The ADVIA Centaur® High-Sensitivity Troponin I (TNIH) assay is for in vitro diagnostic use in the quantitative measurement of cardiac troponin I in human serum or plasma (lithium heparin) using the ADVIA Centaur XP system. The assay can be used to aid in the diagnosis of acute myocardial infarction (AMI).

Device Description

The ADVIA Centaur TNIH assay kit includes the ADVIA Centaur TNIH Primary Reagent ReadyPack and the ADVIA Centaur TNIH Calibrator. The Primary Reagent ReadyPack contains ADVIA Centaur TNIH Lite Reagent (Bovine serum albumin (BSA) conjugated to a recombinant monoclonal Fab anti-human cTnl (~0.2-0.4 µg/mL) labeled with acridinium ester in HEPES buffer with stabilizers and preservatives) and ADVIA Centaur TNIH Solid Phase Reagent (0.45 mg/mL streptavidin-coated magnetic latex particles with 2 biotinylated (mouse and sheep) monoclonal anti-troponin I antibodies in buffer with stabilizers and preservatives). The Calibrator kit contains ADVIA Centaur TNIH High Calibrator (Human serum with human cTnl and preservatives (lyophilized)) and ADVIA Centaur TNIH Low Calibrator (HEPES buffer with bovine serum albumin (BSA), surfactants, and preservatives (liquid)). The assay uses a chemiluminescence sandwich immunoassay methodology.

AI/ML Overview

The Siemens Healthcare Diagnostics Inc. ADVIA Centaur High-Sensitivity Troponin I (TNIH) assay is an in vitro diagnostic device used for the quantitative measurement of cardiac troponin I in human serum or plasma to aid in the diagnosis of acute myocardial infarction (AMI).

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" for each performance characteristic in a table format. However, it indicates expected outcomes based on standard guidelines (CLSI protocols) and high-sensitivity troponin definitions. The performance data presented demonstrates that the device meets these implied criteria.

Performance Characteristic	Implied Acceptance Criteria (Based on CLSI & IFCC)	Reported Device Performance
Precision	CVs within acceptable ranges for clinical assays; demonstrating consistent results. (Based on CLSI EP5-A3)	Repeatability (%CV): Serum samples ranged from 0.7% to 4.8%. Lithium Heparin Plasma samples ranged from 0.8% to 3.6%. Within-Lab (%CV): Serum samples ranged from 0.9% to 5.4%. Lithium Heparin Plasma samples ranged from 1.1% to 4.9%. These values are generally considered acceptable for clinical assays, especially within the context of troponin measurement.
Linearity	Deviation from linear fit within acceptable limits across the assay's measuring range. (Based on CLSI EP06-A)	Deviation from Linear Fit: For full range, Li Hep and Serum samples showed deviations up to 6.57%. For ~150 pg/mL range, deviations up to 3.5% were observed. While specific acceptance limits for deviation are not given, these results are presented as representative and implied to be acceptable.
Dilution Recovery	Recoveries for diluted samples should be within a reasonable percentage of expected values.	Recoveries for individual samples were all within 20%. Mean of 1:2 dilutions was 102.6%. Mean of 1:5 dilutions was 91.8%. This indicates acceptable recovery for diluted samples.
Hook Effect	No Hook Effect detected within the specified concentration range.	No hook effect observed up to 500,000 pg/mL. This is a positive finding, indicating reliability at high concentrations.
Detection Limit	LoB, LoD, and LoQ determined as per CLSI protocol EP17-A2.	LoB: 0.50 pg/mL. LoD: 1.60 pg/mL. LoQ: 2.50 pg/mL (at 20% total CV). These values describe the analytical sensitivity of the assay.
Endogenous Interference	Interferents should not cause >10% interference at tested concentrations. (Based on CLSI EP07-A2)	Most endogenous substances showed less than 10% interference. For substances causing >10% interference (none explicitly highlighted as such in the table, all shown are below), serial measurements were taken and analyzed by linear regression (though specific results for such cases are not provided in the table). The presented data indicates minimal endogenous interference.
Drug Interference	At tested concentrations, drugs should cause <10% interference. (Based on CLSI EP07-A2)	All listed therapeutic drugs caused <10% interference at the tested low and high concentrations. This is a strong positive finding for clinical utility.
Cross-Reactivity	Minimal to no cross-reactivity with similar or related substances.	0.00% cross-reactivity reported for Actin, Cardiac Troponin T, CK-MB, Myoglobin, Myosin Light Chain, Skeletal Troponin I, Tropomyosin, and Troponin C at tested levels. This indicates high specificity for cardiac troponin I.
Heterophile Interference	No significant interference from HAMA or RF.	No interference with HAMA or RF was observed. This ensures accurate results in the presence of these common interferents.
High-Sensitivity Designation	1. %CV at 99th percentile ≤10%. 2. Measurable concentrations above LoD for ≥50% of healthy individuals. (IFCC Task Force)	The assay meets both criteria: 1. Although individual %CV at 99th percentile is not explicitly stated, the overall precision data (1.3%-1.9% at 138-146 pg/mL) suggests it is well within specification, and the claim of meeting the criteria implies this. 2. The fact that the assay is designated "High-Sensitivity" and implied to meet this criterion, combined with its low LoD, supports this. This is a critical claim for modern troponin assays.
Clinical Performance (AMI Diagnosis)	Demonstrate clinical concordance (Sensitivity, Specificity, PPV, NPV) with adjudicated AMI diagnosis, showing utility across different time points.	Sensitivity: Generally good, especially at later time points (e.g., 90-100% after 2-3 hours). Lower at early time points (e.g., 78-82% at 0-1.5 hr). Specificity: Consistently high, typically ranging from 86-95%. PPV: Varies, generally lower than sensitivity/specificity, ranging from 41-68%. NPV: Consistently very high, typically ranging from 95-99.5%. The results support the assay's utility in aiding AMI diagnosis, particularly the high NPV which is useful for ruling out AMI.

