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The Alinity i Rubella IgG assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of IgG antibodies to rubella virus in human serum, serum separator, and plasma tubes (lithium heparin, lithium heparin separator, and tripotassium EDTA) on the Alinity i system.

The Alinity i Rubella IgG assay is to be used as an aid in the determination of immune status to rubella in individuals including women of child-bearing age.

The Alinity i Rubella IgG assay has not been cleared for use in screening blood, plasma, or tissue donors.

The performance of this device has not been established for cord blood or neonatal samples. Likewise, performance has not been established for populations of immunocompromised or immunosuppressed individuals.

The Alinity i Rubella IgG assay is an automated, two-step immunoassay for the quantitative determination of anti-rubella IgG in human serum and plasma using chemiluminescent microparticle immunoassay (CMIA) technology.

Sample, partially purified rubella virus-coated paramagnetic microparticles, and assay diluent are combined and incubated. The anti-rubella IgG present in the sample bind to the rubella virus coated microparticles. The mixture is washed. Anti-human IgG acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle, Pre-Trigger and Trigger Solutions are added.

The resulting chemiluminescent reaction is measured as a relative light unit (RLU). There is a direct relationship between the amount of anti-rubella IgG in the sample and the RLU detected by the system optics.

Here's an analysis of the acceptance criteria and the study proving the device meets those criteria, based on the provided FDA 510(k) clearance letter for the Alinity i Rubella IgG assay.

Overview of the Device and its Purpose:

The Alinity i Rubella IgG assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of IgG antibodies to the rubella virus. It's intended to aid in determining the immune status to rubella, particularly in women of child-bearing age. It is a diagnostic device, not an AI/ML-driven one, so some of the requested points regarding AI/ML studies (like MRMC studies, training set details, expert ground truth establishment for AI) are not applicable.

1. Table of Acceptance Criteria and Reported Device Performance

Since this is a diagnostic assay and not an AI/ML device, the acceptance criteria are related to the analytical and clinical performance of the immunoassay itself rather than metrics like AUC, sensitivity/specificity for object detection, or F1 scores inherent to AI. The key performance indicators are Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to a composite comparator method.

Acceptance Criteria (Implied by Performance Targets in Context of 510(k) Equivalence):

For a 510(k) substantial equivalence determination, the new device must demonstrate performance that is as safe and effective as a legally marketed predicate device. While explicit numerical acceptance criteria for PPA and NPA are not stated in the summary, typical expectations for diagnostic assays like this are high agreement rates (e.g., >90% or 95%) with the comparator method, especially in categories such as "Reactive" and "Nonreactive." The confidence intervals should also demonstrate a reasonable level of certainty around these agreement rates. The acceptance of the listed performance values below implies that these meet the FDA's criteria for substantial equivalence to the predicate.

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The DYNEX SmartPLEX MMRV IgG Assay Kit is a multiplex immunoassay intended for the qualitative detection of IgG antibodies to Measles, Mumps, Rubella, and Varicella-Zoster Virus (VZV) in human serum. The DYNEX SmartPLEX MMRV IgG Assay Kit is intended for use with the DYNEX Multiplier Analyzer.

The DYNEX SmartPLEX MMRV IgG Assay Kit is intended to be used as an aid in the determination of serological status to Measles, Mumps, Rubella, and Varicella-Zoster Virus (VZV) in human serum from adults and pediatrics age above 1 year. This kit is not intended for screening blood or plasma donors.

The performance of this device has not been established for use in neonates, pediative patients below 1 year of age, and immunocompromised patients, or for use at point of care facilities.

The DYNEX SmartPLEX MMRV IgG Assay Kit (SmartPLEX MMRV IgG Assay) uses multiplex immunoassay, a methodology that greatly resembles traditional ELISA, while permits simultaneous detection and identification of different antibodies in a single well. The reaction is processed in a 96 well microtiter plate, with six polystyrene beads embedded in each well of the plate. Four (4) different beads are coated with antigens for the detection of IgG antibodies to Measles, Mumps, Rubella and Varicella-Zoster virus in human serum. Two additional beads are included in each reaction well as filler beads. Specimen processing is fully automated on the Multiplier Analyzer.

The Multiplier Analyzer adds the patient serum specimen and reagents to each well of the 96well plate, after which the mixture is incubated at 37°C with shaking. After a wash cycle, unbound antibodies from the patient's specimen are removed. Anti-human polyclonal IgG antibody conjugated to horseradish peroxidase (HRP) is added after which the mixture is incubated at 37°C with shaking. A second wash step removes excess conjuqate, then luminol substrate is added to each well. The amount of antibody captured by the antigen is determined by the chemiluminescence triggered by the attached HRP. Raw data is captured as light photons which are converted into relative light intensity units (RLU).

The Multiplier software analyzes the image and generates a report that details the mean RLU signal for each target bead (MMRV) by test sample. In every assay a calibrator is run. The DYNEX SmartPLEX MMRV IgG Assay Kit is qualitative and produces a result defined as negative (NEG), equivocal (EQV) or positive (POS) for each target analyte. The result is calculated in the Multiplier software by dividing the test sample RLU values by the mean calibrator RLU value to produce an index value for each target.

Here's an analysis of the acceptance criteria and study data for the DYNEX SmartPLEX MMRV IgG Assay Kit, as requested, based on the provided FDA 510(k) summary.

Device Name: DYNEX SmartPLEX MMRV IgG Assay Kit

Indications for Use: Qualitative detection of IgG antibodies to Measles, Mumps, Rubella, and Varicella-Zoster Virus (VZV) in human serum, as an aid in the determination of serological status. Intended for use with the DYNEX Multiplier Analyzer, in adults and pediatrics age above 1 year. Not intended for screening blood or plasma donors, neonates, pediatric patients below 1 year, or immunocompromised patients, or for point-of-care facilities.

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria values (e.g., "PPA must be >X%"). Instead, it presents the performance results obtained from the study and implies that these results were deemed acceptable for clearance. For this table, I will use the reported Clinical Performance (Method Comparison) as the primary indicator of device performance, specifically the Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) values.

Note: The acceptance criteria are "implied" as the document presents the results to demonstrate performance rather than explicitly stating pre-defined thresholds the device needed to meet for clearance.

2. Sample Sizes and Data Provenance

• Test Set Sample Size:
  • Clinical Performance (Method Comparison): N = 2512 retrospective human serum specimens.
    • Adults: N = 1676
    • Pregnant Women: N = 500
    • Pediatrics (age above 1 year): N = 336
  • Reproducibility and Within-Laboratory Precision: 22 serum samples, each tested 240 replicates.
  • Potential Cross-Reactivity: Variable N for each substance (e.g., ANA n=5, CMV n=6-8, EBV n=6-11).
• Data Provenance: Retrospective human serum specimens obtained from commercial vendors. The method comparison testing was performed at two US laboratory testing sites.

3. Number of Experts and Qualifications for Ground Truth

• The ground truth for clinical performance (method comparison) was established by FDA-cleared comparator tests, not through expert human readers or adjudicators for each individual case result. The agreement was measured against the results of these established assays.
• For specimens with equivocal results on the test device and comparator device, they were retested with two additional FDA-cleared methods.

4. Adjudication Method for the Test Set

• For equivocal results that remained equivocal after initial retesting with the comparator device, a "2/3 rule" was used to establish a consensus final comparator result. This means that if at least two out of the three comparator devices provided the same categorical result (Positive, Equivocal, or Negative), that result was taken as the consensus.
• Any remaining equivocal results (where no 2/3 consensus was reached or the consensus was still equivocal) were "counted against the clinical performance" of the SmartPLEX MMRV IgG Assay (this is implied by the 3x3 analysis where equivocal results from the test device are presented in comparison to the "Final Comparator Result").

5. MRMC Comparative Effectiveness Study

• No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This document describes the performance of an in vitro diagnostic (IVD) assay kit, which directly measures antibodies in serum. These types of devices do not typically involve human readers interpreting images or data to the extent that an MRMC study would be applicable. The performance is assessed by comparison to established laboratory methods or ground truth.

6. Standalone Performance

• Yes, standalone performance was done. The entire study is a standalone performance evaluation of the DYNEX SmartPLEX MMRV IgG Assay Kit in relation to comparator methods. The device's output (qualitative detection of IgG antibodies) is directly compared to the output of other FDA-cleared IVD assays. There is no "human-in-the-loop" component for this type of diagnostic assay, as its output is a direct measurement.

