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The BioPlex 2200 Lyme Total kit is a multiplex flow immunoassay intended for the qualitative detection of total (lgM/IgG) antibodies to Borrelia burgdorferi in human serum and plasma (EDTA, heparin). This assay should be used to test patients with a history and/ or symptoms of infection with B. burgdorferi. The BioPlex 2200 Lyme Total assay is intended for use with the Bio-Rad BioPlex 2200 System. All reactive and equivocal specimens should be tested with a second tier test such as Lyme IgM and IgG Western blot assays. Positive second tier results are supportive evidence of infection with B. burgdorferi. Diagnosis of Lyme borreliosis should be made based on the presence of B. burgdorferi antibodies, history, symptoms, and other laboratory data. Non-reactive first tier or negative second tier results should not be used to exclude borreliosis.

BioPlex 2200 Lyme Total kit includes the following components:

• One (1) 10 mL vial of Bead Set , containing dyed beads coated with recombinant p58, OspC ● type B (OspCB) and synthetic peptide FVlsE (consisting of FlaB and VlsE sequences), an Internal Standard bead (ISB) and a Serum Verification bead (SVB) in MOPS (3-[N-Morpholino] propane sulfonic acid) buffer containing bovine proteins with protein stabilizers. BND (5-bromo-5-nitro-1,3-dioxan) (≤ 0.1%), ProClin 300 (≤ 0.3%), sodium benzoate (≤ 0.1%) and sodium azide (

The document provided is a 510(k) Summary for the BioPlex 2200 Lyme Total kit, which is an in vitro diagnostic (IVD) device for the qualitative detection of total (IgM/IgG) antibodies to Borrelia burgdorferi. It is not an AI/ML-driven device, nor does it involve human readers interpreting images. Therefore, many of the requested criteria in your prompt (such as human readers, AI assistance, expert consensus for ground truth, adjudication methods, or sample size for training sets) are not applicable to this type of device.

However, I can extract information related to the acceptance criteria and performance study from the provided document as it pertains to an IVD device.

Key takeaway: This document describes a traditional in-vitro diagnostic device, not an AI/ML system for diagnostic imaging. Therefore, concepts like "human readers improve with AI vs without AI assistance" or "standalone (i.e. algorithm only without human-in-the-loop performance)" are irrelevant. The "acceptance criteria" for this IVD device would typically refer to predefined performance specifications agreed upon for regulatory clearance.

Here's the relevant information based on the document provided:

1. Table of Acceptance Criteria and Reported Device Performance

For IVD devices, acceptance criteria are generally established for various performance characteristics like sensitivity, specificity, precision, cross-reactivity, and interference. The document presents the results of these studies, and the implicit acceptance is that these results demonstrate substantial equivalence to the predicate device and are clinically acceptable. The performance is compared against a commercial Lyme IgM/IgG immunoassay or a CDC reference panel.

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

• Clinical Method Comparison Study (Test Set): 792 prospectively collected serum samples from patients submitted for Lyme disease testing.
  • Data Provenance: "various geographically distinct locations in the U.S." (retrospective or prospective is not explicitly stated for this part, but implies prospective collection for "patients submitted for Lyme disease testing"). The samples were evaluated at "three (3) U.S. clinical testing sites."
• Sensitivity Study (Test Set): 105 clinically characterized samples from an archived collection.
  • Data Provenance: Not specified for geographical origin beyond "archived collection."
• Analytical Specificity Study (Test Set): 836 samples from asymptomatic individuals from endemic regions (416 asymptomatic non-endemic, 420 asymptomatic endemic). These were "obtained from an asymptomatic population and excluded pre-screened blood donors."
  • Data Provenance: Not explicitly stated (e.g., country of origin), implies collected from relevant populations.
• Cross-Reactivity Study (Test Set): Varies per cross-reactant, e.g., 13 samples for ANA, 49 for EBV, 48 for Syphilis, etc. (Total N for this section is sum of all individual cross-reactant groups). Samples were "known to be positive for each cross-reactant" and "pre-tested by a commercially available Lyme assay and only those that tested negative by the commercially available assay were further tested."
• Precision Study: 80 replicates per panel member (6 panel members evaluated).
• Reproducibility Study: 120 total replicates per panel member (5 panel members evaluated), tested at 3 clinical trial sites.
• Matrix Comparison: Minimum of 40 sets of paired serum and plasma samples, total N for comparison ranged from 74 to 78 pairs.
• CDC Panel: 280 positive and negative specimens from the Centers for Disease Control and Prevention (CDC).
  • Data Provenance: CDC (implies U.S. origin).

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

Not Applicable / Not Provided for this IVD device. The device measures antibodies. The "ground truth" for clinical studies is based on patient clinical history, symptoms, and other laboratory data, or classification by a reference panel (like the CDC panel) or comparison to an already cleared predicate device. There is no mention of "experts" in the context of image interpretation or similar tasks requiring human consensus.

4. Adjudication Method for the Test Set

Not Applicable / Not Provided for this IVD device. Adjudication methods like "2+1, 3+1" are typically used for interpreting ambiguous cases or discordances in human reader studies, often in the context of imaging. For this IVD device, results are quantitative (Antibody Index) and then categorized into discrete "Reactive," "Equivocal," or "Non-Reactive" bins based on defined cut-offs. Discords between the new device and the predicate or clinical diagnosis are reported, but there's no mention of an adjudication process by human experts to resolve these, rather they are statistical comparisons. For equivocal results, the assay states they "should be tested with a second tier test such as Lyme IgM and IgG Western blot assays."

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not Applicable. This document describes an IVD antibody detection kit, not an AI-assisted imaging device or a device involving human readers.

6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done

The BioPlex 2200 Lyme Total kit is a standalone device in the sense that it performs the assay and provides quantitative results (Antibody Index) which are then categorized. There isn't a "human-in-the-loop" performing the primary measurement or interpretation in the way one would for an AI-assisted diagnostic imaging system. The device itself produces the raw data and converts it into the final qualitative result (Reactive, Equivocal, Non-Reactive) based on internal algorithms and calibrated cutoffs. Thus, all the performance data presented (sensitivity, specificity, precision, etc.) represents its standalone performance as an automated IVD assay.

7. The Type of Ground Truth Used

The "ground truth" for this IVD device's performance studies varies:

• Clinical Diagnosis: For the "Sensitivity Study" and "CDC Panel," samples were "clinically characterized" by disease stage (e.g., Acute, Convalescent, Late Lyme) or defined categories (e.g., look-alike diseases, healthy controls).
• Predicate Device Comparison: In the "Method Comparison Study," the new device's qualitative results were compared against an existing "Commercial Lyme IgM/IgG Immunoassay" (the predicate device). This serves as a reference for substantial equivalence.
• Second-Tier Testing (Western Blot): For reactive and equivocal results from both the new device and predicate, a "FDA-cleared IgG and IgM Western blot assays" was used as a confirmatory "second tier test." This provides a more definitive ground truth for those specific samples implicated as positive or equivocal by initial screening assays.
• Archived Collections/Known Status: For the precision, reproducibility, analytical specificity, interfering substances, and cross-reactivity studies, samples with pre-defined characteristics (e.g., specific concentrations, known disease states, known absence of target analyte) were used.

