(49 days)
The Diamedix Is anti-Cardiolipin Screen Test Kit is an indirect enzyme immunoassay (EIA) for the semi-quantitative measurement of IgG, IgM and IgA antibodies to cardiolipin in human serum as an aid in the assessment of the risk of thrombosis in patient with SLE or SLE-like disorders. These reagents can be used either manually or in conjunction with the MAGO® Plus Automated EIA Processor
The Is anti-Cardiolipin Screen Test System is an enzyme-linked immunosorbent assay (ELISA) for the semi-quantitative measurement of IgG, IgM and IgA antibodies to cardiolipin in human serum
Here's a breakdown of the acceptance criteria and the study details for the Is anti-Cardiolipin Screen Test System, based on the provided text:
1. Table of Acceptance Criteria (Implied) and Reported Device Performance
The acceptance criteria are not explicitly stated as numerical targets. Instead, the submission demonstrates the device's performance through comparison to a similar device and its clinical utility in specific patient populations. The "acceptance criteria" can be inferred as achieving satisfactory levels of agreement and correlation with established methods, along with demonstrating clinical sensitivity and specificity.
| Acceptance Criterion (Implied) | Reported Device Performance |
|---|---|
| Relative Sensitivity (vs. comparable ELISA) | 82.2% (95% CI: 74.7-89.6%) |
| Relative Specificity (vs. comparable ELISA) | 100.0% (95% CI: 96.3-100.0%) |
| Overall Agreement (vs. comparable ELISA) | 91.0% (95% CI: 86.2-94.6%) |
| Clinical Specificity (Normals) | 95.3% (205/215) |
| Clinical Specificity (RPR Positive) | 66.7% (10/15) |
| Clinical Sensitivity (APS Patients) | 94.7% (54/57) |
| Clinical Sensitivity (SLE Patients) | 29.4% (10/34) |
| Clinical Sensitivity (Other Autoimmune Diseases) | 25.0% (6/24) |
| Correlation of Manual vs. Automated (MAGO Plus) | Correlation Coefficient (r) = 0.9497 (with scattergrams and regression lines showing good correlation) |
| Precision (Intra-assay and Interassay) | Reported CV% values for various serum samples and methods (manual and MAGO Plus). For example, manual interassay CV% ranged from 6.13% to 15.83%. MAGO Plus interassay CV% ranged from 16.70% to 34.51%. (No explicit acceptance criteria for CV% are given, but the data is provided to demonstrate acceptable precision for a diagnostic kit.) |
| Expected Values in Normal Population | 5.4% prevalence in a normal S. Florida blood donor population (148 tested). |
| Expected Values in Clinical Population (APS) | 94.7% positive in a clinical population with diagnosed APS (57 tested). |
2. Sample Size Used for the Test Set and Data Provenance
- Relative Sensitivity and Specificity Study:
- Sample Size: 203 frozen, retrospective sera.
- Data Provenance: Not explicitly stated, but implied to be from a general population from which frozen sera were collected.
- Clinical Sensitivity and Specificity Study:
- Sample Size: 345 frozen, retrospective, clinically characterized sera.
- Data Provenance: Not explicitly stated, but includes "Normals," "patients with diagnosed anti-phospholipid syndrome (APS)," "patients with systemic lupus erythematosus (SLE)," "patients with other autoimmune diseases," and "patients with positive RPR titers." These are clinical samples.
- Correlation of Manual and MAGO Plus results:
- Sample Size: 152 serum samples.
- Data Provenance: Not explicitly stated, but implies routine clinical samples tested by both methods.
- Precision Study:
- Sample Size: Six serum samples (two negative, four positive), tested in three separate runs, generally in triplicate per run for intra-assay, leading to 9 replicates for interassay (n=9).
- Data Provenance: Not explicitly stated.
- Expected Values Study (Normal Population):
- Sample Size: 148 S. Florida blood donors.
- Data Provenance: Prospective collection from "S. Florida blood donors."
- Expected Values Study (Clinical Population):
- Sample Size: 57 sera from patients with a diagnosis of anti-phospholipid syndrome (APS).
- Data Provenance: Retrospective, clinically characterized sera.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts
There is no mention of experts being used to establish a ground truth for the test sets in the traditional sense of consensus reading or clinical adjudication.
- For the "Relative Sensitivity and Specificity" study, the ground truth was established by comparison to a "commercially available ELISA kit" and further resolved by a "referee EIA method."
- For the "Clinical Sensitivity and Specificity" study, the ground truth was based on "clinically characterized sera" and "diagnosed" patient populations (APS, SLE, etc.). This implies medical diagnosis as the ground truth.
