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.

Device Description

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).

AI/ML Overview

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.

Performance Characteristic	Acceptance Criteria (Implicit)	Reported Device Performance	Study Type
Limit of Blank (LoB)	Not explicitly stated, but lower is better.	0.20 mg/dL	Analytical Performance
Limit of Detection (LoD)	Not explicitly stated, but lower is better.	0.38 mg/dL	Analytical Performance
Limit of Quantitation (LoQ)	%CVs less than 10% for the lowest concentration.	1.14 mg/dL	Analytical Performance
Precision (Within-laboratory %CV)	%CV for each control/sample, at each site.	Range: 1.3% to 4.3% across different sites and samples.	Analytical Performance
Linearity (Nonlinearity)	Absolute value of nonlinearity less than allowable nonlinearity.	Absolute value of nonlinearity was less than allowable nonlinearity at all tested levels. Linear throughout 4.0 - 100 mg/dL.	Analytical Performance
Spike and Recovery (% difference)	Not explicitly stated, but low % difference is desired.	Range: -0.5% to +1.3%.	Analytical Performance
Interferences (Hemoglobin)	Less than 10% difference or 3 mg/dL difference (for low level).	No significant interference up to 1,000 mg/dL.	Analytical Performance
Interferences (Bilirubin)	Less than 10% difference or 3 mg/dL difference (for low level).	No significant interference up to 60 mg/dL (conjugated and unconjugated).	Analytical Performance
Interferences (Chyle)	Less than 10% difference or 3 mg/dL difference (for low level).	No significant interference up to 1,420 FTU.	Analytical Performance
Interferences (Sodium L-ascorbate)	Less than 10% difference or 3 mg/dL difference (for low level).	No significant interference up to 100 mg/dL.	Analytical Performance
Interferences (Intralipid)	Less than 10% difference or 3 mg/dL difference (for low level).	No significant interference up to 10%. (up to 1% wt/vol as soybean oil).	Analytical Performance
Interferences (Uric acid)	Less than 10% difference or 3 mg/dL difference (for low level).	No significant interference up to 15 mg/dL.	Analytical Performance
Interferences (Triglyceride)	Less than 10% difference or 3 mg/dL difference (for low level).	No significant interference up to 1,500 mg/dL.	Analytical Performance
Interferences (Drugs)	No interference at three-times therapeutic levels.	No interference found for listed drugs.	Analytical Performance
Matrix Equivalence (Correlation Coefficient)	Close to 1.00.	Serum (SST): 1.00; Plasma (K2 EDTA): 1.00; Plasma (Lithium Heparin): 1.00.	Analytical Performance
Matrix Equivalence (Slope)	Close to 1.00.	Serum (SST): 1.00; Plasma (K2 EDTA): 0.96; Plasma (Lithium Heparin): 0.99.	Analytical Performance
Matrix Equivalence (Intercept)	Close to 0.	Serum (SST): +0.1; Plasma (K2 EDTA): -0.1; Plasma (Lithium Heparin): -0.4.	Analytical Performance
Clinical Association with CHD	Demonstrates predictive value for incident CHD, and validates clinical cutoff.	sd LDL-C predicted future CHD events. Cutoff of 50.0 mg/dL was validated (HR 1.26 in fully adjusted model, p=0.0006 for sd LDL-C >= 50 mg/dL vs < 50 mg/dL).	Clinical Study

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.

Summary

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510(k) SUMMARY

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. The assigned 510(k) number is K161679.

807.92 (a)(1)- Submitter Information

Submitter	Name:	Denka Seiken Co., Ltd.
	Address:	1359-1 Kagamida, Kigoshi, Gosen-shi,Niigata, Japan
	Phone:	81+250-42-0721 FAX: 81+250-43-8813
Contact	Name:	Thomas M. Tsakeris
		Devices & Diagnostics Consulting Group, Inc.
	Address:	16809 Briardale Road Rockville, MD 20855
	Phone:	301-330-2076 Email: DDCGI@Comcast.net

The Date the Summary was Prepared: August 18, 2017

807.92 (a)(2) Device name- trade name and common name, and classification

Trade Names:

· s LDL-EX "SEIKEN"

Common Names:

· Low-density lipoprotein (LDL) cholesterol sub-fraction test

Classification Names:

REAGENTS Class: Class I, meets the limitation to the exemption 862.9(c)(4) Panel: 75, Clinical Chemistry Product Code: PYP

807.92 (a)(3): Identification of the legally marketed predicate devices

The predicate device is Liposcience's (Liposcience, Inc., Raleigh, NC) NMR Lipoprofile Assay (K111516, cleared September 27, 2011).

