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MPO Flex® reagent cartridge: The MPO method is an in vitro diagnostic test for the quantitative measurement of myeloperoxidase (MPO) in human plasma on the Dimension® clinical chemistry system with the heterogeneous immunoassay module. Myeloperoxidase measurements may be used in conjunction with clinical history, ECG, and cardiac biomarkers to evaluate patients presenting with chest pain that are at risk for major adverse cardiac events, including myocardial infarction, need for revascularization, or death.

MPO Calibrator: The MPO Calibrator is an in vitro diagnostic product intended to be used to calibrate the Myeloperoxidase (MPO) method on the Dimension® clinical chemistry system with the heterogeneous immunoassay module.

MPO Control: The myeloperoxidase control is an in vitro diagnostic product intended for use as an assayed quality control product to monitor the performance of the Myeloperoxidase (MPO) method on the Dimension® clinical chemistry system with the heterogeneous immunoassay module.

The MPO method is a one-step enzyme immunoassay based on the "sandwich" principle. The sample is incubated with chromium dioxide particles coated with monoclonal antibodies specific for MPO, and conjugate reagent (13-galactosidase labeled monoclonal antibodies specific for MPO). A particle/MPO/conjugate sandwich forms during the incubation period. Unbound conjugate is removed by magnetic separation and washing. The sandwich bound fl-galactosidase is combined with the chromogenic substrate chlorophenol red-ß-D-galactopyranoside (CPRG). Hydrolysis of CPRG releases a chromophore (CPR). The concentration of MPO present in the patient sample is directly proportional to the rate of color change due to formation of CPR measured at 577 nm.

The provided text describes the Siemens Healthcare Diagnostics Dimension MPO Flex® reagent cartridge and its associated calibrator and control. The information focuses on demonstrating substantial equivalence to a predicate device, the PrognostiX CardioMPO™ Enzyme Immunoassay. The study does not involve an AI device, therefore, some of the requested information such as MRMC study, and number of experts to establish ground truth is not applicable.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria (from predicate device) and Reported Device Performance:

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The CardioMPO™ Test is comprised of the CardioMPO Reagent Kit, the CardioMPO Calibrator Kit, and the CardioMPO Control Kit.

The CardioMPO Reagent Kit is an enzyme immunoassay intended for the quantitative determination of myeloperoxidase in human plasma, to be used in conjunction with clinical history, ECG and cardiac biomarkers to evaluate patients presenting with chest pain that are at risk for major adverse cardiac events, including myocardial infarction, need for revascularization, or death.

The PrognostiX CardioMPO Calibrator Kit is intended for use with the CardioMPO Reagent Kit to establish a calibration curve that is used to determine MPO concentration.

The PrognostiX CardioMPO Control Kit is intended for use with the CardioMPO Reagent Kit as an assayed quality control sample to monitor and evaluate the precision and accuracy of the CardioMPO Test.

The CardioMPO Test is a sandwich enzyme immunoassay that uses two highly specific antibodies, one monoclonal and one polyclonal, and an enzyme labeled anti-rabbit IgG antibody for the measurement of MPO concentration in human plasma. The CardioMPO Test is comprised of the CardioMPO Reagent Kit, the CardioMPO Calibrator Kit, and the CardioMPO Control Kit.

The CardioMPO Reagent Kit contains the following: a microtiter plate coated with a monoclonal anti-MPO antibody; a solution of primary polyclonal rabbit anti-MPO antibody; a solution of secondary goat anti-rabbit IgG antibody labeled with horseradish peroxidase solution; TMB substrate solution; Stop Solution; Wash Buffer Concentrate; Assay Buffer; and plate sealers.

The CardioMPO Calibrator Kit contains six Calibrators comprised of human MPO in a phosphatebuffered matrix containing proteins, detergents, and stabilizers. Calibrators are intended to establish a calibration curve that is used to determine MPO concentration. Calibrator values are provided on individual Calibrator labels. Calibrators are provided ready-to-use.

The CardioMPO Control Kit contains three Controls comprised of human MPO in a human plasma matrix. Controls are intended to monitor and evaluate the precision and accuracy of the CardioMPO Test. Ranges are provided on individual Control labels. Controls are freated in the same manner as patient samples.

Calibrators are added directly to the appropriate wells of the Microtiter Plate. Assay Buffer is added to all wells that are intended for Control or sample analysis. Aliquots of Controls or samples are added to the appropriate wells and the plate is incubated for 60 minutes at 20-26°C. The wells are then washed with Wash Buffer to remove antigens not specifically bound to the immobilized antibody.

A yellow primary polyclonal rabbit anti-MPO antibody is added to each well and incubated for 60 minutes at 20-26°C. This antibody binds to the MPO captured on the plate. The plate is again washed with Wash Buffer to remove unbound primary antibody.

