result interpretation are automated by the device.

7. The Type of Ground Truth Used

• Clinical Performance Test Set: Culture (for Streptococcus pyogenes). This is the traditional "gold standard" for bacterial identification in clinical microbiology.
• Analytical Performance Test Sets: Defined scientific standards, such as known concentrations of specific bacterial strains (CFU/mL), absence of target (negative matrix), and specific interfering substances, or bioinformatic analysis for sequence specificity.

8. The Sample Size for the Training Set

• This document is a 510(k) summary for an IVD test, not a machine learning or AI algorithm summary. The "device" here refers to a diagnostic assay kit used on an automated instrument.
• The assay's "embedded calculation algorithms" determine the results based on fluorescent signals and pre-set thresholds/cut-offs for RNA/DNA detection. There is no mention of a "training set" in the context of machine learning model training. The cut-offs were determined by testing n=509 native and contrived samples, which could be considered an "assay development" or "validation" dataset rather than a "training set" for a continually learning algorithm.

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

• As noted above, there isn't a traditional "training set" in the machine learning sense. The assay cut-offs were established using a mix of "native (throat swab specimens) and contrived samples" (n=509). The ground truth for these would logically be established by the same reliable reference method (culture) or by known spiked concentrations for contrived samples.

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Alere i Strep A 2 is a rapid, instrument-based, molecular in vitro diagnostic test utilizing isothermal nucleic acid amplification technology for the qualitative detection of Streptococcus pyogenes, Group A Streptococcus bacterial nucleic acid in throat swab specimens obtained from patients with signs and symptoms of pharyngitis. It is intended to aid in the rapid diagnosis of Group A Streptococcus bacterial infections.

Alere™ i Strep A 2 is a rapid, instrument-based isothermal test for the qualitative detection of Streptococus pyogenes Group A Strep from throat swab specimens. The Alere™ i Strep A 2 System utilizes isothermal nucleic acid amplification technology and is comprised of:

• . Sample Receiver - single use, disposable containing the elution buffer
• Test Base – single use, disposable comprising two sealed reaction tubes, each containing a lyophilized pellet
• Transfer Cartridge single use, disposable for transfer of the eluted sample to the Test Base, and ●
• . Alere™ i Instrument – repeat use reader

The reaction tubes in the Test Base contain the reagents required for Streptococcus pyogenes Group A Strep bacterial lysis and the subsequent amplification of the target nucleic acid and an internal control. Alere™ i Strep A 2 utilizes a pair of templates (similar to primers) for the specific amplification of DNA from Streptococcus pyggenes, Group A Strep and fluorescently labeled molecular beacons designed to specifically identify the amplified nucleic acid targets. Alere™ i Strep A 2 is performed within the confinement of the Test Base, and no other part of the Alere™ i Instrument has contact with the sample during the amplification process. This reduces the risk of instrument contamination and sample carry-over between measurements.

To perform the assay, the Sample Receiver and Test Base are inserted into the Alere™ i Instrument. The sample is added to the Sample Receiver and transfer Cartridge to the Test Base, resuspending the lyophilized pellets contained within the Test Base and initiating bacterial lysis and target amplification. Heating, mixing and detection by fluorescence is provided by the instrument, with results automatically reported.

Results are displayed by the Alere™ i Instrument and are also stored in an on-board archive and are assigned to a sample ID that has been entered into the Alere™ i Instrument by the operator, and the date/time the test was performed. Data can be retrieved and downloaded by the operator at any time after testing. An external Alere™ Universal Printer can be attached via USB to the Alere™ i Instrument to print test results.

Here's a summary of the acceptance criteria and study details for the Alere™ i Strep A 2 device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The FDA clearance document doesn't explicitly state all "acceptance criteria" as clear numerical thresholds for performance metrics. However, it presents the clinical performance of the device against a comparator method (bacterial culture), and these reported values implicitly demonstrate that the device met the necessary performance expectations for clearance.

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

• Sample Size (Clinical Study): 981 evaluable throat swab specimens.
• Data Provenance: Multi-center, prospective clinical study conducted at nine (9) US trial sites in 2017.

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

• The document states that the Alere™ i Strep A 2 performance was evaluated "in comparison to bacterial culture." Bacterial culture is typically performed in a laboratory by trained microbiologists using established protocols. The document does not specify the number of experts, nor their specific qualifications (e.g., years of experience), but implies standard laboratory practices for culture results.
• For discrepancies, a "laboratory developed real-time PCR assay" was used for confirmation. This also implies expert analysis within a laboratory setting, but specific expert details are not provided.

4. Adjudication Method for the Test Set

• The primary ground truth for the clinical study was bacterial culture. In cases of discordance between Alere™ i Strep A 2 and bacterial culture, a "laboratory developed real-time PCR assay" was used for further investigation:
  • 38 of 52 samples positive by Alere™ i Strep A 2 and negative by bacterial culture were positive by PCR.
  • 1 of 3 samples negative by Alere™ i Strep A 2 and positive by bacterial culture was negative by PCR.
• This suggests an implicit adjudication based on a tertiary, highly sensitive method (PCR) for resolving some discrepancies.

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 conducted. This device is an in-vitro diagnostic (IVD) molecular test, not an imaging or diagnostic assistant used by human readers in the traditional sense. The output is an automated positive/negative result.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

• Yes, the clinical performance study directly reflects the standalone performance of the device (Alere™ i Strep A 2) without human interpretation affecting the result. The device is "instrument-based" and provides "automated" results. The operator's role is to perform the assay steps, but the diagnostic determination is made by the instrument/algorithm.

