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The ARCHITECT Syphilis TP assay is a chemiluminescent microparticle immunoassay (CMIA) for the qualitative detection of antibodies (IgG and IgM) directed against Treponema pallidum (TP) in human serum and plasma. The ARCHITECT Syphilis TP assay is intended to be used as an initial diagnostic test or in conjunction with a nontreponemal laboratory test and clinical findings to aid in the diagnosis of syphilis infection.

Warning: The ARCHITECT Syphilis TP assay is not intended for use in screening blood, plasma, or tissue donors. The effectiveness of the ARCHITECT Syphilis TP assay for use in screening blood, plasma, or tissue donors has not been established.

The ARCHITECT Syphilis TP Calibrator is for the ARCHITECT iSystem when used for the qualitative detection of antibody to Treponema pallidum (TP) in human serum and plasma.

The ARCHITECT Syphilis TP Controls are for the estimation of test precision of systematic analytical deviations of the ARCHITECT iSystem when used for the qualitative detection of antibody to Treponema pallidum (TP) in human serum and plasma.

The ARCHITECT Syphilis TP assay is a two-step immunoassay for the qualitative detection of antibodies (IgG and IgM) directed against TP in human serum or plasma using CMIA technology with flexible assay protocols, referred to as Chemiflex.

1. Sample, assay diluent, and recombinant TP antigen (TpN15, TpN17 and TpN47) coated microparticles are combined. Anti-TP antibodies present in the sample bind to the TP coated microparticles.
2. After washing, anti-human IgG and IgM acridinium-labeled conjugate is added to create a reaction mixture.
3. Following another wash cycle, Pre-Trigger and Trigger Solutions are added to the reaction mixture.
4. The resulting chemiluminescent reaction is measured as relative light units (RLUs). There is a direct relationship between the amount of anti-TP antibodies in the sample and the RLUs detected by the ARCHITECT iSystem optics.

The presence or absence of anti-TP antibodies in the specimen is determined by comparing the chemiluminescent signal in the reaction to the cutoff signal determined from an active calibration. If the chemiluminescent signal in the reaction is greater than or equal to the cutoff signal, the specimen is considered reactive for anti-TP antibodies.

Here's a breakdown of the acceptance criteria and study information for the ARCHITECT Syphilis TP Reagent Kit:

1. Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for positive and negative percent agreement. Instead, it presents the calculated percent agreements observed in the clinical study. The FDA's substantial equivalence decision implies that these observed performance metrics were deemed acceptable when compared to the predicate device.

Note: NA (not applicable) for some categories indicates that there were no positive or negative cases, respectively, in that specific subpopulation to calculate the agreement.

The document also describes several non-clinical performance acceptance criteria through studies such as:

• Precision: Evaluated within-run, within-laboratory, within-day, between-site, and between-lot variability. Specific SD and %CV values are reported for controls and panels. The implication is that these values demonstrate acceptable precision.
• Interference: Demonstrated that the assay is not susceptible to interference from various substances at specified levels (e.g., conjugated bilirubin ≤ 20 mg/dL, hemoglobin ≤ 500 mg/dL).
• Analytical Specificity: Evaluation against various medical conditions and disease states. While some cross-reactivity was noted for a few specimens in specific categories (e.g., CMV IgG, HIV), the overall performance and context are considered acceptable, with a specific limitation noted for yaws, pinta, and bejel.
• Tube Type Matrix Comparison: Acceptable mean/median S/CO differences and distribution of S/CO differences for different tube types compared to serum.
• Sample On-Board Stability: Up to 3 hours storage on the ARCHITECT i2000SR System.
• Sample Stability: Up to 7 days at 2-8°C, up to 72 hours at room temperature, up to 6 freeze/thaw cycles, and up to 30 days frozen (-10°C or colder).
• High Dose Hook Effect: Determined not to be susceptible.
• Within-Assay Sample Carryover: Determined not to be susceptible.