4. Adjudication Method for the Test Set
There is no mention of an adjudication method like 2+1 or 3+1. The studies rely on comparison to existing commercial assays or established clinical diagnoses. In the "Relative Sensitivity and Specificity" study, there was "further resolution of the discordant samples" using a referee EIA method, which acts as a form of adjudication but not involving human readers/experts.
5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
There was no MRMC comparative effectiveness study and no AI component mentioned in the provided text. This device is an immunoassay kit, not an AI-powered diagnostic system involving human readers.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was done
This refers to an immunoassay kit. The "standalone" performance is assessed by its analytical characteristics (sensitivity, specificity, precision, correlation to other methods) and clinical performance without human interpretation being the primary variable. The device itself generates a semi-quantitative result. The "MAGO Plus Automated EIA Processor" represents an automated, "algorithm-only" (i.e., machine-only) method for running the assay, and its correlation with manual performance was specifically studied.
7. The Type of Ground Truth Used
- Relative Sensitivity and Specificity Study: Comparison to a commercially available ELISA kit and a "referee EIA method." This is a form of reference standard comparison (another validated test).
- Clinical Sensitivity and Specificity Study: Clinical diagnosis of specific conditions (e.g., diagnosed Anti-phospholipid Syndrome (APS), Systemic Lupus Erythematosus (SLE), normal status). This is a form of outcomes data/clinical characterization.
- Expected Values Study:
- Normal population: Healthy blood donor status (absence of disease).
- Clinical population: Clinical diagnosis of Anti-phospholipid Syndrome (APS).
8. The Sample Size for the Training Set
There is no mention of a separate "training set" in the context of machine learning or AI. This is a traditional immunoassay kit. Method development and optimization would have involved internal lab work, but not a distinct "training set" as understood in AI/ML. All samples mentioned in the summaries above would typically be considered "test sets" or "validation sets" for the final device performance.
9. How the Ground Truth for the Training Set was Established
As there is no mention of a training set in the AI/ML context, this question is not applicable. The development of the assay itself would have involved establishing the optimal conditions and reagents, but not "ground truth" for a training set in the AI sense.
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AUG 2 0 2001
510(k) Summary of Safety and Effectiveness
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is:
Applicant Information:
| Date Prepared: | June 29, 2001 |
|---|---|
| Name: | Diamedix Corporation |
| Address: | 2140 N. Miami Avenue |
| Miami, FL 33127 |
| Contact Person: | Dr. Lynne Stirling |
|---|---|
| Phone Number: | 305-324-2354 |
| Fax Number: | 305-324-2388 |
Device Information:
| Trade Name: | Is anti-Cardiolipin Screen Test System |
|---|---|
| Common Name: | Anti-Cardiolipin ELISA test |
| Classification Name: | Anticardiolipin immunological test system |
Equivalent Device:
Orgentec Anti-cardiolipin Screen ELISA Assay
Device Description: The Is anti-Cardiolipin Screen Test System is an enzyme-linked immunosorbent assay (ELISA) for the semi-quantitative measurement of IgG, IgM and IgA antibodies to cardiolipin in human serum
Intended Use: The assay is intended for the semi-quantitative measurement of IgG. IgM and IgA antibodies to cardiolipin in human serum. The results of the assay can be used as an aid in the assessment of the risk of thrombosis in patients with SLE or SLE-like dosorders.
Principle of the Procedure:
The Is-anti-Cardiolipin Screen Test System is an indirect solid-phase enzyme immunoassay. Highly purified cardiolipin is coated onto plastic microwells and saturated with highly purified human B2-Glycoprotein I. Controls and diluted patient samples are added to the wells. Any patient IgG, IgM or IgA antibodies in the sample bind to the well. Anti-human horseradish peroxidase conjugate is then added After incubation and washing, a substrate solution is then added to each well. In the presence of bound enzyme, the substrate is converted to a blue colored product. After acid additon to stop the reaction, a yellow end product is formed that is read spectrophotometrically at 450 nm (reference 600-630 mm) and is directly proportional to the concentration of cardiolipin IgG, IgM and IgA antibodies in the sample.
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SUMMARY OF SAFETY AND EFFECTIVENESS
Performance Characteristics
A. Relative Sensitivity and Specificity
Two hundred and three frozen, retrospective sera were tested for IgG/IgM/IgA cardiolipin antibodies using the I wo hand careen Test Kit and a commercially available ELISA kit for detecting cardiolipin IgG/IgM/IgA antibodies. Based on the results of this resing the relative sensitivity, relative specificity and overall agreement were calculated. The results obtained are shown below. Further resolution of the discordant samplesshowed that were samples that were negative in the Is anti-Cardiolipin Screen and positive by the other EIA were negative by a referee EIA method. The remaining ten discordant samples were positive in the referee test.