7. The Type of Ground Truth Used

• The primary ground truth used for the clinical performance study was bacterial culture of throat swab specimens.
• For discordant results, a laboratory-developed real-time PCR assay was used as a confirmatory method.

8. The Sample Size for the Training Set

• The document does not provide information regarding a specific training set size. For IVD devices, especially molecular diagnostic kits, the "training" (development and optimization) process typically involves internal analytical studies rather than a distinct, prospectively collected "training set" of clinical samples with established ground truth in the same way an AI/ML algorithm might. Clinical studies are primarily for validation.

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

• As a molecular diagnostic test, the "ground truth" for its development (analogous to a training set for AI) would primarily rely on well-characterized clinical samples and reference strains with known Streptococcus pyogenes status confirmed by methods like culture and sequencing during the assay development and optimization phases. However, the document does not detail this. The provided clinical study serves as the primary validation of the device against bacterial culture as the ground truth.

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The Xpert Xpress Strep A test, performed on the GeneXpert Xpress System, is a rapid, qualitative in vitro diagnostic test for the detection of Streptococcus pyogenes (Group A B-hemolytic Strep A) in throat swab specimens from patients with signs and symptoms of pharyngitis. The Xpert Xpress Strep A test can be used as an aid in the diagnosis of Group A Streptococcal pharvngitis. The assay is not intended to monitor treatment for Group A Streptococus infections.

The Xpert Xpress Strep A test is an automated real-time polymerase chain reaction (PCR) in vitro diagnostic test for qualitative detection of Streptococcus pyogenes from throat swab specimens from patients with signs and symptoms of pharyngitis.

The Xpert Xpress Strep A test is performed on the Cepheid GeneXpert® Xpress System. The GeneXpert Xpress System platform automates sample preparation, amplification and real-time detection.

The GeneXpert Xpress System requires the use of single-use, disposable cartridges (the Xpert Xpress Strep A cartridges) that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained and specimens never come into contact with working parts of the instrument modules, cross-contamination between samples is minimized.

The Xpress Strep A test includes primers and probes for the detection of a targeted sequence of the S. pyogenes genome allowing detection of Strep A directly from throat swab specimens collected from patients with signs and symptoms of pharyngitis. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are internal controls utilized by the GeneXpert Xpress System platform. The SPC is present to control for adequate processing of the target bacteria and to monitor for the presence of inhibitor(s) in the PCR assay to avoid false-negative results. The Probe Check Control verifies reagent rehydration, real-time PCR tube filling in the cartridge, probe integrity, and dye stability.

The single-use, multi-chambered fluidic cartridges are designed to complete sample preparation and real-time PCR for the detection of genomic DNA S. pyogenes in ~24 minutes or less. The GeneXpert Xpress System, comprised of the GeneXpert Xpress II and GeneXpert Xpress IV, is capable of performing separate sample preparation and realtime PCR and RT-PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and RT-PCR and detection.

Throat swab specimens are collected using the ESwab collection device and transported to the GeneXpert area and prepared according to package insert instructions. After mixing the specimen, the liquid sample is transferred to the Xpert Xpress Strep A cartridge. The user initiates a test from the system user interface and places the cartridge into the GeneXpert Xpress instrument platform, which performs hands-off real-time, multiplex PCR for detection of DNA. The results are automatically generated at the end of the process in a report that can be viewed and printed.

Here's a breakdown of the acceptance criteria and the study details for the Cepheid Xpert Xpress Strep A device, based on the provided FDA 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined "acceptance criteria" in a bulleted or numbered list with pass/fail thresholds. Instead, it presents the results of various studies and concludes substantial equivalence to a predicate device. For the purpose of this request, I will infer the acceptance criteria from the reported performance of the predicate device and the general regulatory expectations for such assays, then juxtapose it with the Xpert Xpress Strep A's performance.

2. Sample Size and Data Provenance

• Clinical Study Test Set Sample Size: 618 specimens were included in the final analysis (initially 666, with 43 excluded).
• Data Provenance: The clinical study was a prospective, multi-center investigational study conducted at nine clinical sites in geographically diverse regions within the United States between January 2017 and May 2017.

3. Number of Experts and Qualifications for Ground Truth (Clinical Study)

The document specifies that the Xpert Xpress Strep A clinical performance was established relative to culture and latex agglutination for Strep A typing. It also mentions "an alternative PCR/bidirectional sequencing assay" used to investigate discordant results.

• Number of Experts: Not explicitly stated for establishing the primary ground truth (culture and latex agglutination). These methods are standard laboratory procedures typically performed by trained medical technologists or microbiologists.
• Qualifications of Experts: Not explicitly described. However, the use of standard microbiology lab techniques implies performance by qualified laboratory personnel. The "alternative PCR/bidirectional sequencing assay" would also be performed by trained molecular diagnosticians or researchers.

4. Adjudication Method (Clinical Study)

• Primary Adjudication: The primary ground truth for the clinical study was established by culture and latex agglutination for Strep A typing. This acts as the "gold standard" against which the device was compared.
• Discordant Analysis: For specimens where the Xpert Xpress Strep A result differed from the culture result, an "alternative PCR/bidirectional sequencing assay" was used to investigate the discrepancy. This serves as a secondary adjudication method to verify the true status of discordant samples.

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

• No, an MRMC comparative effectiveness study was not done. The Xpert Xpress Strep A is an automated in vitro diagnostic (IVD) test, not an AI system designed to assist human readers in image interpretation or similar tasks. Its performance is evaluated independently against a reference method (culture).

