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The BIOFIRE® SPOTFIRE® Respiratory/Sore Throat (R/ST) Panel Mini is a multiplexed polymerase chain reaction (PCR) test intended for use with the BIOFIRE® System for the simultaneous, qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swab (NPS) specimens obtained from individuals with signs and symptoms of respiratory tract infection, including COVID-19; (Respiratory menu) or in throat swab (TS) specimens from individuals with signs and symptoms of pharyngitis (Sore Throat menu).

The following analytes are identified and differentiated using the SPOTFIRE R/ST Panel Mini:

Respiratory Menu:
Viruses
Coronavirus SARS-CoV-2
Human rhinovirus
Influenza A virus
Influenza B virus
Respiratory syncytial virus

Sore Throat Menu:
Viruses
Human rhinovirus
Influenza A virus
Influenza B virus
Respiratory syncytial virus
Bacteria
Streptococcus pyogenes (group A Strep)

Nucleic acids from the viral and bacterial organisms identified by this test are generally detectable in NPS/TS specimens during the acute phase of infection. The detection and identification of specific viral and bacterial nucleic acids from individuals exhibiting signs and symptoms of respiratory infection and/or pharyngitis is indicative of the presence of the identified microorganism and aids in diagnosis if used in conjunction with other clinical and epidemiological information, and laboratory findings. The results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

Negative results in the setting of a respiratory illness and/or pharyngitis may be due to infection with pathogens that are not detected by this test, or a respiratory tract infection that may not be detected by an NPS or TS specimen. Positive results do not rule out co-infection with other organisms. The agent(s) detected by the SPOTFIRE R/ST Panel Mini may not be the definite cause of disease.

Additional laboratory testing (e.g., bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible respiratory tract infection and/or pharyngitis.

The SPOTFIRE R/ST Panel Mini simultaneously identifies 5 different respiratory viral pathogens in nasopharyngeal swabs (NPS) or 5 different viral and bacterial pharyngitis pathogens in throat swabs (TS) from individuals with signs and symptoms of respiratory tract infections or pharyngitis, respectively, (see Table 1) The SPOTFIRE R/ST Panel Mini is compatible with the BIOFIRE® System, a polymerase chain reaction (PCR)-based in vitro diagnostic system for infectious disease testing. The BIOFIRE System Sottware executes the SPOTFIRE R/ST Panel Mini test and interprets and reports the test results. The SPOTFIRE R/ST Panel Mini was designed to be used in CLIA-waived environments.

A test is initiated by loading Hydration Solution injection solution injection port of the SPOTFIRE R/ST Panel Mini pouch and NPS or TS specimen, mixed with the provided Sample injection port of the SPOTFIRE R/ST Panel Mini pouch and placing it in the SPOTFIRE System. The reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration and Sample/Buffer Mix rehydrates the reagents. After the pouch is prepared, the SPOTFIRE System Software guides the user through the steps of placing the pouch into the instrument, scanning the sample identification, and initiating the run.

The SPOTFIRE System contains coordinated systems of inflatable bladders and seal points, which act on the pouch to control the movement of liquid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liquid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronically-controlled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier devices control heating and cooling of the pouch to drive the PCR reactions and the melt curve analysis.

Nucleic acid extraction occurs within the SPOTFIRE R/ST Panel Mini pouch using mechanical Ivsis followed by purfication using standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, the SPOTFIRE System performs a nested multiplex PCR that is executed in two stage. During the first stage, the SPOTFIRE System performs a single, large volume, highly multiplexed reverse transcription PCR (rt-PCR) reaction. The products from first stage PCR are then diluted and combined with a fresh, primer-free master mix and a fluorescent doublestranded DNA binding dye (LC Green® Plus, BioFire Diagnostics). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the 2nd stage PCR captures fluorescent images of the PCR reactions and software interprets the data.

The SPOTFIRE System Software automatically interprets the results of each DNA melt curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the SPOTFIRE R/ST Panel Mini.

This document describes the BIOFIRE® SPOTFIRE® Respiratory/Sore Throat (R/ST) Panel Mini, a multiplex PCR test.

