(133 days)
The Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit is intended as a qualitative test for the detection of IgG antibodies to B. burgdorferi sensu stricto in human serum from symptomatic patients or people suspected of infection. When used as the first-tier screening test, positive and equivocal results must be supplemented through additional testing by one of the following methods:
· Standard two-tier test methodology (STTT) using an IgG blot test following current interpretation guidelines, OR
• Modified two-tier test methodology (MTT) using the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/ IgM ELISA Test.
The assay can also be used as a second-tier confirmation test using the MTTT methodology when used with the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/IgM ELISA Test as the first-tier screening test.
Positive test results by either the STTT or MTTT methodology are supportive evidence for the presence of antibodies and exposure to Borrelia burgdorferi, the cause of Lyme disease. A diagnosis of Lyme disease should be made based on the presence of Borrelia burgdorferi antibodies, history, symptoms, and other laboratory findings.
The kit includes 12 x 8 well Antigen Coated strips. Conjugate. Substrate, Stop Solution, Wash Buffer, Diluent, Negative Control, Positive Control, and Cutoff Control. The controls are provided to determine if the assay is functioning properly and to determine the antibody level. The reagents are sufficient for 96 determinations.
During the test procedure, antibodies to B. burgdorferi (sensu stricto) if present in the human serum sample will bind to the antigens coated onto the wells forming antigen-antibody complexes. Excess antibodies are removed by washing. A conjugate of goat anti-human IgG antibodies conjugated with horseradish peroxidase is then added, which binds to the antigenantibody complexes. Excess conjugate is removed by washing. This is followed by the addition of a chromogenic substrate, tetramethylbenzidine (TMB). If specific antibodies to the antigen are present in the patients' serum, a blue color will develop. The enzymatic reaction is then stopped with a stopping solution causing the contents of the well to turn yellow. The wells are read photometrically with a microplate reader at 450nm.
The antigens used in the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test kit is a combination of B. burgdorferi sensu stricto strain B31 lysate, B. burgdorferi sensu stricto strain 2591 lysate, and a recombinant VlsE from B. burgdorferi sensu stricto strain B31. The lysates use spirochetes growing in BSK-H complete medium until mid-exponential phase. The recombinant VlsE protein is produced in E. coli SURE2 cells and purified by affinity chromatography. The purity of each antigen is assayed by SDS-PAGE followed by Coomassie staining and/or Western blotting.
This document describes the validation of the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit, including a new proposed Modified Two-tier Testing (MTTT) methodology. The provided text primarily focuses on comparative studies against predicate devices and existing standard methods, rather than defining explicit acceptance criteria in a quantitative table format. However, implied acceptance criteria can be derived from the performance percentages presented.
Based on the provided information, here's a structured response addressing the requested points:
1. Table of Acceptance Criteria (Implied) and Reported Device Performance
The acceptance criteria are not explicitly stated as numerical cutoffs in the document. However, they can be inferred from the reported "Percent Agreement" values in the comparison studies. The studies aim to demonstrate substantial equivalence to established predicate devices and methodologies.
| Study Type / Performance Metric | Implied Acceptance Criteria (Goal: High Agreement/Sensitivity/Specificity) | Reported Device Performance (Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit) |
|---|---|---|
| Comparison with Predicate Device (STTT) | ||
| Positive Percent Agreement (PPA) with Predicate IgG ELISA | High (> 90% typically desired for equivalence) | 90.2% (55/61) [95% CI: 79.8% - 96.3%] |
| Negative Percent Agreement (NPA) with Predicate IgG ELISA | High (> 95% typically desired for equivalence) | 99.6% (460/462) [95% CI: 98.5% - 99.9%] |
| Second-Tier Testing (STTT) - Agreement with FDA Cleared IgG Blot | ||
| 2nd Tier PPA (Tier 1 Pos/Equiv samples) | 100.0% (as reported) | 100.0% (37/37) [95% CI: 92.2% - 100.0%] |
| Clinical Sensitivity (STTT) | ||
| Early Lyme | Improvement over predicate | 46.6% (27/58) vs. Predicate: 27.6% (16/58) |
| Disseminated Lyme | Improvement over predicate | 82.4% (14/17) vs. Predicate: 52.9% (9/17) |
| Late Lyme | High agreement with predicate | 97.4% (38/39) vs. Predicate: 97.4% (38/39) |
| CDC Panel (STTT) | ||
| Healthy | High (> 99% agreement, implying high specificity) | 99.0% (1/100 positive/equivocal) |
| Early Lyme | Improvement over predicate | 68.3% (41/60 positive/equivocal) vs. Predicate: 35.0% (21/60) |
| Cardiac Lyme | Comparable/Improvement | 66.7% (2/3 positive/equivocal) vs. Predicate: 100.0% (3/3) |
| Neurological Lyme | Improvement over predicate | 85.7% (6/7 positive/equivocal) vs. Predicate: 42.9% (3/7) |
| Late Lyme | High agreement with predicate | 100.0% (20/20 positive/equivocal) vs. Predicate: 100.0% (20/20) |
