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Binding assay for the in vitro quantitative determination of folate in erythrocytes (red blood cells, RBC). Folate measurements are used in the diagnosis and treatment of anemia. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

Elecsys Folate III is a binding assay that makes use of a competitive test principle using a ruthenium labeled folate-binding assay.
Elecsys Folate III is a binding assay for the in vitro quantitative determination of folate in erythrocytes (red blood cells, RBC). Folate measurements are used in the diagnosis and treatment of anemia. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
Whole blood treated with anticoagulants (heparin or EDTA) is mixed with ascorbic acid solution and incubated for approximately 90 minutes at 20-25 °C. Lysis of the erythrocytes takes place, with liberation and stabilization of the intracellular folate. The resulting hemolysate sample is then used for subsequent measurement.
Results are determined via a calibration curve, which is instrument-specifically generated by 2point calibration, and a master curve provided via the cobas link.

Here's a summary of the acceptance criteria and study details for the Elecsys Folate III device, based on the provided FDA 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample Sizes and Data Provenance

• Precision (Repeatability & Intermediate Precision): Not explicitly stated, but typically involves multiple replicates over several days/runs with multiple instruments. Specific sample types are "Hemolysate 1" to "Hemolysate 5".
• Lot-to-lot Reproducibility: "three reagent lots" were used.
• Analytical Sensitivity (LoB, LoD, LoQ): Not explicitly stated, but determined according to CLSI EP17-A2, which involves specific numbers of blank and low-concentration samples.
• Linearity and Dilution: "At least seven concentrations using hemolysate samples" for linearity. Dilution study used "high concentration hemolysate samples".
• Endogenous Interferences: Not explicitly stated, but "various endogenous substances" were evaluated.
• Analytical Specificity/Cross-Reactivity: Not explicitly stated.
• Exogenous Interferences: "17 commonly and 1 specially used pharmaceutical" compounds.
• Sample Matrix Comparison: "Whole blood samples were drawn into Na-Heparin and K3-EDTA tubes." (Number not specified).
• Method Comparison to Predicate: 119 samples with concentrations between 132 and 618 ng/mL.
• Reagent Stability (On-board), Lot Calibration Stability, On-board Calibration Stability: Tested on "one cobas e 801 analyzer".

Data Provenance: The document states "NON-CLINICAL PERFORMANCE EVALUATION" and refers to CLSI (Clinical and Laboratory Standards Institute) guidelines, which are standard for in-vitro diagnostic device performance studies. The data is internal to Roche Diagnostics, a company with global operations. The specific country of origin for the studies is not stated, but given the submission is to the U.S. FDA, the studies are expected to meet international and U.S. regulatory standards. These are retrospective studies in the context of device development and validation.

3. Number of Experts and Qualifications for Ground Truth (Test Set)

This device is an in-vitro diagnostic (IVD) assay that produces quantitative measurements of folate. It does not involve human interpretation of images or other subjective data. Therefore, the "ground truth" for its performance is established by reference methods, calibrated standards, and accurate measurement principles, rather than human expert consensus. No human experts were used to establish ground truth in the way one would for an AI imaging device.

4. Adjudication Method (Test Set)

Not applicable, as this is an IVD device producing quantitative results, not an AI imaging device requiring expert adjudication.

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

Not applicable. This is an in-vitro diagnostic device, not an AI device assisting human readers with interpreting cases.

6. Standalone (Algorithm Only) Performance

Yes, the studies described are standalone performance evaluations of the Elecsys Folate III assay (the "algorithm" in a broad sense for an IVD) without human intervention in the measurement process. The device performs the quantitative determination of folate using its defined binding assay and electrochemiluminescence immunoassay (ECLIA) method.

7. Type of Ground Truth Used

The ground truth for evaluating the Elecsys Folate III's performance is established through:

• Reference materials/standards: For analytical sensitivity (LoB, LoD, LoQ) and linearity, where known concentrations are used.
• Performance against a predicate method: For method comparison, the results are compared to a previously cleared, established method (Elecsys Folate RBC).
• CLSI guidelines: Adherence to established scientific and statistical methodologies for validating assay performance, implying well-defined benchmarks for accuracy, precision, and interference.

