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The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is an in vitro test using human plasma (K2EDTA) that combines the results of Lumipulse G pTau 217 Plasma and Lumipulse G β-Amyloid 1-42-N Plasma assays into a ratio of pTau 217 to β-Amyloid 1-42 concentrations using the LUMIPULSE G1200 System.

The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is intended to aid healthcare providers to identify patients with amyloid pathology associated with Alzheimer's disease.

The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is indicated for adult patients, aged 50 years and older, presenting at a specialized care setting with signs and symptoms of cognitive decline.

A test result ≤ 0.00370 is a negative result which is consistent with patients who are unlikely to have amyloid pathology. These patients should be investigated for other causes of cognitive decline.

A test result ≥ 0.00738 is a positive result which is consistent with patients who are likely to have amyloid pathology. This result does not establish a diagnosis of Alzheimer's disease or other cognitive disorders.

A test result between 0.00371 and 0.00737 is an indeterminate result which is consistent with patients who are uncertain to have amyloid pathology. These patients should be considered for further testing.

The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio results must be interpreted in conjunction with other patient clinical information.

This test is not intended as a screening or stand-alone diagnostic test.

The Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio is a test that combines the test results of the Lumipulse G pTau 217 Plasma assay and Lumipulse G β-Amyloid 1-42-N Plasma assay from the same patient specimen (K2EDTA plasma sample) into a numerical ratio from 0.00000 – 1.00000. The numerical ratio will be compared to the established cutoffs.

Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio = Lumipulse G pTau 217 Plasma (results in pg/mL) / Lumipulse G β-Amyloid 1-42-N Plasma (results in pg/mL) = a numerical value targeted up to 1.00000.

The Lumipulse G pTau 217 Plasma and Lumipulse G β-Amyloid 1-42-N Plasma are assay systems including a set of immunoassay reagents for the quantitative measurement of pTau 217 and β-amyloid1-42, respectively, in K2EDTA plasma specimens based on chemiluminescent enzyme immunoassay (CLEIA) technology. The LUMIPULSE G1200 is an instrument platform that can perform automated chemiluminescence immunoassays of specimens using LUMIPULSE G reagents. The LUMIPULSE G1200 reports the results of the two individual assays separately, and the ratio calculation must be done manually by the operator.

This document describes the acceptance criteria and the study proving the device meets those criteria, based on the provided FDA 510(k) Clearance Letter for the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio test.

Acceptance Criteria and Device Performance Study for Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio

The Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio is an in vitro diagnostic test intended to aid healthcare providers in identifying patients with amyloid pathology associated with Alzheimer's disease. The FDA 510(k) clearance letter details various performance characteristics and clinical study results that demonstrate the device meets its intended use.

1. Table of Acceptance Criteria and Reported Device Performance

The device's performance is primarily evaluated against its ability to classify patients into "Positive," "Indeterminate," and "Negative" categories based on their Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio, correlated with amyloid pathology confirmed by PET imaging or CSF testing.

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

• Test Set Sample Size: 499 patients were included in the pivotal clinical study to evaluate the performance of the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio.

• Data Provenance: The patient samples were collected from various sources:

  • Polaris-AD (AriBio) patient samples from the screening period of the clinical phase III study of AR1001.
  • Skåne University Hospital Memory Clinic, Malmö, Sweden plasma samples from BioFINDER-2.
  • Bio-Hermes-001 samples from Global Alzheimer's Platform Foundation.
  • University of Wisconsin Plasma samples from subjects enrolled in Wisconsin Registry for Alzheimer's Prevention (WRAP).

  The study included a mix of diagnostic groups: AD dementia, mild cognitive impairment (MCI), subjective cognitive decline (SCD), and other cognitive diagnoses. The data appears to be retrospective, as samples were collected from "screening period," "enrolled in," or "obtained from" existing studies/biobanks. The provenance includes data from Sweden and the United States (Wisconsin), and possibly other countries if the "Global Alzheimer's Platform Foundation" and "Polaris-AD" studies are international.

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

The clearance letter does not explicitly state the number of experts or their specific qualifications (e.g., Radiologist with X years of experience) used to establish the ground truth for the test set. However, the ground truth for amyloid pathology was established by:

• "Amyloid positivity confirmed by historic amyloid PET with an FDA-cleared tracer"
• "or FDA-cleared amyloid CSF ratio"
• For assay cutoff determination, "Subjects' clinical data included signs and symptoms of cognitive decline, amyloid PET with FDA-cleared tracer and/or FDA-cleared amyloid CSF ratio information."

This implies that the ground truth relies on established clinical and imaging standards (FDA-cleared PET and CSF tests), which are interpreted by qualified medical professionals (e.g., Nuclear Medicine Physicians for PET scans, neurologists for clinical data and CSF interpretation), rather than a specific panel of independent experts adjudicating each case for the study.

4. Adjudication Method for the Test Set

The document does not describe a formal "adjudication method" in the sense of multiple human readers or clinicians arriving at a consensus for the test set's ground truth. Instead, the ground truth was established using objective, FDA-cleared diagnostic modalities: amyloid PET scans and CSF amyloid ratio tests. The results from these cleared modalities inherently define the "amyloid status" used as the reference standard.

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

No Multi Reader Multi Case (MRMC) comparative effectiveness study was done. This device is an in vitro diagnostic test, not an imaging AI algorithm designed to assist human readers. Its performance is evaluated as a standalone diagnostic aid compared to established amyloid positivity criteria.

6. Standalone Performance

The study primarily evaluates the standalone performance of the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio in classifying patients' amyloid status. The device itself generates a ratio, and the interpretation rules ("Positive," "Indeterminate," "Negative") are applied to this ratio to determine the test result. The clinical study results (predictive values, frequency of results) directly demonstrate this standalone performance against the PET/CSF ground truth.

7. Type of Ground Truth Used

The type of ground truth used was amyloid pathology status, confirmed by either a positive amyloid PET scan (with an FDA-cleared tracer) and/or a positive amyloid CSF ratio (with an FDA-cleared test). This is a robust and clinically accepted method for determining amyloid pathology.

8. Sample Size for the Training Set

The document explicitly states that the 499 patients in the clinical study (Section C. Clinical Studies) are "distinct from the subjects evaluated in the pivotal clinical validation study" and refers to "banked K2EDTA plasma samples from the following sources" totaling 208 samples for the assay cut-off determination (Section VII.A.vii).

Therefore, the training set (for establishing cut-offs) consisted of 208 samples.

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

For the 208 samples used to determine the assay cut-offs (which can be considered the training set for the cut-off values), the ground truth was established by:

• Subjects' clinical data, including signs and symptoms of cognitive decline.
• Amyloid PET with FDA-cleared tracer and/or FDA-cleared amyloid CSF ratio information.

"Amyloid positivity was derived from either a positive amyloid PET and/or a positive amyloid CSF ratio." This indicates that the ground truth for the cut-off determination was established similarly to the clinical validation set, using a combination of clinical information and established biomarker positivity (PET/CSF).