8. The Sample Size for the Training Set

Not Applicable / Not Provided. This document does not describe the development of an AI/ML algorithm that requires a specific training set. The device is a traditional immunoassay kit. The "assay cut-off" (similar to a classification threshold in ML) was determined using "1,372 normal sera" and was "retrospectively selected around the 98th percentile." This cohort was used to define the operational cut-off rather than "training" an algorithm in the AI/ML sense.

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

Not Applicable. As above, there is no AI/ML training set. The assay cut-off was established using 1,372 normal sera, identifying a relative fluorescence intensity (RFI) corresponding to the 98th percentile to set the 1.0 AI cut-off. This was then "subsequently evaluated for performance against clinically diagnosed samples."

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The QXDx™ BCR-ABL %IS Kit is an in vitro nucleic acid amplification test for the quantitation of BCR-ABL1 and ABL1 transcripts in total RNA from whole blood of diagnosed (9;22) positive Chronic Myeloid Leukemia (CML) patients expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2. The QXDx BCR-ABL %IS Kit is a reverse transcription-quantitative PCR performed on the Bio-Rad QXDx™ AutoDG™ ddPCR System and is intended to measure BCR-ABL1 to ABL1, expressed as a log molecular reduction (MR value) from a baseline of 100% on the International Scale, in (9;22) positive CML patients during monitoring of treatment with Tyrosine Kinase Inhibitors (TKIs).

The QXDx BCR-ABL %IS Kit is intended for use only on the Bio-Rad QXDx AutoDG ddPCR System.

The test does not differentiate between e13a2 or e14a2 fusion transcripts and does not monitor other rare fusion transcripts resulting from t(9;22). This test is not intended for the diagnosis of CML.

The QXDx AutoDG ddPCR System consists of two instruments, the QXDx Automated Droplet Generator and the QXDx Droplet Reader, and their associated consumables. The QXDx Automated Droplet Generator partitions samples into approximately 20,000 nanoliter-sized droplets and, after PCR on a thermal cycler, droplets from each sample are analyzed individually on the QXDx Droplet Reader. PCR-positive and PCR-negative droplets are counted to provide direct quantification of nucleic acid in digital form. Results are analyzed on QXDx Software running on a Windows based computer.

The QXDx AutoDG ddPCR System contains:

• QXDx Automated Droplet Generator ●
• QXDx Droplet Reader ●
• Laptop Computer with QXDx Software .
• Accessory components: ●
  • o ddPCR Dx AutoDG Consumable Pack
    • Automated Droplet Generation Oil for Probes ■
    • DG32 Cartridges w/ Gaskets ■
    • ddPCR Pipet Tips
    • . ddPCR 96 Well Plates
    • . ddPCR Pierceable Foil Seals
  • o ddPCR Dx AutoDG Droplet Reader Oil Pack

Components of the kit QXDx BCR-ABL %IS KIT:

• QXDXTM BCR-ABL primers & probes
• QXDXTM Nuclease Free Water
• QXDXTM iScript Advanced Reverse Transcriptase
• QXDXTM 5x iScript Select Reaction Mix
• QXDXTM RT Primers
• QXDXTM 2X ddPCRTM Supermix
• QXDXTM BCR-ABL ~0.1%IS
• QXDXTM BCR-ABL ~10%IS
• QXDXTM BCR-ABL Neg-CTRL
• QXDXTM BCR-ABL H-CTRL
• QXDXTM BCR-ABL L-CTRL

The provided document details the analytical and clinical performance of the QXDx BCR-ABL %IS Kit for use on the QXDx AutoDG ddPCR System. This device is an in vitro nucleic acid amplification test for the quantitation of BCR-ABL and ABL1 transcripts in total RNA from whole blood of diagnosed Chronic Myeloid Leukemia (CML) patients.

The document does not describe the acceptance criteria and study for an AI/ML powered medical device, but rather for an in vitro diagnostic (IVD) kit. Therefore, many of the typical acceptance criteria and study elements associated with AI/ML devices (e.g., human-in-the-loop performance, expert consensus for ground truth on images, MRMC studies) are not applicable.

Below is a breakdown of the acceptance criteria and study details provided for this IVD kit, adapted to the requested format where possible, and noting where specific requested information (relevant to AI/ML devices) is not available for this type of device.

Acceptance Criteria and Reported Device Performance

The core acceptance criteria are related to the analytical performance of the kit, primarily precision, reproducibility, cross-reactivity, interference, linearity, and detection capability. The performance is consistently reported in terms of Molecular Reduction (MR) value or %International Scale (%IS), which are standardized measures for BCR-ABL levels.

Table 1: Acceptance Criteria of the QXDx BCR-ABL %IS Kit and Reported Performance

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The BioPlex 2200 25-OH Vitamin D Kit is a multiplex flow competitive immunoassay intended for the quantitative determination of 25-hydroxyvitamin D in human serum. The BioPlex 2200 25-OH Vitamin D assay is to be used as an aid in the assessment of vitamin D sufficiency.

The BioPlex 2200 25-OH Vitamin D kit is intended for use with the Bio-Rad BioPlex 2200 System.

BioPlex 2200 25-OH Vitamin D kit includes the following components:

• One (1) 10 mL vial of Bead Set containing dyed beads coated with anti-25-0H ● Vitamin D antibody (sheep), an Internal Standard bead (ISB), and a Serum Verification bead (SVB) in buffer with protein stabilizers (bovine). ProClin 950 (

The BioPlex 2200 25-OH Vitamin D Kit is a multiplex flow competitive immunoassay intended for the quantitative determination of 25-hydroxyvitamin D in human serum, to be used as an aid in the assessment of vitamin D sufficiency. The device underwent a 510(k) submission, K180577, to demonstrate substantial equivalence to its predicate device, BioPlex 2200 25-OH Vitamin D Kit (K141114). The new kit has been modified by re-assigning calibrators and standardizing the assay in accordance with the Vitamin D Standardization Program (VDSP).

Here's an analysis of the acceptance criteria and the studies performed:

1. Table of Acceptance Criteria and Reported Device Performance:

The document primarily focuses on demonstrating substantial equivalence to a predicate device and adherence to CLSI guidelines for analytical performance. Therefore, "acceptance criteria" for specific performance metrics are often implied by the standards set forth in these guidelines and the performance of the predicate device, rather than explicit numerical targets stated as acceptance criteria in the summary. However, we can infer some criteria from the presented data.

