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HemosIL CL HIT-IgG(PF4-H) is a qualitative, fully automated, chemiluminescent immunoassay (CIA) for the detection of IgG antibodies that react with Platelet Factor 4 (PF4) when complexed to heparin. The assay is for use in human 3.2% citrated plasma on the ACL TOP 970 CL in a laboratory setting.

The result provided by the assay should be interpreted as either positive or negative based on the assay cut-off (1.00 U/mL). The positive or negative result aids in determining the risk for heparin induced thrombocytopenia (HIT) when used in conjunction with other laboratory and clinical findings.

Anti-PF4/Heparin antibodies are commonly found in patients with HIT. For use in adult population suspected of HIT. Not for use in isolation to exclude HIT.

For prescription use only.

HemosIL CL HIT-IgG(PF4-H) assay is a chemiluminescent two-step immunoassay consisting of magnetic particles coated with PF4 complexed to polyvinyl sulfonate (PVS) which capture, if present, PF4/H antibodies from the sample. After incubation, magnetic separation, and a wash step, a tracer consisting of an isoluminol-labeled anti-human IgG antibody is added and may bind with the captured PF4/H IgG on the particles. After a second incubation, magnetic separation, and a wash step, reagents that trigger the luminescent reaction are added, and the emitted light is measured as relative light units (RLUs) by the ACL TOP 970 CL optical system. The RLUs are directly proportional to the PF4/H IgG concentration in the sample.

The HemosIL CL HIT-IgG(PF4-H) assay utilizes a 4 Parameter Logistic Curve fit (4PLC) data reduction method to generate a Master Curve. The Master Curve is predefined and lot dependent and it is stored in the instrument through the cartridge barcode. With the measurement of calibrators, the predefined Master Curve is transformed to a new, instrument specific 4PLC Working Curve. The concentration values of the calibrators are included in the reagent kit calibrator value sheet 2D barcode.

Here's a breakdown of the acceptance criteria and study information for the HemosIL CL HIT-IgG(PF4-H) device, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Precision Study: 5 plasma samples and 2 levels of controls. Tested over 20 days.
• Reproducibility Study: 6 plasma samples. Tested across 3 external sites, twice per day over 5 days with 3 replicates.
• Analytical Sensitivity (LoD): Not explicitly stated, but assessed using "three different lots" of reagent cartridges.
• Analytical Specificity: Not explicitly stated, but involved testing with various interfering substances and 24 citrated plasma samples from APS patients.
• Normal Reference Range Study: 132 Heparin-Exposed, Non-HIT Suspected Patients and 122 Healthy Donors.
• Cut-Off Validation Study (vs. SRA): 91 citrated plasma samples (45 SRA positive, 46 SRA negative).
• Method Comparison Study (vs. Predicate): 341 samples from HIT-suspected patients.

Data Provenance: The document does not explicitly state the country of origin for the patient data. It is implied to be retrospective as the samples were "from HIT-suspected patients" or "patients diagnosed with Antiphospholipid Syndrome (APS)", suggesting they were pre-collected. The reproducibility study explicitly states it was done at "3 external" sites.

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

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

• For the Cut-Off Validation Study, Serotonin Release Assay (SRA) results were used as the reference standard, indicating a highly specialized laboratory assay.
• For the Method Comparison Study, the predicate device (HemosIL AcuStar HIT-IgG(PF4-H)) served as the reference standard.
• For the Normal Reference Range Study, patient classification as "Heparin Exposed, Non-HIT Suspected Patients" or "Healthy Donors" implies a clinical determination, but no expert involvement is specifically detailed.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication method (e.g., 2+1, 3+1) for the test set or for establishing ground truth. The SRA and predicate device results appear to be taken as the reference.

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 device is an in-vitro diagnostic (IVD) immunoassay, not an imaging or software device that would typically involve human readers. The study focuses on the analytical and clinical performance of the assay itself.

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 HemosIL CL HIT-IgG(PF4-H) assay. The device is a "fully automated, chemiluminescent immunoassay (CIA)" and the performance data reflects its direct measurement capabilities on an ACL TOP 970 CL instrument without explicit human-in-the-loop interpretation beyond standard laboratory procedures for running the assay and reporting results. The device provides a qualitative positive or negative result based on a cut-off.

