(328 days)
The BioPlex™ 2200 ANA Screen is intended for the qualitative screening of specific antinuclear antibodies (ANA), the quantitative detection of antibody to dsDNA, and the semi-quantitative detection of ten (10) separate antibody assays (Chromatin, Ribosomal Protein, SS-A, SS-B, Sm, SmRNP, RNP, Scl-70, Jo-1, and Centromere B) in human serum and/or EDTA or heparinized plasma.
The ANA Screen is used to screen serum or plasma (EDTA, heparin) samples and detect the presence of antinuclear antibodies as an aid in the diagnosis of systemic autoimmune diseases (Systemic Lupus Erythematosus [SLE], Mixed Connective Tissue Disease [MCTD], Undifferentiated Connective Tissue Disease [UCTD], Sjögren's Syndrome [SS], Scleroderma [Systemic Sclerosis], Dermatomyositis, Polymyositis, Rheumatoid Arthritis [RA]. CREST Syndrome, and Raynaud's Phenomenon) in conjunction with clinical findings and other laboratory tests.
The ANA Screen is intended for use with the Bio-Rad BioPlex 2200 System.
The BioPlex 2200 Medical Decision Support Software (MDSS), used in conjunction with the ANA Screen. is an optional laboratory tool that associates patient antibody results from the ANA Screen with predefined MDSS profiles that have been correlated with the following systemic autoimmune diseases: Systemic Lupus Erythematosus (SLE), Mixed Connective Tissue Disease (MCTD), Sjögren's Syndrome (SS), Scleroderma (Systemic Sclerosis) and Polymyositis.
The BioPlex 2200 Medical Decision Support Software (MDSS) is a pattern recognition algorithm that can enhance the performance of the ANA Sercen by identifying associated diagnostic patterns among its multiple assay results. The MDSS can suggest one or more possible discase associations after identifying patterns from the cleven ( 1 ) individual antibody results. The MDSS is based on the principles of the "k-nearest neighbor" 11 (kNN) statistical technique. Each "unknown" is compared to a pre-established database that contains the results for over 1,400 characterized scrappasma. Results of MDSS analysis fall into one of the following general outcomes: Negative, No Association, or Association with Disease. When the results of the MDSS analysis fall into the Association with Disease category, the MDSS software will propose a maximum of two disease classifications based upon the similarity of the current analysis to the stored results. The MDSS output can also aid in determining appropriate additional autoimmune serological testing.
Here's a summary of the acceptance criteria and the study that proves the device meets them for the BioPlex™ 2200 Medical Decision Support Software (MDSS).
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are implicitly derived from the "Percent Correct Association" data presented in the tables for both non-targeted and targeted disease classifications. The performance is reported as the percentage of correct associations between the MDSS output and the clinical diagnosis. No explicit threshold for acceptance is stated in the provided text.
| MDSS Output / Disease Classification | Acceptance Criteria (Implied) | Reported Device Performance Range |
|---|---|---|
| Negative (without any Targeted Disease) | High percentage correct | 81.4% (585/719) |
| No Association (without any Targeted Disease) | High percentage correct | 64% (57/89) |
| SLE only (with Targeted Disease) | High percentage correct | 71.7% (142/198) |
| SLE or SS (with Targeted Disease) | High percentage correct | 83.3% (35/42) |
| MCTD or SLE (with Targeted Disease) | High percentage correct | 81.1% (30/37) |
| Scleroderma (with Targeted Disease) | High percentage correct | 40.9% (9/22) |
| SLE or Scleroderma (with Targeted Disease) | High percentage correct | 55% (11/20) |
| Polymyositis only (with Targeted Disease) | High percentage correct | 66.7% (2/3) |
2. Sample Sizes and Data Provenance
- Test Set (Clinical Study):
- Main Cohort: 908 samples (serum, EDTA, and heparinized plasma) collected prospectively from consecutive patients in rheumatology clinics who were suspected of, or had a history consistent with, an autoimmune/connective tissue disease.
- Matched Subset: 214 subjects from the prospective population with matched serum, EDTA (N=214), and sodium heparinized plasma (N=214) samples.
- Additional Normals: 222 normal blood donors were added, presumed negative for autoimmune disease.
- Total for MDSS analysis: 1,130 results (908 clinic patients + 222 normal blood donors).
- Data Provenance: Prospectively collected from three sites in the U.S.
3. Number of Experts and Qualifications
The document states that diagnoses were made "using American College of Rheumatology (ACR) or appropriate established disease classification criteria" or "literature criteria." It also mentions "diagnosis provided by a physician." However, it does not specify the number of experts who established the ground truth for the test set, nor does it explicitly detail their specific qualifications (e.g., "radiologist with 10 years of experience").
4. Adjudication Method
The document does not explicitly describe an adjudication method for the test set. It refers to diagnoses based on established criteria and physician's input, but not a process for resolving discrepancies among multiple experts for individual cases.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No multi-reader multi-case (MRMC) comparative effectiveness study evaluating the effect size of human readers improving with AI vs. without AI assistance is described in the provided text. The study focuses on the standalone performance of the MDSS in relation to clinical diagnoses.
6. Standalone Performance
Yes, a standalone performance study was done. The entire "7.2 MEDICAL DECISION SUPPORT SOFTWARE (MDSS) PERFORMANCE ANALYSIS" section describes the evaluation of the MDSS algorithm's output against established clinical diagnoses. This is a standalone evaluation of the algorithm without human-in-the-loop performance.
7. Type of Ground Truth Used
The ground truth used was clinical diagnosis established by medical criteria. This includes:
- American College of Rheumatology (ACR) criteria
- American-European Consensus Group criteria
- Alaracon-Segovia or Kahn criteria
- Literature criteria (specifically for Polymyositis)
- "Diagnosis provided by a physician"
8. Sample Size for the Training Set
The software's algorithm is described as being "compared to a pre-established database that contains the results for over 1,400 characterized sera." This implies that the training set for the k-nearest neighbor (kNN) algorithm would be derived from these "over 1,400 characterized sera."
9. How Ground Truth for the Training Set Was Established
The document states the pre-established database contains "results for over 1,400 characterized sera." It does not explicitly detail how the ground truth for this training set was established, but given the nature of autoimmune disease diagnosis, it would likely involve similar established medical criteria and clinical diagnoses as the test set, applied retrospectively or through expert review. It uses the term "characterized sera," implying that these samples have known disease associations.