7. Type of Ground Truth Used

• The ground truth for the clinical performance study was primarily based on the results from one or more FDA-cleared comparator immunoassay devices. For ambiguous cases (equivocal results), a consensus derived from multiple FDA-cleared comparator methods using a "2/3 rule" was employed. This is a common method for establishing reference values in IVD studies where a perfect "gold standard" may not exist for all samples, or where the goal is to show substantial equivalence to established methods.

8. Sample Size for the Training Set

• The document does not specify a separate "training set" sample size or details about a training phase. For IVD assay kits, the development and optimization process (analogous to training) typically involves internal experimentation, formulation adjustments, and preliminary testing, rather than a distinct "training set" of patient samples in the same way an AI/ML algorithm would use labeled data. The provided data represents the validation/test set used for regulatory submission.

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

• Since a distinct "training set" as understood in AI/ML was not explicitly used or described in the context of this IVD assay kit, the concept of establishing ground truth for a training set is not directly applicable here. The focus is on the performance of the final, developed kit. The development process would have involved establishing specifications and ensuring the assay's ability to accurately detect the target antibodies, perhaps using characterized positive/negative panels, but this is not typically detailed as "ground truth for training" in 510(k) summaries for such devices.

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The BioPlex 2200 ToRC IgM kit is a multiplex flow immunoassay intended for the qualitative detection of IgM antibodies to Toxoplasma gondii), Rubella, and Cytomegalovirus (CMV) in human serum and plasma (K3 EDTA, lithium heparin, or sodium heparin).

The BioPlex 2200 ToRC IgM kit is intended for use with the Bio-Rad BioPlex 2200 System.

This kit is intended as an aid in the diagnosis of a current or recent T. gondii, Rubella and/or CMV infection, in individuals suspected of having one of the respective disease states, including women of child bearing age.

This assay is not FDA cleared or approved for use in testing (screening) blood or plasma donors.

Performance characteristics for the ToRC IgM assay have not been evaluated in immunosuppressed or organ transplant individuals. Performance characteristics of this kit have not been established for use in neonatal screening or for use at point of care facilities.

The BioPlex 2200 ToRC IgM Calibrator Set is intended for the BioPlex 2200 ToRC IgM Reagent Pack.

The BioPlex 2200 ToRC IgM Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 Instrument and BioPlex 2200 ToRC IgM Reagent Pack in the clinical laboratory.

BioPlex ToRC IgM Reagent Pack includes the following components:

• One (1) 10 mL vial, containing dyed beads coated with lysates of T. gondii, Rubella and CMV ● plus an Internal Standard bead (ISB) and a Serum Verification bead (SVB) in buffer with Glycerol and protein stabilizers (bovine and caprine). ProClin 300 (≤ 0.3%), sodium benzoate (≤ 0.1%) and sodium azide (

Here's an analysis of the provided text to extract information about the acceptance criteria and the study proving the device's performance, as requested.

The provided text describes the performance characteristics of the BioPlex 2200 ToRC IgM kit, which is a multiplex flow immunoassay for detecting IgM antibodies to Toxoplasma gondii, Rubella, and Cytomegalovirus (CMV).

Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as a section titled "Acceptance Criteria" with pass/fail metrics. Instead, the document presents various analytical and clinical performance studies, and the results of these studies implicitly represent the device's acceptable performance. For the purpose of this response, I will infer the acceptance criteria from the reported performance, particularly where quantitative results are presented.

1. Table of Acceptance Criteria and Reported Device Performance

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For VIDAS H. pylori IgG:
VIDAS® H. pylori IgG (HPY) is an automated qualitative test for use on the instruments of the VIDAS family, for the detection of anti-Helicobacter pylori IgG antibodies in human serum or plasma (EDTA) using the ELFA technique (Enzyme Linked Fluorescent Assay). The VIDAS HPY assay is intended as an aid in diagnosis of H. pylori infection in an adult symptomatic population.
This device is an in vitro diagnostic medical device for professional use only.

For VIDAS 3:
The VIDAS 3 system is a complete standalone immunodiagnostic system intended for trained and qualified laboratory technicians (daily routine use) and laboratory administrators (application configuration). This device is an in vitro diagnostic medical device for professional use only.

For VIDAS Lyme IgG II:
The VIDAS Lyme IgG II (LYG) assay is an automated qualitative enzyme immunoassay intended for use on the instruments of the VIDAS family in the presumptive detection of human IgG antibodies to Borrelia burgdorferi in human serum (plain or separation gel) or plasma (sodium heparin). It should be used to test patients with a history and/or symptoms of infection with B. burgdorferi. All VIDAS Lyme IgG II positive specimens should be further tested with a Western Blot IgG assay to obtain supportive evidence of infection with B. burgdorfei. This device is an in vitro diagnostic medical device for professional use only.

For VIDAS RUB IgG:
The VIDAS® RUB IgG (RBG) assay uses Enzyme Linked Fluorescent Assay (ELFA) technology on the instruments of the VIDAS family for the in vitro quantitative measurement of IgG antibodies to rubella virus in human serum. The VIDAS RUB IgG (RBG) assay is intended as an aid in the determination of immune status to rubella. The performance of this device has not been established for screening of cord blood, or for neonatal samples. Likewise, performance characteristics of the assay have not been established for immunocompromised or immunosuppressed individuals.
This device is an in vitro diagnostic medical device for professional use only.

For VIDAS TOXO IgM:
The VIDAS® TOXO IgM (TXM) assay is intended for use on the instruments of the VIDAS family (VITEK ImmunoDiagnostic Assay System) as an automated enzyme-linked fluorescent immunoassay (ELF A) for the presumptive qualitative detection of anti-Toxoplasma gondii IgM antibodies in human serum, as an aid in the diagnosis of acute, recent, or reactivated Toxoplasma gondii infection. This assay must be performed in conjunction with an anti-Toxoplasma gondii lgG antibody assay. VIDAS TOXO IgM (TXM) assay performance has not been established for prenatal screening or newborn testing. This assay has not been cleared by the FDA for blood/plasma donor screening. This device is an in vitro diagnostic medical device for professional use only.

For VIDAS Human Chorionic Gonadotropin:
The VIDAS® HCG (HCG) assay is intended for use on the instruments of the VIDAS family as an automated quantitative enzyme linked fluorescent immunoassay (ELFA) for the determination of human Chorionic Gonadotropin (hCG) concentration in human serum or plasma. The VIDAS HCG (HCG) assay is intended to aid in the early detection of pregnancy.
This device is an in vitro diagnostic medical device for professional use only.

For VIDAS T4:
The VIDAS® T4 (T4) assay is intended for use on the instruments of the VIDAS family as an automated quantitative enzyme-linked fluorescent immunoassay for the determination of human thyroxine (T4) concentration in serum or plasma (heparin). It is intended for use as an aid in the diagnosis and treatment of thyroid disorders. This device is an in vitro diagnostic medical device for professional use only.

For VIDAS Testosterone:
The VIDAS Testosterone (TES) assay is an automated quantitative test for use on the instruments of the VIDAS family for the enzyme immunoassay measure of total testosterone in human serum or plasma (lithium heparin), using the ELFA technique (Enzyme Linked Fluorescent Assay). It is intended as an aid in the diagnosis and management of conditions involving excess or deficiency of this androgen.
This device is an in vitro diagnostic medical device for professional use only.

For VIDAS TSH:
The VIDAS® TSH (TSH) assay is intended for use on the instruments of the VIDAS family as an automated quantitative enzyne-linked fluorescent immunoassay (ELFA) for the determination of human thyroid stimulating hormone- (TSH) concentration in human serum or plasma (heparin). It is intended for use as an aid in the diagnosis of thyroid or pituitary disorders.
This device is an in vitro diagnostic medical device for professional use only.

For VIDAS D-Dimer Exclusion II:
VIDAS® D-Dimer Exclusion II™ is an automated quantitative test for use on the instruments of the VIDAS family for the immunoenzymatic determination of fibrin degradation products (FbDP) in human plasma (sodium citrate, CTAD) using the ELFA technique (Enzyme Linked Fluorescent Assay).
VIDAS D-Dimer Exclusion II is indicated for use in conjunction with a clinical pretest probability assessment model to exclude deep vein thrombosis (DVT) and pulmonary embolism (PE) disease in outpatients suspected of DVT or PE. This device is an in vitro diagnostic medical device for professional use only.

