ADVIA Centaur® NT-proBNPII (PBNPII)
Device Facts
| Record ID | K220265 |
|---|---|
| Device Name | ADVIA Centaur® NT-proBNPII (PBNPII) |
| Applicant | Siemens Healthcare Diagnostics, Inc. |
| Product Code | NBC · Clinical Chemistry |
| Decision Date | Sep 24, 2023 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1117 |
| Device Class | Class 2 |
Intended Use
The ADVIA Centaur® NT-proBNPII (PBNPII) assay is for in vitro diagnostic use in the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP system. In the Emergency Department (ED) and Outpatient (OP) populations, measurements of NT-proBNP are used as an aid in the diagnosis of heart failure (HF) in patients with clinical suspicion of new onset or worsening HF.
Device Story
The ADVIA Centaur NT-proBNP (PBNPII) is a 1-step sandwich immunoassay for the quantitative measurement of NT-proBNP in human serum and plasma. It utilizes monoclonal sheep anti-human NT-proBNP antibodies; one labeled with acridinium ester and the other biotinylated and bound to streptavidin magnetic particles. The device is used on the ADVIA Centaur XP system in clinical settings. The system processes samples to produce a chemiluminescent signal proportional to the NT-proBNP concentration. Healthcare providers use these quantitative results to aid in the diagnosis of heart failure in patients presenting with clinical symptoms. The device assists in clinical decision-making by providing objective biomarker data to rule-in or rule-out heart failure, potentially improving diagnostic accuracy and patient management.
Clinical Evidence
Clinical performance was evaluated in a prospective multi-site study. ED population (N=3128) and OP population (N=1033) were assessed against an independent central adjudication panel of cardiologists. For the ED population, performance was evaluated using age-dependent rule-in/rule-out cut-offs. For the OP population, a single 125 pg/mL cut-off yielded 86.0% sensitivity and 64.3% specificity (AUC 0.839). Analytical performance included precision (CLSI EP05-A3), linearity (CLSI EP06-Ed2), and interference/cross-reactivity testing (CLSI EP07-ed3).
Technological Characteristics
Chemiluminescent immunoassay; reagents include monoclonal sheep anti-human NT-proBNP antibodies (F(ab')2 fragment and biotinylated), streptavidin magnetic particles, and acridinium ester label. Measuring range: 35–35,000 pg/mL. Automated system (ADVIA Centaur XP). Complies with CLSI guidelines (EP05-A3, EP06, EP07, EP17-A2, EP28-A3c, EP37).
Indications for Use
Indicated for use in ED and OP populations with clinical suspicion of new onset or worsening heart failure (HF) to aid in diagnosis. Applicable to all ages.
Regulatory Classification
Identification
The B-type natriuretic peptide (BNP) test system is an in vitro diagnostic device intended to measure BNP in whole blood and plasma. Measurements of BNP are used as an aid in the diagnosis of patients with congestive heart failure.
Special Controls
*Classification.* Class II (special controls). The special control is “Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications; Final Guidance for Industry and FDA Reviewers.”
Predicate Devices
- Roche Elecsys proBNP II assay (K072437)
Related Devices
- K241176 — Alere NT-proBNP for Alinity i Reagent Kit · Axis-Shield Diagnostics, Ltd. · Jan 16, 2025
- K232164 — Access NT-proBNP · Beckman Coulter, Inc. · Apr 12, 2024
- K031038 — ADVIA CENTAUR B-TYPE NATRIURETIC PEPTIDE (BNP) ASSAY · Bayer Healthcare, LLC · Jun 23, 2003
Submission Summary (Full Text)
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September 24, 2023
Siemens Healthcare Diagnostics Inc. Asha Gartland Regulatory Affairs Specialist 511 Benedict Ave Tarrytown, NY 10591
Re: K220265
Trade/Device Name: ADVIA Centaur® NT-proBNPII (PBNPII) Regulation Number: 21 CFR 862.1117 Regulation Name: B-Type Natriuretic Peptide Test System Regulatory Class: Class II Product Code: NBC Dated: November 18, 2022 Received: November 18, 2022
Dear Asha Gartland:
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. 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.
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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) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); 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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). 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 (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
# Marianela Perez-torres -S
Marianela Perez-Torres, Ph.D. Acting Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Ouality Center for Devices and Radiological Health
Enclosure
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# Indications for Use
510(k) Number (if known) K220265
Device Name ADVIA Centaur® NT-proBNPII (PBNPII)
Indications for Use (Describe)
The ADVIA Centaur® NT-proBNPII (PBNPII) assay is for in vitro diagnostic use in the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP system.
In the Emergency Department (ED) and Outpatient (OP) populations, measurements of NT-proBNP are used as an aid in the diagnosis of heart failure (HF) in patients with clinical suspicion of new onset or worsening HF.
| Type of Use (Select one or both, as applicable) |
|-------------------------------------------------|
|-------------------------------------------------|
| <div> <span> <b> Prescription Use (Part 21 CFR 801 Subpart D) </b> </span> </div> | <div> <span> Over-The-Counter Use (21 CFR 801 Subpart C) </span> </div> |
|-------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|
|-------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|
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This 510(k) Summary 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: K220265 1. Date Prepared September 22nd , 2023 Applicant Information 2. Asha Gartland Contact: Regulatory Affairs Specialist Address: Siemens Healthcare Diagnostics Inc. 511 Benedict Avenue Tarrytown, NY 10591-5097 845-327-8296 Phone: Email asha.gartland@siemens-healthineers.com
### Regulatory Information 3.
Table 1. Regulatory Information for ADVIA Centaur® NT-proBNPII (PBNPII) Assay
| Trade Name | ADVIA Centaur® NT-proBNPII (PBNPII) |
|---------------------|----------------------------------------|
| Common Name | Test, Natriuretic Peptide |
| Classification Name | B-type natriuretic peptide test system |
| FDA Classification | Class II |
| Review Panel | Clinical Chemistry (75) |
| Product Code | NBC |
| Regulation Number | 21 CFR 862.1117 |
### Predicate Device Information 4.
Predicate Device Name: Roche Elecsys proBNP II assay
510(k) Number: K072437
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### Intended Use / Indications for Use 5.