1. Table of Acceptance Criteria and Reported Device Performance

The document provides extensive analytical performance data rather than a direct comparison of acceptance criteria to reported clinical performance metrics (like PPA and NPA). However, the "Summary of Performance Data" for clinical studies does present sensitivity/PPA and specificity/NPA, which can be interpreted as the reported device performance against implied clinical acceptance criteria.

Clinical Performance Summary (NPS Specimens - Respiratory Menu)

Clinical Performance Summary (TS Specimens - Sore Throat Menu)

Analytical Acceptance Criteria and Results for key studies:

2. Sample Sizes and Data Provenance

• Clinical Performance (Test Set):
  • NPS Specimens (Respiratory Menu - Prospective): Total of 1115 specimens. The document doesn't explicitly state the country of origin but implies clinical sites (e.g., "as tested by intended users"). This is prospective data.
  • NPS Specimens (Respiratory Menu - Archived): Used for some analytes, e.g., Human Rhinovirus (30 positive, 454 negative), Influenza A (59 positive, 423 negative), Influenza B (30 positive, 28 negative), RSV (37 positive, 447 negative). This is retrospective data.
  • TS Specimens (Sore Throat Menu - Prospective): Total of 876 specimens for most viral targets. Streptococcus pyogenes had 217 positive (PCR) / 177 positive (Culture) and 660 negative (PCR) / 692 negative (Culture). This is prospective data.
  • TS Specimens (Sore Throat Menu - Archived): Used for some analytes, e.g., Human Rhinovirus (2 positive, 57 negative), Influenza A (11 positive, 44 negative), Influenza B (20 positive, 0 negative), RSV (2 positive, 57 negative), Streptococcus pyogenes (39 positive, 10 negative). This is retrospective data.
  • TS Specimens (Sore Throat Menu - Contrived): Used for some analytes, e.g., Influenza A (93 positive, 332 negative), Influenza B (49 positive, 333 negative), RSV (50 positive, 381 negative). This would be laboratory-generated data.

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the number or qualifications of experts used to establish the ground truth for the clinical test set. It mentions using "molecular assays or known specimen composition" as comparator methods for most analytes, and "culture" as the reference method for Streptococcus pyogenes.

4. Adjudication Method

The document does not describe any specific adjudication method (e.g., 2+1, 3+1) for establishing the ground truth or resolving discrepancies in the clinical test set.

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

No MRMC comparative effectiveness study is mentioned or implied, as this device is an in vitro diagnostic (IVD) PCR test for direct pathogen detection, not an AI-assisted diagnostic imaging or interpretation tool for human readers. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply.

6. Standalone Performance

Yes, the studies described are for standalone performance. The BIOFIRE® SPOTFIRE® R/ST Panel Mini provides automated interpretation and reporting of test results based on the PCR assay. It is designed to be used independently to generate a qualitative detection and identification of microbial nucleic acids.

7. Type of Ground Truth Used

• Clinical Performance (Prospective/Archived): The ground truth for most analytes was established using molecular assays or, in some cases, known specimen composition. For Streptococcus pyogenes, culture was also used as a reference method for some comparisons.
• Analytical Performance (LoD, Inclusivity, Exclusivity, Interference, Reproducibility, Matrix Validation, Transport Media Validation, Carry Over): The ground truth was established through known specimen composition (e.g., contrived samples with known concentrations of organisms, presence of interfering substances, specific transport media).

8. Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning or AI algorithm development. This device is a PCR-based test, and its performance is validated through analytical and clinical studies, not typically through a machine learning training phase with a distinct dataset. The "training" in this context refers to the development and optimization of the PCR primers, probes, and reaction conditions.

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

Given that this is a PCR diagnostic device, not an AI algorithm in the typical sense of needing a "training set" for model learning, this question isn't directly applicable. The "ground truth" for developing and optimizing the PCR assays themselves would have been established through:

• Careful selection and validation of synthetic nucleic acid targets.
• Testing with characterized microbial isolates and clinical samples whose status was confirmed by established reference methods (e.g., sequencing, culture, validated molecular tests).
• In silico analysis of genetic sequences to design primers and probes with high specificity and inclusivity.

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The BIOFIRE® SPOTFIRE® Respiratory/Sore Throat (R/ST) Panel is a multiplexed polymerase chain reaction (PCR) test intended for use with the BIOFIRE® System for the simultaneous, qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swab (NPS) specimens obtained from individuals with signs and symptoms of respiratory tract infection, including COVID-19; (Respiratory menu) or in throat swab (TS) specimens from individuals with signs and symptoms of pharyngitis (Sore Throat menu).

