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The Simplexa COVID-19 / Flu A/B & RSV Direct is a real-time RT-PCR assay intended for use on the LIAISON MDX instrument for the simultaneous in vitro qualitative detection and differentiation of nucleic acid from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A (Flu A) virus, influenza B (Flu B) virus and respiratory syncytial virus (RSV) in nasopharyngeal swab and anterior nasal swab specimens from individuals with signs and symptoms of respiratory tract infection. Clinical signs and symptoms of respiratory tract infection due to SARS-CoV-2, influenza A, influenza B, and RSV can be similar.

The Simplexa COVID-19 / Flu A/B & RSV Direct assay is intended for use as an aid in the differential diagnosis of SARS-CoV-2, influenza A, influenza B and RSV infections if used in conjunction with other clinical and epidemiological information, and laboratory findings. SARS-CoV-2, influenza A, influenza B, and RSV viral RNA are generally detectable in nasopharyngeal swab and anterior nasal swab specimens during the acute phase of infection. This test is not intended to detect influenza C virus infections.

Positive results are indicative of the presence of the identified virus, but do not rule out bacterial infection or co-infection with other pathogens not detected by the test. The agent(s) detected by the Simplexa COVID-19 / Flu A/B & RSV Direct real-time RT-PCR assay may not be the definite cause of the disease. Negative results do not preclude SARS-CoV-2, influenza A, influenza B, or RSV infection and should not be used as the sole basis for patient management decisions.

The Simplexa™ COVID-19 & Flu A/B & RSV Direct assay is a qualitative, multiplex real-time reverse transcription polymerase chain reaction (RT-PCR) test intended for the simultaneous detection and differentiation of RNA from SARS-CoV-2, Influenza A, Influenza B, and Respiratory Syncytial Virus (RSV) in nasopharyngeal swabs (NPS) and anterior nasal swabs (NS) in UTM/UVT and M4RT specimen transport media. The assay is performed on the LIAISON® MDX Instrument using a Direct Amplification Disc (DAD) format, enabling sample-to-answer processing without separate nucleic acid extraction.

The LIAISON® MDX Instrument is a benchtop real-time PCR thermocycler that utilizes a self-contained, single-use direct amplification disc (DAD) to process samples. It performs thermal cycling and real-time fluorescence detection using optical detection modules, each with specific excitation and emission wavelengths. The instrument includes a laser enclosed in a laser product housing, with integrated hardware and software interlocks to ensure user safety. It is operated via a USB connection to a dedicated computer running the LIAISON® MDX Studio software.

The LIAISON® MDX Studio software controls the instrument and provides a user interface for assay setup, execution, and result analysis. The software automatically interprets results for in vitro diagnostic (IVD) assays using pre-defined assay definitions encoded in barcode inserts included with the assay kits. It performs spectral compensation, verifies internal control amplification, and checks for sufficient sample volume prior to amplification. The software also includes user authentication, audit logging, laboratory information system (LIS) connectivity, and cybersecurity features.

The assay kit includes single-use reaction mix vials, a positive control pack with inactivated viral particles in transport media, and the Direct Amplification Disc consumable, which supports up to eight simultaneous reactions.

The assay format is designed for direct amplification, with 24 single-use reaction mix vials per kit. The required sample volume input is 50 µL. The reaction mix is provided in single-use vials and includes DNA polymerase, reverse transcriptase, RNase inhibitor, primers, probes, and encapsulated RNA templates. The buffer component in the reaction mix maintains optimal pH and ionic strength to support enzyme activity and amplification efficiency throughout the RT-PCR process.

The assay includes an encapsulated RNA internal control (RNA IC) in each reaction to monitor for potential RT-PCR inhibition or process failure. The RNA IC is derived from bacteriophage MS2. This non-target RNA is co-amplified with the assay's viral targets and detected independently using post-amplification melting curve analysis. The presence of the RNA IC in a negative specimen confirms that the amplification process functioned as expected, while its absence—along with no target detection—results in an invalid outcome. Detection of the RNA IC is not required in the Positive Control but is expected in the No Template Control (NTC) to verify assay validity.

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The Simplexa C. auris Direct is a real-time polymerase chain reaction (RT-PCR) assay intended for use on the LIAISON MDX instrument for the direct in vitro qualitative detection of Candida auris DNA from a composite swab of bilateral axilla/groin from patients suspected of C. auris colonization.

The test is intended to aid in the prevention and control of C. auris infection in healthcare settings by detecting C. auris from colonized patients.

Positive results indicate that the patient is colonized with C. auris. A positive result cannot rule out co-colonization with other pathogens. A negative result does not preclude C. auris colonization or infection and should not be used as the sole basis for treatment or other patient management decisions. Results are meant to be used in conjunction with other clinical, epidemiologic, and laboratory information available to the clinician evaluating the patient. The test is not intended to diagnose or monitor treatment for C. auris infection. Concomitant cultures are necessary to recover organisms for epidemiological typing or for antimicrobial susceptibility testing.

The Simplexa C. auris RT-PCR system is intended for the amplification and qualitative detection of nucleic acid from Candida auris in composite bilateral axilla/groin swab specimens and consists of the following:

1. The Simplexa C. auris Direct is the RT-PCR assay kit that contains all the reagents for the amplification reaction, including the primers and fluorescent probes for the detection of nucleic acid from Candida auris. The primers and fluorescent probes amplifies the C. auris DNA and Internal Control DNA. In addition, the kit comes with a barcode card, which contains assay specific parameters and lot information.
2. The Simplexa C. auris Positive Control Pack is the separately packaged external positive quality control kit for use with the Simplexa C. auris Direct assay.
3. The Simplexa C. auris Sample Prep Kit is the enzymatic buffer solution to receive the sample solution (bilateral axilla/groin swab in Amies transport media) from the patient.

The Simplexa C. auris RT-PCR system is for use with the LIAISON MDX instrument (with LIAISON MDX Studio Software), the RT-PCR thermocycler that amplifies the nucleic acid from biological specimens and uses real-time fluorescence detection to identify targets, and the Direct Amplification Disc (DAD), which is the accessory containing the input sample wells for use on the LIAISON MDX. The instrument and accessory were previously cleared under K102314 and K120413. The instrument is controlled by an external laptop running the software. The DAD consumable is compartmentalized into eight (8) separate wedges and can process up to eight (8) separate specimens or controls on each disc. Each wedge contains sample and reagent input wells, microfluidic channels and laser activated valves to control the fluid flow as well as a reaction/detection chamber.

The provided document describes the analytical and clinical performance of the Simplexa C. auris Direct RT-PCR system. However, it does not explicitly state pre-defined acceptance criteria in a table format that the device needed to meet. Instead, it presents the results of various studies (precision, analytical specificity, limit of detection, inclusivity, clinical performance) and then often concludes whether these results are "acceptable."

For example, for precision, it states: "For the multisite study, the test device showed ≥ 98.9% agreement of the qualitative result and ≤ 8.2% CV for each of the variance components, which is acceptable." This implies that ≥ 98.9% agreement and ≤ 8.2% CV were the internal acceptance criteria for precision.

Similarly, for the clinical performance, the reported Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) values are presented as the device's performance, but explicit pre-defined minimum thresholds for PPA and NPA as acceptance criteria are not given. They are implied by the fact that the De Novo request was granted.

