(30 days)
The LIAISON® Rubella IgM assay uses chemiluminescent immunoassay (CLIA) technology on the LIAISON® Analyzer for the qualitative determination of IgM antibodies to rubella virus in human serum samples. It is intended for use as an aid in the diagnosis of a current or recent Rubella infection in individuals with signs and symptoms of Rubella, or suspected of having rubella virus infection, including women of child bearing age.
The LIAISON® Control Rubella IgM (negative and positive) is intended for use as assayed quality control samples to monitor the performance of the LIAISON® Rubella IgM assay.
The performance characteristics of LIAISON® Rubella IgM controls have not been established for any other assays or instrument platforms.
The LIAISON® Rubella IgM assay is an in vitro diagnostic device consisting of reagents provided in individual compartments within a plastic container called the Reagent Integral. The assay configuration for the LIAISON® Rubella IgM assay allows for the performance of 100 tests.
Reagent Integral Composition:
- a. Magnetic particles mouse monoclonal antibody IgG to human IgM
- b. Calibrator 1 human serum or defibrinated plasma containing low level of Rubella IqM
- c. Calibrator 2 human serum or defibrinated plasma containing high level of Rubella laM
- d. Antigen Inactivated rubella viral particles (HPV 77 strain)
- c. Specimen diluent buffer with BSA added
- d. Conjugate -- mouse monoclonal antibodies to rubella virus conjuqated to an isoluminol derivative
The LIAISON® Control Rubella IgM is an in vitro diagnostic device consisting of 2 levels of controls to monitor the performance of the LIAISON® Rubella IgM assay
Controls (2 vials of each level):
Negative control - human serum or defibrinated plasma non-reactive for Rubella IgM Positive control - human serum or defibrinated plasma reactive for Rubella IgM
Acceptance Criteria and Device Performance Study for LIAISON® Rubella IgM
This document describes the acceptance criteria and the study conducted to demonstrate the performance of the LIAISON® Rubella IgM assay.
1. Table of Acceptance Criteria and Reported Device Performance
The provided document details various analytical performance characteristics. While explicit "acceptance criteria" for all metrics (e.g., precision %CV thresholds) are not stated in a dedicated table, the studies were conducted to demonstrate acceptable performance for the intended use. The LIAISON® Rubella IgM performance is compared against these implicit standards and the FDA-cleared predicate device.
| Performance Characteristic | Acceptance Criteria (Implicit/Reference) | Reported Device Performance (LIAISON® Rubella IgM) |
|---|---|---|
| Precision (Total %CV) | Expected to be low for reliable results | Negative Control*: 12.3% |
| Positive Control: 12.8% | ||
| Rubella IgM-A*: 12.7% | ||
| Rubella IgM-B*: 15.9% | ||
| Rubella IgM-C: 14.8% | ||
| Rubella IgM-D: 14.1% | ||
| Rubella IgM-E: 13.4% | ||
| Rubella IgM-F: 13.0% | ||
| Rubella IgM-G: 11.9% | ||
| Cross-reactivity | No positive results from non-Rubella IgM | 0 positive, 0 equivocal out of 261 samples tested for various cross-reactants |
| High Dose Hook Effect | No misclassification due to high dose | No hook effect observed; samples with >400 AU/mL classified as above measuring range but not misclassified. |
| IgM Specificity | Loss of reactivity after DTT treatment | Absence of IgM anti-Rubella reactivity after DTT treatment for 10 positive samples. |
| Interference | % change in signal ≤ ±10% and no change in qualitative result at tested concentrations | No interference found for all 7 tested substances (Triglycerides, Hemoglobin, Bilirubin, Albumin, Cholesterol, Gamma-globulin, L-Ascorbic acid). |
| Propsective Study (Agreement with Predicate - Negative) | High agreement with predicate device for negative samples | 98.9% (433/438) with 95% CI: 97.3 - 99.5% |
| Propsective Study (Agreement with Predicate - Positive) | Acceptable agreement with predicate device for positive samples | 60.0% (6/10) with 95% CI: 30.8 - 83.3%^1 |
| Retrospective Study (Agreement with Predicate - Positive) | High agreement with predicate device from pre-selected positive samples | 98.9% (175/177) with 95% CI: 96.0 - 99.7% |
*Precision calculations for these samples were based on signal (RLU) as the dose was below the reading range.
^1 The lower positive agreement in the prospective study is likely due to the small number of positive samples in that cohort (only 10 identified as positive by the comparator assay). The retrospective study (designed for positive samples) shows much higher positive agreement.
2. Sample Size Used for the Test Set and Data Provenance
- Precision/Reproducibility Study Test Set: A coded panel was tested. The specific number of individual samples in the panel is not explicitly stated, but it was tested with two replicates per run, in two runs per day for 20 operating days across three sites.
- Data Provenance: The study was conducted at two external laboratories and DiaSorin Inc. The origin of the samples in the coded panel is not specified (e.g., country of origin). The study design (testing over 20 days) implies a prospective collection for the study itself, although the source of the panel samples could be retrospective.
- Cross-reactivity Study Test Set: 261 individual samples, each sero-positive for a specific cross-reactant and sero-negative for Rubella IgM by a commercially available Rubella IgM assay.
- Data Provenance: Not specified (retrospective or prospective, country of origin).
- High Dose Hook Effect Study Test Set: 3 samples with Rubella IgM levels > 400 AU/mL.
- Data Provenance: Not specified.
- IgM Specificity Study Test Set: 10 samples containing Rubella IgM antibodies covering the assay range.
- Data Provenance: Not specified.