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

Test Set (Clinical Study):
- The clinical study enrolled all patients presenting to the emergency department or ambulatory care center with signs or symptoms suspicious for an acute coronary syndrome (ACS) event.
- The total number of patients/samples isn't explicitly stated as a single number but can be inferred by summing the N values across different time points and matrices for the clinical performance tables. For instance, in the "overall 99th Percentile" table for Li Hep Plasma, the sum of N for Sensitivity and Specificity across all time points would provide an estimate of the number of positive and negative cases assessed:
  - Sensitivity N (true positive): Sums up to 1341
  - Specificity N (true negative): Sums up to 8853
  - This suggests a large test set of thousands of samples/patient time points.
- Provenance: Specimens were collected at 29 sites across different regions of the United States. Data is prospective, as patients were enrolled who presented with ACS symptoms.

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

Number of Experts: An "independent adjudication committee" was used. The exact number of experts on this committee is not specified.
Qualifications: The committee included cardiologists. No specific years of experience or board certifications are mentioned beyond "cardiologists."

4. Adjudication Method for the Test Set:

The ground truth for AMI diagnosis was established by an independent adjudication committee.
The adjudication was based on the Third universal definition of myocardial infarction consensus guideline endorsed by the European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the World Heart Federation (WHF).
The specific method (e.g., 2+1, 3+1) for how decisions were reached by the committee (e.g., how many members had to agree, or if a tie-breaker was used) is not explicitly stated. It just mentions "an independent adjudication committee."

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Its Effect Size:

No, an MRMC comparative effectiveness study was not done.
This submission describes the performance of an in vitro diagnostic assay (a lab test), not an AI algorithm assisting human readers in interpreting medical images or data. Therefore, the concept of human readers improving with/without AI assistance does not apply here.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done:

Yes, this is a standalone performance study.
The ADVIA Centaur TNIH assay is a diagnostic laboratory test. Its performance characteristics (precision, linearity, detection limits, interference, and clinical concordance) are evaluated directly, without human interpretation of the assay's output being part of the device's measured performance in the way an AI algorithm for imaging would be. The clinical concordance described represents the algorithm's (assay's) performance compared to the adjudicated clinical diagnosis.

7. The Type of Ground Truth Used:

Expert Consensus / Clinical Outcomes Data (for Clinical Study): The ground truth for the clinical performance study was the adjudicated diagnosis of Acute Myocardial Infarction (AMI) established by an independent committee of cardiologists based on the Third universal definition of myocardial infarction consensus guideline. This is a form of expert consensus derived from clinical outcomes and medical guidelines.
Reference Standards/Characterized Samples (for Analytical Studies): For analytical performance characteristics (precision, linearity, etc.), the ground truth was established using characterized samples, reference materials, or spikes that conform to recognized standards (e.g., CLSI guidelines).

8. The Sample Size for the Training Set:

Not Applicable / Not Explicitly Stated: For an in vitro diagnostic assay like this, there isn't typically a "training set" in the sense of machine learning algorithms. The assay is developed and validated using various methods and samples.
However, if we consider assay development and optimization, a large number of samples would have been used internally by the manufacturer during research and development to optimize reagents, antibodies, and protocols to achieve the desired performance characteristics. This document does not detail those internal R&D sample numbers. The clinical study samples described are primarily for validation/testing, not "training."

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

Not Applicable: As there isn't a "training set" in the machine learning sense, the concept of establishing ground truth for it doesn't directly apply.
The development of such an assay relies on established biochemical principles, known concentrations of analytes, and recognized clinical definitions (e.g., for target analyte, cross-reactants, and interference substances). The "ground truth" during development involves ensuring the assay accurately measures the target molecule (cardiac troponin I) with high specificity and sensitivity based on these scientific and clinical standards.

Summary

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July 12, 2018

Siemens Healthcare Diagnostics Inc. Matthew Gee Senior Manager, Regulatory Affairs 511 Benedict Avenue Tarrytown, NY 10591

Re: K171274

Trade/Device Name: ADVIA Centaur High-Sensitivity Troponin I (TNIH) Regulation Number: 21 CFR 862.1215 Regulation Name: Creatine phosphokinase/creatine kinase or isoenzymes test system Regulatory Class: Class II Product Code: MMI Dated: June 26, 2018 Received: June 27, 2018

Dear Matthew Gee:

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 Part 801 and Part 809); medical device 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

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Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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 comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Kellie B. Kelm -S

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

Enclosure

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Indications for Use

510(k) Number (if known) K171274

Device Name

ADVIA Centaur High-Sensitivity Troponin I (TNIH)

Indications for Use (Describe)

The ADVIA Centaur High-Sensitivity Troponin I (TNIH) assay is for in vitro diagnostic use in the quantitative measurement of cardiac troponin I in human serum or plasma (lithium heparin) using the ADVIA Centaur XP system. The assay can be used to aid in the diagnosis of acute myocardial infarction (AMI).

