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Enzygnost F1+2 (monoclonal) is an enzyme immunoassay for the quantitative determination of human prothrombin F1+2 in plasma. Measurement of F1+2 is used as an aid in the diagnosis, monitoring, and evaluation of acquired or hereditary blood coagulation disorders. It is indicated as an aid in assessing risk of thrombosis and in monitoring efficacy of anticoagulant therapy.

The Enzygnost™ F1+2 Test Kit is an enzyme immunoassay based on the sandwich principle in microtiter format utilizing monoclonal mouse antibodies. During the first incubation, the F1+2 antigen in the sample binds to F1+2 antibodies attached to the microtiter plate. After washing, peroxidase-conjugated antibodies to human prothrombin are bound to a free F1+2 determinant in a second reaction. The excess enzyme-conjugated antibodies are removed by washing; the bound enzyme activity is then determined. The enzymatic reaction between hydrogen peroxide and chromogen is terminated by the addition of dilute sulfuric acid. The color intensity, which is proportional to the concentration of F1+2, is determined photometrically and quantified by means of a calibration curve based on the standards included in the kit.

Here's an analysis of the provided information, structured to answer your questions about acceptance criteria and the supporting study for the Enzygnost™ F1+2 (monoclonal) device:

1. Table of Acceptance Criteria and Reported Device Performance

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Thrombonostika F1.2 is an enzymed-linked immunosorbent assay for the quantitative determination of prothrombin activation fragment 1.2 (F1.2) in human plasma. It is indicated as an aid to both assess the risk of thrombosis and monitor the efficacy of anticoagulant therapy.

Thrombonostika F1.2 is a two-stage enzymed-linked immunosorbent assay for the prothrombin activation peptide F.12. The high specificity of the solid-phase anti-F1.2 monoclonal antibody allows quantitation of nanomolar F1.2 in the presence of micromolar prothrombin that is typically found in plasma. Rabbit polyclonal antibodies to the calcium-dependent conformer of prothrombin (i.e., the amino terminal region present on both prothrombin and F1.2 ) coupled to horseradish peroxidase (HRP) serves as the conjugate with tetramethylbenzidine (TMB) used as the substrate.

In the first stage, test sample or calibrator is incubated with a monoclonal F1.2-specific antibody (murine) coated on a microelisa well. F1.2 binds to the solid-phase antibody. Following an incubation, unbound proteins (including prothrombin) are aspirated and the well washed with buffer. In the second stage, conjugate (rabbit) labeled with HRP is added. The enzyme-labeled antibody is bound to the solid-phase F1.2 complex. Following a wash and incubation with TMB substrate, blue color is produced that turns yellow hen the reaction is stopped with stop solution. Within limits, the amount of prothrombin fragment 1.2 is proportional to the color development.

Here is a summary of the acceptance criteria and study information for the Thrombonostika F1.2 device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The provided document describes a modification to an existing device, Thrombonostika F1.2 (K911434). The study focuses on demonstrating substantial equivalence of the modified device to the original. Explicit, pre-defined quantitative "acceptance criteria" for each performance metric are not clearly stated in the document as separate, distinct criteria. Instead, the results themselves demonstrate that the modified device performs comparably to or within expected ranges of the original or ideal performance.

Therefore, the "acceptance criteria" are inferred from the demonstrated performance that leads to the conclusion of substantial equivalence.

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

• Comparison Data (without 0.25 nM calibrator vs. with 0.25 nM calibrator): 268 test results. Data provenance is not explicitly stated (e.g., country of origin) but is implied to be from laboratory testing to compare versions of the device. The nature (retrospective/prospective) is not specified.
• Comparison Data (51 fresh patient samples): 51 fresh patient samples. Data provenance is implied to be from actual patient samples, likely retrospective or a small prospective collection for this specific comparison.
• Accuracy: 16 plasma samples from 5 different donors. Data provenance is laboratory-controlled, using added (spiked) purified F1.2.
• Precision: "Multiple replicates" of Level I and Level II Controls on "multiple plates and occasions" for "three kit lots." Specific numbers of replicates are not given in the summary, but it implies extensive internal testing. Provenance is laboratory testing.

