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The Sysmex® Automated Blood Coagulation Analyzer CS-2500 is a fully automated blood coagulation analyzer intended for in vitro diagnostic use using plasma collected from venous blood samples in 3.2% sodium citrate tubes to analyze clotting, chromogenic and immunoassay methods in the clinical laboratory. For determination of:

• . Prothrombin Time (PT) seconds and PT INR with Dade® Innovin®
• . Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL
• . Fibrinogen (Fbg) with Dade® Thrombin Reagent
• . Coagulation Factor V with Dade® Innovin®
• . Coagulation Factor VII with Dade® Innovin®
• . Coagulation Factor VIII with Dade® Actin® FSL
• . Coagulation Factor IX with Dade® Actin® FSL
• . Lupus Anticoagulant with LA1 Screening / LA2 Confirmation Reagent
• . Factor V Leiden with Factor V Leiden Assay
• . Protein C with Protein C Reagent
• . Antithrombin (AT) with INNOVANCE® Antithrombin
• Protein C with Berichrom® Protein C
• D-dimer with INNOVANCE® D-Dimer
  The performance of this device has not been established in neonate and pediatric patient populations.

Intended Use for Factor V Leiden Assay:
The Siemens Healthcare Diagnostics Factor V Leiden Assay is a simple functional clotting test system intended for screening of resistance to Activated Protein C (APC) in plasma from individuals with Factor V (Leiden) defect. For in vitro diagnostic use.

Intended Use for Coagulation Factor VIII Deficient Plasma:
In vitro diagnostic reagents for the determination of the activity of coagulation factor VIII, IX, XI and XII in human plasma by coagulation methods.

Intended Use for Coagulation Factor IX Deficient Plasma:
In vitro diagnostic reagents for the determination of the activity of coagulation factor VIII, IX, XI and XII in human plasma by coagulation methods.

Intended Use for LA1 Screening / LA2 Confirmation Reagents:
LA1 Screening Reagent / LA2 Confirmation Reagent are simplified DRVVT reagents for detection of Lupus Anticoagulants (LA) in one-stage clotting tests. LA1 Screening Reagent: Simplified DRVV reagent to the presence of Lupus Anticoagulants. LA2 Confirmation Reagent: Phospholipid-rich DRVV reagent for the specific correction of Lupus Anticoagulants.

The Sysmex® CS-2500 is an automated blood coagulation instrument which can analyze samples using clotting, chromogenic and immunoassay methods. Analysis results are displayed on the Information Processing Unit (IPU) screen. They can be printed on external printers or transmitted to a host computer. Sold separately from the instrument are the associated Reagents, Controls, Calibrators, and Consumable materials. The subject of this 510(k) notification are reagent applications which perform the coagulation tests Factor V Leiden with Factor V Leiden Assay, Coagulation Factor VIII with Dade® Actin FSL®, Coagulation Factor IX with Dade® Actin FSL®, Lupus Anticoagulant with LA 1 Screening Reagent / LA 2 Confirmation Reagent. The analysis principles used on the instrument are reflected by the reagent application testing provided in this 510(k) notification and is described in the below table. The instrument is capable of measuring in Normal mode and Micro-sample mode. Options and accessories include a waste tank and a 2D barcode reader.

The provided document describes the 510(k) premarket notification for the Sysmex® Automated Blood Coagulation Analyzer CS-2500. This is a medical device, and the "study that proves the device meets the acceptance criteria" refers to the performance data submitted to demonstrate substantial equivalence to a predicate device.

It's important to note that this document is for an In Vitro Diagnostic (IVD) device, not an AI/ML algorithm for image interpretation. Therefore, many of the typical acceptance criteria and study designs associated with AI/ML (like multi-reader multi-case studies, expert adjudication for ground truth of imaging, or effect size of AI assistance for human readers) do not directly apply in the same way. Instead, the study focuses on analytical performance characteristics compared to a predicate device.

Here's an interpretation based on the provided document:

Acceptance Criteria and Device Performance

The acceptance criteria for this type of IVD device are typically established based on:

1. Method Comparison: Showing agreement with a legally marketed predicate device. This is evaluated using statistical methods like Passing-Bablok regression and Bland-Altman plots. Acceptance criteria would involve a high correlation coefficient (r), and a slope close to 1 and intercept close to 0, indicating strong agreement.
2. Reproducibility (Precision): Demonstrating the consistency of results when the test is repeated under varying conditions (within-run, between-run, between-day, and total variability). Acceptance criteria are typically expressed as a maximum allowable coefficient of variation (%CV).
3. Detection Capability (Limit of Quantitation): Proving the lowest concentration of an analyte that can be reliably measured. Acceptance criteria are usually based on a predefined maximum total error.
4. Linearity & Measuring Range: Confirming that the device produces results proportional to the concentration of the analyte across its claimed analytical measuring range. Acceptance criteria mean the measured linear range must encompass the claimed clinically reportable range.
5. Reference Interval: Establishing the range of test results expected in a healthy population. Acceptance criteria would be the successful determination of these intervals or confirmation of existing ones.
6. Clinical Performance (e.g., Cut-off Study): For specific assays, validating clinical performance characteristics like diagnostic accuracy against a gold standard (e.g., genotype for Factor V Leiden). Acceptance criteria would typically involve achieving high positive and negative percentage agreement.

