Elecsys proBNP II, Elecsys proBNP II STAT
Device Facts
| Record ID | K223637 |
|---|---|
| Device Name | Elecsys proBNP II, Elecsys proBNP II STAT |
| Applicant | Roche Diagnostics |
| Product Code | NBC · Clinical Chemistry |
| Decision Date | Jul 21, 2023 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1117 |
| Device Class | Class 2 |
Intended Use
Immunoassay for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide in human serum and plasma. This assay is used as an aid in the diagnosis of individuals suspected of having heart failure. It can be used as an aid in the diagnosis of acute decompensated heart failure (ADHF) in patients presenting with signs and symptoms of ADHF to the emergency department (ED). The test is further indicated for the risk stratification of patients with acute coronary syndrome and heart failure. The test may also serve as an aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease.
Device Story
Quantitative immunoassay (ECLIA) for NT-proBNP in human serum/plasma. Input: 15 µL sample; biotinylated monoclonal antibody; ruthenium-labeled monoclonal antibody. Process: Sandwich complex formation; magnetic capture on streptavidin-coated microparticles; chemiluminescent emission via voltage application to electrode; photomultiplier detection. Used in clinical laboratories on cobas e immunoassay analyzers. Output: NT-proBNP concentration (pg/mL) determined via calibration curve. Results aid clinicians in diagnosing ADHF, risk-stratifying acute coronary syndrome/HF, and assessing cardiovascular risk. Provides age-dependent cut-offs for ADHF diagnosis in emergency settings.
Clinical Evidence
Multi-center prospective study (17 US sites, 1,485 ED subjects, age 22-97). Evaluated clinical performance of age-dependent cut-offs for ADHF diagnosis. Results provided as posttest probabilities and likelihood ratios across age groups (<50, 50-75, >75), sex, and comorbidities (eGFR, BMI, history of HF). Analytical performance (precision, linearity, LoB/LoD/LoQ) established via bench testing on cobas e 601 analyzer.
Technological Characteristics
Electrochemiluminescence immunoassay (ECLIA). Reagents: Streptavidin-coated microparticles, biotinylated monoclonal anti-NT-proBNP antibody, ruthenium-labeled monoclonal anti-NT-proBNP antibody. Measuring range: 36-35,000 pg/mL. Analyzers: cobas e 601. Calibration: 2-point calibration with master curve via barcode. Software: Automated analysis on cobas e platform.
Indications for Use
Indicated for individuals suspected of having heart failure, including patients presenting to the emergency department with signs and symptoms of acute decompensated heart failure (ADHF). Also indicated for risk stratification of patients with acute coronary syndrome and heart failure, and assessment of cardiovascular event/mortality risk in patients at risk for heart failure with stable coronary artery disease.
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
- Elecsys proBNP II, Elecsys proBNP II STAT (K210546)
Related Devices
- K072437 — ELECSYS PROBNP II, PRECICONTROL CARDIAC II, PROBNP II CALSET · Roche Diagnostics · Feb 5, 2008
- K210546 — Elecsys proBNP II, Elecsys proBNP II STAT · Roche Diagnostics · Mar 31, 2022
- K051382 — ELECSYS PROBNP IMMUNOASSAY · Roche Diagnostics Corp. · Dec 5, 2005
Submission Summary (Full Text)
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July 21, 2023
Roche Diagnostics Jane Phillips Sr. Regulatory Program Manager 9115 Hague Road Indianapolis, IN 46250
Re: K223637
Trade/Device Name: Elecsys proBNP II, Elecsys proBNP II STAT Regulation Number: 21 CFR 862.1117 Regulation Name: B-type natriuretic peptide test system Regulatory Class: Class II Product Code: NBC Dated: June 20, 2023 Received: June 21, 2023
Dear Jane Phillips:
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.
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
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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.
Paula V. Caposino -S
Paula Caposino, Ph.D. Acting Deputy 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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# k223637 Elecsys proBNP II and proBNP II STAT 510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).
The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the new cut-offs for patients presenting with dyspnea to the emergency department for the Elecsys proBNP II STAT and the Elecsys proBNP.
| Submitter Name | Roche Diagnostics |
|--------------------------------------|-------------------------------------------------------------------------------|
| Address | 9115 Hague Road<br>P.O. Box 50416<br>Indianapolis, IN 46250-0457 |
| Contact | Jane Phillips, PhD<br>Phone: (317) 521 3338<br>Email: jane.phillips@roche.com |
| Date Prepared | November 30th, 2022 |
| Proprietary Name | Elecsys proBNP II and Elecsys proBNP II STAT |
| Common Name | proBNP II and proBNP II STAT |
| Classification Name | B-type natriuretic peptide test system |
| Product Codes,<br>Regulation Numbers | NBC, 862.1117 |
| Predicate Devices | Elecsys proBNP II and Elecsys proBNP II STAT (k210546) |
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| Item | Elecsys proBNP II<br>k210546 | Elecsys proBNP II<br>Candidate Device | Change description |
|------------------|------------------------------------------------------|------------------------------------------------------|--------------------|
| Proprietary name | Elecsys proBNP II | Elecsys proBNP II | None |
| Technology | ECLIA | ECLIA | None |
| Test format | Sandwich | Sandwich | None |
| Test type | Quantitative | Quantitative | None |
| Assay protocol | R1 + R2 + sample, incubation, +<br>beads, incubation | R1 + R2 + sample, incubation, +<br>beads, incubation | None |
| Measuring Range | 36-35000 pg/mL | 36-35000 pg/mL | None |
# Table 1: Similarities and Differences between the Elecsys proBNP II
# Table 2: Similarities and Differences between the Elecsys proBNP STAT
| ltem | Elecsys proBNP II STAT<br>k210546 | Elecsys proBNP II STAT<br>Candidate Device | Change description |
|------------------|-----------------------------------------|--------------------------------------------|--------------------|
| Proprietary name | Elecsys proBNP II STAT | Elecsys proBNP II STAT | None |
| Technology | ECLIA | ECLIA | None |
| Test format | Sandwich | Sandwich | None |
| Test type | Quantitative | Quantitative | None |
| Assay protocol | R1 + R2 + sample + beads,<br>incubation | R1 + R2 + sample + beads,<br>incubation | None |
| Measuring Range | 36-35000 pg/ml | 36-35000 pg/ml | None |
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#### DEVICE DESCRIPTION 1.
Elecsys proBNP II and proBNP II STAT are second-generation assays by Roche Diagnostics for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide (NT-proBNP) in human serum and plasma. The STAT and the 18 Minute assays are intended for use on the cobas e 601
The cobas e family of analyzers emplovs the electrochemiluminescence immunoassay "ECLIA" technology. The assays are sandwich principle methods using two monoclonal antibodies which are specifically directed against NT-proBNP. For the neutralization of free biotin in serum and plasma, Roche developed an antibody, which binds to free biotin. The antibodies are specific for free biotin and do not bind to or interact with the biotin-linker conjugates.
#### 2. INDICATIONS FOR USE
Immunoassay for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide in human serum and plasma. This assay is used as an aid in the diagnosis of individuals suspected of having heart failure. It can be used as an aid in the diagnosis of acute decompensated heart failure (ADHF) in patients presenting with signs and symptoms of ADHF to the emergency department (ED). The test is further indicated for the risk stratification of patients with acute coronary syndrome and heart failure. The test may also serve as an aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
#### 3. PREDICATE DEVICE
The predicate for this submission are the Elecsys proBNP II and the Elecsys proBNP II STAT Immunoassays which we cleared in k210546. No changes have been made to the assay since clearance.