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The Lumipulse G B-Amyloid Ratio (1-42/1-40) is an in vitro cerebral spinal fluid (CSF) test that combines the results of Lumipulse G B-Amyloid 1-42 and Lumipulse & B-Amyloid 1-40 assays into a ratio of ß-amyloid 1-42 to ß-amyloid 1-40 concentrations using the LUMIPULSE G 1200 System. The Lumipulse G B-Amyloid Ratio (1-42/1-40) is intended to be used in adult patients, aged 55 years and older, presenting with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive decline.

A test result ≥ 0.073 is a negative result which is consistent with a negative amyloid positron emission tomography (PET) scan result. A negative result reduces the likelihood that a patient's cognitive impairment is due to AD.

A test result ≤ 0.058 is a positive result which is consistent with a positive amyloid PET scan result. A positive result does not establish a diagnosis of AD or other cognitive disorder.

A test result between 0.059 and 0.072 is considered as a likely positive result as it is more likely consistent with a positive amyloid PET scan result. A likely positive result does not establish a diagnosis of AD or other cognitive disorders and has increased uncertainty in regard to amyloid PET positivity.

The Lumipulse G B-Amyloid Ratio (1-42/1-40) results must be interpreted in conjunction with other patient clinical information .

This test is not intended as a screening or stand-alone diagnostic test.

The Lumipulse G B-Amyloid Ratio (1-42/1-40) is an in vitro cerebral spinal fluid (CSF) test that calculates the ratio of two analytes, Lumipulse G ß-Amyloid 1-42 and Lumipulse & ß-Amyloid 1-40 assays to generate a numeric value between 0.001 to 1.000.

The test system consists of two component assays, Lumipulse & ß-Amyloid 1-42 and the Lumipulse G B-Amyloid 1-40 assay, running on LUMIPULSE G1200 system, and Lumipulse G B-Amyloid Ratio (1-42/1-40) Calculator Tool to calculate the Lumipulse G B-Amyloid Ratio (1-42/1-40). Lumipulse G B-Amyloid 1-42 and the Lumipulse G B-Amyloid 1-40 assays are packed individually. Results of individual assays have not been assessed to support the intended use except for determination of the Lumipulse G ß-Amyloid Ratio (1-42/1-40).

Acceptance Criteria and Device Performance for Lumipulse G ß-Amyloid Ratio (1-42/1-40)

This document describes the acceptance criteria and the study demonstrating the performance of the Lumipulse G ß-Amyloid Ratio (1-42/1-40) device.

1. Acceptance Criteria and Reported Device Performance

The core of the device's utility lies in its ability to predict amyloid PET scan results. The acceptance criteria and reported performance relate to the predictive values of the test for classifying patients as PET positive, likely positive, or negative.

Note on "Predictive Value for Negative Result (Ratio ≥ 0.073) for PET positivity": The table in the provided text for "Clinical Performance" presents the "Predictive Value %" as (Positive (n) / N), where N is the total for that Lumipulse G B-Amyloid Ratio category. Therefore, for the "Negative" category, "16.1% (15/93)" means that out of 93 patients with a negative Lumipulse G B-Amyloid Ratio, 15 (16.1%) were actually PET positive. This implicitly means that 93 - 15 = 78 (83.9%) were indeed PET negative when the Lumipulse test was negative.

2. Sample Size for Test Set and Data Provenance

• Sample Size for Test Set: 292 patients.
• Data Provenance: The data for the clinical performance study (test set) was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) sample bank.
  • Country of Origin: Not explicitly stated, but ADNI is a large-scale North American-based research study.
  • Retrospective or Prospective: The study utilized "banked CSF samples," indicating a retrospective approach to sample collection for the purpose of this device's validation. However, the PET evaluation was conducted, and the time interval between CSF sampling and PET evaluation was analyzed, suggesting that while samples were banked, their correlation to PET was part of the study design.

3. Number of Experts and Qualifications for Ground Truth

• Number of Experts: A minimum of three trained independent readers.
• Qualifications of Experts: The experts were "trained independent readers" who were blinded to all other clinical data. Their specific professional qualifications (e.g., radiologist, neurologist) or years of experience are not explicitly stated in the provided text.

4. Adjudication Method for the Test Set

• Adjudication Method: 2+1 adjudication method. The amyloid PET status for each patient was determined by a minimum of three trained independent readers. If the first two readers disagreed, an adjudicator's reading was used.

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

• Was an MRMC comparative effectiveness study done? No, the provided text does not describe an MRMC comparative effectiveness study comparing human readers with AI assistance versus human readers without AI assistance (i.e., the effect size of how much human readers improve with AI vs without AI assistance). The device is an in-vitro diagnostic (IVD) assay that produces a numerical ratio result, not an AI assisting human image interpretation.

6. Standalone Performance Study

• Was a standalone (algorithm only without human-in-the loop performance) done? Yes, the clinical performance study evaluates the performance of the Lumipulse G B-Amyloid Ratio (1-42/1-40) device in isolation against the ground truth (visual amyloid PET read). The device generates a numerical ratio which is then categorized (positive, likely positive, negative) and compared directly to the PET results, without direct human intervention in interpreting the device's output or integrating it into a diagnostic workflow with human readers.

7. Type of Ground Truth Used

• Type of Ground Truth: The ground truth used was visual amyloid PET scan results. This was determined by "Florbetapir (18F) PET evaluation," with images analyzed by visual read and scored as either amyloid PET positive or amyloid PET negative by trained independent readers with adjudication.

8. Sample Size for the Training Set

• Sample Size for Training Set: 235 patients were used to determine the assay cutoff. This group was from the Amsterdam Dementia Cohort (ADC). It is important to note that this was explicitly stated as "distinct from the subjects ... evaluated in the pivotal clinical validation study (test set)."

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

• How Ground Truth for Training Set was Established: For the 235 patients from the Amsterdam Dementia Cohort (ADC) used to determine the assay cutoff, the ground truth was visual amyloid PET scan status.
  • PET Tracers Used: Florbetaben (18F), Florbetapir (18F), and Flutemetamol (18F).
  • Interpretation: Images were analyzed by visual read and scored as either amyloid PET positive or amyloid PET negative.
  • Protocol: CSF collection, processing, and handling were conducted according to a "standardized ADC protocol." A "pre-analytical bridging study was conducted using fresh prospectively collected individual CSF samples" to account for variations between ADC and ADNI protocols.

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Lumipulse G CA15-3 is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of CA 15-3 in human serum or plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMPULSE G System.

The assay is to be used as an aid in the management of patients previously diagnosed with stage II and III breast cancer. Serial testing for patient CA15-3 assay values should be used in conjunction with other clinical methods used for monitoring breast cancer.

WARNING: The concentration of CA 15-3 in a given specimen, as determined by assays from different manufacturers, can vary due to differences in assay methods and reagent specificity. The results reported by the laboratory to the physician must include the identity of the assay for CA 15-3 used. Values obtained with different assay methods cannot be used interchangeably. If, in the course of monitoring a patient, the assay method used of CA 15-3 is changed, the laboratory must perform additional serial testing to confirm baseline values. Prior to changing assays, the laboratory MUST confirm baseline values for patients being serially monitored. Lumipulse G CA 15-3 should not be used for cancer screening or diagnosis.