8. Sample Size for the Training Set

Not explicitly stated. For an IVD like the Elecsys Folate III, a traditional "training set" as understood in machine learning is not directly applicable. The "training" for such a system would involve the development and optimization of the reagent formulations, assay parameters, and calibration curve algorithms, using various samples and experiments during the research and development phase. However, a specific training set size with corresponding ground truths is not documented in the same way as an AI algorithm.

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

As above, a formal "training set ground truth" isn't directly applicable in the machine learning sense. The "ground truth" during the development and optimization (analogous to training) would have been established through:

• Known concentrations: Using purified folate standards or spiked samples.
• Reference methods: Comparing early-stage assay performance against established, often more labor-intensive or gold-standard methods for folate determination.
• Clinical correlation: (Though "clinical testing" is marked Not Applicable for this 510(k), early development might involve correlation with clinical status or outcomes).
• Statistical optimization: Adjusting reagent ratios, incubation times, and instrument settings to achieve optimal analytical performance characteristics (sensitivity, specificity, precision, linearity) based on these known values and reference method comparisons.

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

Folate levels in serum, lithium heparin plasma, and red blood cells are used to assess folate status. The serum folate levels is an indicator of recent folate intake. A low RBC folate value can indicate a prolonged folate deficiency.

The Access Folate assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of folic acid levels in human serum and lithium heparin plasma or red blood cells using the Access Immunoassay Systems.

The provided text describes the Beckman Coulter Access Folate Assay, a chemiluminescent immunoassay for the quantitative determination of folic acid levels. The submission is a 510(k) premarket notification for demonstrating substantial equivalence to a predicate device.

Here's an analysis of the acceptance criteria and supporting studies based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

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The DiaSorin LIAISON® Folate assay uses chemiluminescent immunoassay (CLIA) technology for the quantitative determination of Folic acid in human serum. Folic acid measurements are used in the diagnosis and treatment of anemias. 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® Folate assay is a competitive chemiluminescence immunoassay (CLIA) for quantitative determination of Folic acid in serum. During the first incubation, Folic acid is dissociated from its binding protein. After five (5) minutes, a high pH buffer is added to prevent re-association to the binding protein. After five (5) minutes, Folic acid binds to a Folate Binding Protein on the solid phase, which competes with a Folic acid linked to an isoluminol derivative. After a third incubation, 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 Folic acid present in calibrators, controls, or samples.

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

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" for each performance characteristic in a pass/fail format. Instead, it presents study results which implicitly demonstrate the device's acceptable performance. For clarity, I've inferred common acceptance standards for such in vitro diagnostic assays where explicit criteria aren't given and formatted the reported performance against these.

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

• Test Set (Method Comparison): 157 human serum samples, spanning the assay range.
• Test Set (Expected Values/Reference Range): 166 prospectively collected serum samples from apparently healthy U.S. adults (21-59 years old) of mixed ethnic backgrounds (30% Caucasian, 32% African American, 38% Hispanic).
• Data Provenance: The method comparison study and the expected value study used human serum samples. The expected values study explicitly mentions "United States" for its population, implying the data is from the US and prospectively collected. The nature of the other analytical performance studies (precision, linearity, recovery, etc.) generally involves contrived or spiked samples and do not typically draw from specific patient populations or geographical locations.

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

• General Context: For an in vitro diagnostic (IVD) device like the LIAISON® Folate assay, the "ground truth" for the test set is established by the predicate device (Abbott Laboratories, ARCHITECT Folate, K092740) for method comparison, or by the inherent concentration of the analyte in the samples for analytical performance characteristics (like precision, linearity, etc.).
• No human "experts" established ground truth for the test set in the way radiologists might agree on an image diagnosis. Instead, the predicate device (an established, cleared medical device) serves as the reference standard for comparative effectiveness.

