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For the quantitative determination of cross-linked fibrin degradation products (D-dimers) in human plasma on Siemens Healthcare Diagnostics and Sysmex® Coagulation Systems. The INNOVANCE® D-Dimer assay is intended for use in conjunction with a non-high clinical pretest probability (PTP) assessment model to exclude deep vein thrombosis (DVT) and pulmonary embolism (PE).

Polystyrene particles covalently coated with a monoclonal antibody (8D3) are aggregated when mixed with samples containing D-dimer. The D-dimer crosslinkage region has a stereosymmetrical structure, i.e. the epitope for the monoclonal antibody occurs twice. Consequently, one antibody suffices in order to trigger an aggregation reaction, which is then detected turbidimetrically via the increase in turbidity.

Here's a breakdown of the acceptance criteria and study information for the INNOVANCE® D-Dimer assay:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct numerical targets in the provided text. However, the study aims to demonstrate that the device performs with sufficient sensitivity and Negative Predictive Value (NPV) to reliably exclude DVT, especially in patients with an unlikely pre-test probability. Based on the presented data, the implied acceptance criteria would be a sensitivity and NPV close to or at 100% for the intended use.

Study Proving Device Meets Acceptance Criteria:

The study referenced is a multi-center clinical evaluation evaluating the INNOVANCE® D-Dimer assay on the BCS® / BCS® XP System to exclude DVT.

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

• Sample Size for Test Set:
  • Total Patients: 455 consecutive patients initially enrolled.
  • Patients for Final Analysis: 426 patients (29 were excluded)
  • Patients with unlikely pre-test probability: 267 patients.
• Data Provenance: The study was a "multi-center study," suggesting data was collected from multiple clinical sites. The text doesn't explicitly state the country of origin, but the manufacturer is German, and the contact information is for the US. It is a prospective study as it involved "consecutive patients presenting to the emergency department" and follow-up for three months.

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

The text does not specify the number of experts used or their qualifications to establish the ground truth for the test set.

4. Adjudication Method for the Test Set

The text does not explicitly state an adjudication method for the test set. The diagnostic certainty (ground truth) appears to have been established through a combination of imaging methods (compression ultrasound and/or venography) for positive D-dimer results, and a three-month follow-up for negative D-dimer and negative imaging results. This implicitly suggests that the attending clinicians/radiologists' assessments, informed by these methods, served as the ground truth.

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

No, an MRMC comparative effectiveness study involving human readers with and without AI assistance was not done. This study focuses on the standalone performance of the D-dimer assay.

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

Yes, a standalone performance study was done. The results presented (Sensitivity, Specificity, NPV) are for the INNOVANCE® D-Dimer assay performed at a specific cutoff, independent of human interpretation of the D-dimer value itself, other than applying the PTP model. The assay's performance is then compared to the established ground truth of DVT.

7. The Type of Ground Truth Used

The ground truth used was a combination of:

• Imaging methods: Compression ultrasound and/or venography for patients with positive D-dimer results.
• Outcomes data: Three-month follow-up for patients with negative D-dimer results and those with negative imaging results, to evaluate for the potential development of DVT.

8. The Sample Size for the Training Set

The document does not specify a separate training set or its sample size. The study described appears to be a validation study of the device against clinical outcomes, rather than a development and training study for an algorithm. D-dimer assays traditionally involve established biochemical principles and cutoffs, rather than machine learning algorithms that require explicit training sets.

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

Since no explicit training set or machine learning algorithm development is described, the method for establishing ground truth for a training set is not applicable in this context. The 0.50 mg/L (FEU) cutoff is a pre-established clinical cutoff for D-dimer assays.

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For the quantitative determination of cross-linked fibrin degradation products (D-dimers) in human plasma on Siemens Healthcare Diagnostics and Sysmex® Coagulation Systems. The INNOVANCE® D-Dimer assay is intended for use in conjunction with a non-high clinical pretest probability (PTP) assessment model to exclude pulmonary embolism (PE) disease and as an aid in the diagnosis of venous thromboembolism (VTE) [deep vein thrombosis (DVT) or pulmonary embolism (PE)].