Lumipulse G CA15-3 is an assay system, including a set of immunoassay reagents, for the quantitative measurement of CA 15-3 in specimens based on CLEIA technology by a two-step sandwich immunoassay method on the LUMIPULSE G System.

Lumipulse G CA15-3 Immunoreaction Cartridges: REF 235102 The Lumipulse G CA15-3 Immunoreaction Cartridges consists of 3 x 14 tests. Each kit contains the following:

1.) Antibody-Coated Particle Solution (Liquid when used, 250 µL/Immunoreaction Cartridge) Contains 150 µg/mL anti-CA 15-3 monoclonal antibody (mouse)-coated particles, protein stabilizers (bovine and mouse) and chemical stabilizers in 0.15 M sodium chloride/Tris buffer. This solution contains gelatin and turns into gel at 15°C or lower. Preservative: sodium azide.

2.) Enzyme-Labeled Antibody Solution (Liquid, 350 µL/Immunoreaction Cartridge) Contains 0.2 µg/mL alkaline phosphatase (ALP: calf)-labeled anti-CA 15-3 monoclonal antibody (mouse), protein stabilizers (bovine and calf) and chemical stabilizers in 0.1 M sodium chloride/MES buffer. Preservative: sodium azide.

Here's an analysis of the acceptance criteria and study detailed in the provided document, restructured to answer your specific questions:

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

The document primarily focuses on validating the Lumipulse G CA15-3 assay as "substantially equivalent" to a predicate device (ARCHITECT CA 15-3) and demonstrating its analytical and clinical performance. The acceptance criteria are largely implicit, based on meeting established guidelines (CLSI) and demonstrating satisfactory performance within defined ranges or against a predicate.

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

• Precision (ARUP 20-day): n=80 for each of 6 panels.
• Precision (Lot-to-Lot Reproducibility): n=90 for each of 6 samples (combined for Lots A, B, and C).
• Precision (Site-to-Site Reproducibility): n=102 for each of 6 panels (for Lot A).
• Linearity: Patient serum samples containing naturally expressed CA15-3. (Specific number not provided, but implies multiple dilutions for a range of samples).
• Detection Limit: Not explicitly detailed on sample size but derived from technical measurements.
• Interfering Substances: Human serum specimen pools with CA 15-3 concentrations ranging from approximately 30-35 U/mL, 80-100 U/mL, and 300-350 U/mL. (Number of pools or individual samples not provided, but implies multiple concentrations for each interferent).
• Method Comparison: n=117 samples.
• Matrix Comparison: Not explicitly detailed sample size, but involved various tube types (SST, K2EDTA, Lithium Heparin, and Sodium Heparin) versus control samples (Red top serum).
• Monitoring of Disease State in Patients Diagnosed with Breast Cancer:
  • Patients: 112 patients previously diagnosed with stage II and III breast cancer.
  • Observations: 566 pairs of observations, with an average of 6.1 observations per patient.
  • Data Provenance: Not explicitly stated as retrospective or prospective, nor country of origin, but described as patients "previously diagnosed with stage II and III breast cancer" and "monitoring recurrence or progressive disease," suggesting real-world patient data likely collected over time.
• Expected values/Reference range (Apparently Healthy): N=356 (120 males, 236 females).
• Expected values/Reference range (Apparently Healthy and Benign Subjects): N=591 (Includes the 356 healthy, plus additional benign groups: Benign Breast N=75, Benign Ovarian N=40, Urogenital N=40, Pregnant N=40, Hypertension N=40).
• Expected values/Reference range (Subjects with Cancer): N=368 (Treatment Naïve Breast N=130, Uterine/Endometrial N=40, Ovarian N=40, Lung N=40, Colorectal N=38, Pancreatic N=40, Liver N=40).

The provenance details (country, retrospective/prospective) are not explicitly mentioned for most studies, although the patient cohorts for disease monitoring and reference ranges imply real clinical data collection.

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

This device is an in vitro diagnostic (IVD) assay for a biomarker (CA15-3).

• For the analytical performance studies (precision, linearity, detection limits, interference, cross-reactivity), the "ground truth" is established through highly controlled laboratory procedures, reference materials, and defined statistical methods (e.g., CLSI guidelines). There is no "expert" per se establishing ground truth in the way a radiologist does for an imaging study. The accuracy is relative to reference measurements or established methods.
• For the method comparison study (against ARCHITECT CA 15-3), the predicate device serves as the comparative reference, which itself would have been validated.
• For the clinical performance study (Monitoring of Disease State), the ground truth for "disease progression" or "no progression" was not established by expert consensus of imaging or pathology specific to this study. Instead, disease status changes were assessed by "other clinical methods used for monitoring breast cancer" which likely includes physician assessment, imaging, and possibly pathology reports. The study assessed changes in CA15-3 levels against these "changes in disease status," which is the outcome used as the ground truth. No specific number or qualification of experts defining the clinical ground truth within this study is provided. However, the initial "staging of the patients was done according to AJCC 7th edition," which implies expert clinical assessment in their initial diagnosis.

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

For an IVD assay measuring a biomarker, adjudication methods like 2+1 or 3+1 (common in image-based AI studies where human readers interpret images) are generally not applicable. The "ground truth" for quantitative assays is based on a reference standard or, in clinical studies, the established clinical diagnosis/status.

In the clinical monitoring study, the "change in disease status" serves as the clinical outcome (ground truth), but the method for determining this status retrospectively or prospectively, and if it involved adjudication, is not described.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This is an in vitro diagnostic (IVD) assay for a blood biomarker (CA15-3), not an AI-assisted diagnostic imaging device meant to assist human readers. Therefore, the concept of human readers improving with AI assistance is not applicable here.

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

Yes, the analytical and clinical performance studies are standalone performance evaluations of the Lumipulse G CA15-3 assay. The device provides a quantitative measurement of CA15-3 in a sample. The performance characteristics (precision, linearity, detection limit, interference, method comparison) and the clinical utility for monitoring disease progression are all evaluated based on the assay's output directly, without a human in the loop interpreting the assay's numerical result in a subjective way. The clinical monitoring study, for instance, directly correlates changes in the assay's output with disease progression, demonstrating its standalone utility for this purpose.

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

• Analytical Studies: For analytical performance characteristics (precision, linearity, detection limit, interference, cross-reactivity), the ground truth is established by carefully prepared reference materials, spiked samples, and highly controlled laboratory procedures consistent with CLSI guidelines, aiming for accurate measurement against these known values.
• Method Comparison: The ground truth is the measurement obtained by the legally marketed predicate device (ARCHITECT CA 15-3).
• Clinical Monitoring Study: The ground truth for disease progression/no progression was based on outcomes data defined as "changes in disease status" over time, using "other clinical methods used for monitoring breast cancer." This likely refers to a combination of clinical assessments, imaging, and possibly pathology results, but no specific details on the exact methods or their adjudication are provided within the document.