6. Standalone Performance

• Yes, a standalone performance study was done. The entire clinical study, analytical sensitivity, specificity, interference, and reproducibility studies assess the performance of the algorithm and instrument (Xpert Xpress Strep A test on the GeneXpert Xpress System) directly against various reference standards and controlled conditions, without human interpretation of the final result. The device provides a "Strep A DETECTED" or "Strep A NOT DETECTED" result automatically.

7. Type of Ground Truth Used (Clinical Study)

• The primary ground truth used for the clinical study was bacterial culture and latex agglutination for Strep A typing.
• For discordant sample resolution, an alternative PCR/bidirectional sequencing assay was used.

8. Sample Size for the Training Set

The document describes pre-market validation studies typically conducted for IVD devices, not machine learning model development. Therefore, there is no explicit "training set" sample size mentioned as would be the case for an AI/ML device. The device's underlying PCR assay design and algorithm are developed based on established scientific principles and analytical verification, rather than being "trained" on a large dataset in the AI sense.

9. How Ground Truth for the Training Set Was Established

As mentioned above, the concept of a "training set" and its "ground truth" in the AI/ML context is not directly applicable here. The device is a PCR assay with a defined molecular target and detection algorithm. The closest analogue to "ground truth establishment" during development would be:

• Analytical Validation: Extensive analytical studies (e.g., Limit of Detection, Inclusivity, Exclusivity, Interference) using well-characterized bacterial strains, spiked samples, and clinical matrices to ensure the assay correctly identifies the target organism and differentiates it from non-targets under various conditions. These studies confirm the assay's fundamental ability to detect S. pyogenes DNA.
• Assay Design and Optimization: The design of the primers and probes for the S. pyogenes genome target would be based on known genetic sequences, and optimized empirically to ensure specificity and sensitivity.

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The ARIES® Group A Strep Assay is a real-time polymerase chain reaction (PCR) based qualitative in vitro diagnostic test for the direct detection of Streptococus pyogenes (Group A beta-hemolytic Streptococcus) in throat swab specimens from patients with signs and symptoms of pharyngitis.

The ARIES® Group A Strep Assay can be used as an aid in the diagnosis of Group A Streptococcal pharyngitis. The assay is not intended to monitor treatment for Group A Streptococcus infections.

The ARIES® Group A Strep Assay is indicated for use with ARIES® Systems.

The ARIES® Group A Strep Assay is a polymerase chain reaction (PCR)-based qualitative in vitro diagnostic test system that consists of the ARIES® System or the ARIES® M1 System with their included ARIES® Software, an assay-specific cassette, and an assay-specific protocol file. The ARIES® Group A Strep Assay cassette is a disposable, single-use cassette containing nucleic acid purification reagents, internal sample process control (SPC), and an assay-specific master mix capable of performing the designated assay on one sample. The ARIES® Group A Strep Assay cassette directly detects Streptococcus pyoqenes (Group A ß-hemolytic Streptococcus) in throat swab specimens collected from the surface of human tonsils and posterior pharyngeal wall.

Throat swab specimens are collected from patients using a commercially available Liquid Amies based transport system (Nylon Flocked Swab with 1 mL modified Liquid Amies (ESwab™). The specimen is then transported to the laboratory for testing.

The specimen is lysed and nucleic acid is extracted using an ARIES® System. An extractable sample processing control (SPC) target is present in the ARIES® Group A Strep Assay cassette and is processed with the specimen. The SPC controls for recovery of extracted nucleic acid, the presence of inhibitory substances and for PCR reagent and instrument integrity. The Ct value of the SPC is designed to verify 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 and SPC are transferred via magnetic beads through the cassette to the ARIES® Group A Strep Assay lyophilized PCR reagents in the PCR tube that contains primer pairs specific to the S. pyogenes DNaseB (sdaB) gene and the SPC sequence. Each of the primer pairs is labeled with a distinct fluorophore and detected in distinct channels of the ARIES® Systems. PCR amplification is performed and assay fluorescence is monitored. Incorporation of a quencher-labeled nucleotide results in a decrease in fluorescence for the associated primer pair. Following amplification, the reaction is slowly heated to separate the fluorescent-labeled strand from the quencher-labeled strand, a process that results in an increase in the fluorescence signal. The reaction fluorescence is measured during this process and the temperature at which the change in fluorescence is the maximum is the T ,, of the amplicon. The instrument fluorescence output is analyzed and test results are determined using the ARIES® System software and the ARIES® Group A Strep Assay protocol and run files. ARIES® Group A Strep Assay results may be reported from the ARIES® Software or from the optional SYNCT® Software.

Here's a breakdown of the acceptance criteria and the study details for the ARIES® Group A Strep Assay, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

Note: For Lot-to-Lot Reproducibility (Low Positive) and Within-Laboratory Precision/Repeatability (Low Positive), additional replicates were tested to achieve an overall positivity >94%, indicating acceptable performance at the LoD.

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

• Sample Size for Clinical Performance (Test Set): A total of 618 unique specimens were available for analysis in the clinical performance study. Initially, 735 specimens were collected, but 112 were excluded due to various reasons (protocol non-compliance, insufficient volume, incorrect device, etc.).
• Data Provenance: The data was prospectively collected from patients suspected of pharyngitis in four geographically distinct clinical sites within the United States.

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

The document does not explicitly state the "number of experts" or their specific "qualifications" (e.g., "Radiologist with 10 years of experience") for establishing the ground truth of the clinical test set.

