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The LIAISON PLEX Yeast Blood Culture (BCY) Assay is a qualitative nucleic acid multiplex in vitro diagnostic test intended for use on the LIAISON PLEX System for simultaneous detection and identification of multiple potentially pathogenic fungal organisms in positive blood culture. The LIAISON PLEX BCY Assay is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system and which contain fungal organisms as determined by Gram Stain. The LIAISON PLEX BCY Assay detects and identifies the following fungal organisms:

Candida albicans
Candida auris
Candida dubliniensis
Candida famata
Candida glabrata
Candida guilliermondii
Candida kefyr
Candida krusei
Candida lipolytica
Candida lusitaniae
Candida parapsilosis
Candida tropicalis
Candida haemulonii / duobushaemulonii
Cryptococcus neoformans / gattii

The detection and identification of specific fungal nucleic acids from individuals exhibiting signs and/or symptoms of bloodstream infection aids in the diagnosis of bloodstream infection when used in conjunction with other clinical information. The results from LIAISON PLEX BCY Assay are intended to be interpreted in conjunction with Gram stain results and should not be used as the sole basis for diagnosis, treatment management decisions.

Negative results in the setting of a suspected bloodstream infection with pathogens that are not detected by this test. Positive results do not rule out co-infection with other organisms; the organism(s) detected by LIAISON PLEX BCY Assay may not be the definite cause of disease. Additional laboratory testing (e.g. sub-culturing of positive blood cultures for identification of organisms not detected by LIAISON PLEX BCY Assay, susceptibility testing and differentiation of mixed growth) and clinical presentation must be taken into consideration in the final diagnosis of bloodstream infection.

The LIAISON PLEX "Yeast Blood Culture Assay (BCY Assay) is performed directly on blood culture media using blood culture bottles identified as positive by a continuous monitoring blood culture system, and which contain a fungal organism, as determined by a Gram stain. The system consists of an instrument, a single-use disposable test cartridge, and a transfer pipette. The user loads the sample into the sample port of the LIAISON PLEX Yeast Blood Culture Assay Cartridge. Next, the user sets up the sample order on the LIAISON PLEX System by first entering the sample information or scanning the barcode ID located on the sample tube, then scanning the barcode ID located on the test cartridge. Last, the user inserts the test cartridge into the processing module to initiate the test. The LIAISON PLEX System identifies the assay being run and automatically initiates the proper testing protocol to process the sample, analyze the data, and generate test results.

The LIAISON PLEX System automates the BCY Assay sample analysis through the following steps: a) Sample Preparation: Nucleic acid extraction via mechanical and chemical cell lysis and magnetic bead-based nucleic acid isolation; b) Amplification: Multiplex PCR based amplification of the extracted nucleic acid to generate target specific amplicons; c) Hybridization: Amplified DNA hybridizes to specific capture DNA arrayed on a glass slide in a microarray format and the bound target DNA, in turn, hybridizes with mediator and gold-nanoparticle probes; d) Signal Analysis: Gold nanoparticle probes bound specifically to target-containing spots in the microarray are silver-enhanced, and light scatter from the spots is measured and further analyzed to determine the presence (Detected) or absence (Not Detected) of a target.

Acceptance Criteria and Device Performance for LIAISON PLEX Yeast Blood Culture Assay

The LIAISON PLEX Yeast Blood Culture (BCY) Assay is a qualitative nucleic acid multiplex in vitro diagnostic test for the simultaneous detection and identification of multiple potentially pathogenic fungal organisms in positive blood cultures. The study summarized below aimed to demonstrate the device meets its acceptance criteria through analytical and clinical performance evaluations.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the LIAISON PLEX BCY Assay clinical study were predefined as:

• Sensitivity: ≥ 90% for all targets
• Specificity: ≥ 95% for each target
• Failure rate: ≤ 15%

The clinical performance data, combining prospective and pre-selected specimens, is summarized in the table below, comparing it against the acceptance criteria.

Table 1: LIAISON PLEX BCY Assay Clinical Performance (Acceptance Criteria vs. Reported Performance)

NA = Not applicable, as there were no positive cases for this target in the combined prospective/pre-selected dataset to calculate sensitivity, or no negative cases to calculate specificity.

