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ACE Hemoglobin A lc (HbA lc) Reagent is intended for the quantitative determination of percent hemoglobin A lc in venous whole blood collected in K2-EDTA tubes using the ACE Axcel® Clinical Chemistry Systems. This test is intended for use in clinical laboratories and physician office laboratories to monitor long term blood glucose control in individuals with diabetes mellitus. For in vitro diagnostic use only.

The ACE Hemoglobin A1c (HbA1c) Reagent assay requires a pretreatment step of denaturation of the whole blood samples, which is performed off-line. The red blood cells in the sample are lysed by the Hemoglobin Denaturant and the hemoglobin chains are hydrolyzed. For determination of HbA1c, a latex agglutination inhibition assay is used. In the absence of HbA1c in the sample, the synthetic polymer containing the immunoreactive portion of HbA 1c Agglutinator Reagent will agglutinate with the antibody-coated microparticles in the HbA1c Antibody Reagent. The presence of HbA1c in the blood sample competes for the antibody binding sites and inhibits agglutination. The increase in absorbance, monochromatically at 692 mm, is inversely proportional to the HbA1c present in the sample. For the determination of total hemoglobin, all hemoglobin derivatives in the sample are converted to alkaline hematin. The reaction produces a green colored solution. which is measured bichromatically at 573 nm/692 nm. The intensity of color produced is directly proportional to the total hemoglobin concentration in the sample. The concentrations of both HbA 1 c and total hemoglobin are measured, the ratio is calculated, and the result reported as percent HbA1c.

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria for the ACE Hemoglobin A1c (HbA1c) Reagent device are implicitly established by demonstrating comparable performance to the predicate device, the DCA 2000+ System for Hemoglobin A1c (K951361), across a range of analytical performance characteristics. While explicit numerical acceptance criteria are not always stated, the study aims to show that the new device's performance aligns with acceptable standards for HbA1c measurement in clinical diagnostics.

Here's a table summarizing the reported device performance:

Study Details:

2. Sample Size and Data Provenance for Test Set:

• Linearity: 11 samples were used for both HbA1c and Total Hemoglobin linearity studies, run in 4 replicates each, for both the ACE Alera and ACE Axcel systems.
• Precision (In-house): 4 samples (A, B, C, D) were tested, but the number of runs/replicates to calculate SD and %CV is not explicitly stated in the table. Typically, precision studies involve multiple replicates over several days.
• Precision (Physician Office Labs - POLs): 4 samples were tested across 3 POLs for each instrument (ACE Alera and ACE Axcel). Similar to in-house, the specific number of runs/replicates per POL for SD and %CV calculation is not detailed.
• Comparative Analysis (In-house): 101 samples for ACE Alera and 102 samples for ACE Axcel were compared against the predicate device (DCA 2000+).
• Comparative Analysis (POLs): 50 samples per POL for a total of 150 samples for ACE Alera, and 52 samples for one POL and 50 samples for the other two POLs (total 152 samples) for ACE Axcel were compared against the predicate device (DCA 2000+).
• Analytical Specificity/Cross-Reactivity: The number of samples for these studies is not explicitly stated, but typically involves spiking known concentrations of interferents into samples and measuring the effect.
• Data Provenance: The studies were conducted in-house by Alfa Wassermann Diagnostic Technologies, LLC, and in external Physician Office Laboratories (POLs). Given the nature of performance validation for a diagnostic device, these studies are prospective, as samples are analyzed using the new device and compared against a reference method or predicate. The "country of origin of the data" is implicitly the United States, where the manufacturer and the POLs are located.

3. Number of Experts and their Qualifications for Ground Truth:

The document does not mention the use of "experts" in the traditional sense (e.g., radiologists, pathologists) to establish ground truth for the test set. For an in vitro diagnostic device measuring a quantitative analyte like HbA1c, the ground truth is typically established by:

• Reference Methods: Highly accurate and precise analytical methods, often traceable to international standards (e.g., NGSP, IFCC), which are considered the "gold standard" for measuring the analyte.
• Predicate Devices: Comparison to a legally marketed device that has already established its safety and effectiveness.

In this case, the ground truth for the comparative studies was derived from the predicate device (DCA 2000+ System for Hemoglobin A1c), which is itself NGSP Certified and traceable to IFCC reference materials.

4. Adjudication Method for the Test Set:

Not applicable. Adjudication methods (like 2+1, 3+1) are typically used in clinical studies involving interpretation of medical images or complex diagnostic assessments by human readers, where discrepancies between readers need to be resolved. For a quantitative in vitro diagnostic device, the ground truth is established analytically through reference methods or predicate comparison, not through expert consensus requiring adjudication.

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

Not applicable. MRMC studies are generally performed for image-based diagnostic aids or other devices where human interpretation plays a significant role in the diagnostic outcome. This document describes the analytical performance validation of an in vitro diagnostic reagent, which is a quantitative measurement, not an interpretative task for human readers in the context of an MRMC study. Therefore, no effect size of human readers improving with AI vs. without AI assistance is relevant or reported.

6. Standalone (Algorithm Only) Performance Study:

Yes, this entire submission focuses on the standalone performance of the ACE Hemoglobin A1c (HbA1c) Reagent when used with the ACE Alera® and ACE Axcel® Clinical Chemistry Systems. The studies presented (linearity, precision, comparative analysis, specificity, cross-reactivity) all evaluate the direct analytical performance of the device itself, without human intervention for interpretation beyond standard laboratory procedures for operating the instrument and processing samples.

7. Type of Ground Truth Used:

The ground truth used for the comparative analysis studies was the predicate device, the DCA 2000+ System for Hemoglobin A1c. The document explicitly states that the DCA Hemoglobin A1c test method is National Glycohemoglobin Standardization Program (NGSP) Certified and is traceable to International Federation of Clinical Chemistry (IFCC) reference materials and test methods. This indicates that the predicate device serves as a highly standardized and accepted reference for HbA1c measurement.

8. Sample Size for the Training Set:

The document does not explicitly mention a "training set" in the context of machine learning or AI models. This device is a diagnostic reagent kit for a clinical chemistry system, not a software algorithm that requires a separate training phase with a distinct dataset. The performance data presented are for the validation of the finalized device.

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

As there is no "training set" in the context of this device being a reagent for a clinical chemistry system, this question is not applicable. The device's design and formulation would have been developed through internal R&D, likely using internal validation and optimization experiments, but these are not typically referred to as a "training set" with established ground truth in the same way as for AI/ML models. The ground truth for the validation of the device's performance (as described above) was established by comparison to the NGSP/IFCC-traceable predicate device.

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The ACE Direct Total Iron-Binding Capacity (TIBC) Reagent is intended for the quantitative determination of total iron-binding capacity in serum using the ACE Alera Clinical Chemistry System. Iron-binding capacity measurements are used in the diagnosis and treatment of anemia. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE Total Iron Reagent is intended for the quantitative determination of iron in serum using the ACE Alera Clinical Chemistry System. Iron (non-heme) measurements are used in the diagnosis and treatment of diseases such as iron deficiency anemia, hemochromatosis (a disease associated with widespread deposit in the tissues of two iron-containing pigments, hemosiderin and hemofuscin, and characterized by pigmentation of the skin), and chronic renal disease. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE LDH-L Reagent is intended for the quantitative determination of lactate dehydrogenase activity in serum using the ACE Alera Clinical Chemistry System. Lactate dehydrogenase measurements are used in the diagnosis and treatment of liver diseases such as acute viral hepatitis, cirrhosis, and metastatic carcinoma of the liver, cardiac diseases such as myocardial infarction and tumors of the lung or kidneys. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

In the ACE Direct Total Iron-Binding Capacity (TIBC) Reagent assay, Direct TIBC Color Reagent, an acidic buffer containing an iron-binding dye and ferric chloride, is added to the serum sample. The low pH of Direct TIBC Color Reagent releases iron from transferrin. The iron then forms a colored complex with the dye. The colored complex at the end of the first step represents both the serum iron and excess iron already present in Direct TIBC Color Reagent. Direct TIBC Buffer, a neutral buffer, is then added, shifting the pH and resulting in a large increase in the affinity of transferrin for iron. The serum transferrin rapidly binds the iron by abstracting it from the dye-iron complex. The observed decrease in absorbance of the colored dye-iron complex is directly proportional to the total iron-binding capacity of the serum sample. The absorbance is measured at 647 nm.

In the ACE Total Iron Reagent assay, transferrin-bound iron in serum is released at an acidic pH and reduced from ferric to ferrous ions. These ions react with ferrozine to form a violet colored complex, which is measured bichromatically at 554 nm/692 nm. The intensity of color produced is directly proportional to the serum iron concentration.

In the ACE LDH-L Reagent assay, lactate dehydrogenase catalyzes the conversion of L-lactate to pyruvate. Nicotinamide adenine dinucleotide (NAD+) acts as an acceptor for the hydrogen ions released from the L-lactate and is converted to reduced nicotinamide adenine dinucleotide (NADH). NADH absorbs strongly at 340 nm whereas NAD+ does not. Therefore, the rate of conversion of NAD+ to NADH can be determined by monitoring the increase in absorbance bichromatically at 340 nm/647 nm. This rate of conversion from NAD+ to NADH is directly proportional to the lactate dehydrogenase activity in the sample.

The provided document describes in vitro diagnostic (IVD) reagents (ACE Direct Total Iron-Binding Capacity (TIBC) Reagent, ACE Total Iron Reagent, and ACE LDH-L Reagent) for use on the ACE Alera Clinical Chemistry System. The acceptance criteria and performance data presented relate to the analytical performance of these reagents/systems, specifically their ability to accurately and precisely measure analytes in serum samples.