2. Sample size used for the test set and data provenance:

• Precision Studies (CLSI EP5-A3):
  • Sample Size: 6 human serum samples and 2 control levels. Each tested in duplicate per run, on two runs per day over 20 days (N=80 results per sample/control).
  • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective), but it was human serum from a "panel".
• Reproducibility Studies (CLSI EP15-A3):
  • Sample Size: 8 panel members (serum matrix and QC controls), tested in replicates of two on two runs per day over five days (20 replicates per panel member).
  • Data Provenance: Performed at "one (1) US testing facility." Not explicitly stated if retrospective or prospective, or specific origin of serum matrix.
• Linearity/Assay Reportable Range (CLSI EP06-A):
  • Sample Size: Five high patient serum samples initially, serially diluted. Each sample and dilution evaluated in replicates of four.
  • Data Provenance: Not explicitly stated.
• Detection Limits (LoB, LoD, LoQ) (CLSI EP17-A2):
  • LoB: Five blank samples, tested in 4 replicates per day for 5 days (100 data points per reagent lot).
  • LoD: Six human samples with low 25-OH vitamin D, tested in 10 replicates per day for five days (50 data points per sample per reagent lot).
  • Data Provenance: Not explicitly stated.
• Interfering Substances (CLSI EP07-A2):
  • Sample Size: Not explicitly stated for number of samples, but "human serum pools" were used.
  • Data Provenance: Not explicitly stated.
• Cross-Reactivity (CLSI EP17-A2):
  • Sample Size: 2 human serum pools. Nine cross-reactants were spiked into these pools. Spiked and non-spiked samples evaluated in replicates of five.
  • Data Provenance: Not explicitly stated.
• Method Comparison with Predicate Device (CLSI EP09-A3):
  • Sample Size: 201 human samples (182 unaltered, 19 spiked with 25-hydroxyvitamin D3).
  • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective).
• Method Comparison to Reference Method (VDSP):
  • Sample Size: 120 native single donor patient serum samples.
  • Data Provenance: "reference sample set provided by the Vitamin D Standardization and Certification Program with assigned values by the RMP at CDC, independent from the samples used for standardization." This indicates a high-quality, external reference set. The origin of the patient samples themselves is not specified beyond "native single donor patient serum samples".
• Bias at Vitamin D Medical Decision Levels:
  • Sample Size: 303 samples overall for bias analysis, with specific numbers at each decision range (e.g., 7 for 19-21 ng/mL, 20 for 29-31 ng/mL, 6 for 95-105 ng/mL).
  • Data Provenance: Presumably a subset or re-analysis of samples from the method comparison studies.
• Expected Values/Reference Range (CLSI EP28-A3c):
  • Sample Size: 288 samples from "apparently healthy donors" (161 males, 127 females).
  • Data Provenance: Samples collected from "three regions (Northern, Central, and Southern) in the US" in spring, summer, and winter. Included African Americans, Hispanics, and Caucasians. This is prospective collection for establishing a reference range.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

This device is an in vitro diagnostic (IVD) quantitative assay for a biomarker (25-OH Vitamin D). The "ground truth" for such devices is established through highly accurate and standardized analytical methods.

• For the Method Comparison to Reference Method, the ground truth was established by the Vitamin D Standardization and Certification Program (VDSP) using an ID-LC/MS/MS Reference Method Procedure (RMP) at CDC. This RMP is traceable to the National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) 2972a. These are highly qualified and internationally recognized reference methods and institutions for chemical measurements, representing the gold standard in analytical chemistry. It is not about expert consensus on interpretations, but rather expert execution and certification of analytical accuracy.
• For other studies (precision, linearity, etc.), the "ground truth" is typically the measured value itself by the reference method or the assigned value of controls and calibrators, which are also traceable to established analytical standards.

4. Adjudication method for the test set:

Not applicable in the conventional sense involving multiple human readers and an adjudication process. This is a quantitative IVD device where sample values are measured against established reference methods and standards, not interpreted by experts in a clinical imaging or diagnostic context that would require adjudication.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, if so, what was the effect size of how much human readers improve with AI vs without AI assistance:

Not applicable. This is a laboratory diagnostic assay, not an AI-assisted diagnostic tool that involves human readers interpreting cases.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

This device performs as a standalone automated multiplex flow competitive immunoassay on the Bio-Rad BioPlex 2200 System. Its performance characteristics (precision, linearity, LLoQ, etc.) were evaluated directly without human intervention in the measurement process, representing a "standalone" analytical performance assessment. However, it's not an "algorithm only" device in the sense of AI; it's a chemical assay. The output is a quantitative measure of 25-OH Vitamin D concentration.

7. The type of ground truth used:

• For method comparison, the ground truth for the 120 samples was assigned values by the RMP at CDC, provided by the Vitamin D Standardization and Certification Program (VDSP). This is a highly accurate and externally certified analytical ground truth.
• For other analytical validation studies, the ground truth is established through internal standards, traceable calibrators, and reference materials specified by CLSI guidelines and traceable to NIST SRM 2972a.

8. The sample size for the training set:

• This submission describes performance validation for a modified in vitro diagnostic kit. The "training set" concept (as used in machine learning) is not directly applicable here. The device itself (the BioPlex 2200 system and its reagents) has established methodologies.
• The document states that Bio-Rad "modified the kit by re-assigning the calibrators and standardizing the assay in accordance with the Vitamin D Standardization Program (VDSP)." This implies that Bio-Rad used samples and measurements to establish these new calibrator assignments and standardization. However, the specific size and nature of such internal development/calibration "training" sets are not detailed in this 510(k) summary. The summary focuses on the validation of the finalized device.

9. How the ground truth for the training set was established:

• Again, the concept of a "training set" for an IVD kit often refers to the samples used during development and calibration. For this device, the key aspect of this "ground truth" for the modified kit is its standardization in accordance with the Vitamin D Standardization Program (VDSP). This means that the calibrators and ultimately the assay's measurements are referenced to the same highly accurate ID-LC/MS/MS RMP and NIST SRM 2972a that were used to establish the ground truth for the external validation sample sets. This ensures analytical accuracy and comparability across different methods and laboratories. The actual process of selecting and assigning values to the new calibrators would involve measuring reference materials and/or highly characterized samples using the VDSP-traceable methods.

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The Hemoglobin Variants System is intended as a qualitative screen for the presence of hemoglobins F, A, S, D, C and E in eluates of neonatal blood collected on filter paper by high-performance liquid chromatography (HPLC). The Hemoglobin Variants System is intended for Professional Use Only. For in vitro diagnostic use. The Hemoglobin Variants System is for use only with the Newborn Hemoglobin System (NHS).

This device, consisting of the reagents, controls, apparatus, HPLC instrumentation, software is indicated for professional laboratory IVD use to isolate and identify inherently determined abnormal (S, D, C, E) and normal (F, A) hemoqlobin types in neonatal blood samples.

The instrument, Newborn Hemoglobin System (NHS) utilizes same principles of ionexchange high-performance liguid chromatography (HPLC). The NHS instrument is a fully automated, high-throughput hemoglobin analyzer. It utilizes principles of ion-exchange highperformance liquid chromatography (HPLC). The NHS provides an integrated method for the separation and determination of relative percent of specific hemoglobins of dried blood spots. The dried blood spot collected from neonatal heel stick is punched and eluted with deionized water. The punched disc is removed and eluted sample is transferred into microplate well. The eluted sample is analyzed to identify specific inherently abnormal (S, D, C, E) as well as normal (F, A) hemoglobins through the system.