The following organism types and subtypes are identified and differentiated using the SPOTFIRE R/ST Panel:

Respiratory Menu Viruses Adenovirus Coronavirus SARS-CoV-2 Coronavirus (seasonal) Human metapneumovirus Human rhinovirus/enterovirus Influenza A virus Influenza A virus/H1-2009 Influenza A virus/ H3 Influenza B virus Parainfluenza virus Respiratory syncytial virus

• Bacteria Bordetella parapertussis Bordetella pertussis Chlamydia pneumoniae Mycoplasma pneumoniae
  Sore Throat Menu Viruses Adenovirus Coronavirus (seasonal) Human metapneumovirus Human rhinovirus/enterovirus Influenza A virus Influenza A virus/H1-2009 Influenza A virus/H3 Influenza B virus Parainfluenza virus Respiratory syncytial virus

Bacteria Chlamydia pneumoniae Mycoplasma pneumoniae Streptococcus dysgalactiae (Group C/G Strep) Streptococcus pyogenes (Group A Strep)

Nucleic acids from the viral and bacterial organisms identified by this test are generally detectable in NPS/TS specimens during the acute phase of infection and identification of specific viral and bacterial nucleic acids from individuals exhibiting signs and symptoms of respiratory infection and/or pharyngtis are indicative of the identified microorganism and aids in diagnosis if used in conjunction with other clinical and epidemiological information, and laboratory findings. The results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

Negative results in the setting of a respiratory illness and/or pharyngitis may be due to infection with pathogens that are not detected by this test, or a respiratory tract infection that may not be detected by an NPS or TS specimen. Positive results do not rule out coinfection with other organisms. The agent(s) detected by the SPOTFIRE R/ST Panel may not be the definite cause of disease.

Additional laboratory testing (e.g., bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible respiratory tract infection and/or pharyngitis.

The SPOTFIRE R/ST Panel simultaneously identifies 15 different respiratory viral and bacterial pathogens in nasopharyngeal swabs (NPS) or 14 viral and bacterial pharyngitis pathogens in throat swabs (TS) from individuals with signs and symptoms of respiratory tract infections or pharyngitis, respectively, (see Intended Use:). The SPOTFIRE R/ST Panel is compatible with the SPOTFIRE System, a polymerase chain reaction (PCR)-based in vitro diagnostic system for infectious disease testing. The SPOTFIRE System Software executes the SPOTFIRE R/ST Panel test and interprets and reports the test results. The SPOTFIRE RIST Panel was designed to be used in CLIA-waived environments. A test is initiated by loading Hydration Solution into one port of the SPOTFIRE R/ST Panel pouch and NPS or TS specimen, mixed with the provided Sample Buffer, into the port of the SPOTFIRE R/ST Panel pouch and placing it in the SPOTFIRE System. The pouch contains all of the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and Sample/Buffer Mix rehydrates the reagents. After the pouch is prepared, the SPOTFIRE System Software guides the user through the steps of placing the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.

The SPOTFIRE System contains coordinated systems of inflatable bladders and seal points, which act on the pouch to control the movement of liguid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liguid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronically controlled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier and cooling of the pouch to drive the PCR reactions and the melt curve analysis.

Nucleic acid extraction occurs within the SPOTFIRE R/ST Panel pouch using mechanical and chemical lysis followed by purification using standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, the SPOTFIRE System performs a nested multiplex PCR that is executed in two stage, the SPOTFIRE System performs a single, large volume, highly multiplexed reverse transcription PCR (rt-PCR) reaction. The products from first stage PCR are then diluted and combined with a fresh, primer-free master mix and a fluorescent doublestranded DNA binding dye (LC Green® Plus, BioFire Diagnostics). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the 2nd stage PCR captures fluorescent images of the PCR reactions and software interprets the data.

The SPOTFIRE System Software automatically interprets the results of each DNA met curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the SPOTFIRE R/ST Panel.

