K Number
K043341
Device Name
BIOPLEX 2200 ANA SCREEN WITH MEDICAL DECISION SUPPORT SOFTWARE FOR USE WITH BIOPLEX 2200 MULTI-ANALYTE DETECTION SYSTEM
Date Cleared
2005-10-27

(328 days)

Product Code
Regulation Number
862.3100
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP Authorized
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 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.
Device Description
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.
More Information

Not Found

Yes
The device description explicitly states that the Medical Decision Support Software (MDSS) is a "pattern recognition algorithm" based on the "k-nearest neighbor" (kNN) statistical technique, which is a common machine learning algorithm used for classification.

No
The device is described as an aid in diagnosis, detecting antibodies and providing statistical analysis for disease association, not for treating conditions.

Yes

Explanation: The device is intended "as an aid in the diagnosis of systemic autoimmune diseases." This clearly indicates its role in the diagnostic process.

Yes

The device is described as "Medical Decision Support Software (MDSS)" and its function is to analyze results from a separate hardware system (Bio-Rad BioPlex 2200 System) to provide disease associations. It does not include or require any hardware components for its operation beyond the input data from the BioPlex 2200 System.

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

  • Intended Use: The "Intended Use / Indications for Use" section explicitly states that the BioPlex™ 2200 ANA Screen is intended for the qualitative, quantitative, and semi-quantitative detection of specific antinuclear antibodies in human serum and/or plasma. This analysis of biological samples outside of the body is the core definition of an in vitro diagnostic.
  • Purpose: The intended use also clearly states that the ANA Screen is used "as an aid in the diagnosis of systemic autoimmune diseases... in conjunction with clinical findings and other laboratory tests." This diagnostic purpose further confirms its classification as an IVD.
  • Device Description: The device description details the analysis of "human serum and/or EDTA or heparinized plasma," which are biological specimens.
  • Performance Studies: The performance studies describe testing conducted on "samples collected prospectively from consecutive patients" and "normal blood donors," demonstrating the analysis of human biological samples.

The BioPlex 2200 Medical Decision Support Software (MDSS) is an optional component that uses the results from the ANA Screen to provide additional information, but the fundamental diagnostic testing of the biological sample is performed by the BioPlex 2200 ANA Screen itself, making the overall system an IVD.

No
The provided text does not contain any explicit statement that the FDA has reviewed and approved or cleared a Predetermined Change Control Plan (PCCP) for this specific device.

Intended Use / 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.

Product codes

NVI

Device Description

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.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Not Found

Indicated Patient Age Range

Not Found

Intended User / Care Setting

Not Found

Description of the training set, sample size, data source, and annotation protocol

Library or training set data on test results from 1,130 patients.

Description of the test set, sample size, data source, and annotation protocol

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. 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.

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

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.

Targeted Disease Analysis (N=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)

MDSS vs. Disease Classification - Targeted and Non-Targeted Connective Tissue Diseases (N=1130):

  • SLE (N=332): % Disease Agreement (Patients with Positive Antibody Only): 85.3% (186/218); % Disease Agreement (Patients with TCTD Classification): 56.0% (186/332)
  • Primary Sjögren's Syndrome (N=16): % Disease Agreement (Patients with Positive Antibody Only): 86.7% (13/15); % Disease Agreement (Patients with TCTD Classification): 81.3% (13/16)
  • Scleroderma (N=44): % Disease Agreement (Patients with Positive Antibody Only): 51.6% (16/31); % Disease Agreement (Patients with TCTD Classification): 36.4% (16/44)
  • Mixed Connective Tissue Disease (MCTD) (N=16): % Disease Agreement (Patients with Positive Antibody Only): 81.3% (13/16); % Disease Agreement (Patients with TCTD Classification): 81.3% (13/16)
  • Polymyositis (N=12): % Disease Agreement (Patients with Positive Antibody Only): 33.3% (2/6); % Disease Agreement (Patients with TCTD Classification): 16.7% (2/12)

MDSS Agreement with Disease Classification (excluding patients with other MDSS associations) and (including patients with multiple MDSS associations) provided with Odds Ratio (OR), Positive Likelihood Ratio (PLR), and Negative Likelihood Ratio (NLR) for various TCTDs.