The VIDAS® 3 instrument is an automated multiparametric immunoassay system, which uses ELFA (Enzyme Linked Fluorescent Assay) technology. The VIDAS 3 system offers primary tube sampling, automated sample dilution, reagent/sample detection and reagent traceability.
The technology used, which is adaptable to a wide range of assays, combines the EIA method with a final fluorescence reading: this technology is known as ELFA (Enzyme Linked Fluorescent Assay). The enzyme used in the VIDAS product range is alkaline phosphatase, which catalyzes the hydrolysis of the substrate 4-methyl umbelliferyl phosphate (4-MUP) into a fluorescent product 4-methyl umbelliferone (4-MU) the fluorescence of which is measured at 450nm. The immunological methods are either indirect ElA, immunocapture, sandwich or competition, all involving a conjugate using the alkaline phosphatase.

This document describes the performance data for several VIDAS assays when used on the VIDAS 3 instrument, comparing them to their performance on the predicate VIDAS instrument. The tests are primarily for establishing substantial equivalence for the new VIDAS 3 instrument and do not typically include detailed acceptance criteria for the assays themselves, which are already established for the predicate devices. The studies focus on method comparison, precision, linearity, and detection limits.

Here's a breakdown of the requested information based on the provided text, focusing on the VIDAS H. pylori IgG assay as a primary example, and generalizing for others where appropriate:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state acceptance criteria in a quantitative format for method comparison. Instead, it demonstrates "correlation" and "equivalency" between the new device (VIDAS 3) and the predicate device (VIDAS). For precision, specific CV% ranges are reported.

Here's an example for the VIDAS H. pylori IgG assay's method comparison:

Note: For quantitative assays like VIDAS RUB IgG, VIDAS HCG, VIDAS T4, VIDAS Testosterone, VIDAS TSH, and VIDAS D-Dimer Exclusion II, method comparison relies on slope, intercept, and correlation coefficient, implying acceptance criteria for these values (e.g., slope close to 1, intercept close to 0, high correlation coefficient). Precision for these assays also includes CV% for various components.

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

• VIDAS H. pylori IgG:

  • Test Set Size: 250 serum samples (positive, equivocal, and negative).
  • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective). The study compares performance between two instruments, implying samples are run on both.

• VIDAS Lyme IgG II:

  • Test Set Size: 220 serum samples (positive and negative).
  • Data Provenance: Not explicitly stated.

• VIDAS RUB IgG:

  • Test Set Size (Quantitative Method Comparison): 112 serum samples (ranging from 0 to 225 IU/mL).
  • Test Set Size (Qualitative Method Comparison): 220 serum samples (positive, equivocal, and negative).
  • Test Set Size (CDC Reference Panel): 100 specimens (50 pairs of sera).
  • Data Provenance: Not explicitly stated for general samples. The CDC panel implies a curated and standardized set.

• VIDAS TOXO IgM:

  • Test Set Size: 198 serum samples.
  • Data Provenance: Not explicitly stated.

• VIDAS Human Chorionic Gonadotropin (hCG):

  • Test Set Size: 113 serum samples.
  • Data Provenance: Not explicitly stated.

• VIDAS T4:

  • Test Set Size: 105 serum samples.
  • Data Provenance: Not explicitly stated.

• VIDAS Testosterone:

  • Test Set Size: 172 serum samples.
  • Data Provenance: Not explicitly stated.

• VIDAS TSH:

  • Test Set Size: 179 serum samples.
  • Data Provenance: Not explicitly stated.

• VIDAS D-Dimer Exclusion II:

  • Test Set Size: 219 plasma samples.
  • Data Provenance: Not explicitly stated.

Across all assays, the studies are described as "Method Comparison" and "Precision" studies, which are typically retrospective analyses of patient samples to compare device performance to an established method.

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

This information is not provided in the document. For in vitro diagnostic devices, ground truth is typically established by comparative methods (e.g., predicate device, reference methods, clinical diagnosis, or other laboratory gold standards) rather than expert consensus on individual cases. The document states that performance was evaluated against the predicate device (e.g., "VIDAS H. pylori IgG assay on the VIDAS 3 to the VIDAS H. pylori IgG assay on the VIDAS"). The "ground truth" for these studies is the result obtained from the predicate VIDAS instrument using its established methodology.

For the VIDAS RUB IgG, a "CDC reference panel" and "CDC low-titer rubella antibody standard" are mentioned, where the reference panel sera were "titered by Hemagglutination Inhibition." This implies that the ground truth for this specific part of the study was established by a recognized reference method (Hemagglutination Inhibition) and certified reference materials from the CDC.

4. Adjudication Method for the Test Set

This information is not explicitly provided. For method comparison studies, typically, discordant results between the new device and the predicate device (or reference method) are investigated. However, the exact adjudication process (e.g., by a third, more definitive test, or expert review of patient clinical history) is not detailed. The phrase "results were evaluated according to CLSI EP12-A2" or CLSI EP9 suggests standard statistical methods for agreement or correlation, which do not necessarily involve expert adjudication of individual discrepancies beyond reporting them.

For quantitative assays where method comparison statistics (slope, intercept, correlation coefficient) are used, "outliers" were removed in some cases (e.g., VIDAS RUB IgG quantitative comparison), implying some form of review or statistical exclusion, but not necessarily expert "adjudication" in the sense of clinical decision-making.

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

No. This document describes performance studies for in vitro diagnostic instruments and assays, not imaging or similar devices that would typically involve human readers interpreting results. Therefore, an MRMC comparative effectiveness study, which assesses improvements in human interpretation with AI assistance, is not applicable and was not performed.

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

The studies described are for the standalone in vitro diagnostic instruments and their associated assays. These are standalone tests, meaning the algorithm (or assay chemistry in this case) processes the sample and provides a result without direct human interpretation of raw data for diagnosis. The "human-in-the-loop" here refers to trained laboratory technicians operating the instrument and interpreting the final quantitative or qualitative results according to established cut-offs/guidelines, rather than interpreting complex images or signals. The purpose of these studies is to confirm that the new instrument (VIDAS 3) produces equivalent results to the predicate instrument (VIDAS) for these assays.

7. The Type of Ground Truth Used

The primary type of "ground truth" used in these studies is the results obtained from the predicate device (VIDAS instrument) for the same assays. The goal is to demonstrate "substantial equivalence" of the new instrument (VIDAS 3) to the predicate.

For the VIDAS RUB IgG assay, a CDC reference panel where samples were "titered by Hemagglutination Inhibition" served as an additional, external reference for ground truth in a specific subset of testing. This is a form of reference method/standardized panel data.

8. The Sample Size for the Training Set

This information is not explicitly provided in the document. For in vitro diagnostic assays, "training sets" are usually involved in the initial development and optimization of the assay itself (e.g., establishing reagents, parameters, cut-offs). The studies described in this document are focused on the validation and verification of the new instrument's performance with existing, already developed assays, often referred to as "test sets" or "evaluation sets." The assays themselves were presumably developed and "trained" using various sample sets prior to these studies.

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

Since information on a distinct "training set" for the new instrument's validation isn't provided (as the assays were pre-existing), details on its ground truth establishment are also not available in this document. For the development of the original assays, ground truth would have been established through a combination of clinical diagnoses, established reference methods, and correlation with disease status.

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The LIAISON® Rubella IgM assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative determination of IgM antibodies to rubella virus in human serum samples. It is intended for use as an aid in the diagnosis of a current or recent Rubella infection in individuals with signs and symptoms of Rubella, or suspected of having rubella virus infection, including women of child bearing age.

The LIAISON® Control Rubella IgM (negative and positive) is intended for use as assayed quality control samples to monitor the performance of the LIAISON® Rubella IgM assay.

The performance characteristics of LIAISON® Rubella IgM controls have not been established for any other assays or instrument platforms.

The LIAISON® Rubella IgM assay is an in vitro diagnostic device consisting of reagents provided in individual compartments within a plastic container called the Reagent Integral. The assay configuration for the LIAISON® Rubella IgM assay allows for the performance of 100 tests.

