cobas u 701 microscopy analyzer
Device Facts
| Record ID | K200811 |
|---|---|
| Device Name | cobas u 701 microscopy analyzer |
| Applicant | Roche Diagnostics |
| Product Code | LKM · Hematology |
| Decision Date | Nov 6, 2020 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 864.5200 |
| Device Class | Class 2 |
| Attributes | Pediatric |
Indications for Use
The cobas u 701 microscopy analyzer is a fully automated urine microscopy system intended for the in vitro quantitative determination of erythrocytes and leukocytes, the semi-quantitative determination of squamous epithelial cells, bacteria, and hyaline casts and the qualitative determination of non-squamous epithelial cells, crystals, yeasts, pathological casts, mucus and sperm in urine. These measurements are useful in the evaluation of renal, urinary and metabolic disorders. This system is intended to be used by trained operators in clinical laboratories. All instrument analyte image decisions may be reviewed and reclassified by a trained operator.
Device Story
The cobas u 701 is a fully automated urine microscopy analyzer for clinical laboratories. It processes barcoded urine samples in racks, using a robotic liquid handling system to pipette aliquots into disposable cuvettes. The system centrifuges samples to bring particles to a single monolayer focal plane. A built-in reverse microscope and high-resolution camera capture images of the sediment. Image processing software detects and classifies particles (RBC, WBC, epithelial cells, bacteria, casts, crystals, yeast, mucus, sperm). Quantitative results are calculated from average counts; semi-quantitative and qualitative results are also reported. Operators review and can reclassify images via a touchscreen. The system automates sediment analysis, reducing manual microscopy requirements, and aids in diagnosing renal, urinary, and metabolic disorders.
Clinical Evidence
Method comparison study against manual KOVA chamber counting using 680 clinical samples (355 female, 334 male, 91 pediatric) across three sites. Quantitative parameters (RBC, WBC) showed high correlation (Pearson's r ≥ 0.98) and Passing-Bablok regression slopes near 1.0. Semi-quantitative and qualitative parameters demonstrated high agreement (NPA/PPA typically >90%). Precision studies (repeatability, intermediate precision) met acceptance criteria. Linearity confirmed for RBC (5-2160 p/μL) and WBC (5-1080 p/μL).
Technological Characteristics
Fully automated, stand-alone urine particle analyzer. Uses robotic liquid handling, disposable cuvettes, and built-in centrifuge for monolayer particle preparation. Features a reverse microscope with movable objective lens and high-resolution camera. Connectivity via touchscreen and inbuilt computer. No calibration required; monthly microscope check using reference cuvette. Software performs automated image processing and classification. Throughput up to 116 samples/hour.
Indications for Use
Indicated for in vitro quantitative determination of erythrocytes and leukocytes, semi-quantitative determination of squamous epithelial cells, bacteria, and hyaline casts, and qualitative determination of non-squamous epithelial cells, crystals, yeasts, pathological casts, mucus, and sperm in human urine. Intended for use by trained clinical laboratory operators for evaluation of renal, urinary, and metabolic disorders.
Regulatory Classification
Identification
An automated cell counter is a fully-automated or semi-automated device used to count red blood cells, white blood cells, or blood platelets using a sample of the patient's peripheral blood (blood circulating in one of the body's extremities, such as the arm). These devices may also measure hemoglobin or hematocrit and may also calculate or measure one or more of the red cell indices (the erythrocyte mean corpuscular volume, the mean corpuscular hemoglobin, or the mean corpuscular hemoglobin concentration). These devices may use either an electronic particle counting method or an optical counting method.
Predicate Devices
- IRIS Iq 200 (K022774)
Related Devices
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- K982301 — MICRO21 WITH URINE SEDIMENT ANALYSIS · Triangle Biomedical Sciences, Inc. · Aug 7, 1998
Submission Summary (Full Text)
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FDA
U.S. FOOD & DRUG
ADMINISTRATION
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
INSTRUMENT ONLY
## I Background Information:
A 510(k) Number
K200811
B Applicant
Roche Diagnostics
C Proprietary and Established Names
Cobas u 701 Microscopy Analyzer
D Regulatory Information
| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| LKM | Class II | 21 CFR 864.5200 - Automated Cell Counter | HE - Hematology |
## II Submission/Device Overview:
A Purpose for Submission:
Clearance of a new device
B Type of Test:
Microscopic analysis of formed elements in urine. The analyzer quantitates the following parameters: Red Blood Cells (RBC) and White Blood Cells (WBC), semi-quantitates determination of squamous epithelial cells, bacteria, and hyaline casts and qualitative determination of non-squamous epithelial cells, crystals, yeasts, pathological casts, mucus and sperm in urine.
## III Intended Use/Indications for Use:
A Intended Use(s):
See Indications for Use below.
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
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B Indication(s) for Use:
The cobas u 701 microscopy analyzer is a fully automated urine microscopy system intended for the in vitro quantitative determination of erythrocytes and leukocytes, the semi-quantitative determination of squamous epithelial cells, bacteria, and hyaline casts and the qualitative determination of non-squamous epithelial cells, crystals, yeasts, pathological casts, mucus and sperm in urine. These measurements are useful in the evaluation of renal, urinary and metabolic disorders.
This system is intended to be used by trained operators in clinical laboratories. All instrument analyte image decisions may be reviewed and reclassified by a trained operator.
C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
IV Device/System Characteristics:
A Device Description:
The cobas u 701 is a fully automated urine particle analyzer that is used in the clinical laboratory to analyze formed elements in urine samples quantitatively, semi-quantitatively and qualitatively for the presence of particles in the sample. The cobas u 701 microscopy analyzer is a stand-alone system and incorporates a robotic liquid handling system that pipettes an aliquot of the specimen into a disposable cuvette. The filled cuvette is forwarded to the built-in centrifuge for centrifugation of the non-soluble particles. After the centrifugation, all particles are brought to one monolayer to ensure they are all at the same focal plane. A built-in camera takes pictures through a built-in microscope at several positions of the sediment. All images are evaluated by an image processing software which is able to detect and further classify the following urine particles. Particle concentration is calculated using the average count from the assessed images. The cobas u 701 reports analysis results for two quantitative parameters in urine: RBC and WBC, three semi-quantitative parameters: SEC (Squamous epithelial cells), HYA (Hyaline casts) and BAC (Bacteria), and six qualitative parameters: NEC (Non-squamous epithelial cells), PAT (Pathological casts), CRY (Crystals), YEA (Yeast), SPRM (Sperm) and MUC (Mucus). The cobas u 701 microscopy analyzer performs a maximum theoretical throughput of up to 116 samples per hour.
The cobas u 701 consists of several major components:
- Rack transport system
- Liquid handling system
- Cuvette cassette compartment
- Centrifuge
- Built-in reverse microscope with movable objective lens for focusing procedure
- High resolution camera system
- Touch Screen
- Inbuilt Computer with the imaging and evaluation software for analyzing the sediment pictures
The cobas u cuvette is a cassette, containing cuvettes for the in vitro quantitative determination of erythrocytes and leukocytes, the semi-quantitative determination of squamous epithelial cells,
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bacteria, and hyaline casts and the qualitative determination of non-squamous epithelial cells, crystals, yeasts, pathological casts, mucus, and sperm in urine with the cobas u 701 microscopy analyzer. The cobas u cuvette is for professional use only.
The cobas u cuvette is used by the cobas u 701 microscopy analyzer to transport, centrifuge and analyze patient and control samples. They are provided separately from the analyzer, in a box holding 400 disposable cuvettes.
## Instrument Description Information:
1. Instrument Name:
cobas u 701 microscopy analyzer
2. Specimen Identification:
Human urine
3. Specimen Sampling and Handling:
The analyzer auto-identifies and processes barcoded tube specimens in 5-position racks by mixing, sampling, and analyzing automatically.