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

Not applicable. This is an in-vitro diagnostic (IVD) assay measuring a biomarker. The "ground truth" is established through the analytical measurement process itself using calibrators and controls, rather than expert interpretation of images or clinical cases.

4. Adjudication Method for the Test Set

Not applicable. As an IVD assay, adjudication by multiple experts is not relevant to establishing the ground truth for F1.2 concentration measurements. The assay itself provides a quantitative measurement.

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

No, an MRMC comparative effectiveness study was not performed. This type of study is relevant for diagnostic imaging or interpretation tasks where human readers are involved. This device is an in-vitro diagnostic assay.

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

Yes, the studies described are standalone performance evaluations of the assay itself. The Thrombonostika F1.2 is an ELISA kit, and its performance metrics (sensitivity, accuracy, precision, comparative analysis) measure the device's analytical capability independently. There is no human-in-the-loop component in the performance evaluation of the assay's output itself, although human operators perform the assay.

7. The Type of Ground Truth Used

The ground truth for this device's performance evaluation relies on:

• Quantifiable concentrations: Established by known values of calibrators and spiked samples with purified F1.2 (for accuracy).
• Reference measurements: Comparison to the performance of the original, legally marketed Thrombonostika F1.2 device (K911434) and analysis of fresh patient samples using both current and modified versions.
• Statistical analysis: Based on standard laboratory practices for determining analytical performance parameters like R², slope, intercept, sensitivity, and precision using replicates and controls.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of an algorithm or statistical model. For an ELISA kit, the development and optimization process (analogous to "training") would involve extensive internal testing to establish reagent concentrations, incubation times, wash steps, etc. However, specific sample sizes for such development phases are not detailed in this 510(k) summary. The presented data represents the validation (test) phase.

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

As noted above, there isn't a "training set" in the sense of a dataset used to train an AI algorithm. For an IVD, the "ground truth" during development (training analog) would be established through:

• Known concentrations of F1.2: Using highly purified F1.2 and calibrated standards.
• Reference methods: Comparing experimental results to established, validated methods for F1.2 measurement or related coagulation markers during development.
• Clinical correlation: Indirectly, by ensuring the assay provides values that align with expected physiological states (e.g., elevated in thrombotic risk groups, depressed in anticoagulated patients), although this is more for clinical utility than analytical ground truth for individual measurements.

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The ABS, Inc. TpP™ EIA is an enzyme linked immunoassay for the quantitative determination of soluble fibrin polymers in human plasma. It is indicated as an aid in assessing the risk of intravascular thrombosis and monitoring the efficacy of anticoagulant (heparin) therapy.

The TpP™ EIA employs a murine monoclonal antibody (MAb), specific for soluble fibrin polymer, as a capture antibody immobilized on a microtiter plate (MTP). This MAb recognizes a conformational epitope present only on the TpP™ entities but which is absent from fibrinogen and degradation products of fibrin and fibrinogen. During the first incubation phase TpP™ in human plasma specimens bind to the capture antibody. Afterwards the plate is rinsed, and a conjugate, another murine monoclonal antibody, labeled with horseradish peroxidase (HRP) is added to the well. This peroxidase conjugated MAb binds to a separate site on the TpP™ molecule during a second incubation period. Excess enzyme conjugated MAb is washed out and a subsequent application and incubation with tetramethylbenzidine (TMB) substrate follows. The reaction after TMB incubation is terminated with dilute sulfuric acid. The level of the TpP™ present in the specimen sample is determined colorimetrically from the enzymatic activity of detection MAb conjugate. The intensity of the color is proportional to the concentration of TpP™. Calibrator standard is provided with the kit.

Here's a breakdown of the acceptance criteria and study information for the ABS, Inc. TpP™ EIA, extracted and organized as requested:

Acceptance Criteria and Device Performance

• Within-Run CV: 1.50%
• Total Precision CV: 10.15%
  Sample B (7.91 µg/mL):
• Within-Run CV: 3.70%
• Total Precision CV: 10.80% |
  | Normal Range/Cutoff | Establishment of an effective cutoff value for risk assessment. | Best estimate cutoff: 6.65 µg/mL (determined by percentile evaluation) |
  | Correlation with F1.2 | Positive correlation with F1.2 following surgery. | Positive correlation of 0.58 (p=0.008) observed immediately following surgery. TpP™ levels remained elevated longer than F1.2. |
  | Monitoring Anticoagulant Efficacy | Ability to distinguish patients with inadequate anticoagulant therapy. | In 4 out of 25 PTCA patients with thrombotic complications, TpP™ values never returned to normal after heparinization. |
  | Substantial Equivalence | Substantially equivalent to Organon Teknika Corporation's immunochemical assay Thrombonostika F1.26 (K9911434). | Data and information demonstrate substantial equivalence to Thrombonostika F1.26. |

