BIOPLEX 2200 ANA SCREEN WITH MEDICAL DECISION SUPPORT SOFTWARE FOR USE WITH BIOPLEX 2200 MULTI-ANALYTE DETECTION SYSTEM

K043341 · Bio-Rad Laboratories, Inc. · NVI · Oct 27, 2005 · Clinical Toxicology

Device Facts

• Record ID: K043341
• Device Name: BIOPLEX 2200 ANA SCREEN WITH MEDICAL DECISION SUPPORT SOFTWARE FOR USE WITH BIOPLEX 2200 MULTI-ANALYTE DETECTION SYSTEM
• Applicant: Bio-Rad Laboratories, Inc.
• Product Code: NVI · Clinical Toxicology
• Decision Date: Oct 27, 2005
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.3100
• Device Class: Class 2
• Attributes: AI/ML, Software as a Medical Device

AI Performance

Output	Acceptance	Observed	Dev DS	Test DS
Systemic Lupus Erythematosus (SLE) Association	Not specified	86.7% disease agreement (patients with positive antibody); 81.3% disease agreement (patients with TCTD classification)	Database containing results for over 1,400 characterized sera/plasma	Clinical trial (n=1130) including 332 patients with SLE
Primary Sjögren's Syndrome Association	Not specified	86.7% disease agreement (patients with positive antibody); 81.3% disease agreement (patients with TCTD classification)	Database containing results for over 1,400 characterized sera/plasma	Clinical trial (n=1130) including 16 patients with Primary Sjögren's Syndrome
Scleroderma Association	Not specified	51.6% disease agreement (patients with positive antibody); 36.4% disease agreement (patients with TCTD classification)	Database containing results for over 1,400 characterized sera/plasma	Clinical trial (n=1130) including 44 patients with Scleroderma
Mixed Connective Tissue Disease (MCTD) Association	Not specified	81.3% disease agreement (patients with positive antibody); 81.3% disease agreement (patients with TCTD classification)	Database containing results for over 1,400 characterized sera/plasma	Clinical trial (n=1130) including 16 patients with MCTD
Polymyositis Association	Not specified	33.3% disease agreement (patients with positive antibody); 16.7% disease agreement (patients with TCTD classification)	Database containing results for over 1,400 characterized sera/plasma	Clinical trial (n=1130) including 12 patients with Polymyositis

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 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 Polymyositis.

Device Story

The BioPlex 2200 MDSS is a software-based pattern recognition tool used in clinical laboratories to assist physicians in the differential diagnosis of systemic autoimmune diseases. It takes as input the quantitative/semi-quantitative results of 11 individual antibody assays from the BioPlex 2200 Multi-Analyte Detection System. The software uses a k-nearest neighbor (kNN) statistical algorithm to compare the patient's antibody profile against a database of over 1,400 characterized samples. The output is a classification of the patient's results as 'Negative', 'No Association', or an 'Association with Disease' (proposing up to two disease classifications). This output is intended to aid clinicians in interpreting complex serological data and determining the need for further autoimmune testing. By providing automated pattern matching, the device helps clinicians navigate the diagnostic complexity of autoimmune conditions, where referring and final diagnoses often show low agreement.

Clinical Evidence

Clinical performance was evaluated using 908 prospective samples from rheumatology clinic patients and 222 normal blood donors (total N=1,130). The study compared MDSS outputs against clinical diagnoses based on ACR, literature, or established medical criteria. Primary endpoints included disease agreement and likelihood ratios. Results showed MDSS associations for SLE (85.3% agreement in positive antibody patients), Primary Sjögren's (86.7%), Scleroderma (51.6%), MCTD (81.3%), and Polymyositis (33.3%). The study also reported positive/negative likelihood ratios and odds ratios for each disease association. No clinical data was excluded; performance metrics were calculated for both targeted and non-targeted disease populations.

Technological Characteristics

The MDSS is a software-based data processing module. It utilizes a k-nearest neighbor (kNN) statistical algorithm to analyze 11 antibody assay inputs. The system operates on the BioPlex 2200 Multi-Analyte Detection System platform. It is a standalone software tool that functions as an optional add-on to the primary detection system. No specific hardware materials are described for the software itself; it relies on a pre-established medical database of 1,400 characterized samples for pattern matching.