Given this, I will infer the acceptance criteria from the reported "acceptable" results where possible and present the device performance based on the clinical study results.

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

1. Table of Acceptance Criteria (Inferred) and Reported Device Performance

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

Test Set (Clinical Study):

• Total Evaluable Clinical Specimens (Combined Cohort): 2,020 specimens.
  • Prospective Cohort: 1,930 evaluable specimens.
  • Retrospective/Enriched Cohort: 90 evaluable specimens (11 retrospective pre-selected C. auris positive + 202 enriched specimens, of which 90 were evaluable).
• Data Provenance:
  • Geographic Locations: Six study sites across four geographically diverse locations within the United States and one in Italy.
  • Type of Data:
    • Prospective: Prospectively collected specimens (axilla/groin swabs) from patients suspected of C. auris colonization. Tested either fresh or frozen. Collected from April to July 2023.
    • Retrospective/Enriched: Leftover, de-identified composite bilateral axilla/groin swabs. Included 11 pre-selected C. auris positive retrospective specimens and 202 enriched specimens (identified as positive by a laboratory-verified RT-PCR test, then blinded and tested).

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

The document states that the ground truth for the clinical study was established by a reference method consisting of "standard of care (SOC) culture followed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) for identification." These are laboratory methods, not human expert interpretation of images or other subjective data.

For discordant analysis, "Bi-directional sequencing (BDS) assays were performed when the candidate assay results differed from the comparator method." Again, this is a laboratory method.

The document does not specify human experts or their qualifications for establishing the ground truth for the test set.

4. Adjudication Method for the Test Set

The primary ground truth was established by the reference method (SOC culture + MALDI-TOF MS). For discordant results between the candidate assay and the reference method, Bi-directional Sequencing (BDS) was performed. However, "The results from discordant analysis were not used to alter the original performance but are provided in footnotes to the performance tables."

Therefore, there wasn't a human-based adjudication method in the traditional sense (e.g., 2+1 or 3+1 radiologists making a consensus decision). The reference method and supplemental BDS purely relied on objective laboratory techniques.

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

No, this document describes a diagnostic device (RT-PCR assay) for detecting nucleic acids of Candida auris. It is not an AI-assisted diagnostic imaging device for which an MRMC study comparing human readers with and without AI assistance would be relevant. The study focuses solely on the direct performance of the molecular diagnostic test against a laboratory reference method.

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

Yes, the entire clinical evaluation (Sections VI.C) and analytical performance studies (Sections VI.A) describe the standalone performance of the Simplexa C. auris Direct RT-PCR system. This device is an automated molecular diagnostic test and does not involve human interpretation in a loop, except for the user performing the test steps according to the instructions. The results (Ct values, positive/negative calls) are generated directly by the instrument platform (LIAISON MDX).

7. The Type of Ground Truth Used

The primary ground truth used for the clinical study was Standard of Care (SOC) culture followed by Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) for identification. For discordant results, Bi-directional Sequencing (BDS) was used as a supplemental ground truth, though these results did not alter the original performance metrics. This is a form of laboratory reference standard.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of an AI/ML algorithm that would undergo a distinct training phase. This document describes a molecular diagnostic assay, not a machine learning model. The development of such assays involves establishing parameters (like fluorescence and Ct thresholds) using initial data, which could be considered an internal "calibration" or "development" process rather than a "training set" in the AI sense.

It states: "The fluorescence and Ct thresholds for C. auris and Internal Control were established using 717 sample runs of No Template Control (NTC), Limit of Detection (LoD), Microbial Inhibition, Interference and Limiting Dilution samples. The established thresholds were then confirmed using an independent data set comprising 2,924 sample runs..." These 717 runs could be considered the data used for establishing (or "training") the assay's interpretive parameters.

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

Given that this is a molecular diagnostic assay and not an AI/ML system, the concept of "ground truth for a training set" as it pertains to labeled examples for model learning is not directly applicable.

Instead, the "establishment" of the assay's operating parameters (like Ct thresholds) was based on experimental data where the expected outcome (presence/absence of C. auris, inhibition, etc.) was known by design:

• No Template Control (NTC): Expected negative.
• Limit of Detection (LoD): Contrived samples with known concentrations of C. auris.
• Microbial Inhibition/Interference: Samples with C. auris at known concentrations (e.g., 3x LoD) spiked with other substances/organisms.
• Limiting Dilution: Samples serially diluted to determine the lowest detectable concentration.

These experiments provide the "ground truth" for setting the assay's interpretive parameters and analytical performance characteristics. The known concentrations, presence/absence of target nucleic acids, and presence/absence of interfering substances served as the factual basis for defining how the device should interpret its signals (e.g., Ct value thresholds for positivity).

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The LIAISON® VZV IgG HT assay uses chemiluminescent immunoassay (CLIA) technology for the in vitro qualitative detection of specific IgG antibodies to varicella-zoster virus (VZV) in human serum (with gel and without gel-SST), dipotassium EDTA (K2- EDTA), lithium heparin and sodium heparin plasma samples. This assay is intended as an aid in the determination of previous infection of varicella- zoster virus. The test must be performed on the LIAISON® XL Analyzer. The assay performance in detecting antibodies to VZV in individuals vaccinated with the FDA-licensed VZV vaccine is unknown. The user of this assay is responsible for establishing the performance characteristics with VZV vaccinated individuals.

The LIAISON® VZV IgG HT is an indirect chemiluminescence immunoassay (CLIA) for qualitative detection of specific IgG antibodies to varicella-zoster virus in human serum and plasma.

The LIAISON® Control VZV IgG HT are liquid ready-to-use controls based in human serum and plasma. The negative control is intended to provide an assay response characteristic of negative patient specimens and the positive control is intended to provide an assay response characteristic of positive patient specimens.

The assay and controls are designed for use with DiaSorin LIAISON® analyzer family

Here's an analysis of the provided text regarding the DiaSorin LIAISON® VZV IgG HT device, focusing on acceptance criteria and supporting study details:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for this device are primarily expressed as Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to a predicate device, as well as satisfactory performance in interference, cross-reactivity, precision, and high-dose saturation studies.

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

• Test Set Sample Size:
  • Total Clinical Agreement Study: 1544 clinical human serum samples (1543 used in analysis due to one sample with insufficient volume).
  • Breakdown: 125 known positive, 200 known negative, 135 pregnant women, and 1084 routine lab specimens.
  • Specific sub-studies:
    • Interfering Substances: Not specified, but involved VZV IgG antibody negative, around the cut-off, low positive, and high positive samples.
    • Cross-Reactivity: 226 samples from various conditions.
    • Precision (Within-Lab): 7 samples (panel of coded samples) tested 240 times each.
    • Reproducibility (Multi-site): 7 samples tested 90 times each across sites.
    • High-dose saturation: 3 high-titer samples.
    • Analytical sensitivity: Not a sample size of patient specimens, but derived from serial dilutions of WHO International Standard on 3 assay lots.
• Data Provenance: The general clinical samples were collected within the United States. The study was prospective in execution as it involved testing these samples with the new device and comparing them to a predicate, conducted at three independent external laboratories.

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

The document does not explicitly state the number of experts used and their qualifications for establishing the ground truth of the test set.