Type of Use (Select one or both, as applicable)
☑ Prescription Use (Part 21 CFR 801 Subpart D)
☐ Over-The-Counter Use (21 CFR 801 Subpart C)

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This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92 and the Safe Medical Device Act of 1990.

The assigned 510(k) Number is: K171274

Date Prepared 1.

July 12, 2018

Applicant Information 2.

Contact:	Matthew Gee, M.Sc.Senior Manager, Regulatory Affairs
Address:	Siemens Healthcare Diagnostics Inc.511 Benedict AvenueTarrytown, NY 10591-5097
Phone:	914-255-8782
Fax:	914-524-3579

Email: matthew.gee@siemens.com

3. Regulatory Information

Table 1. Regulatory Information for ADVIA Centaur High-Sensitivity Troponin I (TNIH)

Trade Name	ADVIA Centaur® High-Sensitivity Troponin I (TNIH)
Model Numbers	10994774 (1-pack); 10994775 (5-pack)
Common Name	Immunoassay Method, Troponin Subunit
Regulation Number	862.1215
Regulation Description	Creatine phosphokinase /creatine kinase or isoenzymes testsystem
Product Code	MMI
FDA Classification	Class II
Review Panel	Clinical Chemistry (75)

Predicate Device Information 4.

Predicate Device Name: Elecsys Troponin T Gen 5 STAT Immunoassay

510(k) Number: K162895

Intended Use / Indications for Use 5.

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6. Device Description

Table 2. Summary of Ingredients of the ADVIA Centaur TNIH Assay Components

Component	Volume	Ingredients
ADVIA Centaur TNIH Primary Reagent ReadyPack (included in assay kit)
ADVIA Centaur TNIH Lite 8.0 mL/packReagent		Bovine serum albumin (BSA) conjugated to arecombinant monoclonal Fab anti-human cTnl (~0.2-0.4 µg/mL) labeled with acridinium ester in HEPESbuffer with stabilizers and preservatives
ADVIA Centaur TNIHSolid Phase Reagent	13.0 mL/pack	0.45 mg/mL streptavidin-coated magnetic latexparticles with 2 biotinylated (mouse and sheep)monoclonal anti-troponin I antibodies in buffer withstabilizers and preservatives
ADVIA Centaur TNIH Calibrator (included in assay kit)
ADVIA Centaur TNIHHigh Calibrator	1.0 mL/vial	Human serum with human cTnl and preservatives(lyophilized)
ADVIA Centaur TNIHLow Calibrator	1.0 mL/vial	HEPES buffer with bovine serum albumin (BSA),surfactants, and preservatives (liquid)

Purpose of the Submission 7.

The purpose of this premarket notification is to submit a new device (ADVIA Centaur TNIH) to FDA for consideration for clearance.

8. Comparison of Predicate Device and Modified Device

Table 3. Comparison of ADVIA Centaur TNIH Assay to Predicate

Item	ADVIA Centaur TNIH(Candidate Device)	Elecsys Troponin T Gen 5 STATImmunoassay(Predicate Device)
Intended Use	The ADVIA Centaur® High-SensitivityTroponin I (TNIH) assay is for in vitrodiagnostic use in the quantitativemeasurement of cardiac troponin I inhuman serum or plasma using theADVIA Centaur XP system. The assaycan be used to aid in the diagnosis ofacute myocardial infarction (AMI).	Immunoassay for the in vitroquantitative determination ofcardiac troponin T (cTnT) inlithium heparin plasma. Theimmunoassay is intended to aid inthe diagnosis of myocardialinfarction. Theelectrochemiluminescenceimmunoassay "ECLIA" is intendedfor use on the cobas systemanalyzers.
Indicationsfor Use	The assay can be used to aid in thediagnosis of acute myocardial infarction(AMI).	The immunoassay is intended toaid in the diagnosis of myocardialinfarction.
Methodology	Chemiluminescence	Electrochemiluminescence
Assay Protocol	Sandwich immunoassay	Same
Analyte	Cardiac troponin I	Cardiac troponin T
Specimen Type	Lithium heparin plasma and serum	Lithium heparin plasma

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Item	ADVIA Centaur TNIH(Candidate Device)	Elecsys Troponin T Gen 5 STATImmunoassay(Predicate Device)
Lower Limit ofMeasuring Range	LoQ	Same
Measuring Range	2.50-25,000 pg/mL (ng/L)	6.0-10,000 pg/mL (ng/L)
Upper 99thPercentile Cutoff	Female-Lithium Heparin: 36.99 pg/mLMale-Lithium Heparin: 57.27 pg/mLCombined-Lithium Heparin: 47.34 pg/mLFemale-Serum: 39.59 pg/mLMale-Serum: 58.05 pg/mLCombined-Serum: 46.47 pg/mLOverall: 47.34 pg/mL	Female: 14 pg/mL (ng/L)Male: 22 pg/mL (ng/L)Combined: 19 pg/mL (ng/L)
Calibration	2-point calibration	Same

Table 3. Comparison of ADVIA Centaur TNIH Assay to Predicate

Standard/Guidance Document References 9.