4. Calibration:
No calibration of the device is necessary for its intended use. However, there is a microscope check, which is not a calibration of the device. This microscope check ensures proper functioning of the focusing mechanism of the microscope utilizing a reference cuvette. The reference cuvette is a cuvette with the same dimensions as the sample cuvette, which contains a transparent material with a standardized number of erythrocyte like particles etched in it. For differentiation from the sample cuvettes, the reference cuvette is green and marked with the letter R on the top. This microscope check confirms that the instrument is able to focus accurately on the position of the particles and to count correctly the number of the cells. This microscope check needs to be performed every 4 weeks. A message from the instrument informs the operator when it is due.
5. Quality Control:
Recommendation of commercially available control solutions.
## V Substantial Equivalence Information:
### A Predicate Device Name(s):
Iq 200 System
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B Predicate 510(k) Number(s):
K022774
C Comparison with Predicate(s):
| Device & Predicate Device(s): | K200811 | K022774 |
| --- | --- | --- |
| Device Trade Name | cobas u 701 microscopy analyzer | IRIS Iq 200 |
| General Device Characteristic Similarities | | |
| Intended Use/Indications for Use | The cobas u 701 microscopy analyzer is a fully automated urine microscopy system intended for the in vitro quantitative determination of erythrocytes and leukocytes, the semi-quantitative determination of squamous epithelial cells, bacteria, and hyaline casts and the qualitative determination of non-squamous epithelial cells, crystals, yeasts, pathological casts, mucus and sperm in urine. This system is intended to be used by trained operators in clinical laboratories. All instrument analyte image decisions may be reviewed and reclassified by a trained operator. | The iQ200 system is an in-vitro diagnostic device used to automate the complete urinalysis profile, including urine test strip chemistry panel and microscopic sediment analysis. Optionally, the iQ200 Analyzer can be used as a stand-alone unit, or the results from the iQ200 Analyzer can be combined with other urine chemistry results received from an LIS. It produces quantitative or qualitative counts of all formed sediment elements present in urine, including cells, casts, crystals and organisms. A competent human operator can set criteria for auto-reporting and flagging specimens for review. All instrument analyte image decisions may be reviewed and overridden by a trained technologist. |
| Specimen Type | Random Urine Specimen | Same |
| Specimen Aspiration | Urine in barcode labeled tubes | Same |
| Change of machine assignment | An appropriately trained laboratory operator may manually re-classify or (sub-) sub-classify particles. | Same |
| Maintenance | Daily and periodic maintenance | Same |
| General Device Characteristic Differences | | |
| Principle of Operation | The analyzer auto-identifies and | The iQ200 System auto- |
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| | processes barcoded tube specimens in 5-position racks by mixing, sampling, and analyzing automatically.
cobas u 701 microscopy analyzer incorporates a robotic liquid handling system that pipettes an aliquot of the specimen into a disposable cuvette. The filled cuvette is forwarded to the built-in centrifuge for centrifugation of the non-soluble particles. After the centrifugation, all particles are brought to one monolayer to ensure they are all at the same focal plane. A built-in camera takes pictures through a built-in microscope at several positions of the sediment. All images are evaluated by an image processing software which is able to detect and further classify the following urine particles
•Red blood cells
•White blood cells
•Squamous epithelial cells
•Bacteria
•Hyaline casts
•Non-squamous epithelial cells
•Crystals
•Yeast
•Pathological casts
•Mucus
•Sperm
An appropriately trained laboratory user may manually re-classify or sub-classify particles on the basis of the acquired pictures.
Particle concentration is calculated using the average count from the assessed images. | identifies and processes barcoded tube specimens in 10-position racks by mixing, sampling, and analyzing automatically. The iQ200 system incorporates an iQ200 Automated Urine Microscopy Analyzer, in which a sample is presented as a lamina sandwiched between enveloping layers of suspending fluid to a microscope coupled to a CCD (charge coupling device) video camera.
This lamination positions the specimen exactly within the depth of focus and field of view of the objective lens of the microscope. Lamination is the planar equivalent of axial hydrodynamic focusing, used to position cells in certain types of blood cell counters and flow cytometers. It has the added advantage of achieving orthoscopic particle orientation, thereby presenting asymmetric particles with their largest profile facing the direction of view.
A CCD digital camera captures five hundred frames per sample, as each microscopic field of view is illuminated by the flash of a strobe lamp. The resulting pictures are digitized and delivered to the Analysis Processor computer. A previously stored image of a blank background is subtracted from the individual fields of view, enhancing the morphology of the captured particle.
Individual particle images are isolated within each frame. The Auto-Particle Recognition |
| --- | --- | --- |
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| | | (APR™) software, a highly trained neural network, uses size, shape, contrast and texture features to classify each image into one of 12 categories: RBCs, WBCs, WBC Clumps, Hyaline Casts, Unclassified Casts, Squamous Epithelial Cells, Non-squamous Epithelial Cells, Bacteria, Yeast, Crystals, Mucus and Sperm. Particle concentration is calculated using the number of images and the volume scanned. User-defined release criteria are checked and results are sent to an operator review screen or directly uploaded to the LIS based on these criteria. Specimen results can be edited, archived, retrieved, imported, exported and formatted into custom reports |
| --- | --- | --- |
| Detected and counted particles present in a specimen | •Red blood cells
•White blood cells
•Squamous epithelial cells
•Bacteria
•Hyaline casts
•Non-squamous epithelial cells
•Crystals
•Yeast
•Pathological casts
•Mucus
•Sperm
It is possible to manually sub-classify particles (e.g. RBC morphologies, CRY)
It is possible to manually identify further particles (e.g. trichomonas, red blood cell clumps, oval fat | •Red Blood Cells
•White Blood Cells
•White Blood Cell Clumps
•Non-Squamous Epithelial Cells
•Squamous Epithelial Cells
•Hyaline Casts
•Bacteria
•Crystals
•Yeast
•Artifact
•Unclassified Casts
It is possible to manually sub-classify Unclassified Crystals, Unclassified Casts, Yeast and Non-Squamous Epithelial Cells.
It is possible to manually identify the following particles
•Sperm |
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| | bodies, artifacts). | •Mucus
•Trichomonas
•Fat Red Blood Cell Clumps
•Oval Fat Bodies |
| --- | --- | --- |
| QC | Recommendation of commercially available control solutions | IQ Control material |
| Calibration | No calibration needed due to different particle detection technology | Monthly focus with iQ Focus and calibration with IQ Calibrator Material (suspension of fixed human red blood cells in a particulate-free solution) |
| Specimen Volume | Minimum volume 2 mL of un-spun urine. Aspiration volume < 0.8 mL | Minimum volume 3 mL of un-spun urine. Aspiration volume approx. 1.3 mL |
| Measurement Principle | Digital imaging after automated centrifugation | Flow digital imaging |
| Fluid Waste | Waste container capacity is 5L. This capacity is sufficient to run 400 tests.
A direct waste discharge is possible (max. height = instrument level) | Waste is pumped from the instrument to a sink, floor drain or suitable container. Drain must be below or at same height as bench and should be less than 10 feet (3 meters) from the back of the instrument |
VI Standards/Guidance Documents Referenced:
CLSI EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline – Third Edition
CLSI EP06-A, Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline – Third Edition
CLSI EP12-A2, User Protocol for Evaluation of Qualitative Test Performance; Approved Guideline – Second Edition
CLSI EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline – Second Edition
CLSI EP28-A3c, Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline – Third Edition
VII Performance Characteristics (if/when applicable):
A Analytical Performance:
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# 1. Precision/Reproducibility:
# a. Repeatability Study
Repeatability (within-run precision) was evaluated using 3 control samples and 3 residual natural urine specimens without preservatives around the low and high end of the analytical measuring range. All used specimen (controls, human samples) were measured in 2 runs, 21 determinations each, producing $n = 42$ results per specimen. Testing was conducted across two sites using a single analyzer at each site and four different cuvette lots. All predefined acceptance criteria were met.