| Look-alike Disease | High (> 85% agreement, implying high specificity) | 87.8% (11/90 positive/equivocal) vs. Predicate: 88.9% (10/90) |
| Method Comparison MTTT – IgG (vs. STTT) | ||
| PPA (second-tier test of MTTT vs. STTT) | 100.0% (as reported) | 100.0% (23/23) [95% CI: 85.2% - 100.0%] |
| NPA (second-tier test of MTTT vs. STTT) | High (implied > 95%) | 0.0% (0/15) [95% CI: 0.0% - 21.8%] - Note: This NPA is for a subset of samples that were negative by IgG Immunoblot, not overall. The overall NPA is 96.7% |
| PPA (Overall MTTT vs. STTT) | 100.0% (as reported) | 100.0% (23/23) [95% CI: 85.2% - 100.0%] |
| NPA (Overall MTTT vs. STTT) | High (implied > 95%) | 96.7% (443/458) [95% CI: 94.7% - 98.2%] |
| Clinical Sensitivity (MTTT) | ||
| Early Lyme | Improvement over predicate STTT | 48.4% (30/62) vs. Predicate STTT: 8.1% (5/62) |
| Disseminated Lyme | Improvement over predicate STTT | 81.8% (18/22) vs. Predicate STTT: 22.7% (5/22) |
| Late Lyme | Comparable/Improvement | 97.6% (40/41) vs. Predicate STTT: 95.1% (39/41) |
| CDC Reference Panel (MTTT) | ||
| Healthy | 100.0% (as reported) | 100.0% (0/100 positive/equivocal) |
| Early Lyme | Improvement over predicate STTT | 60.0% (36/60 positive/equivocal) vs. Predicate STTT: 33.3% (12/60) |
| Cardiac Lyme | Improvement over predicate STTT | 66.7% (2/3 positive/equivocal) vs. Predicate STTT: 33.3% (1/3) |
| Neurological Lyme | Improvement over predicate STTT | 85.7% (6/7 positive/equivocal) vs. Predicate STTT: 14.3% (1/7) |
| Late Lyme | 100.0% (as reported) | 100.0% (20/20 positive/equivocal) vs. Predicate STTT: 100.0% (20/20) |
| Look-alike Disease | 100.0% (as reported) | 100.0% (0/90 positive/equivocal) vs. Predicate STTT: 100.0% (0/90) |
2. Sample Size Used for the Test Set and Data Provenance
-
Determination of Assay Cutoff (Nonclinical):
- Sample Size: 210 normal sera (105 endemic, 105 non-endemic) + 194 samples (114 Lyme disease stages, 8 healthy negative, 72 negative Lyme disease with other conditions). Total = 404 samples.
- Data Provenance: Not explicitly stated, but "endemic region of Lyme disease" and "non-endemic region of Lyme disease" suggest geographical diversity. Retrospective, as these are "tested" samples for cutoff determination.
-
Precision (Nonclinical):
- Sample Size: 48 runs for each of 4 panel members (negative, high negative, low positive, moderate positive) + kit controls. This is a repetitive testing design, not individual patient samples.
-
Reproducibility (Nonclinical):
- Sample Size: 90 runs (3 sites x 2 runs/day x 5 days x 3 replicates) for each of 4 panel members (negative, high negative, low positive, moderate positive) + kit controls (30 runs for Pos/Neg control, 60 runs for Cutoff control).
-
Analytical Specificity:
- Sample Size: 208 asymptomatic individuals (103 from endemic regions, 105 from non-endemic regions).
- Data Provenance: Endemic and non-endemic regions. Retrospective (asymptomatic individuals' samples).
-
Cross Reactivity:
- Sample Size: 377 samples.
- Data Provenance: Samples obtained from "serum vendors who confirmed their positivity for each respective marker," implying retrospective, controlled samples.
-
Comparison/Prospective Study (Clinical):
- STTT Comparison: 523 serum samples.
- MTTT Comparison: 481 serum samples for the initial screening. 38 positive/equivocal samples were carried forward for second-tier testing comparison.
- Data Provenance: "Prospective samples submitted for Lyme serology testing" from "three sites (one internal and two external reference laboratories)." This indicates a prospective study design with samples from potentially diverse geographical locations (clinical labs).
-
Sensitivity Study (Clinical):
- STTT: 114 clinically characterized samples.
- MTTT: 125 clinically characterized samples.
- Data Provenance: "Clinically characterized samples" from unspecified sources; likely retrospective collection of known patient cohorts.
-
CDC Panel (Clinical):
- Sample Size: 280 positive and negative specimens.
- Data Provenance: From the "Center of Disease Control (CDC)." These are reference panels, typically collected and characterized over time, so retrospective.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts
The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the test sets.
- For "clinically characterized samples" and "CDC panel" samples, the implication is that these samples have a pre-defined and reliable "clinical diagnosis" or "reference characterization" based on established medical criteria. This often involves consensus from clinical experts (e.g., infectious disease specialists) and/or a combination of clinical presentation, symptoms, and other laboratory findings, but the specifics are not detailed here.
- For the "Second-Tier Testing" comparison, the "FDA cleared IgG blot assay" and "predicate B. burgdorferi IgG blot test" serve as the ground truth. These are approved diagnostic methods, and their interpretation would follow established guidelines.
4. Adjudication Method for the Test Set
The document does not describe any specific adjudication method (e.g., 2+1, 3+1) for resolving discrepancies in the test results or for establishing the initial ground truth diagnoses. The comparisons are based on the results of the different assays and against established clinical characterizations or CDC panels.