Here's a breakdown of the acceptance criteria and study proving the device meets those criteria, based on the provided FDA 510(k) summary for the BIOFIRE® SPOTFIRE® Respiratory/Sore Throat (R/ST) Panel:

The document describes the BIOFIRE® SPOTFIRE® Respiratory/Sore Throat (R/ST) Panel, a multiplexed PCR test for simultaneous, qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids. The data presented primarily focuses on analytical performance and clinical performance to demonstrate substantial equivalence to a predicate device.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the performance metrics reported, specifically the Positive Percent Agreement (PPA) / Sensitivity and Negative Percent Agreement (NPA) / Specificity. For analytical studies, acceptance criteria related to percentages of positive results and agreement levels are explicitly stated.

Clinical Performance Acceptance Criteria (Implied by Data Reported):
For each analyte, the acceptance criteria are generally to achieve high PPA and NPA. While specific numerical thresholds for PPA/NPA are not explicitly listed as "acceptance criteria" in the clinical tables themselves, the FDA's clearance implies that the presented performance met their internal requirements for substantial equivalence. For diagnostic tests, generally, PPA and NPA values in the high 90s are expected.

Analytical Performance Acceptance Criteria and Reported Performance:

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

The sample sizes vary by analyte and study type (prospective, archived, contrived).

• Clinical Performance (Test Set):

  • NPS Specimens (Respiratory Menu):
    • Prospective Data: The total number of NPS specimens tested across all viruses and bacteria is not explicitly stated as a single number but can be aggregated from the "Positive" and "Negative" counts for each analyte. For example, for Adenovirus, there were 33 positives and 1082 negatives, totaling 1115 prospective NPS specimens where Adenovirus was assessed. This appears to be the total number of clinical samples evaluated in the prospective study.
    • Archived Data: Similarly, for Adenovirus, there were 31 positives and 439 negatives, totaling 470 archived NPS specimens.
    • Contrived Data: Indicated as 0/0 for all NPS analytes, suggesting contrived samples were not used for clinical performance evaluation of NPS specimens.
  • TS Specimens (Sore Throat Menu):
    • Prospective Data: For Adenovirus, 65 positives and 810 negatives (total 875). This seems to be the total number of clinical throat swab specimens assessed.
    • Archived Data: For Adenovirus, 11 positives and 48 negatives (total 59).
    • Contrived Data: For Adenovirus, 50 positives and 381 negatives (total 431). Contrived samples were used for TS clinical performance studies.
  • Data Provenance: The document states "as tested by intended users," implying clinical sites. No specific country of origin is mentioned, but typically, these studies for FDA clearance involve sites within the US. The "Prospective" studies indicate prospective collection, while "Archived" refers to retrospective samples. "Contrived" samples are laboratory-prepared.

• Analytical Performance (Test Set):

  • Limit of Detection (LoD): At least 20 replicates (e.g., 19/20) tested at LoD and 10-fold below LoD for each analyte.
  • Analytical Reactivity (Inclusivity): 3/3 or 4/5 replicates tested within 10x LoD for each isolate.
  • Near-LoD/Reproducibility: Not explicitly stated but mentions "multiple days," "multiple operators," "three unique SPOTFIRE Systems," "three distinct clinical sites holding a CLIA waiver." The reported positive and negative agreement totals are 2070 (BioFire) and 1380 (clinical sites) tests.

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

The document does not specify the number of experts or their qualifications (e.g., radiologist with 10 years of experience) used to establish the ground truth. This is a common characteristic of in vitro diagnostic (IVD) submissions focusing on molecular diagnostic tests.

• For molecular tests, the "ground truth" is typically established by comparator methods, often laboratory-developed tests (LDTs) or other cleared/validated molecular diagnostic assays (e.g., PCR followed by sequencing, or highly sensitive and specific reference PCR methods).
• For bacterial culture (used for Streptococcus dysgalactiae and Streptococcus pyogenes), the ground truth is established by standard microbiological culture and identification techniques, performed by trained laboratory personnel.

4. Adjudication Method for the Test Set

The document does not describe a formal adjudication method (e.g., 2+1, 3+1) for the clinical test sets. This is expected given that the ground truth is established by laboratory reference methods (molecular or culture), which typically do not involve human reader adjudication in the same way imaging studies might. Any discrepancies between the investigational device and the reference method would be investigated by the manufacturer, rather than through an expert consensus adjudication.

