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The LZI Methadone II Enzyme Immunoassay is an in vitro diagnostic test intended for the qualitative and semi-quantitative determination of methadone in human urine. The cutoff for both the qualitative and semi-quantitative modes of the assay is 300 ng/mL for methadone. The assay is designed for prescription use on automated clinical chemistry analyzers.

The semi-quantitative mode is for purposes of (1) enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as gas or liquid chromatography/mass spectrometry (GCMS or LC/MS) or (2) permitting laboratories to establish quality control procedures.

The assay provides only a preliminary analytical result. A more specific alternative analytical chemistry method must be used in order to obtain a confirmed analytical result. Gas or liquid chromatography/mass spectrometry (GC/MS or LC/MS) is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary test result is positive.

The LZI Methadone II Enzyme Immunoassay is a homogeneous enzyme immunoassay with ready-to-use liquid reagents. The assay is based on competition between methadone in the sample and methadone labeled with the enzyme glucose-6-phosphate dehydrogenase (G6PDH) for a fixed amount of antibody in the reagent. Enzyme activity decreases upon binding to the antibody, and the methadone concentration in the sample is measured in terms of enzyme activity. In the absence of methadone in the sample, methadone-labeled G6PDH conjugate is bound to antibody, and the enzyme activity is inhibited. On the other hand, when free methadone is present in the sample, antibody would bind to free methadone; the unbound methadone-labeled G6PDH then exhibits its maximal enzyme activity. Active enzyme converts nicotinamide adenine dinucleotide (NAD) to NADH, resulting in an absorbance change that can be measured spectrophotometrically at 340 nm.

The LZI Methadone II Enzyme Immunoassay is a kit comprised of two reagents, an R1 and R2 which are bottled separately but sold together within the kit.

The Ri solution contains mouse monoclonal anti-methadone antibody, glucose-6-phosphate (G6P) nicotinamide adenine dinucleotide (NAD), stabilizers, and sodium azide (0.09 %) as a preservative. The R2 solution contains glucose-6-phosphate dehydrogenase (G6PDH) labeled with methadone in buffer with sodium azide (0.09 %) as a preservative.

The LZI Methadone II Enzyme Immunoassay is an in-vitro diagnostic test for qualitative and semi-quantitative determination of methadone in human urine, with a cutoff of 300 ng/mL. The device's performance was evaluated through various studies demonstrating its precision, linearity, accuracy against LC/MS, cross-reactivity with other substances, and interference from endogenous compounds and pH levels.

Here is a summary of the acceptance criteria and reported device performance from the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Precision Studies (Qualitative & Semi-quantitative):
  • Within Run: 22 data points (2 replicates, 1 run/day for 22 days) for each concentration level (0 ng/mL, 75 ng/mL, 150 ng/mL, 225 ng/mL, 300 ng/mL, 375 ng/mL, 450 ng/mL, 525 ng/mL, 600 ng/mL).
  • Total Precision: 88 data points (2 replicates, 2 runs/day for 22 days) for each concentration level.
  • Provenance: Samples were prepared by spiking a methadone standard into a pool of negative human urine. Therefore, this data is from controlled laboratory conditions, not directly from patients.
• Method Comparison - Clinical Samples (Accuracy Study):
  • Sample Size: A total of ninety-four (94) unaltered clinical samples.
  • Provenance: Samples were collected by Lin-Zhi International, Inc. (LZI) and from the University of California, San Francisco (UCSF). This indicates human clinical data.
• Linearity: Serially diluted methadone spiked urine, each run in 10 replicates for a range of 0 to 1000 ng/mL.
• Cross-reactivity and Endogenous Compound Interference: Various concentrations of each substance spiked into pooled negative human urine. (Not specified if replicates were performed for all, but for structurally unrelated compounds, it states "All samples were tested in replicates.")
• Specific Gravity and pH Interference: Urine samples (negative and spiked with methadone) adjusted to different specific gravity and pH levels respectively.

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

The document does not explicitly state the number or qualifications of experts used to establish ground truth.
For the accuracy studies with clinical samples, the ground truth was established by LC/MS (Liquid Chromatography/Mass Spectrometry), which is an independent and highly sensitive analytical chemistry method. This method itself acts as the "gold standard" or "ground truth" for drug concentration determination, rather than relying on human expert interpretation of the test results.

4. Adjudication Method for the Test Set

Not applicable. The ground truth for concentrations (precision, linearity, cross-reactivity, interference studies) was determined analytically. For clinical samples, the ground truth for methadone concentration was established by LC/MS, acting as an objective reference standard. No human adjudication process involving multiple readers is described for the test results.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic assay for chemical analysis, not an imaging device or AI diagnostic tool that typically involves human reader interpretation. Therefore, the concept of human readers improving with or without AI assistance is not relevant here.

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

Yes, the studies presented are all standalone performance evaluations of the LZI Methadone II Enzyme Immunoassay device itself, without human interpretation in the results. The device outputs a quantitative or qualitative result, which is then compared against established ground truths (e.g., LC/MS, spiked concentrations).

7. The Type of Ground Truth Used

• For Precision, Linearity, Cross-reactivity, and Interference Studies: The ground truth was established by preparing urine samples with known, spiked concentrations of methadone or other compounds.
• For Method Comparison (Accuracy) with Clinical Samples: The ground truth for methadone and methadone metabolite concentrations was established using LC/MS (Liquid Chromatography/Mass Spectrometry).

8. The Sample Size for the Training Set

The document describes performance studies, which represent a test set. It does not mention a specific "training set" or "validation set" in the context of an algorithm or machine learning. For an immunoassay, the "training" typically refers to the assay development and optimization process, not a separate data set in the same way as an AI model.

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

As noted above, the concept of a "training set" for an algorithm with specific ground truth establishment is not directly applicable to this immunoassay device in the provided document. The development and optimization of the immunoassay (analogous to "training" in AI) would involve establishing reactivity to methadone and minimal cross-reactivity via laboratory experiments and chemical principles, rather than a distinct training data set with ground truth in the AI sense.

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