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The Copalis® EBV-M Assay uses Coupled Particle Light Scattering technology in a microparticle agglutination-based assay for the qualitative detection of IgM antibodies to the EBV VCA antigen. The assay is designed for human serum using the Copalis® I Immunoassay System. The presence of VCA IgM antibodies is used as an aid in the diagnosis of EBV associated mononucleosis when used in conjunction with other EBV serologies in pediatric, adult, transplant donor and transplant recipient populations.

The Copalis® EBV-M Antibody Assay uses Coupled Particle Light Scattering technology in a microparticle agglutination-based assay for the qualitative detection of IgM antibodies to the EBV VCA antigen. The assay is designed for human serum using the Copalis I® Immunoassay System. The presence of VCA IgM antibodies is used as an aid in the diagnosis of EBV associated mononucleosis when used in coniunction with other EBV serologies in pediatric, adult, transplant donor and transplant recipient populations.

KIT DESCRIPTION: Coupled Particle Light Scattering (Copalis®) technology provides a rapid method for the measurement of antibodies to specific pathogens. The Copalis® EBV-M Antibody Assay is a microparticle agglutination test using the Copalis® light scattering technology. Polystyrene microparticles are coated with svnthetic VCA antigen and are contained within a special covered reaction well in the test cup. The dried reagent is reconstituted with a reaction buffer on the instrument at the start of the assay. Patient sample is added to the reaction mixture and incubated for 10 minutes. The presence of IgM antibodies specific to the VCA antigen in the patient sample results in agglutination of the monomer microparticles to form aggregates. The reaction mixture is passed through a flow cell and the instrument uses light scattering technology to measure the monomer concentration. The decrease in the monomer population resulting from agglutination is related to the amount of antibody in the sample. The residual monomer concentration in each reaction mixture is compared to a cutoff values to determine sample reactivity and nonreactivity.

Acceptance Criteria and Study for Copalis® EBV-M Antibody Assay

1. Acceptance Criteria and Reported Device Performance

The provided document describes the performance of the Copalis® EBV-M Antibody Assay against various patient populations. The acceptance criteria for a diagnostic assay typically involve evaluating its sensitivity and specificity in relevant disease states. While explicit numerical acceptance criteria are not stated as "acceptance criteria," the reported performance metrics serve as the evidence for meeting the implicit criteria of a clinically effective diagnostic. The data is presented for different patient populations (Primary Disease, Reactivated Disease, SeroNegative, Apparently Healthy Adult, Transplant Recipients, Transplant Donors), with the focus on Sensitivity and Specificity of detecting EBV VCA IgM.

The predicate device for comparison is the Gull Laboratories EBV IgM IFA, and the performance is presented in comparison to "expected marker patterns" which represent the established diagnostic criteria based on a panel of EBV markers.

Here's a table summarizing the reported device performance for specificity, as this appears to be a key metric where the device might differ from a simple expectation of 0% IgM in non-primary infection states. Sensitivity for Primary Disease is 100%, indicating perfect detection in acute cases.

Note on "Acceptance Criteria": The document does not explicitly state numerical thresholds as "acceptance criteria." However, regulatory submissions often rely on demonstrating performance that is "substantially equivalent" to a legally marketed predicate and is deemed clinically acceptable by experts. The high sensitivity for primary disease (100%) and generally high specificity across various non-primary infection groups, along with direct comparison to IFA results and expected serological patterns, serve as the basis for acceptance. The presence of IgM in reactivated disease is specifically addressed by referencing literature, indicating a nuanced understanding of expected results rather than a rigid "no IgM" rule.

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

The study utilized a total of 421 distinct samples across various disease states and populations.

• Primary Disease: 12 pediatric, 59 adult samples (total 71)
• Reactivated Disease: 39 samples
• SeroNegative: 42 pediatric, 8 adult samples (total 50)
• Apparently Healthy Adult Population: 97 samples
• Transplant Recipients (Reactivated): 41-42 samples (reported as 41 for specificity, 42 for agreement and prevalence Copalis)
• Transplant Donors: 50-53 samples (reported as 50 for specificity and agreement, 46 for prevalence Copalis, 53 for prevalence IFA)
• EBV Screening Population: 14 pediatric, 29 adult samples (total 43) - this appears to be an inclusive group where primary, reactivated, seronegative, or past cases were assessed for VCA IgM presence.
• Serial Samples: 7 patients

Data Provenance:

• Country of Origin: The samples were collected from patients representing the "eastern, midwestern and western United States." Specific cities or institutions are not detailed.
• Retrospective or Prospective: Samples were a mix of "Fresh (12%) and frozen (88%) samples," which generally indicates a retrospective collection of banked samples. However, the exact nature of how these samples were obtained in relation to the study design (i.e., whether they were specifically collected for this assay validation or were pre-existing clinical samples) is not explicitly stated as retrospective or prospective, but the use of frozen samples leans heavily towards retrospective.

