(63 days)
The Dimension EXL High-Sensitivity Troponin I (TNIH) assay is for in vitro diagnostic use in the quantitative measurement of cardiac troponin I in human plasma using the Dimension EXL integrated chemistry system with LOCI module. The assay can be used to aid in the diagnosis of acute myocardial infarction (AMI).
The Dimension EXL TNIH assay is a homogeneous, sandwich chemiluminescent immunoassay based on LOCl® technology. The LOCI reagents include two synthetic bead reagents and two biotinylated anti-cardiac troponin I monoclonal antibody fragments. The first bead reagent (Sensibeads) is coated with streptavidin and contains photosensitizer dye. The second bead reagent (Chemibeads) is coated with a third anticardiac troponin I monoclonal antibody and contains chemilyminescent dve. Sample is incubated with Chemibeads and biotinylated antibodies to form bead-cardiac troponin Ibiotinylated antibody sandwiches. Sensibeads are added and bind to form bead-pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direct function of the cardiac troponin I concentration in the sample. Lithium heparin plasma specimens may be used. The reagent is stored unopened at 2 -8 °C, is stable sealed on system for 30 days and opened on the system for 7 days. Calibration is performed every 21 days for a reagent lot.
Here's a summary of the acceptance criteria and study details for the Dimension EXL High-Sensitivity Troponin I (TNIH) Assay, extracted from the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Metric | Acceptance Criteria (implicit from compliance) | Reported Device Performance |
|---|---|---|
| Limit of Blank (LoB) | Consistency with claim of 1.1 pg/mL | 1.0 pg/mL |
| Limit of Detection (LoD) | Consistency with claim of 2.7 pg/mL | 1.0 - 1.8 pg/mL |
| Limit of Quantitation (LoQ) | CV ≤ 20.0% | 1.1 pg/mL (Lot-1), 2.1 pg/mL (Lot-2), 2.3 pg/mL (Lot-3). Claimed LoQ of 4.0 pg/mL. (The LoQ of 4.0 pg/mL is explicitly stated to be consistent with the data, implying it met the 20% CV criteria). |
| 10% CV Limit | CV ≤ 10.0% | 3.2 pg/mL (Lot-1), 5.3 pg/mL (Lot-2), 5.8 pg/mL (Lot-3). Claimed 10% CV limit of 12.0 pg/mL. (The 10% CV limit of 12.0 pg/mL is explicitly stated to be consistent with the data, implying it met the 10% CV criteria). |
| Precision (Repeatability %CV) | All precision goals were met (specific target not provided, but values shown are low) | Plasma 1: 2.3%, Plasma 2: 2.0%, Plasma 3: 1.8%, QC: 2.0% |
| Precision (Within-Lab %CV) | All precision goals were met (specific target not provided, but values shown are low) | Plasma 1: 6.0%, Plasma 2: 2.9%, Plasma 3: 3.0%, QC: 3.3% |
| Linearity | p-values of nonlinear terms > 0.05 OR allowable bias ≤ 10% or 4 pg/mL | Confirmed linearity from 4.0 - 25,000.0 pg/mL. |
| Interferences (Bias) | Bias exceeding 10% is considered interference. | Hemoglobin: <10%, Bilirubin (conjugated): <10%, Bilirubin (unconjugated): <10%, Lipemia: <10%. No interference from a wide range of therapeutic/toxic substances (listed in detail, all <10%). |
| Cross-reactivity | Lower values indicate less cross-reactivity (no explicit threshold provided, but shown to be very low) | Cardiac Troponin T: 0.003%, Skeletal Troponin I: 0.001%, Tropomyosin: ND, Actin: ND, Troponin C: ND, Myosin Light Chain: ND, Myoglobin: ND, CK-MB: ND. |
| High Dose Hook Effect | No hook effect | No hook effect found at 1,000,000 pg/mL troponin. |
| Dilution Recovery | Testing supported use of diluent for over-range samples. | Supported use of CTNI SDIL as diluent for 1:2 and 1:5 dilutions of native human plasma samples with high TNIH levels. |
| Calibration Stability | p-value of regression slope ≥ 0.05 OR drift ≤ LoQ or ≤ 10% (up to 20,000 pg/mL), ≤ 13% (> 20,000 pg/mL) | Calibration interval was measured to be 21 days. (This implies it met the acceptance criteria for 21 days). |
| Open Well Stability | p-value of regression slope ≥ 0.05 OR drift ≤ LoQ or ≤ 10% (up to 20,000 pg/mL), ≤ 13% (> 20,000 pg/mL) | Stability of reagents opened onboard the instrument was 7 days per well set. (This implies it met the acceptance criteria for 7 days). |
| Sample Stability | Lower bound of 95% CI of regression line ≤ -10% AND all data points bias ≤ -20% vs time zero | Separated samples stable for 8 hours at room temperature, 24 hours at 2-8°C, up to 40 days at or below -20°C (non-frost free), and up to 1 year at or below -70°C. (This implies these storage conditions met the specified bias criteria). |
| 99th Percentile Expected Values | Determined using non-parametric statistical method (CLSI EP28-A3c). | Overall: 60.4 pg/mL (90% CI: 43.2 to 81.3); Female: 51.4 pg/mL (90% CI: 35.6 to 109.2); Male: 76.2 pg/mL (90% CI: 42.3 to 117.0). No statistical basis for using separate values based on gender or sample type. |
| Clinical Performance | No explicit quantitative acceptance criteria provided in the extract, but the data presented supports its diagnostic utility. | Pooled Gender (60.4 pg/mL cutoff): Sensitivity ranging from 78.3% (0-<1.5h) to 95.5% (4.5-<6h), Specificity ranging from 86.2% (≥9-<24h) to 92.9% (0-<1.5h). NPV consistently high (e.g., 96.8% at 0-<1.5h, up to 99.3% at 4.5-<6h).Female-specific (51.4 pg/mL cutoff): Sensitivity ranging from 83.3% (0-<1.5h) to 100.0% (≥24h), Specificity ranging from 82.0% (≥24h) to 94.6% (0-<1.5h). NPV consistently high (e.g., 98.2% at 0-<1.5h, up to 99.5% at 4.5-<6h).Male-specific (76.2 pg/mL cutoff): Sensitivity ranging from 74.0% (0-<1.5h) to 90.9% (≥9-<24h), Specificity ranging from 87.2% (≥9-<24h) to 92.7% (≥3.5-<4.5h). NPV consistently high (e.g., 95.5% at 0-1.5h, up to 97.7% at 3.5-<4.5h). |
2. Sample size used for the test set and the data provenance
- Clinical Performance (diagnostic accuracy):
- Sample Size: Approximately 2500 subjects.