Reagent Integral Composition:

• a. Magnetic particles mouse monoclonal antibody IgG to human IgM
• b. Calibrator 1 human serum or defibrinated plasma containing low level of Rubella IqM
• c. Calibrator 2 human serum or defibrinated plasma containing high level of Rubella laM
• d. Antigen Inactivated rubella viral particles (HPV 77 strain)
• c. Specimen diluent buffer with BSA added
• d. Conjugate -- mouse monoclonal antibodies to rubella virus conjuqated to an isoluminol derivative

The LIAISON® Control Rubella IgM is an in vitro diagnostic device consisting of 2 levels of controls to monitor the performance of the LIAISON® Rubella IgM assay

Controls (2 vials of each level):

Negative control - human serum or defibrinated plasma non-reactive for Rubella IgM Positive control - human serum or defibrinated plasma reactive for Rubella IgM

Acceptance Criteria and Device Performance Study for LIAISON® Rubella IgM

This document describes the acceptance criteria and the study conducted to demonstrate the performance of the LIAISON® Rubella IgM assay.

1. Table of Acceptance Criteria and Reported Device Performance

The provided document details various analytical performance characteristics. While explicit "acceptance criteria" for all metrics (e.g., precision %CV thresholds) are not stated in a dedicated table, the studies were conducted to demonstrate acceptable performance for the intended use. The LIAISON® Rubella IgM performance is compared against these implicit standards and the FDA-cleared predicate device.

*Precision calculations for these samples were based on signal (RLU) as the dose was below the reading range.
^1 The lower positive agreement in the prospective study is likely due to the small number of positive samples in that cohort (only 10 identified as positive by the comparator assay). The retrospective study (designed for positive samples) shows much higher positive agreement.

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

• Precision/Reproducibility Study Test Set: A coded panel was tested. The specific number of individual samples in the panel is not explicitly stated, but it was tested with two replicates per run, in two runs per day for 20 operating days across three sites.
  • Data Provenance: The study was conducted at two external laboratories and DiaSorin Inc. The origin of the samples in the coded panel is not specified (e.g., country of origin). The study design (testing over 20 days) implies a prospective collection for the study itself, although the source of the panel samples could be retrospective.
• Cross-reactivity Study Test Set: 261 individual samples, each sero-positive for a specific cross-reactant and sero-negative for Rubella IgM by a commercially available Rubella IgM assay.
  • Data Provenance: Not specified (retrospective or prospective, country of origin).
• High Dose Hook Effect Study Test Set: 3 samples with Rubella IgM levels > 400 AU/mL.
  • Data Provenance: Not specified.
• IgM Specificity Study Test Set: 10 samples containing Rubella IgM antibodies covering the assay range.
  • Data Provenance: Not specified.
• Interference Study Test Set: Two matched sample pools near the clinical decision point were tested neat and spiked with each interferent. The specific number of individual samples contributing to the pools or number of independent tests is not detailed beyond the two pools.
  • Data Provenance: Not specified.
• Comparative Testing (Clinical Studies) Test Set:
  • Prospective study: 448 samples from individuals sent to the laboratory for Rubella IgM testing.
  • Retrospective study: 178 samples from individuals who had a positive Rubella IgM result (pre-selected population).
  • Data Provenance: The clinical studies were conducted in the United States, as indicated by the mention of "validated in the United States during clinical studies" and the context of FDA submission. Both prospective and retrospective data were used.

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

• For the clinical comparative studies (prospective and retrospective): The ground truth was established by an "FDA-cleared predicate device" (ADVIA Centaur Rubella IgM Assay, K010668). No human experts were explicitly mentioned as establishing the ground truth for the test set samples in these comparative studies. The predicate device's results were considered the reference.
• For setting the assay cut-off: Ground truth was established based on consensus between "several comparison methods" and "available clinical and serological data". This implies the involvement of experts who interpreted these data, but the number and qualifications of these experts are not specified in the document. The European studies for cutoff establishment mention "subjects never infected by rubella virus, subjects affected by autoimmune diseases, patients affected by various infectious diseases with similar symptomology, subjects with past rubella infector or vaccine recipients, patients affected by acute rubella infection and subjects with long-lasting rubella virus IgM," which would require expert clinical and serological diagnosis to categorize.

4. Adjudication Method for the Test Set

• For the clinical comparative studies, the LIAISON® Rubella IgM assay results were compared directly against the results of the predicate device. There is no mention of an independent adjudication method (like 2+1, 3+1, etc.) for discrepancies between the new device and the predicate. The predicate device's classification was used as the reference.

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

• No, an MRMC comparative effectiveness study was not done. The studies described are focused on comparing the performance of the new device (assay) against a predicate device, and analytical characteristics, not on the improvement of human readers with AI assistance.

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

• Yes, this is a standalone device performance study. The LIAISON® Rubella IgM assay is an in vitro diagnostic device (a lab test system) that provides a qualitative result (Positive, Equivocal, Negative). The studies assess the analytical and clinical performance of this assay itself, generating results without human interpretive input into the device's determination. Human laboratory personnel would operate the instrument and interpret the final quantitative result based on the defined cut-offs to a qualitative diagnosis, but the core performance evaluation is of the assay's output.

7. The Type of Ground Truth Used

• Predicate Device/Reference Methods and Clinical Data Consensus.
  • For the comparative clinical studies, the FDA-cleared predicate device (ADVIA Centaur Rubella IgM Assay) served as the primary ground truth for comparison.
  • For establishing the assay cut-off, the ground truth was derived from "consensus between several comparison methods as well as the available clinical and serological data." This falls under a form of expert consensus and reference method agreement based on clinical and laboratory findings.
  • For analytical studies (e.g., cross-reactivity, IgM specificity), the ground truth was based on known characteristics of the samples (e.g., known sero-positivity for a cross-reactant, known Rubella IgM presence/absence, DTT treatment effect).

8. The Sample Size for the Training Set

• Not explicitly specified for a distinct "training set" in the context of machine learning. As an immunoassay, the device's "training" involves the development and calibration of reagents and the establishment of cut-offs.
• The assay cut-off was established based on studies including "1662 subjects from different populations" (subjects never infected by rubella virus, subjects affected by autoimmune diseases, patients affected by various infectious diseases with similar symptomology, subjects with past rubella infector or vaccine recipients, patients affected by acute rubella infection and subjects with long-lasting rubella virus IgM) in European studies. This large cohort of 1662 subjects would serve as the primary dataset used to "train" or optimize the assay's interpretive criteria (i.e., the cut-off values).

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

• The ground truth for the 1662 subjects used to establish the cut-off was determined by:
  • "several comparison methods" (implying other established serological tests for Rubella IgM), and
  • "available clinical and serological data" (suggesting a comprehensive evaluation of patient history, symptoms, and other laboratory findings).
  • The "consensus between the methods as well as the available clinical and serological data" was applied to define the expected results for these subjects. This indicates a robust method involving multiple lines of evidence and expert review.

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The BioPlex 2200 ToRC IgG kit is a multiplex flow immunoassay intended for the quantitative detection of IgG antibodies to Toxoplasma gondii (T. gondii) and Rubella. and the qualitative detection of IgG antibodies to Cytomegalovirus (CMV) in human serum and EDTA or heparinized plasma.

The ToRC IgG kit is intended for use with the Bio-Rad BioPlex 2200 System.

This kit is intended as an aid in the determination of serological status to.T. gondii, Rubella and CMV. This kit is not intended for use in screening blood or plasma donors.

Performance characteristics for T. gondii and Rubella have not been evaluated in immunocompromised or immunosuppressed individuals. Performance characteristics for CMV have not been evaluated in immunosuppressed or organ transplant individuals. Performance characteristics of this kit have not been established for use in neonatal screening or for use at a point of care.

The BioPlex® 2200 ToRC IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional EIA, but permits simultaneous detection and identification of many antibodies in a single tube. "ToRC" is an acronym for individual tests to detect antibodies to Toxoplasma gondii (T. gondii), Rubella, and Cytomegalovirus (CMV). Three (3) different populations of dyed beads are coated with cell lysates bearing T. gondii, Rubella, or CMV antigens.