3. Number of Experts and Qualifications for Ground Truth

The document does not explicitly state the "number of experts used to establish the ground truth" or their specific qualifications (e.g., "radiologist with 10 years of experience").

However, the ground truth was established by comparison to "expected patterns of serological testing results for the 4 EBV markers (EBV VCA IgG and IgM, EBNA, and EA), and for primary infection, heterophile test," and IFA results. This implies that the interpretation of these serological patterns is based on established clinical guidelines and expert consensus in the field of infectious disease diagnostics, likely developed through the collective knowledge of clinical pathologists, infectious disease specialists, and laboratory professionals. The serological pattern itself acts as the "expert consensus" ground truth.

4. Adjudication Method for the Test Set

The adjudication method is implicit and based on a multi-marker serological panel.

• The "expected marker patterns for the 4 EBV markers (EBV VCA IgG and IgM, EBNA, and EA), and for primary infection, heterophile test" served as the primary adjudication criterion for classifying samples into disease states (Seronegative, Primary, Reactivated, Past). This means that multiple established tests were used to categorize each sample.
• For cases where the Copalis® assay results differed from the expected pattern or IFA, the report notes cases of "Copalis equivocal/IFA positive," "Copalis equivocal/IFA negative," "Copalis equivocal/IFA non-specific staining," and "Copalis negative/IFA nss."
• "Equivocal results by Copalis or IFA or non-specific staining by IFA were not included in the calculations" of sensitivity and specificity, indicating a form of exclusion or consensus-based adjudication where ambiguous cases from either the test device or the reference method were set aside for the core performance metrics.

There is no mention of a traditional expert panel consensus (e.g., 2+1 or 3+1 radiologists) typically found in imaging studies, as this is a laboratory assay.

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

No. A Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study focuses on the performance of human readers, sometimes with and without AI assistance, especially in medical imaging. The Copalis® EBV-M Antibody Assay is an automated in vitro diagnostic (IVD) assay; its performance is measured directly by the instrument, not by human interpretation of its raw output in a way that would lend itself to an MRMC study. The comparison is between the assay's results and established serological patterns/predicate device (IFA).

6. Standalone Performance Study

Yes. The entire performance data section describes the standalone performance of the Copalis® EBV-M Antibody Assay. The assay's ability to detect IgM antibodies to the EBV VCA antigen is evaluated directly against the established serological ground truth for different patient populations. The results for sensitivity, specificity, and agreement are for the algorithm (assay) itself.

7. Type of Ground Truth Used

The type of ground truth used is a multi-marker serological panel and comparison to a predicate device (IFA), representing expert consensus derived from established diagnostic criteria.

• For classification into disease states (Primary, Reactivated, Seronegative, Past infection), the ground truth relied on a combination of:
  • EBV VCA IgG and IgM (IFA results)
  • EBNA (Epstein-Barr Nuclear Antigen)
  • EA (Early Antigen)
  • Heterophile test results (for primary infection)
• The expected patterns of reactivity for these markers define the "true" disease state. This is a form of "expert consensus" based on established clinical diagnostic algorithms for EBV infection.

8. Sample Size for the Training Set

The document does not specify a separate training set or its sample size. The performance data provided is for the test set. For an in vitro diagnostic assay, the "training" may refer to the internal development and calibration of the assay during its creation, which is typically not disclosed in detail in a 510(k) summary, or samples used for optimization that are distinct from the final validation set. There's no indication that machine learning was used in a way that would require a distinct "training set" in the modern sense of AI/ML; this is a traditional immunoassay.

9. How Ground Truth for the Training Set Was Established

As no separate training set is explicitly mentioned or detailed, the method for establishing its ground truth is not provided. If internal development samples were used, their ground truth would likely have been established by similar serological panels and predicate device comparisons as described for the test set.

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