Repeatability for Quantitative Parameters Using Controls
| | | | | | | Run 1 | | | Run 2 | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Site | Parameter | Number of Runs | N Total | Control Level* | Target Range (p/μL) | Mean (p/μL) | SD (p/μL) | CV (%) | Mean (p/μL) | SD (p/μL) | CV (%) |
| Site 1 | RBC | 2 | 42 | 1 | 0-25 | 0.00 | 0.00 | NA | 0.00 | 0.00 | NA |
| Site 1 | RBC | 2 | 42 | 2 | 425-1280 | 803 | 39.4 | 4.91 | 764 | 54.2 | 7.10 |
| Site 1 | RBC | 2 | 42 | 3 | 50-120 | 70.6 | 9.19 | 13.0 | 53.8 | 7.94 | 14.8 |
| Site 1 | WBC | 2 | 42 | 1 | 0-25 | 0.00 | 0.00 | NA | 0.00 | 0.00 | NA |
| Site 1 | WBC | 2 | 42 | 2 | 75-240 | 138 | 15.0 | 10.9 | 133 | 11.6 | 8.71 |
| Site 1 | WBC | 2 | 42 | 3 | 50-70 | 59.1 | 5.37 | 9.09 | 51.5 | 7.57 | 14.7 |
| Site 2 | RBC | 2 | 42 | 1 | 0-25 | 0.04 | 0.19 | 458 | 0.08 | 0.26 | 316 |
| Site 2 | RBC | 2 | 42 | 2 | 425-1280 | 641 | 31.9 | 4.97 | 890 | 48.3 | 5.42 |
| Site 2 | RBC | 2 | 42 | 3 | 50-120 | 76.4 | 8.45 | 11.1 | 112 | 10.7 | 9.52 |
| Site 2 | WBC | 2 | 42 | 1 | 0-25 | 0.00 | 0.00 | NA | 0.00 | 0.00 | NA |
| Site 2 | WBC | 2 | 42 | 2 | 75-240 | 131 | 11.5 | 8.78 | 146 | 10.4 | 7.13 |
| Site 2 | WBC | 2 | 42 | 3 | 50-70 | 62.7 | 6.74 | 10.8 | 67.4 | 7.34 | 10.9 |
*BioRad Liquichek control levels include: Level 1, Level 2, Level 3 (Low positive control prepared by diluting Bio-Rad Level 1 and Level 2; obtained values for low pos controls depend on dilution factor).
Repeatability for Quantitative Parameters Using Human Samples
| | | | | | Run 1 | | | Run 2 | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Site | Parameter | No. of Runs | N Total | Concentration | Mean (p/μL) | SD (p/μL) | CV (%) | Mean (p/μL) | SD (p/μL) | CV (%) |
| Site 1 | RBC | 2 | 42 | Neg | 0.75 | 0.98 | 129 | 1.17 | 1.05 | 89.8 |
| Site 1 | RBC | 2 | 42 | Low pos | 17.4 | 4.90 | 28.1 | 80.3 | 16.8 | 20.9 |
| Site 1 | RBC | 2 | 42 | Pos | 1336 | 155 | 11.6 | 899 | 48.0 | 5.34 |
| Site 1 | WBC | 2 | 42 | Neg | 2.26 | 1.26 | 55.8 | 2.58 | 2.38 | 92.3 |
| Site 1 | WBC | 2 | 42 | Low pos | 14.1 | 4.06 | 28.8 | 63.9 | 8.86 | 13.9 |
| Site 1 | WBC | 2 | 42 | Pos | 813 | 29.2 | 3.59 | 631 | 29.0 | 4.59 |
| Site 2 | RBC | 2 | 42 | Neg | 0.92 | 1.02 | 111 | 0.59 | 1.12 | 192 |
| Site 2 | RBC | 2 | 42 | Low pos | 125 | 11.3 | 9.03 | 13.0 | 4.48 | 34.4 |
| Site 2 | RBC | 2 | 42 | Pos | 989 | 74.4 | 7.52 | 1175 | 50.8 | 4.33 |
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| Site 2 | WBC | 2 | 42 | Neg | 0.53 | 0.82 | 154 | 0.00 | 0.00 | NA |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Site 2 | WBC | 2 | 42 | Low pos | 22.8 | 5.28 | 23.2 | 56.4 | 7.18 | 12.7 |
| Site 2 | WBC | 2 | 42 | Pos | 496 | 56.6 | 11.4 | 620 | 90.2 | 14.5 |
*BioRad Liquicheck control levels include: Level 1, Level 2, Level 3 (Low positive control prepared by diluting Bio-Rad Level 1 and Level 2; obtained values for low pos controls depend on dilution factor).
Repeatability for Semi-Quantitative and Qualitative Parameters
| | | | | | Run 1 | | | Run 2 | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Site | Parameter | No. of Runs | N Total | Concentration | Mean (p/μL) | SD (p/μL) | CV (%) | Mean (p/μL) | SD (p/μL) | CV (%) |
| Site 1 | BAC | 2 | 42 | Neg | 79.6 | 12.7 | 15.9 | 32.7 | 5.88 | 18.0 |
| Site 1 | BAC | 2 | 42 | Low pos | 107 | 8.83 | 8.23 | 176 | 10.1 | 5.73 |
| Site 1 | BAC | 2 | 42 | Pos | 2380 | 169 | 7.10 | 1175 | 38.3 | 3.26 |
| Site 1 | CRY | 2 | 42 | Neg | 0.21 | 0.58 | 279 | 0.61 | 0.87 | 144 |
| Site 1 | CRY | 2 | 42 | Pos | 22.5 | 7.07 | 31.5 | 81.7 | 19.1 | 23.4 |
| Site 1 | HYA | 2 | 42 | Neg | 0.08 | 0.18 | 211 | 0.10 | 0.24 | 226 |
| Site 1 | HYA | 2 | 42 | Low pos | 4.00 | 1.16 | 29.1 | 6.81 | 2.09 | 30.6 |
| Site 1 | HYA | 2 | 42 | Pos | 14.4 | 3.40 | 23.7 | 15.4 | 3.62 | 23.5 |
| Site 1 | MUC | 2 | 42 | Neg | 26.5 | 8.63 | 32.5 | 4.44 | 2.55 | 57.5 |
| Site 1 | MUC | 2 | 42 | Pos | 298 | 41.1 | 13.8 | 618 | 88.1 | 14.3 |
| Site 1 | NEC | 2 | 42 | Neg | 0.21 | 0.30 | 143 | 0.00 | 0.00 | NA |
| Site 1 | NEC | 2 | 42 | Pos | 27.7 | 3.89 | 14.1 | 7.08 | 2.23 | 31.5 |
| Site 1 | PAT | 2 | 42 | Neg | 0.08 | 0.30 | 357 | 0.02 | 0.10 | 458 |
| Site 1 | PAT | 2 | 42 | Pos | 2.10 | 0.90 | 43.0 | 3.25 | 1.05 | 32.5 |
| Site 1 | SEC | 2 | 42 | Neg | 0.21 | 0.58 | 279 | 0.00 | 0.00 | NA |
| Site 1 | SEC | 2 | 42 | Low pos | 14.4 | 2.49 | 17.4 | 15.9 | 4.25 | 26.7 |
| Site 1 | SEC | 2 | 42 | Pos | 44.4 | 14.3 | 32.2 | 67.2 | 14.9 | 22.1 |
| Site 1 | SPRM | 2 | 42 | Neg | 0.04 | 0.13 | 316 | 0.00 | 0.00 | NA |
| Site 1 | SPRM | 2 | 42 | Pos | 17.7 | 5.87 | 33.1 | 36.7 | 5.98 | 16.3 |
| Site 1 | YEA | 2 | 42 | Neg | 0.06 | 0.16 | 251 | 0.00 | 0.00 | NA |