Is-anti-Cardiolipin Screen
| Positive | Negative | *Equivocal | ||
|---|---|---|---|---|
| OtherEIA | Positive | 83 | 18 | 3 |
| Negative | 0 | 99 | 0 | |
| *Equivocal | 0 | 0 | 0 | |
| **95% CI | ||||
| Relative Sensitivity | 83/101 | = 82.2 % | 74.7-89.6% | |
| Relative Specificity | 99/99 | = 100.0% | 96.3-100.0% | |
| Overall Agreement | 182/200 | = 91.0% | 86.2-94.6% | |
| * Equivocal results were excluded from calculations. | ||||
| ** 95% Confidence Intervals (CI) calculated by the Exact Method. |
NOTE : Please be advised that 'refers to the comparison of the assay's results to that of a similar assay. There was not an attempt to correlate the assay's results with disease presence or absence. No judgement can be made on the comparison's accuracy to predict disease.
B. Clinical Sensitivity and Specificity
Diseases
A total of three hundred and forty-five frozen retrospective, clinically characterized sera were assayed using the Is anti-Cardiolipin Screen Test Kit in order to assess both the clinical sensitivity and clinical specificity of the test system. These samples consisted of 215 normal sera, 57 sera from patients with diagnosed anti-phospholipid syndrome (APS), 34 sera from patients with systemic lupus erythematosus (SLE), 24 sera from patients with other autoimmune diseases such as Sjogren's Syndrome, scleroderma, polymyositis and rheumatoid arthritis and 15 samples from patients with positive RPR titers. Results are summarized below. Note that the all positive samples were also positive when tested by another commercially available ELISA test.
| Patient Group | Total | Positive | Negative | Equivocal |
|---|---|---|---|---|
| Normals | 215 | 9 | 205 | 1 |
| APS | 57 | 54 | 3 | 0 |
| SLE | 34 | 10 | 19 | 5 |
| Other AutoimmuneDiseases | 24 | 6 | 18 | 0 |
| RPR Positive | 15 | 5 | 10 | 0 |
| Clinical Specificity: | # Neg/Total # | |||
| Normals | 205/215 | $=$ 95.3% | ||
| RPR Positive | 10/15 | $=$ 66.7% | ||
| Clinical Sensitivity : | # Pos/Total # | |||
| APS | 54/57 | $=$ 94.7% | ||
| SLE | 10/34 | $=$ 29.4% | ||
| Other Autoimmune | 6/24 | $=$ 25.0% |
000170
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C. Correlation of Manual and MAGO Plus results
The Is anti-Cardiolipin Screen Test Kit has been developed for automated as well as manual use. To demonstrate the equivalence of the manual and MAGO Plus procedures, the results of 152 serum samples tested for anti-Cardiolipin IgG/IgM/IgA antibodies by both the manual and automated methods, and whose values were within the reportable range of the assay, were plotted. Scattergrams and regression lines of the results obtained with 95% confidence intervals are shown in FIGURE 1. The data indicate good correlation with a Correlation Coefficient (r) of 0.9497.
Image /page/2/Figure/2 description: The image is a scatter plot titled "FIGURE 3: Is anti-Cardiolipin Screen Manual vs MAGO Plus Correlation". The x-axis is labeled "MANUAL U/ML" and ranges from 0 to 100. The y-axis is labeled "MAGO Plus U/ML" and ranges from 0 to 120. The plot shows a positive correlation between the two variables, with data points scattered around a regression line.
D. Precision
To assess the precision of the Is anti-Cardiolipin Screen Test Kit six serum samples of varying reactivity (two negative and four positive) were tested in three separate runs. Precision was assessed both manually and using the MAGO Plus Automated EIA Processor. The results obtained are shown in below.