Crucially, this is not a study about an AI/ML powered medical device. Therefore, many of the typical acceptance criteria and study aspects requested in your prompt regarding AI/ML (e.g., ground truth established by experts, multi-reader multi-case studies, human-in-the-loop performance, training/test set sample sizes for AI, adjudication methods) are not applicable to this type of device and submission.

The "study" described here is a series of analytical performance tests (linearity, precision, method comparison, detection limits, interference) to demonstrate that the new device (ACE Alera system with these reagents) performs comparably to the predicate device (ACE Clinical Chemistry System with the same reagents) and meets established analytical performance specifications for clinical chemistry assays.

Here's a breakdown of the relevant information from the document in the format you requested, with an explanation of why certain AI/ML-centric points are not applicable:

Device: ACE Direct Total Iron-Binding Capacity (TIBC) Reagent, ACE Total Iron Reagent, ACE LDH-L Reagent (for use on ACE Alera Clinical Chemistry System)

1. Table of acceptance criteria and reported device performance:

Since the document does not explicitly present "acceptance criteria" alongside "reported performance" in a single table, I will infer the acceptance criteria from the context of method comparison, linearity, and precision studies, which are standard for IVD device validation, often aiming for performance comparable to predicate devices or within clinically acceptable limits. The reported performance is directly extracted from the tables provided.

Interference:
The acceptance criterion for interference studies in IVD assays is typically that the interferent, up to a specified concentration, does not cause a "significant interference" (e.g., a bias exceeding a defined clinical or analytical threshold). The document lists the concentrations at which no significant interference was observed.

Precision (POL - Point of Care/Physician Office Lab):
Similar to in-house precision, specific %CV or SD limits would be the acceptance criteria. The data shows results from 3 POLs compared to in-house.

Method Comparison (POLs vs. In-House (ACE Alera (x) vs. POL ACE Alera (y))):
Similar to the in-house method comparison, the acceptance criteria are for slopes to be near 1, intercepts near 0, and high correlation coefficients (e.g., >0.99), indicating consistent performance across different lab environments.

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

• Sample Sizes for analytical performance studies (Test Set):

  • Method Comparison:
    • TIBC: 50 samples
    • Iron: 48 samples
    • LDH-L: 58 (in-house comparison) / 51 (POL comparison) samples
  • Linearity: The number of samples/levels for linearity is not explicitly stated as 'n', but standard practice involves multiple levels (typically 5-7) prepared from diluted/spiked samples.
  • Precision: Standard runs (e.g., 2 runs per day for 20 days for total precision, with replicates per run for within-run precision) would involve a substantial number of measurements (e.g., 20 days x 2 runs/day x 2 replicates/run = 80 measurements per level). The POL precision data shows n=20, likely referring to 20 days of testing.
  • Interference: The number of samples used for interference studies is not explicitly stated.

• Data Provenance: "In-House" and "POL" (Physician Office Laboratories). The specific country of origin is not explicitly stated, but given the company's location (New Jersey, USA) and FDA 510(k) submission, it's highly likely to be United States. The studies are prospective analytical validation studies, meaning the data was collected specifically to demonstrate the performance of the device.

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

Not applicable. This is an in vitro diagnostic (IVD) chemistry analyzer and reagent system. "Ground truth" for IVD analytical performance is established by reference methods, certified reference materials, or highly accurate comparative methods, not by human expert consensus or radiologists. The performance is assessed against quantitative values, not qualitative interpretations requiring expert review.

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

Not applicable. Adjudication methods like 2+1 or 3+1 are used in studies involving human interpretation (e.g., imaging studies where radiologists disagree). For analytical performance of a chemistry analyzer, the "ground truth" is typically the quantitative value obtained from a reference method or the predicate device, and differences are assessed statistically (e.g., bias, correlation).

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. MRMC studies are specific to evaluating the impact of a device on human readers' performance, typically in diagnostic imaging with AI assistance. This device is an automated chemistry analyzer, not an AI-assisted diagnostic imaging tool. There are no human "readers" in the context of this device's operation.

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

Yes, in essence. The performance data provided (linearity, precision, detection limits, interference, method comparison) represents the "standalone" analytical performance of the automated chemistry system (ACE Alera with the new reagents) in measuring the target analytes in patient samples. There isn't an "algorithm only" in the AI sense, but the chemical reactions and photometric measurements are entirely automated by the device. The data shown is the raw analytical output.

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

The "ground truth" for these analytical studies is primarily:

• Highly characterized samples: For linearity, samples with known, precise concentrations (often prepared by dilution of high-concentration materials or spiking low-concentration materials).
• Comparative method/Predicate device: For method comparison, the results generated by the predicate device (ACE Clinical Chemistry System) are treated as the reference or comparative method against which the new ACE Alera system's results are compared. This is a common and accepted "ground truth" for chemical analyzers seeking substantial equivalence.
• Reference materials/controls: For precision and detection limits, control materials with established target values are used.

8. The sample size for the training set:

Not applicable. This is a traditional IVD device (chemical reagents and analyzer), not an AI/ML device that requires a "training set" in the context of machine learning model development. The reagents perform chemical reactions, and the analyzer reads photometric changes; it does not "learn" from data.

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

Not applicable, as there is no training set in the AI/ML sense for this device.

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ACE Albumin Reagent is intended for the quantitative determination of albumin concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Albumin measurements are used in the diagnosis and treatment of numerous diseases involving primarily the liver or kidneys. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

ACE Total Protein Reagent is intended for the quantitative determination of total protein concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Total protein measurements are used in the diagnosis and treatment of a variety of diseases involving the liver, kidney, or bone marrow as well as other metabolic or nutritional disorders. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

ACE Calcium-Arsenazo Reagent is intended for the quantitative determination of calcium concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Calcium measurements are used in the diagnosis and treatment of parathyroid disease, a variety of bone diseases, chronic renal disease and tetany (intermittent muscular contractions or spasms). This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

ACE Inorganic Phosphorus U.V. Reagent is intended for the quantitative determination of inorganic phosphorus concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Measurements of inorganic phosphorus are used in the diagnosis and treatment of various disorders, including parathyroid gland and kidney diseases and vitamin D imbalance. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

In the ACE Albumin Reagent assay, Bromcresol green binds specifically to albumin to form a green colored complex, which is measured bichromatically at 629 nm/692 nm. The intensity of color produced is directly proportional to the albumin concentration in the sample.

In the ACE Total Protein Reagent assay, cupric ions react with the peptide bonds of proteins under alkaline conditions to form a violet colored complex, which is measured bichromatically at 544 nm/692 nm. The intensity of color produced is directly proportional to the total protein concentration in the sample.

In the ACE Calcium-Arsenazo Reagent assay, calcium reacts with Arsenazo III in an acidic solution to form a blue-purple colored complex, which is measured bichromatically at 647 nm/692 nm. The intensity of color produced is directly proportional to the calcium concentration in the sample.

In the ACE Inorganic Phosphorus U.V. Reagent assay, under acidic conditions, inorganic phosphorus in serum reacts with ammonium molybdate to form an unreduced phosphomolybdate complex, which absorbs strongly at 340 nm. The increase in absorbance, measured bichromatically at 340 nm/378 nm, is directly proportional to the amount of phosphorus in the sample.

Here's an analysis of the acceptance criteria and study information for the ACE Albumin Reagent, ACE Total Protein Reagent, ACE Calcium-Arsenazo Reagent, and ACE Inorganic Phosphorus U.V. Reagent, based on the provided text.

1. Table of Acceptance Criteria and Reported Device Performance

The provided documentation does not explicitly state formal "acceptance criteria" with specific thresholds for each performance metric. However, it presents detailed performance data, particularly precision (within-run and total %CV) and method comparison (regression analysis, correlation coefficient), comparing the new reagents on various ACE clinical chemistry systems (ACE, ACE Alera, ACE Axcel) against existing predicate devices and among themselves. The implied acceptance is that the new reagents perform comparably to, or as effectively as, the predicate devices and demonstrate acceptable precision and linearity for clinical use.

Below is a summary of the reported device performance based on the "In-House Precision" and "In-House Matrix Comparison" tables. Since explicit acceptance criteria are not given, the performance data itself is presented as the evidence of meeting implied clinical utility and equivalence to predicate devices.

ACE Albumin Reagent

ACE Total Protein Reagent

ACE Calcium-Arsenazo Reagent

ACE Inorganic Phosphorus U.V. Reagent

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

The studies mentioned are "In-House Precision," "In-House Matrix Comparison: Serum vs. Plasma," "POL - Precision," and "POL – Method Comparison."