MDSS Correct Association with Disease Classification:

  • Negative MDSS Output: Correct Association 81.4% (585/719) (95% CI 78.4 - 84.3%)
  • No Association MDSS Output: Correct Association 64% (57/89) (95% CI 53.3 - 74.8)
  • SLE only MDSS Output: Correct Association 71.7% (142/198) (95% CI 65.1 - 78.3%)
  • SLE or SS MDSS Output: Correct Association 83.3% (35/42) (95% CI 70.2 - 96.5%)
  • MCTD or SLE MDSS Output: Correct Association 81.1% (30/37) (95% CI 66.3 - 95.9%)
  • Scleroderma MDSS Output: Correct Association 40.9% (9/22) (95% CI 23.3 - 61.3%)
  • SLE or Scleroderma MDSS Output: Correct Association 55% (11/20) (95% CI 34.2 - 74.2%)
  • Polymyositis only MDSS Output: Correct Association 66.7% (2/3) (95% CI 20.8 - 93.9%)

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Sensitivity: TP/(TP+FN) x 100
Specificity: TN/(FP+TN) x 100
Prevalence: (TP+FN)/(TP+FN+J·P+TN) x 100
Overall Agreement: (TP+TN)/(TP+FN+FP+TN) x 100
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

For Targeted CTD Disease (N=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

Predicate Device(s)

K941596

Reference Device(s)

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

§ 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).

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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 |
|----------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 11122
12
1 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 AddressBio-Rad Laboratories, Inc.
Clinical Systems Division
4000 Alfred Nobel Drive
Hercules, CA 94547
Telephone(510) 724-7000
Establishment Registration No.2915274
Owner / OperatorBio-Rad Laboratories, Inc.
4000 Alfred Nobel Drive
Hercules, CA 94547
Owner / Operator No.9929003
Official Correspondent for the BioPlex 2200 ANA Screen
Official Correspondent AddressBio-Rad Laboratories
6565 185th Ave NE
Redmond, WA 98052
Telephone425-881-8300
Establishment Registration No.3022521
Owner / OperatorBio-Rad Laboratories, Inc.
4000 Alfred Nobel Drive
Hercules, CA 94547
Official CorrespondentMr. 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 NameAmphetamine Test System
Common Name:Medical Decision Support Software
Product Trade NameBioPlex 2200 Medical Decision Support Software (MDSS) on the
BioPlex 2200 Multi-Analyte Detection System
Device ClassClass II
Classification PanelClinical Toxicology
Regulation Number862.3100

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Classification NameAntinuclear Antibody (Enzyme-Labeled). Antigen, Controls
Common Name:Multi-Analyte Detection System. ANA Screen
Product Trade NameBioPlex 2200 ANA Screen on the
BioPlex 2200 Multi-Analyte Detection System
Device ClassClass 11
Classification PanelImmunology and Microbiology
Regulation Number866.5100