7. The Type of Ground Truth Used

The types of ground truth used include:

• Serotonin Release Assay (SRA): For the cut-off validation study, which is considered a gold standard for HIT diagnosis.
• Predicate Device Results (HemosIL AcuStar HIT-IgG(PF4-H)): For the method comparison study, establishing equivalence to a previously cleared device.
• Clinical Diagnosis/Patient Classification: For the normal reference range study (e.g., "Heparin Exposed, Non-HIT Suspected Patients" and "Healthy Donors") and sample collection for methodology studies (e.g., "HIT-suspected patients", "patients diagnosed with Antiphospholipid Syndrome (APS)").

8. The Sample Size for the Training Set

The document does not explicitly describe a separate "training set" for the device. As an IVD immunoassay, the development process typically involves internal optimization and validation studies, but these are not usually structured as a distinct "training set" in the same way as machine learning algorithms. The mentioned studies are primarily for performance validation and substantial equivalence claims. A "Master Curve" is generated for the assay, which is "predefined and lot dependent" and stored in the instrument, indicating calibration and internal standardization but not a "training set" in the common sense for AI/ML.

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

Since an explicit "training set" in the context of AI/ML is not described, the method for establishing its ground truth is not applicable. The "Master Curve" concept implies calibration and validation using known standards and controls, which are part of the assay's design and manufacturing process.

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ACL TOP 970 CL: The ACL TOP 970 CL is a bench top, fully automated, random access analyzer designed specifically for in vitro diagnostic use by health care professionals in a clinical laboratory. The system provides results for both direct measurements and calculated parameters.
HemosIL CL Anti-Cardiolipin IgM: HemosIL CL Anti-Cardiolipin IgM is a fully automated chemiluminescent immunoassay for the semi-quantitative measurement of anti-cardiolipin (aCL) IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACL TOP 970 CL in the laboratory setting by a healthcare professional, as an aid in the diagnosis of Antiphospholipid Syndrome (APS) when used in conjunction with other laboratory and clinical findings. For use with adult population. For prescription use only.
HemosIL CL Anti-ß2 Glycoprotein-I IgM: HemosIL CL Anti-B2 Glycoprotein-I IgM is a fully automated chemiluminescent immunoassay for the semi-quantitative measurement of anti-B2 Glycoprotein-I (anti-B2GPI) IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACL TOP 970 CL in the laboratory setting by a healthcare professional, as an aid in the diagnosis of Antiphospholipid Syndrome (APS) when used in conjunction with other laboratory and clinical findings. For use with adult population. For prescription use only.

ACL TOP 970 CL Instrument: The ACL TOP 970 CL is an instrument that integrates new chemiluminescent test capability similar to the ACL AcuStar, K083518.
HemosIL CL Anti-Cardiolipin IgM: HemosIL CL Anti-Cardiolipin IgM is a chemiluminescent two-step immunoassay consisting of magnetic particles coated with cardiolipin and human purified ß2GPI, which capture, if present, the aCL antibodies from the sample. After incubation, magnetic separation, and a wash step, a tracer consisting of an isoluminol-labeled anti-human IgM antibody is added and may bind with the captured aCL IgM on the particles. After a second incubation, magnetic separation, and wash step, reagents that trigger the luminescent reaction are added, and the emitted light is measured as relative light units (RLU) by the ACL TOP 970 CL optical system. RLUs are directly proportional to the aCL IgM concentration in the sample.
HemosIL CL Anti-ß2 Glycoprotein-I IgM: HemosIL CL Anti-ß2 Glycoprotein-I IgM is a chemiluminescent two-step immunoassay consisting of magnetic particles coated with human purified ß2GPI, which capture, if present, the aß2GPI antibodies from the sample. After incubation, magnetic separation, and a wash step, a tracer consisting of an isoluminol-labeled anti-human IgM antibody is added and may bind with the captured aß2GPI IgM on the particles. After a second incubation, magnetic separation, and wash step, reagents that trigger the luminescent reaction are added, and the emitted light is measured as relative light units (RLUs) by the ACL TOP 970 CL optical system. RLUs are directly proportional to the aß2GPI IgM concentration in the sample.