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#### ANALYTICAL PERFORMANCE EVALUATION 4.
Analytical experiments were run on the cobas e 601 using the Elecsys proBNP II.
### PRECISION (CLSI EP05-A3)
Precision was evaluated on a single cobas e 601 for Elecsys proBNP II. The experiment was conducted according to CLSI guideline EP05-A3.
The protocol consisted of testing the eight serum samples and two controls in single determinations in four separate aliquots (divided into two runs per day) for 21 operating days (n=84). Testing was conducted at one internal site.
#### Results
#### Elecsys proBNP II
#### Lot MP01: Elecsys proBNP II
| cobas e 601 analyzer | | | | | | | | | |
|------------------------------|---------------|-------------|------------------------|---------|------------------------|-------------|---------------------------|---------|--------------------|
| | Repeatability | | | | Intermediate precision | | | | |
| Sample<br>(Serum) | Mean<br>pg/mL | SD<br>pg/mL | SD 95%<br>UCL<br>pg/mL | CV<br>% | CV 95%<br>UCL<br>% | SD<br>pg/mL | SD<br>95%<br>UCL<br>pg/mL | CV<br>% | CV 95%<br>UCL<br>% |
| Human serum 1 | 68.3 | 1.96 | 2.39 | 2.9 | 3.5 | 3.26 | 4.05 | 4.8 | 5.9 |
| Human serum 2 | 145 | 3.24 | 3.96 | 2.2 | 2.7 | 5.95 | 7.42 | 4.1 | 5.1 |
| Human serum 3 | 314 | 4.31 | 5.27 | 1.4 | 1.7 | 11.5 | 14.7 | 3.7 | 4.7 |
| Human serum 4 | 467 | 12.8 | 15.7 | 2.7 | 3.4 | 17.6 | 21.2 | 3.8 | 4.5 |
| Human serum 5 | 1004 | 20.0 | 24.4 | 2.0 | 2.4 | 34.6 | 42.0 | 3.5 | 4.2 |
| Human serum 6 | 2075 | 38.9 | 47.6 | 1.9 | 2.3 | 68.6 | 84.8 | 3.3 | 4.1 |
| Human serum 7 | 15985 | 371 | 454 | 2.3 | 2.8 | 579 | 712 | 3.6 | 4.5 |
| Human serum 8 | 34624 | 609 | 744 | 1.8 | 2.1 | 1367 | 1725 | 3.9 | 5.0 |
| PreciControl<br>Cardiac II 1 | 140 | 2.48 | 3.03 | 1.8 | 2.2 | 4.94 | 6.13 | 3.5 | 4.4 |
| PreciControl<br>Cardiac II 2 | 4721 | 70.2 | 85.8 | 1.5 | 1.8 | 156 | 198 | 3.3 | 4.2 |
#### Conclusion
The results of precision studies performed with the Elecsys proBNP II assay met predetermined acceptance criteria.
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# ANALYTICAL SENSITIVITY
### Limit of Blank (LoB) and Limit of Detection (LoD) (CLSI EP17-A2)
LoB of the Elecsys proBNP II on the cobas e 601 was determined according to CLSI EP17-A2. Limit of Blank determines the highest observed measurement values for samples free of analyte. The Limit of Blank was determined as the 95th percentile of measurements of blank samples.
LoD of the Elecsys proBNP II on the cobas e 601 analyzer was determined according to CLSI EP17-A2. The LoD determines the lower limit for samples with analyte. The LoD was determined as the lowest amount of analyte in a sample that can be detected with a 95% probability.
#### Methods LoB
In total 60 determinations of an analyte-free sample were obtained on one instrument over ≥ three days in 6 runs with 10-fold determination per run. Three lots of reagent were used in the experiment design.
As the analyzer does not report negative sample concentrations, the data set was truncated and the data were evaluated as the linear interpolation of the 57th ranked observation.
#### Methods LoD
Five low level human serum samples were measured on one instrument over ≥ three days in 6 runs with a two-fold determination per run. In total sixty determinations per reagent lot. The experiment was conducted using three reagent lots.
A pooled estimate of the precision (SD total) for the 5 low level samples was calculated.
LoD was calculated according to EP17-A2, chapter 5.3.3.2 as:
LoD = LoB + 1.653 x SD total (of low analyte samples)
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# Results
# Elecsys proBNP II
| Instrument 1 | | | | | | | |
|--------------|----------|------------------|------------------|------------------|------------------|------------------|------------------|
| | Date Run | 31-Jul-2019<br>1 | 31-Jul-2019<br>2 | 31-Jul-2019<br>3 | 01-Aug-2019<br>4 | 22-Aug-2019<br>5 | 23-Aug-2019<br>6 |
| Analyte-free | Value_1 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.966 |
| | Value_2 | 0.0000 | 0.0000 | 0.0000 | 0.145 | 0.0000 | 0.0000 |
| | Value_3 | 0.0000 | 0.0000 | 0.783 | 0.0000 | 0.0000 | 0.844 |
| | Value_4 | 0.0000 | 0.0000 | 0.0000 | 0.343 | 0.407 | 1.44 |
| | Value_5 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 |
| | Value_6 | 0.0000 | 0.0000 | 0.0000 | 0.145 | 0.721 | 1.21 |
| | Value_7 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 |
| | Value_8 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 1.56 |
| | Value_9 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 |
| | Value_10 | 0.0000 | 0.0000 | 0.471 | 0.0000 | 0.0000 | 0.0000 |
| Analyte-low | Date Run | 31-Jul-2019<br>1 | 31-Jul-2019<br>2 | 31-Jul-2019<br>3 | 01-Aug-2019<br>4 | 22-Aug-2019<br>5 | 23-Aug-2019<br>6 |
| | Value_1 | 5.11 | 6.25 | 7.86 | 6.95 | 7.80 | 7.49 |
| | Value_2 | 7.70 | 4.41 | 4.52 | 5.27 | 5.64 | 5.64 |
| | Value_3 | 6.68 | 3.59 | 6.74 | 6.57 | 7.16 | 5.05 |
| | Value_4 | 4.46 | 6.41 | 5.16 | 5.22 | 6.01 | 6.36 |
| | Value_5 | 3.26 | 2.60 | 6.79 | 6.68 | 6.41 | 4.03 |
| | Value_6 | 6.03 | 4.45 | 3.70 | 4.62 | 4.41 | 6.47 |
| | Value_7 | 7.91 | 5.48 | 5.69 | 5.43 | 5.96 | 6.75 |
| | Value_8 | 5.54 | 7.11 | 9.18 | 8.71 | 7.91 | 8.81 |
| Value_9 | 5.69 | 4.79 | 7.91 | 7.91 | 7.65 | 5.59 | |
# Lot MP01 Elecsys proBNP II (concentrations in pg/mL)
| calculation<br>factor (Cβ) | 1.653 |
|----------------------------|-------|
| SD value 1/2 | 1.30 |
| SD value 3/4 | 1.08 |
| SD value 5/6 | 1.46 |
| SD value 7/8 | 1.43 |
| SD value 9/10 | 1.14 |
| SD total | 1.29 |
| SD total x Cβ | 2.13 |
| LoD | 3.22 |
| Result: | LoB | 1.48 | LoD | 2.57 | pg/mL |
|---------|-----|------|-----|------|-------|
|---------|-----|------|-----|------|-------|
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### Conclusion
The LoD claim in the labeling will be set to ≤ 10 pg/mL. LoB will be set to ≤ 8 pg/mL.