4. Adjudication Method for the Test Set:

• This is not applicable to the analytical performance studies of an in vitro diagnostic assay. Adjudication methods (like 2+1, 3+1) are typically used in clinical studies, particularly for diagnostic imaging or pathology, where human interpretation of results is involved and consensus among experts is needed to define the "true" diagnosis or finding for a given sample/case. Here, the comparison is against an instrument's measurement (predicate device) or against known concentrations.

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 question is not applicable to this type of device. The LIAISON® Folate assay is an automated in vitro diagnostic device, not an AI-assisted diagnostic tool that humans interpret. There are no "human readers" involved in interpreting the results from this specific device.

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

• Yes, this entire submission describes the standalone performance of the LIAISON® Folate assay. It is an automated chemiluminescent immunoassay (CLIA) system (LIAISON® XL Analyzer) that quantitatively determines Folic acid in human serum. Its performance characteristics (precision, linearity, accuracy, etc.) are evaluated intrinsically as a standalone device, without human intervention in the result determination process once the sample is loaded.

7. The Type of Ground Truth Used:

• Method Comparison: The "ground truth" was established by measurements from the predicate device, the Abbott Laboratories, ARCHITECT Folate (K092740).
• Other Analytical Performance (e.g., Precision, Linearity, Recovery, Specificity): The "ground truth" was established internally through various experimental designs:
  • Precision: By repeated measurements of samples with known or target concentrations.
  • Linearity: By testing serial dilutions from a high-concentration sample, where the "expected" concentration is mathematically derived from the initial concentration and dilution factor.
  • Recovery: By comparing measured concentrations of diluted samples to their calculated expected concentrations.
  • Analytical Specificity: By comparing results of samples spiked with potential interferents/cross-reactants to unspiked samples.
  • Limits (LoB, LoD, LoQ): Through statistical analysis of repeated measurements of blank and low-level samples.

8. The Sample Size for the Training Set:

• For an IVD like the LIAISON® Folate assay, there isn't a "training set" in the context of machine learning. The technology is based on established biochemical principles (chemiluminescence immunoassay) and reagents, rather than an AI/ML algorithm that learns from data. Therefore, this question is not applicable.

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

• As mentioned above, there is no "training set" for this type of device. The design and validation are based on chemical and biological principles and rigorous experimental testing, not machine learning model training.

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The Atellica™ Folate assay is for in vitro diagnostic use in the quantitative determination of folate in serum or red blood cells using the Atellica IM Analyzer. Folic acid measurements are used in the diagnosis and treatment of anemias.

The Atellica™ IM Folate Assay is an immunoassay with the following components: Atellica™ IM Folate Primary Reagent ReadyPack (including Lite Reagent, Solid Phase Reagent, and Folate Binding Protein), Atellica™ IM Folate Calibrator (including Low and High Calibrators), Atellica IM Folate DTT/Releasing Agent (sold separately, including Dithiothreitol and Sodium hydroxide), and Atellica IM RBC Folate (sold separately, including Lyophilized ascorbic acid and RBC Folate Ascorbic Acid Diluent).

The provided text is a 510(k) summary for an in vitro diagnostic device (Atellica™ IM Folate Assay), not an AI/ML medical device. Therefore, much of the requested information regarding AI/ML device acceptance criteria and study design (such as multi-reader multi-case studies, expert adjudication, training set ground truth, etc.) is not applicable to this document.

However, I can extract information related to the acceptance criteria for this diagnostic assay and how its performance was proven.

Here's a summary based on the provided document, addressing the applicable points:

Device Name: Atellica™ IM Folate Assay

Indications for Use: For in vitro diagnostic use in the quantitative determination of folate in serum or red blood cells using the Atellica IM Analyzer. Folic acid measurements are used in the diagnosis and treatment of anemias.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a singular table, but rather presents performance characteristics of the device, implying that the observed performance met internal or regulatory (CLSI) standards. The predicate device (ADVIA Centaur Folate Assay, K010050) serves as the benchmark for substantial equivalence.