3.0 LEGALLY MARKETED EQUIVALENT (SE) DEVICES

BioPlex 2200 SystemComparative FDA Cleared Device510(k) NumberProduct CodeDecision Date
Medical Decision Support
Software (MDSS)Remedi HS™ Drug Profiling SystemK941596DNIMarch 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 | Internal
Output
Abbreviations |
|-----|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|
| 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 MDSS
associations 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 MDSS
associations from patients with RA should be interpreted with caution. | No Association
(NA) |
| # | MDSS Text Output | Internal
Output
Abbreviations |
| 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 autoimmune
disease. 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" do
not rule out autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE
association from MDSS thus MDSS associations from patients with RA should be
interpreted 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 out
autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE association
from MDSS, thus MDSS associations from patients with RA should be interpreted with
caution. | 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 out
autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE association
from MDSS, thus MDSS associations from patients with RA should be interpreted with
caution. | 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 out
autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE association
from MDSS, thus MDSS associations from patients with RA should be interpreted with
caution. | 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 rule
out autoimmune disease. 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 /
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 rule
out autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE association
from MDSS, thus MDSS associations from patients with RA should be interpreted with
caution. | 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 not
rule out autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE
association from MDSS, thus MDSS associations from patients with RA should be
interpreted 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 "No
Association" do not rule out autoimmune disease. Patients with Rheumatoid Arthritis may
result in an SLE association from MDSS, thus MDSS associations from patients with RA
should be interpreted with caution. | Polymyositis /
SS |
| # | MDSS Text Output | Internal
Output
Abbreviations |
| 12* | Antibody levels show association with MDSS profiles for systemic autoimmune disease.
Consider Polymyositis or Scleroderma. 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 MDSS associations from patients with RA should be
interpreted 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 SLE
association from MDSS, thus MDSS associations from patients with RA should be
interpreted 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 not
rule out autoimmune disease. Patients with Rheumatoid Arthritis may result in an SLE
association from MDSS, thus MDSS associations from patients with RA should be
interpreted 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 "No
Association" do not rule out autoimmune disease. Patients with Rheumatoid Arthritis may
result in an SLE association from MDSS, thus MDSS associations from patients with RA
should be interpreted with caution. | Scleroderma /
SS |

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Page 3 of 21

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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 between
Data Processing
Modules | BioPlex 2200 Medical Decision
Support Software | Remedi HS Drug Profiling System |
|----------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|
| Input | Library or training set data on test
results from 1,130 patients. | Library of known drug spectra
stored in memory. |
| Function | Data processing module for
association of patient specific
information with the current
condition of the patient. | Data processing module for
association of patient specific
information with the current
condition of the patient. |
| Technology | Computer based, software driven,
data driven algorithm. | Sophisticated computer algorithm. |
| Output | Test results as compared to
training set. | Test results as compared to known
library. |

Table 1 (a): Similarities between data processing modules

Table 1 (b): Differences between data processing modules

| Differences between
Data Processing
Modules | BioPlex 2200 Medical Decision
Support Software | Remedi HS Drug Profiling System |
|---------------------------------------------------|-------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|
| Input | Results from serological analysis
of patient serum or plasma for
specific autoantibodies. | Results from chromatographic
analysis of patient urine or serum
for drugs. |
| Function | Identification of possible disease
associations. | Identification of possible drugs in
the biological specimen. |
| Algorithm
Technology | k-Nearest Neighbor data analysis
algorithm and pre-established
medical database. | Peak Identification for comparison of
unknown 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 a
Chromatogram. |

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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 908BioPlex ANA Screen
PositiveNegativeTotal
Targeted CTD Disease280134414
All Others
non targeted and no CTD110384494
Total390518908
Sensitivity67.6% 95% CI 63.0 - 72.3%
Specificity77.7% 95% CI 73.9 - 81.5%
Overall Agreement73.1% 95% CI 70.2 - 76.1%
Positive Likelihood Ratio3.04 95% CI 2.54 – 3.62
Negative Likelihood Ratio0.42 95% CI 0.36 – 0.48
Odds Ratio7.29 95% CI 5.43 – 9.80
Prevalence45.6% 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 PositiveTN True Negative
FP = False PositiveFN 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)