# Limit of Quantitation (LoQ) (CLSI EP17-A2)
LoQ determines the lowest amount of analyte that can be quantitatively determined with stated accuracy and stated experimental conditions. The LoQ was determined as the lowest concentration of analyte which can be reproducibly measured with an intermediate precision of 20% CV.
### Methods LoQ
A low level sample set of 10 native, unaltered serum samples using the cobas e 601 analyzer of known measurand concentration was tested in 5 replicates (aliquots) on one instrument in singleton per day, over 5 days with 1 run per day. Three lots of reagent were used in the LoQ experiment. A total of n=25 measured values were obtained for each sample. The mean value and the intermediate precision as coefficient of variation (CV) and standard deviation (SD) were calculated for each LoQ sample.
#### Results
#### Elecsys proBNP II
Lot MP01: Elecsys proBNP II
| Day 1 | | | | | | | | | | |
|----------------|-----------------------------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|---------------|
| Date Run | 11-Feb-2019 | | | | | | | | | |
| Sample<br>Type | Sample<br>_1 | Sample<br>_2 | Sample<br>_3 | Sample<br>_4 | Sample<br>_5 | Sample<br>_6 | Sample<br>_7 | Sample<br>_8 | Sample<br>_9 | Sample<br>_10 |
| Replicate | NT-proBNP concentrations in pg/mL | | | | | | | | | |
| 1 | 12.1 | 11.6 | 17.3 | 16.4 | 30.1 | 46.2 | 53.0 | 74.1 | 63.9 | 77.4 |
| 2 | 11.9 | 8.70 | 19.8 | 17.1 | 29.8 | 47.4 | 56.1 | 68.6 | 60.7 | 80.9 |
| 3 | 8.26 | 11.8 | 16.2 | 17.2 | 33.6 | 48.7 | 55.5 | 59.0 | 71.8 | 98.9 |
| 4 | 10.4 | 10.5 | 23.5 | 16.3 | 29.7 | 47.6 | 58.4 | 66.9 | 73.8 | 97.3 |
| 5 | 9.25 | 13.7 | 18.4 | 22.7 | 33.3 | 46.7 | 57.3 | 60.4 | 72.4 | 99.2 |
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| Day 2 | | | | | | | | | | |
|----------------|-----------------------------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|---------------------|
| Date Run | 12-Feb-2019 | | | | | | | | | |
| Sample<br>Type | Sample<br>_1 | Sample<br>_2 | Sample<br>_3 | Sample<br>_4 | Sample<br>_5 | Sample<br>_6 | Sample<br>_7 | Sample<br>_8 | Sample<br>_9 | Sam<br>ple -<br>_10 |
| Replicate | NT-proBNP concentrations in pg/mL | | | | | | | | | |
| 1 | 13.1 | 14.1 | 18.3 | 22.0 | 33.1 | 45.5 | 59.6 | 65.9 | 80.8 | 103 |
| 2 | 9.64 | 10.5 | 19.2 | 18.6 | 30.2 | 45.8 | 58.5 | 63.9 | 82.8 | 103 |
| 3 | 10.1 | 10.3 | 21.4 | 24.1 | 33.9 | 46.8 | 60.6 | 64.9 | 82.6 | 105 |
| 4 | 13.9 | 10.6 | 22.2 | 22.8 | 29.9 | 49.7 | 55.2 | 63.1 | 78.6 | 107 |
| 5 | 10.5 | 10.1 | 20.1 | 13.7 | 22.6 | 30.1 | 49.6 | 57.8 | 64.6 | 78.9 |
| Day 3 | | | | | | | | | | |
|----------------|-----------------------------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|---------------|
| Date Run | 13-Feb-2019 | | | | | | | | | |
| Sample<br>Type | Sample<br>_1 | Sample<br>_2 | Sample<br>_3 | Sample<br>_4 | Sample<br>_5 | Sample<br>_6 | Sample<br>_7 | Sample<br>_8 | Sample<br>_9 | Sample<br>_10 |
| replicate | NT-proBNP concentrations in pg/mL | | | | | | | | | |
| 1 | 12.1 | 12.0 | 18.1 | 21.3 | 31.5 | 42.6 | 54.9 | 58.3 | 76.0 | 99.8 |
| 2 | 11.4 | 8.64 | 18.8 | 21.7 | 31.7 | 42.8 | 54.2 | 60.1 | 77.4 | 99.6 |
| 3 | 8.37 | 12.5 | 17.7 | 21.7 | 27.9 | 46.5 | 52.9 | 65.4 | 76.1 | 98.4 |
| 4 | 12.3 | 12.5 | 21.1 | 22.0 | 33.2 | 45.9 | 53.1 | 60.3 | 79.5 | 102 |
| 5 | 8.98 | 12.5 | 16.8 | 18.2 | 33.4 | 46.3 | 57.0 | 62.9 | 79.4 | 101 |
| | Day 4 | | | | | | | | | | |
|----------------|--------------|-----------------------------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|-------------------|--|
| Date Run | | 14-Feb-2019 | | | | | | | | | |
| Sample<br>Type | Sample<br>_1 | Sample<br>_2 | Sample<br>_3 | Sample<br>_4 | Sample<br>_5 | Sample<br>_6 | Sample<br>_7 | Sample<br>_8 | Sample<br>_9 | Sam<br>ple<br>_10 | |
| Replicate | | NT-proBNP concentrations in pg/mL | | | | | | | | | |
| 1 | 9.31 | 10.0 | 20.7 | 21.7 | 29.0 | 48.8 | 57.8 | 64.6 | 77.2 | 103 | |
| 2 | 12.9 | 13.4 | 21.4 | 18.2 | 33.4 | 50.1 | 56.2 | 65.7 | 82.3 | 108 | |
| 3 | 9.42 | 10.6 | 18.2 | 22.0 | 29.4 | 50.6 | 56.5 | 66.9 | 83.4 | 105 | |
| 4 | 13.1 | 14.1 | 18.8 | 19.8 | 32.4 | 46.2 | 57.1 | 64.8 | 80.1 | 108 | |
| 5 | 10.0 | 13.2 | 19.1 | 23.1 | 33.3 | 47.5 | 60.2 | 63.3 | 81.9 | 104 | |
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| Day 5 | | | | | | | | | | |
|----------------|-----------------------------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|---------------|
| Date Run | 18-Feb-2019 | | | | | | | | | |
| Sample<br>Type | Sample<br>_1 | Sample<br>_2 | Sample<br>_3 | Sample<br>_4 | Sample<br>_5 | Sample<br>_6 | Sample<br>_7 | Sample<br>_8 | Sample<br>_9 | Sample<br>_10 |
| Replicate | NT-proBNP concentrations in pg/mL | | | | | | | | | |
| 1 | 12.4 | 9.14 | 21.7 | 18.7 | 31.4 | 48.1 | 53.8 | 62.8 | 78.8 | 102 |
| 2 | 10.0 | 9.69 | 21.1 | 21.0 | 33.1 | 45.1 | 54.6 | 60.5 | 75.4 | 104 |
| 3 | 8.87 | 12.6 | 17.6 | 21.2 | 29.0 | 48.6 | 54.9 | 65.2 | 81.7 | 98.1 |
| 4 | 9.53 | 12.9 | 21.4 | 21.5 | 29.4 | 49.6 | 58.0 | 65.9 | 80.6 | 107 |
| 5 | 12.8 | 13.6 | 21.8 | 18.6 | 28.0 | 51.3 | 56.2 | 65.1 | 78.1 | 104 |
| Sample<br>Type | Sample<br>_1 | Sample<br>_2 | Sample<br>_3 | Sample<br>_4 | Sample<br>_5 | Sample<br>_6 | Sample<br>_7 | Sample<br>_8 | Sample<br>_9 | Sam<br>ple<br>_10 |
|---------------------------------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|--------------|-------------------|
| Measured<br>conc<br>Mean of 5<br>days | 10.8 | 11.6 | 19.6 | 20.1 | 30.9 | 46.6 | 56.0 | 63.9 | 76.8 | 99.9 |
| SD of 5<br>days | 1.70 | 1.70 | 1.91 | 2.60 | 2.59 | 4.05 | 2.55 | 3.59 | 6.09 | 8.43 |
| Conc.<br>CV%<br>of 5 days | 15.7 | 14.7 | 9.7 | 13.0 | 8.4 | 8.7 | 4.6 | 5.6 | 7.9 | 8.4 |
#### Conclusion
The LoQ claim in the labeling will be set to 36 pg/mL.