Here's a compilation of key performance characteristics, acting as de-facto acceptance criteria for a new in vitro diagnostic assay, and the reported performance. The "Acceptance Criteria" here are implicitly derived from CLSI guidelines and comparison to the predicate.

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The Diazyme Folate Assay is a homogeneous enzyme immunoassay intended for use in the quantitative analysis of folate in human serum. Folic acid measurements are used in the diagnosis and treatment of anemias. For in-vitro diagnostic use only.

The Diazyme Folate Calibrator Set is intended for use in the calibration of the Diazyme Folate Assay. For in vitro diagnostic use only.

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

Not Found

The provided text describes the FDA 510(k) clearance for the Diazyme Folate Assay, Diazyme Folate Calibrator Set, and Diazyme Folate Control Set. It focuses on the regulatory approval process and includes an "Indications for Use" statement.

Crucially, the document is a regulatory approval letter and not a study report. Therefore, it does not contain the detailed performance data, study design, or methodology information required to answer most of your questions about acceptance criteria verification and study details.

The information provided only allows for a very limited and generic answer:

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

• Acceptance Criteria (Implied): The device must be "substantially equivalent" to legally marketed predicate devices for the stated indications for use.
• Reported Device Performance: The FDA determined that the device is "substantially equivalent" to legally marketed predicate devices.

2. Sample size used for the test set and the data provenance
NOT PROVIDED IN THE DOCUMENT. This document does not detail the specific performance studies that Diazyme Laboratories conducted to demonstrate substantial equivalence.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
NOT PROVIDED IN THE DOCUMENT.

4. Adjudication method for the test set
NOT PROVIDED IN THE DOCUMENT.

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 (IVD) assay for measuring folate levels, not an AI-assisted diagnostic imaging device. Therefore, MRMC studies and human reader improvement with AI are not relevant.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
NOT APPLICABLE. As an IVD assay, its performance is inherently "standalone" in a laboratory setting, meaning it measures a biomarker without human interpretation of complex images or AI algorithms. However, the document does not contain the specific performance data (e.g., accuracy, precision, linearity) that would typically be generated in such a study.

7. The type of ground truth used
NOT PROVIDED IN THE DOCUMENT. For an IVD assay, ground truth would typically be established through reference methods, clinical diagnosis, or patient outcomes for the condition being diagnosed/monitored (anemia in this case).

8. The sample size for the training set
NOT PROVIDED IN THE DOCUMENT.

9. How the ground truth for the training set was established
NOT PROVIDED IN THE DOCUMENT.

In summary, the provided FDA 510(k) clearance letter confirms regulatory approval based on substantial equivalence but does not contain the detailed study data, methodologies, or acceptance criteria that would typically be found in a clinical study report or a 510(k) submission's performance section. To answer your questions comprehensively, you would need to review the actual 510(k) submission materials, which are not included in this document.

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Binding assay for the in vitro quantitative determination of folate in human serum. The binding assay is intended for use on Elecsys and cobas e immunoassay analyzers. Folic acid measurements are used in the diagnosis and treatment of anemias.

The Folate III Assay employs a competitive test principle using natural folate binding protein (FBP) specific for folate. Folate in the sample competes with the added folate (labeled with biotin) for the binding sites on FBP (labeled with a ruthenium complex). Results are determined using a calibration curve that is generated specifically on each instrument by a 2 point calibration and a master curve (5-point-calibration) provided with the reagent bar code.

Roche Diagnostics' Elecsys Folate III Assay is a quantitative in vitro diagnostic device designed for measuring folate levels in human serum, primarily for the diagnosis and treatment of anemias. The following outlines its acceptance criteria and the studies performed to demonstrate its performance.

Acceptance Criteria and Reported Device Performance

The acceptance criteria for the Elecsys Folate III Assay are primarily established through comparison to a predicate device, the Roche Elecsys Folate III (K082340). The device demonstrates comparable or improved analytical performance characteristics.

