(192 days)
The GSP Neonatal Biotinidase kit is intended for the quantitative in vitro determination of human biotinidase activity in blood specimens dried on filter paper as an aid in screening newborns for biotinidase deficiency using the GSP instrument.
The GSP Neonatal Biotinidase kit contains sufficient reagents to perform 1152 assays. The GSP Neonatal Biotinidase test system measures biotinidase activity, combining an enzyme reaction with a solid phase time-resolved immunofluorescence assay. The GSP Neonatal Biotinidase assay is based on the ability of the biotinidase enzyme to cleave the amide bond in Eu-labeled biotin. The enzyme reaction is stopped by addition of streptavidin which has high affinity for biotin (either Eu-labeled or free biotin). The streptavidin-biotin complexes are captured by the solid phase monoclonal antibody directed against streptavidin. DELFIA Inducer dissociates the molecules into the solution where the europium fluorescence is measured. The measured fluorescence is inversely proportional to the biotinidase activity of the sample.
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
| Acceptance Criteria Category | Specific Criteria | Reported Device Performance |
|---|---|---|
| Precision (Variation) | Total variation (CV) for dried blood spot samples across 3 kit lots and 3 GSP instruments. | Total variation ranged from 7.5% to 12.7% CV. |
| Analytical Sensitivity | Limit of Blank (LoB) | LoB = 9.5 U/dL (95th percentile of blank samples, n=150) |
| Limit of Detection (LoD) | LoD = 14.8 U/dL (based on 360 determinations of five low-level samples) | |
| Limit of Quantitation (LoQ) | LoQ = 14.8 U/dL (lowest activity with total CV ≤ 20%) | |
| Linearity | Demonstrate linearity throughout the measuring range. | Demonstrated linear throughout the measuring range (from 14.8 U/dL to 325 U/dL). |
| Interference | Ampicillin, sulfisoxazole, glutathione, unconjugated bilirubin, and conjugated bilirubin/triglyceride effects. | Interfering: Ampicillin (≥1.4 mg/dL at low biotinidase, 2.8 mg/dL at high biotinidase), Sulfisoxazole (≥7.5 mg/dL at low biotinidase), Glutathione (>30 mg/dL), Unconjugated bilirubin (10 mg/dL at low biotinidase), Conjugated bilirubin (≥2.5 mg/dL), Triglyceride (≥250 mg/dL). |
| Non-interfering: Adrenocorticotropic hormone, ascorbic acid, biotin, Gammaglobulin, gentamicin sulphate, hemoglobin, human serum albumin, kanamycin sulphate, penicillin G, phenytoin, phenobarbital, sulfmethoxazole, trimethoprim, valporic acid, vitamin K1 (at specified concentrations). | ||
| Clinical Performance | Agreement with predicate device for screening newborns for biotinidase deficiency. | Overall percent agreement: 99.6% (CI 99.2% - 99.8%) |
| Positive percent agreement: 92.0% (CI 74.0% - 99.0%) | ||
| Negative percent agreement: 99.7% (CI 99.3% - 99.9%) | ||
| Classification of confirmed biotinidase deficient samples. | All 20 retrospective confirmed biotinidase deficiency specimens were classified as screening positive by the predicate. The GSP method initially classified 19/20 as positive, with one initially negative specimen testing positive in 4 repeat tests. |
Study Details
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Sample size used for the test set and the data provenance:
- Clinical Study Test Set: 2008 specimens (1988 routine newborn screening specimens and 20 retrospective confirmed biotinidase deficiency specimens).
- Provenance: This information is not explicitly stated, but it can be inferred that these are human blood specimens from newborn screening programs. The "retrospective confirmed biotinidase deficiency specimens" suggest historical data, implying a retrospective study design for these specific samples. The routine screening specimens would be prospective in nature from a screening program. No specific country of origin is mentioned.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document does not explicitly state the number of experts or their qualifications for establishing the ground truth.
- For the "retrospective confirmed biotinidase deficiency specimens," the ground truth is implied to be established through confirmation methods for biotinidase deficiency, but no details on expert involvement are provided.
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Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- The document does not describe any specific adjudication method for establishing the ground truth of the clinical test set. The term "confirmed biotinidase deficiency specimens" implies that a definitive diagnosis was reached, but the process is not detailed.
- For the one discrepant clinical case, it was subjected to "multiple (4) repeat tests." This could be considered a form of internal adjudication/re-testing rather than external expert consensus.
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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 MRMC or human-in-the-loop study was conducted or described. This device is an in vitro diagnostic kit, meaning it is an automated assay, not an AI assisting human readers. The comparison is between the new automated device and a predicate manual method.
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If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, the core of the clinical study involved evaluating the performance of the GSP Neonatal Biotinidase kit (an automated instrument-based assay) as a standalone device in comparison to the existing manual predicate device. The results are reported as direct comparisons between the two methods on the same samples.
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The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- The ground truth for the clinical study was based on the classification of specimens as "biotinidase deficient" or "normal." For the 20 known deficient specimens, the ground truth was "retrospective confirmed biotinidase deficiency." For the routine screening specimens, it is implied that the predicate device's result (manual Neonatal Biotinidase method) served as a comparative reference, which itself would have a ground truth based on established clinical diagnostic criteria for biotinidase deficiency. The cut-offs used for both devices (0.5th percentile for GSP and 30% of mean + 2SD for the predicate) are tied to population distributions expected for the condition.
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The sample size for the training set:
- The document describes the GSP Neonatal Biotinidase kit as a diagnostic assay, and its development would typically involve internal validation and optimization data. The provided text, being a 510(k) summary, primarily focuses on the test set performance to demonstrate substantial equivalence.
- There is no explicit mention of a separate "training set" in the context of machine learning or AI models, as this is an in vitro diagnostic kit based on an enzymatic reaction. The calibrators and controls used in the kit are standardized and prepared from human whole blood, aiding in the assay's calibration and ongoing quality control during operation.
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How the ground truth for the training set was established:
- Not applicable in the context of a "training set" for a traditional in vitro diagnostic assay.
- For the calibrators, they were "calibrated against in-house primary calibrators (dried blood spots, stored at -80 to -60°C) prepared using adult human blood (endogenous biotinidase activity in serum) and washed red blood cells as blood matrices." This describes how the reference values for the assay's internal calibration curve are established.
§ 862.1118 Biotinidase test system.
(a)
Identification. The biotinidase test system is an in vitro diagnostic device intended to measure the activity of the enzyme biotinidase in blood. Measurements of biotinidase are used in the treatment and diagnosis of biotinidase deficiency, an inborn error of metabolism in infants, characterized by the inability to utilize dietary protein bound vitamin or to recycle endogenous biotin. The deficiency may result in irreversible neurological impairment.(b)
Classification. Class II (special controls). The special control is sale, distribution, and use in accordance with the prescription device requirements in § 801.109 of this chapter.