- Data Provenance: Prospective study, specimens collected at 29 emergency departments across the United States from subjects presenting with symptoms consistent with acute coronary syndrome (ACS).
- Expected Values (99th percentile):
- Sample Size: 2020 apparently healthy individuals (1017 female, 1003 male).
- Data Provenance: Lithium heparin plasma specimens collected from apparently healthy individuals from the United States.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
- Number of Experts: Panels of certified cardiologists and emergency physicians (specific number not given, but implied to be multiple for "panels").
- Qualifications: Certified cardiologists and emergency physicians.
4. Adjudication method for the test set
- Adjudication Method: "All subject diagnoses were adjudicated by panels of certified cardiologists and emergency physicians according to 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)." This indicates a consensus-based adjudication following established clinical guidelines. Specific numerical adjudication (e.g., 2+1) is not explicitly stated.
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 comparative effectiveness study was done, nor is this applicable as it is an in vitro diagnostic assay, not an AI-assisted imaging device or system. The study focuses on the standalone performance of the assay compared to a clinically adjudicated diagnosis.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
- Yes, a standalone study was done. The entire performance evaluation here describes the analytical and clinical performance of the assay itself (the Dimension EXL TNIH assay) as a direct measurement tool, without any human-in-the-loop interpretation or AI assistance. The clinical performance section explicitly evaluates the assay's sensitivity, specificity, PPV, and NPV against the adjudicated diagnoses.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
- Ground Truth Type: Expert consensus based on a recognized international clinical guideline (Third Universal Definition Of Myocardial Infarction endorsed by various cardiology and heart associations).
8. The sample size for the training set
- The document does not explicitly mention a "training set" in the context of an algorithm or AI. This is a traditional immunoassay, and its development would typically involve internal optimization and validation, not a distinct "training set" like that for machine learning. The data presented here describes the performance evaluation during regulatory submission.
9. How the ground truth for the training set was established
- Not applicable, as a distinct training set with established ground truth, as understood in the context of AI/ML, is not described for this immunoassay.
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May 17, 2019
Siemens Healthcare Diagnostics, Inc. Laura Duggan Sr. Mgr. Regulatory Affairs 500 GBC Drive Newark, DE 19714
Re: K190675
Trade/Device Name: Dimension EXL High-Sensitivity Troponin I (TNIH) Assay Regulation Number: 21 CFR 862.1215 Regulation Name: Creatine phosphokinase/creatine kinase or isoenzymes test system Regulatory Class: Class II Product Code: MMI Dated: March 18, 2019 Received: March 19, 2019
Dear Laura Duggan:
We have reviewed vour 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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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
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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) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.html; good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; 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,
for Kellie B. Kelm. Ph.D. Acting Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Ouality Center for Devices and Radiological Health
Enclosure:
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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration
Indications for Use
510(k) Number (if known) K190675
Device Name
Dimension EXL High-Sensitivity Troponin I (TNIH) assay
Indications for Use (Describe)
The Dimension EXL High-Sensitivity Troponin I (TNIH) assay is for in vitro diagnostic use in the quantitative measurement of cardiac troponin I in human plasma using the Dimension EXL integrated chemistry system with LOCI module. The assay can be used to aid in the diagnosis of acute myocardial infarction (AMI).
X Prescription Use (Part 21 CFR 801 Subpart D)
] Over-The-Counter Use (21 CFR 801 Subpart C)
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SECTION 7: 510(K) SUMMARY
This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of SMDA 1990 and 21 CFR §807.92.
