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The s LDL-EX"SEIKEN" test is for the quantitative determination of small, dense (sd) LDL cholesterol (-C) in human serum or plasma. The s LDL-EX"SEIKEN" test is used in conjunction with other lipid measurements and clinical evaluations to aid in the risk management of lipoprotein disorders associated with cardiovascular disease.

The assay consists of two steps and is based on the technique to use well-characterized surfactants and enzymes that selectively react with certain groups of lipoproteins.

In the first step, non-sd LDL lipoproteins, that is, chylomicrons, VLDL, IDL, L-LDL and HDL are decomposed by a surfactant and sphingomyelinase in Reagent-1 that is reactive to those non-sd LDL lipoproteins. The cholesterol released from such non-sd LDL lipoproteins is then degraded to water and oxygen by the action of enzymes. Cholesterol ester is hydrolyzed by the cholesterol esterase (CHE) and then oxidized by the cholesterol oxidase (CO). Produced hydrogen peroxides are finally decomposed to water and oxygen by the catalase.

In the second step, another surfactant in Reagent-2 releases cholesterol only from sd LDL particles and cholesterol released from sd LDL is then subject to the enzymatic reactions. As catalase in the reaction mixture is inhibited by sodium azide in Reagent-2, hydrogen peroxides, produced from the reaction with the cholesterol esterase and cholesterol oxidase, develop a purple-red color with the coupler in the presence of peroxidase (POD).

The provided text describes the acceptance criteria and a study demonstrating that the device meets these criteria. The device is the s LDL-EX "SEIKEN" test, which is for the quantitative determination of small, dense (sd) LDL cholesterol (-C) in human serum or plasma.

Here's an analysis of the requested information based on the provided text:

1. Table of acceptance criteria and the reported device performance

The document details performance characteristics rather than explicit "acceptance criteria" for a specific disease detection task, as this is a quantitative diagnostic test. The acceptance is based on the device's analytical performance and its ability to distinguish risk groups for CHD.

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

• Analytical Performance Studies (Nonclinical Data):

  • Precision: 80 results per sample, for 5 different samples at each of 3 sites.
  • Linearity: 13 samples, tested in duplicate.
  • Spike and Recovery: 3 samples tested in triplicate (before and after spiking).
  • Interferences: 3 human serum samples per compound, assayed in triplicate.
  • Matrix Equivalence: 48 subjects, with multiple serum and plasma samples drawn.
  • Provenance: Not explicitly stated for all non-clinical data, but Denka and two "external sites" are mentioned for precision testing, implying various locations.

• Clinical Data (Reference Range Study & Clinical Studies):

  • Reference Range Study:
    • Total subjects: 210 male, 232 female across two U.S. regions.
    • Provenance: U.S. regions, single blood draw.
    • Retrospective/Prospective: Not explicitly stated, but implies prospective collection for this study from "volunteers."
  • Clinical Studies (ARIC Study Data):
    • Test Set (Patient Cohort): 7123 individuals with sd LDL-C < 50 mg/dL, and 3167 individuals with sd LDL-C ≥ 50 mg/dL for the cutoff verification. Cohort for quartile analysis would be the full dataset (7123 + 3167 = 10290 subjects).
    • Data Provenance: Banked samples and clinical outcome data from Visit 4 of the Atherosclerosis Risk in Communities (ARIC) study. The ARIC study is a long-term, prospective cohort study conducted in the United States.
    • Retrospective/Prospective: The use of "banked samples and clinical outcome data" from a prior study (ARIC) means this specific validation was retrospective in nature, utilizing pre-existing data. Incident CHD outcomes were tracked until December 31, 2011, indicating a follow-up period.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

• For the s LDL-EX "SEIKEN" device (a quantitative lab test): Ground truth is typically established through a reference method or clinical outcomes, not expert independent evaluation for each case.
• For the Clinical Study (ARIC data):
  • The "ground truth" for CHD events was established using "clinical outcome data" from the ARIC study. This includes "self-reported myocardial infarction (MI) before Visit 1 or silent MI (diagnosed by electrocardiographic changes), validated MI, or revascularization between Visits 1 and 4," and "hospitalized MI, fatal CHD, or cardiac procedure by December 31, 2011."
  • The document implies that these outcomes were part of the ARIC study's established protocols for event adjudication, which typically involves medical professionals (e.g., physicians, cardiologists) reviewing medical records and diagnoses.
  • The specific number and qualifications of experts involved in the original ARIC study's outcome adjudication are not specified in this submission.

4. Adjudication method for the test set

• For the s LDL-EX "SEIKEN" device itself (analytical performance): Adjudication methods like 2+1 or 3+1 are not applicable since it's a quantitative measurement of a biomarker. Analytical accuracy is assessed by comparing to known values, reference methods, or statistical measures of precision and linearity.
• For the Clinical Study (ARIC data): The "ground truth" for CHD events was based on the ARIC study's established definitions:
  • "Prevalent CHD was defined as self-reported myocardial infarction (MI) before Visit 1 or silent MI (diagnosed by electrocardiographic changes), validated MI, or revascularization between Visits 1 and 4."
  • "Incident CHD was defined as those participants with hospitalized MI, fatal CHD, or cardiac procedure by December 31°, 2011 as previously described in publications."
  • This is a form of outcome-based adjudication based on clinical records and pre-defined criteria from a large epidemiological study. Specific expert consensus methods like "2+1" for individual case review are not described for this particular study, but it is implied that the original ARIC study had robust and documented methods for outcome ascertainment.

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 MRMC study was done. This device is a quantitative in vitro diagnostic (IVD) assay for a biomarker, not an AI-assisted imaging or diagnostic tool requiring human reader interpretation studies. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable here.

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

• The device is a standalone quantitative assay. Its performance (analytical and clinical association) is evaluated without a human-in-the-loop component for the measurement itself. The s LDL-EX "SEIKEN" device provides a direct numerical output (mg/dL) of sd LDL-C. Clinical interpretation of this value (e.g., using the 50.0 mg/dL cutoff) is done by a clinician, but the device's measurement is "standalone."

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

• Analytical Performance: The ground truth for analytical performance characteristics (LoB, LoD, LoQ, precision, linearity, interference, matrix equivalence) is established through controlled laboratory experiments and comparison against established analytical principles and/or known concentrations.
• Reference Range Study: Ground truth for a reference range is defined by the distribution of values in a healthy, defined population.
• Clinical Studies: The ground truth for the clinical validation was outcomes data from the ARIC study, specifically incident Coronary Heart Disease (CHD) events (hospitalized MI, fatal CHD, cardiac procedure).

8. The sample size for the training set

• The document does not explicitly describe a "training set" for the s LDL-EX "SEIKEN" device in the context of an AI/ML model. This device is a biochemical assay, not an AI model that requires a distinct training and test set in the same way.
• The clinical study utilized banked samples from the ARIC study, effectively using this existing cohort as the "test set" to validate the device's clinical relevance and a previously established cutoff. The "training" of the concept of sd LDL-C as a biomarker and the 50.0 mg/dL cutoff was "established in a previous study" (MESA), not within the scope of this submission's data.

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

• As noted above, there's no explicitly defined "training set" for an AI/ML model in this submission.
• For the validation of the 50.0 mg/dL cutoff, the ground truth was clinical outcomes from the ARIC study, but the cutoff itself was "established in a previous study" (MESA). The methodology for establishing ground truth in the MESA study is not detailed in this provided text.

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