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The Access Vitamin B12 assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of vitamin B12 levels in human serum and plasma (heparin) using the Access Immunoassay Systems. Measurements obtained by this device are used in the diagnosis and treatment of anemias of gastrointestinal malabsorption.

The Access Vitamin B12 assay is a competitive binding immunoenzymatic assay. The Access Vitamin B12 reagent kit is in a liquid ready-to-use format designed for optimal performance on Beckman Coulter's immunoassay analyzers. Each reagent kit contains two reagent packs. Other items needed to run the assay include substrate, calibrators, and wash buffer.

The provided document is a 510(k) Premarket Notification from the FDA for a diagnostic device, the "Access Vitamin B12" assay, manufactured by Beckman Coulter, Inc. It details the device's technical characteristics, its intended use, a comparison to a predicate device, and summaries of performance studies.

Here's the breakdown of the acceptance criteria and study proving the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document describes the acceptance criteria and observed performance for several analytical studies conducted to demonstrate substantial equivalence of the new Access Vitamin B12 assay on the Dxl 9000 Access Immunoassay Analyzer to the predicate device.

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

• Method Comparison: N = 122 samples.
• Imprecision: 6 serum samples with varying Vitamin B12 concentrations were assayed. Each sample was assayed in duplicate, twice per day, over 21 days (resulting in 84 replicates per sample, 6 samples x 84 replicates = 504 total assays for imprecision).
• Linearity, LoB, LoD, LoQ: Specific sample sizes for these studies are not explicitly stated as 'N' values in the text, but the studies were performed (e.g., "verification studies") following CLSI protocols.
• Data Provenance: The document does not specify the country of origin of the data or whether the studies were retrospective or prospective. Given it's a clinical laboratory device study for regulatory submission, they are typically prospective analytical validation studies conducted in a controlled lab environment.

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

N/A. This device is a quantitative diagnostic assay (Vitamin B12 levels) rather than an AI/ML-based image analysis or pattern recognition device that would typically rely on expert human consensus for ground truth. The "ground truth" for these analytical performance studies is established by the reference methods (predicate device measurements, defined concentrations for linearity/imprecision, and analytical standards for LoB/LoD/LoQ).

4. Adjudication Method (e.g., 2+1, 3+1, none) for the Test Set

N/A. Adjudication methods are not applicable here since the "ground truth" is determined by established analytical measurements and reference values, not by human interpretation requiring consensus.

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

N/A. MRMC studies are typically performed for imaging devices or AI-assisted diagnostic tools where human readers interpret cases, and the AI's impact on reader performance is assessed. This is a standalone in-vitro diagnostic (IVD) assay designed to provide quantitative results, not assist human readers in interpreting complex cases. The study effectively compares the new instrument (Dxl 9000) to the predicate instrument (Access Immunoassay System), not human readers.

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

While the term "standalone" is often used in the context of AI algorithms, this device functions as a standalone quantitative diagnostic assay. The performance studies (Method Comparison, Imprecision, Linearity, LoB/LoD/LoQ) demonstrate the analytical performance of the device itself (the "algorithm" being the assay chemistry and instrument processing) without human intervention in the result determination. The results are quantitative outputs (pg/mL or pmol/L of Vitamin B12).

7. The Type of Ground Truth Used

The ground truth for the analytical performance studies was established through:

• Method Comparison: Comparison against the predicate Access Vitamin B12 assay run on the Access Immunoassay System.
• Imprecision: Known or consistent concentrations of Vitamin B12 samples measured repeatedly.
• Linearity: Serially diluted samples or samples prepared with known, varied concentrations.
• LoB/LoD/LoQ: Use of blank samples, low-concentration samples, and statistical methods (CLSI EP17-A2 protocol) to determine limits.
  Overall, the ground truth relies on analytical reference methods, known sample concentrations, and statistical methods as per industry best practices (CLSI guidelines) for IVD devices.

8. The Sample Size for the Training Set

N/A. This is a specific analytical test kit (immunoassay) that functions based on established biochemical principles, not a machine learning algorithm that requires a "training set" in the conventional sense of AI. Its performance is inherent to its design and chemical reagents, validated through the analytical performance studies described.

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

N/A. As stated above, this device does not utilize a training set in the AI sense. Its "ground truth" for development and validation are based on chemical and analytical principles and reference standards.

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The DxA 5000 is a high-speed, modular, automated sample handling system that performs pre-analytical and postanalytical sample processing and storage. The automation system also sorts, routes, and presents sample tubes to analyzers for analysis. The DxA 5000 also consolidates a variety of analytical instruments, such as an Immunoassay analyzer, into a unified workstation on a track system.

The DxI 800 Access Immunoassay System is a microcomputer controlled, random and continuous access analyzer that includes an external computer. This computer stores the system user interface (UI) software and allows the operator to interface with and direct the instrument software. The UniCel DxI 800 System uses enzyme immunoassays (utilizing paramagnetic particle solid phase and chemiluminescent detection) for the quantitative or qualitative or qualitative determination of various analyte concentrations found in human body fluids. The UniCel DxI 800 System is an in vitro diagnostic device for use in the clinical laboratory.

The Access Ferritin assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of ferritin levels in human serum and plasma (heparin) using the Access Immunoassay Systems. Measurements of ferritin aid in the diagnosis of diseases affecting iron metabolism.

The Access Folate assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of folic acid levels in human serum and plasma (heparin) or red blood cells using the Access Immunoassay Systems. Folate levels in serum and plasma (heparin) or red blood cells are used to assess folate status. The serum folate level is an indicator of recent folate intake. A low RBC folate value can indicate a prolonged folate deficiency. Folic acid measurements are used in the diagnosis and treatment of megaloblastic anemia.

