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510(k) Data Aggregation
(73 days)
QUANTA Flash HMGCR is a chemiluminescent immunoassay for the semi-quantitative determination of IgG autoantibodies against HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) antigen in human serum. The presence of anti-HMGCR antibodies, in conjunction with clinical findings and other laboratory tests, is an aid in the diagnosis of idiopathic inflammatory myopathy (IIM).
The principle of the assay is chemiluminescent microparticle immunoassay, a variation of solid phase immunoassay. The QUANTA Flash® HMGCR 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® HMGCR assay utilizes a reagent cartridge format, which is compatible with the BIO-FLASH® instrument.
HMGCR (3-hydroxy-3-methylglutary)-coenzyme A reductase) antigen is coated on to paramagnetic beads, which are stored in the reagent cartridge lyophilized. When the assay cartridge is ready to be used for the first time, a buffer solution is added to the tube containing the beads, and the beads are resuspended with the buffer. The reagent cartridge is then loaded onto the BIO-FLASH instrument.
A patient serum sample is diluted 1:17 by the instrument in a disposable plastic cuvette. An aliquot of the diluted patient serum, HMGCR-coupled beads, and assay buffer are combined into a second cuvette, and mixed. This cuvette is incubated at 37°C. The beads are then magnetized and washed several times. lsoluminol conjugated anti-human 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 "Trigger" reagents are added to the light produced from this reaction is measured as Relative Light Units (RLU) by the BIO-FLASH optical system. RLU values are proportional to the amount of bound isoluminol conjugate, which in turn is proportional to the amount of anti-HMGCR antibodies bound to the antigen on the beads. The QUANTA Flash HMGCR assay utilizes a predefined lot specific Master Curve that is uploaded into the instrument through the reagent cartridge barcode. Based on the results obtained by running two calibrators, an instrument specific Working Curve is created, which is used by the software to calculate chemiluminescent units (CU) from the RLU value obtained for each sample.
QUANTA Flash HMGCR Calibrators and QUANTA Flash HMGCR Controls are sold separately.
The QUANTA Flash HMGCR Reagents kit contains the following materials:
- a. One (1) QUANTA Flash HMGCR Reagent Cartridge
- b. One (1) tube of Resuspension Buffer
- One (1) transfer pipette
The QUANTA Flash HMGCR reagent cartridge contains the following reagents for 50 determinations:
- a. HMGCR coated paramagnetic beads, lyophilized.
- b. Assay buffer colored pink, containing protein stabilizers and preservatives.
- c. Tracer IgG Isoluminol labeled anti-human IgG antibody, containing buffer, protein stabilizers and preservative.
The provided information describes the analytical and clinical performance characteristics of the QUANTA Flash HMGCR Reagents for the semi-quantitative determination of IgG autoantibodies against HMGCR antigen in human serum. This device aids in the diagnosis of idiopathic inflammatory myopathy (IIM).
Here's an breakdown of the acceptance criteria and the study that proves the device meets those criteria:
1. Table of Acceptance Criteria and Reported Device Performance
The document provides specific acceptance criteria for analytical performance studies, along with the results.
| Acceptance Criteria Category | Specific Acceptance Criteria | Reported Device Performance |
|---|---|---|
| Analytical Performance | ||
| Precision (Total %CV) | < 12% | Achieved a maximum Total %CV of 8.5% (Sample 7, 400.5 CU). All individual sample Total %CVs (within-laboratory precision) were < 12%. |
| Reproducibility (Between Sites, Total %CV) | < 12% | Achieved a maximum Total %CV of 9.4% (Sample 4, 344.2 CU). All individual sample Total %CVs (Within-Laboratory Precision) were < 12%. |
| Reproducibility (Between Lots, Total %CV) | < 12% | Achieved a maximum Total %CV of 9.4% (Sample 2, 15.1 CU). All individual sample Total %CVs (Within-Laboratory Precision) were < 12%. |
| Limit of Quantitation (LoQ) | Total imprecision CV% < 20% | The LoQ for the assay was found to be 1.4 CU, with the AMR starting at 1.5 CU. (Implicitly, the CV% at this point met the criterion). |
| Linearity | Best fitting polynomial is a linear one, otherwise, the difference between the best-fitting nonlinear and linear polynomial is less than 15% or ±3 CU for negative samples (allowable nonlinearity). | All four samples showed dilution linearity individually and in combination. For Sample 3, where a second-order polynomial was the best fit, the nonlinearity ranged from -0.4 CU to 0.6 CU, fulfilling the acceptance criteria. Slopes were close to 1 and Y-intercepts close to 0, with high R2 values (1.00). |