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BIOPLEX™ 2200 MEDICAL DECISION SUPPORT SOFTWARE FOR USE WITH THE BIOPLEX 2200 MULTI-ANALYTE DETECTION SYSTEM 510(k) SUMMARY
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.
| 510(k) Number | 510/k)Summary Report Date |
|---|---|
| 11122121 8 % | 0000(1) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1 (1 ) 1 ) 1. Ictoher. |
| 1.0 MANUFACTURER INFORMATION | |
|---|---|
| Medical Decision Support Software (MDSS) Manufacturing Site | |
| Manufacturer Address | Bio-Rad Laboratories, Inc.Clinical Systems Division4000 Alfred Nobel DriveHercules, CA 94547 |
| Telephone | (510) 724-7000 |
| Establishment Registration No. | 2915274 |
| Owner / Operator | Bio-Rad Laboratories, Inc.4000 Alfred Nobel DriveHercules, CA 94547 |
| Owner / Operator No. | 9929003 |
| Official Correspondent for the BioPlex 2200 ANA Screen | |
| Official Correspondent Address | Bio-Rad Laboratories6565 185th Ave NERedmond, WA 98052 |
| Telephone | 425-881-8300 |
| Establishment Registration No. | 3022521 |
| Owner / Operator | Bio-Rad Laboratories, Inc.4000 Alfred Nobel DriveHercules, CA 94547 |
| Official Correspondent | Mr. Christopher Bentsen |
| Telephone | (425) 498-1709 |
| Fax | (425) 498-1651 |
1.0 MANUFACTURER INFORMATION
2.0 CLASSIFICATION INFORMATION
BioPlex 2200 Medical Decision Support Software (MDSS) Classification
| BioPlex 2200 Medical Decision Support Software (MDSS) Classification | |
|---|---|
| Classification Name | Amphetamine Test System |
| Common Name: | Medical Decision Support Software |
| Product Trade Name | BioPlex 2200 Medical Decision Support Software (MDSS) on theBioPlex 2200 Multi-Analyte Detection System |
| Device Class | Class II |
| Classification Panel | Clinical Toxicology |
| Regulation Number | 862.3100 |
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| Classification Name | Antinuclear Antibody (Enzyme-Labeled). Antigen, Controls |
|---|---|
| Common Name: | Multi-Analyte Detection System. ANA Screen |
| Product Trade Name | BioPlex 2200 ANA Screen on theBioPlex 2200 Multi-Analyte Detection System |
| Device Class | Class 11 |
| Classification Panel | Immunology and Microbiology |
| Regulation Number | 866.5100 |
3.0 LEGALLY MARKETED EQUIVALENT (SE) DEVICES
| BioPlex 2200 System | Comparative FDA Cleared Device | 510(k) Number | Product Code | Decision Date |
|---|---|---|---|---|
| Medical Decision SupportSoftware (MDSS) | Remedi HS™ Drug Profiling System | K941596 | DNI | March 27, 1995 |
4.0 DEVICE DESCRIPTION
Note: The following product description is limited to the BioPlex 2200 ANA Screen Medical Decision Support Software (MDSS). A description of the BioPlex 2200 ANA Screen on the BioPlex 2200 Multi-Analyte Detection System is included in the pre-market notification submission K041658. Please refer to K041658 for a description of the BioPlex 2200 ANA Screen.
The BioPlex 2200 Medical Decision Support Software (MDSS) is a pattern recognition algorithm that can enhance the performance of the ANA Sercen by identifying associated diagnostic patterns among its multiple assay results. The MDSS can suggest one or more possible discase associations after identifying patterns from the cleven ( 1 ) individual antibody results. The MDSS is based on the principles of the "k-nearest neighbor" 11 (kNN) statistical technique. Each "unknown" is compared to a pre-established database that contains the results for over 1,400 characterized scrappasma. Results of MDSS analysis fall into one of the following general outcomes: Negative, No Association, or Association with Disease. When the results of the MDSS analysis fall into the Association with Disease category, the MDSS software will propose a maximum of two disease classifications based upon the similarity of the current analysis to the stored results. The MDSS output can also aid in determining appropriate additional autoimmune serological testing. All possible MDSS disease associations with corresponding definitions are listed in the following table. Note: MDSS outputs 9 through 15 were not observed in the clinical trial.
Table: MDSS Output
| # | MDSS Text Output | InternalOutputAbbreviations |
|---|---|---|
| 1 | All antibody levels for systemic autoimmune disease are below pre-established cutoffs.MDSS outputs of "Negative" or "No Association" do not rule out autoimmune disease.Patients with Rheumatoid Arthritis may result in an SLE association from MDSS. thus MDSSassociations from patients with RA should be interpreted with caution. | Negative |
| 2 | Antibody levels show no association with MDSS profiles for systemic autoimmune diseases.MDSS outputs of "Negative" or "No Association" do not rule out autoimmune disease.Patients with Rheumatoid Arthritis may result in an SLE association from MDSS. thus MDSSassociations from patients with RA should be interpreted with caution. | No Association(NA) |
| # | MDSS Text Output | InternalOutputAbbreviations |
| 3 | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider SLE. MDSS outputs of "Negative" or "No Association" do not rule out autoimmunedisease. Patients with Rheumatoid Arthritis may result in an SLE association from MDSS,thus MDSS associations from patients with RA should be interpreted with caution. | SLE |
| 4 | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider SLE or Sjogren's syndrome. MDSS outputs of "Negative" or "No Association" donot rule out autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLEassociation from MDSS thus MDSS associations from patients with RA should beinterpreted with caution. | SS / SLE |
| 5 | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider Polymyositis. MDSS outputs of "Negative" or "No Association" do not rule outautoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE associationfrom MDSS, thus MDSS associations from patients with RA should be interpreted withcaution. | Polymyositis |
| 6 | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider Scleroderma. MDSS outputs of "Negative" or "No Association" do not rule outautoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE associationfrom MDSS, thus MDSS associations from patients with RA should be interpreted withcaution. | Scleroderma |
| 7 | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider MCTD or SLE. MDSS outputs of "Negative" or "No Association" do not rule outautoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE associationfrom MDSS, thus MDSS associations from patients with RA should be interpreted withcaution. | MCTD / SLE |
| 8 | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider SLE or Scleroderma. MDSS outputs of "Negative" or "No Association" do not ruleout autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE associationfrom MDSS, thus MDSS associations from patients with RA should be interpreted withcaution. | SLE /Scleroderma |
| 9* | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider Polymyositis or SLE. MDSS outputs of "Negative" or "No Association" do not ruleout autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE associationfrom MDSS, thus MDSS associations from patients with RA should be interpreted withcaution. | Polymyositis /SLE |
| 10* | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider Polymyositis or MCTD. MDSS outputs of "Negative" or "No Association" do notrule out autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLEassociation from MDSS, thus MDSS associations from patients with RA should beinterpreted with caution. | Polymyositis /MCTD |
| 11* | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider Polymyositis or Sjogren's syndrome. MDSS outputs of "Negative" or "NoAssociation" do not rule out autoimmune disease. Patients with Rheumatoid Arthritis mayresult in an SLE association from MDSS, thus MDSS associations from patients with RAshould be interpreted with caution. | Polymyositis /SS |
| # | MDSS Text Output | InternalOutputAbbreviations |
| 12* | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider Polymyositis or Scleroderma. MDSS outputs of "Negative" or "No Association" donot rule out autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLEassociation from MDSS. thus MDSS associations from patients with RA should beinterpreted with caution. | Polymyositis /Scleroderma |
| 13* | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider MCTD or Sjogren's syndrome. MDSS outputs of "Negative" or "No Association"do not rule out autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLEassociation from MDSS, thus MDSS associations from patients with RA should beinterpreted with caution. | MCTD / SS |
| 14* | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider MCTD or Scleroderma. MDSS outputs of "Negative" or "No Association" do notrule out autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLEassociation from MDSS, thus MDSS associations from patients with RA should beinterpreted with caution. | MCTD /Scleroderma |
| 15* | Antibody levels show association with MDSS profiles for systemic autoimmune disease.Consider Scleroderma or Sjogren's syndrome. MDSS outputs of "Negative" or "NoAssociation" do not rule out autoimmune disease. Patients with Rheumatoid Arthritis mayresult in an SLE association from MDSS, thus MDSS associations from patients with RAshould be interpreted with caution. | Scleroderma /SS |
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- Note: these MDSS outputs were not observed in the clinical trial.