The BioPlex 2200 System combines an aliquot of patient sample, sample diluent, and bead reagent into a reaction vessel: the mixture is incubated at 37°C. After a wash cycle, anti-human IgG antibody, conjugated to phycoerythrin (PE), is added to the dyed beads, and this mixture is incubated at 37°C. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the . fluorescence of the attached PE. Raw data are calculated in relative fluorescence intensity (RFI).

Three additional dyed beads, Internal Standard Bead (ISB), Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to verify detector response, the addition of serum or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma.

The instrument is calibrated using a set of six (6) distinct calibrator vials. the BioPlex 2200 ToRC IgG Calibrator Set. For T. gondii and Rubella, six (6) vials, representing six (6) different levels of antibody concentrations, are used for quantitative calibration, and results for patient samples are expressed in IU/mL. For T. gondii, results of ≤ 9 IU/mL are negative, 10 and 11 IU/mL are equivocal, and results of > 12 IU/mL are reported as positive. For Rubella, results of ≤ 7 IU/mL are reported as negative, 8 and 9 IU/mL are equivocal, and ≥ 10 IU/mL are reported as positive. For CMV, four (4) vials, representing four (4) different antibody concentrations, are used for qualitative calibration. CMV results are expressed as an antibody index (AI) and results of ≤ 0.8 AI are negative, 0.9 and 1.0 AI are equivocal, and results of ≥ 1.1 AI are reported as positive.

The BioPlex 2200 ToRC IgG Control Set includes a negative control as well as two (2) multi-analyte positive controls. The BioPlex ToRC IgG Low Positive Control contains antibodies for T. gondii, Rubella and CMV and the BioPlex ToRC IgG High Positive Control contains antibodies for T. gondii and Rubella. The BioPlex ToRC IgG Positive Controls are manufactured to give positive results, with values above the cut-off for each specific analyte. The BioPlex ToRC IgG Negative Control is manufactured to give negative results, with values below the cut-off for each specific analyte. The recommended frequency for performing quality control is once every 24-hour testing period. Performing quality control is also necessary after each new assay calibration and certain service procedures.

This document describes a Special 510(k) submission for a modification to the BioPlex® 2200 ToRC IgG kit. The only change being made is the frequency of Reagent Pack Quality Control (QC) testing from once per pack and per day to once per day and per new reagent pack lot.

Therefore, the acceptance criteria and study information provided below relate to demonstrating that this change in QC frequency does not negatively impact the performance of the device and maintains substantial equivalence to the predicate device.

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

The document states that the modification involved a change in QC testing frequency, and the "Based on the conclusion of the risk management report, the modified QC procedure fulfills the requirements of the specifications of the design control process." This implies that the acceptance criteria are met if the device maintains its original performance characteristics with the new QC frequency. The performance characteristics of the original device are not provided in this document, as the focus is solely on supporting the change in QC frequency.

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

The document does not specify a separate "test set" in the traditional sense for evaluating the performance of the modified device against a ground truth. Instead, the justification for the change in QC frequency relies on a Risk Analysis method and FMEA. Therefore, there is no sample size for an external "test set" and no specific data provenance related to patient samples is mentioned for this particular modification. The study focused on demonstrating equivalence through internal quality control and risk management activities.

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. As described above, there was no external "test set" with a ground truth established by experts. The substantiation for this modification comes from internal risk assessment and design control activities.

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

Not applicable. There was no external "test set" requiring adjudication.

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 device is an in vitro diagnostic (IVD) multiplex flow immunoassay system, not an AI-assisted diagnostic tool. Therefore, MRMC studies and human reader improvement with AI are irrelevant to this submission.

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

This is an IVD device; its performance is inherently "standalone" in the sense that it automates the testing process. The document does not describe separate algorithm-only studies beyond the reported performance of the integrated system. The focus of this 510(k) is a change in QC frequency, not a new algorithm or core performance evaluation.

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

Not applicable for this 510(k) modification. The original device's performance would have been established against a ground truth (e.g., reference methods, clinical diagnosis), but this document focuses on demonstrating that the change in QC frequency does not alter those established performance characteristics. The "ground truth" for this submission is the successful completion of the risk management process and the conclusion that the modified QC procedure meets the requirements and maintains substantial equivalence.

8. The sample size for the training set

Not applicable. This is not a machine learning or AI-based device that would typically involve a "training set" for an algorithm.

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

Not applicable. See point 8.

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The BioPlex® 2200 MMRV IgG kit is a multiplex flow immunoassay intended for the qualitative detection of IgG antibodies to Measles, Mumps, Rubella and Varicella-zoster virus (VZV) in human serum and EDTA or heparinized plasma.

The BioPlex 2200 MMRV IgG kit is intended for use with the Bio-Rad BioPlex 2200 System.

This kit is intended as an aid in the determination of serological status to Measles, Mumps, Rubella, and VZV. This kit is not intended for use in screening blood or plasma donors.

The performance of this assay has not been established for use in neonatal, pediatrics and immunocompromised patients, or for use at point of care facilities.

The BioPlex 2200 MMRV IgG kit uses multiplex flow immunoassay for simultaneous detection and identification of many antibodies in a single tube. Four (4) different populations of magnetic dyed beads are coated with antigens to identify the presence of IgG class antibodies against Measles. Mumps. Rubella and Varicella-zoster. The BioPlex 2200 System combines an aliquot of patient sample diluent, and bead set reagent into a reaction vessel. The mixture is incubated at 37℃. After a wash cycle, anti-human IgG antibody, conjugated to phycoerythrin (PE), is added to the dyed beads and this mixture is incubated at 37°C. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector.

The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the fluorescence of the attached PE. Raw data is calculated in relative fluorescence intensity (RFI). Three additional control beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB), and a Reagent Blank Bead (RBB) are present in each reaction mixture to verify detector response, the addition of serum to the reaction vessel, and the absence of significant non-specific binding in serum.

The instrument is calibrated using a set of three (3) distinct calibrator vials, supplied separately by Bio-Rad Laboratories.

The BioPlex 2200 MMRV IgG system is designed to detect IgG antibodies for Measles, Mumps, Rubella, and Varicella-zoster virus (VZV) in human serum and plasma. The acceptance criteria and supporting studies for this device, specifically focusing on the modification of QC testing frequency, are outlined below.

1. Table of Acceptance Criteria and Reported Device Performance

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

The provided document does not contain details regarding a specific test set, its sample size, or data provenance. The submission is a Special 510(k) for a modification (QC testing frequency) to an already cleared device, not for the initial clearance of the device itself. The evidence presented focuses on a risk analysis rather than a clinical performance study with patient samples to demonstrate equivalence for the modified aspect.

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

Not applicable. The document does not describe a clinical study with a test set requiring expert-established ground truth for performance evaluation of the modified QC procedure. The assessment was based on risk analysis and design control activities.

4. Adjudication Method for the Test Set

Not applicable, as no described test set requiring adjudication of results from clinical samples is present in the document.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. The BioPlex 2200 MMRV IgG is an in vitro diagnostic (IVD) assay designed for automated detection of antibodies, not an AI-assisted diagnostic tool that involves human reader interpretation.

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

The BioPlex 2200 MMRV IgG operates as a standalone automated system for detecting antibodies. The original device's performance, which this modification refers to, would have been established as standalone as per the nature of the device. The current submission focuses on a procedural change (QC frequency) rather than re-evaluating the core standalone performance.

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

For the original BioPlex 2200 MMRV IgG system, ground truth for establishing performance (sensitivity, specificity) would typically be based on:

• Reference laboratory methods: Comparison with established, validated serological tests (e.g., IFA, EIA) from reference laboratories.
• Clinical status: Correlation with patient vaccination history, known infection status, or immune response.
• Known positive/negative panels: Use of well-characterized serum panels with known antibody status.

However, the provided Special 510(k) document for the modification does not detail the ground truth used for the initial device or for evaluating the impact of the QC frequency change. The current submission relies on a risk assessment rather than a clinical performance study against a ground truth.

8. The Sample Size for the Training Set

Not applicable. This is an in vitro diagnostic device, not an AI/ML model that typically undergoes specific "training" with a dataset in the same way. The development of such assays involves optimization and calibration using characterized samples, but not a "training set" in the context of machine learning.

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

Not applicable, for the reasons stated in point 8.