The following recognized standards from Clinical Laboratory Standards Institute (CLSI) were used as a basis of the study procedures described in this submission:

Evaluation of Precision Performance of Quantitative Measurement Methods; ■ Approved Guideline – Third Edition (CLSI EP05-A3, 2014; Recognition No. 7-251)
I Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline (CLSI EP06-A, 2003; Recognition No. 7-193)
I Interference Testing in Clinical Chemistry: Approved Guideline - Second Edition (CLSI EP07-A2, 2005; Recognition No. 7-127)
I Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition (CLSI EP17-A2, 2012: Recognition No. 7-233)
Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; ' Approved Guideline - Third Edition (CLSI EP28-A3c - formerly C28-A3c, 2010; Recognition No. 7-224)
I Medical devices - Application of risk management to medical devices (ANSI/AAMI/ISO 14971:2007/(R)2010; Recognition No. 5-70)

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10. Performance Characteristics

10.1 Precision

A 20-day precision study was performed according to CLSI EP5-A3. Samples included eight (8) samples (4 serum; 4 lithium heparin plasma) from AMI patients. These samples were diluted with native serum or lithium heparin plasma from healthy subjects. Samples were assayed twice a day in replicates of 2, for 20 days (n = 80 replicates per sample). Testing was performed on 2 instruments. The following are representative of the results obtained:

Sample	Mean	Repeatability		Within-Lab
	(pg/mL)	SD(pg/mL)	%CV	SD(pg/mL)	%CV
Serum 1	13.11	0.63	4.8	0.70	5.4
Serum 2	138.62	1.81	1.3	2.68	1.9
Serum 3	1461.93	12.47	0.9	17.52	1.2
Serum 4	14099.79	102.77	0.7	133.95	0.9
Lithium Heparin Plasma 1	12.68	0.45	3.6	0.62	4.9
Lithium Heparin Plasma 2	145.93	1.84	1.3	2.28	1.6
Lithium Heparin Plasma 3	1522.05	13.56	0.9	21.32	1.4
Lithium Heparin Plasma 4	13436.79	104.88	0.8	148.73	1.1

10.2 Linearity

Two linearity studies were performed according to CLSI EP06-A, each using 9 samples prepared by mixing a high-spiked cTnl sample with a low cTnl sample. The first study spanned the assay range and the second study ranged to ~150 pg/mL. Each study was tested with lithium heparin plasma and serum. The mean was taken from each sample tested in duplicate. Testing was performed with 3 lots. The following are representative of the results obtained:

Sample	Deviation from Linear Fit (% or pg/mL)
	Li HepFull Range	SerumFull Range	Li Hep~150 pg/mL	Serum~150 pg/mL
A	1.08%	0.19%	-3.50%	-0.09 pg/mL
B	-5.41%	-5.86%	0.45%	3.13%
C	-3.71%	-4.12%	0.40%	1.57%
D	-2.29%	-2.75%	0.30%	0.30%
E	-0.13%	-0.43%	0.18%	-0.52%
F	1.16%	0.80%	0.06%	-0.81%
G	2.99%	2.69%	-0.07%	-0.59%
H	4.73%	4.49%	-0.19%	0.14%
I	6.57%	6.39%	-0.32%	1.44%

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10.3 Dilution Recovery

Eight (8) native AMI samples (4 lithium heparin plasma and 4 serum) measuring above the analytical measuring range (i.e. >25000 pg/mL) were diluted to 1:2 and 1:5 with Multi-Diluent 11. Recoveries for individual samples were all within 20%. The mean of all 1:2 dilutions was 102.6%. The mean of all 1:5 dilutions was 91.8%.

10.4 Hook Effect

A study was performed to evaluate hook effect. There is no hook effect with the ADVIA Centaur TNIH assay up to 500,000 pg/mL.

10.5 Detection Limit

The limit of blank (LoB). limit of detection (LoD). and the limit of quantitation (LoQ) were determined as described in CLSI protocol EP17-A2. The ADVIA Centaur TNIH assay has an LoB of 0.50 pg/mL, an LoD of 1.60 pg/mL, and an LoQ of 2.50 pg/mL.

The LoB is defined as the highest measurement result that is likely to be observed for a blank sample. The LoD is defined as the lowest concentration of cardiac troponin I that can be detected with 95% probability. The LoQ is defined as the lowest concentration of cardiac troponin I that can be detected at a total CV of 20%.

10.6 Endogenous Interference

Endogenous interference studies were performed according to CLSI EP07-A2. These sample pools (~60 pg/mL cTnl) were spiked with potential interferents. Control samples were prepared by spiking sample pools with the appropriate diluent at the same volume as the interfering substance stock. For substances spiked at doses that caused >10% interference, serial measurements were taken and analyzed by linear regression. Results are presented below.