ASSIGNED 510(K) NUMBER
The assigned 510(k) number is k190675_________________________________________________________________________________________________________________________________
APPLICANT AND DATE
Laura J. Duggan, Ph. D., RAC Siemens Healthcare Diagnostics Inc. 500 GBC Drive, M/S 514 Newark, DE 19714-6101 Email: laura.j.duggan@siemens-healthineers.com Phone: 302-631-7654 Fax: 302-631-0493
March 14. 2019
MANUFACTURER
Siemens Healthcare Diagnostics Inc. 500 GBC Drive Newark, DE 19714-6101
Registration Number: 2517506
REGULATORY INFORMATION
Regulatory Submission for the Dimension EXL High-Sensitivity Troponin I (TNIH) Assay
| Device: | Immunoassay method, troponin subunit |
|---|---|
| Regulation Description: | Creatine phosphokinase/creatine kinase or isoenzymes test system |
| Proprietary Name: | Dimension EXL High-Sensitivity Troponin I (TNIH) Assay |
| Regulation Number: | 21CFR862.1215 |
| Classification: | Class II |
| Product Code: | MMI |
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| Panel: | Clinical Chemistry |
|---|---|
| Predicate Device: | Elecsys Troponin T Gen 5 STAT(K162895) |
DEVICE DESCRIPTION
DIMENSION EXL HIGH-SENSITIVITY TROPONIN I (TNIH) ASSAY
The Dimension EXL TNIH assay is a homogeneous, sandwich chemiluminescent immunoassay based on LOCl® technology. The LOCI reagents include two synthetic bead reagents and two biotinylated anti-cardiac troponin I monoclonal antibody fragments. The first bead reagent (Sensibeads) is coated with streptavidin and contains photosensitizer dye. The second bead reagent (Chemibeads) is coated with a third anticardiac troponin I monoclonal antibody and contains chemilyminescent dve. Sample is incubated with Chemibeads and biotinylated antibodies to form bead-cardiac troponin Ibiotinylated antibody sandwiches. Sensibeads are added and bind to form bead-pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direct function of the cardiac troponin I concentration in the sample
Lithium heparin plasma specimens may be used. The reagent is stored unopened at 2 -8 °C, is stable sealed on system for 30 days and opened on the system for 7 days. Calibration is performed every 21 days for a reagent lot.
INTENDED USE/INDICATIONS FOR USE
DIMENSION EXL HIGH-SENSITIVITY TROPONIN I (TNIH) ASSAY
The Dimension EXL High-Sensitivity Troponin I (TNIH) assay is for in vitro diagnostic use in the quantitative measurement of cardiac troponin I in human plasma using the Dimension EXL integrated chemistry system with LOCI module. The assay can be used to aid in the diagnosis of acute myocardial infarction (AMI).
SUBSTANTIAL EQUIVALENCE COMPARISON
Below is a substantial equivalence comparison for the Dimension EXL High-Sensitivity Troponin I (TNIH) Assay vs. the Elecsys Troponin T Gen 5 STAT (K162895) device.
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| Feature | Predicate Device:Elecsys Troponin T Gen 5STAT (K162895) | New Device:DIMENSION EXL HIGH-SENSITIVITY TROPONIN I(TNIH) ASSAY | |
|---|---|---|---|
| Intended Use : | Immunoassay for the in vitroquantitative determination ofcardiac troponin T (cTnT) inlithium heparin plasma. | The Dimension EXL High-Sensitivity Troponin I (TNIH)assay is for in vitro diagnosticuse in the quantitativemeasurement of cardiactroponin I in human plasmausing theDimension EXL integratedchemistry system with LOCImodule. | |
| Indications for Use: | The immunoassay isintended to aid in thediagnosis of myocardialinfarction. | The assay can be used to aidin the diagnosis of acutemyocardial infarction (AMI). | |
| Device Technology: | Electrochemiluminescenceimmunoassay | Homogeneous immunoassay | |
| Sample Type: | Lithium Heparin Plasma | Lithium Heparin plasma | |
| Expected Values: | 99th percentilewere determined to be:• 19 ng/L for both• 14 ng/L for females• 22 ng/L for males | 99th percentile determined forfor plasma60.4 pg/mL overallfemale 51.4 pg/mL plasmamale 76.2 pg/mL plasma | |
| CalibrationFrequency: | after 12 weeks when usingthe same reagent lot | 21 days for any one lot | |
| Analytical MeasuringInterval: | 6-10,000 ng/L | 4.0 - 25,000.0 pg/mL [ng/L] | |
| Interferences: | No interference in plasma at:Hemoglobin - 100 mg/dLBilirubin 25 mg/dLLipemia (Intralipid®) – 1500mg/dL | No interferences in plasma atapproximately 40 pg/mL andapproximately 1350 pg/mL ofcardiac troponin I from:Hemoglobin - 400 mg/dL | |
| Bilirubin (Unconjugated) – 40mg/dLBilirubin (Conjugated) – 30md/dLLipemia (Intralipid®) – 3000mg/dL | |||
| Calibrators: | Elecsys Troponin T Gen 5STAT calibrators (CalSetTroponin T Gen 5 STAT) | LOCI TNIH Calibrator, Cat.No. RC627 |
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SUMMARY OF PERFORMANCE TESTING
Assay performance results for the Dimension EXL High-Sensitivity Troponin I (TNIH) assay was determined by processing the appropriate body fluids. Summary statistics for each are provided. The following data represent typical assay performance. All data were collected on the Dimension EXL with LM System.
