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The QUANTA Flash™ DGP IgA is a chemiluminescent immunoassay for the semi-quantitative determination of of IgA antibodies to synthetic, deamidated gliadin peptides in human serum. The measurement of IgA deamidated gliadin peptide antibodies can be used in conjunction with clinical findings and other laboratory tests to aid in the diagnosis of celiac disease and dermatitis herpetiformis.

The QUANTA Flash™ DGP IgG is a chemiluminescent immunoassay for the semi-quantitative detection of IgG antibodies to synthetic, deamidated gliadin peptides in human serum. The measurement of IgG deamidated gliadin peptide antibodies can be used in conjunction with clinical findings and other laboratory tests to aid in the diagnosis of celiac disease in IgA deficient and IgA deficient patients, as well as dermatitis herpetiformis.

The QUANTA Flash DGP IgA Calibrators are intended for use with the QUANTA Flash DGP IgA chemiluminescent immunoassay (CIA). Each calibrator establishes a point of reference for the working curve that is used to determine Chemiluminescent Unit (CU) values in the measurement of IgA anti-DGP antibodies in serum.

The QUANTA Flash DGP IgA Controls are intended for quality control purposes of the QUANTA Flash DGP lgA chemiluminescent immunoassay (CIA) kit run on the BIO FLASH® instrument that is used for the measurement of IgA anti-deamidated gliadin peptide (DGP) antibodies in human serum.

The QUANTA Flash DGP IgG Controls are intended for quality control purposes of the QUANTA Flash DGP IgG chemiluminescent immunoassay (CIA) kit run on the BIO FLASH® instrument that is used for the measurement of IgG anti-deamidated gliadin peptide (DGP) antibodies in human serum.

Device Description

Synthetic deamidated gliadin peptide is coated onto the surface of paramagnetic beads (microparticles), which are stored in the reagent cartridge under conditions that preserve the antigen in its reactive state. The reagent cartridge is then loaded onto and used by the BIO-FLASH instrument.

Serum samples are prediluted by the instrument with system rinse buffer, and added to disposable plastic cuvettes. Small amounts of the diluted patient serum, the DGP beads, and assay buffer are all combined into a second cuvette, and mixed. This cuvette is incubated at 37℃. The beads are then magnetized and washed several times. Isoluminol conjugated anti-human IgA (or IgG) antibody is then added to the cuvette, and incubated at 37°C. Again, the beads are magnetized and washed repeatedly. The isoluminol conjugate produces a luminescent reaction when reagents ("Triggers") are added to the cuvette. The 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 bound isoluminol conjugate, which in turn is proportional to the amount of anti-DGP antibodies bound to the DGP on the beads.

For quantitation, the QUANTA Flash DGP IgA and IgG assays utilize 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 DGP IgA and IgG Calibrators. Based on the results obtained with the two Calibrators included in the Calibrator set, an instrument specific Working Curve is created, which is used to calculate chemiluminescent units (CU) from the RLU obtained for each patient.

The QUANTA Flash DGP IgA reagent cartridge contains the following reagents:

DGP coated paramagnetic beads in buffer, containing protein stabilizers and a. preservative.
Assay buffer colored pink, containing Tris-buffered saline, Tween 20, protein b. stabilizers and preservatives.
Tracer IgA Isoluminol labeled anti-human IgA antibodies in buffer, containing protein ن stabilizers and preservative.

The QUANTA Flash DGP IgG reagent cartridge contains the following reagents:

DGP coated paramagnetic beads in buffer, containing protein stabilizers and a. preservative.
Assay buffer colored pink, containing Tris-buffered saline, Tween 20, protein ﻗ stabilizers and preservatives.
Tracer IgG Isoluminol labeled anti-human IgA antibodies in buffer, containing protein ﻥ stabilizers and preservative.

The QUANTA Flash™ DGP IgA Calibrators and the QUANTA Flash™ DGP IgG Calibrators kits each contain 2 vials of Calibrators:

QUANTA Flash™ DGP IgA Calibrators:

QUANTA Flash DGP IgA Calibrator 1: Two (2) barcode labeled tubes containing 0.3 mL prediluted, ready to use reagent. Calibrators contain human IgA antibodies to DGP in buffer, protein stabilizers, and preservatives.
QUANTA Flash DGP IgA Calibrator 2: Two (2) barcode labeled tubes containing 0.3 mL . prediluted, ready to use reagent. Calibrators contain human IgA antibodies to DGP in buffer, protein stabilizers, and preservatives.