| Site 1 | YEA | 2 | 42 | Pos | 16.6 | 4.98 | 30.1 | 14.9 | 3.87 | 26.1 |
| Site 2 | BAC | 2 | 42 | Neg | 26.9 | 4.22 | 15.7 | 21.4 | 2.04 | 9.55 |
| Site 2 | BAC | 2 | 42 | Low pos | 117 | 8.11 | 6.95 | 151 | 8.32 | 5.51 |
| Site 2 | BAC | 2 | 42 | Pos (2+) | 239 | 13.8 | 5.80 | 250 | 10.4 | 4.17 |
| Site 2 | BAC | 2 | 42 | Pos | 1612 | 30.1 | 1.87 | 845 | 55.0 | 6.52 |
| Site 2 | CRY | 2 | 42 | Neg | 0.59 | 0.49 | 83.3 | 0.82 | 0.73 | 88.9 |
| Site 2 | CRY | 2 | 42 | Pos | 62.2 | 7.13 | 11.5 | 26.5 | 4.89 | 18.5 |
| Site 2 | HYA | 2 | 42 | Neg | 0.00 | 0.00 | NA | 0.02 | 0.10 | 458 |
| Site 2 | HYA | 2 | 42 | Low pos | 2.89 | 1.33 | 46.0 | 3.86 | 1.32 | 34.2 |
| Site 2 | HYA | 2 | 42 | Pos | 20.9 | 3.51 | 16.8 | 17.0 | 4.10 | 24.1 |
| Site 2 | MUC | 2 | 42 | Neg | 0.63 | 1.21 | 192 | 9.32 | 4.72 | 50.6 |
| Site 2 | MUC | 2 | 42 | Pos | 491 | 34.8 | 7.08 | 426 | 52.9 | 12.4 |
| Site 2 | NEC | 2 | 42 | Neg | 0.04 | 0.13 | 316 | 0.02 | 0.10 | 458 |
| Site 2 | NEC | 2 | 42 | Pos | 7.50 | 1.97 | 26.2 | 8.21 | 1.96 | 23.9 |
| Site 2 | PAT | 2 | 42 | Neg | 0.00 | 0.00 | NA | 0.02 | 0.10 | 458 |
| Site 2 | PAT | 2 | 42 | Pos | 10.9 | 2.29 | 21.0 | 7.56 | 1.72 | 22.8 |
| Site 2 | SEC | 2 | 42 | Neg | 0.00 | 0.00 | NA | 0.02 | 0.10 | 458 |
| Site 2 | SEC | 2 | 42 | Low pos | 10.5 | 3.07 | 29.1 | 14.8 | 3.21 | 21.7 |
| Site 2 | SEC | 2 | 42 | Pos | 53.9 | 9.09 | 16.9 | 63.8 | 6.40 | 10.0 |
| Site 2 | SPRM | 2 | 42 | Neg | 0.00 | 0.00 | NA | 0.00 | 0.00 | NA |
| Site 2 | SPRM | 2 | 42 | Pos | 16.7 | 3.08 | 18.4 | 8.65 | 2.00 | 23.1 |
| Site 2 | YEA | 2 | 42 | Neg | 0.00 | 0.00 | NA | 0.00 | 0.00 | NA |
| Site 2 | YEA | 2 | 42 | Pos | 268 | 19.6 | 7.31 | 236 | 33.0 | 14.0 |
Note: CV (%) cannot be calculated when mean = 0; these instances are marked as NA.
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b. Intermediate Precision
Intermediate precision was performed according to CLSI EP5-A3 to assess long-term precision of the cobas u 701 microscopy analyzer. However, due to the instability of the human urine samples, only control samples were measured for this study. This assessment was limited to the parameters included in the control material (RBC, WBC). All predefined acceptance criteria were met.
Intermediate Precision for Controls at Site 1
| Site 1 | | | | | | Repeatability | | Between-Run | | Between-Day | | Intermediate (Within-site) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Parameter | Number of runs | N Total | Control Level | Mean (p/μL) | Target Value (p/μL) | SD | % CV | SD | % CV | SD | % CV | SD | % CV |
| RBC | 2 | 84 | 1 | 0.105 | 0 - 25 | 0.33 | 317 | 0.14 | 130 | 0.00 | 0.00 | 0.36 | 343 |
| RBC | 2 | 84 | 2 | 751 | 425 - 1280 | 47.1 | 6.26 | 18.5 | 2.46 | 33.6 | 4.47 | 60.7 | 8.08 |
| RBC | 2 | 84 | 3 | 54.3 | 50 - 70 | 6.64 | 12.2 | 4.37 | 8.03 | 6.14 | 11.3 | 10.0 | 18.5 |
| WBC | 2 | 84 | 1 | 0.00 | 0 - 25 | 0.00 | NA | 0.00 | NA | 0.00 | NA | 0.00 | NA |
| WBC | 2 | 84 | 2 | 139 | 75 - 240 | 14.2 | 10.2 | 5.06 | 3.65 | 8.23 | 5.93 | 17.1 | 12.3 |
| WBC | 2 | 84 | 3 | 58.5 | 50 - 70 | 8.43 | 14.4 | 0.00 | 0.00 | 6.93 | 11.8 | 10.9 | 18.7 |
Note: Bio-Rad Liquicheck control levels include: Level 1, Level 2, Level 3 (Low positive control prepared by diluting Bio-Rad Level 1 and Level 2); For Liquichek control Level 1 and Level 2 samples, Target Values are from package insert; For prepared low positive control samples, Target Values will be affected by the variability of the control material.
Intermediate Precision for Controls at Site 2
| Site 2 | | | | | | Repeatability | | Between-Run | | Between-Day | | Intermediate (Within-site) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Parameter | Number of runs | N Total | Control Level | Mean (p/μL) | Target Value (p/μL) | SD | % CV | SD | % CV | SD | % CV | SD | % CV |
| RBC | 2 | 84 | 1 | 0.15 | 0 - 25 | 0.49 | 334 | 0.00 | 0.00 | 0.27 | 187 | 0.56 | 383 |
| RBC | 2 | 84 | 2 | 813 | 425 - 1280 | 42.8 | 5.26 | 20.3 | 2.50 | 30.0 | 3.69 | 56.1 | 6.90 |
| RBC | 2 | 84 | 3 | 69.5 | 50 - 70 | 8.32 | 12.0 | 0.41 | 0.59 | 3.35 | 4.82 | 8.98 | 12.9 |
| WBC | 2 | 84 | 1 | 0.00 | 0 - 25 | 0.00 | NA | 0.00 | NA | 0.00 | NA | 0.00 | NA |
| WBC | 2 | 84 | 2 | 140 | 75 - 240 | 9.36 | 6.69 | 2.31 | 1.65 | 8.17 | 5.84 | 12.6 | 9.03 |
| WBC | 2 | 84 | 3 | 62.8 | 50 - 70 | 8.09 | 12.9 | 2.17 | 3.46 | 2.47 | 3.93 | 8.74 | 13.9 |
Note: Bio-Rad Liquicheck control levels include: Level 1, Level 2, Level 3 (Low positive control prepared by diluting Bio-Rad Level 1 and Level 2); For Liquichek control Level 1 and Level 2 samples, Target Values are from package insert; For prepared low positive control samples, Target Values will be affected by the variability of the control material.