Page 8 of 21

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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= 332ANA ScreendsDNA aChromatinRibosomal ProteinSS-ASS-BSmSmRNPRNPbScl-70Jo-1Centromere B
Bio-Rad and EIA Positive21375861610134306653116
Bio-Rad Positive and EIA Negative793614108191013605
Bio-Rad and EIA Negative57190183299218280280241244323328321
Bio-Rad Negative and EIA Positive55122733103157230
% Overall Agreement81%93%81%95%96%95%92%93%94%98%99%98%
95% Confidence Interval77 - 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=16ANA ScreenDsDNA*ChromatinRibosomal ProteinSS-ASS-BSmSmRNPRNPScl-70Jo-1Centromere B
Bio-Rad and
EIA Positive151101513000000
Bio-Rad Positive
and EIA Negative001000001000
Bio-Rad and
EIA Negative112131612161415161616
Bio-Rad Negative
and EIA Positive001001020000
% Overall
Agreement100%100%88%100%100%94%100%88%94%100%100%100%
95%
Confidence Interval86-
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 | Ribosomal
Protein | SS-A | SS-B | Sm | SmRNP | RNP | Scl-70 | Jo-1 | Centromere B |
|--------------------------------------|------------|-------------|-------------|----------------------|------------|-------------|-------------|-------------|-------------|-------------|-------------|--------------|
| Bio-Rad and
EIA Positive | 28 | 1 | 3 | 0 | 7 | 1 | 0 | 3 | 4 | 6 | 0 | 12 |
| Bio-Rad Positive
and EIA Negative | 1 | 3 | 3 | 0 | 3 | 1 | 2 | 0 | 0 | 1 | 0 | 0 |
| Bio-Rad and
EIA Negative | 5 | 40 | 36 | 44 | 30 | 42 | 42 | 40 | 38 | 36 | 44 | 32 |
| Bio-Rad Negative
and EIA Positive | 10 | 0 | 2 | 0 | 4 | 0 | 0 | 1 | 2 | 1 | 0 | 0 |
| % Overall
Agreement | 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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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-16ANA ScreendsDNAChromatinRibosomal ProteinSS-ASS-BSmSmRNPRNPScl-70Jo-1Centromere B
Bio-Rad and
EIA Positive161312041514011
Bio-Rad Positive
and EIA Negative0111000101100
Bio-Rad and
EIA Negative01321514161011151515
Bio-Rad Negative
and EIA Positive010000100000
% Overall
Agreement100%88%31%100%100%100%88%100%94%94%100%100%
95% Confidence
Interval86-
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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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 | Ribosomal
Protein | SS-A | SS-B | Sm | SmRNP | RNP | Scl-70 | Jo-1 | Centromere B |
|--------------------------------------|------------|-------------|------------|----------------------|-------------|-------------|-------------|-------------|-------------|-------------|-------------|--------------|
| Bio-Rad and
EIA Positive | 6 | 0 | 0 | 0 | 5 | 0 | 0 | 1 | 1 | 0 | 2 | 0 |
| Bio-Rad Positive
and EIA Negative | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Bio-Rad and
EIA Negative | 3 | 12 | 11 | 12 | 7 | 12 | 12 | 11 | 11 | 12 | 10 | 12 |
| Bio-Rad Negative
and EIA Positive | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| % Overall
Agreement | 75% | 100% | 92% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| 95% Confidence
Interval | 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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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=494ANA ScreendsDNAChromatinRibosomal ProteinSS-ASS-BSmSmRNPRNPScl-70Jo-1Centromere B
BioPlex 2200 and
EIA Positive7967128939102213
BioPlex 2200
Positive and EIA
Negative31152056104312601
BioPlex 2200 and
EIA Negative303459437488453474486477465481490479
BioPlex 2200 Negative
and EIA Positive811430071157521
% Overall Agreement77%94%90%99%97%98%99%98%96%98%99.6%99.6%
95% Confidence
Interval74-
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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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 are
below 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 defined
patterns 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 Classification
by Criteria** | | (N) | Negative for all antibodies | Positive for one or more antibody (P) | No Association | MDSS Output * | | | | | % Disease
Agreement | |
|----------------------------------------------|----------------------------------------------|-----|-----------------------------|---------------------------------------|----------------|---------------------|---------------------------------------|-----------------------|----------------------|------------------------------|------------------------------------------------------|------------------------------------------------|