QUANTA Flash™ DGP IgG Calibrators:

QUANTA Flash DGP IgG Calibrator 1: Two (2) barcode labeled tubes containing 0.3 mL . prediluted, ready to use reagent. Calibrators contain human IgG antibodies to DGP in buffer, protein stabilizers, and preservatives.
QUANTA Flash DGP IgG Calibrator 2: Two (2) barcode labeled tubes containing 0.3 mL prediluted, ready to use reagent. Calibrators contain human IgG antibodies to DGP in buffer, protein stabilizers, and preservatives.

The QUANTA Flash™ DGP IgA Controls kit and the QUANTA Flash™ DGP IgG Controls kits each contain 2 vials of Negative Control and two vials of Positive Control:

QUANTA Flash™ DGP IgA Controls:
QUANTA Flash™ DGP IgA Negative Control: Two (2) barcode labeled tubes containing 0.5 ml, ready to use reagent. Controls contain human IgA antibodies to DGP in buffer, protein stabilizers, and preservatives.

QUANTA Flash™ DGP IgA Positive Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human IgA antibodies to DGP in buffer, protein stabilizers, and preservatives.

QUANTA Flash™ DGP IgG Controls:
QUANTA Flash™ DGP IgG Negative Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human IgG antibodies to DGP in buffer, protein stabilizers, and preservatives.

QUANTA Flash™ DGP IgG Positive Control: Two (2) barcode labeled tubes containing 0.5 mL, ready to use reagent. Controls contain human IgG antibodies to DGP in buffer, protein stabilizers, and preservatives.

AI/ML Overview

The provided text describes the performance characteristics of the QUANTA Flash™ DGP IgA and QUANTA Flash™ DGP IgG assays, including various studies conducted to demonstrate their analytical and clinical performance.

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for many of the studies are implicitly stated or are standard for diagnostic assays (e.g., %CV for precision, recovery percentages for interference).

Study Type	Acceptance Criteria (Stated or Implied)	Reported Device Performance (QUANTA Flash DGP IgA)	Reported Device Performance (QUANTA Flash DGP IgG)
Precision	Total %CV ≤ 15%	All total %CV values within 15% (e.g., Sample 1: 8.2%, Sample 8: 9.8%)	All total %CV values within 15% (e.g., Sample 1: 4.5%, Sample 8: 4.3%)
Between-Sites Reproducibility	%CV ≤ 15% for pair-wise comparisons and Total Reproducibility	All pair-wise %CVs met the criteria (e.g., DGP IgA Sample 1: INOVA vs Mitogen 12.6%, INOVA vs Summa 12.6%); Total Reproducibility %CVs met criteria (Sample #1: 14.8%, Sample #2: 12.6%, Sample #3: 14.7%)	All pair-wise %CVs met the criteria (e.g., DGP IgG Sample 1: INOVA vs Mitogen 13.0%, INOVA vs Summa 12.8%); Total Reproducibility %CVs met criteria (Sample #1: 13.5%, Sample #2: 12.9%, Sample #3: 10.9%)
Auto-rerun Function	Differences between manual and automatic results within ± 20%	Differences for DGP IgA: 11% and 15%; Differences for DGP IgG: 19% and 5% (All within acceptance limit)	Differences for DGP IgA: 11% and 15%; Differences for DGP IgG: 19% and 5% (All within acceptance limit)
High Concentration Hook Effect	No hook effect at high concentrations (higher RLU values when "as is" compared to diluted)	Up to 5167.2 CU in DGP IgA assay showed no hook effect.	Up to 4323.7 CU in DGP IgG assay showed no hook effect.
Interference	Recovery of 85-115% or +/- 4 CU difference (whichever is greater)	Hemoglobin: 88.9-114.4%; Triglycerides: 100.2-110.1%; Cholesterol: 100.2-110.1%; Bilirubin: 96.0-114.6% (one exception at 5mg/dL, recovered at 10mg/dL); RF IgM: 86.8-98.5% (one exception at 500 IU/mL, recovered at 100, 300 IU/mL)	Bilirubin: 104-108%; Hemoglobin: 100-110%; Triglycerides: 104-107%; Cholesterol: 104-107%; RF IgM: 99-112% (one exception at 100 IU/mL, recovered at 300, 500 IU/mL)
Cross-reactivity	Minimal cross-reactivity with other autoantibodies/infection-induced antibodies	No positives in 201 patient samples with infectious diseases and connective tissue diseases.	5 out of 185 specimens (3%) were positive, indicating lack of cross-reactivity.
Method Comparison (Overall)	Demonstrated substantial equivalence through high percent agreement	Positive Agreement: 91.5% (82.5-96.8%); Negative Agreement: 90.3% (74.2-98.0%); Total Agreement: 91.2% (83.9-95.9%) (N=96)	Positive Agreement: 95.1% (88.0-98.7%); Negative Agreement: 83.6% (77.0-89.0%); Total Agreement: 87.6% (82.7-91.4%) (N=235)
Clinical Sensitivity (CD)	Implied to demonstrate diagnostic utility	71.4% (63.4-78.6%)	89.2% (83.0-93.7%)
Clinical Specificity (CD)	Implied to demonstrate diagnostic utility	100.0% (99.0-100%)	97.3% (95.0-98.8%)
Clinical Sensitivity (DH)	Implied to demonstrate diagnostic utility	61.9% (38.4-81.9%)	69.6% (47.1-86.8%)
Clinical Specificity (DH)	Implied to demonstrate diagnostic utility	100.0% (99.0-100%)	97.3% (95.0-98.8%)
ROC AUC (CD)	Implied to demonstrate diagnostic utility (closer to 1.0 indicates better performance)	0.94 (0.90 to 0.97)	0.99 (0.98 to 1.00)
ROC AUC (DH)	Implied to demonstrate diagnostic utility (closer to 1.0 indicates better performance)	0.79 (0.63 to 0.96)	0.95 (0.91 to 1.00)