Study Details

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

   • Normal Range Determination:
     • Total Subjects: 140
     • Site #1: 115 healthy volunteers (Country of origin not specified, but the submission is from an American company, suggesting US)
     • Site #2: 8 healthy volunteers and 17 outpatients (Country of origin not specified, but the submission is from an American company, suggesting US)
     • Provenance: Retrospective/Cross-sectional for establishing normal range.
   • Clinical Study (Aortic Aneurysm):
     • Total Patients: 90
     • Location: Johns Hopkins Medical School, Baltimore, MD (USA)
     • Provenance: Prospective (patients recruited "who were undergoing procedures to repair aortic aneurysm").
   • Clinical Study (PTCA):
     • Total Patients: 25
     • Location: Philadelphia Heart Institute (USA)
     • Provenance: Prospective (patients "administered systemic heparin").
   • Interference Testing: Not specified as a patient population, but involved normal plasma samples, likely from the US.
   • Precision Testing: Two samples (A & B) tested with replicates across multiple runs, likely laboratory-prepared or pooled human plasma from the US.

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

   • The document does not specify the number or qualifications of experts used to establish the ground truth for the test sets.
   • For the normal range, the "best estimate of an effective cutoff value was determined to be 6.65 µg/mL by employing a percentile evaluation," implying a statistical method rather than individual expert consensus on specific cases.
   • For the clinical studies, ground truth for patient outcomes (e.g., thrombotic complications, post-surgical recovery, hypercoagulable state) would have been established by attending physicians/medical staff based on clinical presentation and other diagnostic tests, but no specific "experts" for ground truth adjudication are mentioned in the context of this device's evaluation.

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

   • No adjudication method (e.g., 2+1, 3+1) is mentioned or described for establishing ground truth for any of the test sets. Clinical outcomes likely served as the de facto "ground truth" for the efficacy studies.

4. 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 conducted or mentioned. This device is an in-vitro diagnostic (IVD) assay, not an AI-assisted diagnostic imaging or interpretation tool that would involve human "readers."

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

   • Yes, this is an IVD assay, which by nature operates in a standalone mode, providing a quantitative result without direct "human-in-the-loop" interpretation for each specific test result beyond the clinical application of the measured value (e.g., a physician interpreting the 6.65 µg/mL cutoff). The performance metrics (linearity, precision, interference, correlation) represent the standalone performance of the assay.

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

   • Normal Range: Statistical percentile evaluation of healthy individuals.
   • Aortic Aneurysm Study: Clinical outcomes (post-surgical changes, correlation with F1.2 levels, which is a recognized marker for fibrin formation).
   • PTCA Study: Clinical outcomes (occurrence of "serious thrombotic complications" and assessment of anticoagulant therapy efficacy based on these complications).
   • Interference, Linearity, Precision: Laboratory-derived ground truth based on spiking known concentrations/substances and standard reference methods.

7. The sample size for the training set:

   • Training Set (for Normal Range/Cutoff): 140 subjects (115 healthy volunteers, 8 healthy volunteers, 17 outpatients) were used for determining the effective cutoff value of 6.65 µg/mL. This can be considered the dataset used to "train" or establish the normal operating parameters and cutoff for the assay.
   • For the correlation and efficacy studies, these were essentially "validation" sets for the established operational characteristics.

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

   • For the normal range/cutoff determination, the ground truth was established by:
     • Identifying subjects as "healthy volunteers" or "outpatients" (implying a clinical assessment of their health status).
     • Performing the TpP™ EIA on their plasma samples.
     • Employing a "percentile evaluation" method to determine the statistical distribution of TpP™ levels in these populations and derive the "best estimate of an effective cutoff value" (6.65 µg/mL). This is a statistical, rather than case-by-case, ground truth establishment.

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