The KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay is for the semiquantitative determination of autoantibodies to Aquaporin-4 in human serum. The KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay may be useful as an aid in the diagnosis of Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorders (NMOSD). The KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay is not to be used alone and is to be used in conjunction with other clinical, laboratory, and radiological (e.g., MRI) findings.
Device Story
The KRONUS AQP4Ab ELISA is a manual, semi-quantitative assay for detecting autoantibodies to Aquaporin-4 in human serum. The device uses ELISA strip wells coated with human recombinant AQP4 protein. Patient serum is added to the wells; AQP4 autoantibodies form a bridge between the plate-bound AQP4 and liquid-phase biotinylated AQP4. Bound antibodies are detected via streptavidin-peroxidase and a TMB chromogenic substrate. Absorbance is measured at 405 nm using an ELISA plate reader. The assay is performed by laboratory professionals in a clinical laboratory. Results are interpolated from a calibration curve. The test aids in the differential diagnosis of NMO/NMOSD from other conditions like multiple sclerosis, supporting earlier diagnosis and appropriate therapy initiation. It must be used alongside clinical, laboratory, and radiological findings.
Clinical Evidence
Clinical validation included 620 serum samples: 85 NMO, 52 NMOSD, and 483 non-target disease controls (including MS, stroke, infectious, and autoimmune diseases). Using a 3.0 U/mL cut-off, the assay demonstrated 68.6% sensitivity (94/137) and 98.1% specificity (474/483) for NMO/NMOSD. Overall agreement was 91.6%. Syphilis samples showed a 13.33% false-positive rate.
Indicated for the semiquantitative determination of AQP4 autoantibodies in human serum to aid in the diagnosis of Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorders (NMOSD). For prescription use only by laboratory professionals in a clinical setting. Not for use as a standalone diagnostic.
Regulatory Classification
Identification
An Aquaporin-4 autoantibody immunological test system is a device that consists of reagents used to measure by immunochemical techniques autoantibodies in human serum samples that react with Aquaporin-4 (AQP4Ab). The measurements aid in the diagnosis of neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) in conjunction with other clinical, laboratory, and radiological (e.g., magnetic resonance imaging) findings.
Special Controls
An Aquaporin-4 autoantibody immunological test system must comply with the following special controls: 1) Premarket notification submissions must include the following information: i) A detailed device description including: A) A detailed description of all components including all required ancillary reagents in the test. B) If applicable, a detailed description of instrumentation and equipment, including illustrations or photographs of non-standard equipment or manuals. C) If applicable, detailed documentation of the device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software. D) A detailed description of appropriate internal and external quality controls that are recommended or provided. The description must identify those control elements that are incorporated into the specified testing procedures. E) Detailed specifications for sample collection, processing, and storage. F) A detailed description of methodology and assay procedure. G) A description of how the assay cut-off (the medical decision point between positive and negative) was established and validated as well as supporting data. H) Detailed specification of the criteria for test results interpretation and reporting. ii) Detailed information demonstrating the performance characteristics of the device, including: A) Device precision/reproducibility data generated from within-run, between-run, between-day, between-lot, between-site, and total precision for multiple nonconsecutive days, as applicable. A well characterized panel of patient samples or pools from the indicated population that covers the device measuring range must be used. B) Device linearity data generated from samples covering the device measuring range, if applicable. C) Information on traceability to a reference material and description of value assignment of calibrators and controls, if applicable. D) Device analytical sensitivity data, including limit of blank, limit of detection, and limit of quantitation, if applicable. E) Device analytical specificity data, including interference by endogenous and exogenous substances, as well as cross-reactivity with samples derived from patients with other autoimmune diseases or conditions. F) Device instrument carryover data, when applicable. G) Device stability data, including real-time stability under various storage times and temperatures. H) Specimen stability data, including stability under various storage times, temperatures, freeze-thaw, and transport conditions, where appropriate. I) Method comparison data generated by comparison of the results obtained with the device to those obtained with a legally marketed predicate device with similar indications of use. A well-characterized panel of patient samples from the indicated population covering the device measuring range must be used. J) Specimen matrix comparison data, if more than one specimen type or anticoagulant can be tested with the device. Samples used for comparison must be from well-characterized patient samples covering the device measuring range. K) Clinical performance must be established by comparing data generated by testing samples from the indicated population and the differential diagnosis or non-target disease groups with the device to the clinical diagnostic standard. (1) The diagnosis of NMO and NMOSD must be based on clinical findings, laboratory tests (e.g., serological tests), and radiological tests (e.g., Magnetic Resonance Imaging). (2) The differential diagnosis or non-target disease group must include the applicable diseases or conditions, including but not be limited to the following: multiple sclerosis, stroke, lyme disease, shingles, syphilis, human immunodeficiency virus, hepatitis B, tuberculosis, Sjörgen's Syndrome, systemic lupus erythematous, systemic vasculitis, sarcoidosis, Graves' disease, Hashimoto's disease. Type I diabetes, rheumatoid arthritis, Addison's disease, and Myasthenia Gravis. (3) Diagnosis of diseases or conditions for the differential or nontarget disease groups must be based on established diagnostic criteria and clinical evaluation. (4) For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided. (5) The clinical validation results must demonstrate clinical sensitivity and clinical specificity for the test values based on the presence or absence of NMO and NMOSD. (6) The data must be summarized in tabular format comparing the interpretation of results to the disease status. L) Expected/ reference values generated by testing an adequate number of samples from apparently healthy normal individuals. iii) Identification of risk mitigation elements used by the device, including description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing. 2) The device's 21 CFR 809.10(b) compliant labeling must include warnings relevant to the device including: i) A warning statement that reads "The device is for use by laboratory professionals in a clinical laboratory setting." ii) A warning statement that reads "The device is not to be used as a standalone device but as an adjunct to other clinical information. A diagnosis of Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorders (NMOSD) should not be made on a single test result. The clinical symptoms, results from physical examination, laboratory tests (e.g., serological tests), and radiological tests (e.g. Magnetic Resonance Imaging), when appropriate, should always be taken into account when considering the diagnosis of NMO and NMOSD." 3) The device's 21 CFR 809.10(b) compliant labeling must include a detailed description of the protocol and performance studies performed in accordance with special control (1)(ii) and a summary of the results.