However, the ground truth for the clinical test set was established by a "reference method (bacterial culture followed by organism identification by Matrix-Assisted Laser Desorption/Ionization - Time-of-Flight Mass Spectrometry (MALDI-TOF MS))". This work was "performed at a centralized testing facility." It is implied that trained laboratory personnel and microbiologists conducted these reference tests, as is standard practice for such methods, but their specific experience levels are not detailed.

4. Adjudication Method for the Test Set

The document describes a robust "ground truth" establishment process using a reference laboratory technique (bacterial culture + MALDI-TOF MS). For specimens where the ARIES assay and the reference method disagreed, an adjudication method was employed:

• Bidirectional sequencing analysis using analytically validated primers that targeted genomic regions distinct from the ARIES Group A Strep Assay was used.
  • For 2 false negative ARIES results (ARIES negative, culture positive), sequencing showed them to be GAS negative.
  • For 7 false positive ARIES results (ARIES positive, culture negative), sequencing showed them to be GAS positive.
    This indicates a method similar to "Truth by Consensus" with an expert-level tie-breaker (sequencing), effectively refining the ground truth against discrepancies.

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, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) assay that machine-interprets results (qualitative PCR). It does not involve human "readers" assessing images or data in a way that would be "assisted" by AI, hence the concept of a human reader improvement effect size does not apply.

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

Yes, a standalone performance evaluation was done. The ARIES® Group A Strep Assay is an automated qualitative in vitro diagnostic test system. The clinical performance study directly assessed the agreement of the ARIES® Group A Strep Assay (algorithm only within the ARIES® Systems) against the established reference method, without human interpretation of the assay's raw output. The results (Positive, Negative, Invalid) are determined by the ARIES® System software.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc)

The ground truth used for the clinical performance study was primarily bacterial culture followed by organism identification by Matrix-Assisted Laser Desorption/Ionization - Time-of-Flight Mass Spectrometry (MALDI-TOF MS). In cases of discordance with the assay, bidirectional sequencing analysis was used as a confirmatory "higher truth" method. This can be considered a form of expert consensus/gold standard laboratory method.

8. The Sample Size for the Training Set

The document does not explicitly state a sample size for a training set. The ARIES® Group A Strep Assay is a PCR-based diagnostic test, where the "training" typically involves empirical optimization of assay parameters (primers, probes, reaction conditions, and cut-offs) during product development and internal verification studies, rather than machine learning on a distinct "training set" of patient data. The "Initial Assay Protocol File parameters were set during internal optimization studies" and "The final Assay Protocol File parameters were then established during internal verification studies." So, the optimization and verification process served a similar function to "training" for machine learning algorithms.

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

As noted in point 8, a traditional "training set" with separate ground truth establishment isn't described in the context of a PCR assay. Instead, the "ground truth" for optimizing the assay protocol file parameters (Ct cut-off, Tm window, Tm Peak Threshold) was established through internal optimization and verification studies. These studies likely involved testing known positive and negative S. pyogenes samples (e.g., well-characterized strains, spiked samples) to define the optimal performance characteristics of the assay before clinical validation.

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The Xpert Xpress Strep A Assay, performed on the GeneXpert Instrument Systems, is a rapid, qualitative in vitro diagnostic test for the detection of Streptoccus pyogenes (Group A beta-hemolytic Strep A) in throat swab specimens from patients with signs and symptoms of pharyngitis.

The Xpert Xpress Strep A Assay utilizes an automated real-time polymerase chain reaction (PCR) to detect Streptococcus pyogenes DNA.

The Xpert Xpress Strep A Assay is an automated real-time polymerase chain reaction (PCR) in vitro diagnostic test for qualitative detection of Streptococcus pyogenes from throat swab specimens from patients with signs and symptoms of pharyngitis.

The Xpert Xpress Strep A Assay is performed on the Cepheid GeneXpert® Instrument Systems (GeneXpert Dx, GeneXpert Infinity-48s, and GeneXpert Infinity-80 systems). The GeneXpert Instrument System platform automates sample preparation, amplification and real-time detection.

The GeneXpert Instrument Systems require the use of single-use, disposable cartridges (the Xpert Xpress Strep A cartridges) that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained and specimens never come into contact with working parts of the instrument modules, cross-contamination between samples is minimized.

The Xpress Strep A Assay includes primers and probes for the simultaneous detection and differentiation of a targeted sequence of the S. pyogenes genome allowing detection of Strep A directly from throat swab specimens collected from patients with signs and symptoms of pharyngitis. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are internal controls utilized by the GeneXpert Instrument System platform. The SPC is present to control for adequate processing of the target bacteria and to monitor for the presence of inhibitor(s) in the PCR assay to avoid false-negative results. The Probe Check Control verifies reagent rehydration, real-time PCR tube filling in the cartridge, probe integrity, and dye stability.

The single-use, multi-chambered fluidic cartridges are designed to complete sample preparation and real-time PCR for the detection of genomic DNA S. pyogenes in ~24 minutes or less. The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems and the GeneXpert Infinity Systems, have 1 to 80 randomly accessible modules. depending upon the instrument, that are each capable of performing separate sample preparation and real-time PCR and RT-PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and RT-PCR and detection.

Throat swab specimens are collected using the ESwab collection device and transported to the GeneXpert area and prepared according to package insert instructions. After mixing the specimen, the liquid sample is transferred to the Xpert Xpress Strep A Assay cartridge. The user initiates a test from the system user interface and places the cartridge into the GeneXpert instrument platform, which performs hands-off real-time, multiplex PCR for detection of DNA. The results are automatically generated at the end of the process in a report that can be viewed and printed.