Indications for Use

Indicated for use as an optional laboratory tool to associate patient antibody results with predefined profiles correlated to systemic autoimmune diseases (SLE, MCTD, SS, Scleroderma, Polymyositis) in patients undergoing ANA Screen testing.

Regulatory Classification

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.

Special Controls

*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).

Predicate Devices

• Remedi HS™ Drug Profiling System (k941596)

Submission Summary (Full Text)

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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

A. 510(k) Number:
k043341

B. Purpose for Submission:
This is a new device.

C. Manufacturer and Instrument Name:
Bio-Rad Laboratories
BioPlex 2200 Medical Decision Support Software (MDSS) on the BioPlex 2200 Multi-Analyte Detection System.

D. Type of Test or Tests Performed:
The BioPlex™ 2200 Medical Decision Support Software (MDSS) is a separate informatics software module for use with the BioPlex™ 2200 ANA Screen on the BioPlex 2200 Multi-Analyte Detection System

E. System Descriptions:

1. Device Description:
The BioPlex 2200 Medical Decision Support Software (MDSS) is a pattern recognition algorithm that can enhance the performance of the ANA Screen by identifying associated diagnostic patterns among its multiple assay results. The MDSS can suggest one or more possible disease associations after identifying patterns from the eleven (11) individual antibody results. The MDSS is based on the principles of the "k-nearest neighbor" (kNN) statistical techniques. Each "unknown" is compared to a pre-established database that contains the results for over 1,400 characterized sera/plasma. 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.

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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) |
| 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 |

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| # | MDSS Text Output | Internal Output Abbreviations |
| --- | --- | --- |
| 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 |
| 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 |

*Note: these MDSS outputs were not observed in the clinical trial

The MDSS is not, in and of itself, diagnostic for the targeted diseases associations and must be considered in conjunction with other laboratory test results and the clinical presentation of the patient.

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2. Principles of Operation:
When the MDSS module is activated, the autoantibody results are compared to the MDSS database that contain results for over 1,400 sera/plasma, representing test results from patients with systemic autoimmune diseases and from healthy individuals. If one or more results are obtained from a serum or plasma sample, the results are associated with the most appropriate MDSS profiles.

When the MDSS result is positive, the MDSS produces two outputs that BioPlex 2200 can display in its User Interface. The first output is a text result containing the specific disease association(s) results. The second output is a graph of the specific disease association(s) and the patient's analyte results.

3. Modes of Operation:
The MDSS module interacts with the BioPlex 2200 Instrument software (BPX), which runs on a PC running the Windows operating system. MDSS activates the kNN algorithm which runs queries on a database of serum and plasma results from over 1,000 previously-diagnosed systemic autoimmune patients. This database is stored within the BPX database. Using XML (Extensible Markup Language) strings, BPX sends patient analyte data to the MDSS module and retrieves resultant disease associations from the MDSS module.

4. Specimen Identification:
Refer to k041658 (BioPlex 2200 ANA Screen on the BioPlex 2200 Multi-Analyte Detection System)

5. Specimen Sampling and Handling:
Refer to k041658 (BioPlex 2200 ANA Screen on the BioPlex 2200 Multi-Analyte Detection System)

6. Calibration:
Refer to k041658 (BioPlex 2200 ANA Screen on the BioPlex 2200 Multi-Analyte Detection System)

7. Quality Control:
Refer to k041658 (BioPlex 2200 ANA Screen on the BioPlex 2200 Multi-Analyte Detection System)

8. Software:
FDA has reviewed applicant's Hazard Analysis and Software Development processes for this line of product types:
Yes ☑ or No ☐

F. Regulatory Information:

1. Regulation section:
21 CFR § 862.3100 Amphetamine Test System

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2. Classification:
Class II

3 Product code:
NVI, Diagnostic software, k-nearest neighbor algorithm, autoimmune disease

4. Panel:
91 Clinical Toxicology

G. Intended Use:

1. Indication(s) for Use:
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 Polymyositis

2. Special Conditions for Use Statement(s):
For use with the BioPlex 2200 ANA Screen Assay on the BioPlex 2200 Multi-Analyte Detection System. (k041658)

