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Immunoassay for the in vitro quantitative determination of cardiac troponin T (cTnT) in lithium heparin plasma. The immunoassay is intended to aid in the diagnosis of myocardial infarction.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The Elecsys Troponin T Gen 5 STAT Immunoassay is a one-step sandwich immunoassay on the cobas e 601 and cobas e 801 analyzer. The assay uses streptavidin-coated microparticles, a biotinylated monoclonal anti-cardiac Troponin T-specific antibody, a monoclonal anti-cardiac Troponin T-specific antibody labeled with a ruthenium complex and electrochemiluminescence detection. Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve (6-point calibration) provided with the reagent bar code.

Here's an analysis of the acceptance criteria and supporting study for the Elecsys Troponin T Gen 5 device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document primarily focuses on demonstrating substantial equivalence to a predicate device rather than explicitly stating individual acceptance criteria for each analytical performance metric. However, for some metrics, "predetermined acceptance criterion" is mentioned. I will extract those with stated criteria and their outcomes.

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

• Analytical Performance Studies (Precision, LoB, LoD, LoQ, Linearity, Interference, Cross-Reactivity):

  • Sample Types: Human Li-Heparin plasma samples (native, pooled, or spiked with recombinant Troponin T).
  • Provenance: Not explicitly stated for specific samples, but implied to be from internal or external sites where the tests were conducted (e.g., "one internal site," "three different sites (one internal and two external sites)"). These are typically retrospective samples used for method validation.
  • Sample Sizes (examples):
    • Precision (Repeatability/Intermediate): Six human samples (sample pools) for 21 days with two replicates/day (4 replicates total per day for 21 days). Total 6 samples * 4 replicates/day * 21 days = 504 measurements per sample material.
    • Precision (Reproducibility): Five human Li-Heparin plasma samples and two controls, measured five-fold for 5 days on three analyzers at three sites. Total 7 materials * 5 replicates * 5 days * 3 sites = 525 measurements across all sites.
    • LoB: One analyte-free Li-Heparin plasma sample, measured in ten-fold determinations in each of six runs over at least three days. Total 60 measurements.
    • LoD: Five low-analyte Li-Heparin plasma samples, measured in two-fold determination, six runs over at least three days. Total 60 determinations per reagent lot (so 180 for 3 lots).
    • LoQ: Ten native Li-Heparin plasma pools and two controls, collected over 21 days with two runs per day. Total 12 materials * 2 runs/day * 21 days = 504 runs, with variance components calculated from these.
    • Linearity: Three high analyte Li-Heparin plasma samples diluted with three low analyte samples to generate at least sixteen concentrations (15 dilutions). Assayed in 3-fold determinations within a single run.
    • HAMA/Endogenous Interference: Two samples with low cTnT spiked with HAMA (in duplicate); Three native Li-Heparin plasma samples (low, medium, high cTnT) for endogenous interferents (3-fold determination).
    • Cross-Reactivity: Three concentrations of troponin samples spiked with four different cross-reactants, tested in three-fold determination.
    • Exogenous Interference (Drugs): Native Li-Heparin plasma samples spiked with 17 common pharmaceutical compounds and 22 cardiac drugs (3-fold determination).

• Clinical Performance Studies (APACE Trial and second multicenter study):

  • APACE Trial:
    • N: 1074 subjects enrolled, 3023 available samples. 188 adjudicated diagnoses of MI.
    • Provenance: International, multicenter prospective trial.
  • Second Multicenter Study:
    • N: 1679 subjects presenting emergently with chest pain were enrolled. 173 adjudicated MIs. 1675 subjects evaluated on the cobas e 601 analyzer.
    • Provenance: Multicenter study (locations not specified, but typically clinical sites).

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

• APACE Trial: "Independent adjudication committee which included cardiologists."
• Second Multicenter Study: "Independent adjudication committee which included cardiologists and emergency medicine physicians."
• Qualifications: "Cardiologists" and "emergency medicine physicians" are the stated qualifications. Specific years of experience are not provided.