4. Adjudication Method for the Test Set

The document does not explicitly state an adjudication method (like 2+1, 3+1). The "ground truth" for the clinical agreement study appears to be defined by the results of the FDA cleared predicate device (LIAISON® VZV IgG, K150375), which is referred to as the "comparator." It notes that "Specimens which were repeatedly equivocal by the predicate device were graded against the performance of the LIAISON® VZV IgG HT assay which does not have an equivocal zone." This implies a direct comparison to the predicate's results rather than an independent expert adjudication process for the clinical samples. For cross-reactivity, samples were "pre-screened with another commercially available VZV IgG assay" and then confirmed for the presence of potential cross-reactants using "US-marked assays."

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an automated in vitro diagnostic assay (CLIA technology) for qualitative detection of antibodies, not an imaging device requiring human reader interpretation or AI assistance in the human-in-the-loop context.

6. Standalone (Algorithm Only) Performance Study

Yes, the entire clinical performance evaluation described (Clinical Agreement, Interfering Substances, Cross-Reactivity, Precision, Reproducibility, High-dose saturation, Analytical Sensitivity) is essentially a standalone algorithm-only performance study. The LIAISON® VZV IgG HT assay is an automated system run on the LIAISON® XL Analyzer, meaning its performance is evaluated without human interpretation of results beyond reading the automated output.

7. Type of Ground Truth Used

The primary ground truth for the clinical agreement study was established by the FDA cleared predicate device (LIAISON® VZV IgG, K150375). For the "known positive" and "known negative" specimens, their status was pre-determined, likely by previous clinical diagnosis or established VZV serology results (though the exact method for this is not detailed beyond being "known"). For cross-reactivity studies, ground truth was based on positive results from "US-marked assays" for the specific cross-reacting agent.

8. Sample Size for the Training Set

The document does not specify a training set sample size. This is typical for in vitro diagnostic (IVD) assays like this one. While there is an "algorithm" (the CLIA technology and interpretation logic), it's not a machine learning model that undergoes a separate training phase with a distinct dataset in the way a medical imaging AI would. The "development" and "optimization" of such assays usually happen using internal samples and established chemical/biological principles, not a formalized, reported training set size like in AI/ML submissions.

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

Since a formalized "training set" for a machine learning algorithm isn't explicitly mentioned or directly applicable in the typical sense for this type of IVD, the concept of establishing ground truth for it is also not directly addressed. The assay's performance characteristics are developed and validated based on its underlying chemical and biological reactions and internal testing, which ensures it correctly identifies VZV IgG antibodies.

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The DiaSorin Molecular Simplexa™ COVID-19 & Flu A/B Direct is a real-time RT-PCR assay intended for use on the LIAISON® MDX instrument for the in vitro qualitative detection and differentiation of nucleic acid from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza B virus in nasopharyngeal swabs (NPS) from individuals with signs and symptoms of respiratory tract infection.

The Simplexa™ COVID-19 & Flu A/B Direct assay is intended for use as an aid in the differential diagnosis of SARS-CoV-2, influenza A and influenza B infection.

Negative results do not preclude SARS-CoV-2, influenza B infection and should not be used as the sole basis for patient management decisions. Positive results do not rule out coinfection with other organisms. Results should be combined with clinical observations, patient history, and epidemiological information.

The Simplexa™ COVID-19 & Flu A/B Direct assay is intended for use by qualified and trained clinical laboratory personnel specifically instructed and trained in the techniques of real-time PCR and in vitro diagnostic procedures.

The Simplexa™ COVID-19 & Flu A/B Direct assay system is a real-time RT-PCR system that enables the direct amplification, detection and differentiation of SARS-CoV-2 RNA, human influenza A (Flu A) virus RNA and human influenza B (Flu B) virus RNA from unprocessed nasopharyngeal swabs (NPS) that have not undergone nucleic acid extraction. The system consists of the Simplexa™ COVID-19 & Flu A/B Direct assay, the LIAISON® MDX (with LIAISON® MDX Studio Software), the Direct Amplification Disc and associated accessories.

In the Simplexa™ COVID-19 & Flu A/B Direct assay, fluorescent probes are used together with corresponding forward and reverse primers to amplify SARS-CoV-2, Flu A, Flu B and internal control RNA targets. For COVID-19 detection, the assay targets two different regions specific to the SARS-CoV-2 genome; the S gene which encodes the spike glycoprotein and the ORF1ab region which encodes wellconserved non-structural proteins and therefore is less susceptible to recombination. For Flu detection the assay targets conserved regions of influenza A viruses (matrix gene) and influenza B viruses (matrix gene). The assay provides three results; COVID-19 (ORF1ab and/or S gene detection), influenza A viruses (matrix gene detection) and influenza B viruses (matrix gene detection). An RNA internal control is used to detect RT-PCR failure and/or inhibition.

This document describes the analytical and clinical performance studies for the DiaSorin Molecular Simplexa™ COVID-19 & Flu A/B Direct assay.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the clinical performance are generally indicated by the Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) with their corresponding 95% Confidence Intervals (CI).

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

• Prospective Samples: Over 1400 total specimens (nasopharyngeal swabs (NPS)) were collected between August 2021 and March 2022 from six geographically diverse clinical sites within the United States. The exact number of prospective samples used for each target in the agreement analysis can be inferred from the TP/(TP+FN) and TN/(TN+FP) values in Table 2:
  • Influenza A: 1168 (62 positive, 1106 negative, plus 5 and 2 discrepant)
  • Influenza B: 1165 (all negative)
  • SARS-CoV-2: 496 (68 positive, 428 negative, plus 1 and 11 discrepant)
• Retrospective Samples: 82 positive influenza B specimens and 62 negative specimens were used. These were blinded and randomized for the study. The exact number of retrospective samples used for each target in the agreement analysis can be inferred from the TP/(TP+FN) and TN/(TN+FP) values in Table 3:
  • Influenza A: 258 (82 positive, 176 negative)
  • Influenza B: 258 (114 positive, 144 negative)
  • SARS-CoV-2: 252 (all negative)

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

The 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.

4. Adjudication Method for the Test Set

• SARS-CoV-2: For SARS-CoV-2, a composite reference method (CRM) was used. This involved three COVID-19 Emergency Use Authorized (EUA) NAAT assays. The adjudication method was:
  • "Detected" CRM if two out of three EUA assays were positive.
  • "Not Detected" CRM if two out of three EUA assays were negative.
• Influenza A and B: For influenza A and B, the comparator was an FDA-cleared NAAT. There is no mention of a multi-assay composite reference method, suggesting a single FDA-cleared NAAT was used as the ground truth. Discrepancy analysis involved additional FDA cleared NAATs and PCR followed by BDS.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This study focuses on the standalone performance of the diagnostic assay rather than human reader performance with or without AI assistance.

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

Yes, a standalone performance study was done. The entire clinical performance section evaluates the Simplexa™ COVID-19 & Flu A/B Direct assay's ability to detect and differentiate nucleic acids directly, without human interpretation in the results reporting, other than laboratory personnel operating the instrument. The results are presented as the assay's agreement with reference methods.

7. The Type of Ground Truth Used

• SARS-CoV-2: Composite reference method (CRM) based on the consensus of three COVID-19 Emergency Use Authorized (EUA) NAAT assays.
• Influenza A and B: An FDA-cleared NAAT was used as the primary comparator. In cases of discrepancy, additional FDA-cleared NAATs and PCR followed by Bidirectional Sequencing (BDS) were used for confirmation.