#### Linearity/Reportable Range (CLSI EP06-Ed2)
The linearity study was conducted on the proBNP II assays to demonstrate that measurements across the claimed measuring range for each parameter are linear. The study was performed according to CLSI guideline EP06-Ed2.
#### Methods
The experiment was initially designed for evaluation with the preceding edition of the guideline, i.e. CLSI guideline EP06-A. The evaluation was repeated according to the current guideline CLSI EP06-Ed2 using in-house software tool BioWarp.
{12}------------------------------------------------
A weighted least square regression by pooled variance was performed. As one high analyte human, native serum sample above measuring range was diluted with analyte free serum (CLSI Design A1), a regression without intercept was chosen. As variance increases with concentration, weighted linear regression was used. As only 3 replicates are available at each dilution step, the weights were computed based on the pooled variance including also the replicates of the next higher as well as the next lower dilution step ("moving window").
### Results
| Category | Name | Value | |
|---------------------------|-------------------------------|-----------------|--|
| | Unit | pg/mL | |
| | Max Number of Replicates | 3 | |
| Input Data | Number of Levels | 10 | |
| | Range of Levels | 0.000640 - 1.00 | |
| | Measured Range | 24.3 - 35902 | |
| | CLSI Design | Al | |
| Model | Weighting | yes | |
| Precision Specs | Prec. Acc. Limits | Passed | |
| SubRange 1 (21.9 - 50.0) | 10.0 SD | 1 | |
| SubRange 2 (50.0 - 100) | 20.0 CV | 1 | |
| SubRange 3 (100 - 35000) | 10.0 CV | 8 | |
| ADL Specs | Allowed Deviation | Passed | |
| SubRange 1 (21.9 - 50.0) | 10.0 [pg/mL] abs | 1 | |
| SubRange 2 (50.0 - 35000) | 20.0 [%] rel | 9 | |
| Linearity evaluation | between: 24.3 - 35902 [pg/mL] | PASSED | |
#### Linearity Evaluation Summary
### Results of the linear regression analysis
| Level | Relative<br>Concentration | Mean | Expected | Predicted | SubRange | Diff. abs | Diff. rel | Criteria | Specs<br>met |
|-------|---------------------------|-------|----------|-----------|----------|-----------|-----------|----------|--------------|
| 1 | 1.00 | 35902 | 35902 | 34218 | 2 | 1684 | 4.92 | <=20% | yes |
| 2 | 0.700 | 25096 | 25131 | 23953 | 2 | 1144 | 4.78 | <=20% | yes |
| 3 | 0.400 | 12497 | 14361 | 13687 | 2 | -1191 | -8.70 | <=20% | yes |
| 4 | 0.160 | 4646 | 5744 | 5475 | 2 | -829 | -15.1 | <=20% | yes |
| 5 | 0.0640 | 1821 | 2298 | 2190 | 2 | -369 | -16.8 | <=20% | yes |
| 6 | 0.0256 | 737 | 919 | 876 | 2 | -139 | -15.9 | <=20% | yes |
| 7 | 0.0100 | 324 | 359 | 342 | 2 | -18.2 | -5.33 | <=20% | yes |
| 8 | 0.00400 | 136 | 144 | 137 | 2 | -1.06 | -0.778 | <=20% | yes |
| 9 | 0.00160 | 56.5 | 57.4 | 54.7 | 2 | 1.71 | 3.12 | <=20% | yes |
| 10 | 0.000640 | 24.3 | 23.0 | 21.9 | 1 | 2.41 | 11.0 | <=10 | yes |
{13}------------------------------------------------
Linear Regression Plot
Image /page/13/Figure/1 description: The image is a scatter plot that shows the relationship between the expected concentration and the observed measurand. The plot includes predicted values, a linear regression fit, measured mean values, and connected means. The x-axis represents the expected concentration, ranging from 0 to 1, while the y-axis represents the observed measurand, ranging from 0 to 30000. The plot shows a positive correlation between the expected concentration and the observed measurand.
#### Conclusion
The recommended measuring range is 36 to 35000 pg/mL. Linearity specifications were met.
#### Endogenous Interferences (CLSI EP07-A3)
The purpose of this study was to evaluate endogenous substances for potential interference with the parameters measured on the cobas e 601 for Elecsys proBNP II.
#### Methods
The effect on quantitation of analyte in the presence of endogenous interfering substances using the Elecsys proBNP II was determined on the cobas e 601.
Endogenous interferences were determined by testing three different analyte concentration levels (low about 130 pg/mL, medium about 900 pg/mL, high about 20000 pg/mL) in human native serum samples. The high concentrations were spiked with recombinant human NT-proBNP (1-76) for the bilirubin and lipemia testing.
{14}------------------------------------------------
One aliquot of each serum sample was spiked with the interfering substance (= interference pool) and another aliquot was spiked (if applicable) with the same volume of the solvent of the interfering substance (= dilution pool). The interfering pool was then diluted into the dilution pool in 10 % increments. The recovery for each sample was calculated by comparison to the reference (unspiked sample).
| Interfering substance | No interference up to |
|-----------------------|-------------------------------|
| Bilirubin | ≤ 428 µmol/L or ≤25 mg/dL |
| Hemoglobin | ≤ 0.621 mmol/L or ≤1000 mg/dL |
| Lipemia | ≤ 1500 mg/dL |
| Biotin | ≤ 3500 ng/mL |
| Rheumatoid Factor | ≤ 1500 IU/mL |
# Results
{15}------------------------------------------------
#### ડ. CLINICAL PERFORMANCE EVALUATION
Clinical data are required in this submission to support the use of the proposed cutoffs for aiding in the diagnosis of heart failure in acutely dyspneic patients. These patients may include a subset of those with acutely decompensated heart failure (ADHF).
#### Expected values: Acute care setting
To assess the performance of positive and negative cut-points for ADHF in patients presenting with signs and symptoms of ADHF to the ED, a multi-center trial was performed in the United States. 1485 subjects were enrolled at 17 sites, 744 males and 741 females. Subjects were > 22 years of age with symptoms of suspected acute decompensated HF, presenting with dyspnea of a duration no longer than several days. 275 (19 %) were found to have acutely decompensated HF, based on adjudication by a clinical events committee.
