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The LDL-Cholesterol Gen. 3 assay is an in-vitro test for the quantitative determination of LDL-cholesterol in human serum and plasma on Roche/Hitachi cobas c systems. Lipoprotein measurements are used in the diagnosis and treatment of lipid disorders (such as diabetes mellitus), atherosclerosis, and various liver and renal diseases.

Device Description

The LDL-Cholesterol Gen. 3 assay is a homogeneous enzyme colorimetric assay which provides the quantitative measurement of LDL-cholesterol in human serum and plasma. Reagents are packaged in a cassette labeled with their instrument positioning R1 (Reagent 1) and R2 (Reagent 2).

R1 contains Bis-trisb) buffer: 20.1 mmol/L, pH 7.0; 4-aminoantipyrine:0.98 mmol/L; ascorbic oxidase (AOD, Acremonium spec.): ≥ 66.7 µkat/L; peroxidase (recombinant from Basidiomycetes): ≥ 166.7 µkat/L; BSA: 4.0 g/L; preservative R2 contains MOPSC) buffer: 20.1 mmol/L, pH 7.0; EMSE: 2.16 mmol/L, cholesterol esterase (Pseudomonas spec.): ≥ 33.3 µkat/L; cholesterol oxidase (recombinant from E.coli)): ≥ 31.7 µkat/L; peroxidase (recombinant from Basidiomycetes): ≥ 333.3 µkat/L; BSA: 4.0 g/L; detergents; preservative

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the LDLC3 LDL-Cholesterol Gen.3 device, organized as requested:

Acceptance Criteria and Device Performance Summary

Performance Metric	Acceptance Criteria	Reported Device Performance
Limit of Blank (LoB)	Claim: 3.87 mg/dL	Result: 0.406 mg/dL (Meets acceptance criteria as it's below the claim)
Limit of Detection (LoD)	Claim: 3.87 mg/dL	Result: 0.99 mg/dL (Meets acceptance criteria as it's below the claim)
Limit of Quantitation (LoQ)	Claim: 3.87 mg/dL	Result: 2.28 mg/dL (Meets acceptance criteria as it's below the claim)
Drug Interference	Difference in recovery to the reference sample: ≤ ± 10%	All data passed the acceptance criteria for various common drugs, Simvastatin, Bezafibrate, and Nicotinic Acid. Specific highest concentrations shown not to interfere were reported for each drug (e.g., Acetylcysteine: 553 mg/L, Simvastatin: 16 mg/L).
Interference from VLDL, HDL, Chylomicrons	≤ ± 10% in recovery for VLDL-Cholesterol: ≤ 140 mg/dL, HDL-Cholesterol: ≤ 75 mg/dL, Chylomicrons: ≤ 2000 mg/dL triglycerides	All data passed the acceptance criteria for VLDL, HDL, and Chylomicrons within their specified concentration limits. The testing methodology confirmed the device's ability to selectively measure LDL-cholesterol.
Endogenous Substances Interference	≤ 10%	No significant interference was observed up to a Lipemia L index of 1000, Hemolysis H index of 1000, and Bilirubin I index of 60 (both conjugated and unconjugated). All data passed the ≤ 10% acceptance criteria.
Matrix Comparison	Comparisons with plasma vs. serum passed specification (details on specific regression equations and correlation coefficients are provided in the document).	Serum vs. Gel Separation P/B: y = 1.004x + 0.091, r = 1.000; Serum vs. Li-heparin P/B: y = 0.99x - 1.50, r = 0.999; Serum vs. K2-EDTA P/B: y = 0.98x - 0.248, r = 1.000; Serum vs. K3-EDTA P/B: y = 0.95x - 0.246, r = 0.999. All passed specification.
Linearity	3.87 mg/dL - 549 mg/dL: ≤ ± 10%	For both plasma and serum: Range tested: Plasma 3.66 - 584 mg/dL, Serum 3.53 - 565 mg/dL. Range found: Plasma 3.66 - 584 mg/dL, Serum 3.53 - 565 mg/dL. Recommended measuring range: 3.87 - 549 mg/dL. Linear regression equations and r-squared values indicate good linearity (e.g., Plasma: y = 1x + 0, r2 = 0.9995). Data passed the ≤ ± 10% acceptance criteria within the recommended range.
Precision	Not explicitly stated as a single acceptance criterion value in the provided text, but the data indicates typical precision study results, which are generally evaluated based on CV% limits for various concentrations. The reported CVs for both repeatability and intermediate precision are low (mostly <3%), indicating good precision.	Precinorm L: Repeatability CV 0.7%, Intermediate Precision CV 2.3%; Precipath HDL/LDL-C: Repeatability CV 0.7%, Intermediate Precision CV 2.1%; Human Serum pools (various concentrations): Repeatability CVs 0.7% - 1.2%, Intermediate Precision CVs 1.9% - 2.5%.
Method Comparison	Not explicitly stated as a single acceptance criterion in the provided text, but determined by the correlation and agreement with the predicate device.	Passing/Bablok regression: y = 0.984x = 0.786 mg/dL, r = 0.999. This indicates very strong correlation and close agreement with the predicate device.

