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For in vitro diagnostic use with the IMMULITE® 2000 Analyzer - for the quantitative measurement of allergen-specific IgE in human serum, as an aid in the clinical diagnosis of IgE-mediated allergic disorders. The test results are to be used in conjunction with clinical findings and other laboratory tests.

IMMULITE® 2000 3gAllergy™ Specific IgE is a solid-phase, two-step, chemiluminescent immunoassay that exploits liquid phase kinetics in a bead format. It represents a significant advance over conventional methods relying on allergens attached to a solid-phase support, such as a paper disk. The allergens are covalently bound to a soluble polymer matrix, which in turn is labeled with a ligand. The use of an amino acid co-polymer amplifies the amount of allergen that the matrix can support.

The Siemens IMMULITE® 2000 3gAllergy™ Specific IgE Assay is an in vitro diagnostic device for the quantitative measurement of allergen-specific IgE in human serum, assisting in the clinical diagnosis of IgE-mediated allergic disorders. The device met several acceptance criteria to demonstrate its performance.

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria for this diagnostic device are primarily defined by its precision, linearity, and specificity, with clinical performance (sensitivity, specificity, and agreement) validating its utility. The reported performance for these criteria is summarized below:

• Most allergens show within-run CVs below 10%. Some exceptions exist, e.g., Blomia tropicalis (7.69%), Loblolly Pine (5.86%), nDer p 2 (11.80%), Parrot Feathers (39.87% for one sample, indicating a potentially very low concentration or outlier).
  Total CV% Ranges:
• Most allergens show total CVs below 10-15%. Similar to within-run, exceptions exist, e.g., Chicken Feathers (12.95%), nDer p 2 (12.60%), Parrot Feathers (47.01% for one sample, and 12.64% for another).

Overall, the precision is considered acceptable, especially for clinically relevant concentrations, with acknowledgment of higher variability at very low concentrations as is common for many immunoassays. |
| Linearity | Regression analysis of observed vs. expected concentrations should yield slopes close to 1.0 and intercepts close to 0, with narrow 95% confidence intervals (CI) for both the slope and intercept, indicating accurate measurement across the assay's dynamic range. | Slope 95% CI: All allergens show a 95% CI for the slope that includes or is very close to 1.0 (e.g., Aureobasidium pullulans: 0.968 - 1.025, Blomia tropicalis: 0.967 - 1.008, Brazilian Peppertree: 0.939 - 1.024).
Intercept 95% CI: All allergens show a 95% CI for the intercept that includes or is very close to 0 (e.g., Aureobasidium pullulans: -0.089 - 0.029, Blomia tropicalis: -0.063 - 0.119, Brazilian Peppertree: 0.070 - 0.360).

These results demonstrate good linearity across the tested concentration ranges for all allergens. |
| Specificity | Competitive inhibition studies should show concentration-dependent inhibition by relevant extracts, with a target of 50% inhibition at the highest inhibitor concentration. Non-specific cross-reactivity with unrelated allergens should be minimized (e.g., below 7%). | Competitive Inhibition: The inhibition plots demonstrated that the allergens tested were inhibited by the relevant inhibitor extract in a concentration-dependent fashion. The target of 50% inhibition for the highest inhibitor concentration was met for all listed allergens.
Inhibition Using Negative Controls (Cross-Reactivity): Results for most specific allergens when tested with unrelated allergen extracts were below 7%, except for Loblolly Pine. This indicates low cross-reactivity generally, supporting the specificity of the assays. |
| Clinical Performance (Agreement) | High overall agreement (and associated sensitivity and specificity) between IMMULITE® 2000 results and clinical data, indicating that the assay results align with actual patient allergic status. While no specific threshold is stated in the context, a high percentage is expected. | Overall Agreement: 90.5% (Lower Conf 89%, Upper Conf 92%).
Sensitivity: 71.4% (Lower Conf 68%, Upper Conf 74%).
Specificity: 98.3% (Lower Conf 98%, Upper Conf 99%).

The high overall agreement, driven primarily by very high specificity, supports the utility of the assay as an aid in diagnosis, especially in confirming the absence of IgE-mediated allergy. The moderate sensitivity suggests it is a good indicator of allergy when positive, but a negative result needs to be interpreted carefully in conjunction with clinical findings. |

2. Sample Size and Data Provenance

• Test Set (Clinical Performance Study): The clinical performance study used a total of 3,140 serum samples.
  • Data Provenance: The document does not explicitly state the country of origin. It is implied to be retrospective, using "clinically diagnosed atopic and non-atopic individuals," suggesting samples were collected from a clinical setting where diagnoses had already been made.

3. Number of Experts and Qualifications

• Role of Experts: The document does not describe the use of human experts in establishing the ground truth for the clinical test set in the way one might for an imaging AI device.
• Ground Truth Establishment: Clinical performance was evaluated by comparing IMMULITE® 2000 results "to clinical documentation of presence or absence of signs, symptoms and other diagnostic evidence of allergen sensitivity." This implies a clinical diagnosis based on a combination of patient history, physical examination, and potentially other diagnostic tests performed by clinicians (e.g., allergists), rather than a specific panel of experts adjudicating each case.

4. Adjudication Method

• Not applicable in the context of this in vitro diagnostic assay. Adjudication methods like 2+1 or 3+1 are typically used for consensus reading of medical images by multiple human readers, not for establishing ground truth for laboratory tests based on clinical documentation.

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

• Not applicable. This is an in vitro diagnostic assay, not a medical imaging AI device designed to assist human readers. Therefore, an MRMC study and analysis of human reader improvement with AI assistance were not performed.

6. Standalone Performance

• Yes, the performance metrics (precision, linearity, specificity, and the clinical performance data for sensitivity, specificity, and agreement) represent the standalone performance of the IMMULITE® 2000 3gAllergy™ assay. This device is an automated immunoassay system, and its output (quantitative IgE levels) is the direct result of the algorithm/reagent system. There is no "human-in-the-loop" assistance being evaluated in the assay's core operational performance; the results are generated by the instrument.

7. Type of Ground Truth Used

• The ground truth for the clinical performance study was clinical documentation of presence or absence of signs, symptoms, and other diagnostic evidence of allergen sensitivity. This is akin to outcomes data or a composite clinical diagnosis rather than a single definitive gold standard like pathology.

8. Sample Size for the Training Set

• The document does not explicitly state the sample size used for a "training set" in the context of algorithm development. As a traditional immunoassay, rather than a machine learning/AI algorithm in the modern sense, the "training" would refer to the development and optimization of the assay reagents and parameters. This is not detailed in terms of a specific sample size used for that purpose. The studies presented (precision, linearity, specificity) are validation studies on the final product.

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

• Since this is a traditional immunoassay rather than a machine learning model, the concept of establishing "ground truth for a training set" as it pertains to modern AI models is not directly applicable. The development of such assays involves iterative optimization based on known calibrators, controls, and characterized patient samples to ensure accurate and reliable measurement of the analyte (allergen-specific IgE). The documented studies (precision, linearity, specificity) evaluate the performance of the finalized assay itself using controlled samples and clinical samples, confirming its analytical and clinical validity.

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