The Access TSH (3rd IS) assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of human thyroid-stimulating hormone (thyrotropin, TSH, hTSH) levels in human serum and plasma using the Access Immunoassay Systems. This assay is capable of providing 3rd generation TSH results. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

The Access Vitamin B12 assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of vitamin B12 levels in human serum and plasma (heparin) using the Access Immunoassay Systems. Measurements obtained by this device are used in the diagnosis and treatment of gastrointestinal malabsorption.

The DxA system is a high throughput automated sample handling system which can perform the pre and post analytical processing of sample tubes. DxA can identify and track samples, perform centrifugation, decapping, delivery of samples to connected analyzers, recapping, storing in either non-refrigerated or refrigerated storage, and sorting to output racks.

The DxA integrates perianalytic (pre and post analysis) functions with analytical instruments (Beckman Coulter, and other manufacturer's) via a track system to provide fully integrated testing solutions.

This document focuses on the substantial equivalence of the DxA 5000 automated sample handling system and related immunoassay tests (Ferritin, Folate, TSH, Vitamin B12) to previously cleared devices. It describes engineering performance studies rather than clinical efficacy studies. Therefore, many of the typical clinical study criteria requested (like multi-reader multi-case studies, effect size of human improvement with AI, number of experts for ground truth, sample size for training sets) are not applicable or detailed in this submission.

Based on the provided text, here's a breakdown of the acceptance criteria and the study that proves the device meets them:

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

The document states that "The acceptance criteria were met for all method comparisons thereby demonstrating the following:"

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

• Sample Size: The document does not specify the exact sample sizes used for the method comparison studies. It mentions that the studies utilized CLSI EP09, which is a guideline for method comparison and bias estimation using patient samples, but the number of samples is not disclosed.
• Data Provenance: Not specified in the provided text (e.g., country of origin, retrospective/prospective). However, given it's a 510(k) submission for an in vitro diagnostic device, the studies are typically conducted in a controlled laboratory setting, often in a prospective manner or using banked samples that meet specific criteria.

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

This information is not applicable and not provided in the document. The acceptance criteria and performance relate to the comparability of the new automation system and immunoassay tests against predicate devices, not against a "ground truth" established by experts for diagnostic accuracy in a clinical setting in the way an AI imaging device might. The "ground truth" here is the performance of the predicate device/system.

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

This information is not applicable and not provided. Adjudication methods are typically used in studies where human readers are interpreting data (e.g., medical images) and their interpretations need to be reconciled to establish a consensus ground truth. This is an engineering/analytical performance study for a laboratory automation system and immunoassay tests.

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 information is not applicable and not provided. MRMC studies are relevant for imaging devices where human readers are involved in the diagnostic process. This document concerns a laboratory automation system and immunoassay tests, not an AI-assisted diagnostic imaging tool.

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

The studies described are for the performance of the integrated system (DxA 5000 connected to the DxI 800 Access Immunoassay System running specific assays). While the system operates largely automatically (an "algorithm only" in the sense that the mechanical and analytical processes are automated), its performance is compared to a human-operated predicate system or another automated system. This is not an "AI algorithm only" study in the context of diagnostic decision support, but rather an automated analytical system comparison.

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

The "ground truth" in this context is the performance of the legally marketed predicate devices/systems:

• Power Processor Sample Processing System (K110413) for the DxA 5000's automation features.
• Beckman Coulter UniCel® DxI 800 Access® Immunoassay System (K023764), Access® Ferritin assay (K926221), Access® Folate assay (K060774), Access® HYPER sensitive hTSH assay (K042281), and Access® Vitamin B12 assay (K955436) for the immunoassay performance in conjunction with the automation system.

The study aimed to demonstrate that the new device system yielded results "within specifications" when compared to the predicate, implying the predicate's performance served as the benchmark or "ground truth" for equivalence.

8. The sample size for the training set

This information is not applicable and not provided. This is a 510(k) submission for laboratory equipment and assays, not a machine learning/AI device requiring a "training set" in the computational sense. The "development" for such systems involves rigorous engineering, analytical validation, and verification based on established chemical, biological, and mechanical principles.

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

This information is not applicable for the reasons stated in point 8.

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The DiaSorin LIAISON® Vitamin B12 assay uses chemiluminescent immunoassay (CLIA) technology for the quantitative determination of Vitamin B12 in human serum, SST serum and lithium heparin plasma. Measurements obtained by this device are used in the diagnosis and treatment of anemia's of gastrointestinal malabsorption. Assay results should be used in conjunction with other clinical or laboratory data to assist the clinician in making individual patient management decisions.

The assay must be performed on the LIAISON® XL Analyzer.

The LIAISON® Vitamin B12 assay is a competitive chemiluminescence immunoassay (CLIA) for quantitative determination of Vitamin B12 is serum. SST serum and lithium heparin plasma. During the first incubation, Vitamin B12 is dissociated from its binding protein. After the initial incubation of 10.5 minutes. Vitamin B12 binds to an intrinsic factor on the solid phase. After a second incubation of 10.5 minutes, a Vitamin B12 linked to an isoluminol derivative is added to compete with the Vitamin B12 in the sample. After a third incubation of 5.25 minutes, the unbound material is removed with a wash cycle. Subsequently, the starter reagents are added to initiate a flash chemiluminescent reaction. The light signal is measured by a photomultiplier as relative light units (RLU) and is inversely proportional to the concentration of Vitamin B12 present in calibrators, controls, or samples.

