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The BioPlex® 2200 APLS IgG and IgA kits are multiplex flow immunoassays intended for the semi-quantitative detection of IgG and IgA antibodies to Cardiolipin (CL) and Beta-2 Glycoprotein I (ß2GPI) in human serum and plasma (lithium heparin, sodium heparin, and sodium citrate). In conjunction with other clinical findings, the test systems are used as an aid in the diagnosis of primary Antiphospholipid Syndrome (APS) and those secondary to systemic lupus erythematosus (SLE) or SLE-like disorders.
The BioPlex 2200 APLS IgG and IgA kits are intended for use with the Bio-Rad BioPlex 2200 System

The BioPlex® 2200 APLS IgG and IgA IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional EIA, but permits simultaneous detection and identification of many antibodies in a single tube. "APLS" is an acronym for Anti-Phospholipid Syndrome.
Two (2) different populations of dyed beads are coated with the antigens associated with Cardiolipin (CL) and Beta-2-Glycoprpotein I (ß2GPI), respectively. The BioPlex 2200 System combines an aliquot of patient sample, sample diluent, and bead reagent into a reaction vessel. The mixture is incubated at 37°C. After a wash cycle, anti-human IgG or IgA antibody, conjugated to phycoerythrin (PE) is added to the dyed beads and this mixture is incubated at 37℃. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of analyte captured is determined by the fluorescence of the attached PE. Raw data is calculated in relative fluorescence intensity (RFI).
Three additional dyed beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to normalize detector response, to verify the addition of serum to the reaction vessel and the absence of significant non-specific binding in serum or plasma. Refer to the BioPlex 2200 System Operation Manual for more information.
The instrument is calibrated using a set of seven (7) distinct calibrator vials for APLS IgG kit and a set of three (3) distinct calibrator vials for the APLS IgA kit, all supplied separately by Bio-Rad Laboratories. For each aCL IgG and aß2GPI IgG, four (4) vials representing four (4) different antibody concentrations are used for semi-quantitative calibration. For each aCL IgA and aß2GPI IgA assay, two (2) vials representing two (2) different antibody concentrations are used for semi-quantitative calibration. The cut-off value and assignment of the calibrators are determined by performing concordance testing and Receiver Operator Characteristic (ROC) analysis, using clinical diagnosis as the standard. The results for aCL IgG and aCL IgA are expressed in GPL-U/mL and APL-U/mL units, respectively. The results for aß2GPI IgG and aß2GPI IgA are each expressed in U/mL units.
The APLS IgG and APLS IgA Control Sets are intended for use as an assayed quality control to monitor the overall performance of the BioPlex® 2200 instrument and BioPlex 2200 APLS IgG and IgA reagent packs in the clinical laboratory.
Each of the APLS IgG and APLS IgA Control Sets includes a negative control and a positive control for each aCL IgG or IgA and aß2GPI IgG or IgA in a human serum matrix made from defibrinated plasma, containing antibodies present for analytes within the APLS IgG or IgA kit. The positive controls are manufactured to give positive results. with values above the cutoff for each specific bead. The negative control is manufactured to give negative results, with values below the cutoff for each specific bead. The negative control must have a negative result, and the positive control must have a positive result.

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Acceptance Criteria and Study for BioPlex® 2200 APLS IgG and IgA Kits

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally established by the performance metrics shown to be acceptable for the predicate devices and the clinical utility of the test. The document emphasizes achieving clinical accuracy through concordance testing and Receiver Operator Characteristic (ROC) analysis to establish cutoffs, which then dictate sensitivity and specificity. The specific numerical acceptance criteria (e.g., minimum sensitivity/specificity percentages) are not explicitly stated as "acceptance criteria" but are demonstrated by the comparative performance results deemed sufficient for substantial equivalence.

Based on the "Clinical Sensitivity and Specificity" section, the reported device performance is as follows:

2. Sample Size for Test Set and Data Provenance

• Sample Size for Clinical Performance (Comparative Testing & Sensitivity/Specificity):

  • Total Specimens: 804 specimens
    • 300 apparently healthy blood donors
    • 302 patients previously diagnosed with primary or secondary APS
    • 202 patients with other rheumatic or non-APS diseases
  • For the Clinical Sensitivity and Specificity section (which excluded 17 samples due to instrument errors): 487 samples for IgG assays (286 Diagnosed APS + 201 Non-APS Control) and 504 samples for IgA assays (302 Diagnosed APS + 202 Non-APS Control).