8. The Sample Size for the Training Set

The document describes the clinical performance (test set) and analytical studies. It does not explicitly mention a "training set" in the context of machine learning. The assay is a real-time RT-PCR assay, which typically relies on pre-defined primer and probe sequences rather than a machine learning model that requires a distinct training set in the conventional sense. The development and optimization of the primer/probe sets (e.g., analytical reactivity, inclusivity) can be considered analogous to a "training" or development phase, but no specific dataset labeled as such is provided.

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

As noted in point 8, a traditional "training set" with ground truth establishment in the context of machine learning is not applicable to this RT-PCR assay. The analytical studies (Limit of Detection, Analytical Reactivity/Inclusivity, Cross-Reactivity, Interfering Substances, Competitive Interference, Microbial Interference) use quantitated viral stocks, cultured isolates, purified nucleic acids, or in silico analysis against public strain databases (e.g., GISAID) to demonstrate the assay's analytical performance across a wide range of relevant targets and conditions. This ensures the assay's biochemical design (primers, probes) is sound and effective.

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The LIAISON® Anti-HAV assay is an in vitro chemiluminescent immunoassay intended for the qualitative detection of total antibodies to hepatitis A (anti-HAV) in human serum and sodium heparin plasma samples using the LIAISON® Analyzer family*. The assay is indicated as an aid in the laboratory diagnosis of current or previous HAV infections in conjunction with other serological and clinical information and to determine the presence of an antibody response to HAV in vaccine recipients.

This assay is not intended for screening blood or solid or soft tissue donors.

The DiaSorin LIAISON® XS Analyzer is a fully automated, closed, continuous loading of samples and reagents in vitro diagnostic immunoassay system utilizing chemiluminescent technology to provide rapid sample results. The analyzer uses DiaSorin proprietary reagents in which chemiluminescence of an analyte is measured in a sample by the reaction of a magnetic particle solid phase coated with antigen or antibody and a chemiluminescent tracer. The LIAISON® XS Analyzer is intended for use in professional clinical laboratories only.

The method for qualitative determination of anti-HAV is a competitive sandwich chemiluminescence immunoassay (CLIA) based on neutralization. The assay uses magnetic particles (solid phase) coated with IgG antibodies to HAV (mouse monoclonal), and a mouse monoclonal anti-HAV antibody conjugate linked to an isoluminol derivative (isoluminolantibody conjugate).

The provided text describes a 510(k) premarket notification for a modified medical device, the LIAISON® XS Analyzer, used with the LIAISON® Anti-HAV assay. However, the document does not contain specific details about acceptance criteria, reported device performance (in terms of sensitivity, specificity, etc.), sample sizes for test sets, data provenance, number of experts, adjudication methods, MRMC studies, standalone performance, or ground truth details for either test or training sets.

The submission is for a device modification (moving fluid canisters onboard) to an already cleared device (K210272). The focus of the provided text is on demonstrating that these modifications do not negatively impact the device's performance or safety/effectiveness, rather than a full de novo performance study of the Anti-HAV assay itself.

Therefore, most of the requested information cannot be extracted from this document. The "Summary of Performance Data" section states that "Non-clinical verification and validation activities conducted with the LIAISON® XS Analyzer demonstrate that the modified device met predetermined acceptance criteria," but it does not specify what those criteria were or quantitatively report the performance. It merely lists the types of studies conducted.

Here is what can be inferred or stated based on the provided text:

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

The document does not explicitly list the acceptance criteria or quantitative performance results (e.g., sensitivity, specificity, accuracy) for the LIAISON Anti-HAV assay after the modifications. It broadly states: "Non-clinical verification and validation activities conducted with the LIAISON® XS Analyzer demonstrate that the modified device met predetermined acceptance criteria, supporting equivalency of the modified device to the cleared device." And "Testing verified all acceptance criteria were met."

The primary goal of this 510(k) is to demonstrate that the modifications to the analyzer (moving fluid canisters onboard) do not alter the safety and effectiveness of the existing cleared device. The previous clearance (K210272) would have contained the detailed performance data for the LIAISON® Anti-HAV assay itself.

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

Not provided in this document. The document refers to "non-clinical verification and validation activities" which are typically internal testing, not necessarily clinical studies with patient test sets.

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

Not applicable and not provided. This information would be relevant for a de novo clinical study with expert ground truth, which is not the focus of this modification submission.

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

Not applicable and not provided.

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

Not applicable. The LIAISON® XS Analyzer is an in vitro diagnostic immunoassay system, not an AI-assisted diagnostic tool that requires human reader interpretation.

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

The LIAISON® Anti-HAV assay on the LIAISON® XS Analyzer is a standalone diagnostic test. Its performance is evaluated based on its accuracy in detecting antibodies, as indicated by the chemiluminescence signal, and does not involve human interpretation of complex images or signals in the same way an AI algorithm might. The document does not provide the specific performance metrics (e.g., sensitivity, specificity, NPV, PPV) for this standalone device in the context of this specific 510(k) submission, as it refers to these having been established in the previous clearance (K210272).

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

Not explicitly stated in this specific document. For an immunoassay like this, the ground truth for clinical studies would typically be established through a combination of:

• Established reference methods: Usually another FDA-cleared or gold standard HAV antibody test.
• Clinical diagnosis: Based on patient symptoms, epidemiological information, and other laboratory markers.
• Seroconversion panels: Well-characterized samples from individuals demonstrating progression of infection or immune response.

Since this 510(k) is for a modification to an existing device, it relies on the ground truth established during the original clearance of the LIAISON® Anti-HAV assay.

8. The sample size for the training set

Not applicable and not provided. Immunoassays are not "trained" in the same way machine learning models are. Performance characteristics are established through various analytical and clinical studies.

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

Not applicable and not provided (see point 8).

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The DiaSorin Molecular Simplexa™ Congenital CMV Direct is a real-time PCR assay intended for use on the LIAISON® MDX instrument for the in vitro qualitative detection of cytomegalovirus (CMV) from saliva swabs and urine from infants less than 21 days of age. Positive results from saliva are presumptive and should be confirmed with urine. The results of the Simplexa™ Congenital CMV Direct assay should be used in conjunction with the results of other clinical findings as an aid in the diagnosis of congenital CMV infection.

This test has not been cleared for screening of blood products for the presence of CMV or for use with samples other than urine and saliva swabs.

DiaSorin Molecular's Simplexa™ Congenital CMV Positive Control Pack is intended to be used as a control with the Simplexa Congenital CMV Direct kit for use on the LIAISON MDX instrument. This control is not intended for use with other assays or systems.

The Simplexa™ Congenital CMV Direct assay is a real-time PCR system that enables the direct amplification and detection of CMV DNA from either saliva swab or urine specimens without nucleic acid extraction. The system consists of the Simplexa™ Congenital CMV Direct Reaction Mix, the LIAISON® MDX (with LIAISON® MDX Studio Software), the Direct Amplification Disc (DAD) and associated accessories.

In the Simplexa™ Congenital CMV Direct assay, bi-functional fluorescent probe-primers are used together with corresponding reverse primers to amplify CMV DNA. A well-conserved region of the CMV UL83 gene is targeted to identify CMV DNA. An internal control is used to detect PCR failure and/or inhibition.

Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state quantitative acceptance criteria in a dedicated table format. However, the reported performance metrics imply the criteria for acceptance. For the purpose of this response, I'll infer the implicit acceptance criteria based on the demonstrated performance, generally implying "high agreement" for positive and negative cases.

