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The Focus Diagnostics' STRATIFY JCV® DxSelect™ assay is intended for the qualitative detection of antibodies to JC virus in human serum or plasma. The assay is intended for use in conjunction with other clinical data, in multiple sclerosis patients receiving or considering natalizumab therapy, as an aid in risk stratification for progressive multifocal leukoencephalopathy development. The assay is for professional use only.

The assay is not intended for donor screening. The performance of this assay has not been established for use in other immunocompromised patient populations or patients with different disease conditions or undergoing other treatments or in neonates and pediatric patient populations.

The Focus Diagnostics' STRATIFY JCV® DxSelect™ test is an ELISA assay. JC virus-like particles (VLP) are pre-coated onto 96-well microiter plates. Diluted serum or plasma specimens and controls are incubated in the wells to allow JCV-specific antibodies present in the specimens to react with the JC VLP antigen. Nonspecific reactants are removed by washing. Peroxidase-conjugated anti-human antibodies are added to react with JCV-specific antibodies. Excess conjugate is removed by washing. Enzyme substrate and chromogen are added, and the color is allowed to develop. After adding the Stop Reagent, the resultant color change is quantified by a spectrophotometric reading of optical density (OD). Specimen OD readings are compared with Cut-Off Calibrator OD readings to determine results. Each specimen result is reported as an index value. A specimen with an index value that is greater than a specified upper cut-off is reported as positive for detectable JCV-specific antibodies, whereas a specimen with an index value less than the specified lower cut-off is reported as negative for detectable JCV-specific antibodies. A specimen with an index value that is equal to or between the upper and lower cut-off values is reported as indeterminate. An indeterminate result requires further evaluation in the confirmation (inhibition) assay.

In the confirmation assay, soluble JC VLP antigen will compete with plate bound JC VLP antigen for the JCV-specific antibodies present in the serum or plasma specimens. After washing away the unbound antibodies, peroxidase-conjugated anti-human antibodies are added and bind to any captured JCVspecific antibodies. Excess conjugate is removed by washing. Enzyme substrate and chromagen are added, and the color is allowed to develop. After adding the Stop Reagent, the resultant color change is quantified by a spectrophotometric reading of OD. The percent inhibition is calculated to confirm presence of JCV-specific antibodies in the specimens with a percent inhibition value that is greater than the specified cut-off are reported as positive for detectable JCV-specific antibodies, whereas specimens with percent inhibition values less than or equal to the cut-off are reported as negative for detectable JCV-specific antibodies.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Acceptance Criteria and Device Performance for STRATIFY JCV® DxSelect™

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly present a "table of acceptance criteria" in the traditional sense, but rather demonstrates performance against the predicate device and established clinical guidelines. The key performance metrics evaluated are Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) with a validated laboratory methodology (the predicate device) and JCV antibody positivity rate in certain patient populations.

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The STRATIFY JCVTM Antibody ELISA testing service provided by Focus Diagnostics is intended for the qualitative detection of antibodies to John Cunningham virus in human serum or plasma. The assay is intended for use in conjunction with other clinical data, in multiple sclerosis and Crohn's disease patients receiving natalizumab therapy, as an aid in risk stratification for progressive multifocal leukoencephalopathy development. The assay is for professional use only and is to be performed only at Focus Diagnostics' Reference Laboratory.

The assay is not intended for donor screening. The performance of this assay has not been established for use in other immunocompromised patient populations or in neonates and pediatrics patient populations.

The STRATIFY JCV™ Antibody ELISA consists of two devices. The first is an initial detection ELISA and the second device is a confirmatory (inhibition) ELISA. Both tests utilize the same recombinant antigen which is used in two different formats as described in section L. The devices include the following reagents; Recombinant JC virus like particles (VLP), a JCV high and low positive controls, consisting of human sera that is positive for JCV antibodies, and JCV negative control consisting of human sera that is negative for JCV antibodies. The conjugate, substrate, wash buffers and blocking buffers needed for the test are not supplied with the device and are listed together with other reagents and consumables in the device labeling.

Here's a breakdown of the acceptance criteria and the studies that support the performance of the STRATIFY JCV™ Antibody ELISA, based on the provided 510(k) summary:

Acceptance Criteria and Reported Device Performance

Study Details

2. Sample size used for the test set and the data provenance:

• Precision Studies (Detection & Confirmation):
  • Sample Size: 90 aliquots for each plasma and serum level (High Positive, Indeterminate, Low Positive, Negative) in the detection assay. The indeterminate pools then subjected to confirmation (90 plasma indeterminate, 86 serum indeterminate).
  • Data Provenance: Not explicitly stated, but likely from laboratory internal samples/controls, potentially spiked to achieve different concentrations.
• Analytical Specificity (Cross-Reactivity - Spiked Antibodies):
  • Sample Size: 3 replicates for each of 3 spiked antibodies (total 9 tests for serum, 9 for plasma).
  • Data Provenance: Laboratory, using commercially available human antibodies spiked into JCV negative serum/plasma.
• Analytical Specificity (Cross-Reactivity - Seroprevalence):
  • Sample Size: Panels of up to twenty remnant specimens (e.g., 20 for C. pneumoniae, HSV6, VZV, Candida, HSV1, HSV2; 4 for T. pallidum; 9 for M. pneumoniae; 15 for CMV; 20 for HIV1). Total 188 samples across various sero-positive groups.
  • Data Provenance: Remnant clinical specimens, likely retrospective from various patient populations.
• Analytical Specificity (Interferences - Endogenous Substances):
  • Sample Size: Not explicitly stated as a number of samples, but involved spiking a single low-concentration JCV antibody native serum and plasma panel with various interferents and comparing to baseline.
  • Data Provenance: Laboratory, using native serum/plasma samples and spiked interferents.
• Analytical Specificity (Interferences - Concomitant Medications):
  • Sample Size: Subset of 585 MS patients from the AFFIRM study.
  • Data Provenance: Prospective clinical trial (AFFIRM study) data, with serial samples collected over 30 months. Patients were treated for Multiple Sclerosis.
• False Negative Rate (JCV Viruric Patients):
  • STRATA Study: 204 viruric patients.
  • STRATIFY-1 Study: 186 urinary JCV DNA positive subjects (out of 1073 total subjects).
  • Data Provenance: Prospective clinical studies (STRATA and STRATIFY-1), involving MS patients.
• Method Comparison with LDT:
  • Sample Size: 200 samples (62 negative, 71 low positives near cut-point, 67 positive).
  • Data Provenance: Not explicitly stated, but presumably clinical samples, likely retrospective.
• Matrix Comparison:
  • Sample Size: 50 paired plasma and serum samples.
  • Data Provenance: Clinical samples (presumably from patients).
• Clinical Performance (PML Risk Stratification - Pre-PML Samples):
  • Sample Size: 37 available serum samples from confirmed PML patients.
  • Data Provenance: Retrospective collection of serum samples from patients who developed PML, collected specifically from clinical trials and post-marketing reports prior to PML diagnosis.
• Clinical Performance (PML Risk Stratification - MS Population JCV Positivity):
  • Sample Size: 5,896 MS patients.
  • Data Provenance: Clinical trials (AFFIRM, TYGRIS-US, STRATIFY-1) and a national MS registry (Sweden). This is a large, geographically diverse, retrospective and potentially prospective (from ongoing studies) cohort of MS patients.
• Clinical Performance (JCV Antibody Prevalence - CD Patients):
  • Sample Size: 313 CD patients.
  • Data Provenance: Two completed Phase 3 clinical trials (CD301 and CD303) of natalizumab in Crohn's disease patients. Retrospective.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

• The document does not mention the use of experts to establish ground truth for the test sets (patient samples, viruric samples, etc.). The ground truth for these studies relies on other laboratory methods (e.g., urinary JCV DNA positivity for viruric patients) or clinical diagnoses (e.g., confirmed PML diagnosis for the pre-PML samples).

4. Adjudication method for the test set:

• The document does not describe an adjudication method involving experts for any of the test sets. Ground truth is established by laboratory results (e.g., confirmed urinary JCV DNA positivity) or clinical diagnosis of PML, not by expert consensus on the samples themselves.

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 an ELISA (Enzyme-Linked Immunosorbent Assay) for detecting antibodies, not an imaging device or AI-assisted diagnostic tool that would involve human readers. Therefore, an MRMC study is not applicable and was not performed.

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

• Yes, effectively. The STRATIFY JCV™ Antibody ELISA is a laboratory assay. Its performance characteristics (precision, specificity, false negative rates, and clinical performance) are evaluated as a standalone test, meaning the results are generated directly by the assay without real-time human interpretation or modification of the assay output. Human intervention occurs in performing the assay and interpreting the final quantitative (nOD, % Inhibition) or qualitative (Positive/Negative/Indeterminate) results based on predefined cut-offs.

7. The type of ground truth used:

• JCV Viruric Patients: JCV DNA positivity in urine (confirmed infection).
• PML Risk Stratification: Clinical diagnosis of Progressive Multifocal Leukoencephalopathy (PML), along with historical records of natalizumab treatment and prior immunosuppressant use.
• Method Comparison: The Laboratory Developed Test (LDT) served as the comparative method, acting as a de facto reference in that specific study.
• For other analytical studies (precision, cross-reactivity, interference), ground truth was established by known concentrations/statuses of analytes or known presence/absence of cross-reactants/interferents.

8. The sample size for the training set:

• The document does not explicitly describe a "training set" in the context of a machine learning algorithm. This is a traditional IVD ELISA kit.
• However, the cut-off for the assay (nOD > 0.25 positive,

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