As reported in previous studies, the age-based positive cut-points, and the negative cut-point for all ages were determined to be:
| Age Group | Elecsys proBNP II/<br>Elecsys proBNP II STAT<br>Cut-Points | Interpretation |
|----------------|------------------------------------------------------------|-------------------------------------------------|
| <50 years | 450 pg/mL | NT-proBNP > 450 pg/mL indicates ADHF is likely |
| 50 to 75 years | 900 pg/mL | NT-proBNP > 900 pg/mL indicates ADHF is likely |
| >75 years | 1800 pg/mL | NT-proBNP > 1800 pg/mL indicates ADHF is likely |
| Elecsys proBNP II/<br>Elecsys proBNP II STAT<br>Cut-Point | Interpretation |
|-----------------------------------------------------------|----------------------------------------------------|
| 300 pg/mL | NT-proBNP < 300 pg/mL indicates ADHF is not likely |
NT-proBNP values above the respective age-specific cut-points (450 / 900 / 1800 pg/mL) are denoted as positive test results, and NT-proBNP values below the universal age-independent cutpoint (300 pg/mL) are denoted as negative test result. A gray zone exists between the negative and positive cut-points.
{16}------------------------------------------------
| Age<br>Range<br>[years] | Result<br>Interpretation | NT-proBNP<br>concentration<br>[pg/mL] |
|-------------------------|--------------------------|---------------------------------------|
| <50 | Positive | > 450 |
| <50 | Gray | 300-450 |
| <50 | Negative | <300 |
| 50-75 | Positive | >900 |
| 50-75 | Gray | 300-900 |
| 50-75 | Negative | <300 |
| >75 | Positive | >1800 |
| >75 | Gray | 300-1800 |
| >75 | Negative | <300 |
| All Age<br>Groups | Positive | aggregated |
| All Age<br>Groups | Gray | aggregated |
| All Age<br>Groups | Negative | <300 |
In this study, the following NT-proBNP values were found with Elecsys proBNP II (18min):
| Diagnostic category | Median proBNP II | IQRa |
|------------------------|------------------|-------------------------|
| Subjects without ADHFb | 105 pg/mL | 38.64 - 400.38 pg/mL |
| Subjects with ADHF | 3012 pg/mL | 1258.50 - 6673.50 pg/mL |
a) IQR = interquartile range
b) ADHF = acute decompensated HF
{17}------------------------------------------------
Image /page/17/Figure/0 description: This image is a boxplot comparing proBNP II levels in pg/mL between two groups: ADHF (n=275) and No ADHF (n=1210). The y-axis represents proBNP II levels, ranging from 0 to 30000 pg/mL. The ADHF group shows a wider distribution of proBNP II levels, with several outliers above 30000 pg/mL, while the No ADHF group has lower levels, mostly concentrated near 0 pg/mL.
Boxplot of proBNP values per ADHF group, all subjects – 18min assay.
Censoring into measuring range:
- ADHD: lower limit: 1 subjects; upper limit: 2 subjects
Censoring into measuring range:
- ADHF: lower limit: 1 subjects; upper limit: 2 subjects.
- No ADHF: lower limit: 283 subjects; upper limit: 2 subjects.
{18}------------------------------------------------
| Diagnostic category | Median proBNP II STAT | IQRª |
|------------------------|-----------------------|-------------------------|
| Subjects without ADHFb | 105 pg/mL | 37.86 - 402.80 pg/mL |
| Subjects with ADHF | 3054 pg/mL | 1255.50 - 6759.00 pg/mL |
In this study, the following NT-proBNP values were found with Elecsys proBNP II STAT:
a) IQR = interquartile range
b) ADHF = acute decompensated HF
#### Boxplot of proBNP values per ADHF group, all subjects - STAT assay.
Image /page/18/Figure/5 description: This image is a boxplot comparing proBNP II STAT levels in pg/mL between two groups: ADHF (n=275) and No ADHF (n=1210). The y-axis represents proBNP II STAT levels ranging from 0 to 30000. The ADHF group has a higher median and a wider range of proBNP II STAT levels compared to the No ADHF group, which has a lower median and a narrower range.
Censoring into measuring range:
- ADHF: lower limit: 1 subjects; upper limit: 2 subjects.
- No ADHF: lower limit: 291 subjects; upper limit: 2 subjects.
- No ADHF: lower limit: 291 subjects; upper limit: 2 subjects.
{19}------------------------------------------------
An analysis of the primary endpoint included the gray zone, which is the zone between the positive and negative thresholds for each subject age group. This gray zone included NT-proBNP levels ≥ 300 pg/mL but less than or equal to the cut-point for the rule-in for diagnosis (that is. 450 pg/mL for age < 50 years, 900 pg/mL for age 50-75 years and 1800 pg/mL for age > 75 years).
A total of only 228 subjects (15%) had NT-proBNP levels that fell into the gray zone between cutpoints with Elecsys proBNP II. This analysis was performed to better understand the performance of the assay for values that fall between the cut-off for positive and the cut-off for negative.
The likelihood ratio (LR) for all 228 subjects (any age) who fell into the gray zone was 0.91 (95% CI: 0.66-1.25) suggesting no additive diagnostic value. For them, other clinical or diagnostic information would be necessary for the differential diagnosis of acute decompensated HF in patients presenting with acute dyspnea in the emergency department.
The performance of the NT-proBNP-based diagnosis of ADHF through the triple age-specific positive cut-points and the single universal negative cut-point was demonstrated through the calculation of Likelihood ratios (positive likelihood ratios (LR+) and negative likelihood ratios (LR-). Likelihood ratios can provide a quantification of the diagnostic capabilities of the assay for both subjects with reactive Elecsys NT-proBNP results (LR+) and non-reactive Elecsys NTproBNP results (LR-). The likelihood ratio can be used to project the change in the probability of having ADHF from the general disease prevalence (the pre-test probability) to the probability after the test results are interpreted (the post-test probability). Establishing the likelihood ratios for the Elecsys proBNP II and proBNP II STAT assays performed on the cobas e 601 analyzer demonstrated the strength of the assays as an aid in diagnosing ADHF and the ability to understand the implications of the diagnosis in patients presenting emergently with dyspnea.
Analyses were conducted separately for each gender and age sub-population, as well for all agegroups combined and all genders combined.