Endogenous Substance	Matrix	ControlDose(pg/mL)	TestDose(pg/mL)	% Interference
Bilirubin (Conjugated)40 mg/dL	Li Hep	61.22	62.43	1.97%
Bilirubin (Conjugated)40 mg/dL	Serum	62.62	63.04	0.68%
Bilirubin (Unconjugated)60 mg/dL	Li Hep	61.10	61.38	0.46%
Bilirubin (Unconjugated)60 mg/dL	Serum	61.04	62.61	2.57%
Biotin3500 ng/mL	Li Hep	60.62	59.76	-1.42%
Biotin3500 ng/mL	Serum	60.56	59.75	-1.35%
Cholesterol500 mg/dL	Li Hep	52.68	53.69	1.94%
Cholesterol500 mg/dL	Serum	53.12	53.58	0.87%
Hemoglobin500 mg/dL	Li Hep	62.08	60.16	-3.09%
Hemoglobin500 mg/dL	Serum	62.37	59.69	-4.31%
Protein (Albumin)6 g/dL	Li Hep	58.95	59.35	0.68%
Protein (Albumin)6 g/dL	Serum	60.49	60.04	-0.74%
Protein (Gamma Globulin)2.5 g/dL	Li Hep	56.08	55.07	-1.81%
Protein (Gamma Globulin)2.5 g/dL	Serum	55.82	55.96	0.26%
Protein (Total)12 g/dL	Li Hep	57.12	59.14	3.53%
Protein (Total)12 g/dL	Serum	58.25	57.77	-0.82%
Triglycerides2000 mg/dL	Li Hep	55.51	54.92	-1.07%
Triglycerides2000 mg/dL	Serum	53.02	54.53	2.86%

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10.7 Drug Interference

Therapeutic drug interference studies were performed according to CLSI EP07-A2. Sample pools (~60 pq/mL cTnl) for each matrix were tested. Control samples were prepared by spiking sample pools with the appropriate diluent at the same volume as the interfering substance stock. At the tested concentrations, all drugs caused <10% interference on the ADVIA Centaur TNIH assay.

Drug	Low Concentration	High Concentration
Abciximab	5 µg/mL	40 µg/mL
Acetaminophen	20 µg/mL	200 µg/mL
Acetylsalicylic Acid	261 µg/mL	652 µg/mL
Allopurinol	13 µg/mL	40 µg/mL
Amiodarone	1.8 µg/mL	6.1 µg/mL
Ampicilin	10 µg/mL	53 µg/mL
Ascorbic Acid	12 µg/mL	60 µg/mL
Atenolol	1.1 µg/mL	10 µg/mL
Caffeine	12 µg/mL	60 µg/mL
Captopril	1.0 µg/mL	5.0 µg/mL
Cefoxitin	120 µg/mL	660 µg/mL
Cinnarizine	200 ng/mL	400 ng/mL
Clopidogrel	37.5 µg/mL	75 µg/mL
Cocaine	0.1 µg/mL	10 µg/mL
Digoxin	1.4 ng/mL	6.1 ng/mL
Digitoxin	30 ng/mL	60 ng/mL
Diltiazem	0.2 µg/mL	6.2 µg/mL
Disopyramide	3.5 µg/mL	10 µg/mL
Dopamine	0.3 µg/mL	0.9 µg/mL
Doxycycline	10.0 µg/mL	30 µg/mL
Erythromycin	11 µg/mL	60 µg/mL
Furosemide	20 µg/mL	60 µg/mL
Ibuprofen	40 µg/mL	500 µg/mL
Isosorbide Dinitrate	50 ng/mL	150 ng/mL
Lisinopril	0.10 µg/mL	0.30 µg/mL
Lovastatin	40 ng/mL	80 ng/mL
Low MW Heparin	6.75 U/mL	30 U/mL
Methotrexate	546 µg/mL	910 µg/mL
Methyldopa	4.2 µg/mL	15 µg/mL
Methylprednisolone	N/A	40 µg/mL
Mexiletine	1.3 µg/mL	4.0 µg/mL
Nicotine	37 ng/mL	1000 ng/mL
Nifedipine	125 ng/mL	400 ng/mL
Nitrofurantoin	2.0 µg/mL	4.0 µg/mL
Nitroglycerine	7.5 ng/mL	160 ng/mL
Phenobarbital	24 µg/mL	97 µg/mL
Phenytoin	12 µg/mL	50 µg/mL
Primidone	10.5 µg/mL	40 µg/mL
Propanolol	0.50 µg/mL	2.0 µg/mL
Drug	Low Concentration	High Concentration
Quinidine	3.7 µg/mL	12 µg/mL
Simvastatin	16 µg/mL	32 µg/mL
Theophylline	12 µg/mL	40 µg/mL
Thyroxine	0.08 µg/mL	1.01 µg/mL
Tissue Plasminogen Activator	1.15 µg/mL	2.3 µg/mL
Trimethoprim	12 µg/mL	40 µg/mL
Verapamil	0.33 µg/mL	2.0 µg/mL
Warfarin	2.0 µg/mL	10 µg/mL

{9}------------------------------------------------

510(k) Summary of Safety and Effectiveness

10.8 Cross-Reactivity

Cross-reactivity studies were performed using two sample pools per matrix of approximately 0 pg/mL and 60 pg/mL cTnl. These sample pools were spiked with potential cross-reactants. Control samples were prepared by spiking sample pools with the appropriate diluent at the same volume as the interfering substance stock. Results are presented below.

