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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.

Device Description

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 ●

AI/ML Overview

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:

Performance Metric	Acceptance Criteria (Inferred from regulatory context and benefit/risk)	Reported Device Performance (Clinical Study)
Clinical Performance
Ability to screen for DMD	Must effectively identify DMD positive newborns to enable earlier diagnosis and intervention, where benefits outweigh risks of false positives/negatives. (Benefit-risk assessment indicates this was met.)	Cut-off 1250 ng/mL: - 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℃, <80% recovery at 2 days) and hot conditions (+37℃, <80% recovery at 3 days).

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

Test Set Sample Size:
- Routine Newborn Screening Samples: 3,041
- Retrospectively Confirmed DMD Positive Samples: 30
- Total in Clinical Study: 3,071 (for screening performance analysis using both routine and confirmed positive samples)
Data Provenance:
- Routine Samples: Prospective clinical study of routine newborn screening samples. Most (97.3%) were from newborns ≤ 72 hours old. Stored for (b)(4) days prior to testing.
- DMD Confirmed Positive Samples: Retrospective. Ranged from 1 to 12 years of storage.
- Country of Origin: Not explicitly stated but implied to be from the US, given "state U.S. laboratory" mentioned in the "Expected Values" section for a different study (though this doesn't directly refer to the provenance of the clinical study samples).

3. Number of Experts and Qualifications for Ground Truth

Number of Experts: Not explicitly stated for establishing ground truth for the test set. However, "FDA consulted with experts in the field of DMD diagnosis" regarding the acceptance of DMD gene sequencing as a diagnostic method.
Qualifications of Experts: "Experts in the field of DMD diagnosis." More specific qualifications (e.g., years of experience, subspecialty) are not provided.

4. Adjudication Method for the Test Set

Initial Testing: Samples were initially tested in singlicate.
Retest for High Concentration: If the CK-MM concentration was greater than the cut-off, new dried blood spot punches were re-tested in duplicate to confirm high concentration.
Final Categorization for Retested Specimens: Final screening categorization was based on the mean value of the replicate retest results.
Ground Truth Determination:
- DMD Positive Confirmation: Next-generation sequencing of the DMD gene was used for routine samples with CK-MM concentrations above 1250 ng/mL (initially tested) and between 984 and 1210 ng/mL (initially tested).
- Confirmed DMD Positive Samples: Clinical diagnosis of the 30 retrospective positive samples was known.
- This is a form of hierarchical or tiered testing with a retest for "above cut-off" and then a definitive diagnostic test (NGS) for those flagging for further investigation. There is no mention of multiple human readers or a consensus process for the screening test results themselves. The NGS results served as the ground truth.

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

No MRMC study was done. This device is an automated in vitro diagnostic (IVD) assay quantifying CK-MM levels, not an imaging or interpretive AI device where human readers interact with AI. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable here.

6. Standalone (Algorithm Only) Performance

Yes, a standalone performance study was done. The entire clinical study described is a standalone performance evaluation of the GSP Neonatal Creatine Kinase-MM kit. The device operates automatically, performing quantitative analysis of CK-MM. Its output (CK-MM concentration) is then compared against established cut-offs and ground truth (NGS or clinical diagnosis) to determine screening performance metrics like false positive and false negative rates. There is no human-in-the-loop interacting with an AI algorithm for interpretation in the context of this device.

7. Type of Ground Truth Used

Expert Consensus: Not explicitly stated as the primary method for all samples, but "experts in the field of DMD diagnosis" confirmed the validity of DMD gene sequencing.
Pathology: Not applicable in this context as it's not a tissue-based diagnosis.
Outcomes Data: Not primary. The ground truth refers to a definitive diagnosis rather than long-term outcomes.
Genetic Testing / Clinical Diagnosis: This is the primary method of ground truth.
- For the investigated routine samples (those above initial cut-off or in a specific lower range), Next-Generation Sequencing (NGS) of the DMD gene was used as the ground truth.
- For the 30 retrospectively confirmed positive DMD samples, their clinical diagnosis was the ground truth.

8. Sample Size for the Training Set

The document does not provide details on a specific "training set" for an AI algorithm. This device is a fluoroimmunometric assay, not an AI/ML-based diagnostic system that would typically undergo a training phase with a distinct dataset.
The "calibration curve" mentioned in calibration (Section M.5) is part of the analytical process to quantify CK-MM concentration, not training in the AI/ML sense. Similarly, "expected values" are derived from a separate study (2019 routine newborn screening specimens) but are not a "training set" for an algorithm.

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

Since there's no mention of a "training set" in the context of an AI/ML algorithm, this question is not applicable. The device's calibration and analytical performance were established through standard laboratory practices and CLSI guidelines for IVDs, which do not involve AI/ML training concepts or associated ground truth establishment.

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