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
No MRMC study was performed or described. This device is an ELISA test kit, a laboratory diagnostic assay for detecting antibodies, not an AI or imaging diagnostic tool that involves human readers interpreting images. Therefore, the concept of "human readers improving with AI assistance" is not applicable.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the primary performance evaluation is standalone. The Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit operates as a standalone diagnostic assay. Its performance (sensitivity, specificity, agreement) is measured as the output of the kit itself (optical density readings converted to units and qualitative results) without direct human interpretation of complex visual patterns or AI assistance. The results are quantitative and then interpreted qualitatively (positive, equivocal, negative) based on predefined cutoffs.
7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)
The ground truth used varies by study:
- Predicate Devices/Methodologies: For the STTT and MTTT comparison studies, the ground truth for the device's performance is a comparison against the results from legally marketed predicate devices (e.g., Trinity Biotech MarDx Borrelia burgdorferi EIA IgG Test Kit) and/or a FDA cleared IgG blot assay. This is a form of comparative ground truth against established methods.
- Clinical Diagnosis/Characterization: For the Sensitivity Study and CDC Panel, the ground truth is "clinically characterized samples" and "positive and negative specimens from the Centers of Disease Control (CDC)." This implies a clinical diagnosis or consensus diagnosis based on comprehensive patient data (history, symptoms, other laboratory findings) or a reference panel with established disease status.
- Analytical Ground Truth: For non-clinical studies like analytical specificity and cross-reactivity, the ground truth is often the confirmed absence or presence of specific conditions in the tested samples, usually based on prior laboratory testing or sample vendor claims.
8. The Sample Size for the Training Set
The document does not explicitly mention a "training set" in the context of machine learning. The term "training set" is usually associated with the development of AI algorithms. For an ELISA kit, development involves:
- Antigen Selection and Optimization: Which antigens to use (e.g., B31 lysate, 2591 lysate, recombinant VlsE).
- Reagent Formulation: Optimizing conjugate, substrate, buffers, etc.
- Cutoff Determination: "The cutoff was determined by testing a total of 210 normal sera..." and "An additional 194 samples..." This process of determining the cutoff could be considered analogous to a 'calibration' or 'training' phase for a traditional diagnostic test, where a dataset is used to define the diagnostic thresholds. In this sense, a total of 404 samples (210 normal + 194 other known samples) were used for cutoff determination.
9. How the Ground Truth for the Training Set Was Established
As discussed above, for establishing the cutoff (analogous to training/calibration):
- Normal Sera: The 210 normal sera were likely verified as "normal" through standard clinical practice or donor screening, indicating the absence of target antibodies/disease in a healthy population.
- Known Positive/Negative/Other Disease Samples: The additional 194 samples included "different phases of Lyme disease," "negative healthy samples," and "negative Lyme disease samples but do have other diseases that may cause serologic cross-reactivity." The "ground truth" for these samples would be their known clinical status or disease classification, typically established through comprehensive clinical evaluation, follow-up, and/or panels from disease banks. The ROC analysis was used to confirm the chosen cutoff provides the best compromise between sensitivity and specificity, indicating an analytical optimization process based on these known samples.
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March 22, 2021
Gold Standard Diagnostics Jennifer Roth Vice President, Product Development 2851 Spafford St. Davis, California 95618
Re: K203296
Trade/Device Name: Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit Regulation Number: 21 CFR 866.3830 Regulation Name: Treponema Pallidum Treponemal Test Reagents Regulatory Class: Class II Product Code: LSR Dated: November 4, 2020 Received: November 9, 2020
Dear Jennifer Roth:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal
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statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Maria Ines Garcia, Ph.D. Branch Chief Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K203296
Device Name
Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit
Indications for Use (Describe)
The Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit is intended as a qualitative test for the detection of IgG antibodies to B. burgdorferi sensu stricto in human serum from symptomatic patients or people suspected of infection. When used as the first-tier screening test, positive and equivocal results must be supplemented through additional testing by one of the following methods:
· Standard two-tier test methodology (STTT) using an IgG blot test following current interpretation guidelines, OR
• Modified two-tier test methodology (MTT) using the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/ IgM ELISA Test.
The assay can also be used as a second-tier confirmation test using the MTTT methodology when used with the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/IgM ELISA Test as the first-tier screening test.
Positive test results by either the STTT or MTTT methodology are supportive evidence for the presence of antibodies and exposure to Borrelia burgdorferi, the cause of Lyme disease. A diagnosis of Lyme disease should be made based on the presence of Borrelia burgdorferi antibodies, history, symptoms, and other laboratory findings.
| Type of Use (Select one or both, as applicable) | |||
|---|---|---|---|
| X Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) | ||
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510(k) Summary
This 510(k) summary is being submitted in accordance with the requirement of SMDA 1990 and 21 CFR 807.92.
- Submitter's Name: Gold Standard Diagnostics Address: 620 Cantrill Drive Davis, CA. 95618 Phone Number: 530-759-8000 Contact Person: Jennifer Roth Date: November 3, 2020
-
- Product and Trade Name: Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit
Common Name: Lyme ELISA Test
- Product and Trade Name: Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit
Regulation Section:
(21 CFR 866.3830) Treponema pallidum treponemal test reagents.
Classification: Class II
Product Code: LSR; Reagent, Borrelia Serological Reagent
- Note: This clearance is for a modified use (Modified Two-tier Testing or MTTT use) for the previously cleared IVD test, the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit (K200025). The information and study data for the modified use is presented under the heading of "MTTT Comparison" below. With the exception of the intended use, all other information and data remain the same.
