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HemosIL D-Dimer HS 500 is an automated latex enhanced immunoassay for the quantitative determination of D-Dimer in human citrated plasma on the ACL TOP® Family Systems for use, in conjunction with a clinical pretest probability (PTP) assessment model to exclude venous thromboembolism (VTE) in outpatients suspected of deep venous thrombosis (DVT) and pulmonary embolism (PE).

HemosIL D-Dimer HS 500 Controls are intended for the quality control of the D-Dimer HS 500 assay performed on the ACL TOP® Family Systems.

For in vitro diagnostic use.

HemosIL D-Dimer HS 500: The D-Dimer HS 500 Latex Reagent is a suspension of polystyrene latex particles of uniform size coated with the F(ab')2 fragment of a monoclonal antibody highly specific for the D-Dimer domain included in fibrin soluble derivatives. The use of the F(ab'), fragment allows a more specific D-Dimer detection avoiding the interference of some endogenous factors like the Rheumatoid Factor. When a plasma containing D-Dimer is mixed with the Latex Reagent and the Reaction Buffer included in the HemosIL D-Dimer HS 500 kit, the coated latex particles agglutinate. The degree of agglutination is directly proportional to the concentration of D-Dimer in the sample and is determined by measuring the decrease of transmitted light caused by the aggregates (turbidimetric immunoassay).

HemosIL D-Dimer HS 500 Controls: The Low and High D-Dimer HS 500 Controls are prepared by means of a dedicated process and contain different concentrations of partially purified D-Dimer obtained by digestion of Factor XIIIa cross-linked human fibrin with human plasmin.

Here's an analysis of the provided text, outlining the acceptance criteria and the study data that supports the device's performance, as requested:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the HemosIL D-Dimer HS 500 assay are primarily focused on its sensitivity and negative predictive value (NPV) for excluding Venous Thromboembolism (VTE) in outpatients suspected of Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE), when used in conjunction with a clinical pretest probability (PTP) assessment model. The reported performance from the outcome study and multi-center management study directly addresses these criteria.

Study Proving Device Meets Acceptance Criteria:

The device's ability to meet the acceptance criteria is demonstrated through two primary clinical studies and supporting analytical studies:

• "Outcome Study" (Section 2, paragraph 3)
• "Multi-center Management Study" (Section 3, paragraph 1)
• "Precision" study (Section 2, paragraph 1)
• "Method Comparison" study (Section 2, paragraph 2)

These studies collectively show that the HemosIL D-Dimer HS 500, with a clinical cut-off of 500 ng/mL, consistently achieved 100% sensitivity and 100% negative predictive value for both DVT and PE in the studied outpatient populations when used in conjunction with a PTP assessment. This indicates that no VTE events were missed by the test, effectively "excluding" the condition when the D-Dimer result was negative. The precision and method comparison studies demonstrate the analytical reliability and equivalence to existing commercial methods.

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

Due to the nature of this in-vitro diagnostic device (IVD), there isn't a traditional "test set" in the sense of a medical imaging AI algorithm. Instead, there are clinical samples used in performance evaluations.

• Outcome Study (Clinical Performance):

  • Sample Size: 295 frozen samples.
  • Data Provenance: Patients admitted consecutively to an emergency unit with suspected PE or DVT. The country of origin is not explicitly stated but implies a clinical setting. The samples are retrospective as they were "frozen samples" from past admissions.

• Multi-center Management Study (Clinical Performance):

  • Sample Size: 747 samples (401 suspected DVT, 346 suspected PE).
  • Data Provenance: Patients admitted consecutively to the emergency unit with suspected DVT or PE at four hospitals. The country of origin is not explicitly stated. This appears to be a prospective study because it describes patient management pathways and follow-up, indicating data collected as patients were presented.

• Precision and Method Comparison Studies: These appear to be in-house laboratory studies using controls, plasma pools, and patient samples (n=100 for method comparison). Further specifics on provenance are not detailed.