807.92 (a)(4): Device Description

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.

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cholesterol esterase (CHE) and then oxidized by the cholesterol oxidase (CO). Produced hydrogen peroxides are finally decomposed to water and oxygen by the catalase.

807.92 (a)(5): Intended Use

807.92 (a)(6): Technological Similarities and Differences to the Predicate

COMPARATIVE CHART

Parameter	s LDL-EX“SEIKEN”K161679	NMR LipoProfileK111516
Intended Use/Indications for Use	The s LDL-EX“SEIKEN” is for thequantitative determination of small, dense(sd) LDL cholesterol (-C) in human serumor plasma.The s LDL-EX“SEIKEN” test system isused in conjunction with other lipidmeasurements and clinical evaluations toaid in the risk management of lipoproteindisorders associated with cardiovasculardisease.	The NMR LipoProfile® test, when usedwith the NMR Profiler, an automatedNMR spectrometer, measures lipoproteinparticles to quantify LDL particle number(LDL-P), HDL cholesterol (HDL-C), andtriglycerides in human serum and plasmausing nuclear magnetic resonance (NMR)spectroscopy. LDL-P and these NMR-derived concentrations of HDL-C andtriglycerides are used in conjunction withother lipid measurements and clinicalevaluation to aid in the management oflipoprotein disorders associated withcardiovascular disease. This test isperformed and provided as a service byLipoScience Laboratory.

Similarities to Predicate

Differences from Predicate

Methodology	Colorimetric Assay	NMR Spectrometer
-------------	--------------------	------------------

807.92 (b)(1): Brief Description of Nonclinical Data

A series of studies were performed that evaluated traditional laboratory performance characteristics; a summary of each study follows. The Roche Diagnostics Hitachi 917 was used in the studies.

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Limit of Blank, Detection, Quantitation

The testing was based on guidance from the Clinical and Laboratory Standards Institute document CLSI Protocol EP17-A2; LoB and LoD were evaluated using the classical approach, and LoQ was evaluated as functional sensitivity, identifying the lowest concentration with %CVs less than 10%. The LoB was 0.20 mg/dL, the LoD was 0.38 mg/dL, and the LoQ was 1.14 mg/dL.

Precision

Precision testing was performed at a total of three sites (Denka plus two external sites) according to the Clinical and Laboratory Standards Institute (CLSI) EP05-A2 approved guideline. Samples were assayed twice a day, two replicates per run, for 20 days, for a total of 80 results per sample. From these results, within-laboratory (total precision) was analyzed.

The study included five samples, namely the 2-level control set, and three serum-based pools. The three serum based pools used in the sites where different, but were representative of low, intermediate, and high sd LDL-C concentrations. Each site employed one lot of assay reagents.

	Lipid Control I	Lipid Control II	Human Serum L	Human Serum M	Human Serum H
n	80	80	80	80	80
Mean (mg/dL)	17.03	56.89	7.80	43.85	74.55
Within-laboratory SD (mg/dL)	0.39	0.92	0.16	0.58	1.05
Within-laboratory %CV	2.3%	1.6%	2.1%	1.3%	1.4%

Site 1

Site 2

	Lipid ControlI	Lipid ControlII	HumanSerum L	HumanSerum M	HumanSerum H
n	80	80	80	80	80
Mean (mg/dL)	20.98	54.05	7.90	44.53	75.85
Within-laboratory SD (mg/dL)	0.45	1.02	0.25	0.81	1.34
Within-laboratory %CV	2.1%	1.9%	3.2%	1.8%	1.8%

Site 3

	Lipid Control I	Lipid Control II	Human Serum L	Human Serum M	Human Serum H
n	80	80	80	80	80
Mean (mg/dL)	18.05	55.39	7.78	44.96	75.82
Within-laboratory SD (mg/dL)	0.74	1.33	0.34	0.86	1.67
Within-laboratory %CV	4.1%	2.4%	4.3%	1.9%	2.2%

The within-laboratory %CV (total precision) for each control or sample, at each site, ranged from 1.3 % to 4.3%.

Linearity

The linearity study was performed according to the Clinical and Laboratory Standards Institute (CLSI) EP06-A approved guideline. The study included 13 samples that were tested in duplicate

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with results averaged; the concentration span of the 13 samples was 0 to 127 mg/dL, and the study used one lot of reagents.