The NHS consists of two modules — the Newborn Chromatographic Station (NCS) and the Newborn Auto Sampler (NAS). NCS module delivers buffer solutions (See table 4 for kit components) to the Hemoglobin Variants System CE Mini-Columns and the detector. The NAS module through automatic injection introduces eluted sample from microplate wells. Each sample is processed individually. The mini-column contains a cation exchange gel, and the analyzer makes use of a continuous pre-programmed gradient system. The preprogrammed gradient is designed to have the hemoglobins of interest elute from the minicolumn with retention times that fall within pre-determined windows characteristic of known normal and abnormal hemoglobins. The ionic strength of two phosphate buffers passing through the mini-column is changed over three minutes. The eluted hemoglobins introduced through automatic injection are sequentially detected with a dual-wavelength filter photometer. which monitors hemoglobin absorbance at 415 nm and corrects for any gradient induced absorbance changes at 690 nm. Detection is performed at two wavelengths (415 nm and 690 nm) to ensure a stable baseline. Sample of water immediately following a newborn or quality control sample prevents carryover.

A workstation is used to control the Newborn Hemoglobin System using Genetic Disease Management (GDM) software. The GDM software is designed to execute the assay protocol on the NHS instrument using the Hemoglobin Variants System reagent kit components. The software processed HPLC data is outputted in a printed report that contains: 1) sample identification, 2) date and time of analysis, 3) report data (i.e., peak names, retention times, area, relative percent), and 4) chromatogram. Also system assigns a presumptive phenotype "pattern" to each sample result. The pattern is calculated by applying a set of "rules" to the peaks identified in the peak table. The purpose of the pattern rules is to eliminate minor peaks from the pattern, identify system or sample problems, and to focus the operator on the samples that may require further investigation. The pattern rules used by the GDM software were derived from those generated by the Genetic Diseases Laboratory for the state of California, USA, after analysis of 2.5 million newborns by HPLC over a four year period (Eastman, et al., 1996)'. Laboratories using the Newborn Hemoglobin System pattern rules and assignment should perform an internal validation study to confirm the performance of the system for their application. 1.Eastman, J. W.; Wong, R.; Liao, C. L.; Morales, D. R. Automated HPLC Screening of Newborns for Sickle Cell Anemia and Other Hemoglobinopathies. Clin. Chem. 1996, 42 (5), 704—710.

The HbReview Software is to support the review of transmitted result and release of an approved result for each neonate sample analyzed on Hemoglobin Variants System with Newborn Hemoglobin System. A screening site using Newborn Hemoglobin Systems (NHS) transmits results from the Genetic Disease Management (GDM) software to the central site. The central site uses HbReview software to review results, identify samples for retesting, add comments and release results to the reporting site. Features are provided to assist Reviewers and Approvers in their tasks of examining results from the Hemoglobin Newborn Screening test.

The HbReview software is a Client-Server design. The Review process provides a user interface (client) to a relational database, which is located on a separate computer (the server). The Client software permits an authorized user to make changes to the data maintained on the Server.

This submission describes the Bio-Rad Hemoglobin Variants System on Newborn Hemoglobin System with GDM and HbReview Software. This device is intended as a qualitative screen for the presence of hemoglobins F, A, S, D, C and E in eluates of neonatal blood collected on filter paper by high-performance liquid chromatography (HPLC).

Here's an analysis of the provided information:

1. Table of acceptance criteria and the reported device performance:

The document does not explicitly state acceptance criteria or provide a table of performance metrics (like sensitivity, specificity, accuracy) from a validation study for the Hemoglobin Variants System. It focuses on demonstrating substantial equivalence to a predicate device (Bio-Rad VARIANT™nbs Sickle Cell Program).

However, the "Indications for Use" section states: "This device...is indicated for professional laboratory IVD use to isolate and identify inherently determined abnormal (S, D, C, E) and normal (F, A) hemoglobin types in neonatal blood samples." This implies that the device must accurately identify these hemoglobin types.

2. Sample size used for the test set and the data provenance:

The document does not provide information on the sample size used for a test set or the data provenance (country of origin, retrospective/prospective) for a performance study of the modified device.

It mentions that the "pattern rules used by the GDM software were derived from those generated by the Genetic Diseases Laboratory for the state of California, USA, after analysis of 2.5 million newborns by HPLC over a four year period (Eastman, et al., 1996)." This refers to the historical data used to establish the rules for the GDM software, not a specific test set for the current device's performance validation. It also suggests that laboratories using the system should perform an internal validation.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

The document does not explicitly state the number or qualifications of experts used to establish ground truth for a specific test set for the modified device. The reference to the Genetic Diseases Laboratory in California for establishing GDM pattern rules implies expert involvement in the development of those rules, but not necessarily in evaluating a specific test set for the current submission.

4. Adjudication method for the test set:

The document does not describe an adjudication method for a test set.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done:

No, the document does not mention an MRMC comparative effectiveness study for the modified device. The focus is on demonstrating substantial equivalence, not on quantifying the improvement of human readers with AI assistance.

6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:

The device described is a system that combines instrumentation, reagents, and software for analysis. While the GDM and HbReview software play a role, the system is designed for in vitro diagnostic use by professional laboratories. The HbReview software aids in the review and release of results by human operators. Therefore, it's not a standalone "algorithm only without human-in-the-loop" performance in the context of typical AI device submissions. The "pattern rules" in GDM are an automated algorithmic component, but the overall system involves human oversight for result review and release.

7. The type of ground truth used:

The document implies that the ground truth for identifying hemoglobin types (F, A, S, D, C, E) would be established through laboratory methods that definitively identify these hemoglobins. For the historical data used to derive GDM pattern rules, it was based on HPLC analysis with extensive validation as referenced (Eastman, et al., 1996). For the current device, a robust laboratory gold standard (e.g., confirmatory biochemical or genetic testing) for hemoglobin types would be expected to serve as ground truth in any validation studies.

8. The sample size for the training set:

The document does not explicitly state a sample size for a training set for the modified device.

However, it states that the GDM software's pattern rules were derived from "analysis of 2.5 million newborns by HPLC over a four-year period (Eastman, et al., 1996)" by the Genetic Diseases Laboratory for the state of California. This large dataset effectively served as the "training data" for formulating those rules.

9. How the ground truth for the training set was established:

For the 2.5 million newborns analyzed that informed the GDM pattern rules, the ground truth was established through HPLC analysis (ion-exchange high-performance liquid chromatography). This method is a standard laboratory technique for identifying and quantifying hemoglobin variants. The implied ground truth relies on the established accuracy and reliability of this HPLC method, likely supported by expert interpretation and potentially confirmatory testing in ambiguous cases over the four-year period mentioned.

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The BioPlex 2200 ToRC IgM kit is a multiplex flow immunoassay intended for the qualitative detection of IgM antibodies to Toxoplasma gondii), Rubella, and Cytomegalovirus (CMV) in human serum and plasma (K3 EDTA, lithium heparin, or sodium heparin).

The BioPlex 2200 ToRC IgM kit is intended for use with the Bio-Rad BioPlex 2200 System.

This kit is intended as an aid in the diagnosis of a current or recent T. gondii, Rubella and/or CMV infection, in individuals suspected of having one of the respective disease states, including women of child bearing age.

This assay is not FDA cleared or approved for use in testing (screening) blood or plasma donors.