8. The sample size for the training set

The terms "training set" and "test set" are typically used for machine learning or AI models. This document describes the validation of an IVD assay, not an AI system. Therefore, there isn't a traditional "training set" in the machine learning sense. The bulk of the studies (analytical and clinical performance) serve as the validation/testing to demonstrate the device's performance characteristics. If we loosely interpret "training set" as data used during the development phase to optimize the assay before formal validation, this information is not provided in the 510(k) summary, as it focuses on the performance of the finalized device.

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

As explained above, there isn't a "training set" in the context of an AI model for this IVD device. The assay development would involve rigorous chemical and biological optimization, and calibration against reference materials, but this specific "ground truth establishment" for a training set is not applicable or detailed here.

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The Tosoh ST AIA-PACK BNP assay is designed for IN VITRO DIAGNOSTIC USE ONLY for the quantitative measurement of BNP in human K2EDTA plasma on Tosoh AIA System analyzers. BNP is used as an aid in the diagnosis of heart failure (HF) in patients presenting to the emergency department (ED) with clinical suspicion of new onset HF, acutely decompensated or exacerbated HF.

The ST AIA-PACK BNP is a two-site immunoenzymometric assay which is performed entirely in the ST AIA-PACK BNP test cups. BNP present in the test sample is bound with monoclonal antibody immobilized on magnetic beads and enzyme-labeled monoclonal antibody. The magnetic beads are washed to remove unbound enzyme-labeled monoclonal antibody and are then incubated with a fluorogenic substrate, 4-methylumbelliferyl phosphate (4MUP). The amount of enzyme-labeled monoclonal antibody that binds to the beads is directly proportional to the BNP concentration in the test sample. A standard curve is constructed, and unknown sample concentrations are calculated using the curve.

The provided text describes the performance characteristics and clinical study results for the ST AIA-PACK BNP assay, an in vitro diagnostic device. This device is intended for the quantitative measurement of BNP in human K2EDTA plasma as an aid in the diagnosis of heart failure (HF).

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

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

The document does not explicitly state "acceptance criteria" in a table format with pass/fail thresholds. Instead, it presents performance data from various analytical and clinical studies. We can infer performance parameters that would typically be subject to acceptance criteria in such a submission.

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

• Test Set Sample Size:
  • Analytical Performance:
    • Precision: 6 K2EDTA plasma samples tested, each at n=80 per lot across 3 lots (total n=240 for combined lot analysis).
    • Linearity: 14 samples ranging from 3.1 - 2271.5 pg/mL.
    • Detection/Quantitation Limit: 11 low-level samples tested in 10 replicates each (2 replicates over 5 days).
    • Interference: K2EDTA samples with known BNP concentrations spiked with various interferents/cross-reactants. Specific N for each interferent test not explicitly stated but implied multiple samples.
  • Clinical Performance:
    • Number of samples assayed: 825
    • Number of samples used for analysis (test set): 724 (101 excluded due to hemolysis, severe renal insufficiency, etc.)
• Data Provenance:
  • Country of Origin: Not explicitly stated for analytical samples. For clinical study: Samples were collected from patients presenting to Emergency Departments (EDs) at 8 clinical sites. The specific country is not mentioned, but given the FDA submission, it is likely the US or a region adhering to similar clinical trial standards.
  • Retrospective or Prospective:
    • Analytical performance: Appears to be prospective testing (e.g., precision study conducted at one site with specified reagents/analyzers, linearity study explicitly designed).
    • Clinical Performance: Prospective study, as it states "The prospective study enrolled male and female patients from 8 clinical sites comprised of Emergency Departments (ED)."

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

• Number of Experts: An independent central adjudication panel comprised of 4 expert cardiologists and 1 ER physician.
• Qualifications of Experts: Expert Cardiologists and an ER Physician. Their specific years of experience are not stated, but their designation as "expert" and the role in an adjudication panel for a clinical trial implies significant experience and qualifications in their respective fields related to heart failure diagnosis.

4. Adjudication method for the test set

• Adjudication Method: Diagnosis of HF or non-HF was determined by an independent central adjudication panel. The panel had access to patient CRFs and clinical information (including echocardiography, other cardiac/thoracic imaging, and standard of care BNP or NT-proBNP results if available). They were blinded to the attending physician's final diagnosis and NYHA classification. The document states that the adjudication was done "to ensure standardization and accuracy of diagnosis per 2013 ACCF/AHA Guidelines for Management of HF." This indicates a consensus-based approach based on comprehensive clinical data, supervised by multiple blinded experts.

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 was not done. This submission is for an in vitro diagnostic (IVD) device (a blood test for BNP), not an AI-assisted diagnostic imaging device. Therefore, the concept of "human readers improving with AI vs without AI assistance" does not apply in this context. The study evaluates the performance of the assay itself compared to a ground truth established by clinical adjudication.

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

• Yes, a standalone performance was done. The clinical study evaluates the performance of the "ST AIA-PACK BNP assay" itself to quantitatively measure BNP and its ability to aid in the diagnosis of HF. The results (sensitivity, specificity, AUC) are presented as the performance of the device at the given cutoff, without human interpretation of the device's output influencing the performance metrics being reported. The human element (adjudication panel) was used to establish the ground truth for diagnosis, against which the device's measurements were compared.

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

• Type of Ground Truth: The ground truth for the clinical study was established by expert consensus based on comprehensive clinical information and per established guidelines. Specifically, the "Diagnosis of HF or non- HF was determined by an independent central adjudication panel (comprised of 4 expert cardiologists and 1 ER physician) ... per 2013 ACCF/AHA Guidelines for Management of HF." They had access to patient CRFs, echocardiography, other cardiac/thoracic imaging, and standard of care BNP/NT-proBNP results. This represents a robust form of expert consensus based on extensive clinical data.

8. The sample size for the training set

• The document does not explicitly mention a separate "training set" for the device's development. The "Performance Characteristics" section details analytical and clinical validation studies. For a quantitative IVD like this, the "training" aspect is typically related to the assay's development, calibration, and optimization of reagents and protocols, rather than an explicit "training set" used in machine learning. The clinical study described is a validation study (test set).

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

• As a specific "training set" for algorithmic learning is not mentioned (as this is a biochemical assay), the concept of ground truth for a training set in that sense does not apply directly. However, the development of such an assay involves extensive work to ensure its accuracy and reliability across the dynamic range, linearity, precision, and minimizing interference. This often uses well-characterized, sometimes synthetic or spiked, samples with known concentrations to inform the assay's design and calibration. The "Traceability" section mentions that "The ST AIA-PACK BNP CALIBRATOR SET contains assigned concentrations of BNP. The assigned value is determined on a lot-by-lot basis and is designed to provide an assay calibration range of 4.0 to 2,000 pg/mL of BNP. The calibrators in this set are prepared gravimetrically and are compared to internal reference standards." This implies the "ground truth" for the internal calibration and ongoing quality control of the assay is established through gravimetric preparation and comparison to internal reference standards.

