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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

Study Details

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

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The Neonatal Biotinidase kit is intended for the semiquantitative determination of biotinidase activity in blood specimens dried on filter paper as an aid in screening newborns for biotinidase deficiency.

Biotinidase is found in the blood sample itself. Filter paper disks from newborn dried blood spot samples, calibrators and controls are punched into the wells of a microplate. When biotin substrate reagent containing biotin 6-aminoquinoline (6-AQ) is added to a well containing a punched dried blood spot, the reagent extracts and reconstitutes the proteins and enzymes in the spot. The biotinidase enzyme in the sample cleaves the substrate to biotin and fluorescent 6-AQ The addition of the ethanol stops the reaction and precipitates the proteins to cover the bottom of the well and the extracted spot. The fluorescent product (6-AQ) formed during the reaction is measured with a fluorometer. The biotinidase activity is defined against a calibration curve. The biotinidase activity of the sample is determined by comparing the fluorescence intensity of the sample to a calibration curve.

The Neonatal Biotinidase kit is intended for the semi-quantitative determination of biotinidase activity in blood specimens dried on filter paper as an aid in screening newborns for biotinidase deficiency. The study aimed to demonstrate substantial equivalence to the Astoria-Pacific SPOTCHECK® Biotinidase 50-Hour Reagent Kit (K010844).

1. Table of Acceptance Criteria and Reported Device Performance:

The document describes a method comparison study to establish substantial equivalence rather than explicit acceptance criteria with pre-defined thresholds. However, based on the provided results, the implicit acceptance criteria would involve high positive percent agreement (PPA) and overall percent agreement (OPA) with the predicate device.

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

• Test Set Sample Size: 1516 samples.
• Data Provenance: The samples included 1516 newborn dried blood spot specimens representing the US population. The study included:
  • 1496 routine screening specimens (prospective, from the US population).
  • 20 retrospective specimens diagnosed positive for biotinidase deficiency (provenance not explicitly stated but implies confirmed cases, likely from a US population or referral lab).

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

The document does not specify the number or qualifications of experts used to establish the ground truth. It states that 20 retrospective specimens were "diagnosed positive for biotinidase deficiency," implying a clinical diagnosis, but details on who made these diagnoses are not provided. For the routine screening samples, the ground truth is established by the comparison to the predicate device and clinical outcome (diagnosed biotinidase deficiency or not).

4. Adjudication Method for the Test Set:

Not applicable. This study is a method comparison between two assays, not a diagnostic study requiring adjudication against a clinical outcome based on expert review of ambiguous cases. The "ground truth" for the deficient samples appears to be established by prior clinical diagnosis, and routine samples are compared against the predicate as well as clinical diagnosis outcomes.

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

No, an MRMC comparative effectiveness study was not done. This study is a comparison of two diagnostic assays, not an assessment of human reader performance with or without AI assistance.

6. Standalone (Algorithm Only) Performance Study:

Yes, a standalone study was performed. The device (Neonatal Biotinidase kit) was tested on its own and its results were compared to those from a commercially available predicate device. The performance metrics (PPA, OPA) are based on the direct output of the device.

7. Type of Ground Truth Used:

The ground truth for the 20 positive cases was established by clinical diagnosis ("retrospective specimens diagnosed positive for biotinidase deficiency"). For the routine samples, the "ground truth" for comparison purposes within the study was intrinsically linked to the results of the predicate device and the absence of a biotinidase deficiency diagnosis.

8. Sample Size for the Training Set:

The document does not provide information on a specific training set or its sample size for the Neonatal Biotinidase kit. Kits for in vitro diagnostic (IVD) use typically involve extensive assay development and validation, but specific "training sets" in the machine learning sense are not usually reported in this context. The calibration curve and internal controls are part of the assay's design and standardization.

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

As no specific training set in the AI/ML sense is mentioned, information on how its ground truth was established is not provided. The kit's calibration curve is established using six levels of dried blood spots prepared from porcine blood, representing different biotinidase activity levels, which serves as a form of internal reference material.

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This method is for the semi-quantitative determination of biotinidase, EC 3.5.1.12, activity in dried whole blood spots using a spectrophotometer. Measurement of biotinidase activity is primarily for the diagnosis and treatment of biotinidase deficiency in newborns. This method is intended for in vitro diagnostic use in screening for decreased levels of biotinidase activity and not for monitoring purposes.

Biotinidase activity is determined by measuring the color that develops from p-Aminobenzoic Acid (PABA) after PABA is released from Biotinyl-p-Aminobenzoate (Biotin-PAB). Samples with biotinidase activity develop a purple color. Samples without biotinidase activity remain straw-colored. Patient samples of whole blood collected on standardized filter paper are eluted in a standard 96 well microplate. The plate is incubated with Biotin-PAB in a buffer at 37℃ for 240 minutes on a combination incubator/shaker. Following incubation, TCA is added to the sample mixture and the resulting precipitate is removed through filtration. The PABA in the filtrate is subsequently diazotized and coupled to a napthol derivative to form an azo dye by the successive addition of sodium nitrite, acidic ammonium sulfamate and finally, N-1-naphthylethylenediamine dihydrochloride (NED). The azo dye is measured colorimetrically at 550 nm on a commercial microplate absorbance reader with a reference measurement at 690 mm.