Intermediate Precision for Controls at Site 4 (Internal Site)
| Site 4 | | | | | | Repeatability (Within-Run) | | Between-Run | | Between-Day | | Intermediate (Within-Site) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Parameter | Number of Runs | N Total | Control Level | Mean (p/μL) | Target Value (p/μL) | SD (p/μL) | % CV | SD (p/μL) | % CV | SD (p/μL) | % CV | SD (p/μL) | % CV |
| RBC | 2 | 84 | 1 | 0.23 | 0 - 25 | 0.65 | 283 | 0.00 | 0.00 | 0.00 | 0.00 | 0.65 | 283 |
| RBC | 2 | 84 | 2 | 375 | 160 – 495* | 18.7 | 5.00 | 15.3 | 4.09 | 21.5 | 5.75 | 32.4 | 8.65 |
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Note: CV (%) cannot be calculated when mean = 0; these instances are marked as NA; Bio-Rad Liquicheck control levels include: Level 1, Level 2, Level 3 (Low positive control prepared by diluting Bio-Rad Level 1 and Level 2); For Liquichek control Level 1 and Level 2 samples, Target Values are from package insert; For prepared low positive control samples, Target Values will be affected by the variability of the control material.
**This lot had a lower claim for the RBC in Level 2 than the two external sites
## c. Reproducibility Study
Reproducibility measurements for quantitative parameters WBC and RBC were performed based on the compiled intermediate precision datasets for the three study sites each using one cobas u 701 microscopy analyzer.
Reproducibility for Combined Data from Three Sites
| | | | | | Repeatability (Within-Run) | | Between-Run | | Between-Day | | Reproducibility (Within-Site) | | Between-Site | | Reproducibility (Within-System) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Parameter | N Total | Concentration Level | Mean (p/μL) | Target Value p/μL | SD (p/μL) | % CV | SD (p/μL) | % CV | SD (p/μL) | % CV | SD (p/μL) | % CV | SD (p/μL) | % CV | SD (p/μL) | % CV |
| RBC | 252 | 1 | 0.16 | 0 - 25 | 0.51 | 316 | 0.00 | 0.00 | 0.09 | 56.4 | 0.52 | 321 | 0.03 | 21.1 | 0.52 | 322 |
| RBC | 252 | 2 | 846 | 425 - 1280 | 46.2 | 5.46 | 27.9 | 3.30 | 41.5 | 4.90 | 68.1 | 8.05 | 113 | 13.4 | 132 | 15.6 |
| RBC | 252 | 3 | 62.4 | 50 - 70 | 7.35 | 11.8 | 3.43 | 5.50 | 4.03 | 6.45 | 9.06 | 14.5 | 7.50 | 12.0 | 11.8 | 18.8 |
| WBC | 252 | 1 | 0.00 | 0 - 25 | 0.00 | NA | 0.00 | NA | 0.00 | NA | 0.00 | NA | 0.00 | NA | 0.00 | NA |
| WBC | 252 | 2 | 150 | 75 - 240 | 12.6 | 8.45 | 0.00 | 0.00 | 7.79 | 5.21 | 14.9 | 9.92 | 17.6 | 11.8 | 23.0 | 15.4 |
| WBC | 252 | 3 | 60.0 | 50 - 70 | 7.74 | 12.9 | 0.00 | 0.00 | 4.20 | 6.99 | 8.80 | 14.7 | 2.09 | 3.48 | 9.05 | 15.1 |
Note: CV (%) cannot be calculated when mean = 0; these instances are marked as NA
## d. Recovery
Recovery measurements for semi-quantitative parameters BAC, HYA, and SEC were performed in triplicate on the cobas u 701 microscopy analyzer at two sites, each using one cobas u 701 microscopy analyzer. Additionally, one measurement was performed using the manual KOVA counting method. All predefined acceptance criteria were met.
Reproducibility for Semi-quantitative Parameters at Site 1
| Parameter | Target Value | N | cobas u 701 | | | | | | KOVA | Exact Agreement | 2 of 3 results within the specified concentration block | Agreement within 2 adjacent concentration ranges |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Raw Count (bacteria or p/μL) | | | Result | | | Result | [%] | [Yes/No] | [%] |
| | | | 1st | 2nd | 3rd | 1st | 2nd | 3rd | | | | |
| BAC | Negative (NaCl) | 3 | 0.44 | 11.9 | 5.72 | neg | neg | neg | neg | 100 | Yes | 100 |
| | 1+ | 3 | 134 | 123 | 130 | 1+ | 1+ | 1+ | 1+ | 100 | Yes | 100 |
| | 2+ | 3 | 407 | 413 | 394 | 2+ | 2+ | 2+ | 2+ | 100 | Yes | 100 |
| | 3+ | 3 | 896 | 888 | 891 | 3+ | 3+ | 3+ | 3+ | 100 | Yes | 100 |
| HYA | Negative (Urine) | 3 | 0.00 | 0.00 | 0.00 | neg | neg | neg | 0.00 | 100 | Yes | 100 |
| | 5 p/μL | 3 | 3.96 | 3.52 | 8.36 | 5 | 5 | 15 | 2.75 | 66.7 | Yes | 100 |
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| Parameter | Target Value | N | cobas u 701 | KOVA | Exact Agreement | 2 of 3 results within the specified concentration block | Agreement within 2 adjacent concentration ranges |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Raw Count (bacteria or p/μL) | Result | Result | [%] | [Yes/No] | [%] |
| 1st | 2nd | 3rd | 1st | 2nd | 3rd |
| 15 p/μL | 3 | 12.8 | 11.4 | 12.8 | 15 | 15 | 15 | 13.8 | 100 | Yes | 100 |
| SEC | Negative (Urine) | 3 | 0.00 | 0.00 | 0.00 | neg | neg | neg | 0.00 | 100 | Yes | 100 |
| 15 p/μL | 3 | 11.0 | 16.3 | 13.6 | 15 | 15 | 15 | 13.2 | 100 | Yes | 100 |
| 40 p/μL | 3 | 43.1 | 55.0 | 50.6 | 40 | 40 | 40 | 52.8 | 100 | Yes | 100 |
Reproducibility for Semi-quantitative Parameters at Site 2
| Parameter | Target Value | N | cobas u 701 | | | | | | KOVA | Exact Agreement | 2 of 3 results within the specified concentration block | Agreement within 2 adjacent concentration ranges |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Raw Count (bacteria or p/μL) | | | Result | | | Result | [%] | [Yes/No] | [%] |
| | | | 1st | 2nd | 3rd | 1st | 2nd | 3rd | | | | |
| BAC | Negative (NaCl) | 3 | 2.64 | 4.84 | 1.76 | neg | neg | neg | neg | 100 | Yes | 100 |
| | 1+ | 3 | 169 | 157 | 170 | 1+ | 1+ | 1+ | 1+ | 100 | Yes | 100 |
| | 2+ | 3 | 496 | 565 | 533 | 2+ | 2+ | 2+ | 2+ | 100 | Yes | 100 |
| | 3+ | 3 | 1066 | 1280 | 1253 | 3+ | 3+ | 3+ | 3+ | 100 | Yes | 100 |
| HYA | Negative (Urine) | 3 | 0.00 | 0.00 | 0.00 | neg | neg | neg | 0.00 | 100 | Yes | 100 |
| | 5 p/μL | 3 | 6.16 | 4.40 | 8.80 | 5 | 5 | 15 | 5.50 | 66.7 | Yes | 100 |
| | 15 p/μL | 3 | 15.4 | 8.80 | 15.4 | 15 | 15 | 15 | 18.7 | 100 | Yes | 100 |
| SEC | Negative (Urine) | 3 | 0.88 | 0.88 | 0.44 | neg | neg | neg | 1.10 | 100 | Yes | 100 |
| | 15 p/μL | 3 | 20.7 | 11.4 | 13.6 | 15 | 15 | 15 | 17.6 | 100 | Yes | 100 |
| | 40 p/μL | 3 | 49.3 | 36.5 | 47.1 | 40 | 40 | 40 | 56.1 | 100 | Yes | 100 |
## 2. Linearity:
Linearity of the cobas u 701 microscopy analyzer was determined for the two quantitative parameters RBC and WBC using one lot of cobas u cuvette and one cobas u 701 instrument. Linear regression was calculated according CLSI EP6-A.