DETECTION LIMIT
The Limit of Blank (LoB) and Limit of Detection (LoD) were evaluated in accordance with CLSI EP17-A2 Protocols for Determination of Limits of Detection and Limits of Quantitation: Approved Guideline.
Assessment of LoB was the 95th percentile of all values (sorted from lowest to highest), using non-parametric approach. LoB Rank Position = 0.5 +0.95*B, where B=total reps=60; Rank = 57.5
The nonparametric approach described in EP17-A2 was followed to determine the Limit of Detection. LoD was tested separately for lithium heparin specimens.
| Dimension EXL High-Sensitivity Troponin I (TNIH) - Limit of Detection Results | ||
|---|---|---|
| Limit | Protocol | Result |
| LoB | 5 samples with no analyte (calibrator Level A,BSA based with HEPES buffer 5 individual vials)were tested (N=4) for 3 days, one run per day, 3reagent lots | 1.0 pg/mL |
| LoD | At least 5 low analyte samples were tested (N=4)for 3 days for native lithium heparin plasma, onerun per day, 3 reagent lots | 1.0 - 1.8pg/mL |
Results are consistent with the claim of 2.7 pg/mL for LoD and 1.1 pg/mL for LoB.
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The Limit of Quantitation (LoQ) for plasma was determined as the analyte level with a within-lab CV of less than or equal to 20.0%. Testing was completed two times a day (n=2) for at least 20 days for a total of 80 replicates with at least 6 native lithium heparin plasma pools on one instrument.
LoQ Lot Summary
| Reagent Lot | Lot-1 | Lot-2 | Lot-3 |
|---|---|---|---|
| Lithium Heparin Plasma 20% CV (pg/mL) | 1.1 | 2.1 | 2.3 |
The LoQ for TNIH of 4.0 pq/mL is consistent with the data.
10% CV LIMIT
For lithium heparin plasma the analyte level with a within-lab CV of less than or equal to 10.0% was determined using CLSI EP5-A3, Evaluation of Precision Performance of Quantitative Measurement Methods: Approved Guideline - Third Edition. Testing was completed two times a day (n=2) for at least 20 days for a total of 80 replicates with at least 6 native lithium heparin plasma pools on one instrument.
10% CV Lot Summary
| Reagent Lot | Lot-1 | Lot-2 | Lot-3 |
|---|---|---|---|
| Lithium Heparin Plasma 10% CV (pg/mL) | 3.2 | 5.3 | 5.8 |
The 10% CV limit for Dimension EXL TNIH of 12.0 pg/mL is consistent with the data.
PRECISION STUDIES
Precision testing was performed in accordance with CLSI EP05-A3 Evaluation of Precision Performance of Quantitative Measurement Methods: Approved Guideline -Third Edition. Precision was tested n = 2 replicates, two times a day for at least 20 days for a total of 80 replicates with controls and plasma pools on one instrument. Analysis of variance (ANOVA) was used to evaluate the data consistent with the recommendations of EP05-A3. The data are summarized in the following table. All precision goals were met.
| Repeatability | Within-Lab | ||||
|---|---|---|---|---|---|
| Material | Mean pg/mL [ng/L] | SDa pg/mL [ng/L] | %CVb | SD pg/mL [ng/L] | %CV |
| Plasma 1 | 48.0 | 1.11 | 2.3 | 2.87 | 6.0 |
| Plasma 2 | 71.8 | 1.45 | 2.0 | 2.09 | 2.9 |
| Plasma 3 | 155.7 | 2.75 | 1.8 | 4.62 | 3.0 |
| QC | 7411.7 | 145.59 | 2.0 | 246.56 | 3.3 |
ªSD = standard deviation
b CV = coefficient of variation
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Linearity was evaluated with 16 lithium heparin plasma samples which spanned the assay measuring interval. Each was prepared by mixing high and low concentration samples across the measurement interval as described in CLSI Evaluation of the Linearity of Quantitative Measurement Procedure (EP06-A). The high samples and the low samples for lithium heparin plasma were native. At least five replicates were measured for each sample. The mean of these replicates was used for the calculations.
The assay was considered linear across the measuring interval if the p values of nonlinear terms in the quadratic and cubic fit equations are nonsignificant (p ≤ 0.05). If the p-value is > 0.05, then the allowable bias is ≤ 10% or 4 pg/mL, whichever is greater.
The testing confirmed linearity from 4.0 - 25,000.0 pg/mL.
INTERFERENCES
CLSI EP7-A2 was followed for the interference testing. The interference study was conducted using a "paired difference scenario" approach where these compounds were spiked into fresh sample pools containing either low or high levels of troponin in lithium heparin troponin I pools. All exogeneous compounds were spiked into the troponin control pools at two levels. Endogeneous compounds were only tested at elevated levels as they are natively found in specimen samples.