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

Precision Studies: 8 samples containing various concentrations were used for both IgA and IgG assays.
- Provenance: Not explicitly stated, but likely in-house (INOVA) and potentially external labs (Akron City Hospital, Mitogen Advanced Diagnostics Laboratory).
Between-Sites Reproducibility: 3 samples (negative, low positive, medium positive) tested at each of three sites (INOVA, Mitogen Advanced Diagnostics Laboratory in Calgary, Canada, and Akron City Hospital in Akron, Ohio, USA).
- Provenance: Multi-national (USA and Canada), prospective (samples run for the study).
Limit of Detection (LoD): 140 determinations (60 blank and 80 low-level samples) for each assay.
- Provenance: Not explicitly stated, but typical for analytical validations to be in-house.
Linearity: Six serum samples with various concentrations were used for each assay.
- Provenance: Not explicitly stated, likely in-house.
Auto-rerun Function: Two high positive specimens for each assay.
- Provenance: Not explicitly stated.
High Concentration Hook Effect: Not explicitly stated, but high positive specimens were used.
- Provenance: Not explicitly stated.
Interference:
- DGP IgA: Three specimens tested.
- DGP IgG: Five specimens tested (one excluded).
- Provenance: Not explicitly stated.
Cross-reactivity:
- DGP IgA: 201 patient samples (infectious diseases and connective tissue diseases).
- DGP IgG: 185 patient samples (infectious diseases and connective tissue diseases).
- Provenance: Not explicitly stated, but implies patient samples, presumably retrospective from collections.
Method Comparison:
- DGP IgA: N=96 samples (clinical validation studies: CD, non-CD, DH patients). N=21 DH samples.
- DGP IgG: N=235 samples (clinical validation studies: CD, non-CD, DH patients). N=21 DH samples. N=13 IgA deficient samples.
- Provenance: Clinical validation studies (library samples, patients on gluten-free diet, unconfirmed CD, controls, DH patients). The source "library" often implies retrospective.
Clinical Sensitivity/Specificity:
- DGP IgA:
  - Initial validation: 54 CD samples (library), 39 samples (CD on GFD/unconfirmed CD), 103 non-celiac controls, 21 DH samples.
  - External study: 93 CD samples, 98 disease controls. 151 samples (58 adults, 93 pediatric) suspected CD.
  - Control Population for cut-off: 355 subjects (healthy blood bank donors, inflammatory bowel disease, H. pylori, autoimmune thyroid, infectious diseases, rheumatoid arthritis, ANA patients, tTG workshop study controls from Children's Hospital and University of Colorado).
- DGP IgG:
  - Initial validation: 62 CD samples (INOVA library, 7 IgA deficient), 87 non-celiac controls, 39 samples (CD on GFD/unconfirmed CD), 23 DH samples.
  - External study: 102 CD samples (9 IgA deficient), 151 samples (suspected CD, 58 adults, 93 pediatric), 98 disease controls.
  - Control Population for cut-off: 392 subjects (healthy blood bank donors, inflammatory bowel disease, H. pylori, autoimmune thyroid, tTG workshop study controls from Children's Hospital and University of Colorado).
- Provenance: Mixed. "Library" samples indicate retrospective data. "External study" samples could be prospective or retrospective depending on how they were collected for that specific study. Multiple sources are mentioned, including patients from a tTG workshop study, individuals seeking medical attention. Specific geographical provenance (e.g., Colorado, USA for some controls) is mentioned for some control groups.

