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INNOVANCE Antithrombin is a chromogenic assay for the automated quantitation of functionally active antithrombin in human citrated plasma and can be used as an aid in the diagnosis of antithrombin deficiency.

INNOVANCE Antithrombin is indicated as an aid in monitoring antithrombin activity to support QFITLIA (fitusiran) dosing in adult and pediatric patients aged 12 years and older with hemophilia A or B with or without factor VIII or IX inhibitors.

The INNOVANCE Antithrombin assay is suitable for the determination of physiologically active antithrombin on automatic analyzers and enables the diagnosis of inherited or acquired antithrombin deficiencies. The INNOVANCE Antithrombin assay utilizes a chromogenic measuring principle. An excess of human factor Xa is added to citrated plasma. In the presence of heparin, a portion of the enzyme is complexed and inactivated by the antithrombin present in the sample. Excess, uninhibited factor Xa then cleaves a specific chromogenic substrate, causing the release of a dye. The substrate cleavage is determined by the increase in the absorbance value at 405 nm. The release of dye is inversely proportional to the inhibiting activity of antithrombin in the plasma sample, i.e., the smaller the concentration of functionally active antithrombin, the higher the absorbance signal per time unit.

The provided text describes the analytical and clinical performance of the INNOVANCE Antithrombin assay, particularly in relation to guiding QFITLIA (fitusiran) dosing. It's important to note that this document is for an in vitro diagnostic (IVD) device (an assay), not a software-based AI/ML device that typically involves human readers and image analysis. Therefore, some of the requested information (like number of experts for ground truth, adjudication methods, MRMC studies, or training set details for an AI algorithm) are not directly applicable or found in this type of submission.

However, I will extract and infer the closest applicable information based on the provided text.

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

Acceptance Criteria and Reported Device Performance

For an IVD device like the INNOVANCE Antithrombin, acceptance criteria are typically related to analytical performance characteristics that demonstrate the assay's reliability and accuracy. The document highlights precision (repeatability/reproducibility), analytical specificity (interference), and detection capabilities (limit of quantitation).

• Triglycerides 211 mg/dL
• Hemoglobin 1000 mg/dL
• Bilirubin 60 mg/dL
  No interferences from therapeutics up to:
• Desmopressin: 0.0144 µg/mL
• Tranexamic Acid: 0.48 mg/mL
• Recombinant Factor VIIa: 2.16 µg/mL
• Coagulation Factor VIII: 0.96 IU/mL
• Coagulation Factor IX: 1.44 IU/mL
• Activated Prothrombin Complex Concentrate (aPCC): 2.4 IU/mL |
  | Detection Capabilities | Limit of Quantitation (LoQ) | LoQ was determined as 7.32% of norm. (Calculated based on a Total Error goal of not exceeding 4% of norm). |
  | Clinical Performance | Aid in monitoring AT activity for QFITLIA dosing to achieve target range | Clinical data from the ATLAS-OLE study demonstrated that individualized QFITLIA AT-DR using the INNOVANCE Antithrombin assay was successful at achieving AT levels within the targeted AT activity range of 15-35%. Median observed annualized bleeding rate (IQR) for treated bleeds was 3.7 (0.0; 7.5) overall, 1.9 (0.0; 5.6) in inhibitor patients and 3.8 (0.0; 11.2) in non-inhibitor patients. This supports its use for safe and effective dosing. |

Study Information

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

   • Analytical Performance Studies (Test Set):