*Classification.* Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the following information:
(i) A detailed device description including:
(A) A detailed description of all components including all required ancillary reagents in the test;
(B) If applicable, a detailed description of instrumentation and equipment, including illustrations or photographs of non-standard equipment or manuals;
(C) If applicable, detailed documentation of the device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software;
(D) A detailed description of appropriate internal and external quality controls that are recommended or provided. The description must identify those control elements that are incorporated into the specified testing procedures;
(E) Detailed specifications for sample collection, processing, and storage;
(F) A detailed description of methodology and assay procedure;
(G) A description of how the assay cutoff (the medical decision point between positive and negative) was established and validated as well as supporting data; and
(H) Detailed specification of the criteria for test results interpretation and reporting.
(ii) Detailed information demonstrating the performance characteristics of the device, including:
(A) Device precision/reproducibility data generated from within-run, between-run, between-day, between-lot, between-site, and total precision for multiple nonconsecutive days, as applicable. A well characterized panel of patient samples or pools from the indicated population that covers the device measuring range must be used.
(B) Device linearity data generated from samples covering the device measuring range, if applicable.
(C) Information on traceability to a reference material and description of value assignment of calibrators and controls, if applicable.
(D) Device analytical sensitivity data, including limit of blank, limit of detection, and limit of quantitation, if applicable.
(E) Device analytical specificity data, including interference by endogenous and exogenous substances, as well as cross-reactivity with samples derived from patients with other autoimmune diseases or conditions.
(F) Device instrument carryover data, when applicable.
(G) Device stability data, including real-time stability under various storage times and temperatures.
(H) Specimen stability data, including stability under various storage times, temperatures, freeze-thaw, and transport conditions, where appropriate.
(I) Method comparison data generated by comparison of the results obtained with the device to those obtained with a legally marketed predicate device with similar indications of use. A well-characterized panel of patient samples from the indicated population covering the device measuring range must be used.
(J) Specimen matrix comparison data, if more than one specimen type or anticoagulant can be tested with the device. Samples used for comparison must be from well-characterized patient samples covering the device measuring range.
(K) Clinical performance must be established by comparing data generated by testing samples from the indicated population and the differential diagnosis or non-target disease groups with the device to the clinical diagnostic standard.
(
*1* ) The diagnosis of NMO and NMOSD must be based on clinical findings, laboratory tests (*e.g.,* serological tests), and radiological tests (*e.g.,* magnetic resonance imaging).(
*2* ) The differential diagnosis or non-target disease group must include the applicable diseases or conditions, including but not be limited to the following: Multiple sclerosis, stroke, Lyme disease, shingles, syphilis, human immunodeficiency virus, hepatitis B, tuberculosis, Srgen's syndrome, systemic lupus erythematous, systemic vasculitis, sarcoidosis, Graves' disease, Hashimoto's disease, Type I diabetes, rheumatoid arthritis, Addison's disease, and myasthenia gravis.(
*3* ) Diagnosis of diseases or conditions for the differential or non-target disease groups must be based on established diagnostic criteria and clinical evaluation.(
*4* ) For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided.(
*5* ) The clinical validation results must demonstrate clinical sensitivity and clinical specificity for the test values based on the presence or absence of NMO and NMOSD.(
*6* ) The data must be summarized in tabular format comparing the interpretation of results to the disease status.(L) Expected/reference values generated by testing an adequate number of samples from apparently healthy normal individuals.
(iii) Identification of risk mitigation elements used by the device, including description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.
(2) The device's 21 CFR 809.10(b) compliant labeling must include warnings relevant to the device including:
(i) A warning statement that reads “The device is for use by laboratory professionals in a clinical laboratory setting”; and
(ii) A warning statement that reads “The device is not to be used as a stand-alone device but as an adjunct to other clinical information. A diagnosis of Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorders (NMOSD) should not be made on a single test result. The clinical symptoms, results from physical examination, laboratory tests (
*e.g.,* serological tests), and radiological tests (*e.g.* Magnetic Resonance Imaging), when appropriate, should always be taken into account when considering the diagnosis of NMO and NMOSD.”(3) The device's 21 CFR 809.10(b) compliant labeling must include a detailed description of the protocol and performance studies performed in accordance with paragraph (b)(1)(ii) of this section and a summary of the results.
Submission Summary (Full Text)
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#### EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay
#### DECISION SUMMARY
#### A. DEN Number:
DEN150030
#### B. Purpose for Submission:
De Novo request for evaluation of automatic class III designation of the KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay
#### C. Measurand:
Aquaporin-4 Autoantibody (AQP4Ab)
# D. Type of Test:
Manual enzyme-linked immunosorbent assay, semi-quantitative
#### E. Applicant:
KRONUS, Inc.
# F. Proprietary and Established Names:
KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay
# G. Regulatory Information:
- 1. Regulation section:
21 CFR §866.5665, Aquaporin-4 autoantibody immunological test system
- 2. Classification:
Class II (special controls)
- 3. Product code:
PNI - Aquaporin-4 Autoantibody
- 4. Panel: Immunology (82)
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#### H. Indications for use:
The KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay is for the semiquantitative determination of autoantibodies to Aquaporin-4 in human serum. The KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay may be useful as an aid in the diagnosis of Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorders (NMOSD). The KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay is not to be used alone and is to be used in conjunction with other clinical, laboratory, and radiological (e.g., MRI) findings.
Special conditions for use statement(s):
For prescription use only
Special instrument requirements:
ELISA Plate Reader suitable for 96-well format and capable of measuring at 405 nm and ELISA plate shaker capable of 500 shakes/minute.