5.0 INTENDED USE
The BioPlex™ 2200 ANA Screen is intended for the qualitative screening of specific antinuclear antibodies (ANA), the quantitative detection of antibody to dsDNA, and the semi-quantitative detection of ten (10) separate antibody assays (Chromatin, Ribosomal Protein, SS-A. SS-B. Sm, SmRNP, RNP, Scl-70, Jo-1. and Centromere B) in human serum and/or EDTA or heparinized plasma. The test system is used as an aid in the diagnosis of systemic autoimmune diseases.
The ANA Screen is intended for use with the Bio-Rad BioPlex 2200 System.
The BioPlex 2200 Medical Decision Support Software (MDSS), used in conjunction with the ANA Screen. is an optional laboratory tool that associates patient antibody results with predefined MDSS profiles that have been correlated with the following systemic autoimmune diseases: Systemic Lupus Erythematosus (SLE), Mixed Connective Tissue Disease (MCTD), Sjögren's Syndrome (SS), Scleroderma (Systemic Sclerosis) and Polymvositis.
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5.1 Indications For Use
The BioPlex™ 2200 ANA Screen is intended for the qualitative screening of specific antinuclear antibodies (ANA), the quantitative detection of antibody to dsDNA, and the semi-quantitative detection of ten (10) separate antibody assays (Chromatin, Ribosomal Protein, SS-A, Sm, SmRNP. RNP. Scl-70, Jo-1, and Centromere B) in human serum and/or EDTA or heparinized plasma.
The ANA Screen is used to screen serum or plasma (FDTA, heparin) samples and detect the presence of antinuclear antibodies as an aid in the diagnosis of systemic autoimmune discases (Systemic Lupus Frythematosus [SLE], Mixed Connective Tissue Discase [MCTD], Undifferentiated Connective Tissue Disease [UCTD], Sjögren's Syndrome [SS]. Scleroderma [Systemic Sclerosis], Dermatomyositis, Polymyositis. Rheumatoid Arthriis [RA]. CREST Syndrome. and Raynaud' in conjunction with clinical findings and other laboratory tests.
The ANA Screen is intended for use with the Bio-Rad BioPlex 2200 System.
The BioPlex 2200 Medical Decision Support Software (MDSS), used in conjunction with the ANA Screen, is an optional laboratory tool that associates patient antibody results from the ANA Screen with predefined MDSS profiles that have been correlated with the following systemic autoimmune diseases: Systemic Lupus Erythematosus (SLE), Mixed Connective Tissue Disease (MCTD). Sjögren's Syndrome (SS). Scleroderma (Systemic Sclerosis) and Polymvositis.
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6.0 TECHNOLOGICAL CHARACTERISTICS
Note: The following comparison information is limited to the BioPlex 2200 ANA Screen Medical Decision Support Software (MDSS). Comparison information for the BioPlex 2200 ANA Screen on the BioPlex 2200 Multi-Analyte Detection System is included in the pre-market notification submission K041658. currently under review by the U.S. Food and Drug Administration.
The following table summarizes similarities and difference between the Bioplex 2200 Medical Decision Support Software and the Remedi HS'" Drug Profiling System (K 941596).
| Similarities betweenData ProcessingModules | BioPlex 2200 Medical DecisionSupport Software | Remedi HS Drug Profiling System |
|---|---|---|
| Input | Library or training set data on testresults from 1,130 patients. | Library of known drug spectrastored in memory. |
| Function | Data processing module forassociation of patient specificinformation with the currentcondition of the patient. | Data processing module forassociation of patient specificinformation with the currentcondition of the patient. |
| Technology | Computer based, software driven,data driven algorithm. | Sophisticated computer algorithm. |
| Output | Test results as compared totraining set. | Test results as compared to knownlibrary. |
Table 1 (a): Similarities between data processing modules
| Table 1 (b): Differences between data processing modules |
|---|
| Differences betweenData ProcessingModules | BioPlex 2200 Medical DecisionSupport Software | Remedi HS Drug Profiling System |
|---|---|---|
| Input | Results from serological analysisof patient serum or plasma forspecific autoantibodies. | Results from chromatographicanalysis of patient urine or serumfor drugs. |
| Function | Identification of possible diseaseassociations. | Identification of possible drugs inthe biological specimen. |
| AlgorithmTechnology | k-Nearest Neighbor data analysisalgorithm and pre-establishedmedical database. | Peak Identification for comparison ofunknown to spectral library of drugs. |
| Output | List of test results in IU/ml and AI(antibody index). | List of test results in the form of aChromatogram. |
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7.0 PERFORMANCE SUMMARY
Note: Performance testing summarized in this section is limited to additional clinical concordance and MDSS related claims added to the package insert since submission of K041658, BioPlex 2200 ANA Screen on the BioPlex 2200 Multi-Analyte Detection System. Please refer to K041658 for performance testing information relating to the original BioPlex 2200 ANA Screen submission.
Clinical testing to evaluate the clinical performance of the BioPlex 2200 Medical Decision Support Software (MDSS) for use with the BioPlex 2200 Multi-Analyte Detection System, as well as the concordance of the BioPlex 2200 ANA Screen with clinical diagnosis for seven targeted diseases was conducted at three sites located in the U.S. The study was conducted using 908 samples collected prospectively from consecutive patients being seen in a rheumatology clinic and suspected of, or with a history consistent with an autoimmune / connective tissue disease. A subset of 214 subjects from this prospective population was collected and tested as matched serum, EDTA (N =214), and sodium heparinized plasma (N=214) samples.