The reported performance demonstrates that the LIAISON PLEX BCY Assay met all defined acceptance criteria.

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

The test set for the clinical performance evaluation utilized a combination of prospective, pre-selected, and contrived specimens:

• Prospective Specimens (Clinical Study): 69 unique specimens from four geographically diverse clinical sites in the United States. These were collected prospectively between June 2023 and October 2023. One initial specimen was excluded due to an inconclusive Gram stain result.
• Pre-selected Specimens (Clinical Study): 63 remnant, de-identified specimens sourced from 6 different sites/vendors in the United States. The data provenance is retrospective clinical specimens that were pre-characterized.
• Contrived Specimens: 829 specimens were artificially generated. These were blinded, randomized, and tested at all four testing sites during June 2023. These are contrived data.

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

The provided document does not explicitly state the number of experts or their specific qualifications (e.g., radiologist with 10 years of experience) used to establish the ground truth for the test set.

However, the ground truth for the clinical study was established by comparing the LIAISON PLEX BCY Assay's performance against a Standard of Care culture followed by identification by Matrix Assisted Laser Desorption/Ionization coupled to time-of-flight Mass Spectrometry (MALDI-TOF MS) for all fungal targets. For the pre-selected specimens, it is mentioned that they were "characterized by an FDA cleared molecular assay prior to enrollment in the study." This implies that the ground truth relied on established laboratory methodologies and potentially an FDA-cleared reference method.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method like "2+1" or "3+1" using human experts for the clinical study. The comparison was made against a "Standard of Care culture followed by identification by MALDI-TOF MS" as the reference method, which serves as the definitive ground truth for the presence and identification of the fungal organisms. For the pre-selected specimens, an "FDA cleared molecular assay" was used for characterization prior to study entry. These are objective laboratory methods rather than subjective expert interpretations requiring adjudication.

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 reported. This device is an in vitro diagnostic (IVD) assay designed for automated detection and identification of fungal organisms directly from blood culture samples. Its performance is evaluated against laboratory reference methods (culture and MALDI-TOF MS, or existing molecular assays), not against human reader interpretation of images or other subjective assessments. Therefore, there is no discussion of how human readers improve with or without AI assistance, as AI assistance is not part of the described use case for this IVD device.

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

Yes, the performance presented for the LIAISON PLEX BCY Assay in the analytical and clinical performance sections is for the standalone algorithm/device performance directly on the sample, without human interpretation or intervention in the diagnostic output. The system automates sample analysis, including nucleic acid extraction, amplification, hybridization, and signal analysis, to generate detected or not detected results. The indication for use clearly states the results are "intended to be interpreted in conjunction with Gram stain results and should not be used as the sole basis for diagnosis, treatment management decisions," but this refers to the clinical application context, not a human-in-the-loop for the device's fundamental diagnostic accuracy calculation.

7. The Type of Ground Truth Used

The primary ground truth used for the clinical study was:

• Standard of Care culture followed by identification by Matrix Assisted Laser Desorption/Ionization coupled to time-of-flight Mass Spectrometry (MALDI-TOF MS). This is a laboratory-based, objective method for identifying microorganisms.
• For pre-selected specimens, ground truth was established by an previously FDA-cleared molecular assay.
• For contrived specimens, the ground truth was inherently known based on how the samples were prepared (spiking known organisms).

8. The Sample Size for the Training Set

The document does not report specific sample sizes for a separate training set for this device. The information provided heavily details analytical and clinical verification/validation (test set) studies. For diagnostic devices like this (nucleic acid assays), the development process typically involves extensive analytical characterization (Limit of Detection, Inclusivity, Exclusivity, Interference, Reproducibility) and then clinical validation. It is probable that internal development, optimization, and early verification studies used various sets of samples, but these are not explicitly termed "training sets" in the context of machine learning model training as one might expect for AI/ML-based diagnostic software.