Here is the information about the acceptance criteria and the study that proves the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in a tabulated format with specific pass/fail thresholds for each performance characteristic. Instead, it describes various performance studies and their results. The "reported device performance" below summarizes the key findings from these studies. It is implied that these findings meet the FDA's requirements for substantial equivalence.

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

• Method Comparison: 155 samples. Data provenance not explicitly stated (e.g., country of origin) but implied to be patient samples. Retrospective or prospective is not specified, but typically method comparison uses existing samples.
• Sample Matrix Comparison: 48 matched patient sets (serum, SST serum, lithium heparin plasma samples). Data provenance not specified.
• Reference Range: 166 prospectively collected serum samples from apparently healthy adults aged 21-59. Provenance: United States; mixed ethnic backgrounds (30% Caucasian, 31% African Americans, 39% Hispanics). Prospective.
• Precision: Six (6) serum samples and two (2) kit controls.
• Linearity: One (1) high sample of each specimen type (serum, lithium heparin plasma).
• Recovery Study: Five (5) high concentration serum samples and five (5) low concentration serum samples.
• Cross-Reactivity Studies: Controlled spiked samples.
• Interference Studies: Controlled spiked samples.
• Limit of Blank, Limit of Detection, Limit of Quantitation: Not explicitly stated, typically involves multiple replicates of blank and low-concentration samples.

The document refers to various CLSI (Clinical and Laboratory Standards Institute) guidelines, which are commonly used for prospective, standardized studies in laboratory settings.

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

The concept of "experts" to establish "ground truth" as typically understood in AI/imaging studies (e.g., radiologists interpreting images) does not apply directly here. The ground truth for this device (a Vitamin B12 assay) is established through:

• Measurement by a commercially available reference method: For method comparison studies, the predicate device's results serve as a reference.
• Defined concentrations / spiking: For linearity, recovery, analytical specificity, and LoD/LoQ studies, the ground truth is based on accurately prepared samples with known concentrations.
• Clinical criteria: For the reference range study, healthy status was determined by inclusion/exclusion criteria related to medical history, medication use, and fasting status. These criteria are established by medical consensus, not by individual experts "adjudicating" each case.

Therefore, the number and qualifications of experts in the traditional sense are not applicable here.

4. Adjudication Method for the Test Set

Not applicable. As this is an in-vitro diagnostic (IVD) assay quantifying a biomarker, the "ground truth" is determined by established analytical methods, reference materials, or clinical definitions, rather than human interpretation requiring adjudication.

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 is typically performed for diagnostic imaging devices where human readers interpret medical images with and without AI assistance. This document describes an in-vitro diagnostic device that measures a biomarker in a laboratory setting, not an imaging device.

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

Yes, the studies described are standalone (algorithm/device only) performance studies. The entire document focuses on the analytical performance of the LIAISON® Vitamin B12 assay itself, without any human interpretation of its results being part of the primary performance evaluation. The device generates quantitative values for Vitamin B12, and its accuracy, precision, linearity, etc., are evaluated directly.

7. The Type of Ground Truth Used

The ground truth used varies by study:

• Method Comparison: "Reference Method" (another commercially available Vitamin B12 assay, the predicate device, Beckman Coulter Access Vitamin B12 assay, K140496).
• Sample Matrix Comparison: Comparison against its own measurement in serum, which is considered the reference matrix.
• Reference Range: Clinical criteria for "apparently healthy adults" (absence of anemias, B12 deficiency, IBD, celiac disease, malabsorption, specific medication use, pregnancy, etc.).
• Precision, Linearity, Recovery, Analytical Specificity (Cross-Reactivity & Interference), LoB, LoD, LoQ: Defined concentrations in spiked or diluted samples, or blank samples. These are established through gravimetric/volumetric preparation of standards and controls.

8. The Sample Size for the Training Set

The document does not provide information about a "training set" in the context of machine learning. This device is a chemiluminescent immunoassay (CLIA), which is a traditional laboratory analytical method, not an AI/machine learning algorithm that requires training data in the same way. The assay development would involve optimizing reagents and protocols, but this is a different process than "training" an algorithm.

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

Not applicable, as this device does not utilize a training set in the machine learning sense. The "ground truth" (i.e., known concentrations) during the development and optimization of such an assay would be established through primary analytical methods, reference materials, and standardized analytical practices during the assay's R&D phase.

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The ADVIA Centaur Active-B12 (Holotranscobalamin)(AB12) assay is for in vitro diagnostic use in the quantitative measurement of holotranscobalamin (holoTC) in human serum using the ADVIA Centaur XP system. Active-B12 (holotranscobalamin) is used as an aid in the diagnosis and treatment of vitamin B12 deficiency.

The ADVIA Centaur AB12 assay is a fully automated, two-step direct immunoassay using chemiluminescent technology. The assay utilizes an acridinium ester-labeled anti-transcobalamin antibody as the Lite Reagent. The Solid Phase consists of biotinylated anti-holotranscobalamin antibody coupled to streptavidin-coated magnetic latex microparticles.

Here's an analysis of the provided text regarding the ADVIA Centaur Active-B12 (Holotranscobalamin) (AB12) assay, structured to address your specific questions about acceptance criteria and the supporting study:

It's important to note that this document is a 510(k) summary, which is a high-level overview. It describes a modification to an already cleared device (K160757), primarily focusing on a change in calibration traceability. Therefore, detailed study protocols and raw data are not typically included in this summary. The summary focuses on demonstrating that the modified device is substantially equivalent to the predicate device and that the modification did not negatively impact its performance.