Bias is the difference in the results between the control sample (without the interferent) and the test sample (contains the interferent) expressed in percent. Bias exceeding 10% is considered interference. Dilution studies were conducted to determine the level at which the spiked substance no longer displayed significant interference. Dilution studies were conducted at two analyte concentrations, if both sample pools show significant interference.
| Substance Tested | Substance concentration | Bias (%) |
|---|---|---|
| Hemoglobin hemolysate (monomer) | 400 mg/dL [0.25 mmol/L] | <10 |
| Bilirubin (conjugated) | 30 mg/dL [356 µmol/L] | <10 |
| Bilirubin (unconjugated) | 40 mg/dL [684 µmol/L] | <10 |
| Lipemia (Intralipid®) | 3000 mg/dL [33.9 mmol/L] | <10 |
No interference was detected at the following analyte concentrations.
| Low or Therapeutic Concentration | High or Toxic Concentration | |||
|---|---|---|---|---|
| Potential Interferent | Conventional Units | SI Units | Conventional Units | SI Units |
| Abciximab | 0.4 mg/dL | NA | 4.0 mg/dL | NA |
| Acetaminophen | 2.0 mg/dL | 133 µmol/L | 20.0 mg/dL | 1324 µmol/L |
| Acetylsalicylic acid | 26.1 mg/dL | 1.45 mmol/L | 65.2 mg/dL | 3.62 mmol/L |
| Allopurinol | 1.3 mg/dL | 91.9 µmol/L | 4.0 mg/dL | 294 µmol/L |
| Amiodarone | 0.2 mg/dL | 2.6 µmol/L | 0.6 mg/dL | 8.92 µmol/L |
| Ampicillin | 1.1 mg/dL | 29.1 µmol/L | 5.6 mg/dL | 152 µmol/L |
| Ascorbic acid | 1.2 mg/dL | 68.5 µmol/L | 6.0 mg/dL | 342 µmol/L |
| Atenolol | 0.1 mg/dL | 4.1 µmol/L | 1.0 mg/dL | 37.6 µmol/L |
| Biotin | 10 ng/mL | 0.04 µmol/L | 300 ng/mL | 1.2 µmol/L |
| Caffeine | 1.3 mg/dL | 64.4 µmol/L | 6.0 mg/dL | 308 µmol/L |
| Captopril | 0.1 mg/dL | 4.6 µmol/L | 0.5 mg/dL | 23 µmol/L |
| Cefoxitin | 12.63 mg/dL | 281 µmol/L | 69.5 mg/dL | 1546 µmol/L |
| Cholesterol | NA** | NA | 300 mg/dL | 7.8 mmol/L |
| Cinnarizine | 0.0285 mg/dL | 0.8 µmol/L | 2.5 mg/dL | 67.8 µmol/L |
| Clopidogrel | 0.32 mg/dL | 9.9 µmol/L | 7.5 mg/dL | 233 µmol/L |
| Cocaine | 0.05 mg/dL | 1.6 µmol/L | 1.0 mg/dL | 33 µmol/L |
| Dextran 40 | 15 g/L | 375 µmol/L | 45 g/L | 1125 µmol/L |
| Digitoxin | 17 ng/mL | 22.2 nmol/L | 60 ng/mL | 78.4 nmol/L |
| Digoxin | 1.4 ng/mL | 1.8 nmol/L | 6.1 ng/mL | 7.8 nmol/L |
| Diltiazem | 0.025 mg/dL | 0.55 µmol/L | 0.68 mg/dL | 15 µmol/L |
| Disopyramide | 0.45 mg/dL | 10.4 µmol/L | 1.3 mg/dL | 29.5 µmol/L |
| Dopamine | 0.04 mg/dL | 1.96 µmol/L | 0.11 mg/dL | 5.87 µmol/L |
| Doxycycline | 1.1 mg/dL | 22.5 µmol/L | 3.2 mg/dL | 67.5 µmol/L |
| Erythromycin | 1.1 mg/dL | 15 µmol/L | 6.0 mg/dL | 81.6 µmol/L |
| Furosemide | 2.0 mg/dL | 60.4 µmol/L | 6.0 mg/dL | 181 µmol/L |
| Ibuprofen | 4.0 mg/dL | 194.3 µmol/L | 50 mg/dL | 2425 µmol/L |
| Isosorbide dinitrate | 50.1 ng/mL | 212 nmol/L | 150.2 ng/mL | 636 nmol/L |
| Lisinopril | 0.01 mg/dL | 0.25 µmol/L | 0.33 mg/dL | 0.74 µmol/L |
| Low MW Heparin | 0.85 U/mL | NA | 2.0 U/mL | NA |
| Lovastatin | 17.2 ng/mL | 42.4 nmol/L | 80 ng/mL | 197.8 nmol/L |
| Methotrexate | 50 mg/dL | 1.1 mmol/L | 91 mg/dL | 2 mmol/L |
| Methyldopa | 0.48 mg/dL | 20.1 µmol/L | 1.69 mg/dL | 70.9 µmol/L |
| Methylprednisolone | 1.65 mg/dL | 44 µmol/L | 4.0 mg/dL | 106.8 µmol/L |
| Mexiletine | 0.15 mg/dL | 7 µmol/L | 0.48 mg/dL | 22.3 µmol/L |
| Nicotine | 0.004 mg/dL | 0.2 µmol/L | 0.10 mg/dL | 6.2 µmol/L |
| Nifedipine | 0.013 mg/dL | 361.3 nmol/L | 0.04 mg/dL | 1156.1 nmol/L |
| Nitrofurantoin | 0.20 mg/dL | 8.4 µmol/L | 0.40 mg/dL | 16.8 µmol/L |
| Nitroglycerine | 7.5 ng/mL | 33 nmol/L | 160 ng/mL | 704.5 nmol/L |
| Phenobarbital | 2.5 mg/dL | 107.8 µmol/L | 10.0 mg/dL | 431.5 µmol/L |
| Phenytoin | 1.36 mg/dL | 49.6 µmol/L | 5.43 mg/dL | 198 µmol/L |
| Primidone | 1.1 mg/dL | 48.2 µmol/L | 4.0 mg/dL | 183.5 µmol/L |
| Propranolol | 0.06 mg/dL | 1.93 µmol/L | 0.23 mg/dL | 7.71 µmol/L |
| Protein, Albumin | NA** | NA | 6 g/dL | 60 g/L |