Performance characteristics for the ToRC IgM assay have not been evaluated in immunosuppressed or organ transplant individuals. Performance characteristics of this kit have not been established for use in neonatal screening or for use at point of care facilities.

The BioPlex 2200 ToRC IgM Calibrator Set is intended for the BioPlex 2200 ToRC IgM Reagent Pack.

The BioPlex 2200 ToRC IgM Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 Instrument and BioPlex 2200 ToRC IgM Reagent Pack in the clinical laboratory.

BioPlex ToRC IgM Reagent Pack includes the following components:

• One (1) 10 mL vial, containing dyed beads coated with lysates of T. gondii, Rubella and CMV ● plus an Internal Standard bead (ISB) and a Serum Verification bead (SVB) in buffer with Glycerol and protein stabilizers (bovine and caprine). ProClin 300 (≤ 0.3%), sodium benzoate (≤ 0.1%) and sodium azide (

Here's an analysis of the provided text to extract information about the acceptance criteria and the study proving the device's performance, as requested.

The provided text describes the performance characteristics of the BioPlex 2200 ToRC IgM kit, which is a multiplex flow immunoassay for detecting IgM antibodies to Toxoplasma gondii, Rubella, and Cytomegalovirus (CMV).

Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as a section titled "Acceptance Criteria" with pass/fail metrics. Instead, the document presents various analytical and clinical performance studies, and the results of these studies implicitly represent the device's acceptable performance. For the purpose of this response, I will infer the acceptance criteria from the reported performance, particularly where quantitative results are presented.

1. Table of Acceptance Criteria and Reported Device Performance

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The BioPlex Syphilis Total & RPR kit is a multiplex flow immunoassay intended for the qualitative detection of total (IgG/IgM) antibodies to Treponema pallidum and the qualitative detection and/or titer determination of non-treponemal reagin antibodies in human serum or plasma. The Syphilis Total or RPR assays may be used to supplement a previously determined reactive treponemal or non-treponemal test. The test system should be used in conjunction with other laboratory tests and clinical findings to aid in the diagnosis of syphilis infection.

The BioPlex 2200 Syphilis Total & RPR kit is not intended for use in screening blood or plasma donors

The BioPlex 2200 Syphilis Total & RPR kit is intended for use with the Bio-Rad BioPlex 2200 System.

The BioPlex 2200 Syphilis Total & RPR Control Set is intended for use as an assayed quality control to monitor the performance of the BioPlex 2200 Instrument and BioPlex 2200 Syphilis Total & RPR assay in the clinical laboratory. The performance of the BioPlex 2200 Syphilis Total & RPR Control Set has not been established with any other Syphilis Total & RPR assays.

The BioPlex 2200 Syphilis Total & RPR Calibrator Set is intended for the BioPlex 2200 Syphilis Total & RPR Reagent Pack.

BioPlex 2200 Syphilis Total & RPR kit includes the following components:

• One (1) 10 mL vial, containing dyed beads coated with recombinant Syphilis ● rTP47/rTP17 fusion protein, a cardiolipin antigen, an Internal Standard Bead (ISB) and a Serum Verification Bead (SVB) in MOPS (3-[N-Morpholino] propanesulfonic acid) buffer containing bovine proteins with protein stabilizers. ProClin 300 (≤ 0.3%), sodium benzoate (≤ 0.1%) and sodium azide (

Here's an analysis of the provided text, extracting the acceptance criteria and study details as requested:

BIO-RAD BioPlex 2200 Syphilis Total & RPR Kit Evaluation

1. Table of Acceptance Criteria and Reported Device Performance

The document describes internal precision and reproducibility acceptance criteria implicitly through the reported values for %CV within CLSI guidelines. For clinical performance, acceptance criteria are not explicitly stated as numerical thresholds (e.g., minimum sensitivity/specificity), but agreement percentages are reported. The provided tables are direct results from the studies and serve as the reported performance against assumed internal/regulatory acceptance ranges.

For Syphilis Total Assay (Treponemal Test):

For RPR Assay (Non-Treponemal Test):

2. Sample Size and Data Provenance for Test Set

• Total Samples for Clinical Studies: 2008 samples.
• Test Set Breakdown:
  • Prospective Samples: 1001 samples.
    • Country of Origin: Approximately 91% US (23.6% Northeast, 18.7% Southwest, 28.4% Southeast, 9.2% Midwest, 10.8% Unknown), 9% outside US (3.5% Argentina, 3.2% France/Europe, 1.4% China, 1.2% Others).
  • Retrospective Samples: 661 samples.
    • Country of Origin: Not explicitly broken down for retrospective samples, but generally stated to be from "multiple commercial suppliers" with the 91% US / 9% outside US split likely encompassing both.
  • Clinically Diagnosed Individuals: 160 individuals (separate cohort from prospective/retrospective samples with specific diagnoses).
• Data Provenance: Both prospective and retrospective samples were used. Prospectively collected samples were from apparently healthy subjects, syphilis/RPR test ordered patients, pregnant women, and HIV positive individuals. Retrospective samples were from known RPR/VDRL positive, clinically diagnosed syphilis, pregnant syphilis positive, and HIV/Syphilis dual positive individuals.

3. Number of Experts and Qualifications for Ground Truth

The document does not explicitly state the number or qualifications of "experts" used for establishing the ground truth directly. Instead, it relies on a "Final Comparator Algorithm Result" for the Syphilis Total assay, which is derived from multiple commercially available syphilis assays (predicate devices). For the RPR assay, the ground truth is primarily based on a commercially available RPR Card Test (Predicate).

• No specific number of human experts is mentioned for adjudicating individual cases or establishing the final ground truth. The "ground truth" seems to be established algorithmically or through established predicate diagnostic tests.

4. Adjudication Method

• For BioPlex 2200 Syphilis Total assay: The ground truth was established using a "2 out of 3" rule from three commercially available syphilis assays:
  1. Treponemal chemiluminescent immunoassay (primary predicate)
  2. RPR Card Test (non-treponemal assay)
  3. Treponema Pallidum Particle Agglutination (TP-PA) (second treponemal assay)
     If at least two of these predicate assays agreed, that was considered the final comparator result. If there was no agreement (e.g., 1 positive, 1 negative, 1 inconclusive), the result was deemed "indeterminate" and excluded from analysis.
• For BioPlex 2200 RPR assay: The ground truth was established by comparing directly to a commercially available RPR Card Test (Predicate). No explicit "adjudication" among multiple assays is described here.

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

• No MRMC or human-in-the-loop study is described in this document. The device is an automated immunoassay system, and its performance is compared to other diagnostic assays (predicate devices), not to human readers. Therefore, there is no effect size reported for human readers improving with or without AI assistance.

6. Standalone Performance Study

• Yes, a standalone performance study was done. The entire document describes the standalone performance of the BioPlex 2200 Syphilis Total & RPR kit. The device is an algorithm only (automated immunoassay) without a human-in-the-loop component in the diagnostic process itself. The clinical performance tables explicitly show the agreement of the BioPlex 2200 with the "Final Comparator Algorithm Result" (for Syphilis Total) or the "Predicate RPR Result" (for RPR).