H. Substantial Equivalence Information:

1. Predicate Device Name(s) and 510(k) numbers:
Remedi HS™ Drug Profiling System (k941596)

2. Comparison with Predicate Device:
Table 1 (a): 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 patient | Same |
| Technology | Computer based, software driven, data driven algorithm. | Sophisticated computer algorithm. |
| | Test results as compared to training set | |

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Table 1 (b): Differences between data processing modules

| | BioPlex 2200 Medical Decision | 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 |
| Modules | 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. |

# I. Special Control/Guidance Document Referenced (if applicable):

None referenced.

# J. Performance Characteristics:

# 1. Analytical Performance:

Performance testing in this section is limited to additional clinical concordance and MDSS related claims. Clinical performance testing relating to BioPlex ANA Screen on the BioPlex 2200 ANA Screen was presented on prior (k041658) application.

# a. Accuracy:

The following table presents %disease agreement of the MDSS output with the diagnosis provided by a physician. Data is presented as % disease agreement for patients with one or more positive antibodies and for patients with a targeted connective tissue disease (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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MDSS vs. Disease Classification (n = 1130)

| Disease Classification By Criteria** | (N) | MDSS Output | | | | | | | | % Disease Agreement | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | Negative for all antibodies | Positive for one or more antibody (P) | No Association | Any SLE Association | Any Sjogren's syndrome Association | Any SclCR Association | Any MCTD Association | Any Polymyositis Association | Patients with Positive Antibody Only | Patients with TCTD Classification |
| *Systemic Lupus Erythematosus (SLE) | 16 | 1 | 15 | 0 | 15 | 13 | 0 | 0 | 0 | 86.7%
13/15 | 81.3%
13/16 |
| *Primary Sjogren'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 |
| *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 |

* Targeted Connective Tissue Disease (TCTD)
** For these patients, the MDSS outputs suggesting Polymyositis referenced the disorder alone and not in combination with another TCTD

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.

MDSS Assignments in Patients with TCTD and a Positive Antibody Result

| 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% |

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Since some MDSS outputs contain more disease associations with other diseases than the disease association under consideration, the results in the first table were calculated by excluding patients with other diseases listed in the output. The second 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

MDSS Agreement with Disease Classification (excluding patients with other 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) | 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 |

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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 |

Some of the Clinical Disease Classifications encountered do not have an associated MDSS output. These non-targeted connective tissue diseases should be classified as either Negative or No Association by MDSS. The table below presents MDSS results incorrectly associated with a targeted connective tissue disease (% Incorrect Association).

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** |

* Of the 31 patients with only rheumatoid 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 $\alpha$ 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.

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** The clinical status of blood donors tested in this study was not known.

The following tables present % correctness in conjunction with the following prevalence of diseases: study: SLE 29% (332/1130), Sjögren's Syndrome 1.4% (16/1130), Scleroderma 3.9% (44/1130), Mixed Connective Tissue Disease 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. The % correctness is defined as the number of patients with given MDSS association who also have that disease by ACR, literature, or established medical criteria

Correct Association without any Targeted Disease Classification

| 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 |

Correct Association with 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% |

* One of these 3 patients was diagnosed with Dermatomyositis.

# b. Precision/Reproducibility:

Reproducibility testing was performed at three (3) US testing facilities on a total of three (3) lots of the ANA Screen. Each testing facility evaluated reproducibility using one (1) kit lot of the ANA Screen. The eleven (11) panel members consisted of ten (10) positive panel members prepared by combining one (1) or more antibody positive patient samples for one (1) or more of the 13 analytes contained in the ANA Screen (dsDNA, Chromatin, SS-A 52, SS-A 60, SS-B, Sm, RNP 68, RNP A, Sm/RNP, Centromere, Ribosomal Protein, Scl-70, and Jo-1. Five of the 10 members had higher levels of the antibodies and five had antibody levels near the cut-off. One panel member was negative for all 13 analytes. In addition, three lots of the ANA Screen Control set positive control (antibody positive for all 13 analytes), 1 diluted positive control and a negative control (negative for all 13 analytes) were also tested.