| SERUM | INTRA-ASSAY DAY 1 | INTRA-ASSAY DAY 2 | INTRA-ASSAY DAY 3 | INTERASSAY (n=9) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MEAN U/ml | SD | CV% | MEAN U/ml | SD | CV% | MEAN U/ml | SD | CV% | MEAN U/ml | SD | CV% | |
| A | 3.3 | 0.265 | 8.02 | 3.3 | 0.173 | 5.25 | 3.7 | 0.115 | 3.09 | 3.4 | 0.274 | 7.97 |
| B | 2.8 | 0.404 | 14.61 | 3.3 | 0.058 | 1.77 | 3.8 | 0.252 | 6.57 | 3.3 | 0.521 | 15.83 |
| C | 21.4 | 0.945 | 4.41 | 21.9 | 0.950 | 4.33 | 24.6 | 1.443 | 5.86 | 22.7 | 1.787 | 7.88 |
| D | 33.4 | 3.317 | 9.94 | 36.0 | 0.700 | 1.94 | 34.7 | 1.411 | 4.07 | 34.7 | 2.161 | 6.23 |
| E | 52.9 | 2.957 | 5.59 | 58.8 | 6.851 | 11.65 | 72.5 | 2.207 | 3.04 | 61.4 | 9.527 | 15.51 |
| F | 40.1 | 1.528 | 3.81 | 44.8 | 0.954 | 5.83 | 45.0 | 1.473 | 3.27 | 43.3 | 2.654 | 6.13 |
Manual Intra-Assay and Interassay Precision for Is-anti-Cardiolipin Screen
MAGO Plus Intra-Assay and Interassay Precision for Is-anti-Cardiolipin Screen
| SERUM | INTRA-ASSAY DAY 1 | INTRA-ASSAY DAY 2 | INTRA-ASSAY DAY 3 | INTERASSAY (n=9) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MEANU/ml | SD | CV% | MEANU/ml | SD | CV% | MEANU/ml | SD | CV% | MEANU/ml | SD | CV% | |
| A | 4.6 | 0.058 | 1.25 | 6.8 | 0.503 | 7.44 | 9.8 | 1.762 | 17.91 | 7.1 | 2.442 | 34.51 |
| B | 4.2 | 0.289 | 6.82 | 6.5 | 0.300 | 4.62 | 8.7 | 0.306 | 3.50 | 6.5 | 1.966 | 30.29 |
| C | 27.0 | 1.115 | 4.13 | 36.6 | 2.600 | 7.10 | 36.2 | 5.101 | 14.08 | 33.3 | 5.555 | 16.70 |
| D | 42.5 | 1.686 | 3.97 | 63.4 | 3.509 | 5.53 | 53.2 | 6.934 | 13.03 | 53.0 | 9.899 | 18.67 |
| E | 79.3 | 7.927 | 10.00 | 92.2 | 19.931 | 21.62 | 74.9 | 11.243 | 15.00 | 82.1 | 14.390 | 17.52 |
| F | 46.6 | 3.287 | 7.06 | 66.4 | 5.179 | 7.80 | 63.0 | 6.933 | 11.01 | 58.7 | 10.290 | 17.54 |
Image /page/2/Picture/9 description: The image shows the number 000171 in a bold, sans-serif font. The numbers are printed in black ink on a white background. The numbers are slightly distorted, with some of the edges appearing blurred. The number is likely a serial number or some other type of identification number.
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Expected Values
The prevalence of anti-cardiolipin antibodies may vary depending on a number of factors such as age, gender, geographical location, race, type of test used and clinical history of individual patients. Antibodies to anti-cardiolipin are generally absent, or have a very low incidence, in the normal healthy population. Increased incidence can occur in the elderly population. A published study has shown a prevalence of 12% in the elderly population (mean age of 70 years) as opposed to 2% for a younger population. In addition, anti-cardiolipin antibodies were detected in 23% of elderly individuals who were also positive for anti-nuclear antibodies (12).
In the present study, the expected values for a normal, healthy population were assessed by testing sera from one hundred and forty-eight S. Florida blood donors (ninety-eight males and fifty females) in the Is-anti-Cardiolipin Screen Test Kit. One hundred and forty sera (94.6%) were negative for antibodies, eight sera (5.4%) were positive and none were equivocal. The age distribution and antibody prevalence for this population are shown in the table below.
The expected values for a clinical population were assessed by testing fifty-seven sera from patients with a diagnosis of anti-phospholipid syndrome (APS) in the Is-anti-Cardiolipin Screen Test Kit. Fifty-four (94.7%) were positive, three (5.3%) were negative and none were equivocal for IgG/IgM/ IgA antibodies.