7. Type of Ground Truth Used

• For Syphilis Total assay: A composite comparator algorithm based on the results of three commercially available diagnostic assays (predicate Treponemal CIA, RPR Card Test, TP-PA). This could be categorized as a form of expert consensus using established diagnostic tests rather than pathology or direct outcomes data for every individual case.
• For RPR assay: A single predicate diagnostic assay (RPR Card Test).

8. Sample Size for Training Set

• The document does not explicitly state the sample size used for the training set. It mentions the "feasibility phase of BioPlex 2200 Syphilis Total & RPR assay development" where cutoff values were established using "native human samples from apparently healthy subjects, patients sent to the laboratory for syphilis testing and patients diagnosed with syphilis infection." However, specific numbers for this development/training phase are not provided.

9. How Ground Truth for Training Set Was Established

• The cutoff values for the Syphilis Total and RPR assays were established "in the feasibility phase" using Native human samples from:
  • Apparently healthy subjects
  • Patients sent to the laboratory for syphilis testing
  • Patients diagnosed with syphilis infection
• The establishment involved Receiver Operating Characteristics (ROC) analysis using "predicate results as standard". This indicates that the ground truth for establishing the cutoffs was derived from existing, legally marketed assays (predicates). Calibrator values were then adjusted based on this analysis to align with the 1.0 AI cutoff. Further confirmation of cutoff values involved comparing BioPlex results from patient samples to commercially available assays, and ultimately, clinical studies validated the cutoff.

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Liquichek Tumor Marker Control is intended for use as an assayed quality control serum to monitor the precision of laboratory testing procedures for the analytes listed in this package insert.

Liquichek Tumor Marker Control is prepared from human source material with added constituents of human and animal origin, chemicals, stabilizers and preservatives. The control is provided in liquid form for convenience.

This document is a 510(k) Summary for a quality control material, not a medical device that would typically undergo a study with acceptance criteria for diagnostic performance (e.g., sensitivity, specificity, AUC). Instead, the "acceptance criteria" here refer to the stability claims of the control material, and the "study" is the stability testing performed.

Here's a breakdown of the requested information based on the provided text:

1. A table of acceptance criteria and the reported device performance

For a quality control material, "acceptance criteria" are typically related to its stability and ability to maintain its assigned values over specific storage conditions and timeframes. The performance is the duration for which these conditions are met.

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

The document does not explicitly state a "sample size for the test set" in the context of clinical performance or diagnostic accuracy. Instead, it refers to stability studies. The details for these studies are:

• Sample Size: Not specified in terms of number of runs or batches, but implies "a representative sampling of this lot of product" was used for value assignment and stability testing.
• Data Provenance: The studies were performed internally by Bio-Rad Laboratories and/or "independent laboratories." The country of origin is not specified, but Bio-Rad Laboratories is based in California, USA.
• Retrospective or Prospective: These would be prospective studies, as they involve testing the product over time under various storage conditions.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This is not applicable as the device is a quality control material and not a diagnostic device requiring expert interpretation of results to establish "ground truth" for a test set. The "ground truth" for this device relates to the assigned quantitative values of the analytes within the control material, which are established through a process called "Value Assignment."

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

This is not applicable for a quality control material. Value assignment and stability testing are typically performed through replicate analyses and statistical methods, not through expert adjudication.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

This is not applicable. The device is a quality control material, not an AI-powered diagnostic tool, and therefore MRMC studies are not relevant.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

This is not applicable. The device itself is a material, not an algorithm. Its "performance" is its stability and the reproducibility of its assigned values when tested by laboratory instruments.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

For a quality control material, the "ground truth" refers to the established, target values of the analytes within the control. This is established through:

• Value Assignment: "The mean values and corresponding ±3SD ranges in the Assignment of Values Data Charts were derived from replicate analyses and are specific for this lot of product. Data from Unity™ Interlaboratory Program are included in the determination of some ranges." This indicates a process involving extensive laboratory testing and potentially interlaboratory comparisons to determine accurate and precise target values.

8. The sample size for the training set

This is not applicable. This device is a quality control material, not an algorithm that requires a "training set."

9. How the ground truth for the training set was established

This is not applicable, as there is no "training set" for this type of device.

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The D-10™ Hemoglobin A1c Program is intended for the quantitative determination of hemoglobin A1c (IFCC mmol/ mol and NGSP %) in human whole blood using ion- exchange high-performance liquid chromatography (HPLC) on the D-10TM Hemoglobin Testing System.

Hemoglobin Alc measurements are used as an aid in diagnosis of diabetes, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus.

The D-10™ Hemoglobin A1c Program is intended for professional in vitro diagnostic use only.

The D-10™ Hemoglobin Testing System utilizes the principles of ion-exchange highperformance liquid chromatography (HPLC). A dual-piston, low pulsation HPLC pump and a proportioning value deliver the buffer solution to an analytical cartridge and detector. Whole blood samples undergo an automatic two step dilution process and then introduced into the analytical flow path. Pre-diluted samples are aspirated directly and introduced into the analytical flow path. Between sample injections, the sample probe is rinsed with Wash/Diluent Solution to minimize sample carryover.

A programmed buffer gradient of increasing ionic strength delivers the sample to the analytical cartridge where the hemoglobin species are separated based upon their ionic interactions with the cartridge material and the buffer gradient. The separated hemoglobin species then pass through the photometer flow cell where changes in the absorbance are measured at 415 nm and recorded as a digital chromatogram.

The software performs a reduction of raw data collected from each analysis that may indicate use of a calibration factor. A samples report and chromatogram are generated for each sample.

The D-10™ Hemoglobin A1c Program is designed to be used on the D-10™ Hemoglobin Testing System with or without a D-10 Rack Loader.

The provided text describes a 510(k) premarket notification for the D-10 Hemoglobin A1c Program. This device is an in vitro diagnostic (IVD) used for the quantitative determination of hemoglobin A1c (HbA1c) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC).

Here's an analysis of the acceptance criteria and the study that proves the device meets those criteria, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" in a single table, but rather presents performance characteristics derived from various studies. Based on the "Summary of Nonclinical Performance Data" and the conclusion that "The performance criteria as stipulated by the Special Controls requirements for HbA1c systems that diagnose diabetes have clearly been met," we can infer the acceptance criteria from the reported results. The critical performance metrics for an HbA1c assay for diabetes diagnosis typically include precision (CV%), linearity, and method comparison (bias).

