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The Atellica® CH Creatinine_3 (Crea3) assay is for in vitro diagnostic use in the quantitative determination of creatinine in human serum, plasma (lithium heparin, dipotassium EDTA, and sodium heparin), and urine using the Atellica® CH Analyzer. Such measurements are used in the diagnosis and treatment of renal diseases, and in monitoring renal dialysis.

The Atellica CH Crea3 assay is based on the reaction of picrate with creatinine in an alkaline medium to produce a red chromophore creatinine picrate complex. The rate of complex formation is measured at 505/571 nm and is proportional to the creatinine concentration. The Atellica CH Crea3 assay is a modification of the Jaffe method, using rate blanking and intercept correction. Rate blanking is used to minimize bilirubin interference. Also, because non-specific serum/plasma protein interactions with this reagent have been found to produce a positive bias of approximately 0.3 mg/dL (26.5 µmol/L), serum/plasma measurements are automatically corrected by subtracting 0.3 mg/dL (26.5 µmol/L) from each result.

The provided text describes the performance characteristics and studies for the Atellica® CH Creatinine_3 (Crea3) assay, a new in vitro diagnostic device for quantitative determination of creatinine. It compares this new device to a predicate device, the Atellica® CH Creatinine_2 (Crea_2) assay.

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

Important Note: The document focuses on establishing substantial equivalence for an in vitro diagnostic (IVD) test, which primarily relies on analytical performance characteristics rather than clinical outcome studies or multi-reader multi-case (MRMC) comparative effectiveness studies typically seen with imaging AI devices. Therefore, some of your requested information (like number of experts for ground truth, adjudication methods, MRMC studies, and training set details for an AI model) are not directly applicable or provided in this type of submission.

Acceptance Criteria and Reported Device Performance

The acceptance criteria for this device are established through various analytical performance studies, primarily comparing it to a legally marketed predicate device (Atellica® CH Creatinine_2). The acceptance criteria are implicitly defined by the successful demonstration of equivalence or meeting pre-defined performance goals for each characteristic.

Here's a table summarizing the acceptance criteria (inferred from the "designed to have" or "determined in accordance with" statements and the reported results meeting these) and the reported device performance:

Study Details:

1. Sample Size and Data Provenance:

   • Test Set Sample Sizes:
     • Detection Capability: Not explicitly stated as "sample size" but data points obtained according to CLSI EP17-A2.
     • Precision: 80 data points per serum/urine sample type (duplicate runs for 20 days, 2 runs/day).
     • Reproducibility: 225 data points per serum/urine sample type (n=5 in 1 run for 5 days using 3 instruments and 3 reagent lots).
     • Assay Comparison: 151 serum samples and 113 urine samples.
     • Specimen Equivalence: 50 samples for each plasma type (Sodium Heparin, Lithium Heparin, Dipotassium EDTA) compared to serum.
     • Interference (HIL & Non-Interfering Substances): Not explicitly stated as a total sample size, but experiments are designed to test specific analyte concentrations with and without interferents, following CLSI EP07-ED3.
   • Data Provenance: Not explicitly stated in terms of country of origin. Given the manufacturer (Siemens Healthcare Diagnostics Inc. in Tarrytown, New York, USA) and FDA submission, it's highly probable the studies were conducted in the US or in compliance with US regulatory standards. The studies described are retrospective in the sense that they use pre-collected or prepared samples to assess the analytical performance of the device under controlled conditions, not prospective in tracking patient outcomes in a clinical trial.

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

   • For an in vitro diagnostic (IVD) device measuring a quantitative analyte like creatinine, "ground truth" is typically established by reference methods or established laboratory standards and calibrators, not by human expert consensus or labeling of medical images.
   • The "ground truth" for creatinine concentration in this context is based on traceable reference materials (NIST SRM 967) and established laboratory measurement principles, and the performance is compared against a legally marketed predicate device.
   • Therefore, this question (relevant for AI/imaging devices) does not directly apply to this type of IVD submission.

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

   • Not applicable. Adjudication methods are typically used in clinical trials or image labeling pipelines where there's human interpretation involved and a need to resolve disagreements among multiple readers; this is an analytical performance study of an IVD assay.

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

   • Not applicable. This is not an AI/imaging device. It's an in vitro diagnostic assay.

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

   • This is an automated IVD assay performed on the Atellica® CH Analyzer. Its intended use is quantitative determination of creatinine. Therefore, the performance described (precision, accuracy, interference, etc.) is its standalone performance without a human in the loop for the analytical measurement itself, though a human still interacts with the instrument and interprets the results in a clinical context.

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

   • The primary "ground truth" for the Atellica® CH Creatinine_3 assay's performance is traceability to NIST SRM 967 (a certified reference material for creatinine) and comparison to a legally marketed predicate device (Atellica® CH Creatinine_2) using method comparison validated against CLSI guidelines. This is a form of analytical reference standard and comparative performance to an established method.

7. The sample size for the training set:

   • This device is an analytical chemistry assay, not a machine learning/AI algorithm that requires a "training set" in the computational sense. The "development" or "optimization" of the assay would involve various experimental data, but it's not codified as a "training set" for an algorithm.

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

   • Not applicable, as there is no "training set" in the AI/ML context for this type of device. The assay development would rely on scientific principles of analytical chemistry, reagent formulation, and instrument calibration against known standards.

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The Atellica® IM High-Sensitivity Troponin I (TnIH) assay is for in vitro diagnostic use in the quantitative measurement of cardiac troponin I in human serum or plasma (lithium heparin) using the Atellica® IM Analyzer. The assay can be used to aid in the diagnosis of acute myocardial infarction (AMI).

The Atellica IM TnIH assay can be used as an aid in prognosis for 30-, 182-, and 365-day all-cause mortality (ACM) and major adverse cardiac events (MACE) in patients presenting with signs and symptoms suggestive of acute coronary syndrome (ACS). MACE consists of myocardial infarction, urgent revascularization, cardiac death, or heart failure hospitalization.

The Atellica® IM TnIH assay is a 3-site sandwich immunoassay using direct chemiluminescent technology. The Solid Phase reagent consists of magnetic particles conjugated with streptavidin with 2 bound biotinylated capture monoclonal antibodies, each recognizing a unique cTnl epitope.

The Lite Reagent comprises a conjugate with an architecture consisting of a proprietary acridinium ester and a recombinant anti-human cTnl sheep Fab covalently attached to bovine serum albumin (BSA) for chemiluminescent detection.

A direct relationship exists between the amount of cTnl present in the patient sample and the amount of relative light units (RLUs) detected by the system.

The provided document is a 510(k) summary for the Atellica® IM High-Sensitivity Troponin I (TnIH) assay, detailing its substantial equivalence to a predicate device and supporting the addition of a prognostic indication for use. However, it does not explicitly define acceptance criteria as a separate, quantitative table with pass/fail metrics. Instead, the "Performance Characteristics – Clinical Study" section presents the study objective and results that demonstrate the device's performance for the new prognostic indication, implicitly serving as the validation for meeting the FDA's requirements for substantial equivalence.