2. Sample Size and Data Provenance

• Retrospective Study:

  • Saliva Swab: 173 total specimens (3 removed due to indeterminate CRM result, 170 analyzed)
  • Urine: 173 total specimens
  • Provenance: "collected during the clinical study", "stored at a central site", then distributed to three (3) laboratories. The document doesn't explicitly state the country of origin for these retrospective samples, though the testing sites were in the USA. These were pre-selected positive and negative samples based on routine laboratory results.

• Prospective Study:

  • Saliva Swab: 1,859 initially collected, 6 deemed ineligible, resulting in 1,853 analyzed specimens.
  • Urine: 1,656 initially collected, 32 deemed ineligible, resulting in 1,624 analyzed specimens.
  • Provenance: Prospectively collected (frozen and/or fresh) from ten (10) collection sites across the USA and two (2) collection sites outside the USA. Testing was performed at six (6) testing sites located in the USA.

3. Number of Experts and Qualifications

The document states that a "Composite Reference Method (CRM)" was used, which involved "two (2) validated PCR followed by bi-directional sequencing assays." One (1) central laboratory performed these comparator assays.

• The document does not specify the number of experts used to establish the ground truth or their specific qualifications (e.g., radiologist with 10 years of experience). It relies on the validation of the PCR and bi-directional sequencing assays as the basis for ground truth, implying that these are established and reliable laboratory methods.

4. Adjudication Method

The ground truth for the clinical agreement studies (both retrospective and prospective) was established via a "Composite Reference Method (CRM)".
This CRM "utilized two (2) validated PCR followed by bi-directional sequencing assays. A sample had a final sequencing result of 'Detected' if one or both sequencing results were 'Detected'. Conversely a sample had a final sequencing result of 'Not Detected' if both results were 'Not Detected'." This implies a form of 2+0 or 1+1 adjudication model where if either reference method detects CMV, the sample is considered positive, and both must be negative for the sample to be considered negative.

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

No, an MRMC comparative effectiveness study was not done. This study focuses on the diagnostic performance of the device itself against a laboratory-based reference method, not on how human readers/clinicians improve with AI assistance.

6. Standalone (Algorithm Only) Performance

Yes, a standalone performance evaluation was done. The Simplexa™ Congenital CMV Direct assay is a real-time PCR assay and its performance was evaluated directly against the Composite Reference Method (CRM) without human-in-the-loop assistance. The reported PPA and NPA values represent the algorithm's standalone performance.

7. Type of Ground Truth Used

The ground truth used was expert consensus on laboratory results, specifically based on a "Composite Reference Method (CRM) utilized two (2) validated PCR followed by bi-directional sequencing assays." This is a highly robust and objective form of ground truth for nucleic acid detection devices, often considered a gold standard in molecular diagnostics.

8. Sample Size for the Training Set

The document does not provide information on the sample size used for the training set. This is typical for submissions of this nature, where the focus is on the validation of the final device/algorithm using a separate, independent test set, rather than details of the developmental (training) phase.

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

The document does not provide information on how the ground truth for the training set was established, as details about the training phase are not included in this summary.

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The DiaSorin Molecular Simplexa™ COVID-19 Direct is real-time RT-PCR assay intended for use on the LIAISON® MDX instrument for the in vitro qualitative detection of nucleic acid from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal swabs (NPS) and nasal swabs (NS) from symptomatic individuals suspected of COVID 19 by their healthcare provider. The Simplexa™ COVID-19 Direct assay is an aid in the diagnosis of SARS-CoV-2 infection.

Positive results are indicative of the presence of SARS-CoV-2 RNA. Clinical correlation with patient history and other diagnostic information is necessary to determine patient infection status. Positive results do not rule out co-infection with other pathogens. Negative results do not preclude SARS-CoV-2 infection and should not be used as tor patient management decisions.

Results are meant to be used in conjunction with other clinical, epidemiologic, and laboratory data, in accordance with the guidelines provided by the relevant public health authorities.

The Simplexa COVID-19 Direct is a real-time RT-PCR (rRT-PCR) system that enables the direct amplification and detection of SARS-CoV-2 (COVID-19) RNA from nasopharyngeal swab or nasal swab that has not undergone nucleic acid extraction. The system consists of the Simplexa COVID-19 Direct reaction mix, the LIAISON MDX (with LIAISON MDX Studio Software), the Direct Amplification Disc and associated accessories. The assay uses forward and reverse primers and associated fluorescent probe(s) included in the reaction mix to amplify SARS-CoV-2 cDNA reverse transcribed from RNA. The primers and probe sets are designed to detect SARS-CoV-2 ORF 1ab and S gene from the viral RNA in nasopharyngeal swab or nasal swab. An RNA internal control, with associated primers and a fluorescent probe, is included in the reaction mix to detect RT-PCR failure and/or inhibition.

Here's a breakdown of the acceptance criteria and study proving the device meets them, based on the provided text:

Device: Simplexa™ COVID-19 Direct

1. Table of Acceptance Criteria and Reported Device Performance

For the Simplexa™ COVID-19 Direct assay, the primary acceptance criteria revolve around its accuracy in detecting SARS-CoV-2 (COVID-19) RNA in patient samples, as well as its reproducibility, analytical sensitivity (Limit of Detection), analytical reactivity (ability to detect various strains), and specificity (cross-reactivity and interference).

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

• Clinical Agreement Test Set:

  • Total Samples: 1,150 prospective (fresh and/or frozen) samples collected.
  • Samples analyzed: 1,011 samples (114 excluded due to insufficient evidence for media types, 24 invalid results, 1 indeterminate CRM result).
  • Breakdown: 299 Nasopharyngeal Swabs (NPS) and 712 Nasal Swabs (NS).
  • Provenance: Collected from four (4) geographically diverse collection sites, one of which was outside the United States (OUS). Samples were prospective (fresh and/or frozen).
  • Timeframe: October 2020 to April 2021.

• Reproducibility Test Set:

  • Total replicates: 90 replicates per panel member (4 panel members), totaling 360 individual tests.
  • Panel members: 2 contrived low positive (LP), 2 contrived moderate positive (MP), 1 positive control, 1 negative (UTM).
  • Provenance: Tested at two (2) external clinical sites and one (1) internal site.
  • Study Design: Each panel member tested in triplicate per run, for 2 runs per day, for 5 non-consecutive testing days. Each site had two operators.

• Analytical Sensitivity (LoD) Test Set:

  • NPS: 40 replicates for confirmation.
  • NS: 20 replicates for confirmation.
  • WHO International Standard: 40 replicates for confirmation.

• Analytical Reactivity (Wet testing) Test Set:

  • 3 replicates per strain for 5 SARS-CoV-2 strains.

• Cross-Reactivity Test Set:

  • 3 replicates per organism for 47 different viruses, bacteria, and fungi (some 6 replicates for Leptospira interrogans).

• Potential Interfering Substances Test Set:

  • 3 replicates per substance (some 6 replicates for saliva and Zanamivir).

• Interference by Other Microorganisms Test Set:

  • 3 replicates per organism (some 6 replicates for Lactobacillus plantarum 17-5).

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

The ground truth for the clinical agreement test set was established using a "Composite Reference Method (CRM)" based on three (3) COVID-19 EUA approved NAAT assays. The rule for CRM agreement was: "Two out of three positive results determined 'Detected' CRM and two out of three negative results determined 'Not Detected' CRM."