Absolute value of nonlinearity was less than allowable nonlinearity at all tested levels. The assay results obtained by s LDL-EX"SEIKEN" were shown to be linear throughout the entire dynamic range (4.0 - 100 mg/dL).

Spike and Recovery

High Concentration Control (sd LDL-C: 90 to100 mg/dL) was used as a spiking sample. The Control and three levels sd LDL-C serum samples were first assayed in triplicate with s LDL-EX"SEIKEN," and mean values were used to calculate theoretical values. After spiking each sample was assayed in triplicate with s LDL-EX"SEIKEN," and mean values were calculated. The mean values from s LDL-EX"SEIKEN" were then compared to the theoretical values.

	HighConcentrationControl	Serum
		Low	Medium	High
n	3	3	3	3
Mean (mg/dL)	94.5	25.0	40.5	64.5

Each sample (before spiking)

Spiked Sera

	Sample 1	Sample 2	Sample 3	Sample 4	Sample 5	Sample 6
Combination	Low : Control		Medium : Control		High : Control
	1:1	3:1	1:1	3:1	1:1	3:1
Theoretical value (mg/dL)	59.8	42.4	67.5	54.0	79.5	72.0
n	3	3	3	3	3	3
Mean (mg/dL)	59.6	42.2	68.0	54.4	80.2	72.9
%Δ	-0.3%	-0.5%	+0.7%	+0.7%	+0.9%	+1.3%

The % differences for each spiked serum sample ranged from -0.5 to +1.3%.

Interferences

Concentrations of the potential interferents and the testing protocol were based on guidance from the Clinical and Laboratory Standards Institute document CLSI Protocol EP07-A2. Three human serum samples that spanned the dynamic range were used for each compound. The samples were divided into two series of aliquots: one aliquot was spiked to represent the interfering sample, and another aliquot remained neat to represent the control sample. All samples were assayed in triplicate and results were averaged. Non-interference was defined as less than 10% difference or 3 mg/dL difference (for the low level) between neat and spiked samples. The results are summarized below:

Hemoglobin: No significant interference up to 1,000 mg/dL
Bilirubin: No sign No significant interference up to 60 mg/dL of both conjugated and unconjugated bilirubin.

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Chyle: No significant interference up to 1,420 FTU
Sodium L-ascorbate: No significant interference up to 100 mg/dL ●
Intralipid (Intralipid 20%): No significant interference up to 10%. (up to 1% wt/vol as ● soybean oil)
Uric acid: No significant interference up to 15 mg/dL
Triglyceride: No significant interference up to 1.500 mg/dL

Drugs: No interference was found at three-times the therapeutic levels using Pravastatin, Pitavastatin, Atorvastatin, Rosuvastatin, Simvastatin, Ezetimibe, Fenofibrate, Gamma-Oryzanol, Bezafibrate, Probucol, Tocophenol Nicotinate, and Riboflavin Tetrabutyrate.

The differences, or percent differences, for all spiked compounds were within the allowable ranges.

Matrix Equivalence- sample tubes

Multiple serum and plasma samples were drawn from 48 subjects. The tube types were: serum (reference, "plain"), serum separator tubes (SST), K2 EDTA tubes, and lithium heparin tubes. Samples from each tube type were assaved in duplicate, but for the analyses, the x-axis was the mean of the duplicate testing of the plain tube, and the y-axis was the first result from the other four (4) tubes. The plain tube was considered the reference condition.

Calculated correlation coefficients, slopes, and intercepts, with the plain results on the x-axis., are shown in the tables below. Line listings follow.

	Serum(SST)	Plasma(K2 EDTA)	Plasma(LithiumHeparin)
CorrelationCoefficient	1.00	1.00	1.00
Slope	1.00	0.96	0.99
Intercept	+0.1	-0.1	-0.4

807.92 (b)(2): Brief Description of Clinical Data

Reference Range Study

A reference range study was conducted as there are currently no reference intervals established for small dense (sd) low density lipoprotein (LDL) cholesterol (-C). Specimens from four subgroups of volunteers, who were presumptively free from coronary heart disease (CHD) and were representative of normal lipid panel results, were assayed by s LDL-EX"SEIKEN." Specimens were collected from both younger and older men (defined as less than or equal to, or greater than 44 years of age) and women of pre and post-menopausal status (defined as less than or equal to or greater than 54 years of age).