Histograms showing the distribution of values for these normal and clinical populations are shown in FIGURES 1 and 2.
| Number of Donors | Prevalence | |
|---|---|---|
| Total Number | 148 | |
| GeographicLocation: | South Florida : 148 | 5.4% |
| Age | ||
| 10-19 | 7 | 14.3% |
| 20-29 | 36 | 0.0% |
| 30-39 | 73 | 8.2% |
| 40-49 | 22 | 4.5% |
| 50-59 | 8 | 0.0% |
| 60-69 | 2 | 0.0% |
Age Distribution and Prevalence of anti-Cardiolipin IgG/IgM/IgA in a Normal S. Florida Population
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FIGURE 1 Distribution of anti-Cardiolipin IgG/IgM/IgA in a Normal Population
Image /page/4/Figure/1 description: This image is a bar graph that shows frequency on the y-axis and U/ML on the x-axis. The frequency ranges from 0 to 70, and the U/ML ranges from 0 to 60. There are two bars that are significantly higher than the rest, one at 0 U/ML with a frequency of 70, and one at 5 U/ML with a frequency of 64.
FIGURE 2 Distribution of anti-CardiolipinlgG/lgM/ IgA in a Clinical Population
Image /page/4/Figure/3 description: This image is a histogram showing frequency on the y-axis and U/ML on the x-axis. The frequency ranges from 0 to 7, and the U/ML ranges from 0 to 280. The histogram shows the distribution of U/ML values, with the highest frequencies occurring around 80 and 160.
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circle with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is a stylized image of an eagle with three heads.
AUG 2 0 2001
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Lynne Stirling, Ph. D. Diamedix Corporation 2140 N. Miami Avenue Miami, Florida 33127
Re: K012053
K012055
Trade/Device Name: Diamedix Is-anti-Cardiolipin Screen Test System Regulation Number: 21 CFR 866.5660 Regulatory Class: Class II Product Code: MID Dated: June 29, 2001 Received: July 2, 2001
Dear Dr. Stirling:
We have reviewed your Section 510(k) notification of intent to market the device referenced in we have leviewed your becaon b ro(x) x = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = above and we nave determinou the act 1976, the enactment date of the Medical Device intersiale comments, or to devices that have been reclassified in accordance with the provisions of the same issues and issues and issues and issues and issues and issues and Amendments, or to devices mat have been rockes market the device, subject to Federal Food, Drug, and Cosmons Free (10) - 100 general controls provisions of the Act include the general controls provisions of the Freis - Fittigential of the gractice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into either class II (Special Controls) or class III If your device is classifica (see above) into such additional controls. Existing major regulations (Premarket Approval), it may be subject to ade a subject to address, Title 21, Parts 800 to 895.
affecting your device can be found in the Code of Federal Regulations, Title A substantially equivalent determination assumes compliance with the Good Manufactures a A substantally equivalent determination as and and and the mart 820) and that, through Fractice for Mculear Dovies: Seneral (Concertation (FDA) will verify such periodic GMT inspections, the Food and Suns and assumptions. Tantife to comply with the concerning your device in the Federal addition, FDA may publish fullive and concerner of cation submission submission does not affect Register. Please note: under sections 531 through 542 of the Act for devices under the ally obligation you might have ander provisions, or other Federal laws or regulations.
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Page 2
This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed nouncation. The I Dr I mailig of rassification for your device and thus, permits your device to proceed to the market.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and 11 you desire specific acritic diagnostic devices), please contact the Office of Compliance at additionally 607.10 for in in in and advertising on the promotion and advertising of your device, (201) 594-1568. Frauncenf Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small information on your responsive Assistance at its toll-free number (800) 638-2041 or Manufacturers internet address "http://www.fda.gov/cdrl/dsma/dsmamain.html".
Sincerely yours,
Steven Autman
Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health
Enclosure
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Appendix G. Indications for Use Statement
INDICATIONS FOR USE STATEMENT
510(K) NUMBER : KOI2053
DEVICE NAME : Is anti-Cardiolipin Screen Test System
Indications for Use : The Diamedix Is anti-Cardiolipin Screen Test Kit is an indirect enzyme immunoassay (EIA) for the semi-quantitative measurement of IgG, IgM and IgA antibodies to cardiolipin in human serum as an aid in the assessment of the risk of thrombosis in patient with SLE or SLE-like disorders. These reagents can be used either manually or in conjunction with the MAGO® Plus Automated EIA Processor
Josephine Bautista
Division of Clinical Laboratory Devices
510(k) Number
§ 866.5660 Multiple autoantibodies immunological test system.
(a)
Identification. A multiple autoantibodies immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoantibodies (antibodies produced against the body's own tissues) in serum and other body fluids. Measurement of multiple autoantibodies aids in the diagnosis of autoimmune disorders (disease produced when the body's own tissues are injured by autoantibodies).(b)
Classification. Class II (performance standards).