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SynthAFax APTT Reagent is intended for the two-stage activated partial thromboplastin time (APTT) test, specific factor assays, APTT substitution test and monitoring heparin therapy.

Device Description

SynthAFax APTT Reagent is a liquid buffered reagent which contains a blend of synthetic phospholipids formed in liposomes, and a soluble plasma activator, ellagic acid, for optimal activation of the contact phase of coagulation. The use of synthetic phospholipids assures uniformity in the reagent and lot-to-lot consistency.

The activated partial thromboplastin time (APTT) test uses an activating agent and a phospholipid source and calcium to optimally activate the intrinsic pathway of coagulation. SynthAFax is incubated with an anticoagulated plasma sample for a standard period of time, known as the contact activation time (CAT). SynthAFax initiates the contact phase of coagulation through the activation of Factor XII. The addition of calcium chloride allows for the binding of other coagulation factors to the phospholipid and subsequent activation of the coagulation cascade. The generation of thrombin eventually cleaves fibrinogen and activates Factor XIII which crosslinks the fibrin molecules to form a visible clot. This occurs within a specified period of time.

If there is a coagulation factor deficiency in the intrinsic pathway, the time required for the formation of the clot will be prolonged beyond that expected for normal plasma. There will also be a prolongation of clotting caused by the presence of an inhibitor or the anticoagulant effect of heparin.

AI/ML Overview

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied to be "equivalence" or "acceptable correlation" when compared to the predicate device, Activated THROMBOFAX. The specific numerical targets are not explicitly stated as pre-defined criteria but are demonstrated by the results achieving high correlation coefficients and comparable precision/sensitivity.

Acceptance Criteria (Implied)	Reported Device Performance (SynthAFax APTT Reagent)
Precision: Comparable to predicate device across various instruments and control levels (Low %CV for replicates, run-to-run, and between-day).	TABLE 1: Precision Data. Replicate %CV ranged from 0.7-1.1%, Run to Run %CV from 0.6-1.3%, and Between Day %CV from 0.3-1.1% across all instruments and control levels. These values are highly comparable to those reported for Act. THROMBOFAX, which ranged from 0.4-1.2% for Replicate %CV, 0.6-1.4% for Run to Run %CV, and 0.5-1.2% for Between Day %CV. This demonstrates clear comparable precision.
Correlation with Predicate Device: Acceptable correlation (e.g., high correlation coefficient) for clotting times across normal and abnormal plasma samples.	Koagulab 60-S: Correlation coefficient = 0.951. Slope = 1.08 (indicating slightly more sensitivity). ELECTRA 1600C: Correlation coefficient = 0.945. Slope = 1.15 (indicating slightly more sensitivity). Both are described as "acceptable correlation." (See Figure 1 and 2 descriptions).
Factor Assay Standard Curve Responsiveness: Equivalent responsiveness and acceptable correlation (e.g., high correlation coefficient) for coagulation factors (VIII, IX, XI, XII).	Koagulab 60-S: Factor curve responsiveness was equivalent for Factors VIII, IX, XI, and XII compared to Activated THROMBOFAX. All standard curves had correlation coefficients of 0.986 or better. ELECTRA 1600C: Factor curves had correlation coefficients of 0.995 or better. This indicates excellent correlation and equivalent responsiveness.
In Vitro Heparin Sensitivity: Equivalent sensitivity to heparinized plasma samples, as indicated by comparable slopes of heparin response curves.	Koagulab 60-S: Slopes of heparin response curve were equivalent (SynthAFax: 113.9 vs. Activated THROMBOFAX: 119.0). Correlation coefficients: 0.995 (SynthAFax) and 0.997 (Activated THROMBOFAX). ELECTRA 1600C: Slopes were also equivalent (SynthAFax: 86.9 vs. Activated THROMBOFAX: 92.5). Correlation coefficients: 0.999 (SynthAFax) and 0.997 (Activated THROMBOFAX). This confirms equivalent sensitivity. (See Figure 2 description, page 6).

