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(1) Immunoassay for the in vitro qualitative detection of IgM antibodies to CMV in human serum, lithium-heparin plasma, K2-EDTA plasma, and K3-EDTA plasma. The test is intended as an aid in the diagnosis of recent or current CMV infection in individuals for which a CMV IgM test was ordered, including pregnant women. Performance characteristics have not been evaluated in immunocompromised or immunosuppressed individuals. This test is not intended for use in neonatal screening or for use at point of care facilities. This assay is not intended for use in screening blood and plasma donors.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys immunoassay analyzers.

(2) PreciControl CMV IgM is used for quality control of the Elecsys CMV IgM immunoassay on the Elecsys and cobas e immunoassay analyzers.

(1) Elecsys CMV IgM is a u-capture immunoassay with streptavidin microparticles, biotinylated recombinant CMV-specific antigen labeled with a ruthenium complex and electrochemiluminescence detection. The results are determined using a calibration curve which is instrument-specifically generated by a 2-point calibration and a master curve provided via the reagent bar code. The test system contains the human serum-based calibrators intended for use with the system.

The CMV IgM assay begins with an automatic 1:20 predilution of sample with Elecsys Diluent Universal and the addition of biotinylated monoclonal anti-h-IgM-specific antibodies.

During the second incubation, CMV-specific recombinant antigen labeled with a ruthenium complex and streptavidin-coated microparticles are added. Anti-CMV IgM antibodies present in the sample react with the ruthenium-labeled CMV-specific recombinant antigen. The complex becomes bound to the solid phase via interaction of biotin and streptavidin.

The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell. Application of a voltage to the electrode induces chemiluminescent emission which is measured by a photomultiplier.

The analyzer automatically calculates the cutoff based on the measurement of Cal 1 and Cal2. The result of the samples is given either as reactive or non-reactive as well as in the form of a cutoff index (signal samples/cutoff). Samples with a cutoff index (COI) < 0.7 are non-reactive. Samples with a cutoff index between 0.7 and < 1.0 are considered indeterminate (border). Samples with a cutoff index ≥ 1.0 are considered reactive.

(2) Elecsys PreciControl CMV IgM contains liquid control serum based on human serum. The controls are used for monitoring the accuracy of the Elecsys CMV IgM immunoassay.

The reagents and calibrators are packaged together in the Elecsys CMV IgM assay kit, while the associated Elecsys PreciControl CMV IgM is packaged separately.

Here's a breakdown of the acceptance criteria and the study details for the Elecsys CMV IgM Immunoassay, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document primarily focuses on demonstrating that the device met its predefined acceptance criteria rather than explicitly listing the criteria in a single table with performance. However, I can construct a table summarizing the performance metrics and their implicit acceptance criteria from the "Analytical Performance Data" and "Clinical Performance Data" sections.

2. Sample Sizes and Data Provenance for the Test Set

• Clinical Performance Test Set (Method Comparison):

  • Prospective Study (Suspected Infection Population): 617 samples.
    • Data Provenance: US, prospective. Samples were from patients suspected of CMV infection for whom a CMV IgM test was ordered. A subset of 199 were pregnant women.
  • Retrospective Study (Preselected Confirmed Positive Population): 134 samples.
    • Data Provenance: Retrospective. Samples were preselected from patients positive for CMV IgM as determined by comparator device consensus.

• Analytical Performance Test Sets:

  • Precision: Not explicitly stated as a general "test set" size, but individual samples/pools were tested (e.g., Controls 01, 02, HS A-F, HS 01-07).
  • Cross-Reactivity/Analytical Specificity: 205 specimens.
  • High Dose Hook Effect: 5 highly positive, high-titer CMV IgM human samples were diluted.
  • Endogenous and Drug Interferences: 8 CMV IgM samples (negative, near cutoff, positive) for hemoglobin, bilirubin, Intralipid, biotin. 34 samples for rheumatoid factor. 20 pharmaceutical compounds.
  • Sample Matrix Equivalence: Samples (negative, near cutoff, positive) were collected into matched serum and plasma collection tubes (number not explicitly stated per matrix type).
  • Method Comparison Between Analyzer Platforms: Native serum samples (number not specified).
  • Reproducibility (Clinical Reproducibility): 4 serum pools and 2 PreciControl CMV IgM materials (n=90 measurements per sample type across sites).

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

The ground truth for the clinical performance studies was established using comparator FDA-cleared devices, not human experts.

4. Adjudication Method for the Test Set

• For the clinical performance method comparison, a two-out-of-three approach was used when three FDA-cleared devices could be tested to determine the consensus result.
• When only two FDA-cleared devices could be tested, results for which the devices disagreed were omitted.
• Equivocal results from the Elecsys CMV IgM assay were treated as "not in favor of the Elecsys CMV IgM assay" during analysis for the prospective suspected infection population (i.e., if it was equivocal, and the consensus was negative, it was counted against the device).

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

No multi-reader multi-case (MRMC) comparative effectiveness study was mentioned. The device is an in vitro diagnostic (IVD) immunoassay, not an imaging or diagnostic support tool requiring human reader interpretation in the context of MRMC studies.

6. Standalone Performance

Yes, the studies presented are standalone performance of the algorithm (the Elecsys CMV IgM immunoassay) without human-in-the-loop performance. The results are based on the direct output of the immunoassay compared to a comparator consensus or expected values.

7. Type of Ground Truth Used

The ground truth was established by consensus results from multiple (2 or 3) FDA-cleared comparator CMV IgM assays. This is a form of "reference method" ground truth.

8. Sample Size for the Training Set

The document does not explicitly mention a separate "training set" in the context of machine learning. For traditional IVDs like this immunoassay, calibration and assay optimization would be part of the development process.

• Assay Cut-off Establishment:
  • Initial cutoff establishment: Samples characterized using several commercially available CMV IgG and CMV IgM assays (number not specified).
  • Specificity evaluation: 931 samples from a low prevalence cohort.
  • Sensitivity optimization: 152 samples from individuals at different stages of primary CMV infection.
  • Validation of assay cutoff: Performed by external clinical studies (the test set described in #2).

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

As noted in #8, there isn't a "training set" in the common machine learning sense. For the development and optimization of the assay:

• The "ground truth" for developing and optimizing the assay's cutoff was derived from characterizing samples using several commercially available CMV IgG and CMV IgM assays and by using samples from individuals at different stages of primary CMV infection. These are established laboratory methods and clinical diagnoses typically relying on a combination of existing cleared tests and clinical context.

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