4. Adjudication Method for the Test Set

• APACE Trial: "In the case of a disagreement, a third independent cardiologist was used as the tie breaker." This describes a 2+1 or 3-way consensus adjudication method.
• Second Multicenter Study: "Final diagnoses were determined by an independent adjudication committee... using the universal guidelines." The specific tie-breaking method is not explicitly stated, but implies a consensus process.

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

• No, an MRMC comparative effectiveness study was not done. The document describes a method comparison study (comparing the candidate device to a predicate device) and clinical performance studies (diagnostic sensitivity/specificity of the device against a clinical ground truth).
• There is no mention of human readers' performance with and without AI assistance, nor is there an effect size for human improvement with AI. This is an in vitro diagnostic device, not a diagnostic imaging AI algorithm that would typically involve human reader studies.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance)

• Yes, this is a standalone performance study. The Elecsys Troponin T Gen 5 immunoassay is an in vitro diagnostic device that provides quantitative measurements of cardiac troponin T (cTnT). Its performance (analytical and clinical) is evaluated against established methods and clinical endpoints, independent of real-time human interpretation or intervention in the measurement process itself. The "human-in-the-loop" would be the clinician interpreting the result, but the device's measurement itself is standalone.

7. Type of Ground Truth Used

• Clinical Performance Studies (APACE Trial & second multicenter study):

  • Adjudicated Clinical Diagnosis of Myocardial Infarction (MI). This ground truth was established by an independent adjudication committee (cardiologists, sometimes with emergency medicine physicians) using established diagnostic criteria (e.g., ACC/ESC/AHA guidelines, including ECG changes, symptoms, and elevation of cardiac troponin). For the APACE trial, 60-day follow-up information was also used.

• Analytical Performance Studies:

  • For most analytical studies like precision, LoB, LoD, LoQ, linearity, and interference, the ground truth is often defined by:
    • Reference materials/standards: For calibration and standardization.
    • Known concentrations: For spiked samples and dilution series.
    • Analyte-free samples: For LoB determination.
    • Predicate device results: For method comparison studies. This isn't strictly "ground truth" but a reference for comparative equivalence.

8. Sample Size for the Training Set

• The document describes a measurement device (immunoassay), not an AI/ML algorithm that is "trained" in the conventional sense on a dataset. Therefore, there isn't a "training set" in the context of an AI algorithm learning from data.
• The device's calibration and standardization, however, rely on specific procedures:
  • Calibration Curve: Generated specifically on each instrument by a 2-point calibration and a master curve (6-point calibration) provided with the reagent bar code. This essentially "calibrates" the device to provide accurate quantitative results.
  • Standardization: Against Elecsys Troponin T STAT assay (4th generation), which in turn was standardized against the Enzymun-Test Troponin T (CARDIAC T) method. This refers to the traceable method of establishing the quantitative scale.

9. How the Ground Truth for the Training Set Was Established
As noted in point 8, this device does not utilize a "training set" in the context of AI/ML. Its operational "ground truth" or reference for quantitative measurement is established through:

• Known Calibrator Values: The master curve calibration relies on calibrators with accurately assigned values, which are traceable back to a primary reference method (Enzymun-Test Troponin T, and further through the 4th generation assay).
• Analytical Validation Studies: The various analytical studies (precision, linearity, LoB, LoD, LoQ) are validation steps to ensure the device accurately measures cTnT across its intended range, rather than a "training" phase. These studies confirm the device's ability to consistently provide results that align with expected or known values.

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Immunoassay for the in vitro quantitative determination of cardiac troponin T (cTnT) in lithium heparin plasma. The immunoassay is intended to aid in the diagnosis of myocardial infarction. The electrochemiluminescence immunoassay "ECLIA" is intended for use on the cobas system analyzers. CalSet Troponin T Gen 5 STAT is used for calibrating the quantitative Elecsys Troponin T Gen 5 STAT immunoassay on the cobas system analyzers. PreciControl Troponin is used for quality control of the Elecsys Troponin I and Elecsys Troponin I STAT immunoassays on the Elecsys and cobas e immunoassay analyzers. PreciControl Troponin is also used for quality control of the Elecsys Troponin T Gen 5 STAT immunoassay on the cobas system analyzers. The Elecsys Troponin T Gen 5 CalCheck 5 is an assayed control for use in the calibration verification and for use in the verification of the assay range established by the Elecsys Troponin T Gen 5 reagent on the cobas system analyzers.