• In-House Precision (Serum vs. Plasma):
  • Sample Size: Not explicitly stated for each "low, mid, high" concentration level, but implies multiple replicates for each level tested across the three systems (ACE, Alera, Axcel). For example, the ACE Alera precision table (pg. 16) shows 3 levels (low, mid, high) for serum, with reported mean, within-run SD, and total SD. Typically, precision studies involve running samples multiple times a day over several days.
  • Data Provenance: "In-House" suggests it was conducted by Alfa Wassermann Diagnostic Technologies, LLC, likely at their own facilities. It is a prospective study as they are performing experiments to generate data.
• In-House Matrix Comparison: Serum vs. Plasma:
  • Sample Size:
    • Albumin: ACE: 55 pairs, ACE Alera: 56 pairs, ACE Axcel: 56 pairs
    • Total Protein: ACE: 56 pairs, ACE Alera: 56 pairs, ACE Axcel: 81 pairs
    • Calcium-Arsenazo: ACE: 56 pairs, ACE Alera: 56 pairs, ACE Axcel: 81 pairs
    • Inorganic Phosphorus: ACE: 100 pairs, ACE Alera: 102 pairs, ACE Axcel: 56 pairs
  • Data Provenance: "In-House" suggests it was conducted by Alfa Wassermann Diagnostic Technologies, LLC, likely at their own facilities. The comparison between serum and plasma samples implies these were collected from human subjects. This is a prospective study.
• POL (Physician Office Laboratory) - Precision:
  • Sample Size: For each reagent and each system (ACE and ACE Alera), there are 3 "samples" (representing different concentration levels) tested at 3 different POL sites. Each sample/site combination has "Within-Run" and "Total" precision reported, implying multiple replicates for each measurement.
  • Data Provenance: Conducted at "POL 1," "POL 2," and "POL 3" sites, indicating external collection and testing beyond the manufacturer's immediate facilities. This is a prospective study.
• POL (Physician Office Laboratory) - Method Comparison:
  • Sample Size:
    • Albumin: 50 samples for each POL site (x3 POLs)
    • Total Protein: 51 samples for each POL site (x3 POLs)
    • Calcium-Arsenazo: 50 samples for each POL site (x3 POLs)
    • Inorganic Phosphorus: 50 samples for POL 1 & 3, 48 samples for POL 2
  • Data Provenance: Comparisons between "ACE In-House (x)" and "ACE POL (y)" or "ACE In-House (x)" and "ACE Alera POL (y)". This indicates the data for these studies was collected at both in-house facilities and external Physician Office Laboratories. This is a prospective study design, comparing results from different testing environments.
• Detection Limits & Linearity (ACE Alera):
  • Sample Size: Not specified for these specific studies, but typically involves a series of diluted and concentrated samples to define the measuring range.
  • Data Provenance: In-House, prospective.
• Interference (ACE Alera):
  • Sample Size: Not specified, but involves spiking samples with various interferents at different concentrations.
  • Data Provenance: In-House, prospective.

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

For these types of in vitro diagnostic (IVD) assays, the "ground truth" is typically established by reference methods or validated comparative methods, often using certified calibrators and controls. The documentation does not mention the use of human experts to establish ground truth for the test set in the traditional sense of medical image interpretation (e.g., radiologists interpreting images). Instead, the studies rely on quantitative measurements and statistical comparisons with established methods (the predicate devices or in-house reference measurements) to demonstrate performance. Therefore, no information is provided on the number or qualifications of experts for ground truth establishment.

4. Adjudication Method for the Test Set

Not applicable. As described in point 3, the "ground truth" for these quantitative chemical assays is not established through expert consensus or adjudication in the way it would be for qualitative or interpretive diagnostic devices like medical imaging. Performance is evaluated by statistical comparison of numerical 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 device consists of chemical reagents for laboratory measurement, not an AI-assisted diagnostic tool interpreted by human readers. Therefore, an MRMC comparative effectiveness study involving human readers and AI is not relevant to this submission.

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

The performance presented for these reagents is inherently "standalone" in the sense that it reflects the direct analytical performance of the assays on the specified automated clinical chemistry systems. The results are quantitative measurements produced by the device without human interpretation of raw data beyond reading the numerical output. The "without human-in-the-loop" aspect applies here as the device itself performs the measurement and outputs a numerical value of concentration. The method comparison studies demonstrate the standalone performance of the candidate devices compared to predicate devices.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The ground truth for these assays is established through reference methods and comparison to legally marketed predicate devices.

• For precision, the "ground truth" for each replicate is assumed to be the true concentration within the sample, and the study assesses the reproducibility of the device in measuring that concentration.
• For method comparison studies (e.g., In-House vs. POL, or ACE vs. ACE Alera), one method's results (often the predicate or an established in-house method) serve as the comparative 'truth' to evaluate the new method's agreement. The reference method would itself be calibrated against known standards.
• For linearity, samples of known, graded concentrations are used.
• For detection limits, the ground truth involves samples with very low, known concentrations.

These are established analytical chemistry principles rather than "expert consensus" or "pathology" in the diagnostic interpretation sense.

8. The Sample Size for the Training Set

The concept of a "training set" is primarily relevant for machine learning or AI algorithms which are iteratively developed and optimized using data. These reagents are chemical assays with a defined photometric measurement principle. While there is a development phase that involves optimizing reagent formulations and instrument parameters, there isn't a "training set" in the computational sense. The data presented here are from formal "verification and validation studies" to demonstrate performance characteristics (precision, linearity, accuracy/comparison, interference, detection limits).

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

As noted in point 8, the concept of a "training set" is not directly applicable to these chemical reagents. The "ground truth" for establishing and validating the performance of such assays is based on:

• Reference materials/calibrators: Solutions with precisely known concentrations of the analyte (albumin, total protein, calcium, phosphorus) traceable to international standards.
• Validated comparison methods: Measurements made by existing, legally marketed predicate devices or other well-established and accurate laboratory methods.
• Controlled spiking experiments: Adding known amounts of substance to samples to assess recovery, linearity, and interference.

These methods establish the quantitative "truth" against which the performance of the new reagents is measured.

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The ACE Alkaline Phosphatase Reagent is intended for the quantitative determination of alkaline phosphatase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Measurements of alkaline phosphatase are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE Amylase Reagent is intended for the quantitative determination of α-amylase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Amylase measurements are used primarily for the diagnosis and treatment of pancreatitis (inflammation of the pancreas). This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE ALT Reagent is intended for the quantitative determination of alanine aminotransferase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Alanine aminotransferase measurements are used in the diagnosis and treatment of certain liver diseases (e.g., viral hepatitis and cirrhosis) and heart diseases. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE AST Reagent is intended for the quantitative determination of aspartate aminotransferase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Measurements of aspartate aminotransferase are used in the diagnosis and treatment of certain types of liver and heart disease. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

In the ACE Alkaline Phosphatase Reagent assay, alkaline phosphatase catalyzes the hydrolysis of colorless p-nitrophenyl phosphate to p-nitrophenol and inorganic phosphate. In an alkaline solution (pH 10.5), p-nitrophenol is in the phenoxide form and has a strong absorbance at 408 nm. The rate of increase in absorbance, monitored bichromatically at 408 nm/486 nm, is directly proportional to the alkaline phosphatase activity in the sample.

In the ACE Amylase Reagent assay, α-amylase hydrolyzes the 2-chloro-p-nitrophenyl-α-D-maltotrioside substrate to release 2-chloro-p-nitrophenol and form 2-chloro-p-nitrophenyl-α-D-maltoside, maltotriose and glucose. The rate of increase in absorbance, monitored bichromatically at 408 nm/ 647 nm, is directly proportional to the α-amylase activity in the sample.

In the ACE ALT Reagent assay, alanine aminotransferase converts the L-alanine and α-ketoglutarate substrates in the reagent to L-glutamate and pyruvate, respectively. Lactate dehydrogenase (LDH) catalyzes the oxidation of the reduced cofactor to the cofactor. The rate of conversion of the reduced cofactor to the cofactor can be determined by monitoring the decrease in absorbance bichromatically at 340 nm/647 nm. This rate of conversion from the reduced cofactor to the cofactor is a function of the activity of ALT in the sample.

In the ACE AST Reagent assay, aspartate aminotransferase converts the L-aspartate and α-ketoglutarate in the reagent to oxaloacetate and L-glutamate, respectively. The oxaloacetate undergoes reduction, with concurrent oxidation of NADH to NAD+ in the malate dehydrogenase-catalyzed indicator reaction. NADH absorbs strongly at 340 nm, whereas NAD+ does not. Therefore, the rate of conversion of NADH to NAD+ can be determined by monitoring the decrease in absorbance bichromatically at 340 nm/647 nm. This rate of conversion from NADH to NAD+ is a function of the activity of AST in the sample. Lactate dehydrogenase is added to prevent interference from endogenous pyruvate, which is normally present in blood.

Here's an analysis of the provided information regarding the acceptance criteria and study for the ACE reagents:

Summary of Acceptance Criteria and Reported Device Performance

The acceptance criteria for these in vitro diagnostic reagents (ALP, Amylase, ALT, AST) appear to be primarily demonstrated through comparisons with predicate devices and comprehensive performance characteristics like precision, linearity, and interference. The documentation focuses on demonstrating that the new devices perform equivalently to the existing predicate devices and meet established performance expectations for clinical chemistry assays.

1. Table of Acceptance Criteria and Reported Device Performance

Since this document describes multiple reagents and doesn't explicitly state pass/fail acceptance values for each performance metric, I will summarize the demonstrated performance and what can be inferred as the "acceptance criteria" (i.e., that the results are comparable to established predicate device performance and within acceptable clinical ranges).

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

• Precision (Serum vs. Plasma):
  • In-House: Each dataset (low, mid, high for serum and plasma) involved "n=20" (number of replicates, likely over multiple days, contributing to within-run and total precision calculations).
  • POL Precision (ACE & Alera): For each analyte (ALP, AMY, ALT, AST) and each POL site (POL 1, POL 2, POL 3), there were 2 to 3 sample levels (Low, Mid, High), with a reported "n" for each (e.g., n=24 for ALT/AST in initial in-house, but the POL tables don't explicitly state the 'n' for each specific mean/SD/CV, implying a standard number of replicates as per precision studies).
• Matrix Comparison (Serum vs. Plasma):
  • ALP: ACE (108 pairs), ACE Alera (108 pairs), ACE Axcel (62 pairs).
  • Amylase: ACE (104 pairs), ACE Alera (101 pairs), ACE Axcel (52 pairs).
  • ALT: ACE (54 pairs), ACE Alera (52 pairs), ACE Axcel (56 pairs).
  • AST: The number of pairs for AST in the serum vs. plasma matrix comparison is not explicitly stated in the provided snippet. However, based on the pattern of other analytes, it would likely be similar (e.g., 50+ pairs).
• Method Comparison (In-House vs. POL Sites):
  • ALP: 49-50 samples per site.
  • Amylase: 51 samples per site.
  • ALT: 44-49 samples per site.
  • AST: 50 samples per site.
• Linearity: Not explicitly stated as an "n" for samples, but rather as "low level tested," "upper level tested," and "linear to" values, which typically involve preparing a dilution series from a high concentration sample.
• Data Provenance: The studies are labeled "In-House" and "POL" (Point of Care). This suggests:
  • Country of Origin: Likely the USA, given the FDA 510(k) submission.
  • Retrospective or Prospective: These types of performance studies for IVDs are typically prospective, with samples analyzed specifically for the study. The method comparison data often uses a mix of native patient samples and spiked samples to cover the measuring range.