| Protein, Gamma Globulin | 2.5 g/dL | NA | NA | NA |
| Protein, Total | NA** | NA | 12 g/dL | NA |
| Quinidine | 0.38 mg/dL | 11.7 µmol/L | 1.2 mg/dL | 37 µmol/L |
| Rheumatoid Factor | 750 IU/mL | NA | 1500 IU/mL | NA |
| Theophylline | 1.25 mg/dL | 69.4 µmol/L | 4.0 mg/dL | 222.2 µmol/L |
| Tissue plasminogen activator(TPA) | 0.52 µg/mL | NA | 2.3 µg/mL | NA |
| Thyroxine | 0.23 mg/dL | 0.3 µmol/L | 0.6 mg/dL | 0.8 µmol/L |
| Triglyceride | 500 mg/dL | NA | 1000 mg/dL | NA |
| Trimethoprim | 1.25 mg/dL | 43.1 µmol/L | 4.0 mg/dL | 138.3 µmol/L |
| Verapamil | 0.035 mg/dL | 0.8 µmol/L | 0.22 mg/dL | 4.4 µmol/L |
| Warfarin | 0.20 mg/dL | 6.6 µmol/L | 1.0 mg/dL | 32.5 µmol/L |
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** Testing at low concentrations was not appropriate for these endogenous substances.
ANALYTICAL SPECIFICITY
Cross-reactivity was determined following the governing standard CLSI document EP07-A2: Interference Testing in Clinical Chemistry; Approved Guideline-Second Edition.Cross-reactivity was tested at cTnl concentration of range of 20-60 pq/mL in native lithium heparin pools as well as in the absence of cTnl. The cross-reactants were tested at a single concentration near the upper limit of its therapeutic range. TNIH assay results from the spiked samples were compared with those of unspiked control samples. Percent cross-reactivity is calculated as:
% Cross-reactivity = [measured analyte] - [control analyte] x 100 [cross-reactant]
| Cross-reactant | Amount ng/mL [µg/L] | Cross-reactivity (%) |
|---|---|---|
| Cardiac Troponin T | 1000 | 0.003 |
| Skeletal Troponin I | 1000 | 0.001 |
| Tropomyosin | 1000 | ND |
| Actin | 1000 | ND |
| Troponin C | 1000 | ND |
| Myosin Light Chain | 1000 | ND |
| Myoglobin | 1000 | ND |
| CK-MB | 1000 | ND |
*ND= Not detectable
HIGH DOSE HOOK EFFECT
The high dose hook effect of the TNIH assay was assessed. Normal human lithium heparin plasma were spiked with calibrator antigen. A dilution series was created and tested. No hook effect was found at 1,000,000 pg/mL troponin on the Dimension EXL TNIH assay.
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Dilution recovery was evaluated for plasma at 1:2 and 1:5 dilutions using CTNI SDIL as diluent. Native human plasma samples were pooled to obtain at least three unique patient samples with TNIH levels ≥75% of the measuring interval and at least two samples above the measuring interval. For samples above the assay measuring interval the expected or neat value was determined using a 1:2 dilution in normal human plasma. Testing supported use of the diluent for over-range samples.
CALIBRATION STABILITY
The calibration stability for the TNIH assay on the Dimension EXL was determined by reading the recovery of the calibrators, commercial QC, a low patient pool and a high pool over time. The p-value of the regression slope was determined. Passing results were a p-value greater than or equal to 0.05 or drift less than or equal to the LoQ or less than or equal to10% for values up to 20,000 pg/mL and less than or equal to 13% for values greater than 20,000 pg/mL. Calibration interval was measured to be 21 days.
OPEN WELL STABILITY
The open well stability for the TNIH assay on the Dimension EXL was determined by reading the recovery of the calibrators and a low patient pool. On the first day of the study reagent packs were opened on the system and analyte was measured over the desired time interval. The p-value of the regression slope was determined. Passing results were a p-value greater than or equal to 0.05 or drift less than or equal to the LoQ or less than or equal to10% for values up to 20.000 pg/mL and less than or equal to 13% for values greater than 20,000 pg/mL. The stability of the reagents opened onboard the instrument was 7 days per well set.