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Lumipulse® G CA19-9-N is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative measurement of CA 19-9 in human serum or plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMIPULSE G System.

The assay is to be used as an aid in the management of patients diagnosed with cancer of the exocrine pancreas who have detectable levels of CA 19-9 at some point in their disease process. Serial testing for patient CA 19-9 assay values should be used in conjunction with other clinical methods used for monitoring cancer of the exocrine pancreas.

The Lumipulse G CA19-9-N Immunoreaction Cartridges (cat. # 235126) consists of 3 x 14 tests. Each kit contains the following:

1. Antibody-Coated Particle Solution (Liquid when used, 250 µL/Immunoreaction Cartridge) Contains 150 µq/mL anti-CA19-9 monoclonal antibody (mouse)-coated particles, protein stabilizers (bovine and mouse) and chemical stabilizers in 0.15 M sodium chloride/Tris buffer. This solution contains gelatin and turns into gel at 15 ℃ or lower. Preservative: sodium azide.
2. Enzyme-Labeled Antibody Solution (Liquid, 350 µL/Immunoreaction Cartridge) Contains 0.5 µg/mL alkaline phosphatase (ALP: calf)-labeled anti-CA19-9 monoclonal antibody (mouse), protein stabilizers (bovine, calf, and mouse) and chemical stabilizers in 0.05 M sodium chloride/Bis-Tris buffer. Preservative: sodium azide.

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

Context: This document describes a Special 510(k) submission for the Lumipulse G CA19-9-N device, specifically addressing a change in the tested concentration of the therapeutic interferent Tamoxifen. The device is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative measurement of CA 19-9, used as an aid in the management of patients with cancer of the exocrine pancreas.

Acceptance Criteria and Reported Device Performance

Study Details

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

   • Sample Size: Not explicitly stated for the "Supplemental Therapeutic Interference Study." However, the tables comparing the cleared vs. modified device list "Samples (Mean Test Concentrations (U/mL) (n=3))" and "Samples (Mean Control Concentrations (U/mL) (n=3))" for three serum pools. This suggests that for each serum pool, there were likely 3 replicates tested (n=3).
   • Data Provenance: Not specified, but given it's an in vitro diagnostic measuring a biomarker, the samples would be human serum/plasma. The document does not mention country of origin or whether the data was retrospective or prospective, though interference studies are typically laboratory-based and prospective using spiked samples or naturally interfering samples.

2. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications: Not applicable. This study is an interference study for an in vitro diagnostic device measuring a quantitative biomarker (CA 19-9). Ground truth is established by the known concentration of the substance being measured (CA 19-9) and the known concentration of the interferent (Tamoxifen). Expert consensus or pathologist review is not relevant for this type of test.

3. Adjudication Method for the Test Set: Not applicable. This is an interference study for a quantitative assay, not a subjective diagnostic interpretation.

4. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done: No, an MRMC study was not done. This type of study is typically performed for image-based diagnostics where multiple readers interpret cases with and without AI assistance. This document pertains to an in vitro diagnostic assay.

5. If a Standalone Performance Study was done: Yes, a standalone performance study in the form of a "Supplemental Therapeutic Interference Study" was conducted. This study assessed the device's performance (specifically, its susceptibility to Tamoxifen interference) without human interpretation in the loop, by comparing results with and without the interferent to a control.

6. The Type of Ground Truth Used: The ground truth for this interference study is established by:

   • The known, pre-established concentrations of CA 19-9 in the serum pools used.
   • The known concentration of Tamoxifen added to the samples.
   • The "control" measurements (samples without Tamoxifen) serve as the reference for determining the "percent difference."

7. The Sample Size for the Training Set: Not applicable. This is not a machine learning or AI-based device that requires a training set in the conventional sense. The "training" for such an assay is its analytical development and optimization.

8. How the Ground Truth for the Training Set was Established: Not applicable, as there is no training set for this type of in vitro diagnostic device in the context of machine learning. The assay is built on established chemical and immunological principles, with performance characteristics determined through analytical validation studies (like interference studies).

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For in vitro diagnostic use.
Lumipulse G whole PTH is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative measurement of PTH (1-84) in human serum and plasma on the LUMIPULSE G System. Measurements of parathyroid hormone levels are used in the differential diagnosis of hypercalcemia and hypocalcemia resulting from disorders of calcium metabolism.

The Lumipulse G whole PTH Immunoreaction Cartridges consists of 3 × 14 tests. Each kit contains the following:

1. Antibody-Coated Particle Solution (Liquid when used, 200 µL/Immunoreaction Cartridge) Contains 200 µg/mL anti-PTH polyclonal antibodies (goated ferrite particles, protein stabilizers (bovine and goat) and chemical stabilizers in MES buffer. This solution contains gelatin and turns into gel at 15 °C or lower. Preservative: ProClin 300
2. Enzyme-Labeled Antibody Solution (Liquid, 120 µL/Immunoreaction Cartridge) Contains 0.2 µq/mL alkaline phosphatase (ALP: calf)-labeled anti-PTH polyclonal antibody (qoat), protein stabilizers (bovine) and chemical stabilizers in MES buffer. Preservative: ProClin 300

Here's a breakdown of the acceptance criteria and the study details for the Lumipulse G whole PTH device, based on the provided FDA 510(k) summary:

Device: Lumipulse G whole PTH (Fujirebio Diagnostics, Inc.)
Intended Use: Quantitative measurement of PTH (1-84) in human serum and plasma on the LUMIPULSE G System for differential diagnosis of hypercalcemia and hypocalcemia.

1. Table of Acceptance Criteria and Reported Device Performance

The document describes various analytical performance characteristics. For each characteristic, the reported performance is presented. Acceptance criteria are generally implied by the positive outcomes of the studies and their adherence to CLSI guidelines. For example, for precision, a certain percentage of Coefficient of Variation (%CV) is considered acceptable.

2. Sample Size and Data Provenance (for test set/performance studies)

The document refers to various samples for different analytical studies:

• 20-Day Precision: A panel of seven native human serum samples (n=80 replicates for each sample). The study was conducted at an internal laboratory. Origin of samples is "native human serum" but specific country/retrospective/prospective nature is not specified beyond that.
• Lot-to-Lot Precision: A panel of four native human serum samples and two control levels (n=32 replicates per lot, 96 total replicates per sample/control across three lots). Internal laboratory. "Native human serum" for samples.
• Site-to-Site Precision: A panel of five native serum samples (n=combined data for site-to-site analysis). Internal laboratory and two additional sites. "Native serum" for samples.
• Linearity: High and low sample pools created using patient serum samples that contained naturally expressed whole PTH. Specific number of samples not detailed, but the linearity range was derived from these pools.
• Detection Limit (LoB, LoD, LoQ): Four blank and four low-level serum specimens (LoB/LoD: 60 determinations for each panel per lot); five low-level serum (LoQ: on 2 systems with 2 lots across several days).
• Analytical Specificity/Cross Reactivity: A panel of serum samples with naturally occurring whole PTH (n=4 panel members) for cross-reactivity with 10 different substances.
• Interfering Substances: Human serum specimen pools with whole PTH concentrations of approximately 35.1, 81.5, and 235.9 pg/mL.
• Matrix Comparison: Seventy-one (71) matched sets of serum and plasma samples.
• Method Comparison: A total of 275 matched human serum samples.
• Expected Values/Reference Range: 147 serum specimens from an "apparently healthy adult population (22-72 years old)."