3) Legally Marketed Device to Which the Submitter Claims Equivalence:
- a. STTT Trinity Biotech MarDx Borrelia burgdorferi EIA IgG Test Kit (K894224).
- b. MTTT Gold Standard Diagnostics Borrelia burgdorferi IgG Blot Test Kit (K113847)
4) Description of the Device:
The kit includes 12 x 8 well Antigen Coated strips. Conjugate. Substrate, Stop Solution, Wash Buffer, Diluent, Negative Control, Positive Control, and Cutoff Control. The controls are provided to determine if the assay is functioning properly and to determine the antibody level. The reagents are sufficient for 96 determinations.
During the test procedure, antibodies to B. burgdorferi (sensu stricto) if present in the human serum sample will bind to the antigens coated onto the wells forming antigen-antibody complexes. Excess antibodies are removed by washing. A conjugate of goat anti-human IgG
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antibodies conjugated with horseradish peroxidase is then added, which binds to the antigenantibody complexes. Excess conjugate is removed by washing. This is followed by the addition of a chromogenic substrate, tetramethylbenzidine (TMB). If specific antibodies to the antigen are present in the patients' serum, a blue color will develop. The enzymatic reaction is then stopped with a stopping solution causing the contents of the well to turn yellow. The wells are read photometrically with a microplate reader at 450nm.
The antigens used in the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test kit is a combination of B. burgdorferi sensu stricto strain B31 lysate, B. burgdorferi sensu stricto strain 2591 lysate, and a recombinant VlsE from B. burgdorferi sensu stricto strain B31. The lysates use spirochetes growing in BSK-H complete medium until mid-exponential phase. The recombinant VlsE protein is produced in E. coli SURE2 cells and purified by affinity chromatography. The purity of each antigen is assayed by SDS-PAGE followed by Coomassie staining and/or Western blotting.
5) Intended Use of the Device:
The Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit is intended as a qualitative test for the detection of IgG antibodies to B. burgdorferi sensu stricto in human serum from symptomatic patients or people suspected of infection. When used as the first-tier screening test, positive and equivocal results must be supplemented through additional testing bv one of the following methods:
- Standard two-tier test methodology (STTT) using an IgG blot test following current ● interpretation guidelines, OR
- . Modified two-tier test methodology (MTTT) using the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/IgM ELISA Test.
The assay can also be used as a second-tier confirmation test using the MTTT methodology when used with the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/IgM ELISA Test as the first-tier screening test.
Positive test results by either the STTT or MTTT methodology are supportive evidence for the presence of antibodies and exposure to Borrelia burgdorferi, the cause of Lyme disease. A diagnosis of Lyme disease should be made based on the presence of Borrelia burgdorferi antibodies, history, symptoms, and other laboratory findings.
6) Comparison with the Predicate Device:
The tables below provide a comparison of the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test kit with the Trinity Biotech MarDx Borrelia burgdorferi EIA IgG Test kit (predicate device: K894224).
| Similarities | ||
|---|---|---|
| Item | Subject Device: Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit | Predicate Device: Trinity Biotech MarDx Borrelia burgdorferi EIA IgG Test Kit |
| Intended Use | The Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA | Trinity Biotech MarDx Borrelia burgdorferi EIA IgG Test System is a |
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| Test kit is intended as a qualitativepresumptive (first step) test for thedetection of IgG antibodies to B.burgdorferi sensu stricto in humanserum from symptomatic patientsor people suspected of infection.Positive and equivocal resultsmust be supplemented by testingwith a second-step Western blotassay. | qualitative test intended for use in thepresumptive detection of human IgGantibodies to Borrelia burgdorferi inhuman serum. This EIA system shouldbe used to test serum from patients witha history and symptoms of infection withB. burdorferi. All positive and equivocalspecimens should be retested with ahighly specific, second-tier test such asWestern blot. Positive second-tierresults are supportive evidence ofinfection with B. burdorferi. Thediagnosis of Lyme disease should bemade based on history and symptoms(such as erythema migrans), and otherlaboratory data, in addition to thepresence of antibodies to B. burdorferi.Negative results (either first or second-tier) should not be used to exclude Lyme | |||
|---|---|---|---|---|
| Assay Format | Antigen coated microtiter plate -96 wells. | Same | ||
| Technology | ELISA | Same | ||
| Sample Matrix | Human serum | Same | ||
| Sample Processing | Dilute Samples 1:100 in Diluent | Same | ||
| Controls Provided | Positive, Cutoff, Negative | Same | ||
| Reagents Provided | Diluent, Wash, Conjugate,Substrate, Stop Solution | Same | ||
| Reported Results | Positive, Equivocal, Negative | Same | ||
| Interpretation | Optical density readings fromSpectrophotometer | Same |
| Differences | ||
|---|---|---|
| Item | Subject Device: Gold StandardDiagnostics Borrelia burgdorferiIgG ELISA Test Kit | Predicate Device: Trinity BiotechMarDx Borrelia burgdorferi EIAIgG Test Kit |
| Volumes | 100ul sample, 50ul substrate, 50ulstop solution | 100ul sample, 100ul substrate,100ul stop solution |
| Incubation | 15/15/15 minutes at roomtemperature | 30/30/10 minutes at roomtemperature |
| Antigens | B. burgdorferi B31 strain,B. burgdorferi 2591 strain,B. burgdorferi recombinant VlsEB31 strain | B. burgdorferi B31 strain |
| Results Interpretation | Convert to units.Negative <9Equivocal 9.0-11.0 | Convert to units.Negative <0.80Equivocal 0.80-1.19 |
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| Positive >11.0 | Positive >1.2 | |
|---|---|---|
| -- | ---------------- | --------------- |
6(b1): Nonclinical Studies:
Determination of the Assav Cutoff
The cutoff was determined by testing a total of 210 normal sera which consisted of 105 sera from an endemic region of Lyme disease and 105 sera from a non-endemic region of Lyme disease. The mean plus two standard deviations was used to determine the assay cutoff. A known positive sample was then diluted to produce a ready to use cutoff control. An additional 194 samples consisting of 114 samples from different phases of Lyme disease, 8 negative healthy samples, 72 negative Lyme disease samples but do have other diseases that may cause serologic cross-reactivity, were tested. A receiver operating characteristics (ROC) analysis was performed to evaluate the performance of the assay and confirm that the chosen cutoff provided the best compromise between sensitivity and specificity.