Additionally. 222 normal blood donors were added to the MDSS analysis where they were presumed to be negative for autoimmune discase.
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7.1 BioPlex 2200 Ana Screen Clinical Concordance Analysis
7.1.1 Targeted Disease Analysis
In addition to traditional sensitivity. specificity and predictive value analysis. the use of likelihood ratio analysis has been recommended for autoimmune testing. Performance of the ANA Screen was compared against five (5) targeted disease associations with results presented in the following table. Samples were prospectively collected from patients being seen in a theumatology clinic diagnosed using American College of Rheumatology (ACR) or appropriate established disease classification criteria for any mention of the following targeted disease associations:
- . Systemic Lupus Erythematosus (SLE)
- . Sjögren´s Syndrome
- . Scleroderma (Systemic Sclerosis)
- Mixed Connective Tissue Disease (MCTD) .
- . Polymyositis
Table: Targeted Disease Associations
| N 908 | BioPlex ANA Screen | ||
|---|---|---|---|
| Positive | Negative | Total | |
| Targeted CTD Disease | 280 | 134 | 414 |
| All Othersnon targeted and no CTD | 110 | 384 | 494 |
| Total | 390 | 518 | 908 |
| Sensitivity | 67.6% 95% CI 63.0 - 72.3% |
|---|---|
| Specificity | 77.7% 95% CI 73.9 - 81.5% |
| Overall Agreement | 73.1% 95% CI 70.2 - 76.1% |
| Positive Likelihood Ratio | 3.04 95% CI 2.54 – 3.62 |
| Negative Likelihood Ratio | 0.42 95% CI 0.36 – 0.48 |
| Odds Ratio | 7.29 95% CI 5.43 – 9.80 |
| Prevalence | 45.6% 95% CI 42.3 – 48.9 |
The above (as well as subsequent) statistical calculations are defined as follows:
Sensitivity: TP/(TP+FN) x 100 Specificity: TN/(FP+TN) x 100 Prevalence: (TP+FN)/(TP+FN+J·P+TN) x 100 ()verall Agreement: (TP+TN)/(TP+FN+FP+TN) x 100
eement: (TP
where
| TP = True Positive | TN True Negative |
|---|---|
| FP = False Positive | FN False Negative |
| Positive Likelihood Ratio: $Sensitivity/(100-Specificity)$ | |
| Negative Likelihood Ratio: $(100-Sensitivity)/Specificity$ | |
| Odds Ratio: $(TPxTN)/(FPxFN)$ | |
| Prevalence: $(TP+FN)/(TP+FN+FP+TN) x 100$ |
BioPlex 2200 ANA Screen with MDSS 510(k) Summary (revised 9/28/05)
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7.1.2 Individual Disease Analysis
Performance of the ANA Screen was compared against the predicate device in the five (5) targeted discass associations. They are shown in the following set of clinical concordance summary tables where the area(s) in white represent autoantibodies that are clinically relevant for the specific disease classification being discussed. The area(s) in light grey represent autoantibodies that are commonly observed for the specific disease classification. The area(s) in dark grey represent autoantibodies that are not commonly associated with the specific disease classification. Patients may have multiple diagnoses and may be represented in several disease classifications.
Systemic Lupus Erythematosus (SLE)
Performance of the ANA Screen was compared against the predicate device by testing samples prospectively collected from patients being seen in a theumatology clinic diagnosed using American College of Rheumatology (ACR) critcria for any mention of SLE. The specimens were tested by both the ANA Screen and commercially available microplate ElA methods that were specific for the corresponding autoantibodies. Results are summarized in the following table.
| N= 332 | ANA Screen | dsDNA a | Chromatin | Ribosomal Protein | SS-A | SS-B | Sm | SmRNP | RNPb | Scl-70 | Jo-1 | Centromere B |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bio-Rad and EIA Positive | 213 | 75 | 86 | 16 | 101 | 34 | 30 | 66 | 53 | 1 | 1 | 6 |
| Bio-Rad Positive and EIA Negative | 7 | 9 | 36 | 14 | 10 | 8 | 19 | 10 | 13 | 6 | 0 | 5 |
| Bio-Rad and EIA Negative | 57 | 190 | 183 | 299 | 218 | 280 | 280 | 241 | 244 | 323 | 328 | 321 |
| Bio-Rad Negative and EIA Positive | 55 | 12 | 27 | 3 | 3 | 10 | 3 | 15 | 7 | 2 | 3 | 0 |
| % Overall Agreement | 81% | 93% | 81% | 95% | 96% | 95% | 92% | 93% | 94% | 98% | 99% | 98% |
| 95% Confidence Interval | 77 - 86% | 89 - 96% | 77 - 85% | 92 - 97% | 94 - 98% | 92 - 97% | 90 - 96% | 89 - 95% | 91 - 97% | 96 - 99% | 98 - 100% | 97 - 100% |
Table: ANA Screen vs FIA: Clinical Diagnosis - SLE
Note: 95% confidence interval not calculated for antibodies not clinically relevant to disease.
4 46 Bioplex dsDNA indeterminate and EIA dsDNA equivocal results are excluded from the calculations.
b 15 EIA RNP equivocal results are excluded from the calculations.
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Primary Sjögren's Syndrome
Performance of the ANA Screen was compared against the predicate device by testing samples prospectively collected from patients being seen in a theumatology clinic diagnosed with an American-European Consensus Group criteria for any mention of Primary Sjögren's Syndrome. The specimens were tested by both the ANA Screen and commercially available microplate EIA methods that were specific for the corresponding autoantibodies. Results are summarized in the following table.
| N=16 | ANA Screen | DsDNA* | Chromatin | Ribosomal Protein | SS-A | SS-B | Sm | SmRNP | RNP | Scl-70 | Jo-1 | Centromere B |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bio-Rad andEIA Positive | 15 | 1 | 1 | 0 | 15 | 13 | 0 | 0 | 0 | 0 | 0 | 0 |
| Bio-Rad Positiveand EIA Negative | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Bio-Rad andEIA Negative | 1 | 12 | 13 | 16 | 1 | 2 | 16 | 14 | 15 | 16 | 16 | 16 |
| Bio-Rad Negativeand EIA Positive | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 0 |
| % OverallAgreement | 100% | 100% | 88% | 100% | 100% | 94% | 100% | 88% | 94% | 100% | 100% | 100% |
| 95%Confidence Interval | 86-100% | 51-90% | 64-97% | 86-100% | 86-100% | 72-99% | 86-100% | 64-97% | 72-99% | 86-100% | 86-100% | 86-100% |
Table: ANA Screen vs EIA: Clinical Diagnosis – Primary Sjögren's Syndrome
- 3 dsDNA BioPlex indeterminate and EIA equivocal results were excluded from the calculations.