{20}------------------------------------------------
Acutely decompensated cutoff performance
| Age<br>Group | Test Result<br>Interpretation | ADHF | No<br>ADHF | Total |
|--------------|-------------------------------|------|------------|-------|
| <50 | Positive | 31 | 28 | 59 |
| | Gray | 0 | 20 | 20 |
| | Negative | 5 | 394 | 399 |
| | Total | 36 | 442 | 478 |
| 50-75 | Positive | 146 | 114 | 260 |
| | Gray | 25 | 117 | 142 |
| | Negative | 11 | 429 | 440 |
| | Total | 182 | 660 | 842 |
| >75 | Positive | 43 | 31 | 74 |
| | Gray | 14 | 52 | 66 |
| | Negative | 0 | 25 | 25 |
| | Total | 57 | 108 | 165 |
| All | Positive | 220 | 173 | 393 |
| | Gray | 39 | 189 | 228 |
| | Negative | 16 | 848 | 864 |
| | Total | 275 | 1210 | 1485 |
Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II 18min Assay - All Evaluable US Subjects
{21}------------------------------------------------
### Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of Acute Decompensated Heart Failure - Elecsys proBNP II 18min Assay - All Evaluable US Subjects
| | | | | | | | Likelihood Ratio | |
|-----------|-------------------|-------------------------------|-------------------------------|----------------|----------------------------------|----------------|------------------|-----------------|
| | Prevalence of | | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | (ADHF) | |
| Age Group | ADHF<br>(%) (n/N) | Test Result<br>Interpretation | Estimate (%)<br>(n/N) | 95%-CI (%) c) | Estimate (%)<br>(n/N) | 95%-Cl (%) c) | LR d) | 95%-CI e) |
| < 50 | | Positive f) | 52.5<br>(31/59) | 39.2-<br>65.5 | -- | -- | 13.6 | 9.28-<br>19.9 |
| | 7.5<br>(36/478) | Gray g) | 0.0<br>(0/20) | 0.0-<br>20.0 | 100<br>(20/20) | 80.0-<br>100 | 0.00 | 0.00-<br>NaN h) |
| | | Negative i) | -- | -- | 98.7<br>(394/399) | 96.9-<br>99.5 | 0.16 | 0.07-<br>0.35 |
| 50-75 | 21.6<br>(182/842) | Positive | 56.2<br>(146/260) | 49.9-<br>62.2 | -- | -- | 4.64 | 3.87-<br>5.57 |
| | | Gray | 17.6<br>(25/142) | 11.9-<br>25.1 | 82.4<br>(117/142) | 74.9-<br>88.1 | 0.77 | 0.52-<br>1.16 |
| | | Negative | -- | -- | 97.5<br>(429/440) | 95.4-<br>98.7 | 0.09 | 0.05-<br>0.17 |
| > 75 | 34.5<br>(57/165) | Positive | 58.1<br>(43/74) | 46.1-<br>69.3 | -- | -- | 2.63 | 1.89-<br>3.66 |
| | | Gray | 21.2<br>(14/66) | 12.5-<br>33.3 | 78.8<br>(52/66) | 66.7-<br>87.5 | 0.51 | 0.31-<br>0.84 |
| | | Negative | -- | -- | 100.0<br>(25/25) | 83.4-<br>100 | 0.00 | 0.00-<br>NaN |
c) Wilson score confidence intervals with continuity correction
d) LR = likelihood ratios
e) log method confidence intervals
f) Positive: > age-specific cut-point
g) Gray: ≥ 300 pg/mL and ≤ age-specific cut-point
h) NaN (Not a Number) due to empty cells
i) Negative: < 300 pg/mL
{22}------------------------------------------------
Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II 18min Assay- Females ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
| Age Group | Test Result Interpretation | ADHF | No ADHF | Total |
|-----------|----------------------------|------|---------|-------|
| < 50 | Positive | 13 | 8 | 21 |
| | Gray | 0 | 15 | 15 |
| | Negative | 2 | 229 | 231 |
| | Total | 15 | 252 | 267 |
| 50 - 75 | Positive | 58 | 52 | 110 |
| | Gray | 11 | 46 | 57 |
| | Negative | 5 | 228 | 233 |
| | Total | 74 | 326 | 400 |
| > 75 | Positive | 15 | 17 | 32 |
| | Gray | 6 | 26 | 32 |
| | Negative | 0 | 10 | 10 |
| | Total | 21 | 53 | 74 |
| All | Positive | 86 | 77 | 163 |
| | Gray | 17 | 87 | 104 |
| | Negative | 7 | 467 | 474 |
| | Total | 110 | 631 | 741 |
{23}------------------------------------------------
# Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II 18min Assay - Females
| | Prevalence of | | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio<br>(ADHF) | |
|-----------|-------------------|-------------------------------|-------------------------------|---------------|----------------------------------|---------------|----------------------------|-----------------|
| Age Group | ADHF<br>(%) (n/N) | Test Result<br>Interpretation | Estimate (%)<br>(n/N) | 95%-CI (%) c) | Estimate (%)<br>(n/N) | 95%-CI (%) c) | LR d) | 95%-Cl e) |
| < 50 | 5.6<br>(15/267) | Positive f) | 61.9<br>(13/21) | 38.7-<br>81.0 | -- | -- | 27.3 | 13.4-<br>55.5 |
| | | Gray g) | 0.0<br>(0/15) | 0.0-<br>25.3 | 100<br>(15/15) | 74.7-<br>100 | 0.00 | 0.00-<br>NaN h) |
| | | Negative i) | -- | -- | 99.1<br>(229/331) | 96.6-<br>99.8 | 0.15 | 0.04-<br>0.53 |
| 50-75 | 18.5<br>(74/400) | Positive | 52.7<br>(58/110) | 43.0-<br>62.2 | -- | -- | 4.91 | 3.73-<br>6.48 |
| | | Gray | 19.3<br>(11/57) | 10.5-<br>32.3 | 80.7<br>(46/57) | 67.7-<br>89.5 | 1.05 | 0.57-<br>1.93 |
| | | Negative | -- | -- | 97.9<br>(228/233) | 94.8<br>99.2 | 0.10 | 0.04-<br>0.23 |
| > 75 | 28.4<br>(21/74) | Positive | 46.9<br>(15/32) | 29.5-<br>65.0 | -- | -- | 2.23 | 1.38-<br>3.58 |
| | | Gray | 18.8<br>(6/32) | 7.9-<br>37.0 | 81.3<br>(26/32) | 63.0-<br>92.1 | 0.58 | 0.28-<br>1.21 |
| | | Negative | -- | -- | 100<br>(10/10) | 65.5-<br>100 | 0.00 | 0.00-<br>NaN |
{24}------------------------------------------------
Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II 18min Assay - Males
| Age Group | Test Result<br>Interpretation | ADHF | No ADHF | Total |
|-----------|-------------------------------|------|---------|-------|
| < 50 | Positive | 18 | 20 | 38 |
| | Gray | 0 | 5 | 5 |
| | Negative | 3 | 165 | 168 |
| | Total | 21 | 190 | 211 |
| 50 - 75 | Positive | 88 | 62 | 150 |
| | Gray | 14 | 71 | 85 |
| | Negative | 6 | 201 | 207 |
| | Total | 108 | 334 | 442 |
| > 75 | Positive | 28 | 14 | 42 |
| | Gray | 8 | 26 | 34 |
| | Negative | 0 | 15 | 15 |
| | Total | 36 | 55 | 91 |
| All | Positive | 134 | 96 | 230 |
| | Gray | 22 | 102 | 124 |
| | Negative | 9 | 381 | 390 |
| | Total | 165 | 579 | 744 |
{25}------------------------------------------------
# Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II 18min Assay- Males
| | | | | | | | Likelihood Ratio | |