3. Number of Experts Used to Establish Ground Truth and Their Qualifications

This document describes the performance of IVD reagents on clinical chemistry systems. The "ground truth" here is not subjective, human interpretation (like in imaging AI), but rather the quantitative measurement of analytes.

• Number of Experts: Not applicable in the context of IVD reagent performance. The "ground truth" is established by the analytical method itself, or by comparison to a recognized reference method or a legally marketed predicate device.
• Qualifications of Experts: Not applicable. The "experts" would be qualified laboratory professionals operating the instruments and performing the biochemical assays according to established protocols.

4. Adjudication Method for the Test Set

Not applicable. As described above, the "truth" for these quantitative measurements is derived directly from the biochemical reactions and instrument readings, not subjective human judgment requiring adjudication. The predicate device's established performance serves as a comparative benchmark.

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

No. This is a submission for in vitro diagnostic reagents, not an AI-assisted diagnostic device that involves human readers interpreting images or complex data. Therefore, an MRMC study is not relevant.

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

Yes, in essence, the performance data presented is "standalone" in the context of the device's function. The ACE reagents, when used on the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems, operate as an automated system to quantify the target analytes. The performance metrics (precision, linearity, method comparison, interferences) reflect the intrinsic analytical performance of the regent-analyzer combination without human intervention influencing the measurement itself. Human operators are involved in sample loading, quality control, and result review, but not in directly influencing the quantitative output in a way that would require a human-in-the-loop comparison for algorithm performance.

7. The Type of Ground Truth Used

The "ground truth" in this context is established by:

• Comparison to Predicate Devices: The primary method is demonstrating substantial equivalence to previously cleared devices (K113253, K931786, K930104, K113436, K113382). This means the new reagents provide results that are analytically comparable to those already accepted by the FDA.
• Expected Analytical Performance: Meeting industry-standard requirements for precision (low CV%), accuracy (linearity, inter-instrument/site agreement via regression analysis), and specificity (minimal interference).
• Expected Values/Ranges: The devices are expected to produce results that align with established "expected values" for healthy individuals.

8. The Sample Size for the Training Set

Not applicable. These are chemical reagents for quantitative diagnostic tests, not machine learning algorithms that require a "training set" in the conventional sense. The "training" for such systems involves analytical validation experiments to define reagent stability, reaction kinetics, and instrument parameters.

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

Not applicable for the same reason as point 8. The "ground truth" for developing and validating these reagents is based on fundamental principles of analytical chemistry, biochemical reactions, and extensive internal testing to ensure the reagents perform as intended within the specified analytical parameters.

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The ACE y-GT Reagent is intended for the quantitative determination of gamma-glutamyltransferase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Gamma-glutamyltransferase measurements are used in the diagnosis and treatment of liver diseases such as alcoholic cirrhosis and primary and secondary liver tumors. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE Lipase Reagent is intended for the quantitative determination of lipase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Lipase measurements are used in diagnosis and treatment of diseases of the pancreas such as acute pancreatitis and obstruction of the pancreatic duct. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE T4 Reagent is intended for the quantitative determination of total thyroxine (T4) in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Total thyroxine measurements are used in the diagnosis and treatment of thyroid diseases. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

In the ACE γ-GT Reagent assay, γ-GT in serum or heparin plasma catalyzes the transfer of the γ-glutamyl group from L-γ-glutamyl-3-carboxy-4-nitroanilide to glycylglycine in the reagent. The product, 5-amino-2-nitrobenzoate, absorbs strongly at 408 nm. The rate of increase in absorbance, monitored bichromatically at 408 nm/486 nm, is directly proportional to the γ-GT activity in the sample.

In the ACE Lipase Reagent Assay, lipase in serum or heparin plasma acts on a natural substrate, 1,2-diglyceride, to liberate 2-monoglyceride. This is hydrolyzed by monoglyceride lipase (a highly specific enzyme for monoglyceride) into glycerol and free fatty acid. Glycerol kinase acts on glycerol to form glycerol-3-phosphate, which is in turn acted on by glycerol-3-phosphate oxidase to generate hydrogen peroxide. Peroxidase converts the hydrogen peroxide, 4-Aminoantipyrine and TOOS (N-ethyl-N-(2-hydroxy-3-sulfopropyl)-m-toluidine) into a quinine dye. The rate of formation of the dye, determined bichromatically at an absorbance of 573 nm/692 nm, is proportional to the lipase activity in the sample.

The ACE T4 Assay is a homogeneous enzyme immunoassay using ready-to-use liquid ACE T4 Reagent. The assay uses 8-anilino-1-naphthalene sulfonic acid (ANS) to dissociate thyroxine from the plasma binding proteins. Using specific antibodies to thyroxine, this assay is based on the competition of glucose-6-phosphate dehydrogenase (G6PD) labeled thyroxine and the dissociated thyroxine in the sample for a fixed amount of specific antibody binding sites. In the absence of thyroxine from the sample, the thyroxine labeled G6PD in the second reagent is bound by the specific antibody in the first reagent, inhibiting the enzyme's activity. The enzyme G6PD catalyzes the oxidation of glucose-6-phosphate (G6P) with nicotinamide adenine dinucleotide (NADT) to form 6-phosphogluconate and reduced nicotinamide adenine dinucleotide (NADH). NADH strongly absorbs at 340 nm whereas NAD does not. The rate of conversion, determined by measuring the increase in absorbance bichromatically at 340 nm/505 nm during a fixed time interval, is directly proportional to the amount of thyroxine in the sample. The concentration of thyroxine is determined automatically by the ACE Clinical Chemistry Systems using a logarithmic calibration curve established with calibrators, which are provided separately.

The information provided describes the performance of the ACE γ-GT, ACE Lipase, and ACE T4 Reagents on the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. This is not an AI/ML device, however, I will address the other requested points to the best of my ability with the provided text.

Here's a breakdown of the acceptance criteria and study information, where applicable:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in a separate table. However, it provides performance data for precision, matrix comparison (serum vs. plasma), detection limits, linearity, and interference. Based on the "Conclusions" section, the goal was to demonstrate "substantial equivalence" of the reagents for lithium heparin plasma samples (compared to serum) and the ACE Alera System (compared to the predicate ACE Clinical Chemistry System). The performance data presented are implicitly intended to support this substantial equivalence.

Implied Acceptance Criteria (based on predicate comparison and performance data) and Reported Performance:

For POL Precision: Similar acceptable %CV values for low, mid, and high samples across different POL sites and in-house, on ACE and ACE Alera systems. | In-House Precision (Serum vs. Plasma):

• γ-GT: Total %CV generally 0.997, Slope 0.960-0.987, Intercept 1.5-4.0 across systems.
  Lipase: Correlation > 0.994, Slope 0.980-1.024, Intercept -2.5 to -0.9 across systems (for ACE and ACE Alera, Axcel missing intercept CI).
  T4: Correlation > 0.984, Slope 0.963-1.007, Intercept 0.01-0.35 across systems. |
  | Method Comparison (POL) | When comparing results from POL sites to in-house results on the same instrument, correlation coefficients should be high (close to 1), slopes close to 1, and with small intercepts, indicating consistency across testing locations. | ACE System:
• γ-GT: Correlation > 0.9997, Slope 0.964-0.976, Intercept -2.7 to 0.7.
• Lipase: Correlation > 0.9966, Slope 0.994-1.031, Intercept -5.3 to 0.0.
• T4: Correlation > 0.9908, Slope 1.010-1.019, Intercept -0.09 to -0.04.

ACE Alera System:

• γ-GT: Correlation > 0.9996, Slope 0.950-1.028, Intercept 1.9 to 2.9.
• Lipase: Correlation > 0.9960, Slope 0.992-1.028, Intercept -3.5 to 3.3.
• T4: Correlation > 0.9868, Slope 1.022-1.048, Intercept -0.31 to -0.10. |
  | Detection Limits (ACE Alera) | Limits of Blank (LOB), Detection (LOD), and Quantitation (LOQ) should be clinically acceptable. | γ-GT: LOB 3 U/L, LOD 5 U/L, LOQ 7 U/L.
  Lipase: LOB 7 U/L, LOD 11 U/L, LOQ 13 U/L.
  T4: LOB 0.3 µg/dL, LOD 0.8 µg/dL, LOQ 1.3 µg/dL. |
  | Linearity (ACE Alera) | The assay should be linear up to the stated measuring range, with a linear regression equation demonstrating good fit. | γ-GT: Linear to 950 U/L ($y = 1.036x + 0.8$).
  Lipase: Linear to 700 U/L ($y = 0.971x + 0.2$).
  T4: Linear to 19.6 µg/dL ($y = 1.057x - 0.09$). |
  | Interferences (ACE Alera) | No significant interference from common exogenous or endogenous substances at physiologically relevant or elevated concentrations. | γ-GT: No significant interference at or below Icterus 14.2 mg/dL, Hemolysis 125 mg/dL, Lipemia 500 mg/dL, Ascorbic Acid 6 mg/dL.
  Lipase: No significant interference below Icterus 12.5 mg/dL, Hemolysis 1000 mg/dL, Lipemia 803 mg/dL, Ascorbic Acid 6 mg/dL.
  T4: No significant interference below Icterus 47.2 mg/dL, Hemolysis 1000 mg/dL, Lipemia 1000 mg/dL, Ascorbic Acid 6 mg/dL.
  Heterophile (T4): HAMA 800 ng/mL, RF 516 IU/mL.
  Cross-Reactivity (T4): 3,3',5,5'- Tetraiodothyroacetic Acid (18.4%), L-Thyroxine (91.6%), D-Thyroxine (68.0%) at 5 µg/dL. |