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(1) Elecsys Folate RBC Assay: Binding assay for the in vitro quantitative determination of folate erythrocytes (red blood cells, RBCs). The binding assay is intended for use on Elecsys and cobas e immunoassay analyzers. Measurements obtained by this assay are used in the diagnosis and treatment of anemias.
(2) Elecsys Folate RBC CalSet: The Elecsys Folate RBC CalSet is used for calibrating the quantitative Elecsys Folate RBC assay on the Elecsys and cobas e immunoassay analyzers.
(3) Elecsys Folate RBC CalCheck: Elecsys Folate RBC CalCheck is used for the verification of the calibration established by the Elecsys Folate RBC reagent on the indicated Elecsys and cobas e immunoassay analyzers. For in vitro diagnostic use.

(1) The Elecsys Folate RBC assay employs a competitive test principle using natural folate binding protein specific for folate. Manually prepared hemolysate samples are used with this assay. Folate in the sample competes with the added folate (labeled with biotin) for the binding sites on folate binding protein (labeled with ruthenium complex). Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode encoded on the reagent packaging.
(2) The Elecsys Folate RBC CalSet is a lyophilized product consisting of human serum with folate in two concentration ranges. During manufacture, the analyte is spiked into the matrix. This calibrator is used to calibrate the Elecsys Folate RBC assay.
(3) The Elecsys Folate RBC CalCheck is a lyophilized product consisting of a hemolysate with folic acid. During manufacture, the analyte is spiked into the matrix. This solution is used to verify the calibration established with the Elecsys Folate RBC CalSet.

The provided text describes the Elecsys Folate RBC Test System, but it is a device for in vitro quantitative determination of folate in red blood cells and not an AI or imaging device. Therefore, many of the requested categories related to AI performance, such as MRMC studies, ground truth establishment by experts for image data, or training/test set sample sizes for AI models, are not applicable.

However, I can extract information related to the device's analytical performance and the studies conducted to demonstrate its substantial equivalence to a predicate device, focusing on the available information.

Here's the breakdown based on the provided text, adapted for a non-AI diagnostic device:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct pass/fail thresholds in a table format. Instead, the submission demonstrates substantial equivalence by comparing the performance characteristics of the new Elecsys Folate RBC Assay to the predicate device (Elecsys RBC Folate III Assay) in a feature-by-feature comparison. The reported performance of the new device is shown alongside the predicate's performance. The "acceptance criteria" here are implicitly the predicate device's performance, as the goal is to show substantial equivalence.

Study Proving Device Meets Acceptance Criteria:

The study proving the device meets the acceptance criteria is a substantial equivalence comparison study against a legally marketed predicate device, the Elecsys RBC Folate III Test System (K082340). This type of study demonstrates that the new device is as safe and effective as the predicate device by showing that it has similar technological characteristics and performance.

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

The document does not explicitly state a single "test set" sample size in the way an AI model validation might. Instead, it details various analytical performance studies with different "samples" for each attribute:

• Precision (Repeatability & Intermediate Precision): Tested on multiple "Hemolysate" or "Sample" controls at different concentration levels. For each level, measurements were taken to determine SD and CV. The exact number of replicates or runs is not specified in the summary but is typically substantial for precision studies (e.g., multiple runs over several days).
• Analytical Sensitivity (LoB, LoD, LoQ): Determined using analytical methods, likely involving dilutions of folate-containing samples. The specific sample count for these determinations is not provided.
• Interferences: Tested using various interfering substances and pharmaceuticals. The number of samples/donors tested for each interference is not specified, but typically involves spiking known concentrations into samples and assessing recovery.
• Expected Values: Determined from a "Whole Blood Folate (from hemolysate sample)" study and an "RBC Folate (folate in erythrocyte fraction)" study. The sample size for these population studies is not provided in the summary.

Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. For in vitro diagnostic device submissions, such data is typically generated in a controlled laboratory setting (prospective) and may involve samples from different geographical regions, but this is not specified here.