# I. Device Description:
The KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay consists of ELISA strip wells coated with human recombinant AQP4 protein (amino acid position: 23-323) (96 wells in total) and supplied as 12 strips of 8 wells in a frame and sealed in a foil pouch with desiccant; ready-to-use 5 levels of calibrators (1.5, 5, 20, 40, and 80 U/mL), 5 x 0.7 mL; a ready-to-use positive (2 x . 7 mL) and a negative control serum (1 x 0.7 mL); AQP4-Biotin (lyophilized), 3 x 1.5 mL (reconstituted); ready-to-use reconstitution buffer for AQP4-Biotin, 1 x 10 mL; Streptavidin Peroxidase (SA-POD dilute before use) 1 x 0.8 mL; ready-to-use diluent for SA-POD, 1 x 15 mL; ready-to-use peroxidase substrate (TMB), 1 x 15 mL; concentrated wash solution (dilute 1:10 with deionized water before use), 1 x 120 mL and ready-to-use stop solution, 1 x 14 mL.
# J. Standard/Guidance Document Referenced (if applicable):
CLSI EP05-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures: Approved Guideline - Second Edition
CLSI EP6-A: Evaluation of Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline
CSLI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline- Second Edition
CLSI C28-A3c: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory: Approved Guideline- Third Edition
# K. Test Principle:
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The KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay depends on the divalent properties of the AQP4 autoantibodies (AQP4Ab) to form a bridge between AQP4 coated on ELISA plate wells and liquid phase AQP4-biotin. The level of bound AQP4Ab is then quantitated by the sequential addition of streptavidin peroxidase and a chromogenic substrate with reading of final absorbance at (4) nm. The absorbance of each well is directly proportional to the amount of autoantibody present in the patient samples. Calibrator values are plotted on semi-log graph paper and the antibody concentrations of the controls and patient samples are interpolated from the curve.
#### L. Performance Characteristics (if/when applicable):
#### 1. Analytical performance:
- a. Precision/Reproducibility:
Precision: Precision measurements were conducted according to CLSI EP05-A2. A panel consisting of ten human sera samples with levels of AQP4Ab that cover the measuring range was assayed in duplicate, twice a day, for 20 days with one reagent lot (b(4) Trade Secret ). All %CV values were within the manufacturer's pre-determined acceptance limit. The results are summarized in the table below:
| Precision | | | | | | | | |
|------------|------------|-----|-------------|------|-------------|-----|-------|------|
| Mean value | Within-Run | | Between-Run | | Between-day | | Total | |
| (U/mL) | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 2.1 | 0.2 | 8.2 | 0.2 | 10.2 | 0.2 | 7.3 | 0.3 | 14.5 |
| 2.8 | 0.2 | 6.1 | 0.2 | 8.2 | 0.2 | 6.1 | 0.3 | 11.8 |
| 3.5 | 0.2 | 6.5 | 0.2 | 4.5 | 0.2 | 6.0 | 0.4 | 9.9 |
| 4.5 | 0.3 | 5.7 | 0.5 | 10.8 | 0.4 | 8.8 | 0.7 | 15.0 |
| 4.4 | 0.2 | 4.5 | 0.4 | 9.5 | 0.4 | 8.2 | 0.6 | 13.4 |
| 7.8 | 0.4 | 5.2 | 0.8 | 10.6 | 0.6 | 8.2 | 1.1 | 14.3 |
| 9.2 | 0.5 | 5.2 | 0.9 | 9.4 | 0.7 | 7.4 | 1.2 | 13.0 |
| 32.0 | 1.1 | 3.4 | 3.5 | 10.9 | 2.5 | 7.8 | 4.4 | 13.8 |
| 70.2 | 2.9 | 4.1 | 4.6 | 6.6 | 3.3 | 4.6 | 6.7 | 9.6 |
| 72.1 | 3.6 | 4.9 | 2.0 | 2.8 | 3.9 | 5.5 | 5.3 | 6.7 |
Reproducibility: A panel of 50 serum samples with AOP4Ab concentration at various levels across the measuring range was tested in duplicate in one run at three different laboratories (two in the U.K. and one located in the U.S.) with one reagent lot to evaluate the site-to-site reproducibility. The correlation between sites was R2 > 0.99. The results are summarized in the table below:
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| Site-to-site reproducibility | | | | |
|----------------------------------|---------------|----------------------|--------------------------|------|
| Sample | Regression | Slope<br>(95% CI) | Y- Intercept<br>(95% CI) | R2 |
| Laboratory 1 vs.<br>Laboratory 2 | y= 0.96x-0.23 | 0.96<br>b(4) Trade | -0.23<br>b(4) Trade | 0.99 |
| Laboratory 1 vs.<br>Laboratory 3 | y= 1.02x-0.39 | 1.02<br>b(4) Trade | 0.39<br>b(4) Trade | 1.00 |
| Laboratory 2 vs.<br>Laboratory 3 | y= 1.02x-0.16 | 1.0188<br>b(4) Trade | -0.16<br>b(4) Trade | 0.99 |
To evaluate lot-to-lot reproducibility, a panel of 15 samples with AQP4Ab concentration at various levels across the measuring range was assayed with b(4) b(4) Trade production lots of the KRONUS Aquaporin-4 Autoantibody (AQF499) ELISA Assay. Mean and %CV for each sample were calculated and %CV values were from 3.22-14.13% for all samples. The results are summarized in the table below:
| | Lot-to-lot reproducibility | | | |
|--------|----------------------------|----------------|--------------|-------|
| Sample | Number<br>of lots | Mean<br>(U/mL) | SD<br>(U/mL) | %CV |
| 1 | b(4) Trade<br>Secret | 2.49 | 0.35 | 13.98 |
| 2 | | 3.48 | 0.36 | 10.44 |
| 3 | | 4.68 | 0.21 | 4.52 |
| 4 | | 5.60 | 0.54 | 9.70 |
| 5 | | 7.04 | 0.72 | 10.20 |
| 6 | | 13.25 | 1.52 | 11.46 |
| 7 | | 14.89 | 1.45 | 9.72 |
| 8 | | 15.49 | 0.50 | 3.22 |
| 9 | | 27.28 | 2.90 | 10.62 |
| 10 | | 32.29 | 3.65 | 11.29 |
| 11 | | 35.52 | 4.75 | 13.45 |
| 12 | | 53.89 | 5.98 | 11.09 |
| 13 | | 60.35 | 8.08 | 13.38 |
| 14 | | 60.44 | 7.22 | 11.75 |
| 15 | | 63.27 | 8.94 | 14.13 |
#### b. Linearity/assay reportable range:
Linearity: Linearity and recovery characteristics of the KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay were evaluated according to the CLSI EP6-A. b(4) Trade Secret