The ADVIA Centaur® NT-proBNPII (PBNPII) assay is for in vitro diagnostic use in the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP system.
In the Emergency Department (ED) and Outpatient (OP) populations, measurements of NT-proBNP are used as an aid in the diagnosis of heart failure (HF) in patients with clinical suspicion of new onset or worsening HF.
### Special Conditions for Use Statement 6.
For Prescription Use
### 7. Device Description
| Component | Volume | Ingredients |
|------------------------------------------------------------------------|----------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ADVIA Centaur PBNPII Primary Reagent ReadyPack (included in assay kit) | | |
| Lite Reagent | 7.5 mL/pack | Monoclonal sheep anti-human NT-proBNP F(ab')2<br>fragment antibody (~0.36 µg/mL) labeled with acridinium<br>ester in buffer; bovine serum albumin (BSA); bovine<br>gamma globulin; preservatives |
| Solid Phase Reagent | 20.0 mL/pack | Monoclonal sheep anti-human NT-proBNP antibody (~2<br>µg/mL) labeled with biotin bound to streptavidin magnetic<br>particles (~220 mg/L) in buffer; BSA; bovine gamma<br>globulin; sheep gamma globulin; preservatives |
| Ancillary Well Reagent | 7.5 mL/pack | Buffer; BSA; bovine gamma globulin; sheep gamma<br>globulin; preservatives |
| ADVIA Centaur PBNPII Calibrator (included in assay kit) | | |
| ADVIA Centaur PBNPII Low<br>and High Calibrators | 2.0 mL/vial<br>Lyophilized | After reconstitution, low or high levels of NT-proBNP<br>antigen; buffer; BSA; preservatives |
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| | Candidate Device | Predicate |
|---------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Item | ADVIA Centaur<br>NT-proBNP (PBNPII) assay | Roche Elecsys proBNP II assay<br>(K072437) |
| Intended Use | The ADVIA Centaur® NT-proBNPII (PBNPII)<br>assay is for in vitro diagnostic use in the<br>quantitative determination of N-terminal<br>pro-brain natriuretic peptide (NT-proBNP) in<br>human serum and plasma (EDTA and lithium<br>heparin) using the ADVIA Centaur® XP<br>system.<br>In the Emergency Department (ED) and<br>Outpatient (OP) populations, measurements<br>of NT-proBNP are used as an aid in the<br>diagnosis of heart failure (HF) in patients<br>with clinical suspicion of new onset or<br>worsening HF. | Immunoassay for the in vitro<br>quantitative determination of<br>N-terminal pro-Brain natriuretic<br>peptide in human serum and plasma.<br>This assay is used as an aid in the<br>diagnosis of individuals suspected of<br>having congestive heart failure.<br>The test is further indicated for the<br>risk stratification of patients with<br>acute coronary syndrome and<br>congestive heart failure. The test may<br>also serve as an aid in the assessment<br>of increased risk of cardiovascular<br>events and mortality in patients at risk<br>for heart failure who have stable<br>coronary artery disease. |
| Indications for Use | Same as Intended Use (Candidate) | Same (for Predicate) |
| Similarities | | |
| Measurement | Quantitative | Same |
| Technology | Chemiluminescence | Same |
| Sample type | Plasma and Serum | Same |
| Standardization | Traceable to synthetic human NT-proBNP<br>(1-76) through internal standard | Same |
| Calibration | 2 levels | Same |
| Calibrators | Lyophilized | Same |
| Hook Effect | No hook effect up to 300,000 pg/mL | Same |
| Differences | | |
| Operating Principle | 1-Step Sandwich immunoassay | 2-Step Sandwich immunoassay |
| Assay Range | 35-35,000 pg/mL | 5-35,000 pg/mL |
| | Candidate Device | Predicate |
| Item | ADVIA Centaur<br>NT-proBNP (PBNPII) assay | Roche Elecsys proBNP II assay<br>(K072437) |
| Sample Volume | 20 μL | 15 μL |
| LoB | 13 pg/mL | LoB<LoD |