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Each of the eleven (11) panel members and the Autoimmune Control Set was tested in duplicate (x2) on two (2) runs per day (morning and afternoon) for ten (10) days using one (1) lot of ANA Screen Reagent Pack and one (1) lot of ANA Screen. Calibrator Set at each of three (3) sites. [2 times x 2 runs x 10 days = 40 replicates per panel member per site. Total replicates at 3 sites = 120 replicates per panel member.] The data were then analyzed for intra-assay and inter-assay reproducibility according to the National Committee for Clinical Laboratory Standards (NCCLS EP5-A, Vol. 19, No. 2, p7, Eq. (1) and p8 Eq. (4)). The mean Antibody Index (AI), standard deviation (SD), and percent coefficient of variation (%CV) for each panel member is presented. For dsDNA, the mean International Units per ml (IU/mL), standard deviation (SD), and percent coefficient of variation (%CV) for each panel member is presented. Results for Positive Control, High Positive Panel, and Low Positive Panel can be found in the following tables.

Intra-assay- Site 1

| Clinical Site 1, Lot 1 | ANA Screen - Intra-assay | | | | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | dsDNA (IU/mL) | Chromatin (AI) | RibosomalProtein (AI) | SS-A 52 (AI) | SS-A 60 (AI) | SS-B (AI) | Sm (AI) | SmRNP (AI) | RNP A (AI) | RNP 68 (AI) | Sel-70 (AI) | Jo-1 (AI) | Centromere B (AI) |
| High Positive Panel | Mean | 45.6 | 2.7 | 2.4 | 4.1 | 3.4 | 3.6 | 3.3 | 4.0 | 4.1 | 3.8 | 3.3 | 3.9 | 3.7 |
| | SD* | 0.89 | 0.08 | 0.07 | 0.19 | 0.07 | 0.07 | 0.09 | 0.08 | 0.10 | 0.13 | 0.08 | 0.10 | 0.08 |
| | % CV | 2.0% | 2.9% | 2.7% | 4.6% | 1.9% | 2.0% | 2.9% | 2.0% | 2.4% | 3.5% | 2.4% | 2.5% | 2.2% |
| | N= | 40 | 40 | 40 | 36 | 36 | 36 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| Low Positive Panel | Mean | 17.0 | 1.3 | 1.2 | 2.2 | 1.8 | 1.7 | 1.5 | 2.2 | 1.9 | 1.8 | 1.9 | 1.9 | 2.0 |
| | SD* | 0.05 | 0.06 | 0.04 | 0.17 | 0.07 | 0.05 | 0.05 | 0.06 | 0.05 | 0.09 | 0.06 | 0.09 | 0.05 |
| | % CV | 2.9% | 4.4% | 3.9% | 7.9% | 3.9% | 3.1% | 3.2% | 2.6% | 2.6% | 4.9% | 2.9% | 5.0% | 2.7% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 36 | 40 | 40 |
| Positive Control | Mean | 23.2 | 2.5 | 1.7 | 3.1 | 2.5 | 2.7 | 2.8 | 3.0 | 2.7 | 2.5 | 2.7 | 2.7 | 2.8 |
| | SD* | 0.62 | 0.10 | 0.04 | 0.16 | 0.04 | 0.07 | 0.07 | 0.07 | 0.08 | 0.16 | 0.06 | 0.08 | 0.05 |
| | % CV | 2.7% | 4.0% | 2.6% | 5.1% | 1.7% | 2.6% | 2.4% | 2.2% | 3.0% | 6.6% | 2.0% | 2.9% | 1.9% |
| | N= | 36 | 36 | 40 | 36 | 36 | 36 | 36 | 40 | 36 | 36 | 36 | 36 | 36 |