2. Sample Sizes Used for the Test Set and Data Provenance

Test Set Sample Sizes:

• Clinical Study Total Specimens: 2220
  • Prospectively-Collected Intended Use Population: 1145 specimens
    • Routine Syphilis Testing: 442
    • Pregnant Females: 304
    • HIV Positive: 399
  • Pre-Selected Positive for TP Antibodies: 406 specimens
  • Apparently Healthy Individuals: 480 specimens
  • Medically Diagnosed (Primary, Secondary, Latent Syphilis): 179 specimens
  • Spiked Pregnant Female Specimens: 10 specimens

Data Provenance:

• Country of Origin: United States. Specimens for the prospectively-collected intended use population were sourced or collected from various locations: Baltimore, Maryland; Colton, California; Fort Lauderdale, Florida; Hyannis, Massachusetts; Los Angeles, California; Miami, Florida; San Antonio, Texas; and Temple, Texas.
• Retrospective/Prospective:
  • Prospectively-collected: 1145 specimens from the intended use population were collected prospectively.
  • Pre-selected: 406 specimens were "pre-selected positive" based on previous laboratory testing, suggesting a retrospective selection criterion based on existing positive results.
  • Medically diagnosed and Apparently healthy: These populations represent specific cohorts selected for the study.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications

This document describes a diagnostic device for syphilis, not an imaging diagnostic AI. Therefore, the "ground truth" is a laboratory-based composite reference, not expert-read interpretations of images.

The ground truth for the clinical studies was established using comparator assays, not human experts interpreting data for a "ground truth" consensus in the way a radiologist would for an imaging study. The comparator results were determined using a "2 out of 3 rule" from the following assays:

• Treponemal Chemiluminescent Immunoassay (TP-CLIA)
• Rapid Plasma Reagin (RPR) - a nontreponemal assay
• Treponema Pallidum Particle Agglutination (TP-PA) - a second treponemal assay

For the "medically diagnosed" category, the diagnosis was made by a licensed physician based on clinical information and serological testing results (e.g., VDRL, RPR, TP-PA). While a physician's input is a form of expert opinion, it's not described as a multi-expert consensus process specifically for establishing ground truth for the algorithm's direct input.

4. Adjudication Method for the Test Set

The adjudication method for the clinical test set (specifically for the final comparator result) was a "2 out of 3 rule" involving the three comparator assays: TP-CLIA, RPR, and TP-PA. If at least two of these assays were concordant (e.g., both positive or both negative), that determined the final comparator result.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in-vitro diagnostic assay, not an AI-powered imaging or interpretation system designed to assist human readers. Therefore, the concept of "human readers improving with AI vs without AI assistance" does not apply here.

6. Standalone Performance Study

Yes, a standalone performance study was done. The entire document describes the performance of the ARCHITECT Syphilis TP assay as a standalone diagnostic device. Its performance metrics (positive percent agreement, negative percent agreement, precision, specificity, etc.) are all measures of the algorithm's (assay's) performance without human-in-the-loop intervention for result interpretation. The assay outputs a qualitative "Reactive" or "Nonreactive" result based on its internal cutoff calculation (S/CO).

7. Type of Ground Truth Used

The primary type of ground truth used was a composite reference standard derived from the results of three established laboratory assays: a treponemal chemiluminescent immunoassay (TP-CLIA), a nontreponemal assay (Rapid Plasma Reagin [RPR]), and a second treponemal assay (Treponema Pallidum Particle Agglutination [TP-PA]), adjudicated by a "2 out of 3 rule."

Additionally, for some categories, clinical context and medical diagnosis by a licensed physician were used to characterize the patient population (e.g., "medically diagnosed individuals with primary, secondary, or latent syphilis").

8. Sample Size for the Training Set

The document does not explicitly state a separate "training set" sample size for the ARCHITECT Syphilis TP assay. For in-vitro diagnostic devices like this, the "development" or "training" of the assay (e.g., selection of antigens, optimization of reagents, determination of cutoff) is often an iterative process using internal studies and samples, rather than a distinct, large "training set" in the machine learning sense.

The "internal study" for selecting and validating the cutoff is mentioned, indicating some data was used for this purpose, but the size is not specified. The clinical studies described are primarily for validation and performance assessment (akin to a test set).

9. How the Ground Truth for the Training Set was Established

Since a distinct "training set" in the machine learning context is not explicitly described, the method for establishing its ground truth is also not detailed. However, based on the general development of such assays, the "ground truth" for optimizing the assay's components and cutoff during development would likely involve:

• Known positive and negative samples: Samples from individuals with confirmed syphilis infections (e.g., by culture, Western blot, or a panel of established treponemal and non-treponemal tests) and samples from healthy individuals.
• Reference standards: Internal or international reference standards for Treponema pallidum antibodies.

The "internal study" for cutoff selection and validation would have used such characterized samples to ensure the assay's sensitivity and specificity met developmental targets before moving to large-scale clinical validation.