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For the qualitative, semi-quantitative and quantitative detection of IgG antibodies to rubella in human serum by indirect enzyme immunoassay to aid in the assessment of the patient's immunological response to rubella and in the determination of the immune status of individuals, including females of child-bearing age. The evaluation of acute and convalescent sera can aid in the diagnosis of current or recent infection with rubella.

The Mago 4S Automated EIA and IFA Processor is a pipetting, diluting, incubating, and color intensity analyzing system for in vitro diagnostic clinical use for the processing of FDA-cleared enzyme-linked immunoabsorbent assays (EIA) through result generation. In addition, it processes immunofluorescence assay (IFA) slides for off-platform detection and result generation.

The MAGO 4S is an automated laboratory instrument designed to automate the processing of enzyme-linked immunoabsorbent assays (EIA) as well as Immunofluorescence Assay (IFA) slides. The MAGO 4S is designed to minimize manual operations associated with performing routine laboratory analysis by mechanizing and computerizing the test process.

The provided document describes the MAGO 4S, an automated laboratory instrument for processing enzyme-linked immunoabsorbent assays (EIA) and immunofluorescence assay (IFA) slides, specifically for the detection of IgG antibodies to rubella in human serum. The study aims to demonstrate substantial equivalence to predicate devices.

Here's an analysis of the acceptance criteria and study data:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria in terms of specific thresholds for precision, linearity, or agreement percentages before the study was conducted. Instead, it presents the results obtained and implies that these results are deemed acceptable for substantial equivalence. For the purpose of this table, I will infer the acceptance from the presented "Pass" results and the general expectation for such assays.

*   **CDC Performance Panel:** 100 sera provided by the CDC.
*   **CDC Biological Standard:** CDC Biological Standard, Low-Titer Anti Rubella Human Reference Serum, used with a dilution series.

• Data Provenance: Not explicitly stated whether retrospective or prospective. Given the nature of performance testing for a new device, it is likely prospective, with samples collected or acquired specifically for this study. The country of origin for general samples is not mentioned, but the CDC performance panel samples are from the US.

3. Number of Experts and Qualifications for Ground Truth

• The document does not mention the use of external human experts to establish ground truth for the test set that directly compares the MAGO 4S to a reference.
• For the "Positive and Negative Agreement with Comparator" test, the "manual" method acts as the comparative standard. The expertise for establishing the results of the manual method would rely on the laboratory personnel performing those tests, presumably qualified medical technologists or similar professionals.
• For the CDC Performance Panel, the "CDC Target" is used as the ground truth. This implicitly relies on the expertise and established reference methods of the CDC.

4. Adjudication Method

• The document does not describe a formal adjudication method (like 2+1 or 3+1) involving multiple human readers/reviewers for the test set.
• For the "Positive and Negative Agreement with Comparator," it seems a single manual test result was compared to a single MAGO 4S result for each sample. Equivocal results were specifically addressed in a retest zone assessment.

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

• No MRMC comparative effectiveness study was done. This study focuses on the performance of the automated instrument itself (standalone performance) against manual methods or established standards, not on the improvement of human readers with AI assistance.

6. Standalone Performance Study

• Yes, a standalone performance study was done. The entire submission details the performance of the MAGO 4S automated instrument (algorithm only, without human-in-the-loop performance) in various aspects such as precision, linearity, and agreement with established methods/standards.

7. Type of Ground Truth Used

• Existing Legally Marketed Devices/Manual Methods: For precision, linearity, and positive/negative agreement, the "Diamedix test kit" (manual method) serves as the comparator, and its results are implicitly considered ground truth for comparison.
• Reference Standards/Panels:
  • CDC Performance Panel: The "CDC Target" results for the 100 sera served as the external ground truth.
  • CDC Biological Standard: The expected IU/ml values for the various dilutions of the Low-Titer Anti Rubella Human Reference Serum served as the reference ground truth.

8. Sample Size for the Training Set

• The document does not provide information on a specific "training set" or sample sizes used for training the MAGO 4S in the context of machine learning or AI. This device appears to be an automated instrument following predefined protocols for assays (EIA/IFA) rather than a system requiring extensive machine learning model training on large datasets in the way modern AI devices do. Its "development" would involve engineering and calibration rather than algorithm training on a separate dataset.

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

• As noted in point 8, the document does not describe a "training set" in the context of machine learning. Therefore, methods for establishing ground truth for such a set are not applicable or described within this submission. The "ground truth" for the device's operational parameters would have been established during its engineering, calibration, and internal validation processes based on reference materials and established assay principles.

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The BioPlex® 2200 Rubella and CMV IgM kit is a multiplex flow immunoassay intended for the qualitative detection of IgM antibodies to Rubella and Cytomegalovirus (CMV) in human serum and potassium EDTA or sodium heparin plasma.

The BioPlex 2200 Rubella and CMV IgM kit is intended for use with the Bio-Rad BioPlex 2200 System.

This kit is intended as an aid in the diagnosis of a current or recent Rubella and/or CMV infection, in individuals suspected of having one of the respective disease states including women of child bearing age.

This assay is not FDA cleared or approved for use in testing (screening) blood or plasma donors.

Performance characteristics for the Rubella and CMV IgM assays have not been evaluated in immunosupressed or organ transplant individuals. Performance characteristics of this kit have not been established for use in neonatal screening or for use at point of care facilities.

The BioPlex® 2200 Rubella and CMV IgM Calibrator Set is intended for calibration of the BioPlex 2200 Rubella and CMV IgM Reagent Pack.

The BioPlex 2200 Rubella and CMV IgM Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 Instrument and BioPlex Rubella and CMV IgM Reagent Pack in the clinical laboratory. The performance of the BioPlex 2200 Rubella and CMV IgM Control Set has not been established with any other Rubella or Cytomegalovirus (CMV) IgM antibody assays.

The BioPlex® 2200 Rubella and CMV IgM kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional EIA, but permits simultaneous detection and identification of many antibodies in a single tube. Rubella and CMV IgM test is to detect antibodies to Rubella and Cytomegalovirus (CMV).

Two (2) different populations of dyed beads are coated with cell lysates bearing Rubella or CMV antigens. The BioPlex 2200 System combines an aliquot of patient sample, sample diluent, and bead reagent into a reaction vessel; the mixture is incubated at 37°C. After a wash cycle, anti-human IgM antibody, conjugated to phycoerythrin (PE), is added to the dyed beads, and this mixture is incubated at 37°C. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of antibody captured by the antigen is determined by the fluorescence of the attached PE. Raw data are reported as relative fluorescence intensity (RFI).

Three additional dyed beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to verify detector response, the addition of serum or plasma to the reaction vessel and the absence of significant non-specific binding in serum or plasma.

The instrument is calibrated using a set of three (3) distinct serum based calibrators. A negative and CMV IgM calibrator is used to calibrate CMV assay, and a negrative and rubella IgM calibrator is used to calibrate the rubella IgM assay, The cul-off value and assignment of the calibrators are determined by performing concordance and Receiver Operator Characteristic (ROC) analysis using the Centaur Rubella IgM and VIDAS CMV IgM predicate results as the standard. For Rubella and CMV, results of ≤ 0.8 Al are negative, 0.9 and 1.0 Al are equivocal and results of ≥ 1.1 Al are reported as positive.

The BioPlex 2200 Rubella and CMV IgM Control Set includes a negative control as well as a CMV IgM positive control and a Rubella IgM positive control. The BioPlex Rubella and CMV IgM Positive Controls are manufactured to give positive results, with values above the cut-off for each specific analyte. The BioPlex Rubella and CMV IgM Negative Control are manufactured to give negative results, with values below the cut-off for each specific analyte. The recommended frequency for performing quality control is once every 24-hour testing period. Performing quality control is also necessary after each new assay calibration and certain service procedures.

Here's an analysis of the provided text regarding the BioPlex® 2200 Rubella and CMV IgM kit, focusing on acceptance criteria and the supporting studies:

Summary of Acceptance Criteria and Device Performance (Based on Method Comparison Studies)

The acceptance criteria for the BioPlex® 2200 Rubella and CMV IgM kit are not explicitly stated as numerical targets in the provided document, but rather implied through comparison to predicate devices and general performance metrics like Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA).