{11}

Intra-assay Site 2

| Clinical Site 2, Lot 2 | ANA Screen - Intra-assay | | | | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | dsDNA (IU/mL) | Chromatin (AI) | RibosomalProtein (AI) | SS-A 52 (AI) | SS-A 60 (AI) | SS-B (AI) | Sm (AI) | SmRNP (AI) | RNP A (AI) | RNP 68 (AI) | Scl-70 (AI) | Jo-1 (AI) | Centromere B (AI) |
| High Positive Panel | Mean | 44.9 | 2.9 | 2.7 | 3.8 | 3.6 | 3.5 | 3.9 | 3.4 | 3.8 | 3.9 | 3.2 | 3.1 | 2.9 |
| | SD* | 1.06 | 0.09 | 0.07 | 0.09 | 0.09 | 0.07 | 0.11 | 0.12 | 0.10 | 0.16 | 0.10 | 0.12 | 0.10 |
| | % CV | 2.4% | 3.2% | 2.8% | 2.4% | 2.6% | 2.1% | 2.9% | 3.4% | 2.7% | 4.2% | 3.3% | 4.0% | 3.3% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| Low Positive Panel | Mean | 18.2 | 1.5 | 1.6 | 2.2 | 1.9 | 1.6 | 1.7 | 1.9 | 1.8 | 1.8 | 1.8 | 1.4 | 1.6 |
| | SD* | 0.52 | 0.09 | 0.07 | 0.09 | 0.07 | 0.05 | 0.15 | 0.07 | 0.08 | 0.09 | 0.13 | 0.07 | 0.08 |
| | % CV | 2.9% | 5.5% | 4.4% | 4.3% | 3.9% | 3.1% | 8.6% | 3.5% | 4.3% | 5.2% | 7.1% | 5.1% | 5.2% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| Positive Control | Mean | 24.7 | 2.3 | 2.7 | 2.8 | 2.8 | 3.8 | 3.0 | 2.7 | 2.9 | 3.4 | 2.4 | 3.6 | 2.4 |
| | SD* | 0.72 | 0.09 | 0.07 | 0.13 | 0.10 | 0.12 | 0.09 | 0.07 | 0.11 | 0.14 | 0.08 | 0.14 | 0.09 |
| | % CV | 2.9% | 4.1% | 2.5% | 4.7% | 3.5% | 3.1% | 3.0% | 2.5% | 3.8% | 4.2% | 3.2% | 3.8% | 3.7% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |

Intra-Assay Site-3

| Clinical Site 3, Lot 3 | ANA Screen - Intra-assay | | | | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | dsDNA (IU/mL) | Chromatin (AI) | RibosomalProtein (AI) | SS-A 52 (AI) | SS-A 60 (AI) | SS-B (AI) | Sm (AI) | SmRNP (AI) | RNP A (AI) | RNP 68 (AI) | Scl-70 (AI) | Jo-1 (AI) | Centromere B (AI) |
| High Positive Panel | Mean | 52.8 | 2.8 | 2.6 | 4.7 | 4.2 | 4.0 | 3.7 | 3.7 | 4.7 | 4.3 | 3.8 | 3.9 | 4.2 |
| | SD* | 1.16 | 0.11 | 0.07 | 0.41 | 0.11 | 0.10 | 0.09 | 0.11 | 0.13 | 0.16 | 0.09 | 0.13 | 0.09 |
| | % CV | 2.2% | 3.9% | 2.9% | 8.7% | 2.6% | 2.4% | 2.3% | 3.0% | 2.7% | 3.8% | 2.5% | 3.4% | 2.1% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| Low Positive Panel | Mean | 19.9 | 1.4 | 1.3 | 2.8 | 2.2 | 2.1 | 1.8 | 1.9 | 2.2 | 2.3 | 2.3 | 2.0 | 2.5 |
| | SD* | 0.72 | 0.07 | 0.05 | 0.25 | 0.10 | 0.08 | 0.05 | 0.05 | 0.07 | 0.10 | 0.06 | 0.10 | 0.08 |
| | % CV | 3.6% | 4.7% | 3.5% | 9.1% | 4.4% | 3.7% | 3.0% | 2.8% | 3.1% | 4.5% | 2.7% | 4.8% | 3.0% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| Positive Control | Mean | 26.1 | 2.7 | 2.5 | 3.4 | 3.1 | 3.1 | 2.7 | 3.4 | 3.5 | 2.8 | 2.9 | 3.1 | 2.9 |
| | SD* | 0.60 | 0.07 | 0.08 | 0.38 | 0.08 | 0.08 | 0.07 | 0.07 | 0.10 | 0.09 | 0.07 | 0.11 | 0.09 |
| | % CV | 2.3% | 2.7% | 3.1% | 11.1% | 2.8% | 2.5% | 2.5% | 2.2% | 3.0% | 3.4% | 2.5% | 3.6% | 3.1% |
| | N= | 36 | 36 | 40 | 36 | 36 | 36 | 36 | 40 | 36 | 36 | 36 | 36 | 36 |