1. Table of Acceptance Criteria and the Reported Device Performance

The document does not explicitly list the "acceptance criteria" numerical targets. Instead, it states that "Results from each application met the predetermined acceptance criteria." and later, "All reagents met the predetermined acceptance criteria." This implies that Siemens had internal, pre-defined thresholds for these performance metrics, which were successfully met.

Based on the performance data presented, here is a summary table, inferring the intent behind the reported results as meeting acceptance:

2. Sample sizes used for the test set and the data provenance

• Method Comparison:
  • Sample Size (for each application): Varied by site and application, ranging from N=8 to N=173 for individual sites.
    • Factor V Leiden: Total N = 494 (Combined Sites)
    • Coagulation Factor VIII: Total N = 408 (Combined Sites)
    • Coagulation Factor IX: Total N = 459 (Combined Sites)
    • Lupus Anticoagulant (LA1, LA2, Ratio): Total N = 347-402 (Combined Sites)
  • Data Provenance: Conducted at four external sites; 3 in the United States and one in Germany. Samples were patient samples. Retrospective (implied by "patient samples collected," likely frozen/stored retrospectively as this is an analyzer validation, not a live clinical trial for patient outcomes).
• Reproducibility Studies:
  • Sample Size: Not explicitly stated as a number of distinct patient samples. The study design followed CLSI EP05-A2, which involves repetitive testing of control materials or pooled patient samples over multiple days/runs. "Twenty-day precision studies" were performed.
  • Data Provenance: One external site in Germany and two external sites in the United States.
• Detection Capability, Linearity & Measuring Range:
  • Sample Size: Not explicitly stated as a number of distinct patient samples. These studies typically use diluted samples or spiked samples to cover the analytical range.
  • Data Provenance: Not specified, but likely conducted at the same or similar labs as the other analytical performance studies.
• Reference Interval:
  • Sample Size: Between N=187 and N=193 samples per application.
  • Data Provenance: Three clinical study sites in the United States. Study population did not include neonate and pediatric patient populations.
• Factor V Leiden Cut-off Study:
  • Sample Size: N = 381 patients (combined from US and OUS sites), with N=127 patients from the US.
  • Data Provenance: Three different clinical sites (one site in the US and two sites in Germany). Samples were citrated plasma from patients submitted for thrombophilia screening, collected and then frozen.

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

Not applicable in the context of this IVD device. Ground truth for clinical assays is typically established by:

• Comparison to a legally marketed predicate device: As seen in the method comparison.
• Defined analytical standards: For precision, linearity, and detection limits.
• Clinical gold standard: For the Factor V Leiden cut-off study, genetic testing (Factor V Leiden PCR method) served as the "reference," which is an objective laboratory test, not expert interpretation.

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

Not applicable for an IVD device analytical performance study. Adjudication is relevant for subjective assessments, particularly in imaging or clinical endpoints. This study measures quantitative values from blood samples.

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

Not applicable. This is an IVD device (blood coagulation analyzer), not an AI imaging algorithm. There are no "human readers" interpreting images assisted by AI in this context.

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

Yes, in a way. The device (Sysmex® CS-2500) functions as a standalone instrument to measure coagulation parameters. The performance studies (method comparison, reproducibility, detection capability, linearity, reference interval) evaluate the device's output without direct human "interpretation" of raw signals for diagnosis, but rather human use of the device and its generated numerical reports. The "algorithm" here refers to the instrument's internal measurement and calculation procedures rather than a predictive AI model.

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

The "ground truth" or reference for this device's performance evaluation was primarily:

• Predicate Device: For method comparison (Sysmex® CA-1500). The predicate itself is a legally marketed device with established performance.
• Analytical Standards/Reference Materials: For studies like reproducibility, detection capability, and linearity.
• External Laboratory Test (PCR): For the Factor V Leiden study, the "Reference (Factor V Leiden PCR method)" served as the objective ground truth for the genetic variant.

8. The sample size for the training set

Not applicable. This document is for the validation of an IVD medical device (a physical instrument and associated reagents), not a machine learning model that requires a "training set" in the conventional sense. The "training" of such a device refers to its design, calibration, and internal programming by the manufacturer, which is distinct from data-driven machine learning.

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

Not applicable, as there is no "training set" in the context of an AI/ML model. The "ground truth" (or design specifications and analytical performance ranges) for such a device is established through comprehensive engineering, chemical, and biological research and development, following recognized industry standards (e.g., CLSI guidelines).

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