Urine specimen pools were created by diluting and spiking natural urine samples with human RBC and WBC particles to cover the full measuring range for each quantitative parameter. One dilution series was prepared for each parameter (RBC & WBC). The RBC linearity set consisted of 25 serial dilutions. The WBC linearity set consisted of 23 serial dilutions. Each dilution concentration was measured in 4-fold determination in a randomized order. For evaluation, every single result was plotted against expected concentrations. Then linearity regression was calculated according CLSI EP6-A by a statistical software tool. The results obtained for RBC and WBC using the cobas u 701 microscopy analyzer met the defined acceptance criteria. Data analysis showed linearity for RBC and WBC was achieved through polynomial regression. The linearity was confirmed for a linearity range for RBC from $5 - 2160\mathrm{p} / \mu \mathrm{L}$ and WBC from $5 - 1080\mathrm{p} / \mu \mathrm{L}$. The measuring ranges for RBC $(5 - 1800\mathrm{p} / \mu \mathrm{L})$ and WBC $(5 - 900\mathrm{p} / \mu \mathrm{L})$ were covered by the linearity experiment.
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# 3. Analytical Specificity/Interference:
The interference study assessed the potential interferences that may occur on the cobas u 701 microscopy analyzer due to its measurement technology; clinical samples were assessed for the individual interferents. The study was determined by using four instruments and nine cuvette lots, on 670 native urine samples. Because of the imaging technology on the cobas u 701 microscopy analyzer, testing according EP07-A2 considered only visual/physical interferents; interference of drugs or endogenous substances is not applicable. Interference was confirmed, if the analyzer classification result was different than the visual classification result (KOVA manual counting). Native human urine samples containing the following interfering particles were measured on the cobas u 701 microscopy analyzers: high concentrations of mucus strands, artifacts, clumps, cell fragments, dysmorphic cells, shining particles, crowded samples, diluted samples, highly viscous samples, and high turbidity (Intralipid) samples. Furthermore, challenging native urine samples including amorphous crystals and trichomonas were evaluated. Based on the technological characteristics of the manual microscopy method, when measuring the following particles in the sample on the cobas u 701 microscopy analyzer, there is the potential that an incorrect result may be obtained.
Potential interfering particles and results
| Particle / Sample | Result on cobas u 701 microscopy analyzer |
| --- | --- |
| Mucus and artefacts | Particles may be underrepresented in samples with high amounts of mucus. Artifacts like fibers, hairs or dust may interfere with the result. Therefore, clean sampling and storage is important. A wrong classification of these particles can lead to false positive results. Large artefacts may cause defocused particles, which will be misclassified or not detected. |
| Clumps, fragments, aggregations, and dysmorphic cells | Clumps of cells, clumps of cell fragments, cell fragments of particles and or aggregations of particles may lead to misclassification. Also, dysmorphic cells may lead to a misclassification. Therefore, the standard sample stability and sample storage conditions should be followed. The sample itself should be mixed gently before testing. |
| Amorphous urates | Granules of amorphous urates with tendency to aggregate as coarse irregular dark masses may be detected as Bacteria (BAC). This depends on the size of the urates. Urates are a subclass of crystals (CRY) and should be identified as CRY within the image. If the crystals are really small, they may be detected as BAC. BAC is not labeled in the images as the estimation for BAC is based on the ratio of occupied to non-occupied space. |
| Misclassification of Bacteria | Certain forms of Bacteria (BAC) with a tendency to arrange in groups may be detected as Crystal (CRY) or Sperm (SPRM). |
| Shining particles | Shining particles sometimes may lead to misclassification. |
| Crowded samples | In case of high positive samples like RBC, WBC, SEC, BAC and CRY, where the images are crowded, the particles with high concentration may obscure those of lower concentration. This is due to the fact that the particles are centrifuged to a single layer, the focal plane. Such samples are not evaluated by the algorithm, they are marked with an “Uc” and must be reviewed by the user. If the concentration of the quantitative parameters exceeds 1800 p/μL for RBC or 900 p/μL for WBC, the samples are marked with “O” (Parameter is out of range). |
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| Diluted samples | Dilution of samples may cause cell lysis. The degree of cell lysis depends on the osmotic pressure of the diluted sample. Dilution may cause misclassification due to changes in cell size or shape or the decrease in number of the cells. |
| --- | --- |
# 4. Accuracy (Instrument):
To assess the accuracy of the cobas u 701 microscopy analyzer, a method comparison study was performed versus manual counting using KOVA chamber as the defined reference method was performed utilizing clinical samples. Six cobas u cuvette lots and one cobas u 701 instrument per site were used to perform the measurements. Measurements were performed at three sites, each using one cobas u 701 instrument per site and six cobas u cuvette lots. Statistical analysis was then performed comparing the cobas u 701 results and the KOVA chamber results.
Patient demographics included both males and females ranging in age from 1 month old to 98 years of age (355 females, 334 males and 91 pediatrics). A total of 168 subjects with known clinical conditions (kidney, infectious, and metabolic diseases) and 521 subjects with either healthy or unknown clinical condition urine samples were tested. For quantitative parameters, regression analysis (Passing-Bablok), including $95\%$ confidence intervals (CI) and estimates of the bias/difference were calculated for each parameter. In addition, Bland-Altman plots were generated to show the differences between the two devices for all reportable parameters. For both semi-quantitative and qualitative parameters, the agreement rates, including positive percentage agreement (PPA), negative percentage agreement (NPA) and the lower end $95\%$ confidence limits were calculated.
The results of the method comparison studies performed between cobas u 701 microscopy analyzer and visual counting using the KOVA chamber are shown below. All obtained statistical results from the single sites as well as for the compiled data sets were within the defined specifications and confirmed the substantial equivalence of the automated cobas u 701 microscopy analyzer with the manual KOVA counting method.
Method Comparison - Passing-Bablok Regression Analysis for Quantitative Parameters
| Site | Parameter | N* | Range of values | | Passing Bablok regression | | Pearson's | | | Agreement rates (%)** | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | cobas u 701 | KOVA | Slope (LCL, UCL) | Intercept (LCL, UCL) | r | R² | p=value (r=0) | Neg | Pos |
| All sites | RBC | 305 | 5-1746 | 5-1769 | 1.00 (0.99, 1.01) | -0.67 (-1.65, 0.16) | 0.99 | 0.97 | <0.001 | 99% | 92% |
| | WBC | 384 | 5-806 | 5-875 | 0.98 (0.97, 0.99) | -0.99 (-1.91, 0.04) | 0.98 | 0.97 | <0.001 | 98% | 98% |
| Site 3 | RBC | 84 | 6 - 1639 | 5 - 1710 | 1.02 (1.01, 1.04) | 2.60 (-0.09, 3.61) | 0.99 | 0.98 | <0.001 | 99% | 100% |
| | WBC | 111 | 5 - 804 | 5 - 806 | 1.01 (0.98, 1.03) | 1.81 (-0.62, 2.42) | 0.99 | 0.97 | <0.001 | 98% | 100% |
| Site 2 | RBC | 90 | 5 - 1585 | 5 - 1769 | 1.00 (0.99, 1.01) | 0.84 (-0.75, 2.35) | 0.99 | 0.98 | <0.001 | 99% | 96% |
| | WBC | 140 | 5 - 781 | 5 - 801 | 0.97 (0.94, 0.99) | -0.06 (-1.63, 0.49) | 0.99 | 0.97 | <0.001 | 99% | 97% |
| Site 1 | RBC | 131 | 5 - 1746 | 6 - 1753 | 0.93 (0.90, 0.96) | -1.26 (-3.19, -0.50) | 0.98 | 0.96 | <0.001 | 98% | 83% |
| | WBC | 133 | 5 - 806 | 6 - 875 | 0.94 (0.90, 0.97) | -1.77 (-3.13, -0.69) | 0.98 | 0.97 | <0.001 | 98% | 98% |
*includes all data within the defined measuring range on cobas u 701
**negative agreement calculation includes results below measuring range for RBC / WBC
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Method Comparison – Agreement Rates for Semi-quantitative Parameters
| Parameter | All sites | | | |
| --- | --- | --- | --- | --- |
| | N | NPA (LCL) | PPA (LCL) | Cohen's Kappa |
| BAC | 680 | 97% (95%) | 95% (93%) | 0.88 |
| SEC | 670 | 97% (95%) | 99% (96%) | 0.86 |
| HYA | 672 | 98% (97%) | 94% (89%) | 0.83 |
NPA = negative percentage agreement; PPA = positive percentage agreement; LCL = lower confidence limit
Method Comparison – Agreement Rates for Qualitative Parameters
| Parameter | All sites | | | |
| --- | --- | --- | --- | --- |
| | N | NPA (LCL) | PPA (LCL) | Cohen's Kappa |
| CRY | 670 | 97% (95%) | 98% (93%) | 0.95 |
| MUC | 670 | 99% (98%) | 94% (91%) | 0.93 |
| NEC | 675 | 90% (88%) | 94% (88%) | 0.84 |
| PAT | 670 | 93% (91%) | 89% (80%) | 0.82 |
| SPRM | 670 | 95% (93%) | 94% (85%) | 0.89 |
| YEA | 670 | 97% (95%) | 91% (82%) | 0.88 |
NPA = negative percentage agreement; PPA = positive percentage agreement; LCL = lower confidence limit
Predicted bias at medical decision levels, low, middle, and high ends of measurement ranges for RBC and WBC are provided in tables below.