| LoD | 20 pg/mL | 5.00 pg/mL |
| LoQ | 35 pg/mL | 50.0 pg/mL |
| Detection Antibody | Monoclonal sheep anti-human NT-proBNP<br>F(ab')2 fragment<br>antibody (~0.36 µg/mL) labeled with<br>acridinium ester in buffer | Monoclonal anti-NT-proBNP antibody<br>(sheep) labeled with ruthenium<br>complex 1.1 µg/mL in buffer |
| Capture Antibody | Monoclonal sheep anti-human NT-proBNP<br>antibody (~2 µg/mL)<br>labeled with biotin bound to streptavidin<br>magnetic particles<br>(~220 mg/L) in buffer | Biotinylated monoclonal<br>anti-NT-proBNP antibody (mouse) 1.1<br>µg/mL in buffer |
| Precision (Serum)<br>(Total CV) | 6.7% @ 116 pg/mL<br>4.0% @ 271 pg/mL<br>2.3% @ 380 pg/mL<br>2.1% @ 806 pg/mL<br>2.0% @ 1,597 pg/mL<br>2.8% @ 25,073 pg/mL<br>4.2% @ 144 pg/mL<br>2.9% @ 418 pg/mL<br>2.8% @ 4,778 pg/mL | 4.6% @ 44.0 pg/mL<br>2.6% @ 126 pg/mL<br>1.8% @ 2,410 pg/mL<br>3.8% @ 33,606 pg/mL<br>2.8% @ 82.0 pg/mL<br>1.6% @ 2,318 pg/mL |
| Intended Use<br>Population(s) | Emergency Department (ED) and<br>Outpatient (OP) | Single Population |
| Clinical Cut-Off | ED Population<br>Rule out HF:<br>All ages <300 pg/mL<br>Indeterminate<br><50 years ≥300 to ≤ 450 pg/mL<br>50-75 years ≥ 300 to ≤ 900 pg/mL<br>>75 years ≥ 300 to ≤ 1800 pg/mL<br>Rule-in HF<br>< 50 years > 450 pg/mL<br>50–75 years > 900 pg/mL<br>>75 years > 1800 pg/mL<br>OP Population<br>Rule out HF<br>All ages <125 pg/mL | 125 pg/mL for <75 years<br>450 pg/mL for ≥ 75 years |
| | Candidate Device | Predicate |
| Item | ADVIA Centaur<br>NT-proBNP (PBNPII) assay | Roche Elecsys proBNP II assay<br>(K072437) |
| Clinical Data<br>Presentation | ED Population<br>Likelihood Ratio – age dependent rule-out<br>(negative), indeterminate and rule in<br>(positive) cut offs<br>OP Population<br>Sensitivity and Specificity and Positive<br>Predictive Value (PPV) and Negative<br>Predictive Value (NPV) for ages ≤75 and >75<br>years and sex | Sensitivity and Specificity vs age (<45,<br>45-54, 55-64, 65-74, ≥ 75 and <75<br>years) and sex |
### Comparison of Technological Characteristics with the Predicate 8. Device
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# 510(k) Summary
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## 510(k) Summary
### Performance Characteristics: ADVIA Centaur PBNPII assay 9.
### Precision 9.1
Precision was determined in accordance with CLSI Document EP05-A3. Samples were assayed in duplicate in 2 runs per day for 20 days. The following results were obtained:
| | | | Repeatability | | Within-Lab | | |
|------------------|-----------------------------------------|-------------------------|---------------|---------------------------------|-------------------------|------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Specimen<br>Type | Mean of 80<br>reps<br>pg/mL<br>(pmol/L) | SD<br>pg/mL<br>(pmol/L) | % CV | Acceptable<br>Criteria<br>(%CV) | SD<br>pg/mL<br>(pmol/L) | % CV | Acceptable<br>Criteria<br>(%CV) |
| Serum 1 | 116 (13.7) | 6.1 (0.720) | 5.3 | <2.5 | 7.8 (0.920) | 6.7 | ಸಿ ಸರ್ಕಾರಿ ಸಾಧಿಸಿದ ಸಾಧಿಸಿದ ಮಾರ್ಗ್ ಸಾಧಿಸಿದ ಸಂಸ್ಕೃತಿಗಳು ಮಾರ್ಗ್ ಸಾಧಿಸಿದ ಸಂಸ್ಕೃತಿಗಳು ಮಾರ್ಗ್ ಸಾಮಾನ ಮಾರ್ಗ್ ಸಾಮಾನ್ಯ ಸಂಸ್ಕೃತಿಗಳಿಗೆ ಮಾರ್ಗ್ ಸಾಮಾನ ಮಾರ್ಗ್ ಸಾಮಾನ್ಯ ಸಂಸ್ಕೃತಿಗಳಿಗೆ ಮಾರ್ಗ್ ಮ |
| Serum 2 | 271 (32.0) | 9.6 (1.13) | 3.5 | ಸ್ಸ್ ನ | 10.8 (1.27) | 4.0 | ಸಿಕೊಡುವುದು ಸಹಾಯಿತು. ಸಾಮಾನ್ಯ ಸಂಪರ್ಕಗಳು ಸಾಮಾನ ಮಾರ್ಥಿಸಿದ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಸಾಮಾನ್ಯ ಸಂಸ್ಕೃತಿಗಳು ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಸಾಮಾನ್ಯ ಸಾಮಾನ್ಯ ಸಂಸ್ಕೃತಿಗಳು ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಸ |
| Serum 3 | 380 (44.8) | 5.4 (0.637) | 1.4 | ಸ್ಸ್ ನ | 8.9 (1.05) | 2.3 | ಸಿಕೊಡುವುದು ಸಹಾಯಿತು. ಸಾಮಾನ್ಯ ಸಂಪರ್ಕಗಳು ಸಾಮಾನ ಮಾರ್ಥಿಸಿದ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಸಾಮಾನ್ಯ ಸಂಸ್ಕೃತಿಗಳು ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಸಾಮಾನ್ಯ ಸಾಮಾನ್ಯ ಸಂಸ್ಕೃತಿಗಳು ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಸ |
| Serum 4 | 806 (95.1) | 15.3 (1.81) | 1.9 | <7 | 16.7 (1.97) | 2.1 | <10 |
| Serum 5 | 1597 (188) | 25.7 (3.03) | 1.6 | <7 | 31.6 (3.73) | 2.0 | <10 |
| Serum 6 | 25,073<br>(2959) | 416.4 (49.1) | 1.7 | <7 | 690.1<br>(81.4) | 2.8 | <10 |
| QC 1 | 144 (17.0) | 5.6 (0.661) | 3.9 | ಸ್ಸ್ ನ | 6.1 (0.720) | 4.2 | ಸಿಕೊಡುವುದು ಸಾಧಿಸಿದ ಸಮಾರಿಕೆಯಿಂದ ಸಿರ್ವಹಿಸಿದ ಸಂಸ್ಕೃತಿಗಳು ಸಾಮಾನ ಮಾರ್ಥಿಕ ಸಾಮಾನ ಮಾರ್ಥಿಕ ಸಾಮಾನ್ಯ ಸಂಕರ್ಥಿಸಿದ ಮಾರ್ಥಿಕ ಸಾಮಾನ ಮಾರ್ಥಿಕ ಸಾಮಾನ ಮತ್ತು ಮಾರ್ಗ್ ಮತ್ತು ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ |
| QC 2 | 418 (49.3) | 8.7 (1.03) | 2.1 | ಸ್ಸ್ ನ | 12.1 (1.43) | 2.9 | ಸಿಕೊಡುವುದು ಸಹಾಯಿತು. ಸಾಮಾನ್ಯ ಸಂಪರ್ಕಗಳು ಸಾಮಾನ ಮಾರ್ಥಿಸಿದ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಸಾಮಾನ್ಯ ಸಂಸ್ಕೃತಿಗಳು ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಸಾಮಾನ್ಯ ಸಾಮಾನ್ಯ ಸಂಸ್ಕೃತಿಗಳು ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಮಾರ್ಗ್ ಸ |
| QC 3 | 4778 (564) | 93.0 (11.0) | 1.9 | <7 | 134.7<br>(15.9) | 2.8 | <10 |
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### 9.2 Reproducibility
Reproducibility was determined in accordance with CLSI Document EP05-A3. Samples (N=90) were assayed in duplicate in 2 runs per day for 5 days at 3 sites.
| | | Mean | Repeatability | | Between Run | | Between Day | | Between Site | | Reproducibility | |
|--------------|----|----------------|-------------------|------|----------------|------|----------------|------|-------------------|------|-----------------|------|
| Sample<br>ID | N | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| | | pg/mL (pmol/L) | pg/mL<br>(pmol/L) | | pg/mL (pmol/L) | | pg/mL (pmol/L) | | pg/mL<br>(pmol/L) | | pg/mL (pmol/L) | |
| Serum<br>A | 90 | 141 (16.6) | 4.1 (0.484) | 2.9% | 0 (0.000) | 0.0% | 0.8 (0.094) | 0.6% | 5.7 (0.673) | 4.0% | 7 (0.826) | 5.0% |
| Serum<br>B | 90 | 324 (38.2) | 7.6 (0.897) | 2.4% | 0 (0.000) | 0.0% | 2.6 (0.307) | 0.8% | 6.7 (0.791) | 2.1% | 10.5 (1.24) | 3.2% |
| Serum<br>C | 90 | 489 (57.7) | 8.5 (1.00) | 1.7% | 0 (0.000) | 0.0% | 4.9 (0.578) | 1.0% | 15 (1.77) | 3.1% | 18 (2.12) | 3.7% |
| Serum<br>D | 90 | 824 (97.2) | 14.7 (1.73) | 1.8% | 0 (0.000) | 0.0% | 9.8 (1.16) | 1.2% | 18.5 (2.18) | 2.2% | 25.5 (3.01) | 3.1% |
| Serum<br>E | 90 | 1641 (194) | 29.4 (3.47) | 1.8% | 13.9 (1.64) | 0.8% | 9.6 (1.13) | 0.6% | 35 (4.13) | 2.1% | 48.7 (5.75) | 3.0% |
| Serum<br>F | 90 | 10428 (1231) | 184.6 (21.8) | 1.8% | 49.7 (5.86) | 0.5% | 95.7 (11.3) | 0.9% | 374.3 (44.2) | 3.6% | 431.1 (50.9) | 4.1% |
| Serum<br>G | 90 | 19469 (2297) | 349.1 (41.2) | 1.8% | 147.4 (17.4) | 0.8% | 0 (0.000) | 0.0% | 643.1 (75.9) | 3.3% | 746.5 (88.1) | 3.8% |
| Serum<br>H | 90 | 28860 (3405) | 696.8 (82.2) | 2.4% | 0 (0.000) | 0.0% | 127.4 (15.0) | 0.4% | 736.1 (86.9) | 2.6% | 1021.6 (121) | 3.5% |
| Control<br>1 | 90 | 146 (17.2) | 4 (0.472) | 2.8% | 1.2 (0.142) | 0.8% | 1.7 (0.201) | 1.2% | 4.8 (0.566) | 3.3% | 6.6 (0.779) | 4.5% |
| Control<br>2 | 90 | 430 (50.7) | 9.3 (1.10) | 2.2% | 3.8 (0.448) | 0.9% | 1.9 (0.224) | 0.4% | 12.9 (1.52) | 3.0% | 16.5 (1.95) | 3.8% |
| Control<br>3 | 90 | 4965 (586) | 89 (10.5) | 1.8% | 42.9 (5.06) | 0.9% | 32.4 (3.82) | 0.7% | 129 (15.2) | 2.6% | 165.7 (19.6) | 3.3% |
The following results are representative of the performance of the assay:
### 9.3 Linearity
Linearity testing was performed in accordance with CLSI Document EP06-Ed2. The ADVIA Centaur PBNPII assay is linear for the measuring interval of 35-35,000 pg/mL (4.13-4130 pmol/L).
### 9.4 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 PBNPII assay has an LoB of 13 pg/mL (1.53 pmol/L), an LoD of 20 pg/mL (2.36 (pmol/L), and an LoQ of 35 pg/mL (4.13 pmol/L).