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

• Precision/Reproducibility: Four EDTA whole blood samples at target HbA1c concentrations (~5%, ~6.5%, ~8%, ~12%) and five quality control materials were used. Each sample/control was run in duplicate, in 2 runs per day, on 3 instruments for 20 days, and repeated with 3 different kit lots, yielding a total of 720 results per sample over 60 days. The data provenance is not explicitly stated (e.g., country of origin, retrospective/prospective clinical samples), but it implies prospective collection for the study.
• Linearity: Low (3.9% HbA1c) and high (18.8% HbA1c) EDTA whole blood patient samples were mixed in varying ratios to create 11 sample pools. The exact number of individual patient samples generating the pools is not specified.
• Method Comparison: 128 variant-free whole blood K3 EDTA samples were evaluated. The range of HbA1c was from 3.9% to approximately 19.0% (19 to 184 mmol/mol). Data provenance is not explicitly stated for these samples, but they are referred to as "patient samples."
• Endogenous/Drug Interference & Hemoglobin Derivatives Interference: Two EDTA whole blood sample pools (low level ~6.5% HbA1c and high level ~8.0% HbA1c) were used for spiking experiments. Ten replicates of each pool with interferent and control were analyzed. The specific number of individual patient samples that formed these pools is not detailed.
• Hemoglobin Variant Study: A panel of normal and diabetic whole blood EDTA patent variant samples for HbS (n=22), HbC (n=20), HbD (n=22), HbE (n=23), HbA2 (n=20), and HbF (n=24) were used. These are patient samples with known variants.

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

• For Method Comparison: The D-10™ Hemoglobin A1c Program results were compared to "testing performed at a secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay." The NGSP SRL (National Glycohemoglobin Standardization Program Secondary Reference Lab) is itself a highly qualified reference standard, implying expert oversight and standardized methods for ground truth determination, though specific human experts are not named or qualified in this document.
• For Hemoglobin Variant Study: Comparison was made to a "NGSP reference method that has been demonstrated to be free from the hemoglobin interferent." Similar to the method comparison, this relies on a standardized reference method rather than individual expert adjudication for each sample.

4. Adjudication Method for the Test Set:

Not applicable in the traditional sense of image or clinical outcome adjudication by multiple experts. The ground truth for the method comparison and variant studies was established by comparison to a standardized NGSP reference method, which inherently provides a highly controlled and validated "truth" for HbA1c measurements.

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

No, a MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) for laboratory use, not typically subject to human reader interpretation or MRMC studies.

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

Yes, the studies described are all standalone performance evaluations of the D-10™ Hemoglobin A1c Program device. The tests, such as precision, linearity, method comparison, and interference studies, assess the analytical performance of the algorithm and hardware without human interpretation in the loop determining the HbA1c value.

7. The Type of Ground Truth Used:

The ground truth for the performance studies primarily relies on:

• Reference Methods: For method comparison and variant studies, the ground truth was established by a "secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay" and an "NGSP reference method."
• Expected Values/Spiking: For precision, linearity, and interference studies, ground truth was based on preparing samples with known concentrations or by comparing to control samples without interferents.
• Consensus/Certification: The general standardization is traced to IFCC reference calibrators and NGSP certification.

8. The Sample Size for the Training Set:

This document describes premarket notification studies for an in vitro diagnostic device, not a machine learning algorithm. Therefore, there is no explicit "training set" in the context of machine learning model development. The device relies on established chemical and physical principles (ion-exchange HPLC) with programmed parameters, rather than learning from a large dataset. Calibration of the instrument is performed using calibrator materials, but this is distinct from a machine learning training set.

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

As there is no machine learning-based training set, this question is not applicable. The device's operational parameters and calibration are based on established analytical chemistry principles and reference materials. The value assignment for the calibrator materials "were previously reviewed under 510(k) submission K031043," indicating their ground truth was established through a separate, regulated process.

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Amplichek I is intended for use as an external assayed quality control material to monitor the performance of in vitro laboratory nucleic acid testing procedures for the quantitative detection of Human Immunodeficiency Virus Type 1 (HIV-1), Hepatiis B Virus (HBV) and Hepatitis C Virus (HCV) for molecular diagnostic platforms listed in the package insert. This product is not intended to replace manufacturer controls provided with the device. This product is not intended for use with blood donor screening assays in U.S. or Canada.

Amplichek I is a set of quality controls consisting of four levels filled in individual vials with 1.2 mL of material. Each level is packaged separately in configuration of 10 tubes per box and four tubes per box in a MiniPak (trial size). This product is prepared from normal human plasma based material non-reactive to HIV-1 Ribonucleic Acid (RNA), HBV Deoxyribonucleic Acid (DNA) and HCV Ribonucleic Acid (RNA) with added proteins from human sources, antimicrobial agents as preservatives, and stabilizers. The positive levels are prepared using purified preparations of HIV, HBV and HCV isolated from human plasma or grown in cell cultures and are reactive for HIV-1 RNA, HBV DNA and HCV RNA. Amplichek I contains human plasma and purified retroviral and viral hepatitis materials derived from human plasma and/or cultured human cell line sources. Each human unit used in the preparation of this product is tested using licensed reagents and must be found to be non-reactive to HBsAg, antibodies to HIV-1 and HIV-2 and antibodies to HCV. Retroviral and viral hepatitis materials derived from human plasma and/or cultured human cell line sources are treated to inactivate infectious agents. However, no known test method can assure that products derived from human sources will not transmit infection. The labeling recommends that this product and all human specimens be handled in accordance with Biosafety Level 2 practices as described in the United States Department of Health and Human Services Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH), Biosafety in Microbiological and Biomedical Laboratories, or other equivalent guidelines. The package insert will provide lot specific mean and ranges for each analyte on various platforms. The assigned values listed in the proposed package insert were generated in the same manner as used for unknown specimens using FDA approved commercial test kits. The negative control reports qualitative results. The means for the positive controls were calculated from the total laboratory data generated for each analyte on the specific platform and the 3SD range was then assigned. The Amplichek I labeling recommends that each laboratory establish its own acceptable range for each analyte. Procedures for implementing a quality assurance program and monitoring test performance on a routine basis must be established by each individual laboratory. Amplichek I product should not be used as a standard. It is recommended that each laboratory establish its own means and acceptable ranges and use those provided only as quides.

The provided text describes the Bio-Rad Amplichek I, an assayed quality control material, and its substantial equivalence to a predicate device (Amplichek II). It does not contain information about a medical device that requires a study to prove it meets acceptance criteria in the typical sense of a diagnostic or AI-powered device.

Therefore, many of the requested categories for a study on device performance, such as sample size for test sets, data provenance, expert ground truth, adjudication methods, MRMC studies, standalone performance, and training set information, are not applicable to this document. This document primarily focuses on the regulatory submission and comparison of a quality control material.

However, I can extract the acceptance criteria related to product stability based on the provided text.

Here's a summary of the stability acceptance criteria and the device's reported performance:

Acceptance Criteria and Reported Device Performance for Bio-Rad Amplichek I

1. A table of acceptance criteria and the reported device performance

2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)

This information is not provided in the document. The text states "Stability studies have been performed..." but does not detail the methodology, sample sizes, or data provenance for these studies.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

This information is not applicable as the device is an assayed quality control material, not a diagnostic device requiring expert interpretation for ground truth establishment. The "ground truth" for this type of product refers to the pre-assigned values and ranges determined by the manufacturer for the analytes. The document mentions: "The assigned values listed in the proposed package insert were generated in the same manner as used for unknown specimens using FDA approved commercial test kits. The negative control reports qualitative results. The means for the positive controls were calculated from the total laboratory data generated for each analyte on the specific platform and the 3SD range was then assigned." This describes a laboratory-based method using commercial test kits, not a panel of human experts.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

This information is not applicable for a quality control material as there is no human interpretation or adjudication process described for the stability studies.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

An MRMC comparative effectiveness study was not done. This type of study is relevant for AI-powered diagnostic devices involving human readers, which is not the nature of the Amplichek I device.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

A standalone performance evaluation in the context of an algorithm or AI system was not done. The stability studies evaluate the physical and chemical stability of the quality control material itself.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

The "ground truth" for the performance of this quality control material is established through laboratory testing using FDA approved commercial test kits, whereby lot-specific mean and ranges are determined for each analyte on various platforms. For the stability studies, the acceptance criteria are based on whether the material retains its expected performance (e.g., within established ranges) after storage under specified conditions.