A blue secondary goat anti-rabbit IgG antibody, labeled with the enzyme horseradish peroxidase (HRP), is then added to each well and incubated for 30 minutes at 20-26°C. This antibody binds to the primary antibody, and the MPO in the sample is "sandwiched" between the monoclonal antibody on the solid phase and a complex of the rabbit anti-MPO and the HRP-goat anti-rabbit IgG antibody. The wells are washed with Wash Buffer to remove unbound HRP-labeled antibody.

The substrate, tetramethylbenzidine (TMB), is then added to each well and incubated for 10 minutes at 20-26°C resulting in the development of a blue color. Color development is stopped with the addition of Stop Solution, changing the color to yellow.

The enzymatic turnover of the substrate is determined spectrophotometrically at 450 nm, preferably with correction at 630 nm, and is directly proportional to the concentration of MPO. The absorbances of the Calibrators are used to plot a standard curve of absorbance versus MPO concentration from which the MPO concentration in the Controls or samples can be determined.

Here's an analysis of the provided text regarding the acceptance criteria and study for the PrognostiX CardioMPO™ Test:

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

The document does not explicitly state "acceptance criteria" for all performance characteristics in a separate section with numerical targets. Instead, it presents performance characteristic results and implies their acceptability by stating "The PrognostiX CardioMPO Test is acceptably precise, linear, accurate, and is not subject to appreciable cross-reactivity or interference." and "The detection limit of 13 pM is acceptable for the intended use of this test."

However, we can infer acceptance criteria based on the comparison to the predicate device and from general good practices for in vitro diagnostic devices, and report the observed performance:

*   **Data Provenance:** These are laboratory-based analytical studies, likely conducted internally by PrognostiX, Inc. and are prospective in nature for the purpose of this submission (i.e., substances were specifically "tested" and samples "analyzed" for the submission).

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

The ground truth for the clinical study was the occurrence of "major adverse cardiac events (MACE), including myocardial infarction, need for revascularization, or death" over a 30-day and 6-month interval. This outcome was assessed by follow-up phone calls. The document does not specify:

• The number of experts used to establish this ground truth.
• The qualifications of those experts (e.g., cardiologists, emergency physicians).
• The methods used to adjudicate MACE events (e.g., review of medical records, independent committee).
  Given it was "assessed by follow up phone calls," it's highly likely that trained personnel (possibly nurses or research coordinators) collected this information, potentially with physician review for confirmation, but the details are absent.

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

The document does not specify any formal adjudication method (like 2+1, 3+1) for the clinical outcomes (MACE) in the test set. The assessment relied on "follow up phone calls."

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

• No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done.
• The CardioMPO™ Test is an in vitro diagnostic (IVD) assay for measuring a biomarker (myeloperoxidase) in plasma. It is not an imaging AI device that would involve human "readers" interpreting images with or without AI assistance. The test provides a quantitative result which is then used by clinicians in conjunction with other clinical information.

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

Yes, the analytical performance and clinical utility data presented are for the device operating in a standalone manner. The device measures MPO concentration; there is no human-in-the-loop performance component for the measurement itself. The interpretation of the MPO result (in conjunction with clinical history, ECG, and cardiac biomarkers) is where human expertise is applied. The clinical study demonstrated the MPO test's predictive power as a standalone biomarker.

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

The ground truth for the clinical study was outcomes data, specifically the occurrence of "major adverse cardiac events (MACE), including myocardial infarction, need for revascularization, or death" within 30 days and 6 months after presentation with chest pain.

8. The sample size for the training set

The document does not explicitly describe a separate "training set" for the clinical study. The 560 banked plasma samples were used to evaluate the device's performance in predicting MACE. The study used multivariate logistic regression models for analysis, which are typically applied to a dataset to assess relationships, but there's no mention of a separate training phase to develop the MPO test itself or a decision rule based on MPO levels from this dataset, beyond assessing its association with outcomes. It's more of a validation of the biomarker's utility.

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

As there's no explicitly defined separate "training set" for the clinical study from the perspective of developing an AI algorithm, this question isn't directly applicable in the conventional sense of AI/ML model development. However, if we interpret "training set" as the data used to understand the reference ranges or analytical characteristics, the ground truth was established as follows:

• Reference Interval: Plasma samples from "a population of apparently healthy blood donors" were screened, and outliers were removed using a two-stage method (Box-Cox transformation followed by robust outlier detection). The "ground truth" for normality was based on this statistical analysis of healthy individuals.
• Analytical Studies (Precision, Linearity, etc.): Ground truth for these was established by standard laboratory practices (e.g., using known concentrations of MPO, spiked samples, or reference materials) according to NCCLS guidelines. These studies aim to characterize the assay's performance against expected analytical values.

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