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The QUANTA Flash® ß2GP1-Domain1 is an in vitro chemiluminescent immunoassay (CIA) for the semi-quantitative determination of IgG autoantibodies to B2GP1-Domain1 in human serum or citrated plasma. The presence of anti-S2GP1-Domain1 autoantibodies is used in conjunction with clinical and other laboratory findings as an aid in the diagnosis of antiphospholipid syndrome. The QUANTA Flash® ß2GP1-Domain1 is not intended to replace assays for antibodies against the whole B2GP1 molecule. Testing for antibodies to the whole is required according to the classification criteria for antiphospholipid syndrome.

The QUANTA Flash® ß2GP1-Domain1 Controls are intended for quality control purposes of the QUANTA Flash® ß2GP1-Domain1 chemiluminescent immunoassay (CIA) kit.

The HemosIL® AcuStar Anti-S2GPI Domain 1 is an in vitro chemiluminescent immunoassay (CIA) for the semiquantitative determination of IgG autoantibodies to 82GPI Domain 1 in human serum or citrated plasma. The presence of anti-ß2GPI Domain 1 autoantibodies is used in conjunction with clinical and other laboratory findings as an aid in the diagnosis of antiphospholipid syndrome. The HemosIL® AcuStar Anti-S2GPI Domain 1 is not intended to replace assays for antibodies against the whole 82GPI molecule. Testing for antibodies to the whole 13GPI molecule is required according to the classification criteria for antiphospholipid syndrome.

The HemosIL AcuStar Anti-B2GPI Domain 1 Controls are intended for quality control purposes of the HemosIL AcuStar Anti-ß2GPI Domain 1 chemiluminescent immunoassay (CIA) kit.

Device Description

The QUANTA Flash® ß2GP1-Domain1 assay is designed to run on the BIO-FLASH® instrument. This platform is a fully automated closed system with continuous load and random access capabilities that automatically processes the samples, runs the assay and reports the results. It includes liquid handling hardware, luminometer and computer with software-user interface. The QUANTA Flash® ß2GP1-Domain1 assay utilizes a reagent cartridge format, which is compatible with the BIO-FLASH instrument.

The assays included in this submission, the QUANTA Flash ®2GP1-Domain1 marketed by Inova Diagnostics Inc. (9900 Old Grove Road, San Diego, CA 92131) and HemoslL "AcuStar Anti-ß2GPI Domain 1 marketed by Instrumentation Laboratory (180 Hartwell Road Bedford, MA 01730), are equivalent assays. Therefore all data stated hereafter and referred to as: QUANTA Flash ß2GP1-Domain1 data is equivalently also valid for HemosIL * AcuStar Anti-ß2GPI Domain 1.

Recombinant ß2GP1-Domain1 protein is coated onto paramagnetic beads, which are stored lyophilized in the reagent cartridge. The reagent pack is prepared for use in the BIO-FLASH system by pressing down on the grey lid of the reagent pack to pierce the induction seals on the reagent tubes. Once the seals are broken, the beads are rehydrated by adding the entire contents of the vial of resuspension buffer to the bead reagent tube using the transfer pipette supplied with the kit. Only the hole above the bead reagent tube is accessible at this point. The beads are then mixed with the resuspension buffer by pipetting up and down 30 times. This amount of mixing ensures complete resuspension of the beads. The label covering the remaining three reagent holes is now removed, and the reagent cartridge is then loaded onto the BIO-FLASH instrument. Samples are also loaded onto the instrument in sample racks. A patient serum sample is prediluted 1:10 by the BIO-FLASH with system rinse in a small disposable plastic cuvette. Small amounts of the diluted patient serum, the beads, and assay buffer are all combined into a second cuvette, and mixed. This cuvette is then incubated at 37°C. The beads are magnetized and washed several times. lsoluminol conjugated anti-human IgG antibodies are then added to the cuvette, and again incubated at 37°C. The beads are magnetized and washed repeatedly. The isoluminol conjugate is oxidized when Trigger 1 (Fe(III) coproporphyrin in sodium hydroxide solution) and Trigger 2 (urea-hydrogen peroxide in sodium chloride solution) are added to the cuvette, and the flash of light produced from this reaction is measured as Relative Light Units (RLU) by the BIO-FLASH optical system. The RLU are proportional to the amount of isoluminol conjugate that is bound to the human IgG, which is in turn proportional to the amount of anti- ß2GP1-Domain1 antibodies bound to the corresponding ß2GP1-Domain1 on the beads.