The document does not specify the number or qualifications of experts (e.g., medical technologists, clinical lab scientists, or physicians) who performed these NAAT assays or interpreted their results for the CRM. It's implied that these were standard laboratory personnel qualified to run EUA-approved molecular diagnostic tests.

For analytical studies (LoD, reproducibility, reactivity, cross-reactivity, interference), the ground truth was based on the known composition and concentration of the samples (e.g., spiked RNA, cultured organisms, negative matrix). No external experts beyond the study design team would have been needed for this type of ground truth establishment.

4. Adjudication Method for the Test Set

For the clinical agreement test set, the adjudication method for the ground truth (CRM) was clearly defined: "Two out of three positive results determined 'Detected' CRM and two out of three negative results determined 'Not Detected' CRM." This is a form of consensus-based adjudication, specifically a majority rule.

For other analytical studies, adjudication was not described as it involved pre-defined positive/negative samples rather than interpretive human judgment.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This study focuses on the in vitro diagnostic performance of a molecular assay (RT-PCR) in a laboratory setting, not on the interpretative performance of human readers (e.g., radiologists) with or without AI assistance. Therefore, there is no discussion of human readers or an effect size of AI assistance.

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

Yes, the primary clinical performance and analytical studies are standalone (algorithm only) performance. The Simplexa™ COVID-19 Direct is an RT-PCR assay. Its "performance" refers to its ability to detect SARS-CoV-2 RNA based on its set algorithms for signal detection (Ct values for S gene and ORF1ab targets) and interpretation. The results (detected/not detected) are determined directly by the instrument and its software, not by a human interpreting images or complex patterns. The human involvement is in sample preparation and loading, and reviewing the qualitative output from the instrument.

7. The Type of Ground Truth Used

• Clinical Agreement Test Set: Composite Reference Method (CRM) using results from three (3) COVID-19 EUA approved NAAT assays, with a "two out of three" majority rule for determining "Detected" or "Not Detected." This is a form of expert consensus based on other validated diagnostic tests.
• Analytical Studies (Reproducibility, LoD, Reactivity, Cross-Reactivity, Interference): Known analytical truth established by spiking known concentrations of inactivated viral particles or other organisms into negative matrices. This is a laboratory-controlled ground truth.

8. The Sample Size for the Training Set

The provided document describes a premarket notification (510(k)) for an in vitro diagnostic device. For such devices, particularly RT-PCR assays, the "training set" typically refers to internal development and optimization data, rather than a distinct, formally defined "training set" for machine learning algorithms that would be tested on a separate "test set."

The document does not specify a numerical sample size for a training set. The assay's design (primers, probes, conditions) would have been developed and optimized internally by DiaSorin Molecular using various samples and experiments, but these are not enumerated as a specific "training set" in this regulatory submission. The "in silico inclusivity analysis" section points to the use of GISAID databases (millions of sequences) which could be considered a form of "training data" for validating the generalizability of the primer/probe design, but not as a conventional, labeled "training set" in a machine learning context.

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

Since a formal "training set" with established ground truth is not explicitly detailed in the way a machine learning model's training data would be, we can infer the following:

• Assay Development & Optimization: The ground truth for the development phase would have been based on known positive and negative samples, viral loads, and various SARS-CoV-2 strains or synthetic genetic material. This involves standard molecular biology techniques where the presence or absence of the target nucleic acid, and its concentration, are experimentally determined and controlled.
• In Silico Inclusivity: For the evaluation of primer/probe design against genetic variants, the "ground truth" is the published, annotated SARS-CoV-2 genome sequences available in the GISAID database. This involves bioinformatic analysis to determine sequence homology and potential binding efficacy.

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The DiaSorin LIAISON® Calprotectin assay is an in vitro diagnostic chemiluminescent immunoassay (CLIA) intended for the quantitative measurement, in human stool, of fecal calprotectin, a neutrophilic protein that is a marker of mucosal inflammation. The LIAISON® Calprotectin assay can be used as an aid in the diagnosis of inflammatory bowel diseases (IBD), specifically Crohn's disease and ulcerative colitis, and as an aid in differentiation of IBD from irritable bowel syndrome (IBS). Test results are to be used in conjunction with information obtained from the patients' clinical evaluation and other diagnostic procedures.

The test has to be performed on the LIAISON® Analyzer Family.

The DiaSorin LIAISON® Q.S.E.T. Device Plus (Quantitative Stool Extraction and Test) is intended for use in the preparation of human stool specimens for testing in the LIAISON® Calprotectin assay.

The LIAISON® Calprotectin assay is a sandwich assay that uses 2 monoclonal antibodies for capture and detection of calprotectin. The LIAISON® Calprotectin assay must be run on the LIAISON® Analyzer family, a fully automated system with continuous loading.

Calprotectin is first extracted from human stool samples with LIAISON® Q.S.E.T. Buffer using either the weigh method, the LIAISON® Q.S.E.T. Device or the LIAISON® Q.S.E.T. Device Plus. The assay incubates extracted sample, calibrator, control, or calibration verifiers with assay buffer and paramagnetic particles coated with a monoclonal antibody that specifically recognizes the calprotectin heterocomplex. Following incubation, a wash cycle is performed to remove any unbound material. An isoluminol conjuqated monoclonal antibody that recognizes calprotectin is then added to the reaction and incubated. The unbound conjugate is removed with a second wash step. Starter reagents are then added and a flash chemiluminescent reaction is initiated. The light signal is measured by a photomultiplier as relative light units (RLU) and is proportional to the concentration of calprotectin present in the calibrators, controls or samples.

All assay steps and incubations are performed by the LIAISON® XL Analyzer. The analyzer software automatically calculates the concentration of calprotectin in the sample. This concentration is expressed in ug/g.

The Q.S.E.T. Device Plus differs from its predicate Q.S.E.T. Device in that it is provided ready to use, and comes prefilled with the same extract buffer as required for use with the Q.S.E.T. Device, eliminating the need for the user to prepare the buffer and add it to the device themselves. In addition, minor changes to the shape and design of the tube were made.

The provided text is related to the FDA 510(k) premarket notification for the DiaSorin LIAISON® Calprotectin assay and the LIAISON® Q.S.E.T. Device Plus. None of the information requested in your prompt (Acceptance criteria, Study proving device meets criteria, Sample size, data provenance, expert numbers, etc. for AI/clinical studies) is present in the document.

The document describes an in vitro diagnostic (IVD) chemiluminescent immunoassay (CLIA) for fecal calprotectin, intended as an aid in diagnosing Inflammatory Bowel Diseases (IBD) and differentiating it from Irritable Bowel Syndrome (IBS). It also details a device for stool sample preparation.

The performance data included in the document specifically refers to the analytical performance of the IVD device and its sample preparation component, such as:

• Precision/Reproducibility: This section details the reproducibility of the LIAISON® Q.S.E.T. Device Plus extraction using five (5) stool samples with 90 measurements per sample (6 replicates over 5 days by 3 operators). It also shows sampling reproducibility using 5 human stool specimens, sampled by 3 operators with 5 replicates per specimen per operator on 3 lots of devices, totaling 225 sampling events.
• Reagent Stability: Mentions stability of the LIAISON® Q.S.E.T. Device Plus at 2-8°C for 12 months.
• Specimen Stability: Provides stability data for stool specimens under various storage conditions (refrigerated, room temperature, frozen, freeze/thaw cycles) and for sample extracts.