Based on the information provided, here's a breakdown of the requested elements:

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

The document does not provide a formal table of acceptance criteria with quantitative thresholds for "pass/fail". The study's objective was to demonstrate the ability of the device to predict future mortality or adverse cardiac events. The reported performance focuses on:

• Hazard Ratios (Unadjusted and Adjusted): Showing the increased risk of ACM/MACE for patients with cTnI levels >99th percentile compared to those ≤99th percentile.
• Post-test risk: The cumulative incidence of ACM/MACE for the two troponin level groups.
• Kaplan-Meier Curves: Visually representing the absolute risk of events over time for the two groups.

The implicit acceptance criteria for this prognostic indication would be that the device's measurements (specifically, cTnI levels > 99th percentile) demonstrate a statistically significant association with increased future risk of all-cause mortality (ACM) and major adverse cardiac events (MACE) across the specified follow-up periods (30, 90, 182, and 365 days) in the relevant patient populations.

Reported Device Performance (Excerpted from the document, focusing on statistically significant findings):

Note: Bolded Hazard Ratios indicate statistically significant findings (95% CI does not cross 1.0). Italicized Hazard Ratios (e.g., serum at 30, 90, 365 days for Population 2) are explicitly marked as "Not Statistically Significant" in the document.

The overall conclusion states: "The results of the clinical study provided in this submission support the addition of an indication for use as an aid in prognosis for all-cause mortality (ACM) and major adverse cardiac events (MACE) in patients presenting with signs and symptoms suggestive of acute coronary syndrome (ACS)." This implies that the observed effects (higher risk for cTnI > 99th percentile) were deemed sufficient, particularly for the statistically significant findings.

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

• Test Set Sample Size:
  • Population 1: 2064 patients
  • Population 2:
    • Lithium Heparin Plasma: 1190 patients
    • Serum: 1214 patients
  • Population 3: 874 patients
• Data Provenance: The document states, "This prognostic risk analysis utilized the same emergency department cohort previously described in K171566." It does not explicitly state the country of origin. The study was prospective in terms of follow-up for outcomes after initial presentation, as patients were "followed up for 30-, 90-, 182-, and 365-day progression to ACM and MACE."

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

The ground truth for Adjudicated AMI was mentioned ("Entire Population Excluding Subjects with Adjudicated AMI"). The document does not specify the number or qualifications of experts used for establishing this adjudication or for the MACE/ACM outcomes. It says "a detailed symptom history was obtained for each subject" and "the following information was collected from each subject's medical chart." This suggests medical record review, but the specific adjudicators are not detailed.

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

The document mentions "adjudicated AMI" and the collection of outcome data (ACM/MACE events). However, it does not describe the specific adjudication method (e.g., how many reviewers, conflict resolution) for AMI or the MACE/ACM outcomes. It implies that MACE consisted of clearly defined clinical events (myocardial infarction, urgent revascularization, cardiac death, or heart failure hospitalization) which are typically obtained from medical records.

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

No. This is an in vitro diagnostic (IVD) assay for measuring a biomarker (Troponin I). It is not an AI-assisted imaging device or a device involving "human readers" in the typical sense of an MRMC study. The study assesses the prognostic performance of the cTnI assay result itself, not human interpretation enhanced by AI.

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

Yes, in a sense. The performance evaluated is that of the assay (the Atellica® IM High-Sensitivity Troponin I (TnIH) measurement) as a standalone prognostic indicator, reported as a quantitative value. It's the "algorithm" of the assay (producing the cTnI value) that is assessed for its ability to predict outcomes in patient populations, without direct human cognitive input being part of the primary performance metric. Clinical decision-making would then incorporate this result.

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

The ground truth for the prognostic indication was outcomes data, specifically:

• All-Cause Mortality (ACM)
• Major Adverse Cardiac Events (MACE): Consisting of myocardial infarction, urgent revascularization, cardiac death, or heart failure hospitalization.
  This long-term outcome data was collected from patient follow-up over 30, 90, 182, and 365 days.

8. The sample size for the training set

The document describes a clinical performance study for the new prognostic indication. It does not mention a separate "training set" for model development, implying that this was a single-cohort validation study using the full collected dataset (the test set described above). The purpose of the submission is to expand the intended use of an already existing device (cleared under K171566), suggesting the core assay technology was already established.

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

As no separate "training set" is explicitly mentioned for the prognostic model development (if one occurred), this question is not fully answerable from the provided text. The ground truth for the clinical validation (the "test set") was established through prospective follow-up for clinical outcomes (ACM/MACE) as described in point 7.

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The Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay is for in vitro diagnostic use in the quantitative determination of the concentration of C-Reactive Protein (CRP) in human serum and plasma (lithium heparin, sodium heparin or K2 EDTA) on the Atellica® CH Analyzer.

Measurements from Atellica® CH High Sensitivity C -Reactive Protein 2 (hCRP2) may be used as an aid in identification of individuals at risk for future cardiovascular disease. Measurement of hCRP2, when used in coniunction with traditional clinical laboratory evaluation of acute coronary syndromes, may be useful as an independent marker of prognosis for recurrent events in patients with stable coronary disease or acute coronary syndromes.

The Atellica CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay is used for the quantitative determination of C-Reactive protein in human serum and plasma using the Atellica CH analyzer. This device is two ready-to-use reagent packs consisting of 23.1mL Phosphate buffer, polidocanol (1.9g/L), and sodium azide (0.1%) in Pack 1 and 12.3mL Mouse anti-CRP monoclonal antibodies (13mg/L), polystyrene particles (1g/L), human albumin (0.05%) and sodium azide (<0.1%) in Pack 2. This product consists of two (2) kits consisting of 360 tests each for a total of 720 tests.

Polystyrene particles coated with monoclonal antibodies specific to human CRP are aggregated when mixed with samples containing CRP. These aggregates scatter a beam of light passed through the sample. The intensity of the scattered light is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration.

The system automatically performs the following steps:

• 1. For serum/plasma, dispenses 30 µL of primary sample and 90 µL of Atellica CH Diluent into a dilution cuvette.
• 2. Dispenses 100 µL of Reagent 1 into a reaction cuvette.
• 3. Dispenses 3 µL of pre-diluted sample into a reaction cuvette.
• 4. Dispenses 45 µL of Reagent 2 into a reaction cuvette.
• 5. Mixes and incubates the mixture at 37°C.
• 6. Measures the absorbance after Reagent 2 addition.
• 7. Reports results.

Atellica CH High-Sensitivity C-Reactive Protein 2 (hCRP2) assay is used in conjunction with the Atellica CH Analyzer and Atellica CH Protein 2 Calibrator (PROT2 CAL)

Here's a summary of the acceptance criteria and the study that proves the device meets them, based on the provided FDA 510(k) summary:

Device: Atellica® CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay

1. Table of Acceptance Criteria and Reported Device Performance:

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

• Detection Capability:
  • LoB: 3 reagent lots, 6 blank samples, 5 replicates per sample = 90 determinations.
  • LoD: 495 determinations (270 blank, 225 low-level replicates) using 3 reagent lots.
  • LoQ: 5 native low analyte serum samples, 5 replicates each = 25 determinations.
• Precision (Repeatability/Within-Lab): 80 replicates per specimen (5 serum samples + 1 QC, total 6 specimens).
• Reproducibility (Multi-site/Multi-lot): 225 replicates per specimen (5 serum samples + 3 QCs, total 8 specimens).
• Assay Comparison (Method Comparison): 100 patient samples.
• Specimen Equivalency: 55 patient samples for each specimen type (Sodium Heparin, Potassium EDTA, Lithium Heparin).
• Interferences (HIL & Non-interfering Substances): Not explicitly stated, but typically involves a smaller number of samples spiked with interferents at multiple analyte concentrations.