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

Not applicable. This is not an AI/imaging device where expert consensus is used to establish ground truth for a test set. This device quantifies a biomarker (folate in RBCs). The "ground truth" for its analytical performance is established through reference methods and internal validation procedures, not human interpretation or adjudication by experts.

4. Adjudication Method for the Test Set

Not applicable. As this device measures a quantitative biomarker, there is no "adjudication" in the sense of resolving discrepancies in human interpretation or labeling. Analytical performance is typically verified against established laboratory standards and reference methods.

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 not an AI device used for interpretation or diagnosis by human readers, so an MRMC study is irrelevant.

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

This is a standalone device performance study. The Elecsys Folate RBC Test System performs the quantitative measurement of folate in RBCs automatically on immunoassay analyzers (Elecsys and cobas e platforms) without human-in-the-loop interpretative performance. The performance metrics (measuring range, sensitivity, precision, interference) are all measures of the algorithm and system's analytical capability.

7. The Type of Ground Truth Used

The "ground truth" for this device's performance relies on analytical reference methods and established laboratory principles. For example:

• For analytical sensitivity (LoB, LoD, LoQ): Determined using standard statistical methods and known concentrations of analyte.
• For precision: Assessed by running replicate measurements on control samples.
• For accuracy/comparison to predicate: The predicate device itself (Elecsys RBC Folate III Assay) serves as the "reference" for demonstrating substantial equivalence. The traceability of the new device is stated as "Reference method is Folate III (Application on the E2010)", meaning its measurements are compared to the predicate's measurements. The predicate's traceability is to the "Elecsys Folate II assay."

8. The Sample Size for the Training Set

Not applicable. This is not an AI/machine learning device that requires a "training set." The system's underlying principles are based on known biochemistry (competitive binding assay using folate binding protein) and not data-driven learning from a training set.

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

Not applicable, as there is no training set for this type of in vitro diagnostic device.

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The ARCHITECT Folate assay is a chemiluminescent microparticle Folate Binding Protein assay for the quantitative determination of folate in human serum and plasma on the ARCHITECT i System. Folate measurements are used in the diagnosis and treatment of megaloblastic anemia.
The ARCHITECT Folate Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of folate in human serum and plasma.
The ARCHITECT Folate Controls are for the verification of the accuracy and precision of the ARCHITECT i System when used for the quantitative determination of folate in human serum and plasma.

The ARCHITECT Folate assay is a two-step assay for the quantitative determination of folate in human serum and plasma using chemiluminescent microparticle immunoassay (CMIA) technology. Two pre-treatment steps mediate the release of folate from endogenous folate binding protein.
In Pre-Treatment Step 1, the sample and Pre-treatment Reagent 2 (Dithiothreitol or DTT) are aspirated and dispensed into a reaction vessel (RV). In Pre-Treatment Step 2, an aliquot of sample/Pre-Treatment Reagent 2 mixture is aspirated and dispensed into a second RV. Pre-Treatment Reagent 1 (potassium hydroxide or KOH) is then added. An aliquot of the pre-treated sample is transferred into a third RV, followed by the addition of Folate Binding Protein (FBP) coated paramagnetic microparticles and assay specific diluent. Folate present in the sample binds to the FBP coated microparticles. After washing, pteroic acid-acridinium labeled conjugate is added and binds to unoccupied sites on the FBP coated microparticles. Pre-Trigger and Trigger Solutions are then added to the reaction mixture; the resulting chemiluminescent reaction is measured as relative light units (RLUs). An inverse relationship exists between the amount of folate in the sample and the RLUs detected by the ARCHITECT i optical system.

The provided text describes a 510(k) submission for the ARCHITECT Folate assay, a medical device for quantitatively determining folate in human serum and plasma. The study conducted is a non-clinical performance comparison between the new ARCHITECT Folate assay and its predicate device, the AxSYM Folate assay.