- Interference Study Test Set: Two matched sample pools near the clinical decision point were tested neat and spiked with each interferent. The specific number of individual samples contributing to the pools or number of independent tests is not detailed beyond the two pools.
- Data Provenance: Not specified.
- Comparative Testing (Clinical Studies) Test Set:
- Prospective study: 448 samples from individuals sent to the laboratory for Rubella IgM testing.
- Retrospective study: 178 samples from individuals who had a positive Rubella IgM result (pre-selected population).
- Data Provenance: The clinical studies were conducted in the United States, as indicated by the mention of "validated in the United States during clinical studies" and the context of FDA submission. Both prospective and retrospective data were used.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
- For the clinical comparative studies (prospective and retrospective): The ground truth was established by an "FDA-cleared predicate device" (ADVIA Centaur Rubella IgM Assay, K010668). No human experts were explicitly mentioned as establishing the ground truth for the test set samples in these comparative studies. The predicate device's results were considered the reference.
- For setting the assay cut-off: Ground truth was established based on consensus between "several comparison methods" and "available clinical and serological data". This implies the involvement of experts who interpreted these data, but the number and qualifications of these experts are not specified in the document. The European studies for cutoff establishment mention "subjects never infected by rubella virus, subjects affected by autoimmune diseases, patients affected by various infectious diseases with similar symptomology, subjects with past rubella infector or vaccine recipients, patients affected by acute rubella infection and subjects with long-lasting rubella virus IgM," which would require expert clinical and serological diagnosis to categorize.
4. Adjudication Method for the Test Set
- For the clinical comparative studies, the LIAISON® Rubella IgM assay results were compared directly against the results of the predicate device. There is no mention of an independent adjudication method (like 2+1, 3+1, etc.) for discrepancies between the new device and the predicate. The predicate device's classification was used as the reference.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
- No, an MRMC comparative effectiveness study was not done. The studies described are focused on comparing the performance of the new device (assay) against a predicate device, and analytical characteristics, not on the improvement of human readers with AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
- Yes, this is a standalone device performance study. The LIAISON® Rubella IgM assay is an in vitro diagnostic device (a lab test system) that provides a qualitative result (Positive, Equivocal, Negative). The studies assess the analytical and clinical performance of this assay itself, generating results without human interpretive input into the device's determination. Human laboratory personnel would operate the instrument and interpret the final quantitative result based on the defined cut-offs to a qualitative diagnosis, but the core performance evaluation is of the assay's output.
7. The Type of Ground Truth Used
- Predicate Device/Reference Methods and Clinical Data Consensus.
- For the comparative clinical studies, the FDA-cleared predicate device (ADVIA Centaur Rubella IgM Assay) served as the primary ground truth for comparison.
- For establishing the assay cut-off, the ground truth was derived from "consensus between several comparison methods as well as the available clinical and serological data." This falls under a form of expert consensus and reference method agreement based on clinical and laboratory findings.
- For analytical studies (e.g., cross-reactivity, IgM specificity), the ground truth was based on known characteristics of the samples (e.g., known sero-positivity for a cross-reactant, known Rubella IgM presence/absence, DTT treatment effect).
8. The Sample Size for the Training Set
- Not explicitly specified for a distinct "training set" in the context of machine learning. As an immunoassay, the device's "training" involves the development and calibration of reagents and the establishment of cut-offs.
- The assay cut-off was established based on studies including "1662 subjects from different populations" (subjects never infected by rubella virus, subjects affected by autoimmune diseases, patients affected by various infectious diseases with similar symptomology, subjects with past rubella infector or vaccine recipients, patients affected by acute rubella infection and subjects with long-lasting rubella virus IgM) in European studies. This large cohort of 1662 subjects would serve as the primary dataset used to "train" or optimize the assay's interpretive criteria (i.e., the cut-off values).
9. How the Ground Truth for the Training Set Was Established
- The ground truth for the 1662 subjects used to establish the cut-off was determined by:
- "several comparison methods" (implying other established serological tests for Rubella IgM), and
- "available clinical and serological data" (suggesting a comprehensive evaluation of patient history, symptoms, and other laboratory findings).
- The "consensus between the methods as well as the available clinical and serological data" was applied to define the expected results for these subjects. This indicates a robust method involving multiple lines of evidence and expert review.
§ 866.3510 Rubella virus serological reagents.
(a)
Identification. Rubella virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to rubella virus in serum. The identification aids in the diagnosis of rubella (German measles) or confirmation of a person's immune status from past infections or immunizations and provides epidemiological information on German measles. Newborns infected in the uterus with rubella virus may be born with multiple congenital defects (rubella syndrome).(b)
Classification. Class II. The special controls for this device are:(1) National Committee for Clinical Laboratory Standards':
(i) 1/LA6 “Detection and Quantitation of Rubella IgG Antibody: Evaluation and Performance Criteria for Multiple Component Test Products, Speciment Handling, and Use of the Test Products in the Clinical Laboratory, October 1997,”
(ii) 1/LA18 “Specifications for Immunological Testing for Infectious Diseases, December 1994,”
(iii) D13 “Agglutination Characteristics, Methodology, Limitations, and Clinical Validation, October 1993,”
(iv) EP5 “Evaluation of Precision Performance of Clinical Chemistry Devices, February 1999,” and
(v) EP10 “Preliminary Evaluation of the Linearity of Quantitive Clinical Laboratory Methods, May 1998,”
(2) Centers for Disease Control's:
(i) Low Titer Rubella Standard,
(ii) Reference Panel of Well Characterized Rubella Sera, and
(3) World Health Organization's International Rubella Standard.