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

The document does not explicitly use the term "test set" in the context of AI/ML, but rather describes clinical performance studies. The sample sizes for these studies are as follows:

• In-House Matrix Comparison (Serum vs. Plasma):
  • ACE γ-GT Reagent: 100 pairs (ACE), 97 pairs (ACE Alera), 53 pairs (ACE Axcel)
  • ACE Lipase Reagent: 42 pairs (ACE), 43 pairs (ACE Alera), 62 pairs (ACE Axcel)
  • ACE T4 Reagent: 55 pairs (ACE), 55 pairs (ACE Alera), 55 pairs (ACE Axcel)
• Method Comparison (POL vs. In-House):
  • ACE System: 50-54 samples per reagent per POL site (3 POL sites)
  • ACE Alera System: 48-51 samples per reagent per POL site (3 POL sites)
• Precision (In-House and POL): The number of replicates per sample level (Low, Mid, High) is not explicitly stated, but precision studies typically involve multiple runs over several days.
• Detection Limits, Linearity, Interferences, Cross-Reactivity: Sample sizes for these specific experiments are not detailed but are generally conducted with a sufficient number of replicates and concentrations to statistically establish the parameters.

Data Provenance: The studies are described as "In-House" and "POL" (Physician Office Laboratory) studies. This indicates that the data was collected at the manufacturer's facility ("In-House") and potentially at various POL sites. The country of origin is not explicitly stated, but given the 510(k) submission to the FDA, it is likely the studies align with US regulatory requirements and are potentially from US-based labs. The studies are prospective in nature, as they involve newly generated data to demonstrate the performance of the devices.

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

This section is not applicable as the device is a clinical chemistry reagent and not an AI/ML device that generates interpretations requiring expert ground truth for image or diagnostic data. The "ground truth" in this context refers to the measured analyte concentrations obtained from established laboratory methods, calibrators, and reference materials.

4. Adjudication Method for the Test Set

This section is not applicable as the device is a clinical chemistry reagent. Adjudication methods like 2+1 or 3+1 are used in contexts like human reader studies for diagnostic imaging, where discordant interpretations need resolution by additional experts.

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

This section is not applicable as the device is a clinical chemistry reagent. MRMC studies are designed to assess the performance of diagnostic devices or AI algorithms by multiple human readers across multiple cases, especially in imaging.

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

This section is not applicable as the device is a clinical chemistry reagent. This term is relevant for AI/ML diagnostic tools. The "performance" of this device is inherently standalone in that the instrument processes samples and generates quantitative results without human intervention in the measurement process itself, beyond sample loading and general operation.

7. The Type of Ground Truth Used

The "ground truth" for the performance studies presented is based on quantitative chemical measurements of the specific analytes (gamma-glutamyltransferase, lipase, total thyroxine) in control materials, patient samples, and comparison with established reference methods or predicate devices. This includes:

• Known concentrations: For precision, linearity, detection limits, and interference studies, samples with known or spiked concentrations are used.
• Comparison to predicate device: For method comparison studies, the results from the new device/system are compared against the results from the legally marketed predicate device/system.
• Reference materials/calibrators: The accuracy and calibration of the assays depend on traceable reference materials and calibrators.

8. The Sample Size for the Training Set

This section is not applicable as the device is a clinical chemistry reagent and not an AI/ML device. There is no "training set" in the context of machine learning model development.

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

This section is not applicable for the same reasons as #8.

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The ACE BUN/Urea Reagent is intended for the quantitative determination of blood urea nitrogen (BUN) concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. BUN measurements are used in the diagnosis and treatment of certain renal and metabolic diseases. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Creatinine Reagent is intended for the quantitative determination of creatinine concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Creatinine measurements are used in the diagnosis and treatment of renal diseases, in monitoring renal dialysis, and as a calculation basis for measuring other urine analytes. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Uric Acid Reagent is intended for the quantitative determination of uric acid concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Uric acid measurements are used in the diagnosis and treatment of numerous renal and metabolic disorders, including renal failure, gout, leukemia, psoriasis, starvation or other wasting conditions and of patients receiving cytotoxic drugs. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE CK Reagent is intended for the quantitative determination of creatine kinase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Measurement of creatine kinase is used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

In the ACE BUN/Urea Reagent assay, urea in serum is hydrolyzed in the presence of urease to yield ammonia and carbon dioxide. The ammonia formed then reacts in the presence of glutamate dehydrogenase with 2-oxoglutarate and NADH to yield glutamate and NAD. NADH absorbs strongly at 340 nm, whereas NAD+ does not. The initial rate of decrease in absorbance, monitored bichromatically at 340 nm/647 nm, is proportional to the urea concentration in the sample.

In the ACE Creatinine Reagent assay, creatinine reacts with picric acid in an alkaline medium to form a red-orange colored complex, which absorbs strongly at 505 nm. The rate of complex formation, determined by measuring the increase in absorbance bichromatically at 505 nm/573 nm during a fixed time interval, is directly proportional to the creatinine concentration in the sample.

In the ACE Uric Acid Reagent assay, uric acid in serum is oxidized by uricase to allantoin and hydrogen peroxide. The hydrogen peroxide then acts to oxidatively couple dichlorohydroxybenzene sulfonic acid and 4-aminoantipyrine in a reaction catalyzed by peroxidase, producing a red colored quinoneimine complex, which absorbs strongly at 505 nm. The amount of chromogen formed is determined by measuring the increase in absorbance bichromatically at 505 nm/610 nm, and is directly proportional to the uric acid concentration in the sample.

In the ACE CK Reagent assay, serum creatine kinase initiates the conversion of creatine phosphate to creatine with the transfer of a phosphate group to adenosine diphosphate (ADP), forming ATP. The ATP is then used in the phosphorylation of D-glucose to form D-glucose-6-phosphate and ADP. This reaction is catalyzed by hexokinase. The enzyme glucose-6-phosphate dehydrogenase catalyzes the reduction of D-glucose-6-phosphate and nicotinamide adenine dinucleotide phosphate (NADP+). The series of reactions triggered by serum creatine kinase and ending in the formation of NADPH. NADPH strongly absorbs at 340 nm, whereas NADP+ does not. Therefore, the rate of conversion of NADP+ to NADPH can be determined by monitoring the increase in absorbance bichromatically at 340 nm/378 nm. This rate of conversion from NADP+ to NADPH is a function of the activity of CK in the sample.

Here's a summary of the acceptance criteria and supporting studies for the Alfa Wassermann ACE Reagents (BUN/Urea, Creatinine, Uric Acid, CK), based on the provided 510(k) summary.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly derived from comparisons to a predicate device (Alfa Wassermann ACE K930104 reagents) and performance characteristics such as precision, accuracy (correlation/regression with predicate), linearity, detection limits, and interference. The reported device performance is from in-house studies and Point-of-Care (POL) studies.

Note: The document does not explicitly state "acceptance criteria" numerical targets. Instead, it presents performance data for the candidate device, implying that the data's comparability to the predicate and established analytical standards is the basis for acceptance. I will present the reported performance, which demonstrates the device's meeting the necessary equivalency.

Studies Proving Acceptance Criteria:

The studies are described under "Performance Data" and "Device Comparison with Predicate" sections of the 510(k) summary. These studies aim to demonstrate substantial equivalence to the previously cleared predicate device (Alfa Wassermann ACE BUN/Urea Reagent, ACE Creatinine Reagent, ACE Uric Acid Reagent, and ACE CK Reagents, K930104).

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

• Test Set (Matrix Comparison: Serum vs. Plasma):

  • BUN: 95 pairs (ACE), 96 pairs (Alera), 51 pairs (Axcel)
  • Creatinine: 102 pairs (ACE), 102 pairs (Alera), 55 pairs (Axcel)
  • Uric Acid: 97 pairs (ACE), 95 pairs (Alera), 55 pairs (Axcel)
  • CK: 94 pairs (ACE), 96 pairs (Alera), 55 pairs (Axcel)
  • Data Provenance: The document states "In-House Precision" and "In-House Matrix Comparison". This typically implies that the data was generated within the manufacturer's laboratory or a testing facility under their control. The country of origin is not explicitly stated but is implicitly the US, given the 510(k) submission to the FDA. The data is retrospective, as it's being used to characterize reagent performance.

• Test Set (POL - Method Comparison):

  • BUN: 53-54 samples per POL lab for comparison with In-House ACE.
  • Creatinine: 51 samples per POL lab for comparison with In-House ACE.
  • Uric Acid: 49 samples per POL lab for comparison with In-House ACE.
  • Creatinine Kinase: 48-50 samples per POL lab for comparison with In-House ACE.
  • Data Provenance: "POL - Method Comparison" indicates data from Physician Office Laboratories (POLs), likely external to the main testing facility but still considered part of the overall validation. The document refers to "In-House ACE (x) vs. POL 1 ACE (y)", "POL 2 ACE (y)", etc., indicating comparisons against internal reference methods. The data is retrospective.

• Test Set (Detection Limits, Linearity, Interferences, Alera Precision): The sample sizes for these specific studies are not explicitly detailed in the provided summary beyond "Low level tested," "Upper level tested," and "number of replicates for precision measurements (i.e. '3.2, 4.0%') implies multiple measurements. These are likely in-house, retrospective studies.

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

This information is not provided in the document. For in vitro diagnostic devices like these reagents, the "ground truth" is typically established by reference methods or validated comparative methods, often run on established clinical chemistry analyzers. The expertise lies in operating these reference instruments and ensuring proper laboratory practices, rather than expert interpretation of images or clinical cases.