1.5-79.5 U/mL. Each dilution was tested in duplicate. The observed values were graphed against the calculated values and a linear regression
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| Sample<br>pool | Test Range<br>(U/mL) | Slope<br>(95% CI) | Y-Intercept<br>(95% CI) | R2 | % Recovery |
|----------------|----------------------|--------------------|-------------------------|------|---------------|
| 1 | 2.0-10.0 | 1.00<br>b(4) Trade | 0.38<br>b(4) Trade | 0.99 | 101.67-118.38 |
| 2 | 1.5-20.0 | 0.95<br>b(4) Trade | 0.05<br>b(4) Trade | 0.99 | 90.77-106.74 |
| 3 | 8.0-72.0 | 0.97<br>b(4) Trade | -1.42<br>b(4) Trade | 0.99 | 85.31-112.29 |
| 4 | 10.0-79.5 | 0.97<br>b(4) Trade | -3.13<br>b(4) Trade | 0.98 | 80.76-101.40 |
was performed. Results summarized in the table below were within the manufacturer's pre-determined acceptance criteria of recovery.
The assay is linear from 1.5-79.5 U/mL. The Package Insert Calculation Section states: "For samples that result in values greater than the 80 UlmL (greater than the highest calibrator) KRONUS recommends reporting the value as "greater than 80 U/mL".
Hook effect: Three native serum samples having AQP4Ab concentration above assay measuring range (> 80 U/mL) were serially diluted in assay negative control. No hook effect was observed up to 14000 U/mL.
- Traceability, Stability, Expected values (controls, calibrators, or methods): C.
- i) Traceability and value assignment:
There is no recognized standard or reference material for AQP4Ab. The calibrator and control values are directly traceable to a panel of Master Control samples prepared from AQP4Ab positive patient sera that are used to create the linear calibration curves for the KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay.
The calibrators and positive controls are made by b(4) Trade Secret
There are five levels with assigned values from 1.5-80.0 U/mL. Newly manufactured AQP4Ab calibrators are checked against a previous lot of calibrators (as a reference) and a panel of Master Control samples. Each calibrator and positive control level must fall within their previously established OD range.
- ii) Assay stability:
Closed assay stability- An ongoing real-time stability study performed on 2(4) n lots of the KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISS Assay supports a shelf-life claim of 4.5 months at 2-8°C.
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Open assay stability- A real-time stability study supports the stability of the ELISA strip wells after first opening of the foil pouch at four months at 2-8°C. The package insert recommends that unused wells be placed in the self-seal plastic bag provided. Opened and diluted SA-POD and Concentrated Wash Solution are stable at 2-8°C for up to 16 weeks and 11 months, respectively. The AQP4-Biotin is single-use and to be reconstituted immediately before use. Opened calibrators and controls are stable for three months at 2-8°C.
- iii) Sample stability and storage:
The package insert recommends that sera be assayed soon after separation or stored in aliquots at or below -20℃.
- d. Detection limit:
The analytical sensitivity was determined in accordance with CLSI EP17-A2. The limit of blank (LoB) was determined by testing b(4) Trade Secret
. The higher LoB calculated from the b(4) lots i:b(4) JJmL. The limit of detection (LoD) was determined by testing b(4) Trade Secret
higher LoD calculated from theb(4) lots is [4) U/mL. The limit of quantitation (LoQ) was calculated using within-laboratory precision as the acceptance goal. Using an accuracy goal of 20%CV, the higher LoQ calculated
from the b(4) ots is b(4)
- e. Analytical specificity:
- Endogenous interference: i)
Interferences were assessed by testing 5-11 samples with AOP4Ab concentration that covers the entire assay measuring range. Each sample was spiked with known quantities of the interfering substances and analyzed in triplicate, in one assay run, with one assay lot. The recovery was calculated by comparing to control samples spiked with the same volume of diluents. No interference was detected in the samples up to the test concentrations listed in the table below:
| Potential Interfering Substances | Test Concentration |
|----------------------------------|--------------------|
| Bilirubin | 20 mg/dL |
| Intralipid | 3000 mg/dL |
| Hemoglobin | 150 mg/dL |
| Rheumatoid factor | 50 IU/mL |
The Package Insert 'Specimen Collection and Handling Section' lists rheumatoid factor (at > 50 IU/mL) and hemoglobin (at > 250 mg/dL) as interfering substances and states "Do not use lipemic or hemolysed serum samples".
The
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#### ii) Cross-reactivity:
Refer to test results for 483 serum samples from patients in the Non-Target Disease Group in the table presented in the section on Clinical studies.
- f. Assay cut-off:
The assay cut-off (greater than or equal to 3.0 U/mL is positive) for the KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay was determined by testing specimens from 509 healthy blood donors in the U.S. Using the 97.50 percentile value plus 2 SD (1.4) for samples > LoD, a cut-off value of 3.0 U/mL was deemed appropriate. Utilizing the 3.0 U/mL cut-off value, 1.86% (9/483) of the samples from patients in the Non-Target Disease Group were positive for AOP4Ab. Given these results and taking into account the analytical sensitivity of the assay, values less than 3 U/mL are considered negative for AQP4Ab, and values greater than or equal to 3 U/mL are considered positive for AQP4Ab.