Data Provenance: Not explicitly stated, but the sample types are human serum and plasma, diluted with Atellica CH diluent (saline) or enriched as needed. This usually implies a mix of commercially sourced and/or in-house collected human samples. There is no information regarding the country of origin or whether the studies were retrospective or prospective.

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

This device is an in vitro diagnostic test for C-Reactive Protein (CRP) concentration. The "ground truth" for a quantitative assay like this is typically established by:

• Reference methods/standards (e.g., ERM-DA474/IFCC for CRP, as mentioned).
• Comparative analysis against a legally marketed predicate device (BN ProSpec CardioPhase hsCRP).
• Standard preparation and gravimetric/volumetric assurance for spiked samples or known concentrations.

Therefore, "experts" in the sense of clinical reviewers or pathologists establishing a diagnostic ground truth is not applicable here. The accuracy of the measurements is compared against established analytical criteria and methodologies.

4. Adjudication Method for the Test Set:

Not applicable in the context of this type of IVD performance study, as there is no subjective interpretation requiring adjudication of results from different observers. The output is a quantitative value (mg/L).

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

No, an MRMC comparative effectiveness study was not done. This type of study is relevant for imaging or diagnostic tests where human interpretation plays a significant role and AI assistance might influence reader performance. For a quantitative in vitro diagnostic assay like high-sensitivity CRP, the measurement is automated and objective.

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

Yes, the studies described (Detection Capability, Precision, Reproducibility, Assay Comparison, Specimen Equivalency, Interferences, High-Dose Hook Effect) are all standalone performance evaluations of the Atellica CH High Sensitivity C-Reactive Protein 2 (hCRP2) assay as an automated laboratory test on the Atellica CH Analyzer. The device is intended for in vitro diagnostic use, meaning it operates without direct human interpretive input beyond running the test and reading the numerical result.

7. The Type of Ground Truth Used:

The ground truth for this device is established through:

• Analytical Standards: The assay is traceable to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference material ERM-DA474/IFCC, which serves as a primary ground truth for CRP concentration.
• Predicate Device Comparison: The performance is compared against a legally marketed predicate device (BN ProSpec CardioPhase hsCRP assay), where the predicate's measurements serve as a comparative standard.
• Reference Intervals: Expected values for cardiovascular risk prediction are based on established clinical guidelines (Pearson TA et al., 2003).
• Spiked Samples: For interference studies, known concentrations of interfering substances are added to samples, and the known concentration of the analyte is the ground truth.

8. The Sample Size for the Training Set:

Not explicitly stated in the 510(k) summary. For a device like this, the "training set" would refer to the samples used during the development and optimization phase of the assay (e.g., reagent formulation, calibration curve development), rather than a machine learning training set. The approval document focuses on the validation or test sets.

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

Similar to point 7, the ground truth for potential "training" (development/optimization) would involve analytical standards (like ERM-DA474/IFCC), purified CRP, and well-characterized human serum/plasma samples, often with known CRP concentrations determined by reference methods or gravimetric/volumetric preparation. The goal would be to develop a robust assay that accurately measures CRP across its analytical range.

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The Atellica® CH Phencyclidine (Pcp) assay is for in the qualitative or semiguantitative analyses of phencyclidine in human urine using the Atellica® CI Analyzer, using a cutoff of 25 ng/mL. The Pop assay provides only a preliminary analytical test result. A more specific alternative chemical must be used to obtain a confirmed analytical result. Gas chromatography-mass spectrometry (GCMS) is the preferred confirmatory method. The semiquantitative mode is for purposes of enabling laboratories to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as gas chromatography/mass spectrometry (GC-MS) or liquid chromatography/tandem mass spectrometry (LC-MS/MS) or permitting laboratories to establish quality control procedures.

Clinical consideration and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used.

The Atellica® CH Vancomycin (Vanc) assay is for in vitro diagnostic use in the quantitative measurement of vancomycin in human serum and plasma (lithium heparin) using the Atellica® CI Analyzer. Vanc test results may be used in the diagnosis and treatment of vancomycin overdose and in monitoring levels of vancomycin to ensure appropriate therapy.

The Atellica CH Pcp assay is a homogenous enzyme immunoassay based on competition between drug in the specimen and drug labeled with glucose-6-phosphate dehydrogenase (G6PDH) for antibody binding sites. G6PDH activity decreases upon binding to the antibody, so the drug concentration in the specimen can be measured in terms of enzyme activity. Active enzyme converts nicotinamide adenine dinucleotide (NAD+) to NADH in the presence of glucose-6-phosphate (G6P), resulting in an absorbance change that is measured spectrophotometrically at 340/410 nm. Endogenous G6PDH does not interfere because the coenzyme NAD+ functions only with the bacterial (Leuconostoc mesenteroides) enzyme employed in the assay.

The Atellica CH Vanc assay is based on a homogeneous particle enhanced turbidimetric inhibition immunoassay (PETINIA) technique which uses a synthetic particle-vancomycin conjugate (PR) and monoclonal vancomycin specific antibody (Ab). Vancomycin present in the sample competes with vancomycin on the particles for available antibody, thereby decreasing the rate of aggregation. Hence, the rate of aggregation is inversely proportional to the concentration of vancomycin in the sample. The rate of aggregation is measured using bichromatic turbidimetric readings at 545 and 694 nm.

This document describes the analytical performance of two in vitro diagnostic (IVD) assays, the Atellica® CH Phencyclidine (Pcp) assay and the Atellica® CH Vancomycin (Vanc) assay, and does not contain information related to AI/ML clinical studies or multi-reader multi-case (MRMC) comparative effectiveness studies. Therefore, it is not possible to address acceptance criteria and study designs typically found in AI/ML performance evaluations (e.g., sample size for training/test sets, data provenance, expert ground truth, adjudication methods, MRMC studies, standalone performance, etc.).

However, I can extract and present the analytical performance criteria and reported device performance based on the provided text, which are relevant for IVD devices.

Analytical Acceptance Criteria and Reported Device Performance

Atellica® CH Phencyclidine (Pcp) Assay

This assay is for qualitative or semi-quantitative analysis of phencyclidine in human urine. The primary "acceptance" is demonstrated through agreement with a confirmatory method (GC/MS) and robust precision and recovery.

Table 1: Atellica® CH Phencyclidine (Pcp) Assay - Analytical Performance

Atellica® CH Vancomycin (Vanc) Assay

This assay is for quantitative measurement of vancomycin in human serum and plasma.