{12}

Inter-Assay Site 1

| Clinical Site 1, Lot 1 | ANA Screen - Inter-assay | | | | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | dsDNA (IU/mL) | Chromatin (AI) | RibosomalProtein (AI) | SS-A 52 (AI) | SS-A 60 (AI) | SS-B (AI) | Sm (AI) | SmRNP (AI) | RNP A (AI) | RNP 68 (AI) | Scl-70 (AI) | Jo-1 (AI) | Centromere B (AI) |
| High Positive Panel | Mean | 45.6 | 2.7 | 2.4 | 4.1 | 3.4 | 3.6 | 3.3 | 4.0 | 4.1 | 3.8 | 3.3 | 3.9 | 3.7 |
| | SD* | 1.82 | 0.13 | 0.16 | 0.28 | 0.20 | 0.21 | 0.10 | 0.14 | 0.14 | 0.20 | 0.12 | 0.20 | 0.10 |
| | % CV | 4.0% | 4.8% | 6.7% | 6.8% | 5.8% | 5.8% | 3.2% | 3.5% | 3.5% | 5.4% | 3.7% | 5.0% | 2.8% |
| | N= | 40 | 40 | 40 | 36 | 36 | 36 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| Low Positive Panel | Mean | 17.0 | 1.3 | 1.2 | 2.2 | 1.8 | 1.7 | 1.5 | 2.2 | 1.9 | 1.8 | 1.9 | 1.9 | 2.0 |
| | SD* | 0.60 | 0.08 | 0.06 | 0.21 | 0.08 | 0.08 | 0.07 | 0.09 | 0.08 | 0.12 | 0.12 | 0.12 | 0.11 |
| | % CV | 3.5% | 6.1% | 5.6% | 9.7% | 4.6% | 5.0% | 5.0% | 4.0% | 4.0% | 6.3% | 6.3% | 6.2% | 5.3% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 36 | 40 | 40 |
| Positive Control | Mean | 23.2 | 2.5 | 1.7 | 3.1 | 2.5 | 2.7 | 2.8 | 3.0 | 2.7 | 2.5 | 2.7 | 2.7 | 2.8 |
| | SD* | 2.09 | 0.29 | 0.10 | 0.39 | 0.25 | 0.29 | 0.26 | 0.10 | 0.26 | 0.29 | 0.28 | 0.27 | 0.27 |
| | % CV | 9.0% | 11.7% | 5.8% | 12.8% | 10.0% | 10.7% | 9.5% | 3.2% | 9.7% | 11.6% | 10.5% | 10.1% | 9.8% |
| | N= | 36 | 36 | 40 | 36 | 36 | 36 | 36 | 40 | 36 | 36 | 36 | 36 | 36 |