SAMPLE STABILITY
Separated samples are stable for 8 hours at room temperature and for 24 hours when stored at 2-8 °C. Samples can be frozen at or below -20 °C for up to 40 days in a nonfrost free freezer and at or below -70 ℃ for up to 1 year. A linear regression analysis of the observed Troponin % Bias value (Y-axis) versus time (X-axis) was completed for each matrix. The acceptance criteria were the lower bound of the one-sided 95% confidence interval of the regression line is ≤-10% and all individual data points had a bias of ≤ -20% when compared to time zero.
EXPECTED VALUES
Lithium heparin plasma specimens were collected from apparently healthy individuals from the United States who ranged in age from 22-91 years of age. Each specimen
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was frozen, thawed and assayed once. The 99th percentile values were determined using the non-parametric statistical method described in
CLSI Guidance EP28-A3c. Sample type, gender, and age had no statistically significant effect on the 99th percentile.
The combined gender and the more commonly used sample type of lithium heparin were used to determine the overall observed 99th percentile of 60.4 pg/mL [ng/L]. Two female subjects had troponin values of approximately 400 pg/mL and 4700 pg/mL, and were considered to be outliers. These results were not included in the 99th percentile-determination.
The 99th percentile values determined for lithium heparin plasma (female, male, and combined) are shown in the following table. The 90% confidence intervals demonstrate that there is no statistical basis for using separate 99th percentile values based on gender or sample type.
| Sample Type | Gender | n | 99th Percentileapg/mL [ng/L] | 90% CIbpg/mL [ng/L] |
|---|---|---|---|---|
| Lithium Heparin | Female | 1017 | 51.4 | 35.6 to 109.2 |
| Lithium Heparin | Male | 1003 | 76.2 | 42.3 to 117.0 |
| Lithium Heparin | Combined | 2020 | 60.4 | 43.2 to 81.3 |
b confidence interval
CLINICAL PERFORMANCE
A prospective study was performed to assess diagnostic accuracy for approximately 2500 subjects in lithium heparin plasma sample types to evaluate clinical performance. Specimens were collected at 29 emergency departments across the United States, from subjects presenting with symptoms consistent with acute coronary syndrome (ACS).
All subject diagnoses were adjudicated by panels of certified cardiologists and emergency physicians according to 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 observed AMI prevalence in this study was 13.0 %.
The clinical concordance study evaluated clinical sensitivity, clinical specificity, positive predictive value (PPV) and negative predictive value (NPV) of the Dimension EXL TNIH assay in terms of its correlation to the diagnosis of AMI. The results were analyzed using the serial sampling time points collected during the emergency department visit. A positive is defined as a sample exceeding the 99th percentile cutoff at the particular time point. The results are presented using serial timed intervals analyzed according to the time of presentation to the emergency department. The pooled gender results based
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on time of presentation to the emergency department, calculated using the overall 90th percentile of 60.4 pg/mL, are summarized in Table 1.
| Time sincepresentation(hours) | Sensitivity | Specificity | Positive Predictive Value | Negative Predictive Value | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | % | 95% CI | n | % | 95% CI | n | % | 95% CI | n | % | 95% CI | |
| Lithium Heparin Plasma | ||||||||||||
| 0-<1.5 | 138 | 78.3 | 70.7-84.3 | 978 | 92.9 | 91.2-94.4 | 177 | 61.0 | 53.7-67.9 | 939 | 96.8 | 95.5-97.8 |
| ≥ 1.5-<2.5 | 240 | 88.8 | 84.1-92.2 | 1658 | 91.6 | 90.1-92.8 | 353 | 60.3 | 55.2-65.3 | 1545 | 98.3 | 97.5-98.8 |
| ≥ 2.5-<3.5 | 199 | 89.9 | 85.0-93.4 | 1379 | 90.6 | 89.0-92.1 | 308 | 58.1 | 52.5-63.5 | 1270 | 98.4 | 97.6-99.0 |
| ≥3.5-4.5 | 144 | 92.4 | 86.8-95.7 | 1094 | 91.2 | 89.4-92.8 | 229 | 58.1 | 51.6-64.3 | 1009 | 98.9 | 98.1-99.4 |
| ≥ 4.5-<6 | 67 | 95.5 | 87.6-98.5 | 463 | 89.2 | 86.0-91.7 | 114 | 56.1 | 47.0-64.9 | 416 | 99.3 | 97.9-99.8 |
| ≥6-<9 | 191 | 92.7 | 88.1-95.6 | 917 | 88.0 | 85.7-90.0 | 287 | 61.7 | 55.9-67.1 | 821 | 98.3 | 97.2-99.0 |
| ≥9-<24 | 215 | 93.0 | 88.8-95.7 | 849 | 86.2 | 83.7-88.4 | 317 | 63.1 | 57.7-68.2 | 747 | 98.0 | 96.7-98.8 |
| ≥ 24 | 63 | 95.2 | 86.9-98.4 | 256 | 86.3 | 81.6-90.0 | 95 | 63.2 | 53.1-72.2 | 224 | 98.7 | 96.1-99.5 |
| Table1: Pooled gender results based on time from presentation to the emergency department | ||||||
|---|---|---|---|---|---|---|
| -- | -- | -- | -- | -- | ------------------------------------------------------------------------------------------- | -- |
Results for females based on time of presentation to the emergency department, calculated using the female-specific 99th percentile of 51.4 pg/mL for plasma are summarized in Table 2.