Since this is a summary of a modification intended to show substantial equivalence, the "acceptance criteria" discussed are largely in the context of ensuring the modification did not degrade performance.

1. Table of Acceptance Criteria and Reported Device Performance

The document states that "The device passed all of the tests based on pre-determined Pass/Fail criteria." However, the specific numerical acceptance criteria for each test are not explicitly provided in this 510(k) summary. It lists the types of tests performed and implies that the results were satisfactory.

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

The summary does not explicitly state the sample sizes used for the various validation tests (Accuracy, Linearity, Precision, Detection Limits, Recovery, Proficiency, or Reference Range).

• Data Provenance: Not explicitly stated, but the reference range study provides a mean and 95% central reference interval for an "asymptomatic population," implying human serum samples. The device itself is for in vitro diagnostic use in human serum. The data would have been collected in the course of validating the device. The manufacturer is Axis-Shield Diagnostics Ltd. in Scotland, UK, so it's plausible the data collection occurred there or in other regions where they conducted studies. The study is retrospective in the sense that these tests are performed after the device (or its modification) has been developed, but the sample collection itself for the reference range could be prospective.

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

This type of information is not applicable and not provided in the context of this device. This is an in vitro diagnostic (IVD) assay that measures a biomarker (holotranscobalamin) directly. The "ground truth" for the test set is established by the analytical reference methods or reference materials (like the WHO International Standard), not by human experts interpreting images or complex clinical scenarios.

4. Adjudication Method for the Test Set

This is not applicable for this type of IVD device. Adjudication methods (like 2+1, 3+1) are typically used in studies involving human interpretation of medical images or clinical data where there might be inter-reader variability. For an IVD assay, the result is a quantitative measurement, and the "ground truth" is based on the accuracy and precision of the analytical measurement itself, often against a validated reference method or material.

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

No, an MRMC comparative effectiveness study was not done. This type of study is for evaluating human performance, often with and without AI assistance, especially in radiology or pathology. This device is an automated IVD assay, not an AI-assisted human interpretation tool.

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

This device is a standalone algorithm/assay in the sense that it performs the measurement automatically without human intervention during the measurement process. The "performance" mentioned (accuracy, linearity, precision, etc.) are all standalone performance metrics of the assay itself. There is no "human-in-the-loop" once the sample is loaded onto the ADVIA Centaur XP system for this specific measurement.

7. The Type of Ground Truth Used

The ground truth for evaluating the performance of this IVD assay is primarily based on:

• Reference Materials: Specifically, the WHO International Standard for Holotranscobalamin (NIBSC Code 03/178) is highlighted as the new traceability standard for calibration. This serves as a primary ground truth for accurate measurement.
• Comparative Methods: The "Accuracy by correlation" likely involved comparing results from the modified device with those obtained using a reference method or the predicate device.
• Defined Concentrations: For tests like dilution linearity, precision, and detection capability, samples with precisely known or established concentrations of holotranscobalamin are used.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" sample size as this is not a machine learning or AI algorithm in the contemporary sense that would require a separate training phase with a distinct dataset for model building. The calibration process implicitly "trains" the device to measure correctly against known standards. The calibration itself uses "2-point Calibration using 2 level calibrators" (Low – 19 pmol/L, High - 121 pmol/L). However, this is not a "training set" in the context of complex ML models.

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

Given that there isn't a traditional "training set" for a machine learning model, the "ground truth" for the calibration materials (which serve a similar function of establishing correct performance parameters) is established through:

• Reference to the WHO International Standard (NIBSC Code 03/178): The primary modification in this 510(k) is to make the calibration traceable to this international standard. This standard itself would have been value-assigned through a rigorous international collaborative study.
• Internal Reference Material: The predicate device used an "Internal reference material; recombinant holotranscobalamin and phosphate buffer with protein (bovine) stabilizers." This internal standard would have been characterized and assigned values through the manufacturer's own internal assay development and validation processes, likely against an existing recognized reference method or material.

In summary, this 510(k) pertains to a minor modification (calibration traceability) of an existing in vitro diagnostic test. The evaluation focuses on ensuring the modification did not alter the fundamental performance characteristics, and the "acceptance criteria" are implied to be that the modified device performs comparably to the predicate and meets standard analytical performance requirements for IVDs. The "study" refers to a series of analytical verification and validation tests rather than clinical trials with human readers or AI algorithms.

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The Diazyme Vitamin B12 Assay is for the quantitative determination of Vitamin B12 levels in human serum. Measurements of vitamin B12 may be used in the diagnosis of B12 deficiency. For in vitro diagnostic use only.

The Diazyme Vitamin B12 Calibrator Set is intended for use in the Diazyme Vitamin B12 Assay. For in vitro diagnostic use only.

The Diazyme Vitamin B12 Control Set is intended for use as quality controls for the Diazyme Vitamin B12 Assay. For in vitro diagnostic use only.

Not Found

This is a 510(k) clearance letter for the Diazyme Vitamin B12 Assay, which is an in vitro diagnostic device used to quantitatively determine Vitamin B12 levels in human serum for the diagnosis of B12 deficiency. The document describes the regulatory classification and general information about the device, but it does not contain the detailed acceptance criteria and study results you requested for a device proving it meets acceptance criteria.

Therefore, I cannot provide the requested information based on the provided text. The document primarily focuses on regulatory approval and indications for use, not a performance study.