Here's an analysis of the acceptance criteria and study as requested:

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document states "The ARCHITECT Folate assay demonstrated substantially equivalent performance to the AxSYM Folate assay with correlation coefficients of 0.898 for serum samples." The acceptance criteria for "substantially equivalent" in areas like precision, linearity, and interferences are not explicitly quantified with numerical thresholds in the provided text. They are implied by the claim of substantial equivalence to the predicate device.

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

The document does not explicitly state the sample size used for the test set in the comparison study.

The data provenance is not specified in terms of country of origin or whether it was retrospective or prospective. It is a non-clinical performance study.

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 to this type of study. The ground truth for a quantitative diagnostic assay is typically established through a reference method or standardization to an internationally recognized standard. In this case, the investigational assay was standardized to the WHO Serum Folate International Standard (IS) 03/178. Human expert consensus is not the method for establishing ground truth for quantitative laboratory tests like this.

4. Adjudication Method for the Test Set

This information is not applicable to this type of study. Adjudication methods (like 2+1 or 3+1) are typically used in studies where human readers are interpreting images or making subjective diagnoses, which is not the case for a quantitative immunoassay comparison. The comparison is likely done statistically between measured values.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This study is a non-clinical performance evaluation of a quantitative diagnostic assay, not an AI-assisted human reading study.

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

Yes, this was a standalone performance study of the ARCHITECT Folate assay. The document describes the assay's mechanism and then presents its performance characteristics (precision, linearity, interferences, method comparison) against a predicate device. There is no mention of human-in-the-loop performance testing.

7. The Type of Ground Truth Used

The ground truth for the investigational assay was established by standardization to the WHO Serum Folate International Standard (IS) 03/178. For the comparison with the predicate, the predicate device's results serve as a comparative "truth," which were themselves based on gravimetric preparations of folic acid.

8. The Sample Size for the Training Set

The document does not mention a "training set" in the context of machine learning. This is a traditional immunoassay device, not an AI/ML-based device. Therefore, a training set as understood in AI/ML is not applicable. The assay is "standardized" rather than "trained."

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

As explained above, there is no "training set" in the machine learning sense for this device. The assay was standardized to accurately recover WHO Serum Folate International Standard (IS) 03/178. This standardization process involves calibrating the assay's response to known concentrations of the analyte based on this international standard.

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Tosoh AIA-PACK RBC FOLATE is designed for in vitro diagnostic use only for the quantitative measurement of red blood cell folate (RBC FOLATE) in whole blood (Heparin or EDTA) samples on TOSOH AIA system analyzer. Measurement of RBC Folate is used in the diagnosis and treatment of anemia.

The Tosoh AIA-PACK RBC FOLATE is a competitive enzyme immunoassay which, after sample hemolysis and sample pretreatment, is performed entirely within the AIA-PACK. First, sample hemolysis is performed to achieve complete hemolysis of erythrocytes and deconjugation to monoglutamate in the whole blood sample using sample hemolyzing reagents (containing ascorbic acid). After sample hemolysis, sample pretreatment is performed to release folate from endogenous binding proteins in the hemolysate sample using sample pretreatment reagents (containing sodium hydroxide and dithiothreitol). Folate present in the pretreated test sample competes with enzyme-labeled folate for a limited number of binding sites on a fluorescein labeled bovine folate binding protein which then binds to anti-FITC (fluorescein isothiocyanate) antibody immobilized on magnetic beads. The beads are washed to remove the unbound enzyme-labeled folate and are then incubated with a fluorogenic substrate, 4-methylumbelifery| phosphate (4MUP). The amount of enzyme labeled folate that binds to the beads is inversely proportional to the folate concentration in the test sample. A standard curve using a range of known standard concentrations is constructed and unknown folate concentrations are calculated using this curve.

The Tosoh AIA-PACK RBC FOLATE is a device designed for the quantitative measurement of red blood cell folate (RBC FOLATE) in whole blood samples, used in the diagnosis and treatment of anemia. The device's performance was evaluated through various studies to demonstrate substantial equivalence to a predicate device (Bayer K010050, ADVIA Centaur and ACS: 180 Folate Immunoassay).