Precision
To determine the precision of the Borrelia burgdorferi IgG ELISA Test, a within-lab precision study was conducted. A precision panel consisting of a negative sample, a high negative sample, a low positive sample, and a moderate positive sample, along with the kit controls, was tested in-house. The sample panel was masked and randomized. Each of the panel members was tested in duplicate. twice per day, for 12 days. The results are summarized in the following table:
| Sample | N | MeanUnits | Within-Run | Between-Run | Between-Day | Total | |
|---|---|---|---|---|---|---|---|
| ModeratePositive | 48 | 20.3 | SD | 1.488 | 1.312 | 1.257 | 1.439 |
| CV | 7.3% | 6.5% | 6.2% | 7.1% | |||
| LowPositive | 48 | 11.5 | SD | 0.845 | 0.718 | 0.718 | 0.816 |
| CV | 7.4% | 6.2% | 6.2% | 7.1% | |||
| HighNegative | 48 | 8.3 | SD | 0.880 | 0.646 | 0.615 | 0.857 |
| CV | 10.6% | 7.8% | 7.4% | 10.4% | |||
| Negative | 48 | 0.8 | SD | 0.116 | 0.049 | 0.076 | 0.113 |
| CV | 14.2% | 6.5% | 10.0% | 14.8% | |||
| PositiveControl | 48 | 17.2 | SD | 0.947 | 0.649 | 0.739 | .932 |
| CV | 5.5% | 3.8% | 4.3% | 5.4% | |||
| CutoffControl | 48 | 10.1 | SD | 0.241 | 0.115 | 0.285 | 0.264 |
| CV | 2.7% | 1.1% | 2.8% | 2.6% | |||
| NegativeControl | 48 | 0.4 | SD | 0.052 | 0.424 | 0.144 | 0.051 |
| CV | 12.9% | 10.6% | 11.0% | 12.7% |
Reproducibility
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A reproducibility panel consisting of a negative sample, a high negative sample, a low positive sample, and a moderate positive sample, along with the kit controls, was tested at three different sites. The sample panel was masked and randomized. Each of the panel members was tested in triplicate, twice per day, for five days. The Within-Run, Between-Run, Between-Days, and Between-Sites Standard Deviation and Coefficients of Variation (CV) were calculated. The sample panel was masked and randomized. The results are summarized in the following table:
| Sample | N | MeanUnits | Within-Run | Between-Run | Between-Day | Between-Site | Total | |
|---|---|---|---|---|---|---|---|---|
| ModeratePositive | 90 | 21.0 | SD | 1.54 | 0.40 | 1.07 | 0.91 | 1.29 |
| CV | 7.3% | 1.9% | 5.1% | 4.3% | 6.1% | |||
| LowPositive | 90 | 13.7 | SD | 0.72 | 0.34 | 1.09 | 1.24 | 1.28 |
| CV | 5.5% | 2.6% | 8.0% | 9.1% | 9.3% | |||
| HighNegative | 90 | 6.6 | SD | 0.76 | 0.27 | 0.46 | 0.68 | 0.67 |
| CV | 11.7% | 4.1% | 7.0% | 10.3% | 10.2% | |||
| Negative | 90 | 3.0 | SD | 0.33 | 0.56 | 0.49 | 0.56 | 0.55 |
| CV | 21.1% | 18.7% | 16.4% | 18.8% | 18.3% | |||
| PositiveControl | 30 | 19.1 | SD | 0.65 | 0.67 | 0.67 | 0.63 | 0.62 |
| CV | 3.5% | 3.5% | 3.5% | 3.3% | 3.2% | |||
| CutoffControl | 60 | 10.0 | SD | 0.25 | 0.22 | 0.23 | 0.22 | 0.22 |
| CV | 2.4% | 2.2% | 2.3% | 2.2% | 2.2% | |||
| NegativeControl | 30 | 0.5 | SD | 0.08 | 0.06 | 0.06 | 0.50 | 0.50 |
| CV | 11.0% | 11.0% | 11.0% | 9.5% | 9.6% |
Analytical Specificity
The analytical specificity was determined by testing 208 asymptomatic individuals' samples from endemic and non-endemic regions. The Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test results are summarized in the following table:
| Number of Samples | NumberPositive/Equivocal | Analytical Specificity | |
|---|---|---|---|
| Endemic Region | 103 | 4 | 96.1% |
| Non-endemic Region | 105 | 0 | 100.0% |
Cross Reactivity
A study using 377 samples was conducted to evaluate potential cross reactivity from different disease conditions. The samples were obtained from serum vendors who confirmed their positivity for each respective marker. The samples were tested on the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test. The results are summarized in the following table:
| Infection / Diagnosis | Number ofSera Tested | # Positive /(%) |
|---|---|---|
| Tick-borne Relapsing Fever IgG | 21 | 0 / (0%) |
| Treponemal Infections (TPPA) | 23 | 0 / (0%) |
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| Rickettsiosis IgG | 25 | 6 / (24%) |
|---|---|---|
| Ehrlichiosis IgG | 10 | 2 / (20%) |
| Babesiosis IgG | 12 | 0 / (0%) |
| H. pylori IgG | 11 | 0 / (0%) |
| Parvovirus B19 IgG | 12 | 0 / (0%) |
| Influenza A&B IgG | 12 | 0 / (0%) |
| Epstein-Barr Virus IgG | 34 | 1 / (3%) |
| Cytomegalovirus IgG | 31 | 0 / (0%) |
| Herpes Simplex Virus IgG | 21 | 0 / (0%) |
| Varicella Zoster Virus | 16 | 1 / (6%) |
| Fibromyalgia | 32 | 0 / (0%) |
| Rheumatoid Arthritis | 12 | 0 / (0%) |
| Autoimmune Disease | 59 | 0 / (0%) |
| Multiple Sclerosis | 23 | 0 / (0%) |
| Severe Periodontitis | 23 | 0 / (0%) |
Interfering Substances