     • Precision (Single Site): n=240 determinations (3 reagent lots, 20 days, 2 runs/day, 2 samples/run for 2 pathological plasma pools).
     • Reproducibility (Multi-Site): Each of the three internal study sites performed 5 runs per day with 3 replicates of each of the two pathological plasma pools per run (3x5x2x3). The total number of unique samples or determinations isn't given as a single 'n' for the entire reproducibility study, but it involves multiple runs and replicates across sites.
     • Analytical Specificity/Interference: Panel of exogenous substances tested on two plasma pools (low AT activity ~10-15% of norm, and high AT activity ~90% of norm). Specific 'n' values for samples tested per interferent are not given, but described as "paired-difference experiments".
     • Limit of Quantitation (LoQ): n=120 determinations (4 replicates of 5 patient samples, run once per day for 3 days using 2 reagent lots on one BCS XP System).
     • Data Provenance: The analytical studies were performed "internally at the Siemens company site in Germany (Site 1)" and "three (3) internal study sites (Sites 1, 2, and 3)". This implies prospective data collection for these specific validation studies. The clinical data used for drug dosing came from a multicenter clinical trial (ATLAS-OLE study).

   • Clinical Validation Data (Test Set for new indication):

     • QFITLIA ATLAS-OLE Study: A total of 227 patients were treated with QFITLIA. Of these, 213 patients were transitioned to an AT-DR (Antithrombin-based Dosing Regimen) with the target AT activity range of 15-35%. 199 patients started at the 50 mg dose every other month with dosing guided by INNOVANCE Antithrombin.
     • Data Provenance: This was a multicenter, open-label extension study (ATLAS-OLE, ClinicalTrials.gov Identifier NCT03754790). The text indicates AT activity was measured "at baseline (prior to QFITLIA initiation) as well as after QFITLIA exposure throughout the ATLAS-OLE study". This is prospective clinical trial data. The country of origin for the patient data is not explicitly stated but is typically international for large clinical trials.

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

   • This is an IVD assay clearance, not an AI/ML device in image analysis. Therefore, there are no "experts" in the sense of human readers interpreting clinical data for an algorithm's ground truth.
   • The "ground truth" for an IVD device's performance is typically established by:
     • Reference Methods: Highly accurate, established laboratory methods.
     • Clinical Outcomes/Patient Status: For the clinical validation, the "ground truth" is the patient's actual antithrombin activity level using the assay itself, and subsequently, the clinical outcomes related to bleeding rates and successful maintenance of AT levels within the therapeutic range under QFITLIA dosing. The QFITLIA clinical trial (ATLAS-OLE) provides this clinical outcome data.
   • The expertise lies in the chemists, biochemists, and clinical laboratory scientists who designed and ran the analytical validation studies, and the clinical investigators (e.g., hematologists) involved in the QFITLIA clinical trial who managed patient care and assessed clinical outcomes. Their qualifications are inherent to conducting such studies, but not explicitly detailed as "experts establishing ground truth" in the same way as for AI.

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

   • Not applicable for this type of IVD device. Adjudication methods like 2+1 (two readers agree, third resolves discrepancy) are common in AI/ML clinical validation studies involving human interpretation (e.g., radiology reads). For an assay, measurements are quantitative and discrepancies would be resolved through re-testing, calibration checks, or instrument troubleshooting, not human adjudication of a qualitative decision.

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:

   • Not applicable as this is an IVD assay, not an AI/ML device assisting human readers.

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

   • The core "performance" of this device is its analytical measurement. The "standalone" performance here refers to the assay's ability to accurately quantify antithrombin activity itself, which is what the analytical performance studies (precision, interference, LoQ) demonstrate. There isn't an "algorithm" in the typical AI sense; it's a chemical reaction and spectrophotometric measurement. The clinical validation then shows that this standalone measurement (AT activity) is useful in guiding QFITLIA dosing, which is "without human-in-the-loop performance" of the assay itself, though humans still perform the dosing decisions based on the assay output.

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

   • Analytical Ground Truth: For precision, the "ground truth" samples were "pathological plasma pools" with known/target mean AT activities. For interference, the "ground truth" for "no interference" was defined by comparing results with and without interferent, with acceptance based on a predefined allowable difference (e.g., within X% of the control). For LoQ, calibration standards and accepted statistical methods (CLSI document EP17-A2) were used to determine the lowest reliable measurable concentration.
   • Clinical Ground Truth: For the clinical validation, the "ground truth" for the device's utility in QFITLIA dosing was clinical outcomes data from the ATLAS-OLE study, specifically:
     • The ability to achieve and maintain AT activity levels within the target therapeutic range (15-35%).
     • The observed annualized bleeding rates in patients whose dosing was guided by the assay.