Table 2: Atellica® CH Vancomycin (Vanc) Assay - Analytical Performance

Regarding the other points relevant to AI/ML studies:

Since the provided text describes the analytical validation of in vitro diagnostic assays (chemical laboratory tests) and not an AI/ML-driven medical device, the following points are not applicable and thus cannot be addressed from the given information:

2. Sample sizes used for the test set and the data provenance: Not an AI/ML device. The "test set" for the Pcp assay was 157 samples compared against GC/MS. For Vanc, various sample numbers were used for different analytical performance tests (e.g., 107 for assay comparison, 50 for specimen equivalency, 80 for precision studies). Data provenance is not specified (e.g., country of origin, retrospective/prospective).
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: Not applicable; ground truth is established by a reference analytical method (GC/MS for Pcp) or by defined reference materials and methods for quantitative assays (USP standards for Vanc).
4. Adjudication method for the test set: Not applicable.
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.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: Not applicable. These are lab assays, not AI algorithms.
7. The type of ground truth used:
   • For Atellica® CH Phencyclidine (Pcp) assay: The ground truth for accuracy was established using Gas Chromatography/Mass Spectrometry (GC/MS) as the reference method.
   • For Atellica® CH Vancomycin (Vanc) assay: The ground truth/standardization is traceable to United States Pharmacopeia (USP) standards.
8. The sample size for the training set: Not applicable. These assays are laboratory tests and do not involve "training sets" in the AI/ML sense. Validation is performed using established analytical testing protocols with various spiked and clinical samples.
9. How the ground truth for the training set was established: Not applicable.

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The A-LYTE® Integrated Multisensor (IMT Na K Cl) is for in vitro diagnostic use in the quantitative determination of sodium, potassium, and chloride (Na, K, Cl) in human serum, plasma (lithium heparin) and urine using the Atellica® Cl Analyzer. Measurements of sodium obtained by this device are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of arge amounts of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance. Measurements of potassium obtained by this device 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.

The A-LYTE Na, K, and Cl assays use indirect Integrated Multisensor Technology (IMT). There are four electrodes used to measure electrolytes. Three of these electrodes are ionselective for sodium, potassium and chloride. A reference is also incorporated in the multisensor.

A diluted sample (1:10 with A-LYTE IMT Diluent)) is positioned in the sensor and Na+. K+ or Cl- ions establish equilibrium with the electrode surface. A potential is generated proportional to the logarithm of the analyte activity in the sample. The electrical potential generated on a sample is compared to the electrical potential generated on a standard solution, and the concentration of the desired ions is calculated by use of the Nernst equation.

This document describes the performance characteristics of the A-LYTE® Integrated Multisensor (IMT Na K Cl) device, which is used for the quantitative determination of sodium, potassium, and chloride in human serum, plasma, and urine. The information provided outlines the acceptance criteria for various performance metrics and the study results demonstrating that the device meets these criteria.

Here's a breakdown of the requested information:

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

The document doesn't explicitly list "acceptance criteria" in a separate table, but rather describes the design goals or target performance for each characteristic, followed by the obtained results. I will present these as acceptance criteria and reported performance.

Table 1: Acceptance Criteria and Reported Device Performance

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

• Test Set Sample Sizes:

  • Detection Capability (LoQ): 180 determinations for each analyte (Na, K, Cl) in both serum/plasma and urine.
  • Linearity: 5 replicates per level for at least nine levels, implying a minimum of 45 measurements per analyte and sample type.
  • Precision: N ≥ 80 for each sample type (serum and urine) for each analyte (Na, K, Cl).
  • Assay Comparison:
    • Na (Serum): 123 samples
    • Na (Urine): 117 samples
    • K (Serum): 119 samples
    • K (Urine): 117 samples
    • Cl (Serum): 123 samples
    • Cl (Urine): 127 samples
  • Reproducibility: N=225 results for each sample type (serum QC, human serum, human urine) per analyte (Na, K, Cl), with n=5 assays in 1 run for 5 days using 3 instruments and 3 sensor lots.
  • Specimen Equivalency:
    • Na (Lithium heparin plasma vs Serum): 138 samples
    • K (Lithium heparin plasma vs Serum): 56 samples
    • Cl (Lithium heparin plasma vs Serum): 136 samples
  • Interferences: Not explicitly stated as a single "sample size," but implied from the number of test concentrations and conditions evaluated (e.g., specific concentrations of hemoglobin, bilirubin, lipemia).
  • Non-Interfering Substances: Not explicitly stated as a single "sample size," but implied from the number of test concentrations and conditions evaluated.

• Data Provenance: The document does not specify the country of origin of the data or whether the studies were retrospective or prospective. Given it's a 510(k) submission for an in vitro diagnostic device, these studies are typically prospective validation studies conducted at the manufacturer's R&D facilities or contracted labs, adhering to CLSI guidelines.

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

This device is an in vitro diagnostic (IVD) for quantitative determination of electrolytes. The "ground truth" (or reference values) for these types of devices is established through:

• Reference Methods: Comparison against established, well-characterized reference methods or instruments (e.g., the predicate device in the assay comparison, or other highly accurate laboratory methods). In this case, "Atellica CH Na/K/Cl on Atellica CH Analyzer" served as the comparative assay, which itself would have been validated against reference standards.
• Certified Reference Materials: Use of calibrated standards and controls with known analyte concentrations derived from definitive methods.

Therefore, the concept of "experts" (like radiologists interpreting images) establishing ground truth does not directly apply here. Instead, ground truth is based on physical/chemical measurements and their traceability to metrological standards. There are no human experts involved in adjudicating the "truth" of an electrolyte concentration in a sample as there would be in image interpretation.

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

Not applicable. As explained in point 3, the ground truth for this type of quantitative IVD assay is established through comparison to reference methods, not human adjudication of a qualitative or semi-quantitative outcome.

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 is an automated laboratory analyzer, specifically an Integrated Multisensor for electrolyte measurement. It is not an imaging AI device that assists human readers.

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

Yes, the performance data presented (Detection Capability, Linearity, Precision, Reproducibility, Interferences) represent the standalone performance of the A-LYTE® Integrated Multisensor (IMT Na K Cl) on the Atellica® CI Analyzer. These are direct measurements of the device's analytical precision, accuracy, and interference profiles under controlled laboratory conditions, without human interpretation influencing the quantitative results. The Assay Comparison also represents the device's performance against another automated laboratory system (the predicate device).

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

The ground truth for this device's performance studies is based on:

• Reference Standards/Methods: Calibrated reference materials and comparison to a legally marketed predicate device (TD-LYTE Integrated Multisensor on Trinidad CH System, now Atellica CH System). This ensures that the measured concentrations are accurately determined against established analytical benchmarks.
• Known Concentrations: For linearity, precision, and interference studies, samples are often spiked or diluted to known concentrations, or quality control materials with certified values are used.

8. The sample size for the training set:

Not applicable. This device is a measurement instrument based on established potentiometric technology (Ion-Selective Electrodes). It does not employ machine learning or AI models that require a separate "training set" in the conventional sense. The development and calibration of such devices rely on comprehensive analytical chemistry and engineering principles, using calibration standards, quality control materials, and extensive internal testing during the development phase. The data presented here are for the validation of the finalized device, not for its iterative training.

9. How the ground truth for the training set was established:
Not applicable, as there is no "training set" for an AI model. For the development and calibration of the IMT, the ground truth would be established through a combination of:

• Primary Reference Materials: Use of highly pure chemical standards with accurately known concentrations.
• Secondary Reference Standards: Calibrated solutions traceable to primary standards.
• Reference Measurement Procedures: Highly accurate and precise analytical methods (e.g., flame photometry, coulometry, or isotope dilution mass spectrometry for elemental analysis) used to assign values to control materials and calibrators.
• Internal R&D and Optimization: Extensive testing and refinement of the sensor and instrument performance using these traceable standards during the development process.

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The Atellica® CI Analyzer is an automated, integrated system in vitro diagnostic tests on clinical specimens. The system is intended for the qualitative analysis of various body fluids, using photometry, turbidimetric, chemiluminescent, and integrated ionselective electrode technology for clinical use.