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The ADVIA Centaur® Active-B12 (Holotranscobalamin)(AB12) assay is for in vitro diagnostic use in the quantitative measurement of holotranscobalamin (holoTC) in human serum using the ADVIA Centaur XP system. Active-B12 (holotranscobalamin) is used as an aid in the diagnosis and treatment of vitamin B12 deficiency.

The ADVIA Centaur® Active-B12 (AB12) quality control is for in vitro diagnostic use to monitor the precision and accuracy of the ADVIA Centaur AB12 (Holotranscobalamin) assay using the ADVIA Centaur systems.

The ADVIA Centaur® Active-B12 (AB12) Master Curve Material (MCM) is for in vitro diagnostic use in the verification of calibration and reportable range of the ADVIA Centaur AB12 (Holotranscobalamin) assay using the ADVIA Centaur systems.

The ADVIA Centaur AB12 assay is a fully automated, two-step direct immunoassay using chemiluminescent technology. The assay utilizes an acridinium ester-labeled antitranscobalamin antibody as the Lite Reagent. The Solid Phase consists of biotinylated antiholotranscobalamin antibody coupled to streptavidin-coated magnetic latex microparticles.

This document describes the ADVIA Centaur Active-B12 (Holotranscobalamin) (AB12) assay, a device for in vitro diagnostic use in the quantitative measurement of holotranscobalamin (holoTC) in human serum to aid in the diagnosis and treatment of vitamin B12 deficiency.

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

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):

• Linearity: The number of samples used is not explicitly stated, but it involved "Two samples containing high levels of active-B12" mixed with "a pool of artificial serum matrix."
• Dilution Linearity: Five samples were used.
• Detection Capability (LoB, LoD, LoQ): The raw sample sizes for these determinations are not specified but are described as being determined according to CLSI Document EP17-A2, which typically involves multiple replicates and measurements.
• High Dose Hook: Patient samples with "active-B12 levels as high as 1867.80 pmol/L" were tested. The exact number of samples is not stated.
• Cross-reactivity: Populations evaluated included "other B12 proteins apotranscobalamin and haptocorrin" at two different concentrations each. The number of samples per concentration is not stated.
• Interference: The number of unique samples or runs for each interfering substance is not explicitly stated.
• Precision: Five serum precision panel members were used. Each sample was tested in replicates of 2 in two runs per day over 20 days, resulting in 80 observations per sample for each reagent lot.
• Method Comparison: 104 serum samples were used.
• Expected Values (Reference Range): 241 apparently healthy males (n = 103) and females (n = 138) were used. The age range was 21 - 67 years.

The document does not explicitly state the country of origin of the data or whether the studies were retrospective or prospective, beyond stating that the device is manufactured by Axis-Shield Diagnostics Ltd. in Scotland, UK. The reference range study involved "apparently healthy males and females," suggesting prospective collection for that specific study.

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 device is an in-vitro diagnostic assay for quantitative measurement of holotranscobalamin. The "ground truth" for such assays is typically established by established reference methods, calibrated standards, or the concentration values determined by a legally marketed predicate device. Experts are not directly involved in establishing "ground truth" for individual test results in the same way they would be for image interpretation.

• For method comparison, the "ground truth" reference values were obtained from the ARCHITECT Active-B12 (Holotranscobalamin) assay (K112443), which is the legally marketed predicate device.
• For reference range establishment, the "ground truth" is derived from the statistical analysis of results from a healthy population, following established protocols (EP28-A3c).

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

Not applicable. This is not a study involving human interpretation or subjective assessment that would require adjudication. The performance is based on quantitative measurements.

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 an in-vitro diagnostic device, 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:

Yes, the studies presented are standalone performance evaluations of the ADVIA Centaur Active-B12 assay. The performance characteristics (linearity, precision, detection capability, interference, cross-reactivity, method comparison) are intrinsic to the device and do not involve human intervention in the interpretive output generation. The assay quantitatively measures holotranscobalamin levels.

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

The ground truth used depends on the specific performance characteristic:

• Assay values for clinical samples: The ARCHITECT Active-B12 (Holotranscobalamin) assay (CMIA) was used as the comparator or "reference" for method comparison studies.
• Known concentrations: For studies like linearity, dilution linearity, detection capability, high dose hook, cross-reactivity, and interference, the "ground truth" is based on known spiked concentrations of substances or defined samples with expected values (e.g., precision panel members with established active-B12 concentrations).
• Population statistics: For expected values (reference range), the "ground truth" is derived from statistical analysis of a healthy reference population, following CLSI guidelines.

8. The sample size for the training set:

Not applicable. This device is an in-vitro diagnostic assay, not a machine learning or AI model that requires a distinct training set in the conventional sense. The "training" or development of such assays involves reagent formulation, optimization, and calibration based on known standards and samples, but not a "training set" like that used for algorithms.

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

Not applicable. As explained in point 8, there isn't a "training set" for an in-vitro diagnostic assay in the same way there is for an AI algorithm. The assay is developed and optimized using known standards and calibrated samples, where the "ground truth" for these is established through highly accurate reference methods or certified reference materials. The calibration of the device itself relies on "Master Curve Material" (MCM) with established values.

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Binding assay for the in vitro quantitation of vitamin B12 in human serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of gastrointestinal malabsorption. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Vitamin B12 II CalSet is used for calibrating the quantitative Elecsys Vitamin B12 II assay on the Elecsys and cobas e immunoassay analyzers.

The Elecsys Vitamin B12 II assay employs a competitive test principle using intrinsic factor specific for vitamin B12. Vitamin B12 in the sample competes with the added vitamin B12 labeled with biotin for the binding sites on the ruthenium-labeled intrinsic factor complex.