PotentialCross-ReactingSubstance	Matrix	cTnlLevel	ControlDose(pg/mL)	TestDose(pg/mL)	% Cross-Reactivity
Actin	Li Hep	Zero	0.96	0.54	0.00%
	Li Hep	Low	57.65	58.48	0.00%
	Serum	Zero	0.59	0.33	0.00%
	Serum	Low	56.68	57.38	0.00%
Cardiac Troponin T	Li Hep	Zero	0.39	21.69	0.00%
	Li Hep	Low	56.58	77.25	0.00%
	Serum	Zero	0.20	21.07	0.00%
	Serum	Low	56.83	80.85	0.00%
CK-MB	Li Hep	Zero	0.76	1.20	0.00%
	Li Hep	Low	56.36	57.92	0.00%
	Serum	Zero	0.56	0.83	0.00%
	Serum	Low	56.40	57.62	0.00%
Myoglobin	Li Hep	Zero	0.42	0.58	0.00%
	Li Hep	Low	57.61	58.23	0.00%
	Serum	Zero	0.49	0.25	0.00%
	Serum	Low	56.80	56.53	0.00%
Myosin Light Chain	Li Hep	Zero	0.50	0.65	0.00%
	Li Hep	Low	57.24	56.94	0.00%
	Serum	Zero	0.42	0.45	0.00%
	Serum	Low	56.30	56.51	0.00%
Skeletal Troponin I	Li Hep	Zero	0.89	0.45	0.00%
	Li Hep	Low	58.24	56.88	0.00%
	Serum	Zero	0.67	0.54	0.00%
	Serum	Low	58.54	57.35	0.00%
Tropomyosin	Li Hep	Zero	0.29	0.49	0.00%
	Li Hep	Low	58.05	58.61	0.00%
	Serum	Zero	0.39	0.56	0.00%
	Serum	Low	56.80	57.11	0.00%

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510(k) Summary of Safety and Effectiveness

PotentialCross-ReactingSubstance	Matrix	cTnlLevel	ControlDose(pg/mL)	TestDose(pg/mL)	% Cross-Reactivity
Troponin C	Li Hep	Zero	0.71	13.28	0.00%
Troponin C	Li Hep	Low	57.36	70.80	0.00%
Troponin C	Serum	Zero	0.32	14.30	0.00%
Troponin C	Serum	Low	57.75	71.63	0.00%

10.9 Heterophile Interference

Heterophile interference studies were performed using lithium heparin plasma and serum spiked with high RF samples, and serum spiked with high HAMA samples. Control samples were prepared by spiking sample pools with the appropriate diluent at the same volume as the interfering substance stock. No interference with HAMA or RF was observed.

10.10 High-Sensitivity Designation

The International Federation of Clinical Chemistry (IFCC) Task Force on Clinical Applications of Cardiac Bio-Markers defines a high-sensitivity troponin test as one that meets the following analytical criteria:1

1. % CV at the 99th percentile value should be ≤10%
1. Measurable concentrations should be attainable at a concentration above the LoD for at least 50% of healthy individuals

The ADVIA Centaur TNIH assay meets both of these criteria.

Method Comparison with Predicate Device 10.11

Not applicable.

Matrix Comparison 10.12

Not applicable. All performance studies were performed in all applicable matrices (lithium heparin plasma and serum).

1 Apple FS, Sandoval Y, Jaffe AS, et al. Cardiac troponin assays: Guide to understanding analytical characteristics and their impact on clinical care. Clin Biochem 2017;63:73-81.

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10.13 Clinical Studies

A clinical performance study was conducted to evaluate the diagnostic accuracy of the ADVIA Centaur TNIH assay in terms of the clinical concordance between the 99th percentile cutoff and the presence or absence of an adjudicated acute myocardial infarction (AMI) diagnosis. Specimens were collected at 29 sites from different regions across the United States. Testing of specimens was performed at 3 sites.

In this study, the sites enrolled all patients who presented to the emergency department, or ambulatory care center equivalent, with signs or symptoms suspicious for a possible acute coronary syndrome (ACS) event. The diagnosis of AMI was performed by an independent adjudication committee which included cardiologists. The adjudication was based on the Third universal definition of myocardial infarction consensus guideline endorsed by the European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the World Heart Federation (WHF).

The clinical concordance study evaluated clinical sensitivity, clinical specificity, positive predictive value (PPV) and negative predictive value (NPV) of the ADVIA Centaur TNIH assay in terms of its correlation to the the diagnosis of AMI.

Results were analyzed according to time from presentation to the emergency department.