The Atellica® IM Thyroid Stimulating Hormone 3-Ultra (TSH3-UL) assay is for in vitro diagnostic use in the quantitative determination of thyroid-stimulating hormone (TSH, thyrotropin) in human serum and plasma (EDTA and lithium heparin) using the Atellica® CI Analyzer. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

The Atellica® CH Albumin BCP (AlbP) assay is for in vitro diagnostic use in the quantitative measurement of albumin in human serum and plasma (lithium heparin, potassum EDTA) using the Atellica® CI Analyzer. Albumin measurements are used in the diagnosis and treatment of numerous diseases primarily involving the liver or kidneys.

The Atellica® CI Analyzer is an automated, integrated system designed to perform in vitro diagnostic tests on clinical specimens. The system is intended for the qualitative and quantitative analysis of various body fluids, using photometric, turbidimetric, chemiluminescent, and integrated ionselective electrode technology for clinical use.

The Atellica CI Analyzer with Atellica® Rack Handler supports both clinical chemistry (CH) and Immunoassay (IM) features and contains all the necessary hardware, electronics, and software to automatically process samples and generate results, including sample and reagent dispensing, mixing, and incubating.

The Atellica IM TSH3-UL assay is a third-generation assay that employs anti-FITC monoclonal antibody covalently bound to paramagnetic particles, an FITC-labeled anti-TSH capture mouse monoclonal antibody, and a tracer consisting of a proprietary acridinium ester and an anti-TSH mouse monoclonal antibody conjugated to bovine serum albumin (BSA) for chemiluminescent detection

The Atellica CH Albumin BCP (AlbP) assay is an adaptation of the bromocresol purple dy-e binding method reported by Carter and Louderback et al. In the Atellica CH AlbP assay, serum or plasma albumin quantitatively binds to BCP to form an albumin-BCP complex that is measured as an endpoint reaction at 596/694 nm coenzyme NAD+ functions only with the bacterial (Leuconostoc mesenteroides) enzyme employed in the assay.

The document provided is a 510(k) summary for in vitro diagnostic devices (IVDs), specifically the Atellica® CI Analyzer and its associated assays for Thyroid Stimulating Hormone (TSH3-UL) and Albumin (AlbP). IVDs, by their nature, measure specific analytes in biological samples and are evaluated against performance criteria such as precision, accuracy, linearity, and interference, rather than diagnostic accuracy metrics like sensitivity and specificity that would typically apply to AI/ML software. Therefore, many of the requested elements pertaining to AI/ML acceptance criteria and human-in-the-loop studies are not applicable to this type of device.

Here's a breakdown of the relevant information provided:

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

The document describes the performance characteristics for the Atellica IM Thyroid Stimulating Hormone 3-Ultra (TSH3-UL) assay and the Atellica CH Albumin BCP (AlbP) assay. These are performance criteria, which serve as the acceptance criteria for the device's analytical performance.

Atellica IM Thyroid Stimulating Hormone 3-Ultra (TSH3-UL) Assay:

Atellica CH Albumin BCP (AlbP) Assay:

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

• TSH3-UL Assay:
  • Precision: 80 samples for each type (Serum A-F, EDTA Plasma A-C, Heparin Plasma A-C, Control 1-3).
  • Assay Comparison (Serum): 112 samples.
  • Interferences (Specific substances): Not explicitly stated how many samples per substance, but concentrations tested at two analyte levels.
  • Specimen Equivalency: 64 samples for Plasma (Lithium heparin) and 64 for Plasma (EDTA).
  • Onboard Dilution Recovery: 3 samples (Serum and Plasma) tested at two dilution levels.
  • Linearity: Not explicitly stated, but "at least 14 levels created by mixing high and low serum samples" with N=5 replicates per level.
• AlbP Assay:
  • LoD: 486 determinations (270 blank, 216 low level replicates).
  • LoQ: n=5 replicates using 3 reagent lots over 5 days.
  • Precision: N ≥ 80 for each sample (Serum 1-3, Serum QC 1).
  • Reproducibility: 225 samples for each serum level (assayed n=5 in 1 run for 5 days using 3 instruments and 3 reagent lots).
  • Assay Comparison (Serum): 106 samples.
  • Specimen Equivalency: 76 samples for Plasma (Lithium heparin) and 55 for Plasma (Potassium EDTA).
  • HIL: Not explicitly stated how many samples per interferent, but concentrations tested at two analyte levels.
  • Non-Interfering Substances: Not explicitly stated how many samples per substance, but tested at two analyte concentrations.
  • Linearity: "at least nine levels created by mixing the high and low pools of serum" with N=5 replicates per level.

Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given it's a 510(k) submission for a medical device intended for broad use, it's highly likely the studies were prospective analytical validation studies conducted under controlled laboratory conditions, typically in multiple sites to ensure robustness.

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

This information is not applicable to this type of device. The "ground truth" for clinical laboratory assays like TSH and Albumin comes from established analytical methods, reference materials, and accepted scientific principles of chemistry and immunology. It's about measuring the concentration of an analyte, not interpreting an image or diagnosing a condition based on expert consensus. The "experts" involved would be clinical chemists, laboratory scientists, and engineers responsible for assay development and validation, following established guidelines like those from CLSI (Clinical and Laboratory Standards Institute).

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

This is not applicable for this type of device. Adjudication methods are used in studies involving subjective interpretations (e.g., image reading) where multiple readers provide opinions that need to be reconciled to establish ground truth. For quantitative chemical assays, the "truth" is determined by reference methods and the intrinsic properties of the analyte, not by human consensus or adjudication.

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

This is not applicable. An MRMC study is designed for evaluating the impact of a system on human readers' diagnostic performance, typically in the context of imaging. This document describes an automated in vitro diagnostic analyzer and its assays, which do not involve human "readers" in the sense of interpreting outputs like medical images.

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

The performance characteristics presented (precision, linearity, assay comparison, interference, etc.) represent the standalone performance of the device and its assays. The Atellica® CI Analyzer and its assays are automated systems designed to perform measurements without human interpretative input beyond setting up the instrument and following standard laboratory procedures for running samples and quality control.

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

The ground truth for these quantitative assays is established through:

• Reference Methods / Comparability: The performance is evaluated by comparing the new device's results to a legally marketed predicate device (Siemens Trinidad systems) which serve as the reference. This establishes the equivalence of the new device to already accepted technology.
• Traceability to International Standards: For TSH3-UL, traceability is to the World Health Organization (WHO) 3rd International Standard for human TSH (IRP 81/565). For AlbP, traceability is to ERM-DA470k Reference Material. These international standards or reference materials provide the "true" or accepted values against which the device's measurements are calibrated and verified.
• Analytical Procedures: The "ground truth" for characteristics like limit of detection, precision, and linearity are determined by rigorous statistical methods and established protocols (e.g., CLSI guidelines EP05-A3, EP07-ed3, EP09c-ed3, EP17-A2, EP06-ED2) during analytical validation.

8. The sample size for the training set:

This information is not applicable in the context of an IVD where "training set" implies machine learning or AI model development. For an IVD, there is a development and validation process. The number of samples for analytical validation studies (which is what is presented) is given under point 2.