(1) The Elecsys Troponin T Gen 5 STAT Immunoassay is a two-step sandwich immunoassay on the cobas e 411analyzer and a one-step process on the cobas e 601 analyzer. The assay uses streptavidin-coated.

This document describes the analytical and clinical performance of the Elecsys Troponin T Gen 5 STAT Assay and its associated calibrators and quality controls. It demonstrates the device's substantial equivalence to previously marketed devices.

Here's a breakdown of the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the "Results" sections showing that the device's performance metrics either

• met specific numerical targets (e.g., CV% for precision, ng/L for LoQ), or
• were within a defined percentage recovery or range (e.g., ±10% for interferences, 90-110% for control recovery, 80-120% for CalCheck recovery).

Here’s a table summarizing the performance based on the provided text, where acceptance criteria are explicitly stated or clearly implied by the successful results.

2. Sample Size for the Test Set and Data Provenance

• Analytical Performance Test Sets:

  • Precision:
    • Sample size: Multiple human plasma samples (5 distinct pools) and 2 PreciControl levels were tested. For each, measurements were done in single determinations in four separate aliquots (2 runs per day) for 21 operating days (n=84 replicates for each sample type).
    • Data Provenance: Not explicitly stated (e.g., country of origin). The studies appear to be laboratory-based analytical studies (retrospective in nature of samples, but prospective in terms of the testing design).
  • LoQ/Functional Sensitivity:
    • Sample size: Ten Li-Heparin plasma pools and two controls tested. Data collected with two lots over 21 days, two runs per day with two replicates per run. (Total 84 measurements for each sample).
    • Data Provenance: Not explicitly stated. Likely laboratory-based.
  • Linearity:
    • Sample size: One high analyte plasma sample (spiked with recombinant TnT) diluted to 21 concentrations (19 dilutions). Measured in three-fold determination within a single run.
    • Data Provenance: Not explicitly stated. Likely laboratory-based.
  • High Dose Hook Effect:
    • Sample size: Two samples spiked to high TnT concentrations, with dilution series.
    • Data Provenance: Not explicitly stated. Likely laboratory-based.
  • Endogenous Interferences:
    • Sample size: Three native or spiked plasma samples (one low, one medium, one high concentration of Troponin T) for each of 7 interfering substances. Dilution series tested.
    • Data Provenance: Not explicitly stated. Likely laboratory-based.
  • HAMA Interference:
    • Sample size: Samples with three different levels of TnT spiked with HAMA. Tested in duplicate.
    • Data Provenance: The HAMA serum used was tested in an "external laboratory".
  • Analytical Specificity/Cross Reactivity:
    • Sample size: Three concentrations of troponin spiked with potential cross-reacting compounds. Tested in duplicate.
    • Data Provenance: Not explicitly stated. Likely laboratory-based.
  • Exogenous Interference (Drugs):
    • Sample size: 16 common pharmaceutical compounds and 18 cardiac drugs spiked into plasma samples. Tested in 3-fold determination.
    • Data Provenance: Not explicitly stated. Likely laboratory-based.
  • Sample Stability:
    • Study 1 (2-8°C): Nine Li-Heparin Plasma samples.
    • Study 2 (-20°C): Ten Li-Heparin Plasma samples.
    • Data Provenance: Not explicitly stated. Likely laboratory-based.
  • Calibration Stability:
    • Onboard: Three plasma samples and two control levels. Each tested with two-fold determination.
    • Lot: Three human plasma samples and two control levels. Each tested with two-fold determination.
    • Data Provenance: Not explicitly stated. Likely laboratory-based.
  • Reagent Stability: Done in four studies (first opening, on-board, stress, shelf life) with specific testing protocols.
    • Data Provenance: Not explicitly stated. Likely laboratory-based.