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

No, an MRMC comparative effectiveness study was not done. This type of study is primarily relevant for imaging-based AI devices where human readers interpret medical images, and the AI assists or augments their performance. The BIOFIRE SPOTFIRE R/ST Panel is a molecular diagnostic test where the output is an automated detection of nucleic acids, not an interpretation by a human reader that could be augmented by AI.

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

Yes, the performance data presented (Tables 2 and 3 for Clinical Performance, and Table 4 for Analytical Performance) represents the standalone performance of the BIOFIRE SPOTFIRE R/ST Panel, which includes the instrument and its automated software interpretation. The device itself is designed to provide automated results without human interpretive input for the detection of targets. The "as tested by intended users" for clinical performance indicates that the device was used in a realistic setting, but the performance metrics reflect the direct output of the system.

7. The Type of Ground Truth Used

The ground truth for the clinical performance evaluation was established using:

• Comparator molecular assays or known specimen composition for most analytes (referred to as "molecular assays or known specimen composition were used as comparator methods" for PPA/NPA). This suggests a combination of validated PCR assays, and potentially sequencing for confirmation.
• Culture for Streptococcus dysgalactiae (Group C/G Strep) and Streptococcus pyogenes (Group A Strep). This is explicitly stated: "Performance measures of sensitivity and specificity refer to the prospective and archived Streptococcus and archived Streptococcus analytes for which culture was used as the reference method."

For analytical studies, the ground truth was established by:

• Known concentrations of organisms (e.g., viable or infectious units, nucleic acid copies/mL) for LoD and Inclusivity studies.
• Defined panels of organisms or substances for Exclusivity and Interference studies.

8. The Sample Size for the Training Set

This document does not provide information on the training set size directly. The presented studies are for validation/testing of the device's performance. For molecular diagnostic assays like this, the 'training' of the algorithms (e.g., primer design, melt curve analysis interpretation) typically happens during the assay development phase, often using synthetic targets, cultured organisms, and preliminary clinical samples. However, this is not detailed in a 510(k) summary, which focuses on validation data against a defined product. The "software was verified and validated" statement implies that developmental data was used, but details on sample size for that specific phase are not provided in this regulatory summary.

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

Since the training set details are not provided, the method for establishing its ground truth is also not explicitly stated in this document. However, based on typical IVD development practices:

• Ground truth for assay development (which informs the 'training' of a molecular diagnostic system) would involve well-characterized positive and negative controls, reference strains, and potentially sequenced clinical isolates.
• Molecular target sequences (in silico analysis)
• Analytical dilution series where the exact concentration of the pathogen is known.
• Samples confirmed by multiple, orthogonal laboratory methods.

The rigorous analytical and clinical studies described in the results section serve as the validation of the final trained/developed system.

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The ID NOW™ Influenza A & B 2 assay performed on the ID NOW™ Instrument is a rapid molecular in vitro diagnostic test utilizing an isothermal nucleic acid amplification technology for the qualitative detection and discrimination of influenza A and B viral RNA in direct nasal or nasopharyngeal swabs and nasal or nasopharyngeal swabs eluted in viral transport media from patients with signs and symptoms of respiratory infection. It is intended for use as an aid in the differential diagnosis of influenza A and B viral infections in humans in conjunction with clinical and epidemiological risk factors. The assay is not intended to detect the presence of influenza C virus.

Negative results do not preclude influenza virus infection and should not be used as the sole basis for diagnosis, treatment or other patient management decisions.

Performance characteristics for influenza A were established during the 2016-2017 influenza A/H3 and A/H1N1 pandemic 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.

ID NOW™ 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.

ID NOW™ Influenza A & B 2 is a rapid. instrument-based isothermal test for the qualitative detection and differentiation of influenza A and influenza B from nasal swab or nasopharyngeal swabs tested directly or after elution in viral transport media collected from patients presenting with signs and symptoms of respiratory infection.

ID NOW™ Strep A 2 is a rapid, instrument-based isothermal test for the qualitative detection of Group A Strep from throat swab specimens.