Results are determined via a calibration curve which is instrument specifically generated by 2-point calibration and a master curve provided via reagent barcode.

The reagent working solutions include:

• the rackpack (kit placed on instrument) .
• Streptavidin coated microparticles, .
• Reagent 1 (ruthenium labeled intrinsic factor) and .
• Reagent 2 (vitamin B12 labeled biotin). .
• Pretreatment 1 (Dithiothreitol) .
• Pretreatment 2 (sodium hydroxide, sodium cyanide) .

The Vitamin B12 II CalSet is a lyophilized human serum matrix with added vitamin B12 in two concentration ranges.
The CalSet includes:

• Cal 1 (approximately 250 pg/mL vitamin B12 in a Human serum matrix) .
• Cal 2 (approximately 1500 pg/mL vitamin B12 in a Human serum matrix) .

The document describes the Elecsys Vitamin B12 II Assay and Elecsys Vitamin B12 II CalSet, which are used for in vitro quantitative determination of Vitamin B12 in human serum and plasma. The device is intended for use in the diagnosis and treatment of anemias of gastrointestinal malabsorption.

Here's a breakdown of the requested information:

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)

• Precision: Not explicitly stated as a separate "test set" sample size but evaluated using "human serum samples" (HS 1-5) and "PreciControl Varia" (PCV0-2). The protocol involved testing 2 replicates per run, 2 runs per day for 21 days for precision.
• Limit of Blank (LoB): n = 60 LoB measurements (5 replicates, 2 runs per day on 2 instruments over 3 days) using a buffered human serum albumin matrix.
• Limit of Detection (LoD): n = 60 LoD measurements (5 samples, 2 runs per day on 2 instruments over 3 days) using 5 low-level human serum samples.
• Limit of Quantitation (LoQ): Minimum of seven human serum samples, analyzed in replicates of 5, one run per day over 5 days.
• Linearity: Serum samples.
• Analytical Specificity: Two human serum samples (single donors, native) spiked with potential cross-reactant compounds.
• Endogenous Interferences: Three human serum samples (single donors, native as well as spiked) for each interfering substance.
• Exogenous Interferences - Drugs: Two human serum samples (single donors, native) spiked with 16 pharmaceutical compounds.
• Exogenous Interferences - Anticoagulants: Minimum of 90 serum/plasma pairs per sample material (single donors, native as well as spiked).
• Method Comparison: 120 human serum samples (all single donors, native as well as spiked) covering the entire measuring range.
• Reference Range Study: 120 apparently healthy male & female subjects. Data provenance: USA for sample collection, evaluation done at one site in Germany. Samples were native human serum samples.

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 an in-vitro diagnostic (IVD) device for quantitative measurement of a biomarker (Vitamin B12). The "ground truth" for such devices is typically established through analytical methods and highly controlled reference materials, not through expert consensus on qualitative interpretation of images or clinical findings. The document does not describe the use of human experts to establish ground truth for this type of test.

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

Not applicable. As an IVD device, the performance is assessed through analytical validation studies (precision, linearity, accuracy against reference methods/materials) rather than human expert adjudication of results.

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 an in-vitro diagnostic device for measuring Vitamin B12, not an imaging device or AI-assisted diagnostic tool that relies on human readers/interpreters.

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

The device is a standalone in-vitro diagnostic assay (Elecsys Vitamin B12 II assay) intended to quantitatively measure Vitamin B12. Its performance is evaluated analytically, separate from human interpretation of the results for direct diagnostic decision-making, though the results contribute to a physician's overall diagnosis and treatment plan. The studies described (precision, linearity, LoB/LoD/LoQ, interference, method comparison) are all "standalone" evaluations of the device's analytical performance.

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

The ground truth for the analytical and method comparison studies is established based on:

• Reference methods/materials (e.g., specific calibrators, spiked samples with known concentrations, comparison to the legally marketed predicate device).
• Defined analytical standards and statistical methods (e.g., CLSI guidelines).
• The "value assignment" for calibrators is a key part of establishing the reference for the assay.

8. The sample size for the training set

This document does not describe a "training set" in the context of machine learning. The studies described are validation and verification studies for an analytical assay. The "Elecsys Vitamin B12 II CalSet" serves as a calibrator for the assay, analogous to the concept of a "calibration set" for an analytical instrument, but not a training set for an AI/ML algorithm.

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

Not applicable as there is no "training set" in the machine learning sense. However, for the calibrator (Elecsys Vitamin B12 II CalSet), its "target values" are assigned to obtain the best fit with the Master Calibration Curve, using multiple analyzers (at least 3 cobas e 411 and at least 3 cobas e 601/MODULAR ANALYTICS E170 analyzers) and multiple reagent lots. The assigned value for each calibrator is the mean value obtained over at least six runs on at least three analyzers. PreciControl Varia is also used to monitor accuracy and precision of analytes, and acceptance criteria for these controls must be met to release the assigned values for the CalSet. This process establishes the "ground truth" for the calibrators.

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The basic Power Express is an automated sample handling system which processes sample tubes from the precentrifugation, pre-sorting step to presentation of centrifuged and decapped samples into Generic or Personality Racks for specific instruments. The Power Express can be configured with optional software to allow processing of sample tubes on Generic Connection Instruments. The Power Express performs all pre-analytical sample tube preparation, and then sorts the sample tubes directly to Generic Connection Modules where the samples are pipetted by the Generic Connection instrument for testing. After the samples are pipetted, the tubes can route to other instruments for additional testing or to Outlet Racks.