• Sample Size for Analytical Performance (Precision/Reproducibility): 8 human samples (4 panels of serum/plasma containing aCL IgG & IgA, aß2GPI IgG & IgA) tested in quadruplicate over five days (20 replicates per panel member).

• **Sample Size for Linearity: ** 3 APLS-positive patient samples for each analyte tested.

• Sample Size for Limit of Detection (LoD): Low negative and blank samples in 50 replicates.

• Sample Size for Interfering Substances: Samples prepared by blending negative human serum with positive samples and interferent/blank. Specific count not given but refers to multiple concentrations tested.

• Sample Size for Cross-Reactivity: Varies by disease state, ranging from 3 (CREST) to 34 (Systemic Lupus Erythematosus) samples per disease state.

• **Sample Size for Expected Values/Reference Range: ** 300 samples from apparently healthy donors (132 males, 168 females).

• Data Provenance:

  • "Patient specimens were purchased from commercial suppliers or rheumatology clinic labs and were frozen serum."
  • A clinical trial site performed the reproducibility study.
  • Healthy donor samples were used for prevalence and reference range.
  • The document implies the data is from retrospective samples (patients previously diagnosed with APS, purchased samples, etc.). The country of origin is not explicitly stated.

3. Number of Experts and Qualifications for Ground Truth

The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the test set.

• For the clinical sensitivity and specificity study, the ground truth for APS patients is based on a "diagnosed APS" status. For controls, it's either "non-APS disease control patients" or "apparently healthy blood donors." The method by which these diagnoses were confirmed or by how many experts is not detailed.
• For the assay cut-off determination, it mentions "using clinical diagnosis as the standard" and later "103 samples from patients diagnosed as primary and secondary APS and 208 from normal healthy and 123 from non-APS cardiac donors."
• There's no mention of a panel of experts reviewing the cases used for ground truth.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication method (such as 2+1, 3+1, or other consensus methods) for establishing the ground truth of the test set. The clinical diagnosis appears to be a pre-existing classification of the samples.

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

This device is an in vitro diagnostic (IVD) assay, not an AI-assisted diagnostic tool for human readers. Therefore, an MRMC comparative effectiveness study involving human readers with and without AI assistance is not applicable and was not performed. The comparative effectiveness study performed was against predicate IVD devices.

6. Standalone (Algorithm Only) Performance

Yes, a standalone performance study was done. The entire study described for the BioPlex® 2200 APLS IgG and IgA kits (analytical performance, comparative performance, clinical sensitivity and specificity, linearity, precision, LoD, etc.) represents the standalone performance of the algorithm/device system. There is no "human-in-the-loop" component described for the device's function or evaluation. The system automatically measures specific antibodies and reports semi-quantitative results.

7. Type of Ground Truth Used

The primary type of ground truth used is clinical diagnosis (e.g., "patients diagnosed with primary or secondary APS," "normal healthy donors," "non-APS disease control patients").

8. Sample Size for the Training Set

The document does not explicitly describe a separate "training set" in the context of machine learning or AI algorithm development because the device is a multiplex flow immunoassay providing semi-quantitative results, not a machine learning model that is "trained."

However, the "Calibrator assignment" section describes a process that functionally serves a role akin to parameter tuning or establishing operational reference points:

• "Calibrator assignment is established for matched lots of BioPlex 2200 APLS IgG or IgA kit and calibrators using a master set of calibrators as reference and replicate analyses on multiple BioPlex 2200 instruments."
• The "cut-off value and assignment of the calibrators are determined by performing concordance testing and Receiver Operator Characteristic (ROC) analysis, using clinical diagnosis as the standard." This ROC analysis would involve a dataset to determine optimal cutoffs, which could be considered part of an initial "training" or optimization phase. The size of this specific dataset is partially revealed: "one clinical cohort has 103 samples from patients diagnosed as primary and secondary APS and 208 from normal healthy and 123 from non-APS cardiac donors." (Total 434 samples for cutoff determination.)

9. How Ground Truth for the Training Set Was Established

As noted above, there isn't a traditional "training set" for an AI model. For the calibrator assignment and cutoff determination, the ground truth was established by clinical diagnosis. The cut-off value was established by "optimizing for clinical accuracy" using ROC analysis against existing clinical diagnoses of APS (primary and secondary) and control groups (normal healthy, non-APS cardiac donors).

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