# 2. Comparison studies:
- a. Method comparison with predicate device:
Not applicable
- b. Matrix comparison:
Not applicable. Serum is the only recommended matrix. The Package Insert 'Specimen Collection and Handling Section' states "Do not use plasma in the assay".
# 3. Clinical studies:
- Clinical sensitivity and specificity: a.
A total of 620 serum samples were included in the clinical validation for the KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA Assay. The validation set of samples includes 85 patients diagnosed with NMO , 52 patients diagnosed with NMOSD1, and 483 samples from patients with multiple sclerosis- and other nontarget diseases listed in the table below.
<sup>1</sup>Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. 2006. Revised diagnostic criteriafor neuromyelitis optica. Neurology 66:1485-1489.
<sup>2</sup> Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS, 2005. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 58:840-846.
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| Non-Target Disease Group | | | |
|------------------------------------|-----|-----------|-----------|
| | n | #Positive | %Positive |
| Multiple sclerosis (MS) | 75 | 1 | 1.33 |
| Relapsing-Remitting (RRMS) | 53 | 1 | 1.9 |
| Secondary- Progressive (SPMS) | 7 | 0 | 0 |
| Primary-Progressive (PPMS) | 5 | 0 | 0 |
| Progressive-Relapsing (PRMS) | 10 | 0 | 0 |
| Stroke | 21 | 0 | 0 |
| Infectious diseases | 119 | 5 | 4.20 |
| Lyme disease | 30 | 1 | 3.33 |
| Shingles | 10 | 0 | 0 |
| Syphilis | 30 | 4 | 13.33 |
| Human Immunodeficiency Virus (HIV) | 10 | 0 | 0 |
| Hepatitis B | 31 | 0 | 0 |
| Tuberculosis | 8 | 0 | 0 |
| Autoimmune diseases | 268 | 3 | 1.12 |
| Sjogren's Syndrome | 30 | 2 | 6.67 |
| Systemic Lupus Erythematosus (SLE) | 30 | 0 | 0 |
| Systemic Vasculitis | 4 | 0 | 0 |
| Sarcoidosis | 6 | 0 | 0 |
| Graves' disease | 110 | 0 | 0 |
| Type 1 Diabetes | 33 | 0 | 0 |
| Rheumatoid Arthritis | 17 | 1 | 5.9 |
| Hashimoto's Disease | 16 | 0 | 0 |
| Addison's Disease | 12 | 0 | 0 |
| Myasthenia Gravis | 10 | 0 | 0 |
| Combined total non-target diseases | 483 | 9 | 1.86 |
Using a cut-off of 3 U/mL, 69 (81%) of the 85 NMO patient samples and 25 (48%) of the 52 NMOSD tested positive. When combined, 94 (68.6%) of the 137 NMO/NMOSD samples tested positive.
One of 75 MS samples (1.3%) was positive for AQP4Ab. None of the 21 samples from patients with stroke were positive for AQP4Ab. Eight of 387 samples (2.1%) from patients with either infectious or autoimmune diseases tested positive for AQP4 Ab. Four of the 30 samples (13.33%) from patients with syphilis were positive. The package insert states that "a current or past syphilis diagnosis may increase risk of obtaining a false positive result."
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| KRONUS Aquaporin-4<br>Autoantibody (AQP4Ab)<br>ELISA Assay | Diagnosis | | |
|------------------------------------------------------------|-----------------|-----------------------------------|-------|
| | Positive<br>NMO | Negative<br>(Non-Target Diseases) | Total |
| Positive | 69 | 9 | 78 |
| Negative | 16 | 474 | 490 |
| Total | 85 | 483 | 568 |
Clinical sensitivity, specificity and overall agreement in this sample cohort are summarized in the following tables:
| | Diagnosis | | | | | | |
|---------------------------------------------------------|-----------|-----------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--|--|--|--|
| KRONUS Aquaporin-4 | Positive | Negative | | | | | |
| Autoantibody (AQP4Ab) | NMOSD | (Non-Target Diseases) | Total | | | | |
| ELISA Assay | | | | | | | |
| Positive | 25 | 9 | 34 | | | | |
| Negative | 27 | 474 | 501 | | | | |
| Total | 52 | 483 | રેડિયા રહેરાં રહ્યું હતું. સંદર્ભ દિવેલી દિવેલી દિવસ દિવસ દિવસ દિવસ દિવસ દિવસ દિવસ દિવસ દિવસ દિવસ દિવસ દિવસ દિવસ દિવસ દિવેલી દિવસ દિવેલી દિવસ દિવસ દિવસ | | | | |
| Sensitivity: 48.1% (25/52) 95% CI: 35.1%-61.3% | | | | | | | |
| Specificity: 98.1% (474/483) 95% CI: 96.5%-99.0% | | | | | | | |
| Overall agreement: 93.2% (499/535) 95% CI: 90.8%-95.1% | | | | | | | |
| | Diagnosis | | |
|------------------------------------------------------------|-----------------------------|-----------------------------------|-------|
| KRONUS Aquaporin-4<br>Autoantibody (AQP4Ab)<br>ELISA Assay | Positive<br>NMO or<br>NMOSD | Negative<br>(Non-Target Diseases) | Total |
| Positive | 94 | 9 | 103 |
| Negative | 43 | 474 | 517 |
| Total | 137 | 483 | 620 |
| Sensitivity: 68.6% (94/137) 95% CI: 66.4%-75.8% | | | |
| Specificity: 98.1% (474/483) 95% CI: 96.5%-99.0% | | | |
| Overall agreement: 91.6% (568/620) 95% CI: 89.2%-93.6% | | | |
- b. Other clinical supportive data (when a. is not applicable):
Not applicable.
{9}------------------------------------------------
#### 4. Clinical cut-off:
Refer to assay cut-off.