The provided text describes the 510(k) summary for the ACL TOP 970 CL instrument and two associated immunoassays, HemosIL CL Anti-Cardiolipin IgM and HemosIL CL Anti-β2 Glycoprotein-I IgM. The studies presented focus on analytical performance and comparability to predicate devices, rather than AI model performance or human-in-the-loop studies. Therefore, many of the requested elements pertaining to AI-driven diagnostic devices (such as expert adjudication, MRMC studies, or training set details for AI) are not applicable or cannot be extracted from this document.

However, I can extract information related to the acceptance criteria for the analytical performance of the assays and how that performance was demonstrated.

Here's a breakdown of the available information:

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria for these in vitro diagnostic devices are demonstrated through various analytical performance studies, focusing on precision, linearity, analytical sensitivity (LoD/LoQ), analytical specificity, and method comparison to predicate devices. The document does not explicitly state pre-defined acceptance thresholds for each parameter (e.g., minimum CV for precision, minimum slope for linearity). Instead, it presents the results of these studies, implying that the observed performance met internal or regulatory acceptance.

HemosIL CL Anti-Cardiolipin IgM

• Low Multi-Ab Control: 1.6%
• High Multi-Ab Control: 1.2%
• Plasma Samples A-E: 1.6% - 9.6% |
  | Reproducibility (Low CV across sites/runs)| Reproducibility (% CV):
• Low Multi-Ab Control: 7.0%
• High Multi-Ab Control: 7.4%
• Clinical Samples 1-4: 4.5% - 9.5% |
  | Analytical Sensitivity (LoD/LoQ) | LoD: 1.0 U/mL
  LoQ: 1.0 U/mL |
  | Linearity Range | 2.7 - 500.0 U/mL |
  | Analytical Specificity (No interference) | No interference for: Hemoglobin, Bilirubin, Triglycerides, Heparin (LMW/UF), Rheumatoid Factor, Acetylsalicylic acid, Atorvastatin, Warfarin, Prednisone, Acid Citric Dextrose, Hydroxychloroquine, Rituximab at specified concentrations. |
  | Method Comparison (Strong correlation to predicate) | Slope (95% CI): 1.00 (0.98 - 1.01)
  r: 1.00 |
  | Diagnostic Performance (Sensitivity/Specificity vs. APS Classification - provided for context, not a direct "acceptance criterion" in the same way as analytical measures) | Sensitivity: 40.5% (33.8% - 47.6%)
  Specificity: 91.9% (88.4% - 94.5%) |

HemosIL CL Anti-β2 Glycoprotein-I IgM

• Low Multi-Ab Control: 12.8%
• High Multi-Ab Control: 11.5%
• Plasma Samples A-E: 3.6% - 7.2% |
  | Reproducibility (Low CV across sites/runs)| Reproducibility (% CV):
• Low Multi-Ab Control: 8.3%
• High Multi-Ab Control: 7.7%
• Clinical Samples 1-4: 4.8% - 8.3% |
  | Analytical Sensitivity (LoD/LoQ) | LoD: 2.0 U/mL
  LoQ: 2.0 U/mL |
  | Linearity Range | 1.9 - 400.0 U/mL |
  | Analytical Specificity (No interference) | No interference for: Hemoglobin, Bilirubin, Triglycerides, Heparin (LMW/UF), Rheumatoid Factor, Acetylsalicylic acid, Atorvastatin, Warfarin, Prednisone, Acid Citric Dextrose, Hydroxychloroquine, Rituximab at specified concentrations. |
  | Method Comparison (Strong correlation to predicate) | Slope (95% CI): 0.94 (0.92 – 0.96)
  r: 0.99 |
  | Diagnostic Performance (Sensitivity/Specificity vs. APS Classification - provided for context, not a direct "acceptance criterion" in the same way as analytical measures) | Sensitivity: 33.0% (26.7% - 39.9%)
  Specificity: 94.6% (91.4% - 96.6%) |