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

As no explicit "training set" is documented (in the context of AI/ML), there is no description of how ground truth was established for such a set. However, for the analytical studies and development of the assay, ground truth would have been established through well-characterized reference strains and clinical isolates, quantified using standard microbiology techniques (e.g., CFU/mL for Limit of Detection). These methods involve culturing, molecular characterization, and established laboratory practices to confirm the identity and concentration of the microorganisms.

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The GenMark ePlex Blood Culture Identification Fungal Pathogen (BCID-FP) Panel is a qualitative nucleic acid multiplex in vitro diagnostic test intended for use on GenMark's ePlex Instrument for simultaneous detection and identification of multiple potentially pathogenic fungal organisms in positive blood culture. The ePlex BCID-FP Panel is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system and which contain fungal organism.

The following fungal organisms are identified using the ePlex BCID-FP Panel: Candida albicans, Candida auris, Candida dubliniensis, Candida famata, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Cryptococcus gattii, Cryptococcus neoformans, Fusarium and Rhodotorula.

The detection and identification of specific fungal nucleic acids from individuals exhibiting signs and/or symptoms of bloodstream infection aids in the diagnosis of bloodstream infection when used in conjunction with other clinical information. The results from the ePlex BCID-FP Panel are intended to be interpreted in conjunction with Gram stain results and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

Negative results in the setting of a suspected bloodstream infection may be due to infection with pathogens that are not detected by this test. Positive results do not rule out co-infection with other organisms; the organism(s) detected by the ePlex BCID-FP Panel may not be the definite cause of disease. Additional laboratory testing (e.g. sub-culturing of positive blood cultures for identification of organisms not detected by ePlex BCID-FP Panel, susceptibility testing and differentiation of mixed growth) and clinical presentation must be taken into consideration in the final diagnosis of bloodstream infection.

The ePlex Blood Culture Identification Fungal Pathogen (BCID-FP) Panel is based on the principles of competitive nucleic acid hybridization using a sandwich assay format, wherein a single-stranded target binds concurrently to a sequence-specific solution-phase signal probe and a solid-phase electrode-bound capture probe. The test employs nucleic acid extraction, target amplification via polymerase chain reaction (PCR) or reverse transcription PCR (RT-PCR) and hybridization of target DNA. In the process, the double-stranded PCR amplicons are digested with exonuclease to generate single-stranded DNA suitable for hybridization.

Nucleic acid extraction from biological samples occurs within the cartridge via cell lysis, nucleic acid capture onto magnetic beads, and release for amplification. The nucleic acid extraction is processed through microfluidic liquid handling. Once the nucleic acid targets are captured and inhibitors are washed away, the magnetic particles are delivered to the electrowetting environment on the printed circuit board (PCB) and the targets are eluted from the particles and amplified.

During hybridization, the single-stranded target DNA binds to a complementary, single-stranded capture probe immobilized on the working gold electrode surface. Single-stranded signal probes (labeled with electrochemically active ferrocenes) bind to specific target sequence / region adjacent to the capture probe. Simultaneous hybridization of target to signal probes and capture probe is detected by alternating current voltammetry (ACV). Each working electrode on the array contains specific capture probes, and sequential analysis of each electrode allows detection of multiple analyte targets.

This document describes the analytical and clinical performance of the GenMark ePlex Blood Culture Identification Fungal Pathogen (BCID-FP) Panel, an in vitro diagnostic test. The information provided is sufficient to extract the requested details about acceptance criteria and study proving the device meets them.

1. Table of acceptance criteria and reported device performance:

The document implicitly defines acceptance criteria through the reported performance characteristics. While no explicit "acceptance criteria" table is provided, the clinical performance (Sensitivity/PPA and Specificity/NPA) tables against a comparator method serve as the primary evidence of meeting performance expectations. Analytical performance characteristics also define a form of acceptance criteria (e.g., LOD, exclusivity).

Here’s a table summarizing the reported device performance for each target organism, which represents the device meeting its performance objectives. The device demonstrates high sensitivity (positive percent agreement) and specificity (negative percent agreement) across various sample types (prospective, retrospective, and contrived).