Table 2: Results for females based on time from presentation to the emergency department
| Sensitivity | Specificity | Positive Predictive Value | Negative Predictive Value | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Time sincepresentation(hours) | n | % | 95% CI | n | % | 95% CI | n | % | 95% CI | n | % | 95% CI |
| Lithium Heparin Plasma | ||||||||||||
| 0 - < 1.5 | 42 | 83.3 | 69.4-91.7 | 407 | 94.6 | 92.0-96.4 | 57 | 61.4 | 48.4-72.9 | 392 | 98.2 | 96.4-99.1 |
| ≥ 1.5 - < 2.5 | 78 | 91.0 | 82.6-95.6 | 728 | 91.9 | 89.7-93.7 | 130 | 54.6 | 46.0-62.9 | 676 | 99.0 | 97.9-99.5 |
| ≥ 2.5 - < 3.5 | 73 | 94.5 | 86.7-97.8 | 624 | 92.0 | 89.6-93.9 | 119 | 58.0 | 49.0-66.5 | 578 | 99.3 | 98.2-99.7 |
| ≥ 3.5 - < 4.5 | 51 | 94.1 | 84.1-98.0 | 492 | 90.9 | 88.0-93.1 | 93 | 51.6 | 41.6-61.5 | 450 | 99.3 | 98.1-99.8 |
| ≥ 4.5 - < 6 | 25 | 96.0 | 80.5-99.3 | 242 | 85.5 | 80.6-89.4 | 59 | 40.7 | 29.1-53.4 | 208 | 99.5 | 97.3-99.9 |
| ≥ 6 - < 9 | 68 | 94.1 | 85.8-97.7 | 380 | 87.9 | 84.2-90.8 | 110 | 58.2 | 48.8-67.0 | 338 | 98.8 | 97.0-99.5 |
| ≥ 9 - < 24 | 72 | 93.1 | 84.8-97.0 | 348 | 88.5 | 84.7-91.4 | 107 | 62.6 | 53.2-71.2 | 313 | 98.4 | 96.3-99.3 |
| ≥ 24 | 26 | 100.0 | 87.1-100.0 | 111 | 82.0 | 73.8-88.0 | 46 | 56.5 | 42.2-69.8 | 91 | 100.0 | 95.9-100.0 |
Results for males based on time of presentation to the emergency department, calculated using the male-specific 99th percentile of 76.2 pg/mL for plasma are summarized in Table 3.
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| Time since presentation (hours) | n | Sensitivity | Specificity | Positive Predictive Value | Negative Predictive Value | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| % | 95% CI | n | % | 95% CI | n | % | 95% CI | n | % | 95% CI | ||
| Lithium Heparin Plasma | ||||||||||||
| 0-<1.5 | 96 | 74.0 | 64.4-81.7 | 571 | 92.3 | 89.8-94.2 | 115 | 61.7 | 52.6-70.1 | 552 | 95.5 | 93.4-96.9 |
| ≥ 1.5-<2.5 | 162 | 85.2 | 78.9-89.8 | 930 | 92.5 | 90.6-94.0 | 208 | 66.3 | 59.7-72.4 | 884 | 97.3 | 96.0-98.2 |
| ≥ 2.5-<3.5 | 126 | 84.9 | 77.6-90.1 | 755 | 91.0 | 88.7-92.8 | 175 | 61.1 | 53.8-68.1 | 706 | 97.3 | 95.8-98.3 |
| ≥ 3.5-<4.5 | 93 | 86.0 | 77.5-91.6 | 602 | 92.7 | 90.3-94.5 | 124 | 64.5 | 55.8-72.4 | 571 | 97.7 | 96.1-98.7 |
| ≥ 4.5-<6 | 42 | 88.1 | 75.0-94.8 | 221 | 91.4 | 87.0-94.4 | 56 | 66.1 | 53.0-77.1 | 207 | 97.6 | 94.5-99.0 |
| ≥6-<9 | 123 | 88.6 | 81.8-93.1 | 537 | 90.9 | 88.1-93.0 | 158 | 69.0 | 61.4-75.7 | 502 | 97.2 | 95.4-98.3 |
| ≥9-<24 | 143 | 90.9 | 85.1-94.6 | 501 | 87.2 | 84.0-89.9 | 194 | 67.0 | 60.1-73.2 | 450 | 97.1 | 95.1-98.3 |
| ≥ 24 | 37 | 89.2 | 75.3-95.7 | 145 | 91.0 | 85.3-94.7 | 46 | 71.7 | 57.5-82.7 | 136 | 97.1 | 92.7-98.9 |
Table 3: Results for males based on time from presentation to the emergency department
CONCLUSION
The Dimension EXL High-Sensitivity Troponin I (TNIH) Assay is substantially equivalent to the Elecsys Troponin T Gen 5 STAT (K162895) in principle and performance based on the similarity of device designs and function demonstrated through performance attributes presented.
§ 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.