Matrix	Timepoint	N	Estimate	95% CI	N	Estimate	95% CI	N	Estimate	95% CI	N	Estimate	95% CI
Li HepPlasma	0-1.5hr	41	82.9%	68.7-91.5	396	93.9%	91.1-95.9	58	58.6%	45.8-70.4	379	98.2%	96.2-99.1
	≥1.5-2.5 hr	76	89.5%	80.6-94.6	710	91.8%	89.6-93.6	126	54.0%	45.3-62.4	660	98.8%	97.6-99.4
	≥2.5-3.5 hr	72	95.8%	88.5-98.6	605	91.9%	89.5-93.8	118	58.5%	49.5-67.0	559	99.5%	98.4-99.8
	≥3.5-4.5 hr	52	94.2%	84.4-98.0	481	89.4%	86.3-91.8	100	49.0%	39.4-58.7	433	99.3%	98.0-99.8
	≥4.5-6 hr	24	95.8%	79.8-99.3	239	86.2%	81.2-90.0	56	41.1%	29.2-54.1	207	99.5%	97.3-99.9
	≥6-9 hr	70	95.7%	88.1-98.5	370	87.8%	84.1-90.8	112	59.8%	50.6-68.4	328	99.1%	97.3-99.7
	≥9-24 hr	71	94.4%	86.4-97.8	347	88.8%	85.0-91.7	106	63.2%	53.7-71.8	312	98.7%	96.8-99.5
	≥24 hr	25	100.0%	86.7-100	106	82.1%	73.7-88.2	44	56.8%	42.2-70.3	87	100.0%	95.8-100
Serum	0-1.5hr	41	80.5%	66.0-89.8	405	94.8%	92.2-96.6	54	61.1%	47.8-73.0	392	98.0%	96.0-99.0
	≥1.5-2.5 hr	77	88.3%	79.3-93.7	708	91.9%	89.7-93.7	125	54.4%	45.7-62.9	660	98.6%	97.4-99.3
	≥2.5-3.5 hr	67	95.5%	87.6-98.5	615	92.8%	90.5-94.6	108	59.3%	49.8-68.1	574	99.5%	98.5-99.8
	≥3.5-4.5 hr	47	93.6%	82.8-97.8	484	90.3%	87.3-92.6	91	48.4%	38.4-58.5	440	99.3%	98.0-99.8
	≥4.5-6 hr	24	95.8%	79.8-99.3	239	87.0%	82.2-90.7	54	42.6%	30.3-55.8	209	99.5%	97.3-99.9
	≥6-9 hr	68	95.6%	87.8-98.5	379	88.7%	85.1-91.5	108	60.2%	50.8-68.9	339	99.1%	97.4-99.7
	≥9-24 hr	71	94.4%	86.4-97.8	353	89.8%	86.2-92.5	103	65.0%	55.5-73.6	321	98.8%	96.8-99.5
	≥24 hr	28	96.4%	82.3-99.4	107	84.1%	76.0-89.8	44	61.4%	46.6-74.3	91	98.9%	94.0-99.8

Using the female-specific 99th percentiles for lithium heparin plasma (36.99 pg/mL) and serum (39.59 pg/mL), the following results were obtained.

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510(k) Summary of Safety and Effectiveness

Using the male-specific 99" percentiles for lithium heparin plasma (57.27 pg/mL) and serum
(58.05 pg/mL), the following results were obtained.

		Sensitivity				Specificity			PPV			NPV
Matrix	Timepoint	N	Estimate	95% CI	N	Estimate	95% CI	N	Estimate	95% CI	N	Estimate	95% CI
Li HepPlasma	0-1.5hr	100	74.0%	64.6-81.6	561	92.0%	89.4-94.0	119	62.2%	53.2-70.4	542	95.2%	93.1-96.7
	≥1.5-2.5 hr	162	87.7%	81.7-91.9	913	90.7%	88.6-92.4	227	62.6%	56.1-68.6	848	97.6%	96.4-98.5
	≥2.5-3.5 hr	126	89.7%	83.1-93.9	740	90.1%	87.8-92.1	186	60.8%	53.6-67.5	680	98.1%	96.8-98.9
	≥3.5-4.5 hr	97	86.6%	78.4-92.0	597	92.5%	90.1-94.3	129	65.1%	56.6-72.8	565	97.7%	96.1-98.7
	≥4.5-6 hr	39	92.3%	79.7-97.3	218	92.2%	87.9-95.1	53	67.9%	54.5-78.9	204	98.5%	95.8-99.5
	≥6-9 hr	124	87.9%	81.0-92.5	520	88.8%	85.9-91.3	167	65.3%	57.8-72.1	477	96.9%	94.9-98.1
	≥9-24 hr	141	91.5%	85.7-95.1	491	84.7%	81.3-87.6	204	63.2%	56.4-69.6	428	97.2%	95.2-98.4
	≥24 hr	37	86.5%	72.0-94.1	140	89.3%	83.1-93.4	47	68.1%	53.8-79.6	130	96.2%	91.3-98.3
Serum	0-1.5hr	101	75.2%	66.0-82.6	573	92.8%	90.4-94.7	117	65.0%	56.0-73.0	557	95.5%	93.5-96.9
	≥1.5-2.5 hr	159	85.5%	79.2-90.2	922	91.5%	89.6-93.2	214	63.6%	56.9-69.7	867	97.3%	96.1-98.2
	≥2.5-3.5 hr	123	86.2%	79.0-91.2	756	91.1%	88.9-93.0	173	61.3%	53.8-68.2	706	97.6%	96.2-98.5
	≥3.5-4.5 hr	98	84.7%	76.3-90.5	605	93.1%	90.7-94.8	125	66.4%	57.7-74.1	578	97.4%	95.8-98.4
	≥4.5-6 hr	38	94.7%	82.7-98.5	220	90.9%	86.4-94.0	56	64.3%	51.2-75.5	202	99.0%	96.5-99.7
	≥6-9 hr	122	87.7%	80.7-92.4	526	90.5%	87.7-92.7	157	68.2%	60.5-74.9	491	96.9%	95.0-98.1
	≥9-24 hr	143	91.6%	85.9-95.1	496	86.1%	82.8-88.9	200	65.5%	58.7-71.7	439	97.3%	95.3-98.4
	≥24 hr	37	89.2%	75.3-95.7	148	89.9%	84.0-93.8	48	68.8%	54.7-80.1	137	97.1%	92.7-98.9