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

The test set for evaluating clinical performance consisted of:

• Prospective Samples: 21 evaluable samples (11 fresh, 10 frozen) collected at 6 clinical sites. These samples are from patients of all ages and genders. Collection dates are specified from May 2015 through July 2016 (frozen) and July through August 2018 (fresh). The country of origin is not explicitly stated but implied to be the US given the FDA submission. This data is prospective.
• Retrospective Samples: 120 samples collected from 9 sites. This data is retrospective.
• Contrived Samples: 725 evaluable samples prepared by spiking isolates into blood culture bottles. These are laboratory-prepared samples.

The total number of samples evaluated for clinical performance was 866 (11 fresh prospective + 10 frozen prospective + 120 retrospective + 725 contrived).

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., radiologists with 10 years of experience) used to establish the ground truth. Instead, it relies on standard laboratory procedures and analytically validated PCR assays followed by bi-directional sequencing as the comparator methods (ground truth). This implies that the ground truth was established through a combination of traditional microbiological methods and molecular techniques, not through expert consensus reading of images or other subjective assessments.

4. Adjudication method for the test set:

The document describes the "comparator method" as the gold standard. For specific targets like Candida auris, Fusarium, Rhodotorula, and to confirm Candida parapsilosis, PCR/sequencing was used to determine the presence or absence of the organism, effectively acting as an adjudication step for these cases. For other organisms, standard laboratory procedures (culture, MALDI-TOF IVD, etc.) defined the ground truth. There is no mention of a traditional reader adjudication process (e.g., 2+1 or 3+1) as would be common in image-based AI studies, as this is a molecular diagnostic test. For discrepant results (e.g., section "Co-detections in Clinical Samples"), PCR/sequencing was used to investigate.

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 typically performed for AI-assisted diagnostic tools that involve human interpretation of images. The ePlex BCID-FP Panel is an in vitro diagnostic (IVD) test that directly detects and identifies genetic material, so human readers are not involved in its direct interpretation in the way they would be in an AI imaging study. Therefore, there is no effect size of how much human readers improve with AI vs without AI assistance.

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

Yes, the primary clinical performance evaluation is a standalone performance of the algorithm (the ePlex BCID-FP Panel) against a defined ground truth (comparator methods). The reported sensitivity/PPA and specificity/NPA values are purely the device's performance.

7. The type of ground truth used:

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

• Standard laboratory procedures: This includes traditional and automated culture, MALDI-TOF IVD (Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry), and other microbiological and biochemical techniques.
• Analytically validated PCR assays followed by bi-directional sequencing: This advanced molecular method was used for specific targets (Candida auris, Fusarium, Rhodotorula) and to confirm certain identifications (Candida parapsilosis).

This represents a combination of expert consensus (through standard lab practices) and molecular outcomes data.

8. The sample size for the training set:

The document does not explicitly state the sample size for a "training set" in the context of machine learning. As this is a molecular diagnostic assay using nucleic acid hybridization and PCR, not a machine learning algorithm that learns from data in the same way, the concept of a distinct 'training set' for the device's core functionality specification might not apply directly in the conventional AI sense. The development of such assays involves analytical validation using numerous strains and concentrations (analytical reactivity, LOD, exclusivity), which implicitly serve as a form of "training" or optimization data during product development, but this is distinct from machine learning model training. The provided data focuses on the performance evaluation (test set) for regulatory approval.

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

Given that there isn't a "training set" in the typical machine learning sense, the way "ground truth" would be established for the development of such a molecular assay would involve:

• Known Reference Strains: Use of well-characterized microbial strains (e.g., ATCC, CBS, CDC strains) with confirmed identities. These are used in analytical studies like Limit of Detection (LOD) and Analytical Reactivity (Inclusivity), as well as Competitive Inhibition studies. Table 21 ("Contrived Sample Summary") and Table 27 ("Analytical Reactivity (Inclusivity) Results") list numerous specific strains and their origins (e.g., ATCC, CBS, NCPF, CDC#) used in testing.
• Sequencing and Phenotypic Characterization: During the assay's development, target sequences would be determined through genome sequencing, and phenotypic characteristics would be confirmed through established microbiological methods.

Therefore, the "ground truth" during device development (analogous to training/development data in AI) relies on well-characterized laboratory standards and molecular gold standards.

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