Eligible subjects were enrolled at two U.S. regions and consented to a single blood draw after an overnight fast; subjects also consented to completing health and demographic questionnaires, and the measurement of various vital signs; all subjects who entered the study at either center were

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treated in the same manner. Following the CLSI guideline, the normal range for sd LDL-C value was selected as the central 95% interval. removing the lower 2.5% and the upper 2.5%.

Further analysis was carried out to clarify the association between sd LDL-C concentrations and age and/or gender. Subjects were stratified into two groups divided by gender (Table 1a), and by age (Table 1b). Table 1a clearly shows that sd LDL-C levels do not differ by gender (p=0.7564); however, Table 1b shows sd LDL-C levels are significantly higher in the older groups when combining male and female subjects (p<0.0001).

Table 1: Distribution of sd LDL-C concentrations among subjects divided by gender (a) and age (b)

Comparison of Median sd LDL-C Concentrations Dichotomized by Gender a)

Gender	Age (year)	n	sd LDL-C	p value
male	21-75	210	27.4 [20.2, 35.5]	0.7564
female	21-75	232	27.8 [21.9, 34.8]	0.7564

sd LDL-C concentrations are shown in median [25th percentile. 75th percentile] (mg/dL).
-----------------------------------------------------------------------------------------	--	--	--

b) Comparison of Mean sd LDL-C Concentrations Dichotomized by Age
	Gender	Age (year)	n	sd LDL-C	p value
Younger	male	21-44	111	24.5 [18.5, 32.5]	<0.0001*
	female	21-54	129
Older	male	45-75	99	30.5 [24.1, 36.9]
	female	55-75	103

sd LDL-C concentrations are shown in median [25th percentile, 75th percentile] (mg/dL). * p<0.05

Reference Range Conclusions:

The Reference Range study showed that sd LDL-C values differ by age among both males and females, with higher sd LDL-C levels observed with increasing age. Conversely, mean sd LDL-C concentrations were not statistically different when subjects are grouped by gender. The reference range was determined to be 12.7 to 48.3 mg/dL for younger subjects (male: 21-44 yrs and female: 21-54 yrs), 12.6 to 51.7 mg/dL for older subjects (male: 45-75 yrs and female: 55-75 yrs).

Clinical Studies:

The clinical validation utilized banked samples and clinical outcome data from Visit 4 of the Atherosclerosis Risk in Communities (ARIC) study. The objective of this study was to investigate the relationship between levels of sd LDL-C and the risk for incident CHD, and to validate an assay cutoff of 50.0 mg/dL that had been previously established in Multi-Ethnic Study of Atherosclerosis (MESA). Covariates included gender, age group, race/ethnicity, smoking status, body mass index (BMI), systolic blood pressure, hypertension medication use, the standard lipid measures of high-density lipoprotein cholesterol (HDL-C) concentrations and triglycerides, lipid-lowering medication, diabetes, and high sensitivity C-reactive protein. 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

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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.

Statistical analysis was performed using SAS version 9.4 (SAS Institute Inc., Cary, NC) and STATA version 12 (StataCorp LP, College Station, TX). All tests were 2-sided with a p-value <0.05 considered significant. Associations between sd LDL-C and incident CHD was determined using Cox proportional hazards modeling, in both minimal adjusted and fully adjusted models. The basic model (Model 1) adjusted for age, gender, and race as potential confounders. Model 2: Model 1 variables + ever smoker, BMI, hypertension (systolic blood pressure and/or hypertension medications), HDL, log(triglycerides), lipid-lowering medication, diabetes, and log(high sensitivity C-reactive protein). Triglycerides and high sensitivity C-reactive protein were log-transformed to account for their non-Gaussian distributions.

Verification of the cutoff (50.0 mg/dL)

In order to verify the previously established sd LDL-C cutoff value of 50.0 mg/dL, absolute risk and Cox proportional hazards regression analyses were used to investigate the association of incident CHD with baseline levels of sd LDL-C using sd LDL-C <50.0 mg/dL as the reference group.

Results of absolute risk analyses are shown in Table 3.

sd LDL-C < 50 mg/dL	sd LDL-C ≥ 50 mg/dL	P-value
Event/population	Event/population
%	%
(95%CI)	(95%CI)
825/7123	569/3167	<0.0001
11.58%	17.97%
(10.82-12.34%)	(16.60-19.33%)

Table 3: 16-year Absolute Risk for incident CHD by sd LDL-C cut-off (50mg/dL)
-------------------------------------------------------------------------------	--

The Kaplan-Meier survival curves were drawn for incident CHD and sd LDL-C < or ≥ 50.0 mg/dL, as shown in Figure 1. The incidence of CHD events increased proportionately over the follow-up years (16 years) for participants in each group of sd LDL-C levels.