- 5. Expected values/Reference range:
The expected value from 509 healthy individual blood donors was determined in accordance with CSLI C28-A3c. The AQP4Ab values in normal healthy sera (NHS) ranged from <1.04 - 4.20 U/mL. Two NHS samples (0.4%) were positive for AQP4Ab. The 97.5th percentile value for all samples was 1.55 U/mL. Similar values were obtained when evaluations were based on gender, age and sex. It is the responsibility of each laboratory to establish its own reference ranges for the population of patients it serves, as expected values are affected by many different factors.
| Frequency of NHS AQP4Ab Values by Gender | | | | | | | | |
|------------------------------------------|----------------|--------------------|--------------------|--------------------|--------------------|--------------------|-------------------|----------------|
| Gender | <<br>1.04 U/mL | 1.04–<br>1.49 U/mL | 1.50–<br>1.99 U/mL | 2.00–<br>2.49 U/mL | 2.50–<br>2.99 U/mL | 3.00–<br>3.49 U/mL | 3.5–<br>3.99 U/mL | ><br>3.99 U/mL |
| Male | 0.96 | 0.02 | 0.01 | 0 | 0 | 0 | 0 | 0.01 |
| Female | 0.91 | 0.02 | 0.06 | 0.01 | 0 | 0 | 0 | 0 |
| Frequency of NHS AQP4Ab Values by Age | | | | | | | | |
|---------------------------------------|----------------|--------------------|--------------------|--------------------|--------------------|--------------------|-------------------|----------------|
| Age | <<br>1.04 U/mL | 1.04–<br>1.49 U/mL | 1.50–<br>1.99 U/mL | 2.00–<br>2.49 U/mL | 2.50–<br>2.99 U/mL | 3.00–<br>3.49 U/mL | 3.5–<br>3.99 U/mL | ><br>3.99 U/mL |
| < 20 | 0.93 | 0.04 | 0.04 | 0 | 0 | 0 | 0 | 0 |
| 20-39 | 0.95 | 0.02 | 0.02 | 0.01 | 0 | 0 | 0 | 0.01 |
| 40-59 | 0.95 | 0.05 | 0.03 | 0 | 0.01 | 0 | 0 | 0 |
| > 59 | 0.95 | 0.03 | 0.03 | 0 | 0 | 0 | 0 | 0 |
| Frequency of NHS AQP4Ab Values by Race | | | | | | | | |
|----------------------------------------|-------------------|-----------------------|-----------------------|-----------------------|-----------------------|-----------------------|----------------------|-------------------|
| Race | <<br>1.04<br>U/mL | 1.04-<br>1.49<br>U/mL | 1.50-<br>1.99<br>U/mL | 2.00-<br>2.49<br>U/mL | 2.50-<br>2.99<br>U/mL | 3.00-<br>3.49<br>U/mL | 3.5-<br>3.99<br>U/mL | ><br>3.99<br>U/mL |
| Black | 0.98 | 0.01 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| Hispanic | 0.91 | 0.04 | 0.02 | 0.00 | 0.02 | 0.00 | 0.00 | 0.02 |
| Caucasian | 0.91 | 0.04 | 0.04 | 0.01 | 0.00 | 0.00 | 0.00 | 0.01 |
| Unknown | 0.88 | 0.13 | 0 | 0 | 0 | 0 | 0 | 0 |
# M. Proposed Labeling:
The labeling is sufficient and it satisfies the requirements of 21 CFR Parts 801 and 809 and the special controls for this device type.
{10}------------------------------------------------
# N. Identified Risks and Required Mitigations:
| Identified Risks to Health | Required Mitigations |
|-----------------------------------------------------------------------------------------------------------------------------|------------------------------------------|
| Inaccurate test results that provide false<br>positive or false negative results can lead to<br>improper patient management | Special controls (1), (2), and (3) |
| Failure to correctly interpret test results can<br>lead to false positive or false negative results | Special controls (1) (iii), (2), and (3) |
# O. Benefit/Risk Analysis:
| Summary | |
|------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Summary of<br>the Benefit(s) | This is the first serological test to the aid in the diagnosis of NMO/NMSD to<br>be commercially available in the U.S., providing a clinically important unmet<br>medical need. |
| Summary of<br>the Benefit(s) | This is of benefit to patients by providing the possibility of earlier diagnosis<br>of NMO/NMOSD and earlier initiation of appropriate therapy. |
| Summary of<br>the Benefit(s) | The presence of the antibody is useful in helping to distinguish<br>NMO/NMOSD from MS, which is important because the drug treatment for<br>NMO/NMOSD and MS differ. |
{11}------------------------------------------------
| Summary | |
|----------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Summary of<br>the Risk(s) | The primary risks to patients are related to the consequences of clinical<br>decisions based on false negative and false positive results for a patient due to<br>inaccurate test results or failure to correctly interpret test results. For a false<br>positive result, the risks could include unnecessary testing or inappropriate<br>treatment related to an inaccurate result. For a false negative result, the risk<br>could include a missed or delayed diagnosis. The results from this test would<br>be used with results from other clinical, laboratory, and radiological (e.g.,<br>MRI) findings, which would mitigate these risks.<br>The risk to patients of false negative and false positive results are also<br>mitigated by statements in the indications for use statement which states that<br>the assay is not to be used alone and is to be used in conjunction with other<br>clinical, laboratory, and radiological (e.g. MRI) findings. The risks are further<br>mitigated by the special controls established for this device.<br>The test requires that a blood sample be obtained during routine phlebotomy. |
| | This is standard procedure in clinical care, and the risk to patients is minimal.<br>The risk to laboratory workers is no greater than that for the routine collection<br>and handling of blood specimens, given that the test is for use by laboratory<br>professionals in a clinical laboratory setting. |
| Summary of<br>Other Factors | None |
| Conclusions<br>Do the<br>probable<br>benefits<br>outweigh the<br>probable risks? | Given the well characterized performance characteristics, statements in the<br>indications for use statement, the combination of required general controls<br>and the special controls established for this device, the performance data,<br>warnings, and precautions and limitations required in the labeling, the<br>probable benefits outweigh the probable risks for this device. |
# P. Conclusion:
The information provided in this de novo submission is sufficient to classify this device into class II under regulation 21 CFR 866.5665. FDA believes that the stated special controls and applicable general controls, including design controls, provide reasonable assurance of the safety and effectiveness of the device type. The device is classified under the following:
| Product Code: | PNI |
|---------------|----------------------------------------------------|
| Device Type: | Aquaporin-4 autoantibody immunological test system |
| Class: | II (special controls) |
| Regulation: | 21 CFR 866.5665 |
{12}------------------------------------------------
- (a) Identification. An Aquaporin-4 autoantibody immunological test system is a device that consists of reagents used to measure by immunochemical techniques autoantibodies in human serum samples that react with Aquaporin-4 (AOP4Ab). The measurements aid in the diagnosis of Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorders (NMOSD) in conjunction with other clinical, laboratory, and radiological (e.g., MRI) findings.