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

As this is not an AI/ML device, the concept of a "training set" for an algorithm and its associated ground truth establishment methods (e.g., expert annotations) are not applicable. The "ground truth" or reference for the development and validation of these IVD assays is based on established laboratory practices, chemical principles, certified reference materials, and comparison to predicate devices, as described in point 7.

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The Atellica® CH Diazo Direct Bilirubin (D DBil) assay is for in vitro diagnostic use in the quantitative determination of direct bilirubin in human serum and plasma using the Atellica® CH Analyzer. Measurement of direct 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.

Atellica® CH Diazo Direct Bilirubin is a Photometric test using 2,4-dichloroaniline (DCA). Direct bilirubin in presence of diazotized 2,4-dichloroaniline forms a red colored azocompound in acidic solution. Absorbance is measured at 545/658 nm.

The provided text describes the performance characteristics and acceptance criteria for the Atellica® CH Diazo Direct Bilirubin (D DBil) assay. Here's a breakdown of the requested information:

Acceptance Criteria and Device Performance

1. Table of Acceptance Criteria and Reported Device Performance:

Note: Specific acceptance criteria for precision and reproducibility are not explicitly listed as single values but are implied by the comprehensive presentation of the data, demonstrating acceptable variability for a diagnostic assay. The document states that the results "support that the Candidate Device... is substantially equivalent."

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

• Assay Comparison: N = 100 samples
• Specimen Equivalency (Plasma vs. Serum): N = 53 samples for each plasma type (Lithium heparin, Sodium heparin, K2(EDTA)).
• Precision: N = 80 for each serum level (4 serum levels tested, total 320 measurements).
• Reproducibility: N = 225 for each serum level (4 serum levels tested, total 900 measurements).
• Interferences (HIL and Non-interfering Substances): The number of samples for interference testing is not explicitly stated as a single 'N' for the test set. However, the tables indicate specific analyte concentrations tested (e.g., for Hemoglobin, Lipemia, Acetaminophen, etc.), implying multiple measurements were performed for each interference level.

Data Provenance: The document does not explicitly state the country of origin or if the data was retrospective or prospective.

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

This information is not applicable as the device is an in vitro diagnostic assay for quantitative determination of direct bilirubin. The "ground truth" in this context refers to the measured concentration of direct bilirubin, which is established by established laboratory methods, standard reference materials, and comparison to a predicate device, rather than expert interpretation of images or clinical cases.

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

This information is not applicable. Adjudication methods like 2+1 or 3+1 are typically used in studies involving subjective interpretation (e.g., medical imaging interpretation) where multiple readers assess cases and discrepancies are resolved by a super-reader. For a quantitative diagnostic assay, the "ground truth" is determined by objective measurement rather than expert consensus on subjective findings.

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

This information is not applicable. The device is an in vitro diagnostic assay, not an AI-assisted diagnostic tool that would involve human readers interpreting cases. Therefore, an MRMC study or evaluation of human reader improvement with AI assistance is not relevant to this submission.

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

The device is a standalone in vitro diagnostic assay. Its performance is measured independently of human interpretation in the clinical setting, although laboratory personnel operate the analyzer and interpret the numerical results in the context of a patient's overall clinical picture. The studies described (Precision, Reproducibility, Assay Comparison, Specimen Equivalency, Interferences) all reflect the standalone performance of the assay on the Atellica CH Analyzer.

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

The "ground truth" for this device's performance studies is established by:

• Reference Methods/Predicate Device: The "Assay Comparison" section uses the Wako Direct Bilirubin V assay as the comparative method.
• Internal Reference Standards: The assay's traceability is to internal reference standards manufactured by gravimetric methods.
• Control Samples/Spiking: For precision, reproducibility, and interference studies, samples are prepared with known concentrations of analyte or interferents.

8. The sample size for the training set:

This information is not provided in the document. This type of detail is typically associated with machine learning or AI algorithm development, which is not the primary focus of this in vitro diagnostic device submission. The device involves a chemical reaction and photometric measurement, not a "training set" in the machine learning sense.

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

This information is not provided and is not applicable as the device does not involve a "training set" in the context of machine learning. The assay mechanism is based on a defined chemical reaction (diazo colorimetry) rather than a trained algorithm.

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The ADVIA Centaur® Anti-Müllerian Hormone (AMH) assay is for in vitro diagnostic use in the quantitative determination of anti-Müllerian hormone (AMH) in human serum and plasma (lithium heparin) using the ADVIA Centaur® XP system.

The measurement of AMH is used as an aid in the assessment of the ovarian reserve in women presenting to fertility clinics. This assay is intended to distinguish between women with AFC (antral follicle count) values > 15 (high ovarian reserve) and women with AFC values ≤ 15 (normal or diminished ovarian reserve).

This assay is intended to be used in conjunction with other clinical and laboratory findings, such as AFC, before starting fertility therapy. This assay is not intended to be used for monitoring women undergoing controlled ovarian stimulation in an Assisted Reproduction Technology program.

The ADVIA Centaur AMH assay is a sandwich immunoassay using direct acridinium ester-based chemiluminometric technology. Two monoclonal anti-AMH antibodies are employed in the assay. The first antibody in the Lite Reagent is a mouse monoclonal anti-AMH antibody labeled with acridinium ester. The second antibody is a biotinylated mouse monoclonal anti-AMH antibody coupled to streptavidin-coated magnetic particles in the Solid Phase.

A direct relationship exists between the amount of AMH present in the patient sample and the amount of relative light units detected by the system. Dose concentration results (ng/mL) are calculated based on a 2-point calibration from a pre-defined master curve.

Materials include:
ADVIA Centaur AMH ReadyPack® primary reagent pack: Solid Phase (Streptavidin-coated paramagnetic microparticles with biotinylated mouse monoclonal anti-human AMH antibody in buffer; sodium azide (< 0.1%); blocker (bovine); surfactant; preservatives)
ADVIA Centaur AMH ReadyPack® ancillary reagent pack: Ancillary Reagent (Mouse monoclonal anti-human AMH antibody labeled with acridinium ester in buffer (~0.6 µg/mL); sodium azide (<0.1%); blocker (bovine, murine); stabilizers; surfactant; preservatives)
AMH CAL: After reconstitution, low and high levels of AMH antigen (bovine) in defibrinated human plasma; sodium azide (< 0.1%); preservatives

Here's the detailed breakdown of the acceptance criteria and study information for the ADVIA Centaur® Anti-Müllerian Hormone (AMH) assay, based on the provided FDA 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Detection Capability (LoB, LoD, LoQ): Not explicitly stated, but determined as described in CLSI protocol EP17-A2. These are typically derived from analytical studies involving numerous replicates of blank, low-concentration, and relevant samples.
• Precision and Reproducibility:
  • Precision: 480 measurements per sample/control (replicates of 2, 2 runs/day, 20-day protocol). This was across 2 instruments and 3 reagent lots.
  • Reproducibility: 90 measurements per sample/control (triplicate, 2 runs/day, 5 days) across 3 sites and 1 reagent lot.
• Assay Comparison: 120 samples (serum) vs. a commercial AMH assay.
• Specimen Equivalence: 88 samples for Gel-barrier tube (serum) vs. Serum, and 88 samples for Plasma (lithium heparin) vs. Serum.
• Interferences: The number of samples tested for each substance is not specified, but the testing was performed in accordance with CLSI Document EP07-ed3 and EP37-ed1.
• Cross-Reactivity: Number of samples not specified, performed in accordance with CLSI Document EP07-ed3.
• Stability: Not sample-based but rather experimental conditions and time points.
• Expected Values (Reference Intervals):
  • Females (18–25 years): 209 samples
  • Females (26–30 years): 122 samples
  • Females (31–35 years): 123 samples
  • Females (36–40 years): 126 samples
  • Females (41–45 years): 152 samples
  • Females (46–50 years): 121 samples
  • Females (51 years and older): 139 samples
• Clinical Sensitivity and Specificity: 533 women.
• Data Provenance:
  • Clinical Study: Prospectively collected from women presenting to fertility clinics for evaluation.
  • Country of Origin: 11 sites across the United States.
  • Expected Values: Samples were collected retrospectively or prospectively from "apparently healthy subjects," but the exact nature (retrospective/prospective) and location of collection is not explicitly detailed beyond "apparently healthy subjects". Given the clinical study provenance, it's likely linked, but not explicitly stated.