Study Details

This submission describes the performance evaluation of the LDLC3 LDL-Cholesterol Gen.3 assay.

Sample sizes used for the test set and the data provenance:
- LoB Protocol: N=60 determinations (analyte-free sample, tested in five-fold, on two analyzers, over three days).
- LoD Protocol: Five low-analyte samples, measured in singlicate on two analyzers over three days.
- LoQ Protocol: Five low-level samples, tested in five replicates per sample on five days with three reagent lots, one run per day on one analyzer.
- Precision: 5 human serum sample pools and two control samples (4 aliquots per run, 1 run per day, 21 days).
- Drug Interferences: Two sample pools (low and high LDL concentration) for each drug, tested in triplicate. Total number of samples not explicitly stated for all drugs combined, but involves at least 2 pools x 3 replicates x 19 drugs = 114 measurements.
- Interference from VLDL, HDL, Chylomicrons: HDL: Two sample pools (low and high LDL), each divided into two aliquots, tested in triplicate. VLDL: Two sample pools (low and high LDL), spiked with increasing VLDL, measured in duplicate. Chylomicrons: Four sample pools (various chylomicron concentrations, including some ≥ 2000 mg/dL triglycerides), spiked with chylomicrons, measured in duplicate.
- Endogenous Interferences: Two human serum pools (one spiked, one unspiked) mixed in 10 dilution steps; samples tested in triplicate.
- Matrix Comparison: 59 samples for Gel Separation, 59 for Li-heparin, 57 for K2-EDTA, 59 for K3-EDTA. Samples ranged from 12.3 to 495 mg/dL. (Retrospective/Prospective not explicitly stated, but typically clinical lab studies like these are prospective collections or de-identified banked samples).
- Linearity: Two dilution series (serum and plasma), each with 14 concentrations, measured in triplicate.
- Method Comparison: 100 human serum samples (including 5 spiked and 2 diluted).
- Data Provenance: The document does not explicitly state the country of origin for the clinical samples. It refers to "human serum samples" and "human serum and plasma." This type of in-vitro diagnostic device testing would typically use samples collected under IRB-approved protocols, but the specific origins are not detailed. The studies are described in a manner consistent with prospective analytical validation.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- This is an in-vitro diagnostic device (IVD) for quantitative determination of a biomarker (LDL-cholesterol). The "ground truth" for calibrating and evaluating such devices is typically established through reference methods and certified reference materials, not through expert human interpretation of images or clinical cases. The device is being compared against a predicate device (LDL-Cholesterol plus 2nd generation).
- The document states: "This method has been standardized against the beta quantification method as defined in the recommendations in the LDL Cholesterol Method Certification Protocol for Manufacturers." This beta quantification method serves as the analytical ground truth/reference method for LDL-C measurement.
Adjudication method (e.g., 2+1, 3+1, none) for the test set:
- This concept of "adjudication" is not applicable to quantitative IVD studies. Adjudication methods (like 2+1, 3+1) are used in diagnostic imaging studies where multiple readers interpret cases, and discrepancies are resolved by a super-reader or consensus. For this device, direct quantitative measurements are being performed and compared to either a reference method or a predicate device.
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 a standalone quantitative assay for measuring LDL-cholesterol, not an AI-powered diagnostic imaging tool that assists human readers. Therefore, the concept of human reader improvement with/without AI assistance is not relevant here.
If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, the performance studies described are for the device (assay on the cobas c system) operating in a standalone manner. This is a fully automated quantitative measurement system, where the result is generated directly by the instrument, without human-in-the-loop interpretative steps that would influence the quantitative reading.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- The primary ground truth for the analytical validation is the beta quantification method as defined in the LDL Cholesterol Method Certification Protocol for Manufacturers. This is an accepted standardized reference method for truly measuring LDL-cholesterol.
- For the method comparison study, the predicate device (LDL-Cholesterol plus 2nd generation reagent) served as the comparative reference.
The sample size for the training set:
- This document describes an analytical validation for a quantitative in-vitro diagnostic reagent. There is no "training set" in the context of machine learning for this type of device. The assay relies on established chemical and enzymatic reactions, not machine learning algorithms trained on large datasets. The formulation of the reagent itself is based on chemical and biological principles.
How the ground truth for the training set was established:
- As explained above, there is no "training set" for this type of device. Therefore, the concept of establishing ground truth for a training set is not applicable. The assay's "truth" is rooted in its chemical-enzymatic mechanism and its standardization against a reference method (beta quantification).

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