### ਰੇ' ਦ Interference
### Hemolysis, Icterus, Lipemia (HIL)
Interference testing was performed in accordance with CLSI Document EP07-ed3. The following substances do not interfere with the assay when present in serum at the concentrations indicated.
{9}------------------------------------------------
Bias due to these substances does not exceed 10% at NT-proBNP concentrations of 123–137 pg/mL (14.5-16.2 pmol/L) and 1612-1813 pg/mL (190-214 pmol/L).
| Substance | Substance Test Concentration |
|-------------------------|------------------------------|
| Hemoglobin | 1000 mg/dL |
| Bilirubin, conjugated | 60.0 mg/dL |
| Bilirubin, unconjugated | 60.0 mg/dL |
| Lipemia (Intralipid) | 3000 mg/dL |
### Other Substances
The following substances do not interfere with the assay when present in serum at the concentrations indicated. Bias due to these substances does not exceed 10% at NT-proBNP concentrations of 116–163 pg/mL (13.7–19.2 pmol/L) and 1478–2225 pg/mL (174–263 pmol/L).
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# Siemens Healthcare Diagnostics 510(k) Summary
| Substance | Substance Test<br>Concentration | Substance | Substance Test<br>Concentration |
|----------------------------------|---------------------------------|-----------------------------|---------------------------------|
| Abciximab | 21.0 µg/mL | L-dopa (Levodopa) | 0.750 mg/dL |
| Acetaminophen | 20.0 mg/dL | Lidocaine | 8.00 mg/dL |
| Acetylcysteine | 15.0 mg/dL | Lisinopryl | 16.0 µg/mL |
| Allopurinol | 2.50 mg/dL | Lovastatin | 16.0 µg/mL |
| Amiodarone | 20.0 42.0 µg/mL | L-Thyroxine | 60.0 µg/dL |
| Amlodipine Besylate | 4.00 µg/mL | Methyldopa | 2.50 mg/dL |
| Ampicillin | 5.30 7.50 mg/dL | Methylprednisolone | 0.783 mg/dL |
| Ascorbic Acid | 5.00 mg/dL | Metoprolol tartrate | 15.0 mg/dL |
| Atenolol | 1.00 mg/dL | Metronidazole | 12.3 mg/dL |
| Atorvastatin | 32.0 mg/dL | Milrinone lactate | 2.40 µg/mL |
| Biotin | 3510 ng/mL | Molsidomin (Placeholder) | 0.018 mg/dL |
| Bisoprolol | 0.258 µg/mL | Nicotine | 0.100 mg/dL |
| Caffeine | 6.00 10.8 mg/dL | Nifedipine | 6.00 mg/dL |
| Calcium dobesilate | 6.00 mg/dL | Nitrofurantoin | 40.0 µg/mL |
| Captopril | 5.00 mg/dL | Nitroglycerine | 0.160 µg/mL |
| Carvedilol | 4.32 mg/dL | Oxazepam | 12.0 µg/mL |
| Cefoxitin | 660 mg/dL | Oxytetracycline | 100 µg/mL |
| Chloramphenicol | 7.80 mg/dL | Phenobarbital | 69.0 mg/dL |
| Chlordiazepoxide | 1.00 mg/dL | Phenprocoumon (Placeholder) | 1.50 mg/dL |
| Cholesterol | 500 mg/dL | Phenylbutazone | 32.1 mg/dL |
| Cinnarizine | 3.00 mg/dL | Phenytoin | 6.00 mg/dL |
| Clopidogrel bisulfate | 30.0 µg/mL | Pravastatin | 0.021 mg/dL |
| Creatinine | 30.0 mg/dL | Probenecid | 200 µg/mL |
| Cyclosporine | 4000 ng/mL | Propafenone HCL | 30.0 mg/dL |
| Digitoxin | 75.0 ng/mL | Propanolol | 0.150 mg/dL |
| Digoxin | 390 ng/mL | Protein: Albumin | 6.00 g/dL |
| Diltiazem | 120 µg/mL | Protein: Total | 11.1 g/dL |
| Dipotassium EDTA | 9.00 mg/mL | Quinidine | 20.0 µg/mL |
| Dipyridamole | 30.0 µg/mL | Retavase (reteplase) | 3.33 mg/dL |
| Diclofenac | 60.0 µg/mL | Rheumatoid Factor | 1500 IU/mL |
| Disopyramide | 40.0 µg/mL | Rifampicin (Rifampin) | 4.80 mg/dL |
| Dopamine | 16.0 mg/dL | Salicylic Acid | 60.0 mg/dL |
| Doxycycline hyclate | 1.80 mg/dL | Simvastatin | 32.0 µg/mL |
| Enalapril maleate | 16.0 µg/mL | Sotalol hydrochloride | 0.510 mg/dL |
| Epinephrine | 0.050 mg/dL | Spironolactone | 7.50 mg/dL |
| Erythromycin | 13.8 mg/dL | Streptokinase | 150,000 U/L |
| Furosemide | 6.00 mg/dL | Sulfamethoxazole | 320 µg/mL |
| Gentamycin sulfate | 3.51 mg/dL | Theophylline | 4.00 mg/dL |
| HAMA (Human Anti-Mouse Antibody) | 800 ug/L | Tolbutamide | 150 mg/dL |
| Heparin | 330 U/dL | Torasemide | 1.50 mg/dL |
| Hydralazine | 20.0 µg/mL | Triglycerides | 1000 mg/dL |
| Hydrochlorothiazide | 20.0 µg/mL | Trimethoprim | 64.0 µg/mL |
| Immunoglobulin G (IgG) | 5.00 g/dL | Verapamil | 96.0 µg/mL |
| Indomethacin | 16.0 µg/mL | Urokinase | 150,000 U/L |
| Insulin | 0.160 mg/dL | Warfarin | 8.00 mg/dL |
| Isosorbide dinitrate | 6.00 mg/dL | | |
{11}------------------------------------------------
# Siemens Healthcare Diagnostics 510(k) Summary
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### 9.6 Cross-Reactivity
Cross-reactivity was determined in accordance with CLSI Document EP07-ed3. Cross-reactants were tested at NT-proBNP concentrations of 0 pg/mL (0 pmol/L) and 126–158 pg/mL (14.9–18.6 pmol/L).