Here's an analysis of the provided text to extract the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for performance are not explicitly stated in a dedicated section with pre-defined numerical targets. However, based on the clinical study results and comparisons to the predicate, we can infer the demonstrated performance. The key performance metrics are Sensitivity, Specificity, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) relative to culture and latex agglutination.

Inferred Acceptance Criteria (Based on demonstrating substantial equivalence to predicate) and Reported Device Performance (Combined First and Second Swab Data):

Study Proving Acceptance Criteria (Clinical Performance):

• Study Design: A multi-site clinical study that collected throat ESwab specimens from patients with signs and symptoms of pharyngitis. The study combined data from two approaches:
  • One study collected a second prospective throat swab after a standard of care (SOC) swab.
  • Another study used leftover excess SOC throat swab specimens.

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

• Initial Enrolled Specimens: 844
• Excluded Specimens: 261 (due to inclusion criteria failure, reference culture procedural error, delay in reference culture inoculation, delay in shipment, or labeling error).
• Specimens Included in Performance Analysis (Test Set): 583
  • Successful on initial test: 565/583 (96.9%)
  • Valid results after retest (overall): 577/583 (99.0%)
• Data Provenance: Geographically diverse regions within the United States. The study was conducted between December 2016 and March 2017, suggesting it was a prospective or mixed (prospective and retrospective for leftover samples) collection. The text states "one study enrolled consented subjects from whom a second prospective throat swab specimen was collected" and "another study tested specimens from subjects for which leftover excess standard of care (SOC) throat swab specimens were available."

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

• The document does not specify the number of experts or their qualifications for establishing the initial ground truth (culture and latex agglutination). These are standard laboratory procedures, but details about expert reviewers for discordant results are mentioned.

4. Adjudication Method for the Test Set:

• Discordant results between the Xpert Xpress Strep A Assay and the reference method (culture) were investigated.
• Method: An alternative PCR/bidirectional sequencing assay was used for adjudication. The results of this alternative PCR were footnoted in the performance tables (e.g., for 26 discrepant samples in Table 8-7, 21 were confirmed positive by alternative PCR, 4 negative, and 1 not tested). This indicates an independent molecular method was used to resolve discrepancies.

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

• No, a MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) assay, not an imaging device or one that involves human "readers" interpreting results in a variable way that MRMC studies are designed for. Its performance is evaluated biochemically against a reference standard.

6. Standalone Performance Study (Algorithm only without human-in-the-loop):

• Yes, a standalone study was performed. The clinical performance data presented (Sensitivity, Specificity, PPV, NPV) represents the performance of the Xpert Xpress Strep A Assay (the "algorithm/device") functioning independently relative to a microbiological reference method (culture). The results are automatically generated by the GeneXpert Instrument Systems.

7. Type of Ground Truth Used:

• For the clinical performance study (test set), the primary ground truth reference method was culture and latex agglutination for Strep A typing.
• For resolving discordant results, an alternative PCR/bidirectional sequencing assay was used.

8. Sample Size for the Training Set:

• The document does not specify the sample size for a "training set" in the context of an algorithm. For IVDs, the development process typically involves various internal testing and optimization (which could be considered analogous to training) but not usually a distinct "training set" of patient specimens in the same way an AI model would have. The document focuses on analytical and clinical validation studies.

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

• As a training set is not explicitly defined in the context of this IVD device's approval process in this document, the method for establishing its ground truth is not applicable/not provided. The analytical and clinical validation studies use established reference methods as ground truth.

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The Solana® Strep Complete Assay is a rapid in vitro diagnostic test, using isothermal amplification technology (helicase-dependent amplification, HDA), for the qualitative detection of Streptococcus pyogenes (Group A B-hemolytic Streptococcus) and Streptococcus dysgalactiae (pyogenic Group C and G ß-hemolytic Streptococus) nucleic acids isolated from throat swab specimens obtained from patients with signs and symptoms of pharyngitis, such as sore throat. The Solana® Strep Complete Assay is intended for use only with the the Solana® instrument.

The Solana Strep Complete Assay amplifies, detects and differentiates Streptococcus pyogenes DNA and Streptococcus dysgalactiae DNA present in throat swab specimens obtained from symptomatic patients.

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

Patient specimen on a throat swab is transferred to a Lysis Tube and subjected to heattreatment at 95±°C for 5 minutes. The heat-treated sample is added to a Dilution Tube, and then transferred to two Reaction Tubes, GAS Reaction Tube and Strep C/G Reaction Tube. GAS Reaction Tube contains white lyophilized HDA reagents, dNTPs, primers and probes specific for the amplification and detection of S. pyogenes target sequence, while C/G Reaction Tube contains blue lyophilized HDA reagents, dNTPs, primers and probes specific for the amplification and detection of S. dysgalactiae target sequence. Once rehydrated with the diluted sample, the Reaction Tubes are placed in a Solana Instrument for amplification and detection of the target sequences. In Solana, the target sequences are amplified by specific primers and detected by a specific fluorescence probe included in each Reaction Tube. Two competitive process controls (PRCs) are included in the Lysis Tube to monitor sample processing, inhibitory substances in clinical samples, reagent failure or device failure for each target. PRCs are amplified by the target-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. Upon annealing to target or PRC amplicons, the fluorescence signal increases due to physical separation of the fluorophore from the quencher. Solana measures and interprets the fluorescent signal for each Reaction Tube, using on-board method-specific algorithms. Solana then reports the test results for each Reaction Tube to the user on its display screen, and optionally prints out the results via a printer.