All ID NOW™ assays utilize isothermal nucleic acid amplification technology and are 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
• ID NOW™ Instrument repeat use reader

The reaction tubes in the ID NOW™ Influenza A & B 2 Test Base contain the reagents required for amplification of the target nucleic acid and an internal control. ID NOW™ Influenza A & B 2 utilizes a pair of templates (similar to primers) for the specific amplification of RNA from influenza A and B and a fluorescently labeled molecular beacon designed to specifically identify the amplified RNA targets.

The reaction tubes in the ID NOW™ Strep A 2 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. ID NOW™ Strep A 2 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.

All ID NOW™ assays are performed within the confinement of the Test Base, and no other part of the ID NOW™ 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 ID NOW™ 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 (for ID NOW™ Strep A 2) and target amplification. Heating, mixing and detection by fluorescence is provided by the instrument, with results automatically reported.

Results are displayed by the ID NOW™ Instrument and are also stored in an on-board archive and are assigned to a sample ID that has been entered into the ID NOW™ 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 Universal Printer can be attached via USB to the ID NOW™ Instrument to print test results.

The document describes the modified software for the ID Now Instrument, encompassing ID NOW Influenza A & B 2 and ID NOW Strep A 2 assays. The modification specifically addresses false invalid results caused by baseline values being lower than allowed by the original algorithm, leading to incorrect identification as "Empty Tube Values." This is an algorithm update only, with no changes made to the chemistry of the assays.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the modified software address the reduction of false invalid results. The document implies that the "performance" here relates to the analytical performance characteristics of the assays (e.g., sensitivity, specificity) remaining equivalent to the predicate devices despite the software change. While explicit numerical acceptance criteria for reduction in false invalid rate are not provided in this excerpt, the study aims to demonstrate that the new algorithm resolves the "false invalid" issue without compromising the core analytical performance.

For ID NOW™ Influenza A & B 2 (with software modification):

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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 Alere™ i Influenza A & B assay performed on the Alere™ i Instrument is a rapid molecular in vitro diagnostic test utilizing an isothermal nucleic acid amplification technology for the qualitative detection and discrimination of influenza A and B viral RNA in direct nasal or nasopharyngeal swabs eluted in viral transport media from patients with signs and symptoms of respiratory infection. It is intended for use as an aid in the differential diagnosis of influenza A and B viral infections in conjunction with clinical and epidemiological risk factors. The assay is not intended to detect the presence of influenza C virus.

Negative results do not preciude influenza virus infection and should not be used as the sole basis for diagnosis, treatment or other patient management decisions.

Performance characteristics for influenza A were established during the 2012-2013 and the 2014-2015 influenza seasons when influenza A/H1N1 pandemic 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.

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 progeness, 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 preclude infection with Group A Streptococcus and should not be used as the sole basis for treatment.

The Alere™ i RSV assay performed on the Alere™ i Instrument is a rapid molecular in vitro diagnostic test utilizing an isothermal nucleic acid amplification technology for the qualitative detection of respiratory syncytial virus (RSV) virus (RSV) virus (RSV) virus (RSV) virus (RSV) viral RNA in direct nasopharyngeal swabs and nasopharyngeal swabs cluted in viral transport media from patients with signs and symptoms of respiratory infection. It is intended for use as an aid in the diagnosis of RSV in children

Alere™ i Influenza A & B is a rapid, instrument-based isothermal test for the qualitative detection and differentiation of influenza A and influenza B from nasal or nasopharyngeal swab specimens eluted in viral transport media collected from patients presenting with signs and symptoms of respiratory infection.

Alere™ i Strep A is a rapid, instrument-based isothermal test for the qualitative detection of Group A Strep from throat swab specimens.

Alere™ i RSV is a rapid, instrument-based isothermal test for the qualitative detection and differentiation of respiratory syncytial virus (RSV) viral RNA from direct nasopharyngeal swab (NPS) and NPS eluted in viral transport media from patients with signs and symptoms of respiratory infection.

Alere™ i Influenza A & B 2 is a rapid, instrument-based isothermal test for the qualitative detection and differentiation of influenza A and influenza B from nasal swab or nasopharyngeal swabs tested directly or after elution in viral transport media collected from patients presenting with signs and symptoms of respiratory infection.

All Alere™ i assays utilize isothermal nucleic acid amplification technology and are 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 sinqle use, disposable for transfer of the eluted sample to the Test Base, and ●
• Alere™ i Instrument repeat use reader .