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 Reported Device Performance

The document does not explicitly present a formal "acceptance criteria" table with pre-defined thresholds for performance that the new device must meet. Instead, it compares the performance of the new device (SPOTCHECK Biotinidase Microplate Reagent Kit) against a legally marketed predicate device (K010844 Biotinidase Kit, 50-Hour) to demonstrate substantial equivalence, implying that performance comparable to the predicate device is the "acceptance criteria."

However, we can infer some criteria and report the device's performance based on the provided data:

Punctuation for specific values in the table above can be found in the excerpt itself.

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

• Test Set Sample Size:
  • Classification Study: 564 unclassified patient samples, 2 biotinidase deficient patient samples, and 10 deficient controls. Total of 576 samples.
  • Precision Study:
    • Within-Run & Total Precision (main): n = 80 for each activity level (Low, Moderate, Normal) for the Microplate Kit. n = 32 (Low), n = 44 (Moderate), n = 44 (Normal) for the Predicate Device.
    • Additional 5-day Low Activity Precision: n = 80 for the Microplate Kit.
• Data Provenance:
  • Classification Study: The 2 deficient patient samples were "clinically-confirmed." The 10 deficient controls were "provided by the Centers for Disease Control (CDC)." The 564 unclassified patient samples are not explicitly stated in terms of specific country of origin, but generally, patient samples for such studies imply a clinical setting.
  • Prospective/Retrospective: The text implies a retrospective analysis as samples "were treated according to the procedures detailed under SPEDMEN COLLECTION AND PREPARATION FOR ANALYSIS in the product insert," suggesting these were existing samples processed with the new kit.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience):

• The document implies that the ground truth for the two "clinically-confirmed" deficient patient samples was established by clinical diagnosis, as they are referred to as "persons clinically-confirmed as such."
• For the 10 deficient controls, the ground truth was "provided by the Centers for Disease Control (CDC)," which suggests these are established and certified deficient samples.
• The "experts" themselves and their specific qualifications are not detailed in the provided text. The predicate device's classification served as a comparative ground truth for other samples and for discrepancies.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

• The document mentions "Discrepant results ** were not confirmed by follow-up testing." This indicates that for samples where the new Microplate Kit and the Predicate Device yielded different classifications (e.g., Microplate Kit: Normal, Predicate Device: Partial Activity), no explicit expert adjudication or further follow-up gold standard testing was performed to resolve the discrepancy for the purpose of this study report. The discrepancy is simply noted. Therefore, an explicit adjudication method (like 2+1 or 3+1) was not described or applied to resolve discrepancies for the reported results. The predicate device's classification was primarily used as a comparative benchmark, not an adjudicated ground truth in cases of disagreement.

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, an MRMC comparative effectiveness study was not done. This device is an in-vitro diagnostic (IVD) reagent kit that measures biotinidase activity, not an AI-powered diagnostic imaging tool or a system involving human readers interpreting outputs. It's a chemical assay. The comparison is between the new kit and a predicate kit (both laboratory assays), not between humans with and without AI assistance.

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

• Yes, the performance presented is standalone for the device (algorithm/assay only). The kit measures biotinidase activity using a spectrophotometer, which is an automated reading of a chemical reaction. The results described (linearity, sensitivity, precision, classification) are direct outputs of the assay kit itself without human interpretation influencing the measurable outcome, although trained laboratory personnel are required for manual steps (e.g., pipetting, filtration). The "human-in-the-loop" would be the technician performing the assay and reviewing the numerical results, but the performance metrics reported are for the assay's output itself.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

• Clinical Confirmation/Certified Controls and Predicate Device Comparison:
  • For deficient patient samples, "clinical confirmation" of biotinidase deficiency was the ground truth.
  • For deficient controls, the "Centers for Disease Control (CDC)" provided samples with established deficiency.
  • For the bulk of the samples (564 unclassified), the predicate device's classification served as the comparative benchmark. While not a "true" independent ground truth for every sample, it's used as the standard against which the new device's classifications are measured for substantial equivalence.

8. The sample size for the training set:

• The document does not explicitly mention a separate "training set" in the context of machine learning or AI. As a reagent kit for a chemical assay, it does not typically involve explicit "training data" in the AI sense. The development of such kits often involves extensive R&D and optimization, but this is usually not referred to as a "training set" in the same way an AI model would have one.

9. How the ground truth for the training set was established:

• As a "training set" in the AI sense is not specified, the method for establishing its "ground truth" is also not applicable or described within the document. The development of the assay would rely on established biochemical principles and validation using known concentrations and clinical samples.

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