4. Adjudication Method for the Test Set

This concept is not applicable to this type of device. Adjudication methods (like 2+1, 3+1) are common in studies involving subjective interpretations (e.g., medical image analysis by radiologists) where discrepancies among readers need to be resolved to establish ground truth. For quantitative IVD reagents, the reference method provides a direct numerical result, not a subjective interpretation requiring adjudication.

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

This is not applicable to this type of device. MRMC studies are used to assess the effectiveness of an AI system (or any diagnostic aid) for human readers, particularly in medical imaging. The current device is a diagnostic reagent, which directly measures chemical concentrations, not an AI intended to assist human interpretation of cases.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

This is not applicable in the context of an IVD reagent. The "algorithm" here is the chemical reaction and photometric measurement itself. The performance data presented (precision, linearity, method comparison, etc.) is the standalone performance of the reagent on the specified analyzers, without human interpretive input altering the result.

7. Type of Ground Truth Used

The ground truth for all performance studies (precision, matrix comparison, method comparison, linearity) is established by comparison against a reference method or a substantially equivalent predicate method performed on existing, validated clinical chemistry analyzers (specifically, the predicate ACE Clinical Chemistry System and the candidate ACE, ACE Alera, and ACE Axcel systems themselves acting as the "reference" for their own performance claims, and for method comparisons, the "In-House ACE" results). This is a common and accepted approach for demonstrating substantial equivalence for IVD reagents.

8. Sample Size for the Training Set

This information is not provided and is generally not applicable in the way it is asked for AI/ML devices. These are chemical reagents, not AI/ML algorithms that require "training sets" in the conventional sense of machine learning. The development process would involve formulation, optimization, and internal testing to define assay parameters, which is a different concept than an AI training set.

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

As stated above, the concept of a "training set" with established ground truth in the AI/ML sense is not applicable to these chemical reagents. The "ground truth" during their development and optimization would be based on established analytical chemistry principles and performance measurements against known standards or reference materials.

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The ACE Carbon Dioxide (CO2-LC) Reagent is intended for the quantitative determination of carbon dioxide concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Bicarbonate/carbon dioxide measurements are used in the diagnosis and treatment of numerous potentially serious disorders associated with changes in body acid-base balance. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Direct Bilirubin Reagent is intended for the quantitative determination of direct bilirubin concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Measurements of the levels of bilirubin, an organic compound formed during the normal and abnormal destruction of red blood cells, is used in the diagnosis and treatment of liver, hemolytic, hematological and metabolic disorders, including hepatitis and gall bladder block. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Total Bilirubin Reagent is intended for the quantitative determination of total bilirubin concentration in serum and lithium heparin plasma using the ACE, ACE Alera and ACE Axcel Clinical Chemistry System. Measurements of the levels of bilirubin, an organic compound formed during the normal and abnormal destruction of red blood cells, is used in the diagnosis and treatment of liver, hemolytic, hematological and metabolic disorders, including hepatitis and gall bladder block. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Magnesium Reagent is intended for the quantitative determination of magnesium in serum and lithium heparin plasma using the ACE, ACE Alera and ACE Axcel Clinical Chemistry Systems. Magnesium measurements are used in the diagnosis and treatment of hypomagnesemia (abnormally low plasma levels of magnesium) and hypermagnesemia (abnormally high plasma levels of magnesium). This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

In the ACE Carbon Dioxide (CO2-LC) Reagent assay, serum carbon dioxide (in the form of bicarbonate) reacts with phosphoenolpyruvate in the presence of phosphoenolpyruvate carboxylase and magnesium to yield oxaloacetic acid and phosphate. In the presence of malate dehydrogenase, the reduced cofactor is oxidized by oxaloacetic acid. The reduced cofactor absorbs strongly at 408 nm whereas its oxidized form does not. The rate of decrease in absorbance, monitored bichromatically at 408 nm/692 nm, is proportional to the carbon dioxide content of the sample.

In the ACE Direct Bilirubin Reagent assay, sodium nitrite added to sulfanilic acid forms diazotized sulfanilic acid. Bilirubin glucuronide in serum reacts with diazotized sulfanilic acid to form azobilirubin, which absorbs strongly at 554 nm. The increase in absorbance, measured bichromatically at 554 nm/692 nm, one minute after sample addition, is directly proportional to the direct bilirubin concentration.

In the ACE Total Bilirubin Reagent assay, sodium nitrite, when added to sulfanilic acid, forms diazotized sulfanilic acid. Bilirubin in serum reacts with diazotized sulfanilic acid to form azobilirubin, which absorbs strongly at 554 nm. The inclusion of dimethyl sulfoxide (DMSO) in the reagent as an accelerator causes both direct and indirect bilirubin to react rapidly. The increase in absorbance, measured bichromatically at 554 nm/692 nm, is directly proportional to the total bilirubin concentration in the sample.

Magnesium ions in serum react with Xylidyl blue-1 in an alkaline medium to produce a red complex which is measured bichromatically at 525 nm/692 nm. The intensity of color produced is directly proportional to the magnesium concentration in the sample. EGTA prevents calcium interference by preferential chelation of calcium present in the sample. A surfactant system is included to remove protein interference.

The provided text describes several in vitro diagnostic reagents (ACE Carbon Dioxide (CO2-LC) Reagent, ACE Direct Bilirubin Reagent, ACE Total Bilirubin Reagent, and ACE Magnesium Reagent) and their associated performance data. There isn't information about an AI-powered device or software. Therefore, questions related to AI aspects like multi-reader multi-case studies, effect size of AI assistance, or standalone algorithm performance are not applicable.

The acceptance criteria are not explicitly stated as clear thresholds in the provided document; rather, the document presents detailed performance data (precision, linearity, interference, and method comparison) that demonstrates the device's capability to perform as intended and to be substantially equivalent to its predicate devices. The "reported device performance" is presented directly through tables and statistical analyses for each reagent.

Here's an attempt to structure the available information based on the request, interpreting "acceptance criteria" as the performance demonstrated to support substantial equivalence:

1. Table of Acceptance Criteria and Reported Device Performance

Since explicit "acceptance criteria" (i.e., predefined thresholds for performance metrics) are not provided in the document, the "Reported Device Performance" below represents the data presented that presumably met the internal criteria for demonstrating substantial equivalence. The document primarily focuses on precision, linearity, interference, and method comparison with predicate devices and between different systems (ACE, ACE Alera, ACE Axcel).

ACE Carbon Dioxide (CO2-LC) Reagent

ACE Direct Bilirubin Reagent

ACE Total Bilirubin Reagent

ACE Magnesium Reagent

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

The document describes several types of studies:

• In-House Precision:

  • CO2-LC: Low, Mid, High serum and plasma samples were tested (number of replicates per sample and runs is implicitly part of SD/CV calculation, but not explicitly stated).
  • Direct Bilirubin: Low, Mid, High serum and plasma samples.
  • Total Bilirubin: Low, Mid, High serum and plasma samples.
  • Magnesium: Low, Mid, High serum and plasma samples.
  • Data Provenance: In-house (Alfa Wassermann Diagnostic Technologies, LLC, West Caldwell, NJ), prospective testing.

• POL (Physician Office Laboratory) Precision: Studies conducted at 3 POL sites.

  • CO2-LC: 3 samples at each of 3 POL sites and in-house.
  • Direct Bilirubin: 3 samples at each of 3 POL sites and in-house.
  • Total Bilirubin: 3 samples at each of 3 POL sites and in-house.
  • Magnesium: 3 samples at each of 3 POL sites and in-house.
  • Data Provenance: Not explicitly stated but inferred to be from POLs in the USA (prospective testing under typical POL conditions).

• In-House Matrix Comparison (Serum vs. Plasma):

  • CO2-LC: 53-54 pairs (serum/plasma) on ACE and ACE Alera; 51 pairs on ACE Axcel.
  • Direct Bilirubin: 102 pairs on ACE; 101 pairs on ACE Alera; 56 pairs on ACE Axcel.
  • Total Bilirubin: 102 pairs on ACE and ACE Alera; 56 pairs on ACE Axcel.
  • Magnesium: 101 pairs on ACE and ACE Alera; 55 pairs on ACE Axcel.
  • Data Provenance: In-house, retrospective (presumably collected for a range of values).

• POL Method Comparison (In-House ACE vs. POL ACE/Alera):

  • CO2-LC: 45-46 samples per POL site comparison.
  • Direct Bilirubin: 49-51 samples per POL site comparison.
  • Total Bilirubin: 48-50 samples per POL site comparison.
  • Magnesium: 50-52 samples per POL site comparison.
  • Data Provenance: Not explicitly stated but inferred to be from POLs in the USA (prospective testing under typical POL conditions) compared against in-house data.

• Detection Limits (LoB, LoD, LoQ), Linearity, Interferences (ACE Alera):

  • Sample sizes for detection limits and linearity: Not explicitly stated, typically involves multiple replicates at various concentrations.
  • Sample sizes for interferences: Not explicitly stated, typically involves samples spiked with various concentrations of interferents.
  • Data Provenance: In-house.

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

This information is not provided in the document. For in vitro diagnostic assays, the "ground truth" is typically the reference method or established clinical laboratory results obtained from a highly accurate and calibrated instrument or laboratory using validated methods, rather than human expert consensus for image or clinical interpretation. The document compares performance against other (presumably established) methods and predicate devices.

4. Adjudication Method for the Test Set

This concept (e.g., 2+1, 3+1 for resolving discrepancies) is not applicable to these types of in vitro diagnostic device studies. Performance is measured numerically and objectively.

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

No. This is an in vitro diagnostic assay, not an AI-powered diagnostic imaging device.