- (b) Classification. Class II (special controls). An Aquaporin-4 autoantibody immunological test system must comply with the following special controls:
- 1) Premarket notification submissions must include the following information:
- i) A detailed device description including:
- A) A detailed description of all components including all required ancillary reagents in the test.
- B) If applicable, a detailed description of instrumentation and equipment, including illustrations or photographs of non-standard equipment or manuals.
- C) If applicable, detailed documentation of the device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software.
- D) A detailed description of appropriate internal and external quality controls that are recommended or provided. The description must identify those control elements that are incorporated into the specified testing procedures.
- E) Detailed specifications for sample collection, processing, and storage.
- F) A detailed description of methodology and assay procedure.
- G) A description of how the assay cut-off (the medical decision point between positive and negative) was established and validated as well as supporting data.
- H) Detailed specification of the criteria for test results interpretation and reporting.
- ii) Detailed information demonstrating the performance characteristics of the device, including:
- A) Device precision/reproducibility data generated from within-run, between-run, between-day, between-lot, between-site, and total precision for multiple nonconsecutive days, as applicable. A well characterized panel of patient samples or pools from the indicated population that covers the device measuring range must be used.
- B) Device linearity data generated from samples covering the device measuring range, if applicable.
- C) Information on traceability to a reference material and description of value assignment of calibrators and controls, if applicable.
- D) Device analytical sensitivity data, including limit of blank, limit of detection, and limit of quantitation, if applicable.
{13}------------------------------------------------
- E) Device analytical specificity data, including interference by endogenous and exogenous substances, as well as cross-reactivity with samples derived from patients with other autoimmune diseases or conditions.
- F) Device instrument carryover data, when applicable.
- G) Device stability data, including real-time stability under various storage times and temperatures.
- H) Specimen stability data, including stability under various storage times, temperatures, freeze-thaw, and transport conditions, where appropriate.
- Method comparison data generated by comparison of the results obtained I) with the device to those obtained with a legally marketed predicate device with similar indications of use. A well-characterized panel of patient samples from the indicated population covering the device measuring range must be used.
- J) Specimen matrix comparison data, if more than one specimen type or anticoagulant can be tested with the device. Samples used for comparison must be from well-characterized patient samples covering the device measuring range.
- K) Clinical performance must be established by comparing data generated by testing samples from the indicated population and the differential diagnosis or non-target disease groups with the device to the clinical diagnostic standard.
- (1) The diagnosis of NMO and NMOSD must be based on clinical findings, laboratory tests (e.g., serological tests), and radiological tests (e.g., Magnetic Resonance Imaging).
- (2) The differential diagnosis or non-target disease group must include the applicable diseases or conditions, including but not be limited to the following: multiple sclerosis, stroke, lyme disease, shingles, syphilis, human immunodeficiency virus, hepatitis B, tuberculosis, Sjörgen's Syndrome, systemic lupus erythematous, systemic vasculitis, sarcoidosis, Graves' disease, Hashimoto's disease. Type I diabetes, rheumatoid arthritis, Addison's disease, and Myasthenia Gravis.
- (3) Diagnosis of diseases or conditions for the differential or nontarget disease groups must be based on established diagnostic criteria and clinical evaluation.
- (4) For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided.
- (5) The clinical validation results must demonstrate clinical sensitivity and clinical specificity for the test values based on the presence or absence of NMO and NMOSD.
- (6) The data must be summarized in tabular format comparing the interpretation of results to the disease status.
- L) Expected/ reference values generated by testing an adequate number of samples from apparently healthy normal individuals.
- iii) Identification of risk mitigation elements used by the device, including
{14}------------------------------------------------
description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.
- 2) The device's 21 CFR 809.10(b) compliant labeling must include warnings relevant to the device including:
- i) A warning statement that reads "The device is for use by laboratory professionals in a clinical laboratory setting."
- ii) A warning statement that reads "The device is not to be used as a standalone device but as an adjunct to other clinical information. A diagnosis of Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorders (NMOSD) should not be made on a single test result. The clinical symptoms, results from physical examination, laboratory tests (e.g., serological tests), and radiological tests (e.g. Magnetic Resonance Imaging), when appropriate, should always be taken into account when considering the diagnosis of NMO and NMOSD."
- 3) The device's 21 CFR 809.10(b) compliant labeling must include a detailed description of the protocol and performance studies performed in accordance with special control (1)(ii) and a summary of the results.
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Learn the FDA Browser
Two short videos show you everything — or skip straight to the written tutorial if you'd rather read. You can reopen this any time from the Tutorial button in the top bar.
Part 1 — Search, results, and everyday workflows 16 min
Part 2 — Embeddings: the galaxy map 3 min
1. Search: exact and fuzzy
Type a phrase like "coronary artery calcification" into the search box. You get two kinds of results. Exact results match the literal phrase — prefix searches work ("coronary artery calcificati") but suffix searches do not. Fuzzy results match on the meaning and intent of your phrase rather than the exact words, and are sorted by relevance score. Hover over the Exact or Fuzzy badge on any row to see exactly why it matched.
Use the checkboxes above the results to narrow: SaMD keeps only software-only devices, AI / ML keeps only devices with AI.