8. The sample size for the training set

This information is not applicable. The Amplichek I is a quality control material, not a machine learning model, so there is no "training set."

9. How the ground truth for the training set was established

This information is not applicable, as there is no training set for this device.

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Amplichek II is intended for use as an external assayed quality control material to monitor the performance of in vitro laboratory nucleic acid testing procedures for the qualitative detection of Methicillin Resistant Staphylococcus aureus, Methicillin Sensitive Staphylococcus aureus, Clostridium difficile and Vancomycin-resistant Enterococci performed on Cepheid GeneXpert Systems. This product is not intended to replace manufacturer controls provided with the device. This product is only for use with assays and instruments listed in the Representative Results Chart in this labeling.

Amplichek II (Assayed Microbiology Control) is manufactured at three levels, Levels 1, 2 and 3, for each analyte indicated in the package insert. Individual analyte values are listed in the package insert and are specific for the instrument system or method utilized. Each control is prepared in liquid form in a buffer solution with preservatives including 5chloro-2-methyl-2H-isothiazol-3-one at a concentration of 0.1%, stabilizers and added preparations of purified intact microorganisms grown in microbial culture. Source materials are chemically treated and processed to inactivate infectious agents.

The Amplichek II is an assayed quality control material for clinical microbiology assays. Its purpose is to monitor the performance of in vitro laboratory nucleic acid testing procedures for the qualitative detection of Methicillin-Resistant Staphylococcus aureus (MRSA), Methicillin-Sensitive Staphylococcus aureus (MSSA), Clostridium difficile (Cdiff), and Vancomycin-resistant Enterococci (VRE) on Cepheid GeneXpert Systems.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The primary acceptance criteria for the Amplichek II, as demonstrated by the reproducibility studies, is the percent agreement with the expected result for each analyte at various levels (Negative, Level 1, Level 2, Level 3).

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

The document describes two reproducibility studies acting as the test sets:

• Study 1 (Single Lab):

  • Sample Size: For each gene/analyte at each Amplichek II level (Negative, Level 1, Level 2, Level 3), there were 40 tests per lot (2 replicates per run x 2 runs per day x 10 days). With two lots, this totals 80 tests per gene/analyte/level. For instance, for the Cepheid Xpert SA Nasal Complete (MSSA/MRSA), there were 80 tests for SPA, 80 for SCCmec, and 80 for mecA at the Negative level, and similarly for Level 1, Level 2, and Level 3.
  • Data Provenance: The data was generated through prospective testing at one laboratory site in the United States (implied by the FDA De Novo application and regulatory context). The study incorporated different operators and different days.

• Study 2 (Three Labs):

  • Sample Size: For each gene/analyte at each Amplichek II level, there were 9 tests per lot (different operators x 3 different days). With two lots, this totals 18 tests per gene/analyte/level.
  • Data Provenance: The data was generated through prospective testing at three laboratory sites in the United States (implied by the FDA De Novo application and regulatory context). The study incorporated different operators and different days.

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

The Amplichek II is a quality control material intended to monitor the performance of in vitro laboratory nucleic acid testing. The "ground truth" for the test results (i.e., whether a control should be positive or negative for a specific analyte and its approximate Ct value range) is inherent to the design and composition of the Amplichek II material itself. It is not established by human experts in the way clinical diagnostic ground truth might be (e.g., through pathologist review or clinical outcomes).

Instead, the expected results (positive/negative and Ct range) are predetermined by Bio-Rad Laboratories based on their characterization of the control material's content and concentration of purified intact microorganisms. The studies then verify that the Cepheid GeneXpert Systems accurately detect these known compositions.

Therefore, no external experts were used to establish the ground truth for the test set; the ground truth is defined by the manufacturer's formulation.

4. Adjudication Method for the Test Set

Since the ground truth is defined by the known composition of the control material, and the output is a qualitative (positive/negative) or semi-quantitative (Ct value) result from a machine, there is no adjudication method involving human experts for the test set. The device performance is a direct comparison of the instrument's output against the expected result of the control material.

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 type of study (comparing human readers with and without AI assistance on various cases) is typically applied to diagnostic imaging interpretation or other scenarios where human interpretation is the primary method being evaluated.

The Amplichek II is a quality control material for an automated molecular diagnostic system (Cepheid GeneXpert Systems). Its function is to verify the correct operation of these automated systems, not to assist human readers in interpreting complex cases. Therefore, the concept of human readers improving with or without AI assistance does not apply here.

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

The device itself, Amplichek II, is a physical quality control material, not an algorithm. However, the performance of the Cepheid GeneXpert system when using the Amplichek II control material is effectively a standalone performance evaluation of the GeneXpert system's ability to correctly process and interpret the known control substance. The studies assessed the Cepheid GeneXpert system's output (positive/negative and Ct values) without human intervention in the interpretation of the control material results. The Amplichek II simply serves as the standardized input.

Given that the Amplichek II is designed for automated molecular diagnostic systems, the evaluation of its performance (meaning how effectively it allows monitoring of an automated system) inherently relied on the standalone performance of the GeneXpert system.

7. The Type of Ground Truth Used

The ground truth used is based on the known, pre-defined composition and concentration of microorganisms within the Amplichek II control material. Bio-Rad Laboratories engineers and develops the control material to contain specific analytes (e.g., MRSA, MSSA, Cdiff, VRE) at defined levels (Negative, Level 1, Level 2, Level 3).

Therefore, the expected result for each test (e.g., "Positive" for SCCmec at Level 2, "Negative" for Toxin B at Level 1) is a known characteristic of the manufactured control. The studies verify that the Cepheid GeneXpert Systems produce results that agree with these known characteristics.

8. The Sample Size for the Training Set

The document does not explicitly describe a separate training set for the Amplichek II or the Cepheid GeneXpert System in the context of this submission.
The Amplichek II is a quality control material, not an algorithm that requires a training set. The Cepheid GeneXpert Systems are the devices being monitored by the Amplichek II. The GeneXpert systems themselves would have undergone extensive validation and potentially "training" during their development, but this information is not detailed in the Amplichek II's de novo submission.

The studies described are performance evaluations of the control material and how well it helps monitor the performance of the GeneXpert systems.

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

As noted above, there is no explicit "training set" for the Amplichek II control material itself. The ground truth for the performance evaluation (test set) is the known, manufactured composition of the control material. This is established through the Bio-Rad Laboratories' internal manufacturing processes, formulation, and characterization of the specific microorganisms and their target concentrations within each level of the Amplichek II product.

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