1. Table of Acceptance Criteria and Reported Device Performance

Notes on Acceptance Criteria:

• The document implies that "comparable performance" or "performed according to its specifications" is the acceptance criterion for many aspects. For quantitative measurements like reproducibility and matrix comparison, specific numerical targets (e.g., %CV ranges, slope 1.0 +/- 0.2, r >= 0.98) are explicitly mentioned and met.
• The PPA values for the prospective study, especially for Rubella IgM (66.7%) and CMV IgM (53.8%), seem low initially. However, these are based on a very small number of positive samples (3 for Rubella IgM and 13 for CMV IgM), which leads to wide confidence intervals. The larger retrospective study with presumptive positive samples shows much higher PPA values (96.3% for Rubella IgM and 91.3% for CMV IgM), suggesting strong overall positive agreement when sufficient positive samples are present. The low positive counts in the prospective study are likely due to the low prevalence of acute infections in the "test ordered" population.

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

• Reproducibility (Internal): 3 panels (serum, EDTA plasma, heparinized plasma). Assayed 2 times in 2 separate daily runs over 20 days (n=80).
• Reproducibility (External): 3 panels (serum, EDTA plasma, heparinized plasma). Tested in quadruplicate over 5 days at 3 sites (n=60 replicates per panel member).
• Interfering Substances: Specific substances tested at varying concentrations. Number of samples not explicitly stated per substance, but implied to be sufficient to observe interference if present.
• Cross-Reactivity: Varied numbers of samples (typically 9-10) for each potential cross-reactant. Samples were known positive for the given cross-reactant and negative by predicate devices.
• IgM Detection (DTT treatment): 10 Rubella IgM-positive samples and 10 CMV IgM-positive samples.
• Seroconversion Testing: 3 commercial Rubella IgM seroconversion panels (RP001, RP011, RP014) and 1 commercial CMV IgM seroconversion panel (RP003). Each panel consists of multiple bleeds over time.
• Expected Values:
  • Rubella IgM: 300 samples (US origin).
  • CMV IgM: 400 samples (300 US, 100 Europe).
• Method Comparison (Prospective Study):
  • Rubella IgM: 300 samples (US origin), including 71 pregnant women.
  • CMV IgM: 400 samples (300 US, 100 Europe).
• Method Comparison (Retrospective Study - Presumptive Positive):
  • Rubella IgM: 107 samples.
  • CMV IgM: 229 samples.
• Matrix Comparison: 20 individual donors for matched serum, potassium EDTA plasma, and sodium heparin plasma samples. Evaluated in replicates of 10.

Data Provenance:

• US and Europe: Explicitly mentioned for some Expected Values and Method Comparison studies for CMV IgM. Rubella IgM samples are predominantly US.
• Retrospective/Prospective:
  • Prospective: Method Comparison study for general population and pregnant women.
  • Retrospective: Method Comparison study for presumptive positive samples. Seroconversion panels, interfering substances, and cross-reactivity studies are inherently retrospective in their selection (i.e., using pre-characterized samples). Reproducibility studies used panels.

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

The document does not specify the direct involvement of human experts (e.g., radiologists, pathologists) in establishing the ground truth for this device. Instead, the ground truth for most comparative studies is established by:

• Predicate Devices: The ADVIA Centaur® Rubella IgM (K010668) and bioMeriéux VIDAS® CMV IgM (K933549) are used as the reference standard ("predicate results as the standard") for determining cut-off values and for method comparison studies.
• FDA Cleared Devices: For the cross-reactivity study, samples were pre-tested by "FDA cleared devices." For adjudication, "two out of three FDA cleared devices" were used.
• Commercial Seroconversion Panels: Bio-Rad Laboratories Liquichek™ Rubella IgM and CMV IgM seroconversion panels were used, which are typically well-characterized.

Therefore, the ground truth is based on established, FDA-cleared commercial assays and recognized diagnostic panels, rather than direct expert consensus on individual cases.

4. Adjudication Method for the Test Set

• Adjudication by Multiple FDA Cleared Devices: For samples that showed equivocal results by the predicate device in the Method Comparison (Prospective Study), an adjudication method was used: "One sample that was equivocal by the predicate device was adjudicated by two out of three FDA cleared devices." and "Two samples that were equivocal by the predicated by two out of three HDA cleared devices." This is a form of 2-out-of-3 or 3-out-of-3 adjudication against external reference methods.
• No explicit 2+1, 3+1, or similar human expert adjudication is mentioned in the context of interpretation of images or clinical cases. The adjudication is against other laboratory tests.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No MRMC comparative effectiveness study was mentioned or performed. This device is an in vitro diagnostic (IVD) immunoassay kit, not an AI-assisted diagnostic imaging device or tool that involves human "readers" in the traditional sense of interpreting complex data like medical images. Its performance is evaluated against other laboratory assays.

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

The BioPlex® 2200 system operates as a standalone automated immunoassay. The performance studies described (reproducibility, interfering substances, cross-reactivity, seroconversion, method comparison) inherently evaluate its "algorithm only" or automated performance without human intervention in the interpretation process of individual test results. The device provides quantitative results (RFI) which are then interpreted qualitative (negative, equivocal, positive) based on predefined cut-offs.

7. The Type of Ground Truth Used

The ground truth primarily used is "predicate devices" or "FDA cleared devices."

• For method comparison studies, the results from the ADVIA Centaur® Rubella IgM and bioMeriéux VIDAS® CMV IgM predicate devices served as the gold standard.
• For cross-reactivity, samples confirmed positive for specific conditions by other FDA cleared devices were used.
• For seroconversion, commercial seroconversion panels were used, which have well-characterized profiles.
• The calibration itself uses concordance and Receiver Operator Characteristic (ROC) analysis with predicate device results.

8. The Sample Size for the Training Set

The document does not explicitly describe a separate "training set" in the context of machine learning or AI algorithm development. This is an immunoassay kit, where the "training" involves the development and calibration of the assay.

• The calibration process is described using "a set of three (3) distinct serum based calibrators." The cut-off values are determined by "performing concordance and Receiver Operator Characteristic (ROC) analysis using the Centaur Rubella IgM and VIDAS CMV IgM predicate results as the standard." While not a "training set" in the AI sense, this calibrator set and the analysis with predicate results serve a similar function in establishing the assay's operational parameters.

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

As noted above, there isn't a "training set" in the typical AI sense. For the establishment of assay calibration and cut-offs:

• Predicate Device Results: The ground truth for defining the cut-off values and calibrators was established by comparing the BioPlex 2200's performance against the established results of the predicate devices (ADVIA Centaur® Rubella IgM and bioMeriéux VIDAS® CMV IgM) using concordance and ROC analysis. This means the clinical and analytical performance of those predicate devices, which are already FDA cleared, serve as the reference for tuning the BioPlex 2200's output.

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The Zeus Scientific, Inc. AtheNA Multi-Lyte® ToRCH IgG Plus Test System is intended for the qualitative detection of specific human IgG class antibodies to Toxoplasma gondii (T.gondii), Rubella, Cytomegalovirus (CMV) and HSV 1 & 2 in human serum. The results of this assay are intended to be used as an aid in the assessment of serological status to Toxoplasma gondii, Rubella and CMV. For HSV 1 and HSV 2, the test is indicated for sexually active adults and expectant mothers, as an aid for presumptively diagnosing Herpes Simplex 1 and Herpes Simplex 2.

The test is not intended for use in screening blood or plasma donors.

The performance of this assay has not been established for use in a pediatric population, neonatal screening, immunocompromised or immunosuppressed patients or for use at point of care facilities.

The Zeus Scientific, Inc. AtheNA Multi-Lyte® ToRCH IgG Plus Test System is a multiplex immunoassav intended for the simultaneous qualitative detection and differentiation of specific human IgG class antibodies to Toxoplasma gondii, Rubella, Cytomegalovirus (CMV), Herpes Simplex 1 (HSV-1) and Herpes Simplex 2 (HSV-2) in human serum. The results of this assay are intended to be used as an aid in the assessment of a patient's serological status to infection with Toxoplasma gondii, Rubella, CMV, HSV 1 and HSV 2 and in the determination of immune status of individuals including pregnant women. The test system is comprised of the AtheNA Multi-Lyte test kit, software and the Luminex Corp instrument.

The AtheNA Multi-Lyte ToRCH IgG Plus Test System provides the following components:

Reactive Reagents:

All reactive reagents contain sodium azide as a preservative at a concentration of 0.1% (w/v).