The QUANTA Flash® ß2GP1-Domain1 assay utilizes a predefined lot specific Master Curve that is uploaded onto the instrument through the reagent cartridge barcode. Every new lot number of reagent cartridge must be calibrated before first use, with the QUANTA Flash® ß2GP1-Domain1 Calibrators. Based on the results obtained with the two Calibrators included in the reagent kit, an instrument specific Working Curve is created, which is used to calculate chemiluminescent units (CU) from the instrument signal (RLU) obtained for each sample.

The QUANTA Flash® ß2GP1-Domain1 kit contains the following materials:

One (1) QUANTA Flash ß2GP1-Domain1 Reagent Cartridge, containing the following reagents for 50 determinations:

ß2GP1-Domain1 antigen coated paramagnetic beads in a suspension. a.
b. Assay Buffer – buffer containing protein stabilizers and preservatives.
C. Tracer IgG - Isoluminol labeled anti-human IgG antibodies in buffer, containing protein stabilizers and preservative.
d. Sample Diluent - buffer containing protein stabilizers and preservatives.
d. Resuspension Buffer - buffer containing protein stabilizers and preservatives.
e. QUANTA Flash ß2GP1-Domain1 Calibrator 1: One (1) barcode labeled tube containing 1.0 mL prediluted, ready to use reagent. Calibrators contain human antibodies to ß2GP1-Domain1 in stabilizers and preservatives.
f. QUANTA Flash ß2GP1-Domain1 Calibrator 2: One (1) barcode labeled tube containing 1.0 mL prediluted, ready to use reagent. Calibrators contain human antibodies to ß2GP1-Domain1 in stabilizers and preservatives

The QUANTA Flash® ß2GP1-Domain1 Controls kit contains three vials of Low Control and three vials of High Control.