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

• Precision Study (Test Set):
  • HemosIL CL Anti-Cardiolipin IgM & Anti-β2 Glycoprotein-I IgM: 5 plasma samples (3 positive, 2 negative) and 2 levels of controls. Each material was run in duplicate, twice per day over 20 days.
• Reproducibility Study (Test Set):
  • HemosIL CL Anti-Cardiolipin IgM & Anti-β2 Glycoprotein-I IgM: 4 plasma samples (3 positive, 1 negative for Anti-Cardiolipin IgM; 3 positive for Anti-β2 Glycoprotein-I IgM) and 2 levels of controls. Each material tested in triplicate, twice a day for 5 days, totaling 30 replicates per level.
• Analytical Sensitivity (LoD/LoQ):
  • Specific sample numbers for LoD/LoQ for new reagent lots are not detailed, but samples prepared by combining Ab-positive and normal donor plasma were used.
• Linearity:
  • For each assay, samples were prepared by diluting a high antibody plasma sample with a negative antibody plasma sample to create required concentrations. Each level was measured in seven replicates.
• Normal Reference Range:
  • 100 citrated plasma normal donor samples.
• Method Comparison:
  • HemosIL CL Anti-Cardiolipin IgM: N = 131 samples.
  • HemosIL CL Anti-β2 Glycoprotein-I IgM: N = 123 samples.
• APS Outcome Study (Diagnostic Performance):
  • HemosIL CL Anti-Cardiolipin IgM: N = 500 samples.
  • HemosIL CL Anti-β2 Glycoprotein-I IgM: N = 503 samples (indicated by the sum of Positive/Negative categories: 63+17+128+295=503).

Data Provenance: The document does not specify the country of origin for the data or whether the studies were retrospective or prospective, though typical clinical performance studies for diagnostic devices are usually prospective or utilize carefully curated samples. Reproducibility studies were conducted at "3 external sites."

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

This information is not provided. For these in vitro diagnostic immunoassays, the "ground truth" for the analytical performance studies (precision, linearity, etc.) is the quantitative measurement itself, validated against established laboratory methods or reference materials. For the "APS Outcome Study," the ground truth is "APS disease classification per 2006 International Consensus Statement from Miyakis et al." This classification is typically based on a combination of clinical and laboratory findings, interpreted by clinicians, but the specific number and qualifications of experts involved in this classification for the study samples are not detailed.

4. Adjudication Method (e.g., 2+1, 3+1, none) for the Test Set

Not applicable, as this is an in vitro diagnostic device measuring analyte concentrations, not an imaging AI relying on expert interpretations or adjudications. The diagnostic performance (sensitivity/specificity) is compared against pre-defined clinical classification criteria (Miyakis et al. 2006).

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 document describes an in vitro diagnostic device (immunoassay and analyzer), not an AI-driven imaging diagnostic device. There is no mention of human readers or AI assistance in diagnostic interpretation.

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

The performance data provided (precision, linearity, sensitivity, specificity, method comparison) is the standalone performance of the device (instrument + assay). The device provides a semi-quantitative measurement of antibodies, which then aids in diagnosis when used "in conjunction with other laboratory and clinical findings." There is no "human-in-the-loop" component in the assay's direct operation or result generation as described beyond the healthcare professional performing the test.

7. The Type of Ground Truth Used

• Analytical Studies (Precision, Linearity, LoD/LoQ, Specificity): The ground truth is inherent to the nature of these highly controlled analytical tests. For example, for linearity, serially diluted samples with known concentrations are used. For interference, samples spiked with known interferents are used.
• Method Comparison: The ground truth is established by the measurements obtained from the predicate (reference) devices: HemosIL AcuStar Anti-Cardiolipin IgM (K092181) and HemosIL AcuStar Anti-β2 Glycoprotein-I IgM (K091556) on the ACL AcuStar (K083518).
• Normal Reference Range: Established by testing 100 samples from "normal donors."
• APS Outcome Study: "APS disease classification per 2006 International Consensus Statement from Miyakis et al." This is a consensus-based clinical classification criteria.

8. The Sample Size for the Training Set

Not applicable, as this is not an AI/machine learning device that requires a distinct training set. The "development" of the assays would involve internal R&D, but not a "training set" in the context of AI.

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

Not applicable, as there is no training set mentioned for an AI model. For the development/validation of the immunoassay itself, the "ground truth" for calibrators and controls would be established through careful analytical procedures, often traceable to international standards or reference materials, under strict quality control.

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