The document provides performance data for several criteria: Recovery, Dilution, Linearity, Precision, Correlation, Specificity, and Limit of Detection (LoD)/Limit of Quantitation (LoQ). Acceptance criteria are not explicitly stated as distinct numerical targets but are implied by the reported performance and the overall conclusion of substantial equivalence based on established CLSI protocols.

Here's a breakdown of the acceptance criteria and the study results:

1. Table of Acceptance Criteria and Reported Device Performance

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(1) Elecsys Folate III: Binding assay for the in vitro quantitative determination of folate in human serum and plasma. The binding assay is intended for use on Elecsys and cobas e immunoassay analyzers. Measurements obtained by these devices are used in the diagnosis and treatment of anemias. For in vitro diagnostic use.

(2) Elecsys RBC Folate Hemolyzing Reagent: Elecsys RBC Folate Hemolyzing Reagent is used together with the Elecsys Folate III assay for the quantitative determination of folate in erthrocytes (RBC (red blood cell) folate). Binding assay for the in vitro quantitative determination of folate in human serum and plasma. The binding assay is intended for use on Elecsys and cobas e immunoassay analyzers. Measurements obtained by these devices are used in the diagnosis and treatment of anemias.

(3) Elecsys Folate III CalSet: Elecsys Folate III CalSet is used for calibrating the quantitative Elecsys Folate III assay on the Elecsys and cobas e immunoassay analyzers.

(4) Elecsys Folate III CalCheck: Elecsys Folate III CalCheck is used for the verification of the calibration established by the Elecsys Folate III reagent on the indicated Elecsys and cobas e immunoassay analyzers.

(5) Elecsys PreciControl Anemia: Elecsys PreciControl Anemia is used for the quality control of specified Elecsys immunoassays on Elecsys and cobas e immunoassay analyzers.

(1) The Elecsys Folate III assay employs a competitive test principle using natural folate binding protein (FBP) specific for folate. Folate in the sample competes with the added folate (labeled with biotin) for the binding sites on FBP (labeled with ruthenium complex). Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode.

(2) The Elecsys RBC Folate Hemolyzing Reagent is a 0.2% ascorbic acid solution with which whole blood treated with anticoagulants (heparin or EDTA) is diluted. After incubation the erythrocytes are lysed and intracellular folate is liberated and stabilized. The hemolysate is then used as a prediluted sample for subsequent measurement in the Elecsys Folate III assay.

(3) The Elecsys Folate III CalSet is a lyophilized product consisting of human serum with folic acid in two concentration ranges. During manufacture, the analyte is spiked into the matrix. This calibrator is used to calibrate the Elecsys Folate III assay.

(4) Elecsys Folate III CalCheck is a lyophilized product consisting of human serum with folic acid. During manufacture, the analyte is spiked into the matrix. This solution is used to verify the calibration established with the Elecsys Folate III CalSet.

(5) The Elecsys PreciControl Anemia is a lyophilized control serum based on human serum matrix in three concentration ranges. The controls are used for monitoring the accuracy and precision of the Elecsys Ferritin, Folate III, and Vitamin B12 immunoassays.

The Elecsys Folate III Test System, including Elecsys Folate III, Elecsys RBC Folate Hemolyzing Reagent, Elecsys Folate III CalSet, Elecsys Folate III CalCheck, and Elecsys PreciControl Anemia, is designed for the in vitro quantitative determination of folate in human serum, plasma, and erythrocytes. This system is intended for use in the diagnosis and treatment of anemias on Elecsys and cobas e immunoassay analyzers.

The acceptance criteria for the Elecsys Folate III and Elecsys RBC Folate Hemolyzing Reagent assays were established through comparison studies against their respective predicate devices (Elecsys Folate II Assay and Elecsys RBC Folate Hemolyzing Reagent (K051292)). The primary method for proving the device meets these criteria is through Method Comparison studies using Passing-Bablok and Linear Regression analysis.

Here's the breakdown of the acceptance criteria and performance:

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