QUANTA Flash ß2GP1-Domain1 Low Control: Three (3) barcode labeled tubes containing 1.0 mL, ready to use reagent. Controls contain human antibodies to ß2GP1-Domain1 in stabilizers and preservatives.
QUANTA Flash ß2GP1-Domain1 High Control: Three (3) barcode labeled tubes containing 1.0 mL, ready to use reagent. Controls contain human antibodies to ß2GP1-Domain1 in stabilizers and preservatives.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study details for the QUANTA Flash® ß2GP1-Domain1 device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Parameter	Acceptance Criteria	Reported Device Performance
Sample Matrix Comparison
Weighted R	$\geq 0.975$	0.997
Intercept (Constant bias)	$\pm 3 CU$	0.1
Slope (Proportional bias)	0.9 - 1.1	1.01
Weighted S y/x	$\leq 0.5$	0.064
Predicted bias at cut-off	$\pm 3 CU$	0.3
95% Cl of the bias	<20% $\pm 4 CU$	0.00 to 1.03
Precision (Serum)	Total %CV: < 15%	5.6-10.6% (for 8 samples with varying concentrations)
Precision (Plasma)	Total %CV: < 15%	2.5-7.8% (for 3 samples with varying concentrations)
Linearity (Recovery)	80-120%, or $\pm 4 CU$, whichever is greater	Serum: 83.9%-113.9% (combined for 5 samples) Plasma: 86.6%-111.9% (combined for 3 samples)
Linearity (Linear Regression)	Slope: 0.9-1.1, R$^2$: $\geq 0.95$	Serum: Slope 1.01, R$^2$ 1.00 (Combined for 5 samples) Plasma: Slope 0.96, R$^2$ 0.99 (Combined for 3 samples)
Interference	85%-115% recovery, or $\pm 4$ CU difference, whichever is greater, compared to control samples.	Bilirubin (up to 100 mg/dL): 92.9% to 109.4% Hemoglobin (up to 200 mg/dL): 95.6% to 106.3% or 1.7 CU Triglycerides (up to 1000 mg/dL): 92.5% to 107.7% Cholesterol (up to 224.3 mg/dL): 92.5% to 107.7% RF IgM (up to 500 IU/mL): 86.2% to 109.9% or 0.9 CU
Lot to Lot Comparison
Weighted R	$\geq 0.975$	RP3 vs RP11: 0.996 RP11 vs PP1: 0.998 PP1 vs RP3: 0.986
Intercept (constant bias)	$\pm 3$ CU	RP3 vs RP11: 1.9 RP11 vs PP1: 0.06 PP1 vs RP3: -1.3
Slope (Proportional bias)	0.9 - 1.1	RP3 vs RP11: 1.03 RP11 vs PP1: 1.04 PP1 vs RP3: 1.00
Weighted S y/x	$\leq 0.5$	RP3 vs RP11: 0.07 RP11 vs PP1: 0.05 PP1 vs RP3: 0.13
Predicted bias at cut-off	$\pm 3$ CU	RP3 vs RP11: 2.5 RP11 vs PP1: 0.8 PP1 vs RP3: -1.2
95% CI of the bias	$\leq 20%$ or $\pm 4$ CU	RP3 vs RP11: 1.1 to 3.8 RP11 vs PP1: -0.3 to 1.8 PP1 vs RP3: -3.9 to 1.6
Shelf-Life (Accelerated Stability - Beads, Resuspension Buffer, Reagent Kit)	Lower and upper 95% Cl interval of regression line between 85% and 115% recovery at day 14; no individual data point $\leq 75%$ or $\geq 125%$ recovery at day 14.	All components fulfilled acceptance criteria.
Shelf-Life (Accelerated Stability - Controls and Calibrators)	Lower and upper 95% Cl interval of regression line between 90% and 110% recovery at day 14; no individual data point $\leq 80%$ or $\geq 120%$ recovery at day 14.	All components fulfilled acceptance criteria.
Calibrators Onboard Stability	All 5 calibrations successful in 8.5 hours; average Calibrator RLU recovery 90-110% compared to first use; all Controls and patient panel in expected range.	5 successful calibrations in 8.5 hours; Calibrator RLU values within 90-110%; all Controls and patient panel samples ran within expected range. Supports 4 calibrations over 8 hours.
Controls Onboard Stability	All values within established range for all runs; linear regression line for %recovery between 85% and 115% at run 15.	All controls ran within acceptable ranges for all runs (20 runs); regression line remained between 85% and 115% at run 15. Supports 15 uses, 10 min/use.
Reagent Cartridge Onboard Stability	Stability claim at actual measurement day preceding 95% CI of regression line reaching 85% or 115% recovery, OR preceding 2 data points or $\geq 2%$ of recovery data $\leq 75%$ or $\geq 125%$ recovery.	None of the endpoints reached within the test period. Onboard stability set at 60 days.
Real-Time Stability (Reagent Cartridge, Calibrators, Controls)	Results within respective QC ranges for QC panel samples (reagent cartridge, calibrators); individual values within acceptable ranges compared to release values (controls).	All results to date (up to 12-15 months) were within acceptance limits. One year expiration dating verified.
Sample Storage (Room Temp)	Recovery between 85-115% for positive samples; 80-120% or 4 CU for negative samples.	All results fulfilled criteria up to 48 hours.
Sample Storage (2-8°C)	Recovery between 85-115% for positive samples; 80-120% or 4 CU for negative samples.	All results fulfilled criteria up to 14 days.
Sample Storage (Freeze/Thaw)	Recovery between 85-115% for positive samples; 80-120% or 4 CU for negative samples.	All results fulfilled criteria up to 3 freeze/thaw cycles.
Clinical Sensitivity (APS)	Not explicitly stated as a numerical acceptance criterion, but result is provided.	51.1% (95% CI: 45.0-57.2%)
Clinical Specificity (Controls)	Not explicitly stated as a numerical acceptance criterion, but result is provided.	99.6% (95% CI: 98.9-99.9%)
ROC AUC	Not explicitly stated as a numerical acceptance criterion, but result is provided.	0.84 (95% CI: 0.81 to 0.86)
Expected values (Normal Population)	Not explicitly stated as a numerical acceptance criterion, but result is provided.	0.25% positive (1/400 samples) in healthy blood donors.
Cross-Reactivity	Negligible positivity rate in specified autoimmune diseases (Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis, Osteoarthritis, Scleroderma) and infectious diseases (Hepatitis B, Hepatitis C, Syphilis).	Total controls (n=613): 0.5% positive (3 samples). Specifically: Crohn's Disease: 1.0% (1/104); Scleroderma: 1.6% (2/127); all others 0%. No cross-reactivity detected.

(Note: "N/A" is used if the information is not explicitly stated in the provided text.)