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The IMMULITE® 2000 Syphilis Screen test is a treponemal testing procedure for the qualitative detection of antibodies to Treponema pallidum in human serum or heparinized plasma on the IMMULITE 2000 analyzer as an aid in the diagnosis of syphilis.

The IMMULITE 2000 Syphilis Screen is not intended for use in screening blood or plasma donors.

The IMMULITE 2000 Syphilis Screen is a solid-phase, one-step chemiluminescent immunoassay. The solid phase (bead) is coated with biotinylated recombinant Treponema pallidum p17 (Tp17) antigen. The liquid phase consists of alkaline phosphatase (bovine calf intestine) conjugated to purified recombinant Treponema pallidum p17 (Tp17) antigen.

The patient sample and reagent are incubated together with the coated bead for 30 minutes. During this time, total antibody to Treponema pallidum in the sample forms an antigen sandwich complex with biotinylated recombinant Treponema pallidum pl 7 (Tp17) antigen on the bead and enzyme conjugated purified recombinant Treponema pallidum p17 (Tp17) antigen in the reagent. Unbound patient sample and enzyme conjugate are then removed by centrifugal washes. Finally, chemiluminescent substrate is added to the reaction tube containing the bead and the signal is generated in proportion to the bound enzyme.

Here's a breakdown of the acceptance criteria and study information for the IMMULITE® 2000 Syphilis Screen device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" as a separate section with predefined thresholds. Instead, it presents a method comparison study between the IMMULITE® 2000 Syphilis Screen and the predicate device (DiaSorin LIASION® Treponema Assay). The performance of the new device is demonstrated through its agreement with the predicate.

For the purpose of this request, the "acceptance criteria" are inferred from the good performance values observed in the method comparison study, particularly the high positive and negative agreement rates.

2. Sample Sizes Used for the Test Set and Data Provenance:

• Medically Diagnosed Syphilis Patients: 281 samples
• Samples Sent for Routine Syphilis Testing: 924 samples
• Data Provenance: The document does not explicitly state the country of origin. It mentions "samples from various patient populations were tested," which suggests diverse sources, but no specifics are given. The study appears to be retrospective as it involves "samples from various patient populations were tested with both the IMMULITE Syphilis Screen and the LIAISON Treponema Assay," implying pre-collected samples.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:

The document does not mention the use of experts to establish ground truth for the test set. The "ground truth" for comparison is the DiaSorin LIASION® Treponema Assay. For the "Medically Diagnosed Syphilis Patients" cohort, their diagnosis would likely have involved clinical assessments and other laboratory tests by healthcare professionals, but no specific number or qualifications of experts are provided for the study's ground truth determination.

4. Adjudication Method for the Test Set:

No adjudication method is described. The comparison is directly between the IMMULITE 2000 Syphilis Screen and the LIAISON Treponema Assay, which serves as the reference (ground truth for agreement calculations).

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done:

No, a multi-reader, multi-case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) immunoassay, not an imaging or diagnostic device requiring human interpretation of results in the traditional sense of an MRMC study. Its performance is evaluated quantitatively or qualitatively against a reference method.

6. If a Standalone (i.e. algorithm only without human-in-the loop performance) Was Done:

Yes, a standalone performance evaluation of the IMMULITE® 2000 Syphilis Screen was performed. The device, an automated immunoassay, generates results without human intervention in the interpretation of the test itself. The study compared these standalone results directly against those of the predicate device (LIAISON Treponema Assay).

7. The Type of Ground Truth Used:

The primary "ground truth" for determining performance was the DiaSorin LIASION® Treponema Assay.

Additionally, for the "Medically Diagnosed Syphilis Patients" group, the "ground truth" was established by medical diagnosis, likely an aggregation of clinical findings and other laboratory results, preceding the testing with the LIAISON assay. The document states "Medically Diagnosed Syphilis Patients", implying an established patient status.

8. The Sample Size for the Training Set:

The document does not provide information on a training set sample size. As a diagnostic immunoassay, the development process typically involves internal optimization and validation, but specific "training set" and "test set" terminology in the context of machine learning algorithms (which this device is not) is not directly applicable or reported here. The clinical study described focuses on the device's performance against a predicate and existing patient cohorts.

9. How the Ground Truth for the Training Set Was Established:

Since a training set is not explicitly mentioned or relevant in the context of the reported study for this immunoassay device, the method for establishing its ground truth is not provided. Device development would involve rigorous analytical validation, but this is distinct from the type of ground truth establishment relevant to AI/ML model training.

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