7. The sample size for the training set:

   • This is an IVD assay, not an AI/ML algorithm that requires a "training set" in the machine learning sense. The assay works based on established chemical principles, not on being trained on a dataset.
   • The closest analogy might be the samples used for initial assay development, calibration, and internal optimization, but these are not referred to as a "training set" in this context.

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

   • Not applicable, as there is no "training set" for this IVD assay in the AI/ML sense.

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CardioPhase hsCRP is an in-vitro diagnostic reagent for the quantitative determination of C-reactive protein (CRP) in human serum, and heparin and EDTA plasma by means of particle enhanced immunonephelometry using the BN II and BN ProSpec® System. In acute phase response, increased levels of a number of plasma proteins, including C-reactive protein, is observed. Measurement of CRP is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases. High sensitivity CRP (hsCRP) measurements may be used as an independent risk marker for the identification of individuals at risk for future cardiovascular disease. Measurements of hsCRP, when used in conjunction with traditional clinical laboratory evaluation of acute coronary syndromes, may be useful as an independent marker of prognosis for recurrent events, in patients with stable coronary disease or acute coronary syndromes.

The CardioPhase hsCRP assay is an in-vitro diagnostic reagent for the quantitative determination of Creactive protein (CRP) in human serum, and heparinized and EDTA plasma by means of particleenhanced immunoassay determination. The assay is traceable to the international standard ERM-DA474/IFCC. N Rheumatology Standard SL (cleared under K964527) is used for the establishment of reference curves for the immunonephelometric determination of C-reactive protein on the BN II and BN ProSpec® Systems. This calibrator consists of a mixture of human sera and elevated concentrations of CRP. The CardioPhase hsCRP reagent is a suspension of polystyrene (Latex) particles to which mouse monoclonal anti-human CRP antibodies (

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the method comparison study were that "Results from each lot of CardioPhase hsCRP met the predefined acceptance criteria." While the specific numerical acceptance criteria (e.g., maximum allowable bias) are not explicitly detailed in a table format within the provided text, the successful outcome is stated, and the resulting performance is presented as follows:

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

• Sample Size:
  • Lot 1: N = 119
  • Lot 2: N = 116
  • Lot 3: N = 113
  • The total number of samples used in the method comparison study is the sum of these, which is 348.
• Data Provenance: The study was conducted at the "company site in Marburg, Germany." The samples used were "Native serum samples." The text does not explicitly state whether the samples were retrospective or prospective, but the phrasing "Native serum samples were measured" suggests they were existing samples at the time of the study rather than collected specifically for this study.

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

This information is not provided in the text. The study describes a method comparison between two quantitative laboratory assays (CardioPhase hsCRP and RCRP Flex reagent cartridge). For this type of in-vitro diagnostic device, the "ground truth" is typically defined by the reference method or the predicate device's measurement, not by human expert consensus or adjudication in the way it might be for image-based diagnostic AI.

4. Adjudication Method for the Test Set

Not applicable for this type of in-vitro diagnostic device and study design. The comparison is quantitative between two analytical methods, not involving human interpretation requiring 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. This type of study is typically performed for image analysis or other diagnostic tools where human interpretation is a key component. The CardioPhase hsCRP is an in-vitro diagnostic reagent for quantitative measurement, which does not involve human readers in the same way.

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

Yes, the study described is a standalone performance study of the CardioPhase hsCRP assay compared to a predicate device. It evaluates the device's ability to quantitatively determine C-reactive protein concentrations independently. No human-in-the-loop component is mentioned for the performance evaluation itself.

