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The GSP Neonatal Creatine Kinase-MM kit, is intended for the quantitative in vitro determination of creatine kinase MM-isoform (CK-MM) concentration in blood specimens dried on filter paper as an aid in screening newborns for Duchenne Muscular Dystrophy (DMD) using the GSP instrument.

The GSP Neonatal Creatine Kinase-MM assay is a solid phase, two-site fluoroimmunometric assay based on the direct sandwich technique and utilizes standard PerkinElmer DELFIA chemistry with the GSP instrument. The kit contains:

• . The CK-MM Calibrators (containing 0, 30, 120, 500, 2000 and 8000 ng/mL of creatine kinase) consisting of 7 cassettes each containing 1 set of dried blood spots.
• The CK-MM Controls (containing 130, 500 and 2000 ng/mL of creatine kinase) consisting of 5 cassettes each containing 2 set of dried blood spots.
• Anti-CK-MM-Eu Tracer ●
• CK-MM Assay Buffer ●
• Anti-CK-MM Microtitration strips ●
• Extra barcodes for the plates ●

Here's an analysis of the GSP Neonatal Creatine Kinase-MM kit's acceptance criteria and the study proving it meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly list "acceptance criteria" for the overall device performance in a summary table. Instead, it describes analytical performance studies (precision, linearity, detection limits, specificity) with implied acceptance based on CLSI guidelines. For clinical performance, the results are presented with different cut-off values, and the benefit-risk assessment provides the overall conclusion regarding the device's benefit.

However, we can infer some key performance metrics from the clinical study results and regulatory context. The primary clinical acceptance is tied to its ability to aid in screening for DMD.

Inferred Acceptance Criteria and Reported Device Performance:

• DMD Positive identified: 34 out of 34 (100%) |
  | (False Negative Rate) | As low as possible to prevent delayed diagnosis. (Labeling statement: future lots could range from 0% to 0.48% at 99.5th percentile, and 0% to 0.05% at 97.5th percentile) | Cut-off 1250 ng/mL: 0% (0 false negatives out of 34 confirmed DMD positive samples) |
  | (False Positive Rate) | Acceptable trade-off to enable screening benefits, considering the need for confirmatory testing. (Labeling statement: future lots could range from 0.4% to 0.7% at 99.5th percentile, and 2.0% to 3.7% at 97.5th percentile) | Cut-off 1250 ng/mL: 2.26% (Routine samples) (69 presumed negative / 3041 routine samples) |
  | | | Cut-off 2040 ng/mL: 0.53% (Routine samples) (16 presumed negative / 3041 routine samples) |
  | Analytical Performance | | |
  | Reportable Range | Sufficiently broad to cover clinically relevant CK-MM concentrations. (Implied by CLSI EP06 and subsequent claim) | 29.2-8000 ng/mL |
  | Limit of Blank (LoB) | Low enough to reliably distinguish between the absence and presence of analyte with a high degree of confidence. (Based on CLSI EP17-A2) | 0.7 ng/mL |
  | Limit of Detection (LoD) | Low enough to reliably detect the analyte above background noise. (Based on CLSI EP17-A2) | 2.2 ng/mL |
  | Limit of Quantitation (LoQ) | Low enough to quantify the analyte with acceptable precision and accuracy. (Based on CLSI EP17-A2 and (b)% CV acceptance limit) | 6.8 ng/mL |
  | Specificity (Absence of Interference) | Substances commonly found in neonatal blood or used in care should not significantly interfere with results within specified limits. (Limit for significant interference defined as (b)(4)%) | Most tested substances (bilirubin, triglycerides, albumin, acetaminophen, etc.) at high concentrations showed no significant interference. Chlorhexidine digluconate (0.04%) and low hematocrit (35-45% at 159 ng/mL CK-MM) showed interference. |
  | Cross-reactivity (CK-BB, CK-MB) | Clinically relevant levels of related enzymes (CK-BB, CK-MB) should not significantly cross-react to avoid false positives. (Limit for significant cross-reactivity defined as (b)(4)%) | Cross-reactivity results for CK-BB and CK-MB were provided in tables (values redacted). |
  | Stability of DBS Samples | CK-MM in DBS samples must maintain integrity over reasonable storage and shipping conditions for practical use. | - Stable for up to 200 days at +4°C (dry).
• Moderate loss (up to 27%) after 6 days at +4℃ (ambient).
• Stable for up to 25 days at -20℃ (ambient).
• Stable for up to 20 days at +21°C (dry).
• Unstable in humid conditions (+21℃ / +35℃,

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The GSP Neonatal Total Galactose kit is intended for the quantitative determination of total galactose (galactose and galactose-1-phosphate) concentrations in blood specimens dried on filter paper as an aid in screening newborns for galactosemia using the GSP® instrument.

The GSP Neonatal Total Galactose kit contains sufficient reagents to perform 1152 assays. The GSP Neonatal Total Galactose test system measures total galactose, i.e. both galactose and galactose-1-phosphate, using a fluorescent galactose oxidase method. The fluorescence is measured using an excitation wavelength of 505 nm and an emission wavelength of 580 nm. The kit contains Neonatal Total Galactose Assay Reagent 1, Neonatal Total Galactose Assay Reagent 2, Neonatal Total Galactose Assay Buffer, Neonatal Total Galactose Assay Reconstitution Solution, and Neonatal Extraction Solution. Calibrators and Controls are also included.