Therefore, I cannot provide the requested information regarding acceptance criteria for an AI/clinical study, the study setup to prove meeting those criteria, sample sizes for test/training sets in an AI context, expert qualifications, adjudication methods, MRMC studies, or standalone algorithm performance, as these concepts are not applicable to the analytical validation described for this IVD device.

The document solely focuses on the analytical performance validation of an IVD immunoassay, not on clinical performance or AI/machine learning aspects.

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The DiaSorin LIAISON® MeMed BV® is an automated in vitro diagnostic semi-quantitative assay that uses chemiluminescent immunoassay (CLIA) technology to measure three non-microbial (host) proteins (TRAIL, IP-10, and CRP) in adult and pediatric serum samples and is intended for use in conjunction with clinical assessments and other laboratory findings as an aid to differentiate bacterial from viral infection. The LIAISON® MeMed BV® assay is indicated for use in patients presenting to the emergency department or urgent care center and with samples collected at hospital admission from patients with suspected acute bacterial or viral infection, who have had symptoms for seven days or less. The LIAISON® MeMed BV® assay generates a numeric score that falls within discrete interpretation ranges based on the increasing likelihood of bacterial infection. The assay has to be performed on the automated LIAISON® XL Analyzer.

The DiaSorin LIAISON® MeMed BV® Control Set is intended for use as assayed quality control to monitor the performance of the DiaSorin LIAISON® MeMed BV® assay. The performance characteristics of the LIAISON® controls have not been established for any other assays or instrument platforms different from the automated LIAISON® XL Analyzer. The control set is intended for in vitro diagnostic use in a professional laboratory only.

The LIAISON MeMed BV assay consists of three individual chemiluminescence immunoassay (CLIA) for quantitative determination of TRAIL, IP-10, and CRP. The LIAISON MeMed BV test result is a score between 0 and 100 derived from computational integration of the measurements of the three proteins TRAIL, IP-10, and CRP, where low scores are indicative of viral infection and high score of bacterial infection. All three reagent packs must be the same lot and present at the same time on the same instrument used for sample testing. All three reagent packs are individually calibrated and quality controlled. Specimens are to be assigned to the MMBV assay protocol where all three reagent packs will be utilized to provide combined results and a final score.

The TRAIL reagent pack uses a monoclonal antibody for capture of TRAIL and a polyclonal antibody for the detection of TRAIL. The assay incubates sample, calibrator or control with assay buffer and paramagnetic particles coated with a monoclonal antibody that specifically recognizes the TRAL. Following the incubation, an isoluminol conjugated polyconal antibody that recognizes TRAIL is then added to the reaction and incubated. The unbound conjugate is removed with a wash step. Starter reagents are then added and a flash chemiluminescent reaction is initiated. The light signal is measured by a photomultiplier as relative light units (RLU) and is proportional to the concentration of TRAL present in the calibrators, controls or samples. The result of the TRAIL reagent pack is only used to calculate a final LIAISON MeMed BV Score and should not be used individually for diagnosis.

The IP-10 reagent pack uses a monoclonal antibody for the capture of IP-10 and a polyclonal antibody for the detection of IP-10. The assay incubates sample, calibrator or control with assay buffer and paramagnetic particles coated with a monoclonal antibody that specifically recognizes the IP-10. Following the incubation, an isoluminol conjugated polyclonal antibody that recognizes IP-10 is then added to the reaction and incubated. The unbound conjugate is removed with a wash step. Starter reagents are then added and a flash chemiluminescent reaction is initiated. The light signal is measured by a photomultiplier as relative light units (RLU) and is proportional to the concentration of IP-10 present in the calibrators, controls or samples. The result of the IP-10 reagent pack is only used to calculate a final LIAISON MeMed BV Score and should not be used individually for diagnosis.

The CRP reagent pack uses monoclonal antibodies for capture and detection of CRP. First the patient serum sample is pre-diluted 1:196 with assay buffer. The assay incubates the pre-diluted sample, calibrator or control with assay buffer and paramagnetic particles coated with a monoclonal antibody that specifically recognizes the CRP. Following the incubation, an isoluminol conjugated monoclonal antibody that recognizes CRP is then added to the reaction and incubated. The unbound conjugate is removed with a wash step. Starter reagents are then added and a flash chemiluminescent reaction is initiated. The light signal is measured by a photomultiplier as relative light units (RLU) and is proportional to the concentration of CRP present in the calibrators, controls or samples. The result of the CRP reagent pack is only used to calculate a final LIAISON MeMed BV Score and should not be used individually for diagnosis.

The provided document describes the FDA clearance (K213936) for the DiaSorin LIAISON® MeMed BV® assay, which aids in differentiating bacterial from viral infections. Here's a breakdown of the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance

The document primarily focuses on demonstrating substantial equivalence to a predicate device rather than explicitly listing predefined acceptance criteria with numerical targets. However, the performance data presented implies a set of internal acceptance criteria related to statistical significance, agreement with expert adjudication, and reproducibility.

Given the information provided, here's a table summarizing the reported device performance, with implicit acceptance criteria derived from the study's conclusions:

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

• Clinical Agreement Test Set: 285 serum samples.
  • Provenance: Collected at hospital admission, Emergency Department, and Urgent Care Centers. Patients ranged in age from 5 months to 92 years. The origin country is not explicitly stated, but the mention of "21 international experts" suggests a multi-national or at least internationally adjudicated dataset. The study is retrospective in the sense that samples were likely collected before the adjudication process and testing with the device.
• Method Correlation Test Set:
  • Primary Endpoint analysis: 285 clinical samples (the same as the clinical agreement test set).
  • Secondary Endpoint analysis: 257 clinical samples (28 of the 285 were excluded).
• Expected Values Test Set: 150 serum samples from apparently healthy asymptomatic adults.
  • Provenance: Collected in the Southwestern U.S.
• Reproducibility Study Test Set: 4 serum samples (1 normal, 1 viral, 1 bacterial, 1 equivocal) plus kit controls.
• Cross-Reactivity Study Test Set: Two (2) serum samples (one low, one high SCORE) for each cross-reactant being tested.
• Interfering Substances Study Test Set: Two (2) serum samples (one low, one high SCORE) for each interfering substance being tested.
• Matrix Equivalence Study Test Set: 43 fresh serum samples from individual patients, with 20 spiked for range coverage.
• Limit of Blank, Detection, Quantitation Test Set: Varied based on particular limit, ranging from 4-8 serum/spiked matrix samples for LoD/LoQ studies and 5 calibrator matrix samples for LoB.

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

• Number of Experts: A pool of 21 international experts.
• Qualifications of Experts: Clinicians with at least 7 years of relevant clinical experience. Each panel comprised at least three experts.

4. Adjudication Method for the Test Set

• Method: Expert adjudication.
  • Process: Panelists for each subject adjudication were drawn from the pool of 21 international experts. Each panel comprised at least three experts who independently adjudicated the etiologic label for each patient. The etiologic label was determined as bacterial, viral, or non-infectious. The adjudication was based on anonymized patient data. Critically, the adjudicators were blinded to the MeMed BV result (for the primary endpoint) and to CRT and PCT results (for the primary endpoint). For the secondary endpoint, adjudicators were un-blinded to PCT and CRP results.