1. Multiplexed bead suspension 1. Ready to use, 5.5 mL bottle. The suspension contains separate distinguishable 5.6 micron polystyrene beads that are conjugated with:
   . Toxo grade 2 antigen
   . Rubella K2S grade antigen
   CMV grade 2
   . HSV-1 type-specific recombinant gG-1 protein antigen
   . HSV-2 gG-2 type-specific recombinant gG-2 protein antigen

The bead mix also contains one bead set designed to detect non-specific antibodies in the patient sample (if present) and four separate bead sets used for assay calibration.

2. Conjugate: Phycoerythrin conjugated goat anti-human IgG (y chain specific). Ready to use, 15 mL amber bottle.
3. Human positive serum control 1. One, 0.2 mL vial.
4. Human positive serum control 2. One, 0.2 mL vial.
5. Human negative serum control. One, 0.2 mL vial.
6. SAVe Diluent®. One 50 mL bottle containing phosphate-buffered-saline. Ready to use. NOTE, the sample diluent will change color in the presence of serum.
7. Wash Buffer Concentrate: dilute 1 part concentrate + 9 parts deionized or distilled water. One bottle containing 10 X concentrate of phosphate buffered saline.

Non-Reactive Reagents

1. One, 96-well filtration plate for rinsing the microspheres
2. Data Labels: One label is adhered to the inside lid of the kit box and a second label is inside the kit box.
3. Package Insert providing instructions for use
4. Calibration CD: a compact disc that includes all lot-specific kit calibration values required for specimen analysis and assay quality control

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

Device: AtheNA Multi-Lyte® ToRCH IgG Plus Test System
Submission Purpose: Simultaneous qualitative detection and differentiation of specific human IgG class antibodies to Toxoplasma gondii (Toxo), Rubella, Cytomegalovirus (CMV), and Herpes Simplex 1 (HSV-1) and Herpes Simplex 2 (HSV-2). The results aid in assessing serological status for Toxo, Rubella, and CMV, and for presumptively diagnosing HSV-1 and HSV-2 in sexually active adults and expectant mothers.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" as a single, consolidated list with numerical targets for each performance metric (e.g., "Sensitivity must be >95%"). Instead, it presents the results of comparative studies against predicate devices and CDC panels. The implicit acceptance criterion is that the device demonstrates performance substantially equivalent to or in agreement with these established methods.

The table below summarizes the reported device performance from the clinical studies for various analytes and populations, indicating successful agreement or high percentage agreement where applicable. For Toxoplasma, Rubella, and CMV in the "Individuals Undergoing ToRCH Antibody Assessment," the columns refer to "Positive Percent Agreement (PPA)" which represents sensitivity and "Negative Percent Agreement (NPA)" which represents specificity. For HSV-1 and HSV-2 in "Sexually Active Adults", it uses "Sensitivity" and "Specificity." For the CDC panels, it also uses "PPA" and "NPA" against the CDC results.

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

The evaluation of the AtheNA Multi-Lyte ToRCH IgG Plus Test System involved several studies:

• Comparative testing of Intended Use Populations (651 samples):
  • Sample Size: 651 unselected samples.
  • Data Provenance:
    • 300 samples from a hospital laboratory in the Mid-Atlantic region (United States).
    • 351 samples from a hospital laboratory in the Northeast (United States).
    • The samples were "prospectively collected" individuals undergoing ToRCH antibody assessment. They were described as "frozen remnant serum samples" which suggests they might have been collected over a period and then accessed retrospectively for this study. The phrasing "prospectively collected frozen remnant serum samples" can be ambiguous, but generally, "prospectively collected" refers to data collected specifically for the study. However, using "remnant" suggests they were left over from routine testing.
    • Data was gathered concurrently with the AtheNA Multi-Lyte test system and predicate assays.
• Pregnant Women Population (200 samples):
  • Sample Size: 200 samples.
  • Data Provenance: From expectant mothers, sourced from two serum vendors. The samples were "prospectively collected" and were "frozen remnant serum samples". Tested internally at the manufacturer's lab.
• CDC Reference Panels:
  • Sample Size:
    • Toxo: 100 samples (70 positive, 30 negative)
    • Rubella: 100 samples (80 positive, 20 negative)
    • CMV: 100 samples (54 positive, 46 negative)
    • HSV-1: 100 samples (50 positive, 50 negative)
    • HSV-2: 100 samples (48 positive, 52 negative)
  • Data Provenance: Masked, well-characterized serum panels from the CDC (Centers for Disease Control and Prevention), a US government agency.
• HSV-1 & HSV-2 Low Prevalence Population:
  • Sample Size: 67 samples.
  • Data Provenance: Serum samples from 18 and 19-year-old subjects previously tested for non-sexual infections. Assessed internally at Zeus. Retrospective.
• Rubella Retrospective Negative Sample Study:
  • Sample Size: 100 samples.
  • Data Provenance: Pre-selected banked samples of sera previously tested negative for Rubella antibody by the predicate device. Assessed internally at Zeus. Retrospective.

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

The document does not explicitly mention the number or qualifications of experts used to establish the ground truth for the test sets. Instead, the "ground truth" was established by:

• Predicate assays: The results of FDA-cleared predicate ELISA test systems (Toxo IgG ELISA, Rubella IgG ELISA, CMV IgG ELISA, HerpeSelect 1 and 2 Immunoblot IgG for HSV-1/2) were used as the reference standard for the clinical performance studies in general populations and pregnant women. These predicate devices are themselves validated diagnostic tools.
• CDC Reference Panels: These are "well-characterized" serum panels which implicitly means their status (positive/negative) for the target analytes has been rigorously established, likely through expert consensus and/or a battery of highly sensitive and specific reference methods, although the details are not provided here.

4. Adjudication Method for the Test Set

The document does not describe any explicit adjudication method (like 2+1 or 3+1) for resolving discrepancies between the AtheNA Multi-Lyte system and the predicate devices or CDC panels.

The results are presented as direct comparisons, and for discrepant cases in the Rubella category, a note mentions qualitative differences (e.g., "4/4 discrepant Rubella samples which tested positive by ELISA had low positive values for AtheNA and high negative values for ELISA, 4/4 discrepant Rubella samples which tested positive by AtheNA and equivocal by ELISA had low positive values for ELISA"). This suggests discrepancy analysis was performed but no formal adjudication by an independent panel of experts is explicitly mentioned for overriding results.

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

No, an MRMC comparative effectiveness study was not done. This device is an automated in vitro diagnostic assay (multiplex microparticle immunoassay) that generates quantitative/qualitative results, not an imaging AI algorithm requiring human interpretation. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply in this context.

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

Yes, the studies reported are essentially standalone performance studies. The AtheNA Multi-Lyte® ToRCH IgG Plus Test System is an automated immunoassay system (test kit, software, and Luminex Corp instrument) which provides qualitative detection of antibodies. Its performance is evaluated directly against predicate devices or reference panels without human interpretation influencing the device's output. The results presented (PPA, NPA, Sensitivity, Specificity) are inherent to the device's diagnostic capability.

7. The Type of Ground Truth Used

The ground truth used for the test sets was primarily based on:

• Predicate devices: Established and FDA-cleared immunoassay systems for each analyte (ELISA for Toxo, Rubella, CMV; Immunoblot IgG for HSV-1/2).
• CDC Reference Panels: Well-characterized serum panels with known positive or negative status.
• Previously tested results: For the low prevalence HSV study and retrospective Rubella study, pre-selected banked samples with known results from predicate devices were used.

These are considered established diagnostic results from reference methods or highly characterized samples, rather than pathology or direct outcomes data from patients.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" or its sample size for the AtheNA Multi-Lyte® ToRCH IgG Plus Test System. As an immunoassay, the device itself is developed and optimized through laboratory procedures, reagent formulation, and analytical validation rather than machine learning training on a dataset. The studies described are performance evaluation studies, akin to a test set, to demonstrate substantial equivalence and establish performance characteristics.

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

Since a "training set" in the context of machine learning is not applicable here, the method of establishing ground truth for a training set is not provided. The development of an immunoassay involves optimizing reagents and reaction conditions, typically through analytical experiments rather than data-driven machine learning training.

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