Data Provenance Remarks:

• All studies mentioned use "native human serum" or "patient serum samples," indicating biological samples.
• Studies were conducted at "internal laboratory" and "two additional sites," suggesting multi-site evaluation for some parameters.
• The document does not explicitly state geographical origin (e.g., country) or whether samples were retrospective or prospectively collected for most analytical studies. The "apparently healthy adult population" for expected values implies a specific collection for that purpose.

3. Number of Experts and Qualifications for Ground Truth

• The document is for an in vitro diagnostic (IVD) device that measures a biomarker (PTH). The ground truth for such devices is typically established by reference methods, defined concentrations, or clinically characterized samples.
• Therefore, no "experts" (e.g., radiologists) are explicitly mentioned or required to establish a ground truth for diagnostic imaging interpretation, as this is not an imaging device.
• The ground truth for the analytical studies comes from:
  • Known concentrations: For calibrators, controls, and spiked samples (e.g., linearity, detection limits, cross-reactivity, interfering substances).
  • Clinical characterization: For "native human serum" samples, their PTH levels are measured.
  • International standards: Traceability of calibration is to the 1st international standard for Parathyroid Hormone 1-84 (code: 95/646) provided by the NIBSC.

4. Adjudication Method for the Test Set

• Not applicable. This section typically applies to diagnostic imaging studies where expert readers adjudicate findings. For an IVD device measuring a biomarker, the "ground truth" is determined by the analytical measurement process itself using established methods, standards, and controls.

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

• No. An MRMC study is relevant for diagnostic imaging AI, where multiple human readers interpret cases with and without AI assistance. This device is an in vitro diagnostic for quantitative measurement of a biomarker and does not involve human readers interpreting images.

6. Standalone Performance Study

• Yes, for the device itself. All the analytical performance studies (precision, linearity, detection limits, specificity, interference, specimen stability, matrix comparison) described are studies of the Lumipulse G whole PTH device operating in a standalone mode (i.e., the algorithm/assay system without human-in-the-loop performance influencing the measurement output directly).
• The Method Comparison study directly compares the standalone performance of the Lumipulse G whole PTH to a legally marketed predicate device (LIAISON® 1-84 PTH Assay), which also measures PTH quantitatively without human interpretation within the measurement process.

7. Type of Ground Truth Used

The ground truth for the performance studies is established by:

• Reference Materials/International Standards: Calibration is traceable to the 1st international standard for Parathyroid Hormone 1-84 (code: 95/646) provided by the National Institute for Biological Standards and Controls (NIBSC).
• Spiked Samples/Known Concentrations: For studies like linearity, detection limits, cross-reactivity, interfering substances, where specific amounts of analyte or interfering substances are added to samples.
• Clinically Characterized Patient Samples: "Native human serum" or "patient serum samples" are used, with their PTH levels being the "truth" for evaluation against expected performance or comparison with other methods.
• Predicate Device Comparison: For the method comparison study, the results from the legally marketed predicate device (LIAISON® 1-84 PTH Assay) serve as a comparative "ground truth" or reference for evaluating substantial equivalence.

8. Sample Size for the Training Set

• The document does not provide information on a specific "training set" sample size. This submission is for an IVD assay, not typically a machine learning or AI algorithm that undergoes explicit "training" as defined in the context of imaging AI.
• For IVD assays, method development and optimization phases internally use numerous samples, but these are generally considered part of the product development, not a formal "training set" like in AI. The studies presented here are for validation and verification of the developed assay.

9. How Ground Truth for the Training Set Was Established

• Not applicable in the context of an IVD assay as presented. As explained above, there isn't a "training set" in the common AI/ML sense.
• Ground truth for assay development and optimization (analogous to "training" in a broad sense) would rely on the same principles as the validation studies: known concentrations, reference materials, and clinically characterized samples.

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The Lumipulse G B•R•A•H•M•S PCT is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of PCT (procalcitonin) in human serum and plasma (sodium heparin, sodium citrate or dipotassium EDTA) on the LUMIPULSE G System.

Used in conjunction with other laboratory findings and clinical assessments, Lumipulse G B.R.A.H.M.S PCT is intended for use as an:

· Aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission for progression to severe sepsis and septic shock.

· Aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.

· Aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) – in an inpatient setting or an emergency department.

· Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

Lumipulse G B.R.A.H.M.S PCT Calibrators set

Lumipulse G B R A H M S PCT Calibrators set is for in vitro diagnostic use in the calibration of Lumipulse G B.R.A.H.M.S.PCT on the LUMIPULSE G System.

Lumipulse G B+R•A•H•M•S PCT is an assay system, including a set of immunoassay reagents, for the quantitative measurement of PCT in specimens based on CLEIA technology by a two-step sandwich immunoassay method on the LUMIPULSE G1200 System.

Lumipulse G B.R.A.H.M.S PCT Immunoreaction Cartridges: | IRC 235058. The Lumipulse G B•R•A•H•M•S PCT Immunoreaction Cartridges consists of 3 x 14 tests. Each kit contains the following:

1.) Antibody-Coated Particle Solution (Liquid when used, 250 µL/Immunoreaction Cartridge) Contains 150 µg/mL anti-PCT monoclonal antibody (mouse) and anti-calcitonin monoclonal antibody (mouse) coated particles, protein stabilizers (bovine and mouse) and chemical stabilizers in 0.15 M sodium chloride/Tris buffer. This solution contains gelatin and turns into gel at 15°C or lower. Preservative: sodium azide.

2.) Enzyme-Labeled Antibody Solution (Liquid, 350 µL/Immunoreaction Cartridge) Contains 0.25 µg/mL alkaline phosphatase (ALP: calf)-labeled anti-katacalcin monoclonal antibody (mouse), protein stabilizers (bovine, calf and mouse) and chemical stabilizers in 0.1 M sodium chloride/MES buffer. Preservative: sodium azide.

Lumipulse G B+R+A+H+M+S PCT Calibrators set |CAL SET 234150, Lyophilized, 2 x 2 Concentrations

Each calibrator kit contains one bottle each of Calibrators 1 - 2, and Reconstituting Solution. The calibrator kit is packaged separately.

CAL 1 0 ng/mL PCT calibrator (2 x 0.5 mL/vial)

CAL 2 100 ng/mL PCT calibrator (2 x 0.5 mL/vial)

Contains procalcitonin in 0.15 M sodium chloride in Tris buffer with protein stabilizer (bovine). Preservative: ProClin 300.

RS Reconstituting Solution: Liquid, 1 x 10 mL Preservative: sodium azide.

These calibrators are lyophilized and have to be prepared by adding exactly 0.5 mL of Reconstituting Solution to each Iyophilized calibrator.