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

For the clinical performance study (Clinical Sensitivity and Specificity), the ground truth for ovarian reserve was established by Antral Follicle Count (AFC) values determined by transvaginal ultrasound.

• The document does not specify the number of experts (e.g., sonographers, radiologists) who performed or interpreted these ultrasounds.
• It also does not specify the individual qualifications (e.g., years of experience, board certification) of these experts. It only states that the AFC result was determined by transvaginal ultrasound.

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method (such as 2+1, 3+1) for establishing the ground truth (AFC values). The AFC results were simply stated as being "determined by transvaginal ultrasound." This suggests that the individual AFC measurements were taken as the singular truth, without a multi-reader review or adjudication process outlined to resolve discrepancies, if any.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

No, an MRMC comparative effectiveness study involving human readers and AI assistance was not conducted. This device is an in vitro diagnostic (IVD) assay that quantitatively measures a biomarker (AMH) in serum/plasma. It does not involve interpretation of medical images or other data by human readers, and thus, AI assistance in the context of human reading is not applicable here.

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

Yes, the studies reported are essentially "standalone" performance evaluations of the ADVIA Centaur® Anti-Müllerian Hormone (AMH) assay itself. The clinical performance study evaluates the assay's ability to distinguish between high and normal/diminished ovarian reserve based on AMH measurements, against the ground truth of AFC. This is the performance of the device (the assay) as an algorithm or test method, independent of subsequent human interpretation enhancements.

7. The Type of Ground Truth Used

• Analytical Studies (Detection Capability, Precision, Linearity, Interference, Cross-reactivity, Stability, Hook Effect): The ground truth for these studies is typically derived from highly characterized reference materials, spiked samples with known concentrations, or established analytical methods.
• Expected Values (Reference Intervals): Established by collecting samples from "apparently healthy subjects" and calculating statistical percentiles (90th and 95th reference intervals). The ground truth here is the statistical distribution of AMH levels in a healthy population defined by age.
• Clinical Sensitivity and Specificity: The ground truth for ovarian reserve was Antral Follicle Count (AFC) values, as measured by transvaginal ultrasound. This is a clinical measure widely accepted in fertility assessment.

8. The Sample Size for the Training Set

The document does not specify a separate "training set" in the context of a machine learning or AI algorithm development. This is an in vitro diagnostic assay, where performance is typically established through analytical validation and clinical correlation studies, not through AI model training. The data used for most performance characteristics are considered validation data.

• The "Expected Values" data set (totaling 209+122+123+126+152+121+139 = 992 samples) could be seen as reference data used to establish norms, but not a "training set" for an algorithm in the AI sense.
• The "Clinical Sensitivity and Specificity" study of 533 women served as a clinical validation dataset.

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

As no "training set" in the AI sense is explicitly mentioned for algorithm development, there's no described method for establishing ground truth for such a set. For the validation data described:

• Clinical Study Ground Truth: The ground truth was Antral Follicle Count (AFC) values, determined by transvaginal ultrasound by unspecified qualified personnel at 11 sites across the US.
• Expected Values Ground Truth: These are based on AMH measurements from "apparently healthy subjects," where their health status (absence of relevant pathologies) constitutes the ground truth for establishing normal ranges.

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The Atellica® CH Diazo Total Bilirubin (D TBil) assay is for in vitro diagnostic use in the quantitative determination of total bilirubin in adults and children (non-neonates) in human serum and plasma using the Atellica® CH Analyzer. Measurement of total 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.

Atellica CH Diazo Total Bilirubin is a photometric test using 2,4-dichloroaniline (DCA). Direct bilirubin in presence of diazotized 2,4-dichloroaniline forms a red colored azocompound in acidic solution. A specific mixture of detergents enables the determination of the total bilirubin.

The provided document describes the Siemens Atellica® CH Diazo Total Bilirubin (D_TBil) assay, an in vitro diagnostic device, and its performance characteristics to demonstrate substantial equivalence to a predicate device (Dimension TBI Flex reagent cartridge).

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for this in-vitro diagnostic device are generally defined by demonstrating performance within established statistical limits or comparison to a predicate device, as per CLSI (Clinical and Laboratory Standards Institute) guidelines. The "acceptance criteria" themselves are not always explicitly stated as pass/fail thresholds for each performance characteristic in a simple numerical format, but rather as meeting the objectives of the study design (e.g., correlation coefficient of ≥ 0.950).

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

• Detection Capability: Not explicitly stated as a "test set" in the context of patient samples, but the determination was in accordance with CLSI Documents EP17-A2.
• Precision:
  • Repeatability/Within-Lab Precision: 80 measurements for each of the three serum levels (Serum 1, 2, 3), assayed in duplicate over 20 days.
  • Reproducibility: 225 measurements for each of the three serum levels (Sample ID 1, 2, 3), assayed with 5 replicates per run for 5 days using 3 instruments/sites and 3 reagent lots.
• Assay Comparison (Method Comparison): N = 103 patient samples (Serum)
• Specimen Equivalency: N = 57 patient samples for each plasma type (Lithium Heparin, Sodium Heparin, K2 EDTA) compared to serum.
• Interferences (HIL and Non-interfering Substances): The studies were performed with specific interferent concentrations and two bilirubin levels. The sample size refers to the number of spiked samples tested, but not explicitly the number of unique patient samples that may have been used to create these spiked materials.
• Data Provenance: The document does not specify the country of origin for the samples or whether the studies were retrospective or prospective. Given the nature of in-vitro diagnostic development, these are typically prospective studies using a mix of spiked and potentially remnant clinical samples.

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

This information is not applicable and therefore not provided in the document. For an in-vitro diagnostic assay that quantitatively measures an analyte (total bilirubin), the "ground truth" is established by the reference method or comparison method (the predicate device in this case) and the inherent accuracy and traceability of the calibrators, rather than by human expert review of images or clinical cases. The ground truth for quantitative assays typically relies on metrological traceability to certified reference materials (NIST Standard Reference Material 916 in this case) and established laboratory protocols.

4. Adjudication Method for the Test Set

This is not applicable. Adjudication methods (like 2+1, 3+1) are common in studies involving human interpretation of medical images or clinical data, especially for AI applications where consensus among experts establishes the ground truth. For quantitative in-vitro diagnostics, the "ground truth" is determined by established analytical methods and reference standards, not by human adjudication of qualitative results.