| Interference | 85% - 115% recovery, or ± 15% of the cut-off (±3 CU) difference, whichever is greater. | No interference was detected with various substances (bilirubin, hemoglobin, triglycerides, cholesterol, human IgG, rheumatoid factor IgM, atorvastatin, simvastatin, coenzyme Q, pyrroloquinoline quinone, methylprednisolone) within specified concentrations, with recoveries consistently falling within or exceeding the 85-115% range. For instance, bilirubin recovery was 95.5% to 106.7%, hemoglobin 85.2% to 102.4%. |
| Sample Stability and Handling | 85-115% average recovery. | All samples fulfilled the acceptance criteria at each time point (up to 14 days at 2-8°C, up to 48 hours at room temperature, up to 3 freeze/thaw cycles). |
| Reagent Shelf Life (Accelerated) | With regression analysis, the lower and upper 95% CI interval of the regression line is between 80% and 120% recovery at day 14 (equating to one year at 5 ± 3°C). | All components tested (HMGCR beads from 3 lots) fulfilled the acceptance criteria, leading to a one-year expiration dating assignment. |
| Reagent In-use (Onboard) Stability | Stability claim established at the actual measurement day preceding the 95% confidence interval of the regression line reaching 85% or 115% recovery, OR at the actual measurement day preceding the day when ≥2% of the recovery data (3 data points) is <75% or ≥125% recovery. | Onboard stability for the reagent cartridge was set at 60 days (e.g., Lot RP0004: 62 days, Lot 171325: 61 days). |
| Reagent Real-time Stability | Results should fall within their respective ranges. | All results to date (up to 13 months at the time of submission) were within the acceptance limits. |
| Clinical Performance | ||
| Cut-off Establishment | Cut-off established at a value greater than the 99th percentile of the control results and assigned a value of 20 CU (corresponding to 30,000 RLU), ensuring optimal differentiation between negatives and positives. | The cut-off was established at 20 CU (30,000 RLU), which is greater than the 99th percentile of control results, based on a reference population and 12 diagnosed IIM patient specimens. |
| Clinical Sensitivity (IIM target population) | Not explicitly stated as an acceptance criterion in numerical form, but expected to demonstrate utility in aid of diagnosis. | Achieved 25.3% (95% CI: 20.4% - 30.9%) for the IIM patient group (N=257). This value is specifically useful for the IMNM subgroup (82.1%). |
| Clinical Specificity (Controls) | Not explicitly stated as an acceptance criterion in numerical form, but expected to demonstrate utility in aid of diagnosis. | Achieved 99.8% (95% CI: 98.8% - 100.0%) for the control group (N=466). |
| Positive Predictive Value (PPV) | Not explicitly stated as an acceptance criterion. | 98.5% (95% CI: 90.1% - 99.8%). |
| Negative Predictive Value (NPV) | Not explicitly stated as an acceptance criterion. | 70.8% (95% CI: 69.3% - 72.2%). |
| Expected Values in Normal Population | Expected to be "negative". | All 100 apparently healthy blood donors were negative with the QUANTA Flash HMGCR (mean concentration <1.8 CU, range <1.5 to 8.0 CU), at a cut-off of 20 CU. |
2. Sample Sizes Used for the Test Set and Data Provenance
- Clinical Performance Validation Set (Test Set):
- Sample Size: A total of 723 characterized samples were included in the validation set.
- Data Provenance: The document does not explicitly state the country of origin of the data. It refers to a "cohort of characterized samples" and "a panel of 100 apparently healthy blood donors." The nature of the "characterized samples" suggests they were sourced from clinical settings, likely retrospective or a collection of previously diagnosed samples, as they include various patient groups (e.g., infectious diseases, autoimmune diseases, cancers, and IIM subgroups). The "apparently healthy blood donors" would typically be prospective healthy volunteers.
- Retrospective/Prospective: The text does not explicitly state "retrospective" or "prospective" for the 723 characterized samples, but the use of "characterized samples" that were "none of which were used for establishing the reference range" implies they were pre-existing samples used for validation. The 100 healthy donors for expected values are likely prospective or from a biobank of healthy individuals.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
- The document states that the IIM patient samples were classified based on "revised EULAR/ACR classification criteria" and "European Neuromuscular Center criteria (ENMC) 2003 for IMNM."