The provided document describes the Lumipulse G B.R.A.H.M.S PCT Immunoreaction Cartridges and its associated calibrator set. This is an in-vitro diagnostic device, not an AI/ML medical device. Therefore, the questions related to AI/ML device acceptance criteria, performance studies (sample sizes, expert usage, adjudication, MRMC studies, standalone performance), and ground truth establishment are not applicable.

However, based on the provided text, the device's analytical performance and comparison studies can be summarized as follows:

1. A table of acceptance criteria and the reported device performance (for Analytical Performance):

The document refers to CLSI protocols for acceptance criteria, specifically for precision, linearity, and analytical specificity. The acceptance criteria themselves are generally implied by meeting the guidelines or by specific thresholds mentioned in conjunction with the results.

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

• Precision (20-day): n=80 for each sample (Control Levels 1-3, Panels 1-8). Data generated at Fujirebio Diagnostics, Inc. (FDI).
• Precision (Lot-to-Lot Reproducibility): n=120 for each sample (Control Levels 1-3, Panels 1-6).
• Precision (Site-to-Site Reproducibility): n=120 for each panel (Control Levels 1-3, Panels 1-6). Performed at "several sites" (implied, typical for site-to-site reproducibility; specific sites or countries not mentioned).
• Linearity/Reportable Range: High and low sample pools created using patient serum samples. Number of samples not specified, but the study was "consistent with the guidelines in the CLSI Protocol EP6-A."
• Detection Limit (LoB/LoD/LoQ): Seven low-level specimens were tested over 3 days using two LUMIPULSE G1200 Systems and two Lumipulse G PCT lots, giving 120 determinations per panel for LoD. Number of unique samples for LoQ not specified, but involved "modeling analysis."
• Analytical Specificity (Interference): Human serum specimen pools (approximately 0.25 and 2.0 ng/mL PCT) supplemented with potentially interfering compounds. Number of individual samples not specified.
• Analytical Specificity (Cross-Reactivity): Human serum specimens (approximately 0.1, 0.25, 0.5, 2.0 and 80 ng/mL PCT) supplemented with potentially cross-reacting compounds. Number of individual samples not specified.
• Method Comparison: n=207 lithium heparin specimens.
• Expected Values/Reference Range: Population of 213 self-reported healthy individuals.

Data Provenance: The document does not explicitly state the country of origin for all patient samples or whether studies were retrospective or prospective, beyond "human serum," "patient serum samples," or "self-reported healthy individuals." The precision studies were conducted at "FDI" (Fujirebio Diagnostics, Inc. in Malvern, PA, USA) and "across several sites."

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):

Not applicable. This is an immunoassay device for quantitative determination of Procalcitonin (PCT), where the "ground truth" is measured analytically by the device itself or compared to a predicate device. It does not involve human interpretation of images or other subjective data that would require expert consensus for ground truth.

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

Not applicable. As described above, this device is a quantitative immunoassay and does not involve human adjudication methods for its analytical performance or comparison studies.

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

Not applicable. This is an in-vitro diagnostic device, not an AI/ML device, and does not involve human readers interpreting cases.

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

Not applicable. This is an in-vitro diagnostic device, not an AI/ML device. The performance data presented are for the analytical device itself.

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

For the analytical performance studies (precision, linearity, detection limits, specificity), the "ground truth" is typically defined by reference materials, spiked samples with known concentrations, or established analytical methods. For method comparison, the predicate device (B.R.A.H.M.S PCT sensitive KRYPTOR®) serves as the comparator. For establishing expected values, the measured PCT levels in a population of "self-reported healthy individuals" are used.

8. The sample size for the training set:

Not applicable in the context of AI/ML. For analytical performance, the samples used in the various studies (e.g., 20-day precision, lot-to-lot, site-to-site, linearity, detection limits, interference, cross-reactivity) are referred to as test samples or panels to evaluate the device's accuracy and reliability. There is no concept of a "training set" in the AI/ML sense for this type of IVD device.

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

Not applicable, as there is no "training set" in the AI/ML sense. The analytical performance is established through rigorous testing against reference materials and predicate devices following CLSI guidelines.

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For in vitro diagnostic use. Lumipulse G TSH-III is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of thyroid stimulation hormone (TSH) in human serum on the LUMIPULSE G System. Lumipulse GTSHIII is to be used as an aid in the diagnosis of thyroid or pituitary disorders.

Lumipulse GTSH-III is an assay system, including a set of immunoassay reagents, for the quantitative measurement of TSH in specimens based on CLEIA technology by a two-step sandwich immunoassay method on the LUMIPULSE G System. TSH in specimens specifically binds to anti-human TSH monoclonal antibody (mouse) on the particles, and antigen-antibody immunocomplexes are formed. The particles are washed and rinsed to remove unbound materials. Alkaline phosphatase (ALP: calf)-labeled anti-human TSH monoclonal antibody (mouse) specifically binds to TSH of the immunocomplexes on the particles, and additional immunocomplexes are formed. The particles are washed and rinsed to remove unbound materials. Substrate Solution is added and mixed with the particles. AMPPD contained in the Substrate Solution is dephosphorylated by the catalysis of ALP indirectly conjugated to particles. Luminescence (at a maximum wavelength of 477 nm) is generated by the cleavage reaction of dephosphorylated AMPPD. The luminescent signal reflects the amount of TSH.

The Lumipulse® G TSH-III Immunoreaction Cartridges is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of thyroid stimulating hormone (TSH) in human serum on the LUMIPULSE G System. It is intended for in vitro diagnostic use, as an aid in the diagnosis of thyroid or pituitary disorders.

The study presented focuses on demonstrating the analytical performance and method comparison of the Lumipulse G TSH-III assay against the predicate device, Abbott ARCHITECT TSH assay, to establish substantial equivalence.

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample Size for the Test Set and Data Provenance

• Precision/Reproducibility (20-Day): 5 human serum-based panels, assayed in replicates of two at two separate times of the day for 20 days (n=80 for each sample). The origin of these human serum-based panels is not explicitly stated regarding country or retrospective/prospective nature, but they are described as "human serum-based panels."
• Lot-to-Lot Reproducibility: 3 panels, specific sample size (replicates/days) not explicitly stated but part of a larger precision analysis.
• Site-to-Site Reproducibility: 3 panels (Lot A), specific sample size (replicates/days) not explicitly stated but part of a larger precision analysis.
• Linearity/Assay Reportable Range: High and low sample pools, number of samples not explicitly stated beyond "patient samples."
• Detection Limit (LoB & LoD): Eight low-level specimens tested over 6 weeks using two LUMIPULSE G1200 Systems and two Lumipulse G TSH-III lots, giving 480 determinations for each panel.
• Analytical Specificity: Human serum specimens with TSH concentrations of approximately 0.566, 2.530, and 67.515 ulU/mL, supplemented with potentially interfering compounds.
• Cross-reactivity: Human serum specimens with TSH concentrations of approximately 0.566, 2.530, and 67.515 µIU/mL, supplemented with potentially cross-reacting compounds (n=3 for each test concentration).
• Method Comparison: 141 serum samples, ranging from 0.026 to 84.299 µIU/mL (Lumipulse G TSH-III) and 0.030 to 89.930 µIU/mL (ARCHITECT TSH). The provenance (e.g., country of origin, retrospective/prospective) of these samples is not specified beyond being "patient samples."
• Expected values/Reference range: 116 healthy test subjects. Provenance is not specified.