| Cross-reactant | Cross-reactant Concentration | Cross-reactivity (%) | | |
|---------------------------|------------------------------|--------------------------|--|--|
| Adrenomedullin | 1.00 ng/mL | Not Detectable<br>< 1.0% | | |
| Aldosterone | 0.600 ng/mL | Not Detectable<br>< 1.0% | | |
| Angiotensin I | 0.600 ng/mL | Not Detectable<br>< 1.0% | | |
| Angiotensin II | 0.600 ng/mL | Not Detectable<br>< 1.0% | | |
| Angiotensin III | 1.00 ng/mL | Not Detectable<br>< 1.0% | | |
| ANP28 | 3.10 µg/mL | Not Detectable<br>< 1.0% | | |
| Arg-Vasopressin | 1.00 ng/mL | Not Detectable<br>< 1.0% | | |
| BNP32 | 3.50 µg/mL | Not Detectable<br>< 1.0% | | |
| CNP32 | 2.20 µg/mL | Not Detectable<br>< 1.0% | | |
| DNP | 1.00 ng/mL | Not Detectable<br>< 1.0% | | |
| Endothelin | 20.0 pg/mL | Not Detectable<br>-5.0% | | |
| preproANP26-55 | 3.50 µg/mL | Not Detectable<br>< 1.0% | | |
| preproANP56-92 | 1.00 ng/mL | Not Detectable<br>< 1.0% | | |
| preproANP104-123 | 1.00 ng/mL | Not Detectable<br>< 1.0% | | |
| proBNP (glycosylated) | 3000 pg/mL | 1.0%<br>19.0% | | |
| proBNP (non-glycosylated) | 3000 pg/mL | 13.0%<br>30.0% | | |
| Renin; human | 50.0 ng/mL | Not Detectable<br>< 1.0% | | |
| Urodilatin | 3.50 µg/mL | Not Detectable<br>< 1.0% | | |
| VNP | 1.00 ng/mL | Not Detectable<br>< 1.0% | | |
{13}------------------------------------------------
### 9.7 Specimen Equivalency
Specimen equivalency was determined with the Passing-Bablok regression model in accordance with CLSI Document EP09c-ed3.
| Tube (y) vs. Serum (x) | Regression Equation | Sample Interval<br>pg/mL (pmol/L) | r | N |
|--------------------------------------------------------|---------------------------------------------------|-----------------------------------|-------|----|
| Plasma (Dipotassium EDTA) vs<br>Serum (no gel barrier) | y = 1.00x + 1 pg/mL<br>(y = 1.00x + 0.118 pmol/L) | 50-30,134<br>(5.90-3556) | 1.000 | 50 |
| Plasma (Lithium heparin) vs Serum (no<br>gel barrier) | y = 1.00x + 4 pg/mL<br>(y = 1.00x + 0.472 pmol/L) | 57-30,390<br>(6.73-3586) | 0.999 | 50 |
| BD Vacutainer® SST™ Tube vs Serum<br>(no gel barrier) | y = 1.00x - 2 pg/mL<br>(y = 1.00x - 0.236 pmol/L) | 54-30,122<br>(6.37-3554) | 1.000 | 50 |
| BD Vacutainer® RST™ Tube vs Serum<br>(no gel barrier) | y = 1.00x + 4 pg/mL<br>(y = 1.00x + 0.472 pmol/L) | 53-30,237<br>(6.25-3568) | 1.000 | 50 |
### 9.8 Expected Values
#### 9.8.1 Reference Study Group
Expected values were established non- parametrically on the ADVIA Centaur XP system in accordance with CLSI Document EP28-A3c on a population of 723 apparently healthy subjects (362 females and 361 males) without HF.
| Sex | Age<br>(years) | N | Mean pg/mL<br>(pmol/L) | SD pg/mL<br>(pmol/L) | Median pg/mL<br>(pmol/L) | 95th Percentile<br>pg/mL (pmol/L) | % < 125<br>pg/mL | % < 300<br>pg/mL |
|---------|----------------|-----|------------------------|----------------------|--------------------------|-----------------------------------|------------------|------------------|
| Male | <50 | 120 | 56 (6.61) | 95.0 (21.2) | < 35 (4.13) | 124 (14.6) | N/Aa | 97.5 |
| | 50-75 | 121 | 78 (9.20) | 136.4 (16.1) | < 35 (4.13) | 322 (38.0) | N/Aa | 94.2 |
| | >75 | 120 | 56 (6.61) | 50.6 (5.97) | < 35 (4.13) | 154 (18.2) | N/Aa | 98.3 |
| Female | <50 | 122 | 57 (6.73) | 33.1 (3.91) | 37 (4.37) | 133 (15.7) | N/Aa | 100 |
| | 50-75 | 120 | 77 (9.09) | 124.0 (14.6) | 40 (4.72) | 192 (22.7) | N/Aa | 97.5 |
| | >75 | 120 | 89 (10.5) | 216.4 (25.5) | 43 (5.07) | 178 (21.0) | N/Aa | 97.5 |
| Overall | Overall | 723 | 69 (8.14) | 124.9 (14.7) | < 35 (4.13) | 163 (19.2) | 92.0 | 97.5 |
a The cut-off value is not applicable for the age group indicated.