|---------------|-------------------|----------------|-------------------------------|---------------|----------------------------------|---------------|------------------|-----------------|
| Prevalence of | | | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | (ADHF) | |
| | ADHF | Test Result | Estimate (%) | | Estimate (%) | | | |
| Age Group | (%) (n/N) | Interpretation | (n/N) | 95%-CI (%) c) | (n/N) | 95%-CI (%) c) | LR d) | 95%-CI e) |
| < 50 | 10.0<br>(21/211) | Positive f) | 47.4<br>(18/38) | 31.3-<br>64.0 | -- | -- | 8.14 | 5.19-<br>12.8 |
| | | Gray g) | 0.0<br>(0/5) | 0.0-<br>53.7 | 100<br>(5/5) | 46.3-<br>100 | 0.00 | 0.00-<br>NaN h) |
| | | Negative i) | -- | -- | 98.2<br>(165/168) | 94.5-<br>99.5 | 0.16 | 0.06-<br>0.47 |
| 50-75 | 24.4<br>(108/442) | Positive | 58.7<br>(88/150) | 50.3-<br>66.6 | -- | -- | 4.39 | 3.45-<br>5.59 |
| | | Gray | 16.5<br>(14/85) | 9.6-<br>26.4 | 83.5<br>(71/85) | 73.6-<br>90.4 | 0.61 | 0.36-<br>1.04 |
| | | Negative | -- | -- | 97.1<br>(201/207) | 93.5<br>98.8 | 0.09 | 0.04-<br>0.20 |
| > 75 | 39.6<br>(36/91) | Positive | 66.7<br>(28/42) | 50.4-<br>80.0 | -- | -- | 3.06 | 1.88-<br>4.96 |
| | | Gray | 23.5<br>(8/34) | 11.4-<br>41.6 | 76.5<br>(26/34) | 58.4-<br>88.6 | 0.47 | 0.24-<br>0.92 |
| | | Negative | -- | -- | 100<br>(15/15) | 74.7-<br>100 | 0.00 | 0.00-<br>NaN |
{26}------------------------------------------------
Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II STAT Assay - All Evaluable US Subjects
| Age Group | Test Result<br>Interpretation | ADHF | No ADHF | Total |
|-----------|-------------------------------|------|---------|-------|
| < 50 | Positive | 31 | 27 | 58 |
| | Gray | 0 | 23 | 23 |
| | Negative | 5 | 392 | 397 |
| | Total | 36 | 442 | 478 |
| 50 - 75 | Positive | 146 | 114 | 260 |
| | Gray | 25 | 117 | 142 |
| | Negative | 11 | 429 | 440 |
| | Total | 182 | 660 | 842 |
| > 75 | Positive | 43 | 31 | 74 |
| | Gray | 14 | 52 | 66 |
| | Negative | 0 | 25 | 25 |
| | Total | 57 | 108 | 165 |
| All | Positive | 220 | 172 | 392 |
| | Gray | 39 | 192 | 231 |
| | Negative | 16 | 846 | 862 |
| | Total | 275 | 1210 | 1485 |
{27}------------------------------------------------
# Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II STAT Assay - All Evaluable US Subjects
| | Prevalence of | | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio<br>(ADHF) | |
|-----------|-------------------|-------------------------------|-------------------------------|----------------|----------------------------------|----------------|----------------------------|-----------------|
| Age Group | ADHF<br>(%) (n/N) | Test Result<br>Interpretation | Estimate (%)<br>(n/N) | 95%-CI (%) c) | Estimate (%)<br>(n/N) | 95%-CI (%) c) | LR d) | 95%-CI e) |
| < 50 | 7.5<br>(36/478) | Positive f) | 53.4<br>(31/58) | 40.0-<br>66.5 | -- | -- | 14.10 | 9.56-<br>20.79 |
| | | Gray g) | 0.0<br>(0/23) | 0.0-<br>17.8 | 100.0<br>(23/23) | 82.2-<br>100.0 | 0.00 | 0.00-<br>NaN h) |
| | | Negative i) | -- | -- | 98.7<br>(392/397) | 96.9-<br>99.5 | 0.16 | 0.07-<br>0.35 |
| 50-75 | 21.6<br>(182/842) | Positive | 56.2<br>(146/260) | 49.9-<br>62.2 | -- | -- | 4.64 | 3.87-<br>5.57 |
| | | Gray | 17.6<br>(25/142) | 11.9-<br>25.1 | 82.4<br>(117/142) | 74.9-<br>88.1 | 0.77 | 0.52-<br>1.16 |
| | | Negative | -- | -- | 97.5<br>(429/440) | 95.4-<br>98.7 | 0.09 | 0.05-<br>0.17 |
| > 75 | 34.5<br>(57/165) | Positive | 58.1<br>(43/74) | 46.1-<br>69.3 | -- | -- | 2.63 | 1.89-<br>3.66 |
| | | Gray | 21.2<br>(14/66) | 12.5-<br>33.3 | 78.8<br>(52/66) | 66.7-<br>87.5 | 0.51 | 0.31-<br>0.84 |
| | | Negative | -- | -- | 100.0<br>(25/25) | 83.4-<br>100.0 | 0.00 | 0.00-<br>NaN |
c) Wilson score confidence intervals with continuity correction
d) LR = likelihood ratios
e) log method confidence intervals
f) Positive: > age-specific cut-point
g) Gray: ≥ 300 pg/mL and ≤ age-specific cut-point
h) NaN (Not a Number) due to empty cells
i) Negative: < 300 pg/mL
{28}------------------------------------------------
Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II STAT Assay - Females
| Age Group | Test Result<br>Interpretation | ADHF | No ADHF | Total |
|-----------|-------------------------------|------|---------|-------|
| < 50 | Positive | 13 | 8 | 21 |
| | Gray | 0 | 15 | 15 |
| | Negative | 2 | 229 | 231 |
| | Total | 15 | 252 | 267 |
| 50 - 75 | Positive | 58 | 52 | 110 |
| | Gray | 11 | 45 | 56 |
| | Negative | 5 | 229 | 234 |
| | Total | 74 | 326 | 400 |
| > 75 | Positive | 15 | 17 | 32 |
| | Gray | 6 | 26 | 32 |
| | Negative | 0 | 10 | 10 |
| | Total | 21 | 53 | 74 |
| All | Positive | 86 | 77 | 163 |
| | Gray | 17 | 86 | 103 |
| | Negative | 7 | 468 | 475 |
| | Total | 110 | 631 | 741 |
{29}------------------------------------------------
# Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II STAT Assay - Females
| | Prevalence of ADHF | | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio<br>(ADHF) | |
|-----------|--------------------|----------------------------|-------------------------------|---------------|----------------------------------|----------------|----------------------------|-----------------|
| Age Group | (%) (n/N) | Test Result Interpretation | Estimate (%)<br>(n/N) | 95%-CI (%) c) | Estimate (%)<br>(n/N) | 95%-CI (%) c) | LR d) | 95%-CI e) |
| < 50 | 5.6<br>(15/267) | Positive f) | <b>61.9</b><br>(13/21) | 38.7-<br>81.0 | -- | -- | 27.30 | 13.42-<br>55.54 |
| | | Gray g) | 0.0<br>(0/15) | 0.0-<br>25.3 | 100.0<br>(15/15) | 74.7-<br>100.0 | 0.00 | 0.00-<br>NaN h) |
| | | Negative i) | -- | -- | <b>99.1</b><br>(229/331) | 96.6-<br>99.8 | 0.15 | 0.04-<br>0.53 |
| 50-75 | 18.5<br>(74/400) | Positive | <b>52.7</b><br>(58/110) | 43.0-<br>62.2 | -- | -- | 4.91 | 3.73-<br>6.48 |
| | | Gray | 19.6<br>(11/56) | 10.7-<br>32.8 | 80.4<br>(45/56) | 67.2-<br>89.3 | 1.08 | 0.59-<br>1.98 |
| | | Negative | -- | -- | <b>97.9</b><br>(229/234) | 94.8<br>99.2 | 0.10 | 0.04-<br>0.22 |
| > 75 | 28.4<br>(21/74) | Positive | <b>46.9</b><br>(15/32) | 29.5-<br>65.0 | -- | -- | 2.23 | 1.38-<br>3.58 |