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

This is not applicable. An MRMC study is designed to assess the performance of a diagnostic system that involves human readers (e.g., radiologists interpreting images) and typically compares the effectiveness of human readers with and without AI assistance. The Atellica CH Diazo Total Bilirubin assay is an automated in-vitro diagnostic test, meaning it does not involve human readers for interpretation beyond the initial sample collection and analysis setup. It is a standalone analytical device.

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

This is essentially what the entire submission describes. The performance characteristics presented (Detection Capability, Precision, Reproducibility, Assay Comparison, Specimen Equivalency, Interference) are all standalone performance studies of the medical device itself. There is no human-in-the-loop component for the interpretation or output of the assay. The device directly measures and reports total bilirubin levels.

7. Type of Ground Truth Used

The ground truth for this quantitative in-vitro diagnostic assay is established through:

• Metrological Traceability: The assay is traceable to the NIST Standard Reference Material 916. This provides a fundamental basis for accuracy.
• Comparison to a Predicate Device: The performance of the new device is compared against a legally marketed predicate device (Dimension TBI assay), which serves as the "truth" or reference in method comparison studies.
• Controlled Samples: Precision, reproducibility, and interference studies use manufactured control materials, internal validations, and spiked samples with known concentrations or interferent levels, whose 'truth' values are established through rigorous analytical methods and often validated against reference methods.

8. The Sample Size for the Training Set

This information is not provided in the document, and it's generally not applicable in the typical sense of "training set" for traditional in-vitro diagnostic devices. These devices are developed, validated, and optimized through a series of analytical studies using various types of samples (e.g., precision materials, linearity samples, spiked samples, patient samples). The "training" isn't a machine learning training phase, but rather the process of optimizing the reagent formulation, reaction kinetics, and instrument parameters. The data used for these optimizations would be proprietary and extensive, but not typically referred to as a "training set" in regulatory submissions for IVDs. The analytical performance studies (like those detailed above) serve as the validation and verification of the final, optimized product.

9. How the Ground Truth for the Training Set Was Established
As explained in point 8, the concept of a "training set" with a defined "ground truth" for a traditional IVD like this is generally not applicable in the same way as for AI/ML devices. The "ground truth" for the development and optimization of such an assay would be established through:

• Reference Methods: Using established, highly accurate reference methods to determine the true concentration of bilirubin in control materials and patient samples used during development.
• Certified Reference Materials: Calibrating and verifying the assay against NIST or other internationally recognized certified reference materials.
• Known Spiking: Creating samples with precisely known additions of bilirubin or interferents to test linearity, recovery, and interference effects.

In summary, the provided document details a comprehensive set of analytical studies to demonstrate the performance and substantial equivalence of the Atellica® CH Diazo Total Bilirubin assay as a standalone in-vitro diagnostic device. The evaluation follows a different paradigm than AI/ML algorithms, thus many questions related to expert review, adjudication, and MRMC studies are not relevant.

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The C-Reactive Protein Extended Range (RCRP) method used on the Dimension® clinical chemistry system is an in vitro diagnostic test intended for the quantitative determination of CRP in human serum and plasma (lithium heparin). Measurement of C-Reactive Protein is useful for the detection and evaluation of infection, tissue injury, inflammatory disorders and associated diseases.

The RCRP method is based on a particle enhanced turbidimetric immunoassay (PETIA) technique. Synthetic particles coated with antibody to C-Reactive Protein (AbPR) aggregate in the presence of C-Reactive Protein in the sample. The increase in turbidity which accompanies aggregation is proportional to the C-Reactive Protein concentration.

This document describes the RCRP Flex® reagent cartridge, an in vitro diagnostic test for the quantitative determination of C-Reactive Protein (CRP) in human serum and plasma. The submission is a special 510(k) for a modified device, primarily due to an update in traceability from IFCC CRM 470 to ERM-DA474/IFCC reference material and a change in the analytical measurement range (AMR).

Here's an analysis of the acceptance criteria and study data based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria and observed performance are provided for the method comparison studies.

Detection Capability (LoB, LoD, LoQ)

Interference

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

• Method Comparison – Modified RCRP assay vs Predicate RCRP assay:

  • Sample Size: 132 individual human native serum samples.
  • Data Provenance: Samples were obtained from "specimen vendors". The country of origin is not specified, nor is whether the data is retrospective or prospective.

• Method Comparison - RCRP assay on Dimension RXL system vs N High Sensitivity CRP on the BN™ System:

  • Sample Size: 171 for the overall comparison (5.3 to 241.3 mg/L) and 39 for the narrower range (5.3 to 20.2 mg/L).
  • Data Provenance: This study involved "re-analyzed historical IFU data." The original provenance (country, retrospective/prospective) of this historical data is not specified.

• Linearity Testing: Not specified, but generally involves a set of diluted samples or spiked matrix covering the analytical measurement range.

• Detection Capability (LoB, LoD, LoQ): Not specified.

• Precision:

  • Sample Size: 6 serum samples, analyzed with N=10 replicates each day for 5 days (total of 50 replicates per sample level).

• Specimen Equivalency:

  • Sample Size: 73 samples.
  • Data Provenance: Not specified, but likely from specimen vendors similar to the method comparison.

• Interference:

  • Sample Size: Not explicitly stated, but typically involves a control sample and test samples (with interferent) for assessment of bias.

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

This document describes an in vitro diagnostic (IVD) test, specifically an immunoassay for C-Reactive Protein. The "ground truth" for such devices is typically established through a reference method or known concentrations of certified reference materials, not through expert consensus or interpretation in the same way an imaging AI might.

• No human experts (e.g., radiologists) were used to establish ground truth for this type of device. The assessment is based on measured concentrations against established reference standards.

4. Adjudication Method for the Test Set

Not applicable. As described above, the ground truth for an IVD device like this is based on quantitative measurements and reference materials, not subjective interpretations requiring adjudication.

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

Not applicable. This is an in vitro diagnostic assay, not an AI-powered image analysis or diagnostic assist device that would involve human readers.

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

This device is a standalone algorithm/reagent system designed for automated quantitative measurement on a clinical chemistry system. Its performance is evaluated intrinsically through various analytical studies (method comparison, linearity, precision, detection capability, interference) without human-in-the-loop performance influencing the measurement itself. The results are then interpreted by clinicians.

7. The Type of Ground Truth Used

The ground truth for this device is based on:

• Reference Materials: For standardization, the device is traceable to ERM-DA474/IFCC reference material (and previously IFCC CRM 470). These are internationally recognized certified reference materials for CRP.
• Comparative Methods: The performance is benchmarked against a predicate RCRP assay and the N High Sensitivity CRP on the BN™ System. These are established laboratory methods.
• Clinical Laboratory Standards (CLSI): The studies follow guidelines from CLSI, which define how to robustly evaluate analytical performance parameters like precision, linearity, and detection limits.

8. The Sample Size for the Training Set

This document does not describe a machine learning or AI model that requires a distinct "training set" in the conventional sense. The device is a chemical reagent and assay system. Its "training" or development would involve extensive experimentation and optimization during the R&D phase to ensure reagent stability, reaction kinetics, and signal transduction are robust and accurate. This is not typically quantified as a "training set size" like in AI/ML contexts.

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

Not applicable, as this is not an AI/ML device with a defined training set and ground truth in that context. The "ground truth" for the development of such an assay would be through rigorous chemical and biological characterization, using known concentrations of analytes, reference materials, and established analytical chemistry principles.

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