• Clinical Performance (Diagnostic Sensitivity and Specificity) Test Sets:

  • APACE Population:
    • Sample Size:
      • Total enrolled: 718 subjects.
      • Baseline test result: 718 subjects.
      • Second test result (3 hour time point): 515 subjects.
      • Test result (6 hour time point): 310 subjects.
    • Data Provenance: International, multicentric prospective trial (APACE study, ClinicalTrials.gov number NCT00470587.6). Countries of origin are not specified beyond "international".
  • Second Multicenter Study:
    • Sample Size:
      • Total enrolled: 1679 subjects presenting with chest pain.
      • Evaluated on cobas e 411: 1679 subjects.
      • Evaluated on cobas e 601: 1675 subjects.
      • Adjudicated MIs: 173 subjects.
    • Data Provenance: Multicenter study. Countries of origin are not specified. Subjects were prospectively enrolled.

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

• Clinical Performance (APACE Population):
  • Number of Experts: An "independent adjudication committee" was used. The document specifies that this committee "included cardiologists" and, "In the case of a disagreement, a third independent cardiologist was used as the tie breaker." This implies at least two cardiologists for initial adjudication and a third for tie-breaking, so a minimum of 3 experts involved in ground truth establishment for each case.
  • Qualifications: "Cardiologists." No specific experience levels (e.g., "10 years of experience") are mentioned, but their specialization is stated.
• Clinical Performance (Second Multicenter Study):
  • Number of Experts: An "independent adjudication committee" was used, which "included cardiologists and emergency medicine physicians." Similar to APACE, it implies multiple experts, but the exact number or tie-breaking mechanism is not detailed as explicitly as for APACE.
  • Qualifications: "Cardiologists and emergency medicine physicians." No specific experience levels are mentioned.

4. Adjudication Method for the Test Set

• Clinical Performance (APACE Population): "Diagnosis of MI was done through an independent adjudication committee which included cardiologists. This included 60 day follow-up information on each subject. In the case of a disagreement, a third independent cardiologist was used as the tie breaker." This is a "2+1" or similar consensus-based adjudication method.
• Clinical Performance (Second Multicenter Study): "Final diagnoses were determined by an independent adjudication committee which included cardiologists and emergency medicine physicians using the universal guidelines." While an independent committee is stated, the specific "tie-breaker" or "consensus" method is not as explicitly detailed as for APACE. No indication of a lack of adjudication.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. The document focuses on the performance of the immunoassay itself, both analytically (precision, linearity, interference, etc.) and clinically (diagnostic sensitivity and specificity) in aid of myocardial infarction diagnosis. It does not describe a study comparing human readers with and without AI assistance or any other form of AI. This is a submission for an in vitro diagnostic (IVD) assay, not an AI/ML-driven diagnostic device.

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

This question is not directly applicable as the device is a laboratory immunoassay, which naturally performs "standalone" as an analytical instrument. The "performance" described is the standalone performance of the assay. There is no AI algorithm component mentioned or evaluated as a separate entity that would require a human-in-the-loop for its performance to be assessed.

7. The Type of Ground Truth Used

• Clinical Performance:
  • For both clinical studies (APACE and the second multicenter study), the ground truth for Myocardial Infarction (MI) diagnosis was established by an independent adjudication committee composed of medical experts (cardiologists and/or emergency medicine physicians). This adjudication was based on "diagnostic criteria described in the ACC/ESC/AHA guidelines reference including ECG changes, symptoms characteristic for ischemia and elevations of cardiac troponin," and "60 day follow-up information on each subject" for the APACE study. This falls under expert consensus guided by clinical outcomes data and established guidelines.
• Analytical Performance:
  • For analytical studies (precision, linearity, interference, stability, etc.), the ground truth relies on reference methods, spiked samples with known concentrations, or comparison to fresh/unstressed samples, which are standard practices for IVD assay validation.

8. The Sample Size for the Training Set

This information is not applicable/provided. This submission is for an in vitro diagnostic (IVD) assay, not a machine learning or AI model. Therefore, there is no "training set" in the context of an algorithm that learns from data. The studies described are validation studies for the assay's analytical and clinical performance.

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

This information is not applicable/provided for the same reason as above (no training set for an AI/ML algorithm).

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