7. The Type of Ground Truth Used

The "ground truth" for this method comparison study was established by the predicate device, RCRP Flex® reagent cartridge, which runs on the Dimension clinical chemistry system. Both the proposed device (CardioPhase hsCRP) and the predicate device are traceable to the international standard ERM-DA474/IFCC for C-reactive protein measurements. Therefore, the predicate device's measurements serve as the reference for comparison, and that reference itself is traceable to an international standard.

8. The Sample Size for the Training Set

The text does not specify a separate training set or its sample size. The described "method comparison study" is focused on verifying the performance of the device for regulatory submission, using a test set of samples. For in-vitro diagnostic devices, "training sets" are usually relevant for developing the assay itself (e.g., optimizing reagent concentrations, reaction conditions), but this information is not typically detailed in a 510(k) summary with respect to a "training set" of patient data for algorithm development.

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

As no specific "training set" of patient samples is described in the provided text in the context of algorithm development, this information is not applicable. The assay itself relies on a biochemical principle and calibration traceable to an international standard (ERM-DA474/IFCC), and the calibration is established using N Rheumatology Standard SL, which is traceable to Siemens internal Master Calibrator, which is in turn directly traceable to ERM-DA474/IFCC.

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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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The Sysmex® CS-5100 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
• Antithrombin (AT) with INNOVANCE® Antithrombin
• D-dimer with INNOVANCE® D-Dimer

The performance of this device has not been established in neonate and pediatric patient populations.

The Sysmex CS-5100 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 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; Antithrombin (AT) with INNOVANCE® Antithrombin; and D-dimer with INNOVANCE® D-Dimer.

Here's an analysis of the acceptance criteria and the studies performed for the Sysmex CS-5100 device, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria values for most of the performance metrics within the tables. Instead, it states that "Results from each application met the pre-established acceptance criteria" for method comparison, and "The data for all tested reagents met the pre-determined acceptance criteria" for detection capability. For linearity, it states "All reagents met the pre-determined acceptance criteria."

However, we can infer some implied criteria based on the reported values alongside statements of acceptance, especially for Method Comparison, Reproducibility, Detection Capability, and the D-Dimer PE Exclusion Study. For the D-Dimer study, specific lower bounds for 95% LCL are provided for sensitivity and NPV, which act as de facto acceptance criteria.

Inferred Acceptance Criteria and Reported Performance for Sysmex CS-5100:

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

• Method Comparison:

  • Sample Sizes:
    • PT (seconds): n=469 (combined from 3 sites: n=125, n=209, n=135)
    • PT (INR): n=465 (combined from 3 sites: n=122, n=208, n=135)
    • APTT: n=466 (combined from 3 sites: n=126, n=210, n=130)
    • Fibrinogen: n=368 (combined from 3 sites: n=145, n=91, n=132)
    • Antithrombin: n=381 (combined from 3 sites: n=135, n=120, n=126)
    • D-dimer: n=361 (combined from 3 sites: n=137, n=108, n=116)
  • Data Provenance: Conducted at three external sites in the United States (US). The samples were patient samples.

• Reproducibility Studies:

  • Sample Sizes: Not explicitly stated as 'n=' count for each sample tested, but refers to "Sample Range (mean of all sites)" for each application. These studies involved "two runs per day, with two replicates per run, at each of the three sites". Given the "20-day precision studies", this implies a significant number of measurements for each sample type.
  • Data Provenance: Two external sites in Germany and one external site in the United States.

• Detection Capability Studies:

  • Sample Sizes: Not explicitly stated, but performed for specific reagents: Fibrinogen, Antithrombin, and D-dimer.
  • Data Provenance: Not explicitly stated, but typically in vitro studies.

• Linearity & Measuring Range Studies:

  • Sample Sizes: Not explicitly stated, but performed for Fibrinogen, Antithrombin, and D-dimer.
  • Data Provenance: Not explicitly stated, but typically in vitro studies.

• Reference Interval Studies:

  • Sample Sizes: Not explicitly stated as a number, but indicates the study population "did not include neonate and pediatric sample populations".
  • Data Provenance: Conducted at three clinical study sites in the United States.