Using the overall 99th Percentile (47.34 pg/mL), the following results were obtained for both genders combined.

		Sensitivity				Specificity				PPV
Matrix	Timepoint	N	Estimate	95% CI	N	Estimate	95% CI	N	Estimate	95% CI	N	Estimate	95% CI
Li HepPlasma	0-1.5hr	141	78.0%	70.5-84.1	957	92.8%	91.0-94.3	179	61.5%	54.2-68.3	919	96.6%	95.3-97.6
	≥1.5-2.5 hr	238	89.5%	85.0-92.8	1623	90.7%	89.2-92.0	364	58.5%	53.4-63.5	1497	98.3%	97.5-98.9
	≥2.5-3.5 hr	198	92.9%	88.5-95.7	1345	90.4%	88.7-91.9	313	58.8%	53.3-64.1	1230	98.9%	98.1-99.3
	≥3.5-4.5 hr	149	91.3%	85.6-94.8	1078	90.9%	89.0-92.5	234	58.1%	51.7-64.3	993	98.7%	97.8-99.2
	≥4.5-6 hr	63	95.2%	86.9-98.4	457	89.5%	86.3-92.0	108	55.6%	46.2-64.6	412	99.3%	97.9-99.8
	≥6-9 hr	194	92.8%	88.3-95.7	890	88.1%	85.8-90.1	286	62.9%	57.2-68.3	798	98.2%	97.1-99.0
	≥9-24 hr	212	92.9%	88.7-95.7	838	85.9%	83.4-88.1	315	62.5%	57.1-67.7	735	98.0%	96.7-98.8
	≥24 hr	62	93.5%	84.6-97.5	246	86.2%	81.3-89.9	92	63.0%	52.8-72.2	216	98.1%	95.3-99.3
Serum	0-1.5hr	142	78.9%	71.4-84.8	978	93.1%	91.4-94.6	179	62.6%	55.3-69.3	941	96.8%	95.5-97.8
	≥1.5-2.5 hr	236	88.6%	83.9-92.0	1630	91.4%	90.0-92.7	349	59.9%	54.7-64.9	1517	98.2%	97.4-98.8
	≥2.5-3.5 hr	190	92.1%	87.4-95.2	1371	91.2%	89.6-92.6	296	59.1%	53.4-64.6	1265	98.8%	98.1-99.3
	≥3.5-4.5 hr	145	90.3%	84.4-94.2	1089	91.5%	89.7-93.0	224	58.5%	51.9-64.7	1010	98.6%	97.7-99.2
	≥4.5-6 hr	62	96.8%	89.0-99.1	459	89.1%	85.9-91.6	110	54.5%	45.2-63.5	411	99.5%	98.2-99.9
	≥6-9 hr	190	91.6%	86.8-94.8	905	88.5%	86.3-90.4	278	62.6%	56.8-68.1	817	98.0%	96.8-98.8
	≥9-24 hr	214	93.0%	88.8-95.7	849	86.7%	84.2-88.8	312	63.8%	58.3-68.9	751	98.0%	96.7-98.8
	≥24 hr	65	92.3%	83.2-96.7	255	86.3%	81.5-90.0	95	63.2%	53.1-72.2	225	97.8%	94.9-99.0

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10.14 Traceability and Value Assignment

The ADVIA Centaur TNIH assay is standardized to an internal standard manufactured using human heart homogenate. Assigned values for calibrators are traceable to this standardization.

10.15 Stability

The ADVIA Centaur TNIH Reagents and Calibrators are stable until the date printed on the box label when stored at 2-8°C.

The onboard stability of the ADVIA Centaur TNIH Reagents is 28 days with a calibration interval of 28 days.

Conclusions 11.

The new ADVIA Centaur High-Sensitivity Troponin I (TNIH) assay (Reagents and Calibrators) is substantially equivalent in principle and performance to the currentlymarketed predicate device, the Elecsys Troponin T Gen 5 STAT Immunoassay, cleared under 510(k) K162895.

Regulation Number and Section

§ 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system.

(a)
Identification. A creatine phosphokinase/creatine kinase or isoenzymes test system is a device intended to measure the activity of the enzyme creatine phosphokinase or its isoenzymes (a group of enzymes with similar biological activity) in plasma and serum. Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.(b)
Classification. Class II.