| | | | | | | Any SLE Association | Any Sjögren's Syndrome
Association | Any ScICR Association | Any MCTD Association | Any Polymyositis Association | Patients with
Positive
Antibody
Only
(P) | Patients with
TCTD
Classification
(N) |
| Targeted Connective Tissue Disease
(TCTD) | Systemic Lupus
Erythematosus (SLE) | 332 | 114 | 218 | 28 | 186 | 22 | 7 | 18 | 0 | 85.3%
(186/218) | 56.0%
(186/332) |
| | Primary Sjögren's
Syndrome | 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 Connective
Tissue 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 Antibody
Test Results | Disease by Established
Medical Criteria* | MDSS Output** | % Agreement | 95%
Confidence
Interval |
|-----------------------------------|---------------------------------------------|------------------------------------------------|----------------|-------------------------------|
| 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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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 Classification
by Criteria | Systemic
Lupus
Erythematosus
(SLE)
(N = 332) | Primary
Sjögren's
Syndrome
(N = 16) | Scleroderma
(N = 44) | Mixed
Connective
Tissue Disease
(N = 16) | Polymyositis
(N = 12) |
|---------------------------------------|----------------------------------------------------------|----------------------------------------------|-------------------------|---------------------------------------------------|--------------------------|
| Positive Antibody
Test(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% Confidence
Interval | 9.1 - 17.8 | 111.4 -
2065.6 | 10.3 - 47.5 | 111.7 - 2071.9 | 11.9 - 2667.6 |
| Positive Likelihood
Ratio (PLR) | 6.17 | 90.8 | 14.4 | 91.0 | 186.3 |
| (PLR) 95% Confidence
Interval | 4.8 - 7.9 | 41.8 -
196.9 | 7.9 - 26.1 | 41.95 - 197.35 | 18.1 - 1919.2 |
| Negative Likelihood
Ratio (NLR) | 0.48 | 0.19 | 0.65 | 0.19 | 0.83 |
| NLR 95% Confidence
Interval | 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 Classification
by Criteria | Systemic Lupus
Erythematosus
(SLE)
(N = 332) | Primary
Sjögren's
Syndrome
(N = 16) | Scleroderma
(N = 44) | Mixed
Connective
Tissue Disease
(N = 16) | Polymyositis
(N = 12) |
|---------------------------------------|-------------------------------------------------------|----------------------------------------------|-------------------------|---------------------------------------------------|--------------------------|
| Positive Antibody
Test(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% Confidence
Interval | 5.9 - 10.6 | 43.8 -
599.6 | 11.3 - 48.2 | 52.6 - 735.4 | 11.9 - 2667.6 |
| Positive Likelihood
Ratio (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 Likelihood
Ratio (NLR) | 0.51 | 0.19 | 0.65 | 0.19 | 0.83 |
| NLR 95% Confidence
Interval | 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 Disease
Classification | (N) | Negative or No
MDSS
Associations | Incorrect MDSS
Associations | % Incorrect
Association | |
|------------------------------------|----------------------------|----------------------------------------|--------------------------------|----------------------------|-------------|
| 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)

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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 any
Targeted Disease | Correct
Association | 95% Confidence
Interval |
|----------------|-----------|-----------------------------------|------------------------|----------------------------|
| 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 Clinical
Diagnosis | Correct
Association | 95% Confidence
Interval |
|-----------------------|-----------|----------------------------|------------------------|----------------------------|
| 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 or
Scleroderma | 20 | 11 | 55% (11/20) | 34.2 - 74.2% |
| Polymyositis
only | 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.

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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

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Division Sign-On

Office of In Vitro Digan Device Evaluation and Sa

510(k) K043341

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