Here's a summary of the acceptance criteria and study details for the Solana® Strep Complete Assay, based on the provided text:

Solana® Strep Complete Assay Acceptance Criteria and Performance Study

Study Details:

1. Sample Size for Test Set and Data Provenance:

   • Clinical Study: 2688 fresh throat swab specimens.
     • Provenance: Prospective study conducted from February to July 2016 at four (4) external and one (1) internal laboratories across the United States.
     • Additional data for reproducibility (analytical performance): 540 specimens (including controls) tested across three sites for reproducibility.

2. Number of Experts Used to Establish Ground Truth and Qualifications:

   • The document does not explicitly state the number or qualifications of experts used to establish ground truth for the clinical test set. It mentions that "Cultured isolates were typed by latex agglutination" and "species were determined using an FDA-cleared MALDI TOF assay." It also states, "A specimen was recorded as positive for either Streptococcus pyoqenes or Streptococcus dysgalactiae if either the culture or the FDA-cleared NAAT was positive, respectively." This suggests that laboratory personnel performing these standard diagnostic methods established the ground truth, but specific expert qualifications (e.g., radiologist with 10 years of experience) are not provided as this is a molecular diagnostic assay.

3. Adjudication Method for the Test Set:

   • For the clinical study, the ground truth was established by a composite reference method. A specimen was considered positive if either the culture result or an FDA-cleared Nucleic Acid Amplification Test (NAAT) was positive. This acts as a form of retrospective adjudication based on multiple gold standards.

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

   • No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not explicitly described in the provided text. The study focused on the performance of the device itself against established laboratory methods, not on how human readers' performance might improve with AI assistance.

5. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study:

   • Yes, the clinical performance study evaluated the "Solana® Strep Complete Assay" (the device/algorithm) against a composite reference standard (culture + FDA-cleared NAAT). The results presented are for the device's standalone performance in identifying the target pathogens. The device has an "on-board method-specific algorithms" that measures and interprets the fluorescent signal and reports results.

6. Type of Ground Truth Used:

   • Composite Reference Standard: For the clinical study, the ground truth was established by combining the results of:
     • Directly cultured patients' throat swabs (followed by latex agglutination and FDA-cleared MALDI TOF for speciation).
     • Another FDA-cleared Nucleic Acid Amplification Test (NAAT) performed on leftover swab transport fluid.

7. Sample Size for the Training Set:

   • The document does not specify a sample size for a training set. The descriptions provided are for analytical validation (LOD, reproducibility, cross-reactivity, interference, inclusivity) and a clinical performance study (test set). For molecular diagnostic assays, manufacturers typically perform extensive in-house development and optimization, which would involve internal training/validation sets, but these are not usually detailed in 510(k) summaries as separate "training sets" in the context of AI/ML device submissions.

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

   • As no specific "training set" is detailed in the document, how its ground truth was established is not explicitly mentioned. For the analytical and clinical studies, ground truth was established using standard microbiological techniques (culture, latex agglutination, MALDI TOF) and comparison to another FDA-cleared NAAT.

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The Solana™ GAS Assay is a rapid in vitro diagnostic test for the qualitative detection of Group A B-hemolytic Streptococus (Streptococcus pyogenes) nucleic acids isolated from throat swab specimens obtained from patients with signs and symptoms of pharyngitis, such as sore throat. The Solana™ GAS Assay is intended for use only with the Solana™ instrument.

The Solana™ GAS Assay amplifies and detects GAS DNA present in throat swab specimens obtained from symptomatic patients.

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

Patient specimen on a throat swab is transferred to a Lysis Tube and subjected to heattreatment at 95°C for 5 minutes. The heat-treated sample is added to a Dilution Tube, and then transferred to a Reaction Tube. 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 GAS-specific target sequence. In Solana, the target sequence is amplified by GAS specific primers and detected by a GAS specific fluorescence probe included in the Reaction Tube. A competitive process control (PRC) is included in the Lysis Tube to monitor sample processing, inhibitory substances in clinical samples, reagent failure or device failure. The PRC target is amplified by GAS 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 GAS 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 instrument will then report the test results to the user on its display screen, and it can print out the results via a printer.

The Solana™ GAS Assay is a rapid in vitro diagnostic test for the qualitative detection of Group A β-hemolytic Streptococcus (Streptococcus pyogenes) nucleic acids isolated from throat swab specimens obtained from patients with signs and symptoms of pharyngitis, such as sore throat. The assay is intended for use only with the Solana™ instrument.

1. Table of Acceptance Criteria and Reported Device Performance

*The predicate device's performance (Lyra™ Direct Strep Assay) in the "Comparison with predicate" section is used as a proxy for implicit acceptance criteria, as the submission aims to demonstrate substantial equivalence. Explicit acceptance criteria beyond this are not detailed in the provided text for the Solana™ GAS Assay's clinical performance.

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

• Sample Size: 1082 fresh throat swab specimens.
• Data Provenance: Prospective study conducted from December 2014 to February 2015 at four distinct geographical sites across the United States.

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

The document does not explicitly state the number of experts or their specific qualifications (e.g., radiologists with 10 years of experience). However, the ground truth was established by "conventional streak-stab culture technique onto a trypticase soy agar plate containing 5% horse red blood cells" and "typed as Lancefield group A by latex agglutination." This implies standard microbiology laboratory procedures and interpretation, which would typically be performed by trained clinical microbiologists or laboratory technologists.