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Scleroderma (Svstemic Sclerosis)
Performance of the ANA Screen was compared against the predicate device by testing sumples prospectively collected from patients being seen in a rheumatology clinic diagnosed using ACR criteria for any mention of Scleroderma. The specimens were tested by both the ANA Screen and commercially available microplate E1A methods that were specific for the corresponding autoantibodies. Results are summarized in the following table.
| Table: ANA Screen vs EIA: Clinical Diagnosis - Scleroderma (Systemic Sclerosis) - | ||
|---|---|---|
| ----------------------------------------------------------------------------------- | -- | -- |
| N=44 | ANA Screen | dsDNA | Chromatin | RibosomalProtein | SS-A | SS-B | Sm | SmRNP | RNP | Scl-70 | Jo-1 | Centromere B |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bio-Rad andEIA Positive | 28 | 1 | 3 | 0 | 7 | 1 | 0 | 3 | 4 | 6 | 0 | 12 |
| Bio-Rad Positiveand EIA Negative | 1 | 3 | 3 | 0 | 3 | 1 | 2 | 0 | 0 | 1 | 0 | 0 |
| Bio-Rad andEIA Negative | 5 | 40 | 36 | 44 | 30 | 42 | 42 | 40 | 38 | 36 | 44 | 32 |
| Bio-Rad Negativeand EIA Positive | 10 | 0 | 2 | 0 | 4 | 0 | 0 | 1 | 2 | 1 | 0 | 0 |
| % OverallAgreement | 75% | 93% | 89% | 100% | 84% | 98% | 96% | 98% | 96% | 96% | 100% | 100% |
| 95%Confidence Interval | 60-90% | 84-100% | 78-100% | 99-100% | 72-97% | 92-100% | 88-100% | 92-100% | 88-100% | 87-100% | 99-100% | 99-100% |
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Image /page/11/Picture/0 description: The image shows the logo for BIO-RAD. The logo is in white text on a black background. The text is bold and sans-serif.
Mixed Connective Tissue Disease (MCTD)
Performance of the ANA Screen was compared against the predicate device by testing samples prospectively collected from patients seen in a rheumatology clinic who were diagnosed with an Alaracon-Segovia or Kahn criteria for any mention of MCTD. The specimens were tested by both the ANA Screen and commercially available microplate EIA methods that were specific for the corresponding autoantibodies. The high incidence of anti-chromatin antibodies in patients with MCTD has been previously documented. Results are summarized in the following table.
| N-16 | ANA Screen | dsDNA | Chromatin | Ribosomal Protein | SS-A | SS-B | Sm | SmRNP | RNP | Scl-70 | Jo-1 | Centromere B |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bio-Rad andEIA Positive | 16 | 1 | 3 | 1 | 2 | 0 | 4 | 15 | 14 | 0 | 1 | 1 |
| Bio-Rad Positiveand EIA Negative | 0 | 1 | 11 | 0 | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 0 |
| Bio-Rad andEIA Negative | 0 | 13 | 2 | 15 | 14 | 16 | 10 | 1 | 1 | 15 | 15 | 15 |
| Bio-Rad Negativeand EIA Positive | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| % OverallAgreement | 100% | 88% | 31% | 100% | 100% | 100% | 88% | 100% | 94% | 94% | 100% | 100% |
| 95% ConfidenceInterval | 86-100% | 64-97% | 14-56% | 86-100% | 86-100% | 86-100% | 64-97% | 86-100% | 72-99% | 72-99% | 86-100% | 86-100% |
Table: ANA Screen vs EIA: Clinical Diagnosis – Mixed Connective Tissue Disease (MCTD)
BioPlex 2200 ANA Screen with MDSS 510(k) Summary (revised 9/28/05)
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Image /page/12/Picture/0 description: The image shows the logo for Bio-Rad Laboratories, a company that manufactures and distributes products for the life science research and clinical diagnostics markets. The logo is in black and white, with the words "BIO-RAD" in bold, sans-serif font. The logo is enclosed in a rounded rectangle.
Polymyositis
Performance of the ANA Screen was compared against the predicate device by testing samples prospectively collected from patients seen in a rheumatology clinic who were diagnosed with literature criteria for Polymyositis. The specimens were tested by both the ANA Screen and commercially available microplate EIA methods that were specific for the corresponding autoantibodies. Note: The presence of antibodies to Jo-1 in patients diagnosed with Polymyositis has been well documented. Results are summarized in the following table.
| N=12 | ANA Screen | dsDNA | Chromatin | RibosomalProtein | SS-A | SS-B | Sm | SmRNP | RNP | Scl-70 | Jo-1 | Centromere B |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bio-Rad andEIA Positive | 6 | 0 | 0 | 0 | 5 | 0 | 0 | 1 | 1 | 0 | 2 | 0 |
| Bio-Rad Positiveand EIA Negative | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Bio-Rad andEIA Negative | 3 | 12 | 11 | 12 | 7 | 12 | 12 | 11 | 11 | 12 | 10 | 12 |
| Bio-Rad Negativeand EIA Positive | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| % OverallAgreement | 75% | 100% | 92% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| 95% ConfidenceInterval | 47-91% | 82-100% | 65-99% | 82-100% | 82-100% | 82-100% | 82-100% | 82-100% | 82-100% | 82-100% | 82-100% | 82-100% |
Table: ANA Screen vs EIA: Clinical Diagnosis – Polymyositis
BioPlex 2200 ANA Screen with MDSS 510(k) Summary (revised 9/28/05)
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Image /page/13/Picture/0 description: The image shows the logo for Bio-Rad. The logo is in a black rounded rectangle. The text "BIO-RAD" is in white and is centered in the rectangle.
Non-Targeted and No Connective Tissue Disease
Performance of the ANA Screen was compared against the predicate device by testing samples prospectively collected from patients seen in a rheumatology clinic who were not diagnosed with a targeted connective tissue disease by established medical criteria. The specimens were tested by both the ANA Screen and commercially available microplate EIA methods that were specific for the corresponding autoantibodies. Results are summarized in the following table.
| Tahle: ANA Screen vs EIA: Clinical Diagnosis - Non-Targeted and No Connective Tissue Diseas. | ||||||||
|---|---|---|---|---|---|---|---|---|
| ---------------------------------------------------------------------------------------------- | -- | -- | -- | -- | -- | -- | -- | -- |
| N=494 | ANA Screen | dsDNA | Chromatin | Ribosomal Protein | SS-A | SS-B | Sm | SmRNP | RNP | Scl-70 | Jo-1 | Centromere B |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| BioPlex 2200 andEIA Positive | 79 | 6 | 7 | 1 | 28 | 9 | 3 | 9 | 10 | 2 | 2 | 13 |
| BioPlex 2200Positive and EIANegative | 31 | 15 | 20 | 5 | 6 | 10 | 4 | 3 | 12 | 6 | 0 | 1 |
| BioPlex 2200 andEIA Negative | 303 | 459 | 437 | 488 | 453 | 474 | 486 | 477 | 465 | 481 | 490 | 479 |
| BioPlex 2200 Negativeand EIA Positive | 81 | 14 | 30 | 0 | 7 | 1 | 1 | 5 | 7 | 5 | 2 | 1 |
| % Overall Agreement | 77% | 94% | 90% | 99% | 97% | 98% | 99% | 98% | 96% | 98% | 99.6% | 99.6% |
| 95% ConfidenceInterval | 74-81% | 92-96% | 87-93% | 98-100% | 96-99% | 96-99% | 98-100% | 97-100% | 94-98% | 96-99% | 99-100% | 99-100% |
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Image /page/14/Picture/0 description: The image shows the logo for BIO-RAD. The logo is white text on a black background. The text is bold and sans-serif.