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

The document does not mention the use of "experts" in the traditional sense (e.g., radiologists interpreting images) for establishing ground truth. The ground truth for the clinical studies appears to be based on:

Clinical Diagnosis: Celiac Disease (CD) and Dermatitis Herpetiformis (DH) status.
Biopsy Results: Mention of Marsh III and Marsh II biopsies for some CD patients. While a pathologist is involved in biopsy interpretation, the document doesn't specify how many pathologists or their specific qualifications, or if a consensus process was used.
Other Laboratory Tests: The intended use states the device should be used "in conjunction with clinical findings and other laboratory tests to aid in the diagnosis." This implies other methods were used to confirm CD/DH status for the clinical validation.
Pre-existing sample cohorts: "54 CD samples from library", "62 CD samples from INOVA's serum library". This suggests the diagnosis was established clinically through a standard diagnostic pathway prior to the samples being included in the library.

There is no mention of "experts" specifically establishing ground truth for the test set in the traditional sense of independent review.

4. Adjudication Method for the Test Set

No explicit adjudication method (like "2+1" or "3+1") is described for establishing the ground truth for the test set. The diagnoses (CD, DH) appear to be pre-determined based on clinical and pathological findings before the samples were included in the studies.

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. This is a diagnostic immunoassay that measures antibody levels in serum, not an imaging device that requires human readers/interpreters. Therefore, an MRMC study is not applicable.

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

Yes, the studies presented (Precision, LoD, Linearity, Interference, Cross-reactivity, Clinical Sensitivity/Specificity, Method Comparison) represent standalone performance of the assay. The device generates a quantitative (CU) result, and the performance characteristics evaluate the accuracy and reliability of this direct measurement.

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

The ground truth for the clinical validation studies appears to be:

Clinical Diagnosis: Established diagnoses of Celiac Disease (CD) and Dermatitis Herpetiformis (DH).
Pathology: Biopsy results (e.g., Marsh III classification for CD) are mentioned for some patients, indicating histological confirmation contributed to the ground truth for CD cases.
Other Diagnostic Tests/Criteria: The statement emphasizes the device aids diagnosis "in conjunction with clinical findings and other laboratory tests," suggesting a multi-faceted diagnostic approach established the true disease status of the patients whose samples were tested.

For control populations, healthy blood bank donors and patients with other diseases (e.g., autoimmune liver disease, viral hepatitis, inflammatory bowel disease) were used. Their ground truth is their confirmed disease status or health status.

8. The Sample Size for the Training Set

The document does not explicitly delineate separate "training sets" and "test sets" in the context of machine learning. The studies described are performance validation studies for an immunoassay.

However, for establishing the assay's internal parameters:

Master Curve: A predefined lot-specific Master Curve is uploaded onto the instrument, which would have been established using a set of samples during manufacturing/development. The size and nature of this "training" data are not specified.
Cut-off establishment:
- DGP IgA: Control population of 355 subjects, supplemented by 37 CD specimens for sensitivity/specificity optimization.
- DGP IgG: Control population of 392 subjects, supplemented by 37 CD specimens for sensitivity/specificity optimization.
  These populations were used to define the CU cut-offs (20 CU for IgA, 20 CU for IgG).

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

Given the context, the "training set" would refer to the data used to establish the assay's intrinsic parameters like the Master Curve and cut-off values.

Master Curve: This is likely established by the manufacturer using a comprehensive set of characterized samples (controls, various concentrations) during the development and manufacturing process of each reagent lot. The details of how these samples were characterized are not provided in this summary.
Cut-off values:
- Control Population: For both IgA and IgG, control populations (355 for IgA, 392 for IgG) consisted of healthy blood bank donors and patients with various other conditions. The "ground truth" for these samples was their established health status or specific disease diagnosis (not CD/DH).
- DGP IgA/IgG Positive Samples for Optimization: 37 CD specimens were used to optimize the cut-off. The ground truth for these samples would have been their confirmed Celiac Disease diagnosis, obtained through clinical findings and other laboratory tests, including biopsy in some cases.
- Method: The cut-off was established in accordance with CLSI C28-A3c ("Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory") using the non-parametric percentile method (99th percentile for IgA, 99th/98th percentile for IgG RLU values). The software "Analyse-it for Excel" was used for calculations. The final cut-off was selected to provide the "combination of the highest sensitivity and specificity" based on the results from the CD patient specimens and control population.

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