• D-Dimer PE Exclusion Validation Study:

  • Initial Patients: 1930 consecutive outpatients.
  • Excluded Patients: 96.
  • Patients for Final Analysis: n=1467 (US: n=1424, OUS: n=43).
  • Data Provenance: Multi-center study using frozen specimens collected prospectively from outpatients presenting to emergency or ambulatory departments with suspected PE. Data from both the US and "OUS" (Outside US, specifically European population for prevalence) were included.

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

• For Method Comparison, Reproducibility, Detection Capability, Linearity, and Reference Intervals: The ground truth for these analytical performance studies is established by the methods themselves, often comparing the device to a reference method or evaluating inherent precision characteristics against statistical benchmarks. No human experts are described for establishing ground truth in these sections.

• For D-Dimer PE Exclusion Validation Study:

  • Ground Truth Establishment: The ground truth for PE diagnosis was established through imaging methods (e.g., spiral CT and/or VO scan) and 3-month follow-up for patients with initial negative diagnosis.
  • Number/Qualifications of Experts: The document mentions "physician's discretion" for imaging and that "All potentially eligible patients were evaluated using the Wells' rules...". This implies that medical professionals (e.g., emergency physicians, radiologists, other clinicians) were involved in the diagnosis and follow-up, but the specific number and detailed qualifications of these individual experts are not provided.

4. Adjudication Method for the Test Set

• For Method Comparison, Reproducibility, Detection Capability, Linearity, and Reference Intervals: No adjudication method as typically understood for human interpretation of data (e.g., 2+1 rule) is described. These are analytical performance studies where results are quantitative values compared against other instruments or statistical metrics.

• For D-Dimer PE Exclusion Validation Study: The ground truth involved a combination of imaging and 3-month follow-up. While a final diagnosis would likely involve a consensus among the treating clinicians or specialists (e.g., radiologists, internists), no explicit "adjudication method" (like multiple readers reaching a consensus on an image) is described for the final PE diagnosis. The process relies on standard clinical diagnostic pathways and follow-up.

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, an MRMC comparative effectiveness study involving human readers with/without AI assistance was not done. The Sysmex CS-5100 is an automated blood coagulation analyzer, not an AI-powered diagnostic imaging tool that assists human readers. The studies focus on the analytical performance of the instrument itself and its diagnostic utility (e.g., D-dimer for PE exclusion).

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 device (or algorithm if you consider the reagent-instrument combination an 'algorithm') in an automated setting. The device operates automatically, and the performance data (method comparison, reproducibility, detection capability, linearity, D-dimer PE exclusion) reflect its direct analytical output without direct human interpretation influencing the measurement itself at the point of testing. Human input is involved in sample collection, entering patient data, and clinical interpretation of the results, but not in the "reading" of the output in a way that an AI for image analysis would be 'standalone'.

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

• For Method Comparison: The ground truth is the result from the predicate device (Sysmex CA-1500), which is a legally marketed device for the same intended use.
• For D-Dimer PE Exclusion Validation Study: The ground truth for the presence or absence of PE was based on a combination of imaging methods (e.g., spiral CT and/or VO scan) and 3-month clinical outcomes data (follow-up) to confirm the absence of PE in initially negative cases.

8. The sample size for the training set

The document describes premarket notification for a medical device (instrument), not an AI/ML algorithm that typically requires a distinct training set for model development and a test set for performance evaluation. For this type of device, the "training" analogous to an AI model would be the internal development and calibration of the instrument by the manufacturer using their own data, which is not typically detailed in a 510(k) summary in terms of "training set sample size." The studies presented are all performance validations of the final device. Therefore, a specific "training set sample size" is not applicable/provided in this context.

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

As there is no "training set" described in the context of an AI/ML algorithm development, this question is not applicable to this device submission. The device's internal calibration and development would have used reference materials and established laboratory methods, but these are not referred to as a "training set" with ground truth established in the same manner as for an AI model.

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