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Image /page/7/Figure/0 description: The image is a survival plot titled "Incident CHD survival by sdLDL-C < or >= 50mg/dL". The x-axis is labeled "Follow-up years" and ranges from 0 to 15. The y-axis represents survival probability and ranges from 0.75 to 1.00. There are two survival curves, one for sdLDL-C<50mg/dL and one for sdLDL-C >=50mg/dL, with the former showing higher survival rates.

Figure 1: Kaplan-Meier survival curves of incident CHD and sd LDL-C < or ≥ 50.0 mg/dL

Over the follow-up years (16 years), proportional hazards regression analyses were used to investigate the association of incident CHD with baseline levels of sd LDL-C in medians, using sd LDL-C <50.0 mg/dL as the reference group (Table 4). The HRs are presented by the aforementioned Models 1 and 2.

	sd LDL-C <50.0 mg/dL	sd LDL-C ≥50.0 mg/dL
Events/Population	825/7123	569/3167
Model 1	Reference	1.55 (1.39 - 1.73)(p<0.0001)
Model 2	Reference	1.26 (1.10 - 1.43)(p=0.0006)

Table 4: Hazard ratio (95% CI) for incident CHD by sd LDL-C cutoff (50,0 mg/dL)

In Model 1, individuals with sd LDL-C levels in the higher sd LDL-C group demonstrated approximately a 1.6-fold higher risk for incident CHD compared to those in the lower group (HR 1.55; 95% CI 1.39-1.73). In Model 2, risk for incident CHD was somewhat attenuated, but remained significant (HR 1.26; 95% CI 1.10-1.43).

As supplemental information, the Kaplan-Meier survival curves of CHD risk for sd LDL-C quartiles, adjusted by age, race, and gender, are shown in Figure 2, and hazard ratios (95% CI) for incident CHD by sd LDL-C quartiles are shown in Table 5.

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Image /page/8/Figure/0 description: The image is a survival plot titled "Incident CHD survival by sdLDL-C quartile". The x-axis is labeled "Follow-up years" and ranges from 0 to 15. The y-axis ranges from 0.75 to 1.00. There are four lines on the plot, representing the 1st, 2nd, 3rd, and 4th sdLDL quartiles.

Figure 2: Kaplan-Meier survival curves of risk of CHD by sd LDL-C quartiles.

Table 5: Hazard ratios (95% CI) for incident CHD by sd LDL-C quartiles (p-values (Pr > chiSq) for linear hypothesis testing results of sd LDL-C quartiles).

	sd LDL-C, Quartile
	1(< 27.8 mg/dL)	2(27.8 mg/dL –39.5 mg/dL)	3(39.5 mg/dL –54.6 mg/dL)	4(54.6 mg/dL ≤)	p-trend
Model 1	ref	1.20(1.01-1.42)	1.43(1.22 - 1.68)	1.95(1.67 - 2.28)	<0.0001
Model 2	ref	1.10(0.92 - 1.31)	1.19(0.99 - 1.43)	1.47(1.21 - 1.80)	0.0006

Clinical Studies Conclusions

1. Using banked samples and clinical outcome data from the ARIC study, the results showed that sd LDL-C predicted future CHD events.
1. The cutoff value of 50.0 mg/dL sd LDL-C that was established in a previous study was validated.

Conclusion:

The results of the non-clinical data and the clinical data demonstrate that the s LDL-EX "SEIKEN" test is substantially equivalent to the predicate device.

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

DENKA SEIKEN CO., LTD. THOMAS TSAKERIS PRESIDENT 16809 BRIARDALE ROAD ROCKVILLE MD 20855

Re: K161679

Trade/Device Name: s LDL-EX "SEIKEN" Regulation Number: 21 CFR 862.1475 Regulation Name: Lipoprotein test system Regulatory Class: I, meets the limitation to the exemption 862.9(c)(4) Product Code: PYP Dated: August 10, 2017 Received: August 11, 2017

Dear Mr. Tsakeris:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration. listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled. "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Courtney H. Lias Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

Regulation Number and Section

§ 862.1475 Lipoprotein test system.

(a)
Identification. A lipoprotein test system is a device intended to measure lipoprotein in serum and plasma. Lipoprotein measurements are used in the diagnosis and treatment of lipid disorders (such as diabetes mellitus), atherosclerosis, and various liver and renal diseases.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 862.9.