RBC Predicted Bias at Medical Decision Levels
| Study Site: | Concentration [p/μL] | Bias | Bias (95% LCL) | Bias (95% UCL) |
| --- | --- | --- | --- | --- |
| All sites | 10 | -0.63 p/μL | -1.44 p/μL | 0.08 p/μL |
| | 15 | -0.61 p/μL | -1.45 p/μL | 0.06 p/μL |
| | 100 | -0.30 % | -1.72 % | 0.56% |
| | 500 | 0.24 % | -1.13 % | 1.23 % |
| | 1000 | 0.30 % | -1.06 % | 1.32 % |
| | 1500 | 0.33 % | -1.04 % | 1.36 % |
| Site 1 | 10 | -1.99 p/μL | -3.81 p/μL | -1.48 p/μL |
| | 15 | -2.35 p/μL | -4.15 p/μL | -1.83 p/μL |
| | 100 | -8.56 % | -12.2 % | -4.31 % |
| | 500 | -7.55 % | -11.0 % | -2.73 % |
| | 1000 | -7.43 % | -10.9 % | -2.53 % |
| | 1500 | -7.39 % | -10.9 % | -2.48 % |
| Site 3 | 10 | 2.83 p/μL | 0.36 p/μL | 4.50 p/μL |
| | 15 | 2.94 p/μL | 0.48 p/μL | 4.60 p/μL |
| | 100 | 4.86 % | 1.53 % | 6.86 % |
| | 500 | 2.78 % | 0.63 % | 4.59 % |
| | 1000 | 2.52 % | 0.50 % | 4.36 % |
| | 1500 | 2.43 % | 0.46 % | 4.28 % |
| Site 2 | 10 | 0.86 p/μL | -0.59 p/μL | 2.29 p/μL |
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WBC Predicted Bias at Medical Decision Levels
| Study Site: | Concentration [p/μL] | Bias | Bias (95% LCL) | Bias (95% UCL) |
| --- | --- | --- | --- | --- |
| All sites | 25 | -1.47 p/μL | -2.32 p/μL | -0.57 p/μL |
| | 100 | -2.93 % | -4.37 % | -1.52 % |
| | 200 | -2.43 % | -3.78 % | -1.10 % |
| | 400 | -2.18 % | -3.62 % | -0.84% |
| | 800 | -2.06 % | -3.52 % | -0.68% |
| Site 1 | 25 | -3.31 p/μL | -4.79 p/μL | -2.20 p/μL |
| | 100 | -7.91 % | -13.00% | -4.49 % |
| | 200 | -7.02 % | -12.2 % | -3.43 % |
| | 400 | -6.58 % | -11.9 % | -2.81 % |
| | 800 | -6.35 % | -11.7 % | -2.53 % |
| Site 3 | 25 | 2.01 p/μL | -0.94 p/μL | 2.76 p/μL |
| | 100 | 2.60% | -1.38 % | 4.23 % |
| | 200 | 1.70% | -1.33 % | 3.55 % |
| | 400 | 1.24 % | -1.47 % | 3.40 % |
| | 800 | 1.02 % | -1.57 % | 3.39 % |
| Site 2 | 25 | -0.84 p/μL | -2.55 p/μL | -0.20 p/μL |
| | 100 | -3.19 % | -6.35 % | -0.75 % |
| | 200 | -3.16 % | -6.39 % | -0.47 % |
| | 400 | -3.15 % | -6.49 % | -0.33 % |
| | 800 | -3.14 % | -6.54 % | -0.28 % |
5. Carry-Over:
Carryover was evaluated by testing residual urine samples without preservatives with high RBC, WBC, BAC, SEC, HYA, YEA, SPRM, and CRY at two sites, using five cobas u cuvette lots and one cobas u 701 instrument per site. First, a negative sample was measured in 25 determinations (reference run). Afterwards, sample blocks with five samples each were measured in alternate measurement mode. Alternating measurements of samples with high and negative concentrations were performed, meaning a high concentration sample block (n=5) was measured, then a negative sample block (n=5) was measured, and then a high concentration sample block was measured (n=5), etc.
Each block was measured 5 times for a total of 25 results for the high sample and 25 results for the negative sample. Statistical calculations for the quantitative parameters comprised calculation of mean and standard deviation for the reference run. For the semi-quantitative
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and qualitative parameters, the results of the negative samples after positive sample testing were assessed to confirm that they were still "negative". The results of the Sample Carry-over assessment for the defined parameters performed on the cobas u 701 microscopy analyzer using the cobas u cuvette met the predefined acceptance criteria.
## B Other Supportive Instrument Performance Characteristics Data:
### 1. Detection Limit:
#### Limit of Blank (LoB)
Limit of Blank (LoB) of the cobas u 701 microscopy analyzer was determined using one lot of cobas u cuvette and three cobas u 701 microscopy analyzers. The LoB is the highest observed measured value for samples free of analyte. The Limit of Blank was determined as the 95th percentile of the measurement of blank samples. Five samples per analyte were prepared fresh every day and tested on 3 days. Each day, two runs were performed with five samples measured in singlicate per run. Thirty results were collected for each parameter on each instrument for a total of 90 results per parameter. To determine the LoB, the 90 results for each parameter were sorted low to high. Using the nonparametric approach, determination of the 95th percentile was calculated from the mean of the 85th and 86th ranked results. All predefined acceptance criteria were met. The LoB was determined as follows:
| Parameter | Units | LoB Result |
| --- | --- | --- |
| RBC | RBC/μL | 0.0 |
| WBC | WBC/μL | 0.0 |
| SEC | SEC/μL | 0.0 |
| HYA | HYA/μL | 0.0 |
| BAC | BAC/μL | 2 |
#### Limit of Detection (LoD)
Limit of Detection (LoD) of the cobas u 701 microscopy analyzer was determined using one lot of cobas u cuvette and three cobas u 701 microscopy analyzers. LoD determines the detection limit for samples with low analyte concentration. The LoD was determined as the lowest amount of analyte in a sample that can be detected with a 95% probability. Five samples per parameter were measured. Each sample was measured in a 10-fold determination on each of the three analyzers. Measurements were performed on minimum 3 days. In total, 150 results were collected for each parameter. All predefined acceptance criteria were met. The LoD was calculated as follows:
$$
\mathrm{LoD} = \mathrm{LoB} + (1.648 \times \mathrm{SD})
$$
| Parameter | Units | LoD Result |
| --- | --- | --- |
| RBC | RBC/μL | 4.0 |
| WBC | WBC/μL | 3.0 |
| SEC | SEC/μL | 4.0 |
| HYA | HYA/μL | 1.4 |
| BAC | BAC/μL | 1.9 |
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Limit of Quantitation (LoQ)
Limit of Quantitation (LoQ) of the cobas u 701 microscopy analyzer was determined using one lot of cobas u cuvette and three cobas u 701 microscopy analyzers. LoQ is defined as the lowest analyte concentration in a sample that can be reproducibly measured. LoQ was determined for the quantitative parameters RBC and WBC with the same set of samples applied for the LoD determination. LoQ for RBC and WBC parameters met the predefined acceptance criteria.