As with all in vitro diagnostic assays, each laboratory should determine its own reference interval for the diagnostic evaluation of patient results. Consider these values as guidance only.
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### 9.8.2 Disease Study Group
#### ED Population 9.8.2.1
Samples were obtained from 1148 patients (476 females and 672 males) that were adjudicated with a diagnosis of acute HF in the ED. ADVIA Centaur PBNPII values are presented for subjects with acute HF (ED Population- Disease Study Group) by subgroups based on age group and NYHA Functional Class. Each group of females and males was divided into three age groups as follows: < 50 years, 50-75 years and>75 years.
The data for the ED population with acute HF for combined male and female (All) is presented in this summary.
| ED Population – All Subjects with Acute HF | | | |
|--------------------------------------------|---------------|---------------|---------------|
| Age Group | < 50 years | 50–75 years | > 75 years |
| Mean pg/mL (pmol/L) | 6004 (708) | 6820 (805) | 8591 (1014) |
| SD pg/mL (pmol/L) | 7601 (897) | 8182 (965) | 8984 (1060) |
| Median pg/mL (pmol/L) | 3552 (419) | 3677 (434) | 5295 (625) |
| 95th Percentile pg/mL (pmol/L) | 25,401 (2997) | 26,473 (3124) | 34,451 (4065) |
| % > 300 pg/mL | 94.3 | 95.0 | 98.4 |
| % > 450 pg/mL | 90.9 | N/A* | N/A* |
| % > 900 pg/mL | N/A* | 83.8 | N/A* |
| % > 1800 pg/mL | N/A* | N/A* | 85.8 |
| N | 230 | 481 | 437 |
* The cut-off value is not applicable for the age group indicated.
#### 9.8.2.2 OP Population
Samples were obtained from 185 patients (102 females and 83 males) adjudicated with new onset of HF.
The data for the OP population with new onset of HF for combined male and female (All) is presented in this summary.
| OP Population – All Subjects with Adjudicated New Onset HF | | |
|------------------------------------------------------------|------------|---------------|
| Age Group | ≤ 75 years | > 75 years |
| Mean pg/mL (pmol/L) | 1313 (155) | 2418 (285) |
| SD pg/mL (pmol/L) | 3756 (443) | 5536 (653) |
| Median pg/mL (pmol/L) | 449 (53.0) | 661 (78.0) |
| 95th Percentile pg/mL (pmol/L) | 4547 (537) | 13,518 (1595) |
| % > 125 pg/mL | 82.1 | 96.1 |
| N | 134 | 51 |
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| | NYHA Functional Classa | NYHA I | NYHA II | NYHA III | NYHA IV |
|-----------------------------------|------------------------|--------------|--------------|---------------|---------|
| Mean pg/mL (pmol/L)b | 880 (104) | 3340 (394) | 7139 (842) | 7466 (881) | |
| SD pg/mL (pmol/L) | 1161 (137) | 6262 (739) | 8480 (1001) | 8277 (977) | |
| Median pg/mL (pmol/L) | 387 (46) | 996 (118) | 4018 (474) | 4409 (520) | |
| 5th Percentile pg/mL<br>(pmol/L) | 135 (15.9) | 73 (8.6) | 261 (30.8) | 449 (52.9) | |
| 95th Percentile pg/mL<br>(pmol/L) | 2612 (308) | 17357 (2048) | 29643 (3498) | 30,824 (3637) | |
| N | 4c | 265 | 573 | 474 | |
The NYHA classifications for the ED and OP population with acute HF for combined male and female (All) is presented in this summary.
a Unable to determine NYHA classification for 16 subjects.
b p = <0.0001 for increasing mean NT-ProBNP concentration between NYHA Class II and NYHA Classes III and IV per Jonckheere-Terpstra. The mean NT-ProBNP concentration for NYHA Class IV are not statistically different.
ৎ One male subject, identified as an outlier with an abnormally high NT-ProBNP concentration, was excluded from the NYHA I classification summary.
### OP Population – Receiver Operating Characteristic Curve
The Receiver Operating Characteristic (ROC) curve presents the clinical sensitivity and specificity for the enrolled 185 subjects diagnosed with new onset HF and 848 subjects without HF. The area under ROC curve for the ADVIA Centaur PBNPII assay is 0.839 with a 95% confidence interval of 0.804 to 0.868.
Image /page/15/Figure/8 description: This image shows a receiver operating characteristic (ROC) curve. The ROC curve plots the true positive rate (sensitivity) against the false positive rate (1-specificity). The area under the curve (AUC) is 0.839 with a 95% confidence interval of (0.804, 0.868). The ROC curve is a graphical representation of the performance of a binary classifier system as its discrimination threshold is varied.
{16}------------------------------------------------
### 510(k) Summary
### 9.9 Dilution Recovery
Samples that exceed the high end of the measuring interval may be diluted 1:5 and 1:10 with ADVIA Centaur Multi-Diluent 1 using automated dilution. The percent recovery of diluted samples up to 63,128 pg/mL (7449 pmol/L) ranged from 80.5% to 88.2% with a mean recovery of 83.9%.
### 9.10 High Dose Hook
High NT-proBNP concentrations can cause a paradoxical decrease in the RLUs (high-dose hook effect). In this assay, patient samples with NT-proBNP concentrations above the measuring interval and as high as 300,000 pg/mL (35,400 pmol/L) will report >35,000pg/mL (4130 pmol/L).