7.2 MEDICAL DECISION SUPPORT SOFTWARE (MDSS) PERFORMANCE ANALYSIS
BioPlex ANA Sereen Medical Decision Support Software (MDSS) results, when compared with disease classification by ACR. literature or appropriate established medical criteria for targeted connective tissue disease (TCTD), are presented in the following tables. The MDSS can suggest one or more possible discase associations after identifying patterns from the eleven (11) individual antibody results. Suggesting one on more possible discase associations may aid a physician in the differential diagnosis of certain systemic autoimmune diseases, since a recent study demonstrated only a 49% agreement between the referring and final diagnosis. In addition. MDSS can report that antibody levels show no association with MDSS defired patterns (No Association), or may report that all antibody results are below the established cut-offs (Negative). A total of 1.130 results, a combination of the 908 subjects seen in rheumatology clinics and the 222 normal blood donors presumed to be negative for autoimmune diseases, were analyzed.
Note: It is sometimes difficult to distinguish SLE and Sjögren's disease, even when both serological and clinical data are considered. The complexity inherent in diagnosing autoimmune disease is further illustrated in a recent study that demonstrated only a 49% agreement between the referring physician and final diagnosis.
| Negative for all antibodies | All antibody levels for systemic autoimmune disease arebelow pre-established cutoffs |
|---|---|
| Positive for one or more antibody | Any one of the BioPlex 2200 ANA 11 analytes is positive |
| SLE | Systemic Lupus Erythematosus |
| SS | Sjögren's Syndrome |
| Scleroderma | same |
| MCTD | Mixed Connective Tissue Disease |
| Polymyositis | same |
| No Association | Antibody levels show no association with MDSS definedpatterns for systemic autoimmune diseases |
MDSS descriptions used in the following MDSS clinical performance tables are defined as follows:
7.2.1 MDSS vs. Disease Classification - Targeted and Non-Targeted Connective Tissue Diseases
The following table presents percent disease agreement of the MDSS output with the diagnosis provided by a physician. Data is presented as percent diseases agreement for patients with one or more positive antibodies and for patients with a targeted connective tissue (TCTD) classification, regardless of antibody response. The difference between disease agreements is the inclusion of negative results for all antibodies in the TCTD patients. MDSS does not provide an association with a patient with negative test results for all antibodies.
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| Disease Classificationby Criteria** | (N) | Negative for all antibodies | Positive for one or more antibody (P) | No Association | MDSS Output * | % DiseaseAgreement | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Any SLE Association | Any Sjögren's SyndromeAssociation | Any ScICR Association | Any MCTD Association | Any Polymyositis Association | Patients withPositiveAntibodyOnly(P) | Patients withTCTDClassification(N) | ||||||
| Targeted Connective Tissue Disease(TCTD) | Systemic LupusErythematosus (SLE) | 332 | 114 | 218 | 28 | 186 | 22 | 7 | 18 | 0 | 85.3%(186/218) | 56.0%(186/332) |
| Primary Sjögren'sSyndrome | 16 | 1 | 15 | 0 | 15 | 13 | 0 | 0 | 0 | 86.7%(13/15) | 81.3%(13/16) | |
| Scleroderma | 44 | 13 | 31 | 3 | 19 | 1 | 16 | 3 | 0 | 51.6%(16/31) | 36.4%(16/44) | |
| Mixed ConnectiveTissue Disease(MCTD) | 16 | 0 | 16 | 0 | 15 | 0 | 1 | 13 | 0 | 81.3%(13/16) | 81.3%(13/16) | |
| Polymyositis | 12 | 6 | 6 | 0 | 4 | 0 | 0 | 1 | 2*** | 33.3%(2/6) | 16.7%(2/12) |
Table: MDSS vs. Disease Classification (N=1130)
- See Appendix A for a complete list of possible MDSS outputs. Note: as indicated in Appendix A, not all MDSS outputs were observed in the clinical trial. Sjögren's Syndrome alone and MCTD alone are not outputs of MDSS.
**Targeted diseases presented include all patients with each disease classification, and patients may have multiple disease classifications, with the exception of Primary Sjögren's Syndrome.
***For these patients, the MDSS outputs suggesting Polymyositis referenced the disorder alone and not in combination with another Targeted Connective Tissue Disease
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7.2.2 MDSS Assignments in Patients with TCTD and a Positive Antibody Result
Laboratory measurement of autoantibodies has historically been driven by a presumptive diagnosis. For example, a request for anti-Sm would follow from a presumptive diagnosis of SLE. A positive result for anti-Sm would be supportive of the presumptive diagnosis. The table below presents the % agreement of the MDSS output when a specific positive antibody result is present and the diagnosis provided by the physician is consistent with the presence of that antibody. The table shows that for such samples, the MDSS associations are in good agreement with the diagnosis by established medical criteria.