The effect of potential interfering substances on samples using the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test was evaluated. Three samples, a high negative, an equivocal and a low positive were spiked with high levels of interferants and were tested along with serum without spiked interferants. The recommended concentrations from the guideline "Interference Testing in Clinical Chemistry" EP07-A3 from the Clinical and Laboratory Standards Institute were used (see table below). The tested substances did not affect the performance of the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test.
| Substance | Concentration | Interference |
|---|---|---|
| Albumin | 60 mg/ml | None detected |
| Bilirubin | 0.4 mg/ml | None detected |
| Cholesterol | 4.0 mg/ml | None detected |
| Hemoglobin | 10 mg/ml | None detected |
| Triglycerides | 15 mg/ml | None detected |
6(b2): Clinical Studies:
Comparison with Predicate Device
Comparison studies were conducted at three sites (one internal and two external reference laboratories) using prospective samples submitted for Lyme serology testing. Five hundred twenty three (523) serum samples were tested on both the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test and on the predicate B. burgdorferi IgG ELISA Test. The results are summarized in the following table:
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| Predicate IgG ELISA | |||||
|---|---|---|---|---|---|
| Positive | Equivocal* | Negative | Total | ||
| Gold Standard DiagnosticsBorrelia burgdorferi IgGELISA Test Kit | Positive | 40 | 5 | 2 | 47 |
| Equivocal* | 3 | 7 | 0 | 10 | |
| Negative | 2 | 4 | 460 | 466 | |
| Total | 45 | 16 | 462 | 523 |
*Equivocal samples counted as positive
| Positive percent agreement = 90.2% (55/61) | 95% CI (79.8% - 96.3%) |
|---|---|
| Negative percent agreement = 99.6% (460/462) | 95% CI (98.5% - 99.9%) |
Second-Tier Testing
All positive and equivocal samples by the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test and by the Predicate IgG ELISA were tested by a FDA cleared IgG blot assay. The results are summarized in the following table:
| Tier 1 Positiveor Equivocal | IgG BlotPositive | IgG BlotNegative | |
|---|---|---|---|
| Predicate IgG ELISA | 61 | 37 | 24 |
| Gold StandardDiagnostics Borreliaburgdorferi IgGELISA Test Kit | 57 | 37 | 20 |
| Predicate IgG ELISA+Gold StandardDiagnostics Borreliaburgdorferi IgGELISA Test Kit | 55 | 37 | 18 |
| Percent Agreement with Predicate Device | ||
|---|---|---|
| 2nd Tier PPA(95% CI) | 100.0%(92.2% - 100.0%) | 37/37 |
Clinical Sensitivity
Sensitivity Study
A sensitivity study was performed on 114 clinically characterized samples. The samples encompass early, disseminated, and late stages of Lyme disease. The samples were tested on both the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test and on the predicate B. burgdorferi IgG ELISA Test. The results are summarized in the following table:
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| DiseaseStage | n | Gold StandardDiagnostics Borreliaburgdorferi IgG ELISATest Kit | PredicateIgG ELISA |
|---|---|---|---|
| Early | 58 | 46.6% (27/58) | 27.6% (16/58) |
| Disseminated | 17 | 82.4% (14/17) | 52.9% (9/17) |
| Late | 39 | 97.4% (38/39) | 97.4% (38/39) |
CDC Panel
A panel of 280 positive and negative specimens from the Center of Disease Control (CDC) for Lyme disease detection was tested on both the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test and on the predicate device. The results are presented as a means to convey further information on the performance of the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test with a masked characterized serum panel. This does not imply an endorsement of the assay by the CDC. The results are summarized in the following table:
| Gold Standard DiagnosticsBorrelia burgdorferi IgGELISA Test Kit | PredicateIgG ELISA | ||||
|---|---|---|---|---|---|
| Disease Stage | n | PositiveorEquivocal | % Agreementwith ClinicalDiagnosis | PositiveorEquivocal | % Agreementwith ClinicalDiagnosis |
| Healthy | 100 | 1 | 99.0% | 1 | 99.0% |
| Early Lyme | 60 | 41 | 68.3% | 21 | 35.0% |
| Cardiac Lyme | 3 | 2 | 66.7% | 3 | 100.0% |
| Neurological Lyme | 7 | 6 | 85.7% | 3 | 42.9% |
| Late | 20 | 20 | 100.0% | 20 | 100.0% |
| Look-alikeDisease | 90 | 11 | 87.8% | 10 | 88.9% |
Expected Values
The range of values and positivity rate among different studies and population for the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test are as follows:
| Population | # Samples | Unit Results | Qualitative Results | |||
|---|---|---|---|---|---|---|
| Mean | Range | Std. Dev. | # Positive/ Equivocal | % Positive/ Equivocal | ||
| NormalEndemic | 103 | 3.7 | 0.5 - 14.3 | 2.452 | 4 | 3.9% |
| NormalNon-Endemic | 105 | 3.9 | 0.6 - 9.0 | 2.002 | 0 | 0.0% |
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| ProspectiveStudy | 523 | 4.3 | 0.1 - 22.2 | 4.409 | 57 | 10.9% |
|---|---|---|---|---|---|---|
| SensitivityStudy | 114 | 13.6 | 0.9 – 40.4 | 7.994 | 81 | 71.1 % |
Note: It is recommended that each laboratory determine its own normal range based on the population.