4. Adjudication Method for the Test Set

The document describes discordant specimens. Of the 24 specimens that were Solana™ GAS Assay positive but Composite Culture negative, 16 were tested with an additional FDA-cleared molecular device, and 8 were negative. Of the 4 specimens that were Solana™ GAS Assay negative but Composite Culture positive, 3 were tested with an additional FDA-cleared molecular device. This indicates a form of secondary testing or adjudication for discordant results, though a formal 2+1 or 3+1 method is not explicitly named.

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, an MRMC comparative effectiveness study involving human readers and AI assistance was not done. This device is an in-vitro diagnostic test for qualitative detection of nucleic acids, not an imaging or diagnostic aid for human readers.

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

Yes, the clinical performance study evaluated the Solana™ GAS Assay as a standalone device. The "Solana instrument measures and interprets the fluorescent signal, using on-board method-specific algorithms" and "report the test results to the user on its display screen."

7. The Type of Ground Truth Used

The ground truth used was composite bacterial culture. A specimen was considered positive if either the swab or the transport media was positive for β-hemolytic Streptococcus and typed as Lancefield group A by latex agglutination.

8. The Sample Size for the Training Set

The document does not explicitly mention a separate "training set" for the clinical performance evaluation. The clinical sensitivity and specificity were established using a prospective clinical study where 1082 fresh throat swab specimens were collected and tested. This dataset largely serves as the evaluation or test set. For analytical performance, various specified quantities of bacterial strains were used.

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

Given that a specific "training set" for clinical performance with a separate ground truth establishment method is not described, the approaches described for the test set (composite bacterial culture as detailed in point 7) would apply if any training data were used from clinical samples. For analytical studies, ground truth was established by using quantified (CFU/mL) cultures of known bacterial strains.

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Alere™ i Strep A is a rapid, instrument-based, molecular in vitro diagnostic test utilizing isothermal nucleic acid amplification technology for the qualitative detection of Streptococcus pyogenes, Group A Streptococcus bacterial nucleic acid in throat swab specimens obtained from patients with signs and symptoms of pharyngitis. It is intended to aid in the rapid diagnosis of Group A Streptococcus bacterial infections.

All negative test results should be confirmed by bacterial culture because negative results do not prection with Group A Streptococcus and should not be used as the sole basis for treatment.

Alere™ i Strep A is a rapid, instrument-based isothermal test for the qualitative detection of Group A Strep from throat swab specimens. The Alere™ i Strep A System utilizes isothermal nucleic acid amplification technology and is comprised of:

• . Sample Receiver – single use, disposable containing the elution buffer
• . Test Base – single use, disposable comprising two sealed reaction tubes, each containing a lyophilized pellet
• Transfer Cartridge – single use, disposable for transfer of the eluted sample to the Test Base, and
• Alere™ i Instrument – repeat use reader

The reaction tubes in the Test Base contain the reagents required for Group A Strep bacterial lysis and the subsequent amplification of the target nucleic acid and an internal control. Alere™ i Strep A utilizes a pair of templates (similar to primers) for the specific amplification of DNA from Group A Strep and a fluorescently labeled molecular beacon designed to specifically identify the amplified nucleic acid target. Alere™ i Strep A is performed within the confinement of the Test Base, and no other part of the Alere™ i Instrument has contact with the sample during the amplification process. This reduces the risk of instrument contamination and sample carry-over between measurements.

To perform the assay, the Sample Receiver and Test Base are inserted into the Alere™ i Instrument and the elution buffer is automatically heated by the instrument. The sample is added to the Sample Receiver and transferred via the Transfer Cartridge to the Test Base, resuspending the lyophilized pellets contained within the Test Base and initiating bacterial lysis and target amplification. Heating, mixing and detection by fluorescence is provided by the instrument, with results automatically reported.

Results are displayed by the Alere™ i Instrument and are also stored in an on-board archive and are assigned to a sample ID that has been entered into the Alere™ i Instrument by the operator, and the date/time the test was performed. Data can be retrieved and downloaded by the operator at any time after testing. An external Alere™ Universal Printer can be attached via USB to the Alere™ i Instrument to print test results.

Here's an analysis of the acceptance criteria and the study that proves the device (Alere™ i Strep A) meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Strict "acceptance criteria" are not explicitly stated in a quantitative manner (e.g., "Sensitivity must be >90%"). However, the clinical study's performance metrics act as the de facto demonstration of acceptable performance for regulatory purposes. The reported performance is what was considered sufficient for substantial equivalence.

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

• Sample Size (Clinical): 481 evaluable throat swab specimens.
• Data Provenance: Multi-center, prospective clinical study conducted at 8 US trial sites in 2014.

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

The document does not specify the number or qualifications of experts used to establish the ground truth. It states that the device performance was "compared to bacterial culture," implying independent laboratory analysis, but details about the personnel involved in interpreting these cultures are not provided.

4. Adjudication Method for the Test Set

The document doesn't explicitly describe an "adjudication method" in the typical sense (e.g., 2+1 reader adjudication for imaging studies). For samples with discordant results between the Alere™ i Strep A and the initial bacterial culture, a "laboratory developed real-time PCR assay" was used for further investigation:

• Of 18 samples positive by Alere™ i Strep A and negative by bacterial culture, 13 were positive by RT-PCR.
• Of 6 samples negative by Alere™ i Strep A and positive by bacterial culture, 4 were negative by RT-PCR.

This suggests that the PCR assay acted as a secondary confirmation method for discordant results, but it's not a formal "adjudication method" agreed upon by multiple human readers in the context of interpretation.