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 document describes the analytical and clinical performance of an in vitro diagnostic assay (a laboratory test that measures protein levels and computes a score), not an AI-assisted diagnostic tool that human readers interpret. Therefore, an MRMC comparative effectiveness study involving human readers assisting with AI is not applicable and was not performed. The device itself is the "AI" (computational algorithm) that processes biomarker data.

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

• Yes, the performance presented for the "LIAISON MeMed BV" assay is a standalone performance of the device (assay and its integrated computational scoring). The "SCORE" is generated by the device's algorithm based on the measured protein levels (TRAIL, IP-10, and CRP), without a human in the loop for the scoring itself. The clinical utility is then evaluated by comparing this score to expert adjudication.

7. The Type of Ground Truth Used

• Type of Ground Truth: Expert consensus (physician expert adjudication). Specifically, physicians were forced to make a bacterial, viral, or non-infectious diagnosis.

8. The Sample Size for the Training Set

• The document does not specify the sample size used for training the algorithm (the "SCORE" computation). This document focuses on the validation of the device for FDA clearance. Typically, details of the training dataset are considered proprietary or part of the algorithm development process prior to clinical validation.

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

• Since the training set size and details are not provided, information on how its ground truth was established is also not available in this document. It is typical for such algorithms to be trained on large, well-characterized datasets, often with similar expert-adjudicated ground truth, but these details are not part of the premarket notification summary.

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The DiaSorin LIAISON® Ferritin assay is a quantitative automated chemiluminescent immunoassay (CLIA) for the in vitro detection of ferritin in human serum, serum separator tubes (SST), or lithium (Li) heparin plasma to aid in the diagnosis of iron deficiency anemia and iron overload.

This assay must be performed on the LIAISON® XL Analyzer.

The chemiluminescence immunoassay method for the quantitative determination of ferritin is a sandwich immunoassay.

A specific mouse monoclonal antibody is coated on the magnetic particles (solid phase); another monoclonal antibody (mouse) is linked to an isoluminol derivative (isoluminolantibody conjugate).

During the incubation, ferritin present in calibrators, samples or controls binds to the solid phase monoclonal antibody, and subsequently the antibody conjugate reacts with ferritin already bound to the solid phase.

After incubation, the unbound material is removed with a wash cycle.

Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminol-antibody coniugate, is measured by a photomultiplier as relative light units (RLU) and is indicative of ferritin concentration present in calibrators, samples or controls.

The provided document is a 510(k) Summary for the DiaSorin LIAISON® Ferritin assay, a chemiluminescent immunoassay for the quantitative determination of ferritin in human serum, serum separator tubes (SST), or lithium (Li) heparin plasma. Its intended use is to aid in the diagnosis of iron deficiency anemia and iron overload.

This document details the performance characteristics required to demonstrate substantial equivalence to a legally marketed predicate device (Roche Elecsys® Ferritin assay), rather than defining and proving against acceptance criteria in the context of an AI/ML device or a complex diagnostic with multiple discrete outcomes. The data presented are for an in vitro diagnostic immunoassay, which relies on analytical performance metrics rather than clinical outcome studies of the type implied by the original request's questions about expert consensus, MRMC studies, human-in-the-loop performance, etc.

Therefore, many of the requested elements are not applicable to the type of device and study described in this document.

Below, I've addressed the applicable points from your request based on the provided text.

Device: DiaSorin LIAISON® Ferritin assay (K193650)

Type of Device: Quantitative automated chemiluminescent immunoassay (CLIA) for the in vitro detection of ferritin.

Purpose of the Study (as presented in the 510(k) Summary): To demonstrate substantial equivalence of the DiaSorin LIAISON® Ferritin assay to the predicate device, Roche Elecsys® Ferritin assay, based on analytical performance characteristics.

Acceptance Criteria and Reported Device Performance

For an in vitro diagnostic assay, acceptance criteria typically relate to analytical performance metrics to ensure accuracy, precision, linearity, and other factors. While the document does not explicitly list "acceptance criteria" against each performance metric in a table format, it reports the results of various studies (e.g., method comparison, precision) which would have been previously agreed upon with the FDA as sufficient to demonstrate substantial equivalence.

Here's a summary of the reported performance. The implied "acceptance criteria" are that these results fall within acceptable ranges for diagnostic assays of this type, often relative to a predicate device or industry standards (e.g., CLSI guidelines).

Applicable Information from the Request (Based on provided document):

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

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

   • Method Comparison: 173 samples. Provenance not specified (e.g., country of origin, retrospective/prospective), but it usually implies clinical samples collected for analytical validation purposes.
   • Sample Matrix Comparison: 37 matched patient sets (serum, Li Heparin plasma) and 6 contrived matched patient samples. Provenance not specified.
   • Expected Values/Reference Range: 78 human serum samples; 39 healthy female, 39 healthy male subjects (age 18+). Provenance not specified.
   • Precision: 2 kit controls and 6 samples assayed 320 times each (twice per day in duplicate, over 20 operating days on two LIAISON® XL Analyzers using two reagent lots). Provenance: DiaSorin GmbH, implying internal lab testing.
   • Linearity: Dilution series of 4 samples.
   • Recovery: 4 representative human serum samples. Provenance not specified.
   • Interference, Cross-Reactivity, LoB/LoD/LoQ studies also involved specific numbers of samples/replicates, but detailed sample sizes for each are not individually listed beyond the overall study design (e.g., "controlled studies... at Ferritin level of approximately 20 ng/mL and 2000 ng/mL").

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: Not applicable. This document describes an in vitro diagnostic device measuring a quantitative biomarker (Ferritin). Ground truth is established through reference methods, calibration materials traceable to international standards (e.g., NIBSC 94/572 for Ferritin), and gravimetric/dilution/spiking studies, not by expert interpretation of images or clinical outcomes that require human experts for ground truth.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set: Not applicable. Adjudication methods are relevant for studies involving human interpretation (e.g., radiology reads) where discrepancies need to be resolved. This is an automated analytical test.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, if so, what was the effect size of how much human readers improve with AI vs without AI assistance: Not applicable. This is an in vitro diagnostic assay, not an AI/ML device that assists human readers.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: Not applicable in the context of an "algorithm" as typically referred to in AI/ML. The device itself is an automated analyzer that performs the "standalone" measurement of ferritin. No human interpretation is involved in the measurement process after sample loading.

7. The type of ground truth used:

   • For Method Comparison, the "Reference Method" was used as ground truth. This would typically be a highly accurate and precise method, often the predicate device itself or a laboratory developed test that is well-validated.
   • For Linearity and Recovery, ground truth was established by preparing samples with known concentrations through spiking and dilution from a characterized stock solution or pool.
   • For Precision, samples with known (or previously characterized) ferritin concentrations were used.
   • For Traceability, the calibrators are traceable to an internal reference standard "oriented at the 2nd reference standard NIBSC 94/572." This international standard serves as a form of ground truth for absolute concentration.

8. The sample size for the training set: Not applicable. This is a traditional immunoassay, not an AI/ML device that requires a "training set" in the computational sense. The "training" of such a system involves calibrating it with known standards, which were traceable to an international reference standard (NIBSC 94/572).

9. How the ground truth for the training set was established: Not applicable, as there is no "training set" in the AI/ML sense. Calibration is performed using materials traceable to an international reference standard.

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