7) Conclusion:
From the comparison data, we conclude that the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test is substantially equivalent to the Trinity Biotech MarDx Borrelia burgdorferi EIA IgG Test kit (predicate device: K894224).
MTTT Comparison:
Comparison with the Predicate Device - MTTT:
The Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit, when used as the firststep or second-step test in combination with the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/IgM ELISA Test Kit in the Modified Two-tier Testing (MTTT) method, was compared to the Standard Two-tier testing (STTT) method using the predicates Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA (K200025) Test Kit as the first-step test followed by testing all the positive and equivocal results on the Gold Standard Diagnostics Borrelia burgdorferi IgG Blot Test (K113847). Below are tables comparing the two devices.
| Similarities | ||
|---|---|---|
| Item | Subject Device: Gold StandardDiagnostics Borrelia burgdorferi IgGELISA Test Kit | Predicate Device: Gold StandardDiagnostics Borrelia burgdorferiIgG Blot (K113847) |
| Intended Use | The Gold Standard Diagnostics Borreliaburgdorferi IgG ELISA Test Kit isintended as a qualitative test for thedetection of IgG antibodies to B.burgdorferi sensu stricto in human serumfrom symptomatic patients or peoplesuspected of infection. When used as thefirst-tier screening test, positive andequivocal results must be supplementedthrough additional testing by one of thefollowing methods:•Standard two-tier test methodology(STTT) using an IgG blot test followingcurrent interpretation guidelines, OR•Modified two-tier test methodology(MTTT) using the Gold StandardDiagnostics Borrelia burgdorferi VlsE-OspC IgG/IgM ELISA Test.The assay can also be used as a second-tier confirmation test using the MTTT | The Gold Standard DiagnosticsBorrelia burgdorferi B31 IgG LineBlot Test Kit is intended for thequalitative detection of IgG antibodiesto B. burgdorferi sensu stricto (B31)in human serum. This test is intendedfor use in testing human serumsamples which have been foundpositive or equivocal using an ELISAor IFA test procedure to providesupportive evidence of infection withB. burgdorferi. |
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| methodology when used with the GoldStandard Diagnostics Borreliaburgdorferi VlsE-OspC IgG/IgM ELISA | ||
|---|---|---|
| Test as the first-tier screening test. | ||
| Positive test results by either the STTTor MTTT methodology are supportiveevidence for the presence of antibodiesand exposure to Borrelia burgdorferi, thecause of Lyme disease. A diagnosis ofLyme disease should be made based onthe presence of Borrelia burgdorferiantibodies, history, symptoms, and otherlaboratory findings. | ||
| Antigens | B. burgdorferi B31 strain, | Same |
| Sample Matrix | Human serum | Same |
| Controls Provided | Positive, Cutoff, Negative | Same |
| Sample Processing | Dilute Samples 1:100 | Same |
| Assay Type | Qualitative | Same |
| Differences | ||
|---|---|---|
| Item | Subject Device: Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test Kit | Predicate Device: Gold Standard Diagnostics Borrelia burgdorferi IgG Blot (K113847) |
| Assay Format | Antigen coated microtiter plate – 96 wells. | Nitrocellulose Strips |
| Reagents Provided | Diluent, Wash, Conjugate, Substrate, Stop Solution | Diluent/Wash, Conjugate, Substrate |
| Volumes | 100ul sample, 50ul substrate, 50ul stop solution | 1500ul sample, 1500ul substrate, |
| Incubation | 15/15/15 minutes at room temperature | 30/30/10-13 minutes at room temperature |
| Interpretation | Optical density readings from Spectrophotometer | Visual |
| Results Interpretation | Convert to units.Negative <9Equivocal 9.0-11.0Positive >11.0 | Compare to cutoff band |
| Reported Results | Positive, Equivocal, Negative | Positive, Negative |
Method Comparison MTTT – IgG
The following studies were conducted to determine the performance of the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test as a first-tier or second-tier assay in the modified two-tier testing (MTTT) methodology.