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

No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic (IVD) test, where performance is typically evaluated against a gold standard (like bacterial culture or PCR), not by comparing human reader performance with and without AI assistance, as would be common for imaging AI.

6. Standalone (Algorithm Only) Performance Study

Yes, the clinical study (and analytical studies) assess the standalone performance of the Alere™ i Strep A device. It's an automated, instrument-based test, meaning its performance is inherently "algorithm only" in the sense that the instrument provides the result without human interpretation of the primary signal. The comparator (bacterial culture) serves as the ground truth.

7. Type of Ground Truth Used

• Clinical Study: Bacterial culture was the primary ground truth. For discordant results, a laboratory developed real-time PCR (RT-PCR) assay was used as a secondary method.
• Analytical Sensitivity: Defined by the concentration of Group A Strep bacteria producing positive results 95% of the time, determined by testing known bacterial concentrations.

8. Sample Size for the Training Set

The document does not provide information about a separate "training set" for the Alere™ i Strep A. This is typical for IVD devices where the "training" (development and optimization) of the assay is conducted internally by the manufacturer, rather than through publicly documented machine learning training datasets. The presented clinical and analytical studies are validation studies, not training studies.

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

As no separate training set details are provided, the method for establishing its ground truth is also not elaborated. The development of such assays involves extensive internal research, optimization, and verification using characterized bacterial strains and clinical samples, but these are not typically documented as a "training set" in the same way an AI model's training data would be.

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The Focus Diagnostics Simplexa™ Group A Strep Direct assay is intended for use on the 3M Integrated Cycler for the in vitro qualitative detection of Group A Streptococcus (GAS) from throat swabs collected from human patients with signs and symptoms of pharyngitis, such as sore throat. This test is intended for use as an aid in the diagnosis of GAS infection. The assay is intended for use in hospital, reference, or state laboratory settings. The device is not intended for point-of-care use.

The Simplexa™ Group A Strep Direct assay system is a real-time PCR system that enables the direct amplification and qualitative detection of Group A Strep bacterial DNA from throat swabs that have not undergone a nucleic acid extraction. The system consists of the Simplexa™ Group A Strep Direct assay, the 3M Integrated Cycler (with Integrated Cycler Studio Software), the Direct Amplification Disc (DAD) and associated accessories.

In the Simplexa™ Group A Strep Direct assay, bi-functional fluorescent probe-primers are used together with corresponding reverse primers to amplify Group A Strep bacterial DNA and the Internal Control (DNA IC). The assay targets a conserved region of Group A Strep (pyroqenic exotoxin B gene) to identify this bacteria in the specimen. The DNA IC is used to detect PCR failure and/or inhibition.

Here is a summary of the acceptance criteria and study information for the Simplexa™ Group A Strep Direct device, based on the provided text:

Acceptance Criteria and Device Performance for Simplexa™ Group A Strep Direct

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for the clinical study's sensitivity and specificity. However, the performance characteristics of the device and its predicate device are compared. For the purpose of this response, we will consider the reported "Performance Characteristics" of the predicate device as a benchmark or implicit acceptance criteria, though the device has slightly lower specificity than the predicate.

Note: The device's sensitivity (97.4%) is numerically higher than the predicate's (96.5%), and its specificity (95.2%) is numerically lower than the predicate's (98.0%). The FDA's substantial equivalence determination implies these results were acceptable.

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

• Sample Size for Test Set: 1352 evaluable samples.
• Data Provenance: Prospectively collected from four geographically diverse sites. The country of origin is not explicitly stated but can be inferred to be the USA given the FDA submission document.

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

The document does not mention the use of "experts" in the traditional sense (e.g., radiologists) for establishing ground truth. Instead, for the clinical prospective study, the comparator culture method was used as the primary reference for ground truth, and discrepant results were further analyzed.

4. Adjudication Method for the Test Set

The primary comparison was against a "comparator culture method" performed at one central laboratory.
For discrepant analysis, a "validated bidirectional sequencing assay" was performed.

• 46 out of 57 samples where Simplexa™ was Positive and Culture was Not Detected were confirmed as Group A Strep Positive by sequencing.
• 2 out of 4 samples where Simplexa™ was Not Detected and Culture was Detected were confirmed as Group A Strep Positive by sequencing.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed. This device is a molecular diagnostic assay (PCR-based system) for the qualitative detection of Group A Streptococcus, not an imaging device requiring human reader interpretation. Therefore, the concept of improving human readers with AI assistance is not applicable here.

6. Standalone Performance Study

Yes, a standalone performance study (algorithm only without human-in-the-loop performance) was performed. The entire clinical prospective study and analytical studies evaluate the device's performance independently. The device's results are compared directly against a culture method and a sequencing assay, not against human interpretation of the device's output.

7. Type of Ground Truth Used

• Primary Ground Truth: Comparator culture method.
• Confirmatory Ground Truth for Discrepancies: Validated bidirectional sequencing assay.

8. Sample Size for the Training Set

The document describes the performance of the device and does not explicitly mention a "training set" in the context of machine learning. The studies described are validation studies (e.g., Limit of Detection, Analytical Reactivity, Cross Reactivity, Interference, Clinical Prospective Study) that assess the device's performance characteristics. If the device's internal algorithms underwent a "training" phase during its development, the details are not provided in this regulatory summary.

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

As no specific "training set" is mentioned for an algorithm, the method for establishing its ground truth is not provided. The document focuses on the validation of the finalized device.

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