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

Sample Matrix Comparison: 79 matched serum and citrated plasma samples. Data provenance is not specified (e.g., country of origin, retrospective/prospective).
Precision (Serum): 8 serum samples. Data provenance not specified.
Precision (Plasma): 3 plasma samples. Data provenance not specified.
Limit of Blank (LoB) and Limit of Detection (LoD): 140 determinations (60 blank samples, 80 low-level samples). Data provenance not specified.
Auto-rerun function: 3 high positive specimens. Data provenance not specified.
High concentration hook effect: 2 high positive samples. Data provenance not specified.
Linearity (Serum): 5 serum samples. Data provenance not specified.
Linearity (Plasma): 3 plasma samples. Data provenance not specified.
Interference: 5 specimens (3 serum, 2 plasma). Data provenance not specified.
Cross-reactivity: 613 control samples from patients with autoimmune diseases or infections. Data provenance not specified.
Lot to Lot Comparison: 26 samples. Data provenance not specified.
Shelf-Life (Accelerated Stability): Various sealed components (Reagent Kit, beads, Resuspension Buffer, Calibrators, Controls) – quantities not specified beyond number of lots (e.g. 1 lot Reagent Kit, 3 lots beads).
Calibrators Onboard Stability: Calibrators (number not specified); Controls and a panel of characterized patient specimens (number not specified).
Controls Onboard Stability: 2 vials of each Control; patient panel samples (number not specified).
Reagent Cartridge Onboard Stability: Three lots of reagent cartridge; up to 4 serum specimens; Low and High Controls.
Real-Time Stability: QC panel samples (number not specified); Calibrators, Controls (number not specified beyond "all results to date").
Sample Stability: 8 samples (4 serum, 4 plasma). Data provenance not specified.
Cut-off, Reference Range: 30 subjects (5 healthy blood donors, 4 viral hepatitis, 10 SLE without thrombotic events, 10 Syphilis, 1 HIV). All serum matrix. Data provenance not specified.
Clinical Sensitivity, Specificity: 1090 characterized samples (270 APS, 71 infectious diseases, 566 other diseases, 183 conditions "without APS"). These samples were not used for establishing the reference range. Data provenance is not specified beyond "characterized samples."
Expected Values (Normal Population): 400 apparently healthy blood donors. Data provenance not specified.
Comparison with Predicate Device: 238 samples (all samples from clinical validation study within reportable range + 8 additional contrived samples). Data provenance not specified.

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

The text does not specify the number of experts or their qualifications used to establish the ground truth for the test set. It mentions "characterized samples" for the clinical validation study and "clinical and other laboratory findings" as an aid in diagnosis, but no details on expert review or adjudication.

4. Adjudication Method for the Test Set

The text does not specify any adjudication method (e.g., 2+1, 3+1, none) for the test set.

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

This device is a chemiluminescent immunoassay (CIA) for the semi-quantitative determination of autoantibodies. It is an in-vitro diagnostic (IVD) device that performs automated laboratory testing. Therefore, an MRMC study related to "human readers improving with AI vs without AI assistance" is not applicable to this type of device. The device itself is the "reader" or analytical instrument.

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

Yes, the studies described are for the device (the immunoassay kit and BIO-FLASH instrument system) operating in a standalone manner, generating semi-quantitative results without human intervention in the measurement process. Human intervention would be for sample collection, preparation, loading, and interpretation of the results by a clinician. The performance metrics (sensitivity, specificity, precision, linearity, etc.) are for the algorithm and assay system as a whole.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The ground truth for the clinical studies (clinical sensitivity and specificity) is based on diagnosis of Antiphospholipid Syndrome (APS), as well as diagnoses of infectious diseases, other autoimmune diseases (Crohn's, UC, RA, Osteoarthritis, Scleroderma), and conditions "without APS" (pre-eclampsia/eclampsia, fetal loss no APS, SLE no APS, thrombosis no APS, atopic dermatitis). The specific methods for establishing these clinical diagnoses (e.g., based on established clinical criteria, expert consensus, pathology, or long-term outcomes) are not detailed in the provided text.

For analytical studies, the "ground truth" often refers to reference methods or known concentrations, which are implied for linearity, precision, and interference studies (e.g., spiking known concentrations).

8. The Sample Size for the Training Set

The text does not specify a separate "training set" sample size in the context of machine learning or AI models. This device is an immunoassay, the "training" equivalent would be the development and optimization of the assay reagents, protocols, and the establishment of master curves.

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

Similarly, as there's no explicitly mentioned "training set" in an AI/ML context, the concept of "ground truth for the training set" isn't directly applicable. The assay's performance and cut-offs were established through various analytical and clinical studies described (e.g., cutoff established using 99th percentile of 30 subjects, analytical measuring range defined by master curve standards), which could be seen as the data used to "train" or validate the assay's operational parameters.

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