#### 9.11 Stability
The ADVIA Centaur NT-proBNP (PBNPII) reagents and calibrators are stable until the date printed on the box label when stored at 2-8°C.
The onboard stability and calibration interval of the ADVIA Centaur NT-proBNP (PBNPII) reagents is 36 days. The ADVIA Centaur PBNPII Calibrators are stable for 48 hours at 2-8°C and 31 days at < -20°C after reconstitution. The Calibrators are stable onboard at Room Temperature for 6 hours.
### 9.12 Clinical Performance
#### ED Population 9.12.1
A total of 3128 subjects with signs and symptoms of acute HF who presented to the ED, were prospectively enrolled in a multi-site clinical evaluation of the ADVIA Centaur PBNPII assay. Diagnosis and severity of HF were determined by an independent central adjudication panel of expert clinicians (Cardiologists).1148 subjects were adjudicated as acute HF and 1980 subjects were adjudicated as without HF.
Clinical results were evaluated and Post-test risk (%), Positive Likelihood ratio (LR+), and respective two-sided confidence intervals (CI) were computed. Subgroup analyses were performed by using age group and sex.
Clinical Agreement between ADVIA Centaur PBNPII Results and Adjudicated Diagnosis Entire ED Population by Age Group with combined male and female (All) is presented in this summary:
| Adjudicated Diagnosis | | | | | | | | | |
|-----------------------|---------------|---------------------------|----------|----------|-------|---------------------------------|------------------------------|------|--------------|
| Age Group<br>(years) | NT-proBNP | Rule-in Cutoff<br>(pg/ml) | Positive | Negative | Total | Post-test<br>Risk (%) | 95% CI Post-test<br>Risk (%) | LR+ | 95% CI LR+* |
| <50 | Positive | > 450 | 209 | 123 | 332 | 63.0% (209/332) | (57.5%,68.2%) | 5.01 | (4.25, 5.91) |
| | Indeterminate | 300 - ≤450 | 8 | 19 | 27 | 29.6% (8/27) | (13.8%,50.2%) | 1.24 | (0.55, 2.80) |
| | Negative | <300 | 13 | 536 | 549 | 2.4% (13/549) | (1.3%,4.0%) | 0.07 | (0.04, 0.12) |
| | Total | | 230 | 678 | 908 | Pre-Test Risk = 25.3% (230/908) | | | |
{17}------------------------------------------------
| Adjudicated Diagnosis | | | | | | | | | |
|-----------------------|---------------|---------------------------|----------|----------|-------|-----------------------|----------------------------------|------|--------------|
| Age Group<br>(years) | NT-proBNP | Rule-in Cutoff<br>(pg/ml) | Positive | Negative | Total | Post-test<br>Risk (%) | 95% CI Post-test<br>Risk (%) | LR+ | 95% CI LR+* |
| 50-75 | Positive | > 900 | 403 | 185 | 588 | 68.5% (403/588) | (64.6%,72.3%) | 3.71 | (3.25, 4.24) |
| | Indeterminate | 300 - ≤900 | 54 | 160 | 214 | 25.2% (54/214) | (19.6%,31,6%) | 0.58 | (0.43, 0.77) |
| | Negative | <300 | 24 | 475 | 499 | 4.8% (24/499) | (3.1%,7.1%) | 0.09 | (0.06, 0.13) |
| | Total | | 481 | 820 | 1301 | | Pre-Test Risk = 37.0% (481/1301) | | |
| >75 | Positive | > 1800 | 375 | 174 | 549 | 68.3% (375/549) | (64.2%,72.2%) | 2.38 | (2.10, 2.69) |
| | Indeterminate | 300-≤1800 | 55 | 186 | 241 | 22.8% (55/241) | (17.7%,27.7%) | 0.33 | (0.25, 0.43) |
| | Negative | <300 | 7 | 122 | 129 | 5.4% (7/129) | (2.2%,10.9%) | 0.06 | (0.03, 0.13) |
| | Total | | 437 | 482 | 919 | | Pre-Test Risk = 47.6% (437/919) | | |
*Two-sided 95% score intervals will be present risk and positive likelihood ratio estimates.
#### 9.12.2 OP Population
A total of 1033 OP subjects with signs and symptoms of new onset HF were prospectively enrolled in a multi-site clinical evaluation of the ADVIA Centaur PBNPII assay. The clinical performance was assessed using a single cut-off value of 125 pg/mL.
Diagnosis and severity of HF were determined by an independent central adjudication panel of expert clinicians (Cardiologists).185 subjects were adjudicated as new onset HF and 848 subjects were adjudicated as without HF.
Diagnostic accuracy was computed as the Clinical Sensitivity, Clinical Specificity, Negative Predictive (NPV), and Positive Predictive (PPV).
The OP population clinical performance for All subjects is presented below:
| Cut off Value | Sensitivity | Specificity | PPV | NPV |
|---------------|------------------|------------------|------------------|------------------|
| 125 pg/mL | 86.0% (159/185) | 64.3% (545/848) | 34.4% (159/462) | 95.5% (545/571) |
| | (80.1%, 90.6%) * | (60.9%, 67.5%) * | (30.1%, 39.0%) * | (93.4%, 97.0%) * |
*Confidence Interval
The OP population clinical performance by sex and age group is presented below:
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# Siemens Healthcare Diagnostics
# 510(k) Summary
| Group | | Sensitivity | Specificity | PPV | NPV |
|-----------------------|----------|---------------|-----------------|----------------|-----------------|
| Males<br>≤ 75 years | Estim…