| Parameter | LoQ Result | Measuring Range Claim |
| --- | --- | --- |
| RBC | 4.0 p/μL | 5 – 1800 p/μL |
| WBC | 3.1 p/μL | 5 – 900 p/μL |
| SEC | 6.9 p/μL | neg | 1+ | 2+
neg | 15 | 40 p/μL |
| HYA | 1.4 p /μL | neg | 1+ | 2+
neg | 5 | 15 p/μL |
| BAC | 99.6 p/μL | neg | 1+ | 2+ | 3+ |
2. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
Calibration:
No calibration of the device is necessary due to different particle detection technology. However, there is a microscope check, which is not a calibration of the device. This microscope check ensures proper functioning of the focusing mechanism of the microscope utilizing a reference cuvette. This microscope check needs to be performed every 4 weeks. A message from the instrument informs the operator when it is due.
Quality control:
Recommendation of commercially available control solutions.
3. Sample Stability:
Sample stability testing was performed using anonymized fresh human urine samples and measuring these samples at three different time points: 1) T0 - 0 h sample lifetime; 2) T1 - 2 h sample lifetime, and; 3) T2 - 3 h sample lifetime.
The urine samples were divided into four aliquots, thereof one for each time point and one for visual determination of the parameters SG (specific gravity) and pH with Chemstrip 10 UA test strips. Prior to and between the measurements of the different time points, the samples were stored at room temperature. For each testing point, a 4-fold determination was performed of urine samples on the cobas u 701 microscopy analyzer to rule out imprecision effects, unrelated to the analyte stability. In parallel to the instrument reading, a single determination with Chemstrip 10 UA was done at each time point of the same sample to determine the SG and pH values. The results obtained for sample stability using the cobas u 701 microscopy analyzer met the defined acceptance criteria. The pH and SG measured values remain unchanged over the entire measuring time. Data analysis showed sample stability for negative and positive flagged samples passed at time T2 (3 h) when stored at room temperature, one time-point below the sample stability claim of 2 hours.
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4. Assay Cut-Off:
For semi-quantitative and qualitative assay cut-off determination, range limits were set using empirical and theoretical information from literature, knowledge from clinical practice and the available data from external performed studies.
Definition of comparison of cobas u 701 and KOVA ratings
| Parameter | Reported unit | | cobas u 701 Range Limit [p/μl] | Kova Range Limit [p/μl] |
| --- | --- | --- | --- | --- |
| | Arbitrary | Conventional | | |
| BAC | | | | |
| 1 | neg | N/A | ≤ 100.0 | ≤ 0.5* |
| 2 | 1+ | N/A | > 100.0 ≤ 220.0 | > 0.5 ≤ 1.5* |
| 3 | 2+ | N/A | > 220.0 ≤ 750.0 | > 1.5 ≤ 2.5* |
| 4 | 3+ | N/A | > 750.0 | > 2.5* |
| NEC | | | | |
| 1 | neg | N/A | ≤ 1.4 | ≤ 3.0 |
| 2 | pos | N/A | > 1.4 | > 3.0 |
| SEC | | | | |
| 1 | N/A | neg | ≤ 5.0 | ≤ 9.0 |
| 2 | N/A | 15 | > 5.0 ≤ 25.0 | > 9.0 ≤ 38.0 |
| 3 | N/A | 40 | > 25.0 | > 38.0 |
| HYA | | | | |
| 1 | N/A | neg | ≤ 2.0 | ≤3.0 |
| 2 | N/A | 5 | > 2.0 ≤ 8.0 | > 3.0 ≤ 9.0 |
| 3 | N/A | 15 | > 8.0 | > 9.0 |
| PAT | | | | |
| 1 | neg | N/A | ≤ 1.2 | ≤ 1.2 |
| 2 | pos | N/A | > 1.2 | > 1.2 |
| CRY | | | | |
| 1 | neg | N/A | ≤ 5.0 | ≤ 5.0 |
| 2 | pos | N/A | > 5.0 | > 5.0 |
| YEA | | | | |
| 1 | neg | N/A | ≤ 1.0 | ≤ 5.0** |
| 2 | pos | N/A | > 1.0 | > 5.0** |
| MUC | | | | |
| 1 | neg | N/A | ≤ 100.0 | ≤ 5.0** |
| 2 | pos | N/A | > 100.0 | > 5.0** |
| SPRM | | | | |
| 1 | neg | N/A | ≤ 0.80 | ≤ 5.0** |
| 2 | pos | N/A | > 0.80 | > 5.0** |
* arbitrary rating
K200811 - Page 19 of 20
{19}
** no real count result, only operator's rating of neg and pos: "0" indicates a negative, "10" a positive result (see table below)
$\mathrm{N / A} =$ parameter is not reported in those units
Example table of how a final result is calculated using only operator's ratings of "0" and "10"
| Slide 1 / Operator 1 | Slide 1 / Operator 2 | Slide 2 / Operator 1 | Slide 2 / Operator 2 | Average | Result |
| --- | --- | --- | --- | --- | --- |
| 0 | 0 | 0 | 0 | 0 | Neg |
| 0 | 0 | 0 | 10 | 2.5 | Neg |
| 0 | 0 | 10 | 10 | 5 | Neg |
| 0 | 10 | 10 | 10 | 7.5 | Pos |
| 10 | 10 | 10 | 10 | 10 | Pos |
# 5. Expected Values/Reference Range:
To establish reference values for RBC and WBC on the cobas u 701 microscopy analyzer, "urine healthy" residual samples were measured. Measurements were performed at three sites, each using one cobas u 701 microscopy analyzer and a total of four cobas u cuvette lots.
Reference Range Study Results for RBC
| Site | Gender | N | Min | Max | Mean | Median | 97.5th percentile (90% CI) | 99th percentile (90% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| All sites combined | Female | 310 | 0.00 | 7.92 | 1.20 | 0.88 | 6.16 (5.28, 7.92) | 7.92 (6.16, 7.92) |
| | Male | 311 | 0.00 | 9.68 | 1.13 | 0.00 | 6.16 (5.28, 7.92) | 7.92 (6.16, 9.68) |
| | Total | 621 | 0.00 | 9.68 | 1.16 | 0.00 | 6.16 (5.28, 7.92) | 7.92 (7.04, 7.92) |
Reference Range Study Results for WBC
| Site | Gender | N | Min | Max | Mean | Median | 97.5th percentile (90% CI) | 99th percentile (90% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| All sites combined | Female | 310 | 0.00 | 17.8 | 1.72 | 0.66 | 10.6 (7.26, 13.9) | 13.2 (11.9, 17.8) |
| | Male | 311 | 0.00 | 15.8 | 1.02 | 0.00 | 5.94 (5.28, 12.5) | 9.90 (5.94, 15.8) |
| | Total | 621 | 0.00 | 17.8 | 1.37 | 0.66 | 7.92 (5.94, 11.9) | 12.5 (9.90, 16.5) |
# VIII Proposed Labeling:
The labeling supports the finding of substantial equivalence for this device.
# IX Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
K200811 - Page 20 of 20