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Gold Standard Diagnostics MTTT-IgG ELISA Method Comparison: The Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test was utilized in a MTTT (2-ELISA) protocol with the Gold Standard Diagnostics Borrelia burgdorferi VlsE-OspC IgG/IgM ELISA Test. The MTTT (2-ELISA) results were compared to the standard two-tier testing (STTT) using the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA followed by testing all positive and equivocal results on the predicate Gold Standard Diagnostics Borrelia burgdorferi IgG blot test.
Prospective Study
Comparison studies were conducted at three sites (one internal and two external reference laboratories) using prospective samples submitted for Lyme serology testing. Four hundred eighty-one (481) serum samples were tested on the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test. A total of 38 positive and equivocal samples were obtained.
In the STTT protocol the samples that were positive or equivocal (n=38) were tested with the predicate B. burgdorferi IgG blot test. In the MTTT protocol the samples (n=38) were tested on a second ELISA, the Gold Standard Diagnostics Borrelia burgdorferi VIsE-OspC IgG/IgM ELISA Test. In the second-tier ELISA test, positive and equivocal results were considered positive.
The results of the second-tier test of the STTT when compared to the second-tier test of the MTTT, including only the samples that were positive in the first tier, are summarized in the following table:
| Predicate IgG Immunoblot | ||||
|---|---|---|---|---|
| Positive | Negative | Total | ||
| Gold Standard Diagnostics | Positive | 23 | ો ર | 38 |
| Borrelia burgdorferi IgG | Negative | 0 | 0 | 0 |
| ELISA | Total | 23 | 15 | 38 |
| Positive percent agreement = 100.0%AT - - - Linne - un - - use - - use1 - 1 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - | 95% CI (85.2% - 100.0%)000/ CT /0 00/ 01 00/ \ |
Negative percent agreement = 0.0%
95% Cl (0.0% - 21.8%)
The results of the MTTT when compared to the STTT, including all samples that were part of the prospective study (n=481), are summarized in the following table:
| Predicate STTT- IgG | ||||
|---|---|---|---|---|
| Positive | Negative | Total | ||
| Gold Standard DiagnosticsMTTT- IgG | Positive | 23 | 15 | 38 |
| Negative | 0 | 443 | 443 | |
| Total | 23 | 458 | 481 |
Positive percent agreement = 100.0% Negative percent agreement = 96.7%
95% CI (85.2% - 100.0%) 95% CI (94.7% - 98.2%)
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Sensitivity Study
A sensitivity study was performed on 125 clinically characterized samples. The samples encompass early, disseminated, and late stages of Lyme disease. The samples were tested on both the Gold Standard Diagnostics MTTT-IgG and on the predicate STTT-IgG. The results are summarized in the following table:
| DiseaseStage | n | Gold Standard DiagnosticsMTTT - IgG | PredicateSTTT - IgG | ||
|---|---|---|---|---|---|
| PositiveorEquivocal | % Agreementwith ClinicalDiagnosis | PositiveorEquivocal | % Agreementwith ClinicalDiagnosis | ||
| Early | 62 | 30 | 48.4% | 5 | 8.1% |
| Disseminated | 22 | 18 | 81.8% | 5 | 22.7% |
| Late | 41 | 40 | 97.6% | 39 | 95.1% |
CDC Reference Panel
A panel of 280 positive and negative specimens from the Centers of Disease Control (CDC) for Lyme disease detection was tested on both the Gold Standard Diagnostics MTTT-IgG and on the predicate STTT-IgG. The results are summarized in the following table:
| n | Gold Standard DiagnosticsMTTT-IgG | Predicate STTT- IgG | |||
|---|---|---|---|---|---|
| Disease Stage | PositiveorEquivocal | % Agreementwith ClinicalDiagnosis | PositiveorEquivocal | % Agreementwith ClinicalDiagnosis | |
| Healthy | 100 | 0 | 100.0% | 0 | 100.0% |
| Early Lyme | 60 | 36 | 60.0% | 12 | 33.3% |
| Cardiac Lyme | 3 | 2 | 66.7% | 1 | 33.3% |
| Neurological Lyme | 7 | 6 | 85.7% | 1 | 14.3% |
| Late | 20 | 20 | 100.0% | 20 | 100.0% |
| Look-alike Disease* | 90 | 0 | 100.0% | 0 | 100.0% |
*infectious mononucleosis, fibromyalgia, multiple sclerosis, rheumatoid arthritis, syphilis and severe periodontitis
8) Conclusion:
From the comparison data, we conclude that the Gold Standard Diagnostics Borrelia burgdorferi IgG ELISA Test is substantially equivalent to the Gold Standard Diagnostics Borrelia burgdorferi IgG Blot Test Kit (K113847) when used for the Modified Two-tier Testing (MTTT) Lyme testing.
§ 866.3830
Treponema pallidum treponemal test reagents.(a)
Identification. Treponema pallidum treponemal test reagents are devices that consist of the antigens, antisera and all control reagents (standardized reagents with which test results are compared) which are derived from treponemal sources and that are used in the fluorescent treponemal antibody absorption test (FTA-ABS), theTreponema pallidum immobilization test (T.P.I.), and other treponemal tests used to identify antibodies toTreponema pallidum directly from infecting treponemal organisms in serum. The identification aids in the diagnosis of syphilis caused by bacteria belonging to the genusTreponema and provides epidemiological information on syphilis.(b)
Classification. Class II (performance standards).