The UniCel DxI 800 Access Immunoasav System with laboratory automation is a microcomputer-controlled. random and continuous access analyzer that includes an external computer stores the system user interface (UI) software and allows the operator to interface with and direct the instrument software. The UniCel DxI 800 System uses enzyme immunoassays (utilizing paramagnetic particle solid phase and chemiluminescent detection) for determination of various analytes, such as Vitamin B12. Ferritin, Folate and hTSH along with other various enzyme immunoassays assays that may be adaptable to the analyzer depent used to induce the enzyme immunoassay reaction. The UniCel Dxl 800 System is an in vitro diagnostic device for use in the clinical laboratory.

The Access Ferritin assay is a paramagnetic particle, chemiluminescent assay for the quantitative determination of ferritin levels in human serum and plasma (heparin) using the Access Immunoassay Systems. Measurements of ferritin aid in the diagnosis of diseases affecting iron metabolism.

The Access Folate assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of folic acid levels in human serum, plasma (heparin) and red blood cells using the Access Immunoassay Systems. Folic acid measurements are used in the diagnosis and treatment of megaloblastic anemia.

The Access HYPER sensitive hTSH assay is a paramagnetic particle, chemiluminescent assay for the quantitative determination of human thyroid-stimulating hormone (thyrotropin, hTSH) levels in human serum using the Access Immunoassay Systems. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

The Access Vitamin B12 assay is a paramagnetic particle, chemiluminescent assay for the quantitative determination of vitamin B12 in human serum and plasma (heparin) using Access Immunoassay Systems. Measurements obtained by this device are used in the diagnosis and treatment of gastrointestinal malabsorption.

The Power Express is Beckman Coulter's Power Processor Sample Processing System with the modifications noted in this premarket submission. The Power Express and the Power Processor Sample Processing System are scalable laboratory automation systems (LAS) designed to streamline peri-analytical processes in the clinical laboratory.

The Power Express is an automated sample handling system which processes sample tubes from the pre-centrifugation, pre-sorting steps to presentation of centrifuged and decapped samples into racks for chemistry, immunoassay, hematology, and coagulation systems. The Power Express is designed to free laboratory personnel from biohazard exposure and routine sample preparation.

The Power Express software can be configured with optional hardware to allow processing of sample tubes on physically connected analyzers using common communication protocols (Generic Connection Instruments). The Power Express performs pre-analytical sample tube preparation then sorts the sample tubes directly to the optional hardware interface between the LAS and analyzer (Generic Connection Module) where the samples are pipetted by the analyzer for testing. After the samples are pipetted, the tubes can be routed to other instruments for additional testing or to Outlet Racks.

A basic Power Express System is comprised of a Line Control Computer, a system console with Cennexus software, Inlet Module, Centrifugation Module, Decapper Module, track transport system and Outlet Module. Additional modules may be added for aliquot capability, sample capping, and ambient or refrigerated storage.

Here's an analysis of the provided text, focusing on acceptance criteria and study details.

Important Note: The provided document is a 510(k) summary for a medical device. This type of document focuses on demonstrating substantial equivalence to a previously cleared predicate device, rather than proving the efficacy of new clinical features from scratch. This influences the nature of the "acceptance criteria" and "study" described. The document largely asserts that the modifications to the Power Processor system did not introduce new risks to the performance of the integrated assays, and therefore formal V&V testing was sufficient rather than full clinical studies.

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

The document does not explicitly present a table of "acceptance criteria" in the traditional sense of numerical thresholds for clinical performance (e.g., sensitivity, specificity, accuracy). Instead, the "acceptance criteria" can be inferred from the statement that "all software design, development and verification activities have been completed and passed to supports equivalency of Power Express to the Power Processor V5.0 Sample Processing System." The performance reported is that the device "functions as intended, meeting the requirements of the design specifications."

Let's infer acceptance criteria based on the modifications and the intent of substantial equivalence:

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

The document does not specify sample sizes for test sets in the context of clinical or performance data for the assays themselves. The testing described is primarily software and system verification and validation (V&V). These are typically internal engineering tests rather than studies involving patient samples in a clinical setting with formal sample sizes as understood in clinical trials.

• Sample Size for Test Set: Not specified, as the testing was primarily V&V of the automated system's components and software.
• Data Provenance: Not applicable in the context of system V&V. This would typically be relevant for clinical studies involving patient data. This was internal Beckman Coulter testing.

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 to the type of V&V testing described. "Ground truth" in this context would likely refer to expected system behaviors, software outputs, or known operational parameters, which would be established by the device's design specifications and engineering teams, rather than by external clinical experts.

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

Not applicable. Adjudication methods are typically used in clinical studies to resolve discrepancies in expert opinions on diagnosis or outcome. For system V&V, "adjudication" would be a matter of comparing test results against predefined functional requirements and expected outputs, often automated or reviewed by a single test engineer or a team.

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. An MRMC study is relevant for imaging devices or diagnostic tools where human interpretation is involved. The Power Express is an automated sample processing system and immunoassay platform; its function is to prepare samples and run assays, not to assist human interpretation of complex data in the way AI assistance might.

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

Yes, the testing described is effectively "standalone" for the automated system. The Power Express system, as an automated sample handling and processing system, operates without direct human intervention in its core tasks (centrifugation, decapping, sorting, routing, pipetting, running assays on connected instruments). The performance data mentioned refers to the verification and validation of this automated system's functionality and software.