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

Not applicable. This is not an AI algorithm. The performance data presented are for the reagent and instrument system.

7. The Type of Ground Truth Used

For precision studies, the "ground truth" is the true concentration of the analyte in the control material or patient sample, which is established by reference methods or manufacturing specifications of the control materials. For method comparison studies, the predicate device's results or an established in-house method are used as the comparative reference. The document states the intended use is for "quantitative determination" of analytes, implying comparison to a quantitative gold standard.

8. The Sample Size for the Training Set

Not applicable. This is not a machine learning device and therefore does not have a "training set" in that context. The development of reagents and the establishment of their performance characteristics do not involve machine learning training sets.

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

Not applicable, as there is no "training set" for these reagents in the context of AI/ML.

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The ACE Alera Clinical Chemistry System is an automated, discrete, bench-top, random access analyzer that is intended for in vitro diagnostic use in the quantitative measurement of general chemistry assays, such as glucose, sodium, potassium, and chloride, for clinical use in physician office laboratories or clinical laboratories. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma. Sodium measurements are used in the diagnosis and treatment of diseases involving electrolyte imbalance. Potassium measurements are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels. Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such as cystic fibrosis and diabetic acidosis.

ACE Glucose Reagent is intended for the quantitative determination of glucose in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE Ion Selective Electrode (ISE) module on the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems is used to measure concentrations of sodium, potassium, and chloride in undiluted serum and lithium heparin plasma. Sodium measurements are used in the diagnosis and treatment of diseases involving electrolyte imbalance. Potassium measurements are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels. Chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such as cystic fibrosis and diabetic acidosis. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE Alera Clinical Chemistry System is an automated, discrete, bench-top, random access analyzer that is intended for in vitro diagnostic use in the quantitative determination of general chemistry assays for clinical use in physician office laboratories or clinical laboratories. The ACE Alera Clinical Chemistry System consists of a bench-top analyzer and an internal computer. The bench-top analyzer includes a single pipettor (syringe module/fluid arm/probe), a temperature-controlled reagent compartment, a reaction wheel and a holographic diffraction grating spectrophotometer.

In the ACE Glucose Reagent assay, glucose in serum or heparin plasma reacts with adenosine triphosphate in the presence of hexokinase and magnesium with the formation of glucose-6-phosphate and adenosine diphosphate. Glucose-6-phosphate dehydrogenase catalyzes the oxidation of glucose-6-phosphate with NAD+ to form 6-phosphogluconate and NADH. NADH absorbs strongly at 340 nm, whereas NAD+ does not. The total amount of NADH formed is proportional to the concentration of glucose in the sample. The increase in absorbance is measured bichromatically at 340 nm/378 nm.

The ACE Ion Selective Electrode (ISE) Module, as part of the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems, uses a potentiometric method via ion-specific electrodes to simultaneously measure sodium, potassium and chloride in undiluted serum. Ion-specific membranes measure the difference in ionic concentrations between an inner electrolyte solution and the sample. The connection of the amplifier and ground (reference electrode) to the ion selective electrode forms the measuring system. A two-point calibration utilizes ACE CAL A and CAL B undiluted ISE Calibration Solutions with precisely known ion concentrations. The measured voltage difference of the sample and the CAL A and CAL B solutions determines the ion concentration in the sample on the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems.

The device is the ACE Alera Clinical Chemistry System, ACE Glucose Reagent, and ACE Ion Selective Electrode (ISE) Module. The study assesses the performance of these components, focusing on the quantitative measurement of glucose, sodium, potassium, and chloride.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical targets that the device must meet in a formal, quantifiable way (e.g., "Accuracy must be > 95%"). Instead, the study aims to demonstrate substantial equivalence to predicate devices, showing that the performance of the ACE Alera system is comparable to established systems. The performance data presented focuses on precision (reproducibility) and method comparison with existing devices.

Since specific numerical acceptance criteria were not listed, one reasonable interpretation for implied acceptance criteria for laboratory diagnostic devices typically includes:

• Acceptable Precision: Coefficients of Variation (CV) or Standard Deviations (SD) for within-run and total precision across different concentration levels should be within generally accepted laboratory limits for each analyte. For clinical chemistry, these are often defined considering medical usefulness.
• Acceptable Method Agreement: Linear regression analysis (slope, intercept, correlation coefficient) and standard error between the new device and a reference method (or predicate device) should indicate good agreement. Slopes close to 1, intercepts close to 0, and high correlation coefficients (e.g., >0.975) are generally desired.
• No Significant Interference: The device should not be significantly affected by common interfering substances (icterus, hemolysis, lipemia, ascorbic acid) at clinically relevant levels.

Here's the performance data as reported, which serves as the evidence that these implicit acceptance criteria are met:

The study essentially acts as a validation against these implied criteria, demonstrating that the ACE Alera system's performance is acceptable for its intended use, comparable to the predicate devices.

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

• Precision Studies: The document does not explicitly state the number of individual sample replicates for the core (non-POL) precision studies. However, for the POL Precision studies, for each analyte (Glucose, Sodium, Potassium, Chloride), there were 3 samples tested in each of 4 labs (In-House and 3 POLs). The tables show means, within-run, and total standard deviations/CVs, which typically imply multiple replicates per sample (e.g., 20 or more replicates are common in such studies).
• Method Comparison Studies:
  • Glucose: n = 46 samples for each of the three POL comparisons.
  • Sodium: n = 42 samples for each of the three POL comparisons.
  • Potassium: n = 43 samples for each of the three POL comparisons.
  • Chloride: n = 41 samples for each of the three POL comparisons.
• Data Provenance: The method comparison data is identified as "(2012 Data)" and collected from an "In-House" lab comparing against "ACE Alera system POL" data from three different Physician Office Laboratories (POLs 1, 2, 3), suggesting multi-center evaluation within the United States. The data is retrospective in the sense that it's reported for a 510(k) submission, but the studies themselves would have been conducted prospectively as a part of the device validation. The term "POL" indicates that these are real-world, clinical laboratory settings.

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

There were no human experts establishing ground truth in the context of interpretation for these types of in vitro diagnostic devices. The "ground truth" or reference values for chemical assays like glucose, sodium, potassium, and chloride are established by:

• Reference Methods: Often, a more established or gold-standard laboratory analyzer (in this case, the predicate ACE system in the In-House lab) is used to generate the "reference" values for comparison.
• Certified Reference Materials: Calibrators and controls with precisely known concentrations are used to calibrate and verify the accuracy of the instruments.

The qualifications of personnel operating these instruments are typically trained medical technologists or clinical laboratory scientists, but they do not establish "ground truth" in the way an expert radiologist might interpret an image.

4. Adjudication Method for the Test Set

Not applicable for this type of in vitro diagnostic device study. Adjudication methods (like 2+1, 3+1 consensus) are used for subjective interpretations, such as medical image analysis, where human experts might disagree. For quantitative chemical measurements, the comparison is directly between numerical results from different instruments.

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 quantitative chemical analysis, not an AI-assisted diagnostic tool that involves human interpretation of "cases" or "reads" in the way an MRMC study would evaluate.

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

Yes, the studies presented are essentially standalone performance evaluations of the ACE Alera Clinical Chemistry System, the ACE Glucose Reagent, and the ACE Ion Selective Electrode (ISE) Module. The tables show the performance characteristics (precision, method comparison, interference) of the device itself in generating quantitative results. Human involvement is limited to operating the instrument, performing quality control, and routine maintenance, not subjective interpretation of results. The output (e.g., glucose concentration) is a direct numerical value from the instrument.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The ground truth for the test set (the samples used in the method comparison studies) was established by comparison against a legally marketed predicate device, the Alfa Wassermann ACE system (specifically the ACE plus ISE/Clinical Chemistry System, K930140, K933862), effectively treating the predicate device's measurements as the reference standard. This is a common approach for demonstrating substantial equivalence for new IVD devices.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of a machine learning algorithm. For clinical chemistry analyzers, the "training" analogous to machine learning would be:

• Instrument Calibration: The device is calibrated using commercially available calibrator solutions with known concentrations. The specific number of calibration points is not detailed but is typically specified by the manufacturer.
• Reagent Development and Optimization: The reagents themselves (like ACE Glucose Reagent) undergo extensive development and optimization, which involves testing on numerous samples to establish their performance characteristics (e.g., linearity, stability, interference). The exact sample sizes used during this development are not provided in this regulatory summary.

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

As above, for an IVD analyzer, the "ground truth" for calibration or reagent development typically relies on:

• Certified Reference Materials: These are materials with highly accurate and traceable analyte concentrations, used to set the instrument's measurement scale.
• Validated Reference Methods: Established laboratory methods, often more complex or time-consuming, that are known to be highly accurate and precise for measuring the analyte.

The document implies that the ground truth for comparison samples was the predicate ACE system, and it is reasonable to assume that the calibration and internal controls for the ACE Alera system would rely on industry-standard reference materials and methods to establish accurate known values.

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The ACE Cholesterol Reagent is intended for the quantitative determination of cholesterol concentration in serum and lithium heparin plasma using the ACE Axcel Clinical Chemistry System. Cholesterol measurements are used in the diagnosis and treatment of disorders involving excess cholesterol in the blood and lipid and lipoprotein metabolism disorders. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE HDL-C Reagent is intended for the quantitative determination of high density lipoprotein cholesterol (HDL-C) concentration in serum and lithium heparin plasma using the ACE Axcel Clinical Chemistry System. Lipoprotein measurements are used in the diagnosis and treatment of lipid disorders (such as diabetes mellitus), atherosclerosis, and various liver and renal diseases. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE LDL-C Reagent is intended for the quantitative determination of low density lipoprotein cholesterol (LDL-C) concentration in serum and lithium heparin plasma using the ACE Axcel Clinical Chemistry System. Lipoprotein measurements are used in the diagnosis and treatment of lipid disorders (such as diabetes mellitus), atherosclerosis, and various liver and renal diseases. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Triglycerides Reagent is intended for the quantitative determination of triglyceride concentration in serum and lithium heparin plasma using the ACE Axcel Clinical Chemistry System. Triglyceride measurements are used in the diagnosis and treatment of patients with diabetes mellitus, nephrosis, liver obstruction, other diseases involving lipid metabolism or various endocrine disorders. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Cholesterol Reagent is composed of a single reagent bottle. The reagent contains 4-aminoantipyrine, p-hydroxybenzoic acid, cholesterol oxidase, cholesterol esterase and peroxidase.