- The determination of patient groups (e.g., Infectious, SLE, SSc, MCTD, different myositis subgroups) implies a clinical diagnosis.
- The document does not specify the number of experts used or their specific qualifications (e.g., "radiologist with 10 years of experience") for establishing the ground truth. It relies on the widely accepted EULAR/ACR classification criteria and ENMC criteria, which are expert consensus guidelines used by clinicians (e.g., rheumatologists, neurologists) to diagnose these conditions. This suggests an reliance on clinical diagnoses made by qualified professionals adherence to these criteria.
4. Adjudication Method for the Test Set
- The document does not describe a specific "adjudication method" in the traditional sense (e.g., 2+1, 3+1 review by multiple readers for an imaging study).
- Instead, the ground truth for the clinical performance validation set was based on established clinical classification criteria (EULAR/ACR, ENMC). This implies that patient diagnoses (the "ground truth") were determined by clinicians following these standardized guidelines, rather than through an adjudication process of multiple independent assessors specifically for this device study.
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 was not done.
- This device is an in vitro diagnostic (IVD) immunoassay; it measures autoantibodies in human serum. It is not an AI-powered image analysis device or a diagnostic tool that would typically involve "human readers" or "AI assistance" in the way described for an MRMC study. The comparison is between the device's output (presence/absence of antibodies) and a clinical diagnosis, not human reader performance with or without AI.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) Was Done
- Yes, this was a standalone performance study in the context of an IVD. The QUANTA Flash HMGCR assay measures the presence and semi-quantitative level of IgG autoantibodies in serum. The device, the BIO-FLASH instrument with the QUANTA Flash HMGCR Reagents, operates as a fully automated closed system that processes samples and reports results. The clinical performance study (sensitivity, specificity) evaluated the algorithm (the assay's ability to detect antibodies and classify as positive/negative based on its cutoff) against established clinical diagnoses, without human interpretation of raw assay signals in the loop for classification.
7. The Type of Ground Truth Used
- The ground truth for the clinical performance validation was clinical diagnosis based on established classification criteria.
- For the IIM patient cohorts, the ground truth was "idiopathic inflammatory myopathy" (IIM), further subclassified into Dermatomyositis (DM), Amyopathic Dermatomyositis, Juvenile Dermatomyositis, Polymyositis (PM), Inclusion Body Myositis, Overlap, and Immune Mediated Necrotizing Myopathy (IMNM), all determined by adherence to EULAR/ACR classification criteria (with a score of 5.5, not considering biopsy) and ENMC criteria for IMNM.
- For the control groups (e.g., SLE, Scleroderma, RA, various infectious diseases, cancers, healthy donors), the ground truth was the absence of IIM or the presence of a different diagnosed condition.
- This is a form of outcomes data / expert consensus applied through established clinical criteria.
8. The Sample Size for the Training Set
- The document doesn't explicitly refer to a "training set" in the context of a machine learning algorithm.
- However, for the establishment of the cut-off value, a reference population of 145 subjects was used:
- 23 Apparently healthy donors
- 22 Infectious Disease Controls (HBV, HCV, Syphilis)
- 18 Scleroderma Controls
- 20 Systemic Lupus Erythematosus Controls
- 48 End Stage Renal Disease Controls
- 14 False Positive Cohort (high reactivity samples)
- Additionally, 12 diagnosed idiopathic inflammatory myopathy (IIM) patient specimens were assayed to aid in the determination of the cutoff.
- This combined set (145 + 12 = 157 samples) served as the data used to define the diagnostic threshold (cutoff).
9. How the Ground Truth for the Training Set Was Established
- For the cut-off establishment:
- The reference population (145 subjects) consisted of "apparently healthy donors" and "controls" for various other conditions. These are presumed to have established diagnoses or healthy status.
- The 12 diagnosed IIM patient specimens were identified as having IIM.
- The cut-off was established in accordance with CLSI EP28-A3c: Defining, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition.
- The method involved:
- Analyzing the distribution of results from the reference population.
- Using the non-parametric percentile method due to non-normal distribution (Shapiro-Wilk p<0.0001).
- Considering the distribution of results in the 12 known positive IIM samples.
- The cut-off of 30,000 RLU (assigned 20 CU) was set greater than the 99th percentile of the control results to ensure optimal differentiation.
In summary, the study validates an IVD laboratory test for autoantibodies. Its performance is demonstrated through rigorous analytical studies and clinical validation against defined patient cohorts and controls using established clinical diagnostic criteria. The concept of "AI assistance" or "human readers" is not applicable to this type of device.
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