The reaction tubes in the Alere™ i Influenza A & B and Alere™ i Influenza A & B 2 Test Base contain the reaqents required for amplification of the target nucleic acid and an internal control. Alere™ i Influenza A & B utilizes a pair of templates (similar to primers) for the specific amplification of RNA from influenza A and B and a fluorescently labeled molecular beacon designed to specifically identify the amplified RNA targets.

The reaction tubes in the Alere™ i Strep A 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.

The reaction tubes in the Alere™ i RSV Test Base contain the reagents required for amplification of the target nucleic acid and an internal control. Alere™ i RSV utilizes a pair of templates (similar to primers) for the specific amplification of RNA from RSV A and B and a fluorescently labeled molecular beacon designed to specifically identify the amplified RNA targets.

All Alere™ i assays are 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 Iyophilized pellets contained within the Test Base and initiating bacterial lysis (for Alere™ i Strep A) 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.

This document describes a Special 510(k) submission for the Alere™ i Instrument and its associated assays (Influenza A & B, Strep A, RSV, and Influenza A & B 2). The purpose of this submission is to address a software modification to the Alere™ i Instrument's algorithm to mitigate issues with false invalid results due to baseline values being lower than allowed, which were incorrectly identified as "Empty Tube Values." The submission states that there have been no changes made to the chemistry of the assays.

The document highlights the substantial equivalence of the modified devices to their legally marketed predicate devices. However, it does not contain specific acceptance criteria or detailed study data to prove the device meets these criteria. Instead, it focuses on comparing the modified devices with their predicates, stating that all parameters (FDA Product Code, Assay Target, Intended Use, Intended Environment for Use, Instrumentation, Sample Type, Viral/Bacterial Target, Technology, Internal Control, Result Interpretation, Assay Result, and Time to Result) are "Same" as the predicate devices.

Given the information provided, it is not possible to complete a table of acceptance criteria and reported device performance, nor can we detail the study that proves the device meets the acceptance criteria, as this specific information is not present in the provided text. The document asserts "substantial equivalence" based on the described software modification and the consistency of other parameters with the predicate devices.

Therefore, the following information can be extracted or derived based on the provided text, with many fields remaining unascertainable:

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

This information is not provided in the document. The document states that the modified devices are "substantially equivalent" to their predicate devices and lists various parameters which are "Same" as the predicates. No specific numerical acceptance criteria or performance metrics (like sensitivity, specificity, accuracy) are detailed for the modified device or its predicate.

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective):

This information is not provided in the document. The submission focuses on the software modification and states that no changes were made to the assay chemistry. It does not describe any new clinical studies or test sets with sample sizes for the modified device to demonstrate its performance against new acceptance criteria. It refers to historical performance characteristics for influenza A established during certain influenza seasons for the Alere™ i Influenza A & B and Alere™ i Influenza A & B 2 assays.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience):

This information is not provided in the document. As there is no description of a new clinical study with a test set and ground truth establishment, these details are absent.

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

This information is not provided in the document.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

This is not applicable. The device is an in vitro diagnostic test for detecting viral/bacterial RNA/DNA, not an AI-assisted diagnostic imaging device that involves human readers.

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

The device is described as an "instrument-based, molecular in vitro diagnostic test utilizing an isothermal nucleic acid amplification technology" with "automated" result interpretation. This implies a standalone (algorithm only) performance, i.e., without human-in-the-loop performance influencing the assay result. However, specific standalone performance study details are not provided.

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

For the original performance characteristics mentioned for the influenza assays, it can be inferred that the ground truth would have been established by a reference method for detecting viral RNA, likely PCR or viral culture, rather than expert consensus or pathology in the context of an IVD. However, the document does not explicitly state the ground truth used for performance characteristics, nor does it detail ground truth for any new studies related to the software modification.

8. The sample size for the training set:

This information is not provided in the document. Since this is a software modification to an existing algorithm for an IVD, it's possible the "training set" concept as used in AI/ML might not directly apply, or details about algorithm development data are not included.

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

This information is not provided in the document.

In summary, the provided document is a 510(k) summary for a software modification to existing IVD devices, asserting substantial equivalence to predicates without detailing new clinical studies, acceptance criteria, or performance data for the modified device.

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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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