Polystyrene particles covalently coated with a monoclonal antibody (8D3) are aggreated when mixed with samples containing D-dimer. The D-dimer crosslinkage region has a stereosymmetrical structure, i.e. the epitope for the monoclonal antibody occurs twice. Consequently, one antibody suffices in order to trigger an aggregation reaction, which is then detected turbidimetrically via the increase in turbidity.

The INNOVANCE® D-Dimer assay was evaluated in a multicenter clinical study to validate its ability to assist in the exclusion of pulmonary embolism (PE).

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

1. Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state quantitative acceptance criteria in a dedicated section. However, the performance is reported as key metrics (Sensitivity, Specificity, and Negative Predictive Value) with 95% Confidence Limits (CL), which are typically compared against pre-defined thresholds for acceptance in clinical trials. Given the context of a 510(k) submission for exclusion of PE, a high Negative Predictive Value (NPV) is crucial.

Note: The "Acceptance Criteria (Implied)" column reflects the expected performance for a D-dimer assay used to exclude PE. A very high NPV is generally the primary focus for such an exclusion test.

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

• Sample Size:
  • Initial patients presenting: 701
  • Patients available for final analysis (test set): 647
• Data Provenance: The study was a multicenter study, suggesting data was collected from multiple clinical sites. It was a prospective study, as patients were "consecutive patients presenting to the emergency department with suspected PE." The country of origin is not explicitly stated, but the manufacturer is based in Germany and the contact information is in the US, indicating an international context or a US-based multicenter study.

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

This information is not explicitly stated in the provided text. The document mentions that "Patients with a positive D-dimer result and/or a high PTP were evaluated by imaging methods, e.g. spiral CT and/or VQ scan." It also states, "Patients with a negative D-dimer result and a low or moderate PTP (these patients underwent imaging at the physician's discretion), and patients with negative imaging results, were followed for three months to evaluate potential development of PE." This implies that the ultimate diagnosis of PE (the ground truth) was established through a combination of imaging, clinical follow-up for events, and physician assessment, but the number or specific qualifications of experts involved in reviewing these results are not detailed.

4. Adjudication Method for the Test Set:

The document does not explicitly describe an adjudication method for conflicting interpretations of imaging or follow-up results. The ground truth seems to be derived from a combination of recognized medical diagnostic procedures (imaging, follow-up) as performed by attending physicians, rather than a separate, blinded expert adjudication panel of the test results themselves.

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

This was not an MRMC comparative effectiveness study in the context of human readers vs. AI. The device is an in-vitro diagnostic (IVD) assay (D-dimer blood test), not an AI imaging or diagnostic algorithm designed to assist human readers. Therefore, this section is not applicable.

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

Yes, this was a standalone performance study of the INNOVANCE® D-Dimer assay. The study evaluated the direct output of the assay (D-dimer levels) in conjunction with clinical pretest probability (PTP) assessment, without explicit human-in-the-loop performance comparison for the assay itself. The physician's role was to use the assay's results as part of a diagnostic algorithm (along with PTP).

7. The Type of Ground Truth Used:

The ground truth for the presence or absence of PE was established through a combination of:

• Imaging methods: e.g., spiral CT and/or VQ scan for patients with positive D-dimer and/or high PTP, and for some patients with negative D-dimer and low/moderate PTP at physician's discretion.
• Outcomes data/Clinical Follow-up: Three-month follow-up for patients with negative D-dimer and low or moderate PTP (and those with negative imaging) to evaluate potential development of PE.

This is a robust method leveraging established clinical diagnostic pathways for PE.

8. The Sample Size for the Training Set:

The document does not provide information about a separate training set. This study describes the clinical validation of the INNOVANCE® D-Dimer assay, implying that the assay itself (and its cutoff values) were already developed and "trained" (if applicable to the assay's development process) prior to this multicenter clinical validation. IVD assays typically undergo extensive R&D and analytical validation before clinical studies like this for regulatory submission.

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

As no specific training set is detailed for this 510(k) submission, the method for establishing its ground truth is not provided.

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