| Positive AntibodyTest Results | Disease by EstablishedMedical Criteria* | MDSS Output** | % Agreement | 95%ConfidenceInterval |
|---|---|---|---|---|
| dsDNA (N = 119) | SLE (N = 92) | Any SLE (N = 87) | 87/92 or 95% | 89-100% |
| Chromatin (N = 168) | SLE (N = 122) | Any SLE (N = 112) | 112/122 or 92% | 86-97% |
| Ribosomal Protein(N = 37) | SLE (N = 30) | Any SLE (N = 29) | 29/30 or 97% | 83-99% |
| SSA (N = 173) | SS (N = 15) | SS or SLE (N = 13) | 13/15 or 87% | 62-96% |
| SLE (N = 111) | Any SLE (N = 106) | 106/111 or 96% | 91-100% | |
| SSB (N = 76) | SS (N = 13) | SS or SLE (N = 13) | 13/13 or 100% | 83-100% |
| Sm (N = 60) | SLE (N = 49) | Any SLE (N = 49) | 49/49 or 100% | 99-100% |
| SmRNP (N = 103) | MCTD (N = 15) | MCTD or SLE(N = 13) | 13/15 or 87% | 62-96% |
| RNP (N = 112) | MCTD (N = 15) | MCTD or SLE(N = 13) | 13/15 or 87% | 62-96% |
| Scl-70 (N = 23) | Scleroderma (N = 7) | Scleroderma:SLE or Scleroderma(N = 5) | 5/7 or 71% | 36-92% |
| Jo-1 (N = 6)*** | Polymyositis (N = 2) | Polymyositis(N = 2) | 2/2 or 100% | 43-100% |
| Centromere (N = 38) | Scleroderma (N = 12) | Scleroderma:SLE or Scleroderma(N = 11) | 11/12 or 92% | 65-99% |
| SLE (N = 11) | Any SLE (N = 9) | 9/11 or 82% | 52-95% |
Table: MDSS Assignments in Patients with TCTD and a Positive Antibody Result
- Targeted diseases presented include all patients with each disease classification, and patients may have multiple disease classifications. Established medical criteria used in this study include criteria established by the American College of Rheumatology (ACR). American-European Consensus Group. Alarcon-Segovia or Kahn, as well as literature criteria for Polymyositis.
***Note: The presence of antibodies to Jo-1 in patients diagnosed with Polymyositis has been well documented
BioPlex 2200 ANA Screen with MDSS 510(k) Summary (revised 9/28/05)
Page 17 of 21
**See Appendix A of the Instructions For Use for a complete list of possible MDSS onlines.
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Image /page/17/Picture/0 description: The image shows the logo for Bio-Rad Laboratories, a company that manufactures and distributes products for the life science research and clinical diagnostics markets. The logo is a black rounded rectangle with the words "BIO-RAD" in white letters. The letters are bold and sans-serif, and the logo is simple and recognizable.
7.2.3 MDSS Agreement with Disease Classification by Criteria
For each of the targeted connective tissue diseases encountered in the tables below present the number of patients with a positive antibody test and the number of correct MDSS associations in addition to calculations of Odds Ratio, Positive Likelihood Ratio, and Negative Likelihood Ratio. Since some MDSS outputs contain more disease associations than the discase association under consideration, the results in the first table were calculated by excluding patients with other diseases listed in the output. The scond table presents results where these patients were not excluded. Not all patients with a targeted connective tissue disease produce antibodies that may be detected with the BioPlex 2200 ANA Screen.
| Disease Classificationby Criteria | SystemicLupusErythematosus(SLE)(N = 332) | PrimarySjögren'sSyndrome(N = 16) | Scleroderma(N = 44) | MixedConnectiveTissue Disease(N = 16) | Polymyositis(N = 12) |
|---|---|---|---|---|---|
| Positive AntibodyTest(s) | 218 | 15 | 31 | 16 | 6 |
| MDSS Associations | 186 | 13 | 16 | 13 | 2 |
| Odds Ratio (OR) | 12.8 | 479.8 | 22.1 | 481 | 223.4 |
| OR 95% ConfidenceInterval | 9.1 - 17.8 | 111.4 -2065.6 | 10.3 - 47.5 | 111.7 - 2071.9 | 11.9 - 2667.6 |
| Positive LikelihoodRatio (PLR) | 6.17 | 90.8 | 14.4 | 91.0 | 186.3 |
| (PLR) 95% ConfidenceInterval | 4.8 - 7.9 | 41.8 -196.9 | 7.9 - 26.1 | 41.95 - 197.35 | 18.1 - 1919.2 |
| Negative LikelihoodRatio (NLR) | 0.48 | 0.19 | 0.65 | 0.19 | 0.83 |
| NLR 95% ConfidenceInterval | 0.43 - 0.54 | 0.07 - 0.52 | 0.52 - 0.81 | 0.07 - 0.52 | 0.65 - 1.07 |
| Total N after exclusions | 1059 | 798 | 798 | 800 | 1130 |
Table: MDSS Agreement with Disease Classification (excluding patients with other MDSS associations)
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| Table: MDSS Agreement with Disease Classification (including patients with multiple MDSS associations) | ||
|---|---|---|
| -------------------------------------------------------------------------------------------------------- | -- | -- |
| Disease Classificationby Criteria | Systemic LupusErythematosus(SLE)(N = 332) | PrimarySjögren'sSyndrome(N = 16) | Scleroderma(N = 44) | MixedConnectiveTissue Disease(N = 16) | Polymyositis(N = 12) |
|---|---|---|---|---|---|
| Positive AntibodyTest(s) | 218 | 15 | 31 | 16 | 6 |
| MDSS Associations | 186 | 13 | 16 | 13 | 2 |
| Odds Ratio (OR) | 7.9 | 162.1 | 23.3 | 196.8 | 223.4 |
| OR 95% ConfidenceInterval | 5.9 - 10.6 | 43.8 -599.6 | 11.3 - 48.2 | 52.6 - 735.4 | 11.9 - 2667.6 |
| Positive LikelihoodRatio (PLR) | 4.03 | 31.21 | 15.19 | 37.71 | 186.3 |
| (PLR) 95%Confidence Interval | 3.3 - 4.9 | 20.3 - 47.9 | 8.8 - 26.2 | 23.8 - 59.8 | 18.1 - 1919.2 |
| Negative LikelihoodRatio (NLR) | 0.51 | 0.19 | 0.65 | 0.19 | 0.83 |
| NLR 95% ConfidenceInterval | 0.45 - 0.57 | 0.07 - 0.53 | 0.52 - 0.81 | 0.07 - 0.53 | 0.65 - 1.07 |
| Total N | 1130 | 1130 | 1130 | 1130 | 1130 |
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7.2.4 MDSS vs. Non-Targeted Connective Tissue Diseases
Some of the Clinical Disease Classifications encountered do not have an associated MDSS output. These nontargeted connective tissue diseases should be classified as cither Negative or No Association by MDSS. However, in some instances, a MDSS association was incorrectly presented. The MDSS results incorrectly associated with a targeted connective tissue discase can be classified as % Incorrect Association. The results are summarized in the following table:
Table: MDSS vs. Non-Targeted Connective Tissue Diseases
| Clinical DiseaseClassification | (N) | Negative or NoMDSSAssociations | Incorrect MDSSAssociations | % IncorrectAssociation | |
|---|---|---|---|---|---|
| Non TCTD | Dermatomyositis- only | 15 | 12 | 3 | 20% (3/15) |
| Rheumatoid Arthritis- only | 341 | 310 | 31* | 9% (31/341) | |
| Other CTD- only | 45 | 36 | 9 | 20% (9/45) | |
| No CTD | 77 | 77 | 61 | 16 | |
| Blood Donor Samples | 222 | 222 | 214 | 8** |
- ()f the 31 patients with only theumatoid arthritis, 27 were associated with SLE by MDSS. Patients with Rheumatoid Arthritis may result in an SLE association from MDSS. Additionally patients with Rheumatoid Arthritis who are receiving anti-TNF a blockers as part of their therapy have been reported to produce antibodies against both dsDNA and Chromatin. For these reasons, MDSS associations from patients with Rheumatoid Arthritis should be interpreted with caution. See also Limitations of the Procedure.