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

Precision Study:
- Sample Size: For each OPCC level (I, II, III), across four instruments and two reagents, there were:
  - Grand Mean: n=180 (presumably 30 runs x 3 replicates/run x 2 days, or similar, as other n values add up to 180 total measurements from precision data).
  - Replicate %CV: n=90
  - Run to Run %CV: n=30
  - Between Day %CV: n=5
  - The samples used were commercial control plasmas: ORTHO® Plasma Coagulation Control (OPCC) Level I (normal), II and III (abnormal).
- Data Provenance: The study was performed at Ortho Diagnostic Systems, Inc., Raritan, NJ, USA. It is prospective data collection for the controls.
Reagent Correlation Study:
- Sample Size:
  - 100 fresh normal donor plasma samples.
  - 79 frozen abnormal plasma samples (from 41 patients on heparin, 11 patients on oral anticoagulants, 3 patients with liver disease, and 24 lupus anticoagulant patients).
- Data Provenance: Not explicitly stated, but given the location of Ortho Diagnostic Systems, Inc. (Raritan, NJ), it is highly likely that these were collected in the USA. The samples were a mix of "fresh normal donor plasma samples" and "frozen abnormal plasma samples," suggesting a blend of prospective and retrospective collection, though this is not explicitly detailed.
Factor Assay Standard Curves:
- The sample size for generating these curves is not explicitly stated, but it involves dilutions of specific factor-deficient plasmas or calibrated factor activity levels.
In Vitro Heparin Sensitivity:
- Sample Size: A fresh normal plasma pool consisting of 10 normal donors was used. Dilutions were made to achieve 0 to 0.5 units/ml of heparin.
- Data Provenance: Not explicitly stated, but likely from the same location as the other studies (USA).

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

This type of study (comparative performance of an in-vitro diagnostic reagent) does not typically involve human experts establishing "ground truth" in the way an imaging AI study would. The "ground truth" here is the measurement obtained by the predicate device (Activated THROMBOFAX® Reagent-Optimized), which is an established method for APTT determination. There were no human experts classifying outputs that required adjudication.

4. Adjudication Method for the Test Set

Not applicable. This is a quantitative reagent comparison study, not a study involving human interpretation that would require adjudication. The performance is measured directly by clotting times and statistical correlation.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is relevant for imaging or diagnostic tasks where human readers interpret results, and the AI's impact on human performance is assessed. This submission concerns the analytical performance of an in-vitro diagnostic reagent.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance)

Yes, the studies conducted are standalone performance studies of the SynthAFax APTT Reagent. The reagent's performance is measured directly (e.g., clotting times, precision, correlation coefficients) and compared to the predicate device, or demonstrated through its own intrinsic capabilities (e.g., generating standard curves). There is no "human-in-the-loop" aspect to these performance evaluations as the device is for automated laboratory analysis.

7. Type of Ground Truth Used

The "ground truth" for this device's performance evaluation is primarily its concurrence and equivalence with a legally marketed predicate device (Activated THROMBOFAX® Reagent-Optimized), which has established analytical performance for APTT determination.

For precision, the ground truth is the inherent variability of the measurements themselves, evaluated against typical acceptable CVs for such assays and, more directly, against the predicate.
For correlation, the ground truth is the result obtained by the predicate device on the same samples.
For factor assays and heparin sensitivity, the "ground truth" is the known concentration or activity of the analytes (factors, heparin) in the prepared samples, and the comparison is again made against the responsiveness of the predicate device.

8. Sample Size for the Training Set

This submission does not discuss a "training set" in the context of machine learning. The device is a chemical reagent, not an AI/ML algorithm that requires training data. The "development" of the reagent would involve chemical formulation and optimization, not data-driven training.

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

Not applicable, as there is no "training set" in the machine learning sense for this device.

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