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

The concept of "experts" establishing ground truth in this context is different from image-based AI where radiologists annotate images. Here, the ground truth for VTE (DVT and PE) status was established through "standard objective tests" and clinical follow-up, not by a panel of human reviewers interpreting the D-Dimer test itself.

• Outcome Study: VTE positive cases (75 samples) were confirmed by "standard objective tests." VTE negative cases (220 samples) were also confirmed. The specific tests (e.g., ultrasound, CT angiography) are not detailed, nor are the number or qualifications of the clinicians/technicians who performed or interpreted these objective tests.

• Multi-center Management Study: VTE status for DVT and PE was confirmed through a combination of imaging techniques (for positive D-Dimer or high PTP patients) and importantly, 3-month clinical follow-up for patients with negative D-Dimer and low/moderate PTP. Again, the number and specific qualifications of the clinicians involved in these diagnostic methods or follow-ups are not specified.

4. Adjudication Method for the Test Set

Not applicable in the conventional sense of human reviewers adjudicating results. The "adjudication" of definitive VTE status relied on a combination of objective diagnostic tests and clinical follow-up, which are the accepted standards for determining the presence or absence of DVT/PE. The clinical pretest probability (PTP) assessment using the Wells model served as an initial clinical judgment tool, guiding further diagnostic pathways, but the ultimate ground truth was based on objective methods and patient outcomes.

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 as described for AI assistance. This device is an in-vitro diagnostic (IVD) assay, a lab test intended to provide quantitative results directly, not to assist human readers in interpreting complex images or data in the same way an AI algorithm might augment a radiologist. The study evaluates the assay's performance in a clinical pathway, not 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, the performance data presented is for the standalone performance of the HemosIL D-Dimer HS 500 assay, specifically the quantitative determination of D-Dimer. The "human-in-the-loop" aspect here refers to the physician integrating the D-Dimer result with the clinical pretest probability (PTP) assessment model. The device itself (the assay) provides a direct quantitative reading (e.g., 500 ng/mL) without human interpretation to arrive at that numerical value. The clinical utility is then determined by how this standalone result integrates into a diagnostic algorithm. The sensitivity and NPV reported are based on the assay's output.

7. The Type of Ground Truth Used

The ground truth used for the clinical studies (Outcome Study and Multi-center Management Study) was primarily:

• Objective Diagnostic Tests: For confirmed VTE cases (DVT and PE), standard objective tests (e.g., imaging techniques like ultrasound for DVT, CT angiography for PE) were used. These are considered highly definitive.
• Outcomes Data (Clinical Follow-up): Crucially, for patients with negative D-Dimer and low/moderate PTP, the absence of VTE was confirmed by 3-month clinical follow-up where the development of DVT or PE was monitored. This represents outcomes data as ground truth, which is a very strong form of evidence for exclusion criteria.

8. The Sample Size for the Training Set

The provided summary does not explicitly mention a "training set" in the context of machine learning. This is an in-vitro diagnostic device, which is typically developed through analytical validation (reagent formulation, calibration, interference studies) and clinical validation.

• The "Method Comparison" study (n=100) could be considered part of the validation data used to refine or confirm equivalence, but it's not a training set for an algorithm in the AI sense.
• The "Precision" study uses controls and a plasma pool, which are analytical samples for assessing assay performance, not a training set.

If earlier development involved optimizing the assay's parameters (e.g., antibody concentration, reaction conditions), that would have used various experimental samples, but a defined "training set" like in AI is not applicable here.

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

As there isn't a "training set" in the AI sense for this IVD, this question is not directly applicable. For analytical development and validation, the "ground truth" would be established through:

• Defined D-Dimer concentrations: For calibrators and controls used in precision studies.
• Comparison to established reference methods: For method comparison, the predicate device (VIDAS D-Dimer Exclusion Assay) served as the reference for comparison. The ground truth for the samples tested would be their D-Dimer concentration as determined by the predicate device.

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