Inter-Assay Site 2

| Clinical Site 2, Lot 2 | ANA Screen - Inter-assay | | | | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | dsDNA (IU/mL) | Chromatin (AI) | RibosomalProtein (AI) | SS-A 52 (AI) | SS-A 60 (AI) | SS-B (AI) | Sm (AI) | SmRNP (AI) | RNP A (AI) | RNP 68 (AI) | Scl-70 (AI) | Jo-1 (AI) | Centromere B (AI) |
| High Positive Panel | Mean | 44.9 | 2.9 | 2.7 | 3.8 | 3.6 | 3.5 | 3.9 | 3.4 | 3.8 | 3.9 | 3.2 | 3.1 | 2.9 |
| | SD* | 3.40 | 0.25 | 0.19 | 0.28 | 0.24 | 0.30 | 0.22 | 0.25 | 0.24 | 0.28 | 0.21 | 0.28 | 0.18 |
| | % CV | 7.6% | 8.8% | 7.2% | 7.4% | 6.8% | 8.4% | 5.8% | 7.2% | 6.3% | 7.2% | 6.5% | 9.0% | 6.2% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| Low Positive Panel | Mean | 18.2 | 1.5 | 1.6 | 2.2 | 1.9 | 1.6 | 1.7 | 1.9 | 1.8 | 1.8 | 1.8 | 1.4 | 1.6 |
| | SD* | 1.15 | 0.16 | 0.10 | 0.19 | 0.15 | 0.14 | 0.20 | 0.13 | 0.15 | 0.18 | 0.17 | 0.12 | 0.17 |
| | % CV | 6.3% | 10.2% | 6.6% | 8.4% | 8.1% | 8.8% | 11.9% | 6.8% | 8.7% | 10.2% | 9.5% | 9.0% | 10.6% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| Positive Control | Mean | 24.7 | 2.3 | 2.7 | 2.8 | 2.8 | 3.8 | 3.0 | 2.7 | 2.9 | 3.4 | 2.4 | 3.6 | 2.4 |
| | SD* | 1.71 | 0.19 | 0.19 | 0.24 | 0.21 | 0.32 | 0.23 | 0.18 | 0.24 | 0.29 | 0.18 | 0.30 | 0.20 |
| | % CV | 7.0% | 8.3% | 7.1% | 8.6% | 7.3% | 8.4% | 7.8% | 6.8% | 8.4% | 8.6% | 7.3% | 8.2% | 8.6% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |

{13}

Inter-Assay Site 3

| Clinical Site 3, Lot 3 | ANA Screen - Inter-assay | | | | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | dsDNA (IU/mL) | Chromatin (AI) | RibosomalProtein (AI) | SS-A 52 (AI) | SS-A 60 (AI) | SS-B (AI) | Sm (AI) | SmRNP (AI) | RNP A (AI) | RNP 68 (AI) | Scl-70 (AI) | Jo-1 (AI) | Centromere B (AI) |
| High Positive Panel | Mean | 52.8 | 2.8 | 2.6 | 4.7 | 4.2 | 4.0 | 3.7 | 3.7 | 4.7 | 4.3 | 3.8 | 3.9 | 4.2 |
| | SD* | 2.05 | 0.16 | 0.15 | 0.47 | 0.21 | 0.20 | 0.17 | 0.18 | 0.20 | 0.23 | 0.16 | 0.24 | 0.15 |
| | % CV | 3.9% | 5.6% | 5.9% | 9.8% | 5.1% | 5.0% | 4.5% | 5.1% | 4.2% | 5.5% | 4.3% | 6.0% | 3.6% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| Low Positive Panel | Mean | 19.9 | 1.4 | 1.3 | 2.8 | 2.2 | 2.1 | 1.8 | 1.9 | 2.2 | 2.3 | 2.3 | 2.0 | 2.5 |
| | SD* | 1.29 | 0.11 | 0.09 | 0.28 | 0.15 | 0.15 | 0.10 | 0.11 | 0.13 | 0.13 | 0.13 | 0.15 | 0.14 |
| | % CV | 6.5% | 7.9% | 7.0% | 10.0% | 6.8% | 7.2% | 5.5% | 5.8% | 5.6% | 5.9% | 5.7% | 7.2% | 5.5% |
| | N= | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| Positive Control | Mean | 26.1 | 2.7 | 2.5 | 3.4 | 3.1 | 3.1 | 2.7 | 3.4 | 3.5 | 2.8 | 2.9 | 3.1 | 2.9 |
| | SD* | 1.06 | 0.15 | 0.23 | 0.41 | 0.15 | 0.14 | 0.12 | 0.25 | 0.16 | 0.18 | 0.13 | 0.19 | 0.14 |
| | % CV | 4.1% | 5.6% | 9.5% | 12.0% | 5.0% | 4.5% | 4.5% | 7.5% | 4.6% | 6.4% | 4.4% | 6.0% | 4.8% |
| | N= | 36 | 36 | 40 | 36 | 36 | 36 | 36 | 40 | 36 | 36 | 36 | 36 | 36 |

c. Linearity:

Refer to k041658

d. Carryover:

Refer to k041658

e. Interfering Substances:

Refer to k041658

2. Other Supportive Instrument Performance Data Not Covered Above:

None

K. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

L. Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence determination.