** The clinical status of blood donors tested in this study was not known.
Page 20 of 21 BioPlex 2200 ANA Screen with MDSS 510(k) Summary (revised 9/28/05)
140
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7.2.5 MDSS Correct Association with Disease Classification
Traditional evaluation strategies for diagnostic tests do not always directly apply to the evaluation of decision support systems, because decision support systems often do not provide one answer, and each subject may have more than one diagnosis. The percent correctness is delined for this study as the number of patients with a given MDSS association who also have that disease by ACR, literature, or established medical criteria. The percent correctness results illustrated in Tables T and U should be considered in conjunction with the following prevalence of disease observed in this study: SLF 29% (332/1130), Sjögren's Syndrome 1.4% (16/1130), Scleroderma 3.9% (44/1130), Mixed Connective Tissue Diseasc 1.4% (16/1130), Polymyositis 1.1% (12/1130), Other Connective Tissue Disease 36.9% (417/1130), and No Connective Tissue Disease 6.8% (77/1130). Note: the Correct Association values presented in the following tables may change in different patient populations.
| MDSS Output | # by MDSS | # Without anyTargeted Disease | CorrectAssociation | 95% ConfidenceInterval |
|---|---|---|---|---|
| Negative | 719 | 585 | 81.4% (585/719) | 78.4 - 84.3% |
| No Association | 89 | 57 | 64% (57/89) | 53.3 - 74.8 |
Table: Correct Association without any Targeted Disease Classification
| MDSS Output | # by MDSS | # by ClinicalDiagnosis | CorrectAssociation | 95% ConfidenceInterval |
|---|---|---|---|---|
| SLE only | 198 | 142 | 71.7% (142/198) | 65.1 - 78.3% |
| SLE or SS | 42 | 35 | 83.3% (35/42) | 70.2 - 96.5% |
| MCTD or SLE | 37 | 30 | 81.1% (30/37) | 66.3 - 95.9% |
| Scleroderma | 22 | 9 | 40.9% (9/22) | 23.3 - 61.3% |
| SLE orScleroderma | 20 | 11 | 55% (11/20) | 34.2 - 74.2% |
| Polymyositisonly | 3* | 2 | 66.7% (2/3) | 20.8 - 93.9% |
Table: Correct Association with Targeted Disease Classification
- One of these 3 patients was diagnosed with Dermatomyositis.
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
OCT 2 7 2005
Food and Druq Administration 2098 Gaither Road Rockville MD 20850
Bio-Rad Laboratories c/o Mr. Christopher Bentsen Manager, Regulatory, Quality and Clinical Affairs 6565 185" Ave., NE Redmond, WA 98052
Re: K043341
Trade/Device Name: BioPlex™ 2200 ANA Screen with Medical Decision Support Software (MDSS) for use with the BioPlex™ 2200 Multi-Analyte Detection System Regulation Number: 21 CFR 862.3100 Regulation Name: Liquid Chromatography, Amphetamine Regulatory Class: Class II Product Code: NVI Dated: December 2, 2004 Received: December 3, 2004
Dear Mr. Bentsen:
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. 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.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
{22}------------------------------------------------
Page 2
This letter will allow you to begin marketing your device as described in your Section 510(k) I ms letter will and w you to cogni maing of substantial equivalence of your device to legally premarket notification. Presults in a classification 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), please 11 you debile of Compliance at (240) 276-0131. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its Internet address
http://www.fda.gov/cdrh/dsma/dsmamain.html
Sincerely yours.
Robert L. Backer Jr.
Robert L. Becker, Jr., M.D., PhD Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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Bio-Rad Laboratories BioPlex™ 2200 ANA Screen with MDSS
INDICATIONS FOR USE STATEMENT
510(k) Number (if known):
BioPlex™ 2200 ANA Screen with Medical Decision Support Device Name: Software (MDSS) for use with the BioPlex"" 2200 Multi-Analyte Detection System
Indications for Use:
The BioPlex™ 2200 ANA Screen is intended for the qualitative screening of specific antinuclear antibodies (ANA), the quantitative detection of antibody to dsDNA, and the semi-quantitative detection of ten (10) separate antibody assays (Chromatin, Ribosomal Protein, SS-A, SS-B, Sm, SmRNP, RNP, Scl-70, Jo-1, and Centromere B) in human serum and/or EDTA or heparinized plasma.
The ANA Screen is used to screen serum or plasma (EDTA, heparin) samples and detect the presence of antinuclear antibodies as an aid in the diagnosis of systemic autoimmune diseases (Systemic Lupus Erythematosus [SLE], Mixed Connective Tissue Disease [MCTD], Undifferentiated Connective Tissue Disease [UCTD], Sjögren's Syndrome [SS], Scleroderma [Systemic Sclerosis], Dermatomyositis, Polymyositis, Rheumatoid Arthritis [RA]. CREST Syndrome, and Raynaud's Phenomenon) in conjunction with clinical findings and other laboratory tests.
The ANA Screen is intended for use with the Bio-Rad BioPlex 2200 System.
The BioPlex 2200 Medical Decision Support Software (MDSS), used in conjunction with the ANA Screen. is an optional laboratory tool that associates patient antibody results from the ANA Screen with predefined MDSS profiles that have been correlated with the following systemic autoimmune diseases: Systemic Lupus Erythematosus (SLE), Mixed Connective Tissue Disease (MCTD), Sjögren's Syndrome (SS), Scleroderma (Systemic Sclerosis) and Polymyositis.
Prescription Use: X ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------(Per 21 CFR 801.109)
AND/OR
Over-The-Counter Use: (Optional Format 1-2-96)
(PLEASE DO NOT WRITE BELOW THIS LINE – CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Maria Chan
Page 1 of 1
Division Sign-On
Office of In Vitro Digan Device Evaluation and Sa
510(k) K043341
120
§ 862.3100 Amphetamine test system.
(a)
Identification. An amphetamine test system is a device intended to measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained by this device are used in the diagnosis and treatment of amphetamine use or overdose and in monitoring levels of amphetamine to ensure appropriate therapy.(b)
Classification. Class II (special controls). An amphetamine test system is not exempt if it is intended for any use other than employment or insurance testing or is intended for Federal drug testing programs. The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9, provided the test system is intended for employment and insurance testing and includes a statement in the labeling that the device is intended solely for use in employment and insurance testing, and does not include devices intended for Federal drug testing programs (e.g., programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military).