| | | Gray | 18.8<br>(6/32) | 7.9-<br>37.0 | 81.3<br>(26/32) | 63.0-<br>92.1 | 0.58 | 0.28-<br>1.21 |
| | | Negative | -- | -- | <b>100.0</b><br>(10/10) | 65.5-<br>100.0 | 0.00 | 0.00-<br>NaN |
{30}------------------------------------------------
| Age Group | Test Result Interpretation | ADHF | No ADHF | Total |
|-----------|----------------------------|------|---------|-------|
| < 50 | Positive | 18 | 19 | 37 |
| | Gray | 0 | 8 | 8 |
| | Negative | 3 | 163 | 166 |
| | Total | 21 | 190 | 211 |
| 50 - 75 | Positive | 88 | 62 | 150 |
| | Gray | 14 | 72 | 86 |
| | Negative | 6 | 200 | 206 |
| | Total | 108 | 334 | 442 |
| > 75 | Positive | 28 | 14 | 42 |
| | Gray | 8 | 26 | 34 |
| | Negative | 0 | 15 | 15 |
| | Total | 36 | 55 | 91 |
| All | Positive | 134 | 95 | 229 |
| | Gray | 22 | 106 | 128 |
| | Negative | 9 | 378 | 387 |
Three-by-Two Contingency Table for the ICON Cut-Points - Elecsys proBNP II STAT Assay - Males
{31}------------------------------------------------
# Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II STAT Assay - Males
| | Prevalence of<br>ADHF<br>(%) (n/N) | Test Result<br>Interpretation | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio<br>(ADHF) | |
|-----------|------------------------------------|-------------------------------|-------------------------------|---------------|----------------------------------|----------------|----------------------------|-----------------|
| Age Group | | | Estimate (%)<br>(n/N) | 95%-CI (%) c) | Estimate (%)<br>(n/N) | 95%-CI (%) c) | LR d) | 95%-CI e) |
| < 50 | 10.0<br>(21/211) | Positive f) | <b>48.6</b><br>(18/37) | 32.2-<br>65.3 | -- | -- | 8.57 | 5.41-<br>13.59 |
| | | Gray g) | 0.0<br>(0/8) | 0.0-<br>40.2 | 100.0<br>(8/8) | 59.8-<br>100.0 | 0.00 | 0.00-<br>NaN h) |
| | | Negative i) | -- | -- | <b>98.2</b><br>(163/166) | 94.4-<br>99.5 | 0.17 | 0.06-<br>0.48 |
| 50-75 | 24.4<br>(108/442) | Positive | <b>58.7</b><br>(88/150) | 50.3-<br>66.6 | -- | -- | 4.39 | 3.45-<br>5.59 |
| | | Gray | 16.3<br>(14/86) | 9.5-<br>26.1 | 83.7<br>(72/86) | 73.9-<br>90.5 | 0.60 | 0.35-<br>1.02 |
| | | Negative | -- | -- | <b>97.1</b><br>(200/206) | 93.5<br>98.8 | 0.09 | 0.04-<br>0.20 |
| > 75 | 39.6<br>(36/91) | Positive | <b>66.7</b><br>(28/42) | 50.4-<br>80.0 | -- | -- | 3.06 | 1.88-<br>4.96 |
| | | Gray | 23.5<br>(8/34) | 11.4-<br>41.6 | 76.5<br>(26/34) | 58.4-<br>88.6 | 0.47 | 0.24-<br>0.92 |
| | | Negative | -- | -- | <b>100.0</b><br>(15/15) | 74.7-<br>100.0 | 0.00 | 0.00-<br>NaN |
{32}------------------------------------------------
### Renal cohort (ED)
Renal disease can alter NT-proBNP values because the peptide is known to be cleared by the kidneys. Below are analyses of performance in patients with and without compromised renal function.
# Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II 18min Assay - Renal Disease (eGFR < 60 mL/min/1.73 m²)
| Age Group | Prevalence of ADHF (%) (n/N) | Test Result Interpretation | Post-test Probability of ADHF | | Post-test Probability of No ADHF | | Likelihood Ratio (ADHF) | |
|-----------|------------------------------|----------------------------|-------------------------------|---------------|----------------------------------|----------------|-------------------------|-----------------|
| < 50 | 40.9<br>(9/22) | Positive m) | 81.8<br>(9/11) | 47.8-<br>96.8 | -- | -- | 6.50 | 1.82-<br>23.26 |
| | | Gray n) | 0.0<br>(0/4) | 0.0-<br>60.4 | 100.0<br>(4/4) | 39.6-<br>100.0 | 0.00 | 0.00-<br>NaN o) |
| | | Negative p) | -- | -- | 100.0<br>(7/7) | 56.1-<br>100.0 | 0.00 | 0.00-<br>NaN |
| 50-75 | 40.5<br>(85/210) | Positive | 64.2<br>(77/120) | 54.8-<br>72.6 | -- | -- | 2.63 | 2.05-<br>3.39 |
| | | Gray | 22.6<br>(7/31) | 10.3-<br>41.5 | 77.4<br>(24/31) | 58.5-<br>89.7 | 0.43 | 0.19-<br>0.95 |
| | | Negative | -- | -- | 98.3<br>(58/59) | 89.7-<br>99.9 | 0.03 | 0.00-<br>0.18 |
| > 75 | 40.4<br>(38/94) | Positive | 60.0<br>(33/55) | 45.9-<br>72.7 | -- | -- | 2.21 | 1.56-<br>3.13 |
| | | Gray | 16.1<br>(5/31) | 6.1-<br>34.5 | 83.9<br>(26/31) | 65.5-<br>93.9 | 0.28 | 0.12-<br>0.67 |
| | | Negative | -- | -- | 100.0<br>(8/8) | 59.8-<br>100.0 | 0.00 | 0.00-<br>NaN |
i) Wilson score confidence intervals with continuity correction
- k) LR = likelihood ratios
I) log method confidence intervals
m) Positive: > age-specific cut-point
n) Gray: ≥ 300 pg/mL and ≤ age-specific cut-point
o) NaN (Not a Number) due to empty cells
{33}------------------------------------------------
# Pre- and Post-Test Probabilities as well as informative LRs for NT-proBNP Cut-Points for the Diagnosis or Exclusion of ADHF - Elecsys proBNP II 18min Assay - No Renal Disease (eGFR ≥ 60 mL/min/1.73 m²)
| | Prevalence of<br>ADHF<br>(%) (n/N) | Test Result<br>Interpretation | Post-test Probability of ADHF<br>Estimate (%)<br>(n/N) | 95%-CI (%) j) | Post-test Probability of No ADHF<br>Estimate (%)<br>(n/N) | 95%-CI (%) j) | Likelihood Ratio<br>(ADHF)<br>LR k) | 95%-CI I) |
|-------|------------------------------------|-------------------------------|--------------------------------------------------------|---------------|-----------------------------------------------------------|----------------|-------------------------------------|-----------------|
| < 50 | 6.9<br>(25/361) | Positive m) | 47.7<br>(21/44) | 32.7-<br>63.1 | -- | -- | 12.27 | 7.98-<br>18.86 |
| | | Gray n) | 0.0<br>(0/13) | 0.0-<br>28.3 | 100.0<br>(13/13) | 71.7-<br>100.0 | 0.00 | 0.00-<br>NaN o) |
| | | Negative p) | -- | -- | 98.7<br>(300/304) | 96.4-<br>99.6 | 0.18 | 0.07-<br>0.44 |
| 50-75 | 15.5<br>(95/592) | Positive | 50.0<br>(65/130) | 41.5-<br>58.5 | -- | -- | 5.43 | 4.18-<br>7.06 |
| | | Gray | 16.4<br>(18/110) | 10.2-<br>24.9 | 83.6<br>(92/110) | 75.1-<br>89.8 | 1.06 | 0.68-<br>1.67 |
| | | Negative | -- | -- | 97.4<br>(343/352) | 95.0-<br>98.7 | 0.14 | 0.08-<br>0.27 |
| > 75 | | Positive | 50.0<br>(9/18) | 29.0-<br>71.0 | -- | -- | 2.72 | 1.29-<br>5.76 |
| | 26.9<br>(18/67) | Gray | 27.3<br>(9/33)…