Exact vs. fuzzy search: what's the difference?
Exact matches on the literal phrase (prefix search works, suffix does not). Fuzzy matches on the meaning and intent of the phrase rather than the exact words. Hover over the badge on any row to see why it matched.
You search "coronary artery calcification" and want only software devices with AI. What two filters do you apply?
Narrow by SaMD (software-only devices), then narrow by AI/ML (devices with AI).
2. The results table
Scroll right in the results table. The intended use is extracted for you — no need to open the PDF. The device story gives a high-level snapshot of what the device does and how it's used. The AI Performance sub-table shows each output name, acceptance criteria, observed values, and development/test dataset descriptions — the same format Innolitics uses for regulatory strategy outputs, and the fastest high-level fingerprint of an AI device. It is AI-generated but has been very reliable in practice.
Where do you find a device's intended use without opening the PDF?
Scroll right in the search results table. The intended use column is extracted for you; no need to dig into the 510(k) summary PDF.
What does the AI Performance sub-table show, and why is it useful?
Output name, acceptance criteria, observed values, development dataset description, and test dataset description. It's the same format we use for regulatory strategy output and Fast 510(k) input, and the fastest high-level fingerprint of an AI device. AI-generated but reliable in practice.
3. Judging fuzzy relevance
Fuzzy results trail off in relevance as you scroll. Use three signals to decide how far down to go: the fuzzy badge explanations, the intended use column, and whether your target output (e.g., Cobb angle) still appears in the AI Performance sub-table. Once it stops appearing, you're past the relevant zone. A top hit with a low score (~0.4) and a stretched explanation is a hint the closest predicates are far away — the project may be headed for De Novo. Note the fuzzy search is a pattern match: it doesn't handle negation ("not") well, and hardware devices can appear — filter by SaMD/AI ML to cut them.
How do you judge how far down fuzzy search results to go?
Use the relevancy signals: the fuzzy badge explanations, the intended use column, and whether the target output (e.g., Cobb angle) still appears in the AI Performance sub-table. Once it stops appearing, results are trailing off in relevancy.
4. Device detail page: chat and citations
Click a device name to open its detail page: device facts on the left, a chat window on the right. Ask something like "Describe the training data". The answer carries little citation bubbles — click one to jump to the highlighted passage in the source PDF, so you can verify every AI answer against the document. There's also a Download PDF button for sharing.
How do you verify an AI chat answer on the device detail page?
Click the citation bubbles to jump to the relevant highlight in the source document.
Reading rule for every project: how many summaries do you read in full?
At least the three most relevant 510(k) or De Novo summaries, in full. After that, use targeted chat questions to confirm your memory quickly. The tool supports this professional habit — it doesn't replace it.
5. Side-by-side comparison
Select multiple rows in the results table (aim for under ~10), then open the PDF Viewer tab. Ask one question — it goes to all selected devices in parallel, each with citations. This is the fastest way to compare and contrast devices: training data, PCCP scope, how they handled adding new scanners, and so on.
What does the side-by-side PDF viewer mode do?
Select multiple devices, open the PDF viewer tab, and ask one question (e.g., "Describe the training data"). It queries all selected devices simultaneously with citations, so you can compare and contrast quickly.
6. Collections
With rows selected, go to the Collections tab and create a labeled collection (e.g., "Cobb Angle Project"). Reload that selection any time — before a client call, pull up the collection and ask questions across all of its devices at once.
How do you save a set of selected devices for later use?
Select the rows, go to the Collections tab, and create a labeled collection (e.g., "Cobb Angle Project"). You can reload the selection anytime and carry it into the PDF viewer and other tabs that support selections.
7. Product codes and the regulations tree
Click a product code in the results to jump to it in the regulations tree — identification text, sibling product codes, and devices you can open in a PDF viewer on the right. Click a regulation number to see its identification, special controls, and related product codes. You can also search by product code or regulation number at the top of the tree. Always read the special controls if any exist for your device — it broadens your search and sharpens pre-kickoff research.
What can you do from the regulations tree view?
Browse product codes and regulation numbers, read the identification text and special controls, browse sibling product codes, open device PDFs on the right, and search by product code or regulation number at the top of the tree.
8. Chart view
Click Show Chart and segment by regulation number (or product code) to see which regulations dominate your result set. Clicking a regulation takes you into the regulations tree. Great for spotting that most matches are, say, hardware laparoscopic devices — a cue to go back and filter.
How do you see which regulations dominate a search result set?
Click "Show Chart" and segment by Regulation Number. Clicking a regulation takes you to the regulations tree.
9. The predicate graph
Open the Predicates tab for a family-tree view of predicate relationships. Click a node to trace its parents and children; selections from search carry over pre-selected. Commonly predicated devices are worth reading — a lot of people predicated them for a reason. The visual lineage is also handy on client calls, e.g. to show how a predicate family evolved and justify why your predicate still holds.
In the predicate graph, why are commonly predicated devices worth reading?
A lot of people predicated them for a reason. Clicking a node traces parents and children, and selections from search carry over pre-selected.
10. Embeddings: the galaxy map
The Embeddings tab plots every matching document in a 2-D "galaxy map" where semantically similar devices cluster together. Hover or click clusters to explore, and let AI label the clusters for you. Embeddings beat product codes for grouping: two devices can carry different product codes (LLZ vs. QIH) yet do the same thing — the embedding captures the meaning of the intended use and device story. This is also exactly how retrieval-augmented generation (RAG) works under the hood, and it makes a great visual on client calls.
Try it yourself
Head to the search page and work through a few of these AI/ML fuzzy searches to build intuition: perivascular fat on CT · aortic valve calcification opportunistic screening on noncontrast CT · breast cancer prediction on digital pathology slides · autism detection · gestational age prediction · a hearing aid that can also detect a pulse · foundation model based analysis of ECG · large language models · penetration test. Watch how the relevance scores, intended use, and AI Performance tables tell you when results stop being meaningful.