The HDL-C Reagent assay utilizes two reagent bottles, the second containing a unique detergent. This detergent solubilizes only the HDL lipoprotein particles, thus releasing HDL cholesterol to react with the cholesterol esterase and cholesterol oxidase, in the presence of a chromogen to produce color. The detergent also inhibits the reaction of the cholesterol enzymes with LDL, VLDL and chylomicron lipoproteins by adsorbing to their surfaces. The amount of chromogen formed, determined by measuring the increase in absorbance bichromatically at 592/692 nm, is directly proportional to the HDL cholesterol concentration in the sample.

In the ACE LDL-C Reagent assay, detergent 1 solubilizes non-LDL lipoprotein particles (HDL, VLDL and chylomicrons) and releases cholesterol. The cholesterol is consumed by cholesterol esterase and cholesterol oxidase in a non-color forming reaction. In a second reaction, detergent 2 solublizes the remaining LDL particles and forms peroxide, via the enzymes cholesterol esterase and cholesterol oxidase. The peroxide, in the presence of peroxidase and two peroxidase substrates, 4-aminoantipyrine and DSBmT, results in a purple-red color. The amount of color formed, determined by measuring the increase in absorbance bichromatically at 544/692 nm, is directly proportional to the LDL cholesterol concentration in the sample.

In the ACE Triglycerides Reagent assay, triglycerides in serum are hydrolyzed by lipase to form glycerol and free fatty acids. In the presence of adenosine triphosphate (ATP) and glycerol kinase, the glycerol is converted to glycerol-1-phosphate and the ATP to adenosine diphosphate. Glycerol-1-phosphate is oxidized by glycerol phosphate oxidase to yield hydrogen peroxide. The hydrogen peroxide then acts to oxidatively couple p-chlorophenol and 4-aminoantipyrine in a reaction catalyzed by peroxidase, producing a red colored quinoneimine complex which absorbs strongly at 505 nm. The amount of chromogen formed, determined by measuring the increase in absorbance bichromatically at 505 nm/692 nm, is directly proportional to the triglycerides concentration in the sample.

The provided text describes a 510(k) submission for the ACE Axcel Clinical Chemistry System and its associated reagents for Cholesterol, HDL-C, LDL-C, and Triglycerides. The submission focuses on demonstrating substantial equivalence to a predicate device (K113262) by showing that the new device has "Same" intended use, instrument platform, basic principle, and reagent composition, with the only difference being the expanded sample type (serum and lithium heparin plasma for the candidate device vs. serum only for the predicate device).

The acceptance criteria are implicitly defined by the performance characteristics demonstrated in the study, which aim to show that the expanded sample type (lithium heparin plasma) does not negatively impact the accuracy and precision of the measurements compared to serum. The study largely relies on analytical performance data rather than clinical outcomes or expert consensus on interpretations.

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical targets in the document; instead, the study intends to demonstrate comparable performance to the predicate device and acceptable analytical characteristics. The reported device performance for precision and matrix comparison is provided below, which implicitly became the "accepted" performance for the expanded sample type.

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

• Precision/Reproducibility Study (Test Set):
  • For each analyte (Cholesterol, HDL-C, LDL-C, Triglycerides), for both serum and plasma, 3 levels of samples were used.
  • Each level was tested with 2 replicates, twice a day, on 5 separate days, yielding a total of 20 replicates per level (3 levels * 2 sample types * 20 replicates/level = 120 total measurements per analyte category, e.g., Cholesterol on Serum).
  • Data Provenance: Not explicitly stated, but typically these studies are conducted in a laboratory setting, likely in the US (given the FDA submission). It is a prospective analytical study designed to evaluate device performance under controlled conditions.
• Matrix Comparison Study (Test Set):
  • Cholesterol: 54 paired serum and lithium heparin plasma specimens.
  • HDL-C: 53 paired serum and lithium heparin plasma specimens.
  • LDL-C: 54 paired serum and lithium heparin plasma specimens.
  • Triglycerides: 55 paired serum and lithium heparin plasma specimens.
  • These specimens covered the assay's dynamic range.
  • Data Provenance: Not explicitly stated, but likely from a clinical laboratory setting, potentially within the US. The samples are retrospective specimens collected for analytical comparison.

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

This type of submission for in vitro diagnostic reagents does not typically involve human experts establishing "ground truth" through interpretation. The "ground truth" for the test set is established by comparative measurements against a reference method or the predicate device, and by the inherent chemical/physical properties of the samples used in reproducibility studies. No information about experts or their qualifications is provided or relevant in this context.

4. Adjudication method for the test set

Not applicable. This is an analytical performance study for laboratory reagents, not a clinical study involving human interpretation that would require an adjudication method.

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/imaging device, nor does it involve human readers or case interpretations. It is an in vitro diagnostic reagent.

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

This is an analytical device, and its performance is inherently standalone in terms of generating a quantitative result. The results are then interpreted by clinicians in the overall diagnostic process. The study evaluates the standalone performance of the reagents on the ACE Axcel Clinical Chemistry System.

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

The "ground truth" for this type of analytical validation is established by:

• Reference methods and/or the predicate device: For the matrix comparison, the serum measurements on the candidate device (which is substantially equivalent to the predicate) serve as the reference against plasma measurements. The predicate device's performance also implicitly serves as a benchmark for comparison.
• Known concentrations: For precision studies, samples are "clinically relevant decision levels" meaning they have known or well-characterized concentrations of the analytes. These concentrations are typically determined by highly accurate laboratory methods.

8. The sample size for the training set

Not applicable. This is not an AI or machine learning device that requires a training set. The reagents are chemical formulations, and the system is an automated analyzer.

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 ACE Magnesium Reagent is intended for the quantitative determination of magnesium concentration in serum using the ACE Axcel Clinical Chemistry System. Magnesium measurements are used in the diagnosis and treatment of hypomagnesemia (abnormally low serum levels of magnesium) and hypermagnesemia (abnormally high serum levels of magnesium). This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

Magnesium ions in serum react with Xylidyl blue-1 in an alkaline medium to produce a red complex which is measured bichromatically at 525 nm/692 nm. The intensity of color produced is directly proportional to the magnesium concentration in the sample. EGTA prevents calcium interference by preferential chelation of calcium present in the sample. A surfactant system is included to remove protein interference.

The ACE Axcel Clinical Chemistry System consists of two major components, the chemistry instrument and an integrated Panel PC. The instrument accepts the physical patient samples, performs the appropriate optical or potentiometric measurements on those samples and communicates that data to an integral Panel PC. The Panel PC uses keyboard or touch screen input to manually enter a variety of data, control and accept data from the instrument, manage and maintain system information and generate reports relative to patient status and instrument performance. The Panel PC also allows remote download of patient requisitions and upload of patient results via a standard interface.

Here's a breakdown of the acceptance criteria and study information for the ACE Magnesium Reagent based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria values (e.g., "The CV must be less than X%"). Instead, it reports the performance values achieved by the device. The "acceptance criteria" are implied by the reported performance being deemed sufficient for substantial equivalence.

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

• Sample Size for Accuracy Test Set: 110 samples for the primary correlation study.
• Sample Size for Precision Test Set: Not explicitly stated as a count of individual samples, but "four magnesium levels for ≥21 days" and "three separate Physician Office Laboratory (POL) sites over 5 days" implies multiple measurements across different samples or levels.
• Data Provenance: The document does not specify the country of origin. It conducted studies "at four magnesium levels" and "at three separate Physician Office Laboratory (POL) sites," suggesting internal testing and potentially external POL sites. The studies are retrospective as they involve analyzing samples for performance.

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

The document describes an in vitro diagnostic reagent for quantitative determination of magnesium. The ground truth for such devices is established by comparison to a reference method or predicate device, not by expert interpretation of images or clinical assessments.

• Number of Experts: Not applicable in the context of this type of diagnostic device.
• Qualifications of Experts: Not applicable.

4. Adjudication Method for the Test Set

Not applicable for this type of quantitative diagnostic device. Ground truth is established by comparing the device's output to a known reference method or another validated device (the predicate).

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

• MRMC Comparative Effectiveness Study: No, this is not an AI/human reader study. This document describes a chemical reagent for an automated clinical chemistry system.

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

Yes, the performance data presented (precision, accuracy, detection limit) are for the ACE Magnesium Reagent operating on the ACE Axcel Clinical Chemistry System in a standalone manner. The measurements are automated, and the results are quantitative values obtained directly from the system.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The ground truth for the accuracy study was established by comparing the results from the ACE Magnesium Reagent on the ACE Axcel Clinical Chemistry System against the results from the predicate device, the "Alfa Wassermann ACE Clinical Chemistry System."

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning or AI. For an in vitro diagnostic reagent, the development process involves formulating the reagent and optimizing its performance characteristics. The validation studies (precision, accuracy, detection limit) on the ACE Axcel Clinical Chemistry System served as the testing of the final product, not a training set for an algorithm.

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

Not applicable, as this is not an AI/machine learning device with a distinct training set in that sense. The "ground truth" during the development and validation phase would be derived from known-concentration controls, reference materials, and comparative analysis against established methods (like the predicate device).

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