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

The "ground truth" for the verification and validation (V&V) described would be the design specifications and functional requirements of the Power Express system. This includes:

• Expected software behaviors and outputs.
• Correct execution of mechanical tasks (e.g., decapping, sorting, pipetting).
• Correct communication protocols with connected instruments and the LIS.
• Adherence to performance metrics like throughput.
• The known performance characteristics of the integrated commercial assays (Ferritin, Folate, hTSH, Vitamin B12) which were previously established and not re-evaluated.

8. The sample size for the training set

Not applicable. The Power Express is an automated sample processing system, not an AI or machine learning model that requires a "training set" of data. The software within the system is likely rule-based or deterministic, rather than learned.

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

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

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The VB12 method is an in vitro diagnostic test for the quantitative measurement of Vitamin B12 (B12) in human serum and plasma on the Dimension® EXL™ with LM integrated chemistry system. Measurements of Vitamin B12 may be used in the diagnosis of vitamin B12 deficiency.

The LOCI ANEMIA CAL is an in vitro diagnostic product for the calibration of the LOCI FOLA and LOCI VB12 assays on the Dimension® EXL™ with LM integrated chemistry system.

The vitamin B12 method is a homogeneous, competitive chemiluminescent immunoassay based on LOCI® technology. LOCI® reagents include two synthetic bead reagents and biotinylated intrinsic factor (IF). The first bead reagent (Chemibead) is coated with a B12 derivative and contains a chemiluminescent dve. The second bead reagent (Sensibead) is coated with streptavidin and contains photosensitive dve. The patient sample is pretreated with sodium hydroxide (NaOH) and dithioerythritol (DTE) to release the serum B12 from its carrier proteins. Potassium cyanide (KCN) is added to convert all the forms of B12 into a single, cyanocobalamin form, and dicyanocobinamide is added to keep the B12 from rebinding with the carrier proteins. After the sample pretreatment, the biotinylated IF and chemibead reagents are added sequentially to the reaction vessel. Vitamin B12 from the sample competes with the B12-chemibead for a limited amount of biotinylated IF. Sensibead reagent is then added and binds to the biotin to form bead pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from the Sensibeads which diffuses to the Chemibeads triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is an inverse function of the concentration of vitamin B12 in the sample.

LOCI ANEMIA CAL is a multi-analyte liquid, frozen product containing Folate and Vitamin B12. All levels are prepared in a bovine serum albumin base. The kit consists of ten vials, two each of five levels containing 2 mL per vial.

The provided 510(k) summary focuses on establishing substantial equivalence for an in vitro diagnostic (IVD) device, specifically the LOCI Vitamin B12 Flex® reagent cartridge and the LOCI Anemia Calibrator, to predicate devices. This type of filing differs from those for AI/ML-enabled devices, which often involve comparative effectiveness studies with human readers.

As a result, the information required for a typical AI/ML-driven device's acceptance criteria and study design (such as sample size for test sets, data provenance, number of experts for ground truth, adjudication methods, MRMC studies, standalone performance metrics, training set details) is not present in this document. The study described here is primarily a method comparison and reproducibility study for an IVD assay, not an AI/ML algorithm that predicts or interprets clinical data for human-in-the-loop use.

However, I can extract the acceptance criteria and reported performance relevant to this IVD device's analytical validation.

Acceptance Criteria and Reported Device Performance (Analytical Validation)

Since this is an IVD device submission establishing substantial equivalence to a predicate, the "acceptance criteria" are implicitly tied to demonstrating comparable analytical performance to the predicate device and meeting analytical precision expectations.

Study Details (as inferable from the document):

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

   • Reproducibility Study: Not explicitly stated as a "test set" in the AI/ML sense, but for the precision study, multiple runs over 20 days were performed for each material (3 Bio-Rad controls, 4 serum/plasma pools). Each test level was analyzed twice per day for 20 days.
   • Sample Type Equivalency Study: 78 matched serum, lithium heparin plasma, sodium heparin, and EDTA plasma samples. 71 were native, 6 spiked, 1 diluted. Data provenance is not specified (e.g., country of origin, retrospective/prospective).
   • Method Comparison Study: 166 native human serum samples. These ranged from 60 - 1966 pg/mL (predicate) and 86 - 1901 pg/mL (new device). 35 samples were positive for Intrinsic Factor Blocking Antibody (IFBA). Data provenance is not specified.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: Not applicable. For IVD devices, "ground truth" typically refers to the reference method or assigned values, not expert interpretation of images or clinical scenarios. In the method comparison, the predicate device's measurements served as a reference for comparison. Calibrator values were assigned from a master pool with traceability to USP Grade Vitamin B12.

3. Adjudication method (e.g., 2+1, 3+1, none) for the test set: Not applicable, as this is an analytical performance study for an IVD, not a diagnostic interpretation study.

4. 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 submission is for an IVD assay, not an AI/ML-enabled diagnostic imaging or clinical decision support system that involves human readers.

5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: The studies described assess the standalone analytical performance of the IVD assay without human interpretation of results beyond standard laboratory practices.

6. The type of ground truth used:

   • For the method comparison, the predicate device's measurements (Dimension Vista® VB12 method, K121994) served as the comparative reference.
   • For the calibrator, values are assigned from a master pool which has traceability to USP Grade Vitamin B12.
   • For precision, the established analytical performance characteristics for laboratory controls and serum/plasma pools serve as benchmarks.

7. The sample size for the training set: Not applicable. This is an IVD assay, not an AI/ML device requiring a training set in that context. The device's calibration involves specific calibrator materials with assigned values.

8. How the ground truth for the training set was established: Not applicable. The "ground truth" for the IVD's calibration is established via a master pool traceable to USP Grade Vitamin B12.

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