1. Table of Acceptance Criteria and Reported Device Performance

• Conjugated Bilirubin: Concentrations above 16.6 mg/dL caused a significant decrease (>15%) in measured total galactose. At 24.9 mg/dL and above, the decrease was 100% at some total galactose concentrations.
• Intralipid: Concentrations above 250 mg/dL (at 5 and 10 mg/dL total galactose) or 375 mg/dL (at 15 mg/dL total galactose) caused a significant increase (>15%) in measured total galactose. Maximum tested (1500 mg/dL) caused an increase of ~52-77%.
• Hemoglobin (with Bilirubin): Hemoglobin levels at 198 g/L and above in combination with an elevated bilirubin level of 15 mg/dL caused a significant increase (>15%) in measured total galactose at certain total galactose concentrations. For example, at 5 mg/dL total galactose, 198 g/L Hb led to a 26.3% increase.
• Non-Interfering Substances: Unconjugated bilirubin (20 mg/dL), ß-Nicotinamide adenine dinucleotide (100 µmol/L), Glutathione (3 mmol/L), Human Serum Albumin (30 mg/mL), Ascorbate (6 mg/dL), D-glucose (1000 mg/dL), D-mannose (100 mg/dL), D-fructose (18 mg/dL), Ampicillin (152 µmol/L), and Lithium heparin (0.375 mg/ml), and Hematocrit levels from 30% to 66% (102-230 g/L Hemoglobin) were found not to interfere. |
  | Screening Performance vs. Predicate (95th percentile) | Overall percent agreement = 96.0%
  Positive percent agreement = 63.6%
  Negative percent agreement = 97.9% |
  | Screening Performance vs. Predicate (99th percentile) | Overall percent agreement = 98.8%
  Positive percent agreement = 53.3%
  Negative percent agreement = 99.4% |

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

• Sample Size for Precision Study: 7 samples, with 216 total measurements per sample (4 replicates per sample, in 27 runs over 21 days using 3 kit lots and 3 GSP instruments).
• Sample Size for LoD: 216 determinations of 4 low-level samples.
• Sample Size for LoB: 150 blank samples.
• Sample Size for Recovery: 3 contrived dried blood spot samples.
• Sample Size for Interference Studies: Not explicitly stated for each concentration, but involved various concentrations of interfering substances at three total galactose concentrations (5, 10, and 15 mg/dL).
• Sample Size for Internal Method Comparison: 141 routine screening and spiked blood spot specimens.
• Sample Size for Screening Performance Study: 2320 samples (6 confirmed positive samples and 2314 routine samples).
• Data Provenance: The screening performance study was conducted at "one newborn screening laboratory in the United States." Other non-clinical studies (precision, linearity, LoB/LoD/LoQ, recovery, interference) appear to be internal laboratory studies without specific geographic provenance mentioned, but presumably also conducted in the US or Finland (Wallac Oy headquarters). The studies were retrospective, using banked samples and contrived samples.

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

The document does not mention the use of experts to establish ground truth for the test set. For the screening performance study, "6 confirmed positive samples" are mentioned, implying prior clinical diagnosis as the ground truth. The qualifications of who confirmed these positive cases or how the "routine samples" were classified as normal are not specified.

4. Adjudication Method for the Test Set

Not applicable. The document does not describe any expert adjudication process for the test set. Ground truth for confirmed positive samples likely came from clinical diagnosis.

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

Not applicable. This device is an in-vitro diagnostic test kit (laboratory assay) for quantitative determination, not an imaging device or AI-assisted diagnostic tool that would involve human readers interpreting results in a MRMC study.

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

This refers to the performance of the assay itself. The entire submission details the standalone performance of the GSP Neonatal Total Galactose kit (assay only) without human-in-the-loop interpretation beyond standard laboratory procedures and reporting. The "GSP® instrument" is automated, as stated in the comparison chart ("GSP instrument, automated").

7. The Type of Ground Truth Used

• For Analytical Performance (Precision, LoB, LoD, LoQ, Linearity, Recovery, Interference): Ground truth was established by preparing samples with known concentrations of total galactose or specific interfering substances. For example, for recovery, the "recovery of galactose, galactose-1-phosphate, and both combined was determined from three contrived dried blood spot samples," meaning these samples were prepared with known amounts.
• For Screening Performance Study: The ground truth for the 6 positive samples was "confirmed positive." This implies a clinical diagnosis of galactosemia, likely through follow-up diagnostic testing. The other 2314 samples are referred to as "routine samples" and classified as "normal" in the context of screening performance, likely based on either their negative predicate device result or their actual clinical status. The document also compares the new device's results against the predicate device's results as a reference for "Manual result."

8. The Sample Size for the Training Set

Not applicable in the conventional sense of machine learning training sets. This is a chemical assay, not an AI/ML device that requires a distinct training set for model development. The development and optimization of the assay would involve various experiments, but these are not referred to as "training sets" in this context.

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

Not applicable, as there is no "training set" in the context of an AI/ML model for this chemical assay. The development of the calibrators and controls (which are prepared with known concentrations of galactose and galactose-1-phosphate) serves an analogous function in ensuring accuracy and consistency of the assay.

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