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

This type of immunoassay performance study typically does not involve human expert adjudication for ground truth of individual measurements in the same way imaging or diagnostic accuracy studies might. The "ground truth" for the performance characteristics (precision, linearity, detection limits, specificity) is based on the inherent analytical properties of the reference materials, calibrated instruments, and statistical methodologies (e.g., CLSI protocols). For the method comparison, the predicate device (Abbott ARCHITECT TSH) serves as the comparator, and its established performance is implicitly relied upon.

4. Adjudication Method for the Test Set

Not applicable in the conventional sense. The "ground truth" for analytical performance is derived from well-defined reference materials, established concentrations, and statistical analyses following recognized CLSI protocols. For method comparison, the reference measurements from the predicate device serve as the comparison point.

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

No, an MRMC comparative effectiveness study was not done. This device is an automated in vitro diagnostic assay, not an imaging or diagnostic aid that involves human readers interpreting cases with or without AI assistance. Therefore, there is no effect size reported for human readers improving with or without AI assistance.

6. Standalone Performance

Yes, a standalone performance study was done. All performance characteristics (precision, linearity, detection limits, analytical specificity, and method comparison) evaluate the Lumipulse G TSH-III assay's performance as a standalone algorithm/device. The results reported are direct measurements from the LUMIPULSE G System.

7. Type of Ground Truth Used

• Precision/Reproducibility: Based on repeated measurements of samples with established concentrations, and statistical analysis of variability.
• Linearity/Assay Reportable Range: Established using prepared high and low sample pools with known TSH concentrations and assessed by linear regression analysis.
• Detection Limits (LoB, LoD, LoQ/FS): Determined statistically from measurements of very low concentration samples according to CLSI guidelines.
• Analytical Specificity/Cross-reactivity: Determined by measuring samples spiked with known concentrations of interfering or cross-reacting substances.
• Method Comparison: Compared against the measurements obtained from a legally marketed predicate device (Abbott ARCHITECT TSH), which itself has established performance characteristics.
• Traceability of Calibrators: Traceable to the 3rd International Standard, 2003 (code: 81/565) by the National Institute for Biological Standards and Control (NIBSC).

8. Sample Size for the Training Set

The document describes performance studies, which are typically validation studies. It does not explicitly mention a "training set" in the context of an AI/machine learning model. For a traditional immunoassay, the "training" aspect is more akin to the assay development and optimization process, not a distinct dataset used for machine learning. The calibrators and controls are used for instrument calibration and assay quality control, not as a training set for an AI algorithm.

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

Not applicable in the context of an AI training set. For an immunoassay, the "ground truth" for calibrators and controls is established through gravimetric preparation and traceability to international standards (e.g., NIBSC 3rd International Standard for TSH).

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Lumipulse G Progesterone-N Calibrators are for in vitro diagnostic use in the calibration of Lumipulse G Progesterone-N on the LUMIPULSE G System.

Lumipulse G Progesterone-N Calibrator kit contains 3 bottles (1.5 mL each) of Lumipulse G Progesterone-N Calibrators 1, 2, and 3. Calibrators 1, 2, and 3 contain progesterone in 0.15 M sodium chloride in MES buffer with protein (bovine) and chemical stabilizers. Preservative: sodium azide.

Lumipulse G Progesterone-N Calibrators CAL 230893, Liquid 1x3 concentrations Each calibrator kit contains one bottle each of Calibrators 1 – 3. The calibrator kit is packaged separately.

CAL 1 0 ng/mL Progesterone calibrator (1 × 1.5 mL) CAL 2 0.5 ng/mL Progesterone calibrator (1 x 1.5 mL) 40 ng/mL Progesterone calibrator (1 x 1.5 mL) CAL 3 *Contains progesterone in 0.15 M sodium chloride in MES buffer with protein (bovine) and chemical stabilizers. Preservative: sodium azide.

This document is a 510(k) Premarket Notification for the Lumipulse® G Progesterone-N Calibrators. It focuses heavily on the stability and traceability of the calibrators rather than the performance of a diagnostic device in terms of clinical sensitivity or specificity. Therefore, many standard AI device performance metrics (like those relying on true positives, negatives, and human reader studies) are not applicable.

Here's an analysis of the provided text based on your request, highlighting what is and isn't available for this type of device:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria and performance data are primarily related to the stability and manufacturing consistency of the calibrators.

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

The "test set" in this context refers to the samples and calibrator lots used in the stability and value assignment studies.

• Long-Term Stability & Open-Vial/Real-Time Stability:
  • Calibrator Lots: 3 lots of reagents were used.
  • Calibrator Samples: Lumipulse G Progesterone-N Calibrator 1 and Calibrator 2 were tested in duplicate at each time point for sensitivity.
  • Serum Samples (for accuracy and reproducibility): 3 serum samples (concentrations: 3.15 - 24.42 ng/mL) were tested in replicates of 6 at each time point.
  • Data Provenance: Fujirebio, Inc. (Tokyo, Japan) and Fujirebio Diagnostics, Inc. (Malvern, PA). The studies are prospective in nature, as they involve monitoring stability over time.
• Value Assignment:
  • Replicates for provisional value: 6 replicates for initially assigned provisional value.
  • Replicates for assigned value: 10 replicates for primary calibrators and original calibrators over 3 runs on LUMIPULSE G.
  • Data Provenance: Implied to be internal studies at Fujirebio.
• Transport Simulation (Tokyo):
  • Specific sample count not provided beyond "the concentration of the panel replicates were determined."
  • Data Provenance: Fujirebio, Inc. (Tokyo, Japan).
• Transport Simulation (Malvern):
  • Calibrators were tested in duplicate, controls in singlicate, and panels in triplicate.
  • Data Provenance: Fujirebio Diagnostics, Inc. (Malvern, PA).

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

• Not Applicable. For a calibrator, the "ground truth" is established through highly controlled gravimetric preparations and traceability to international reference materials (ERM-DA347 and BCR-348R). This process does not involve human experts in the typical sense of interpreting diagnostic images or clinical outcomes. The "experts" would be analytical chemists or metrologists defining the concentration of the progesterone standard.

4. Adjudication Method for the Test Set

• Not Applicable. Adjudication methods like 2+1 or 3+1 are used in clinical studies involving interpretation of results by multiple human readers (e.g., radiologists, pathologists). This document describes the analytical performance and stability of a calibrator, which involves quantitative measurements against predefined criteria, not human interpretation.

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

• No. MRMC studies are used to evaluate the impact of a diagnostic device (often AI-based) on human reader performance. This document concerns a calibrator, which is a component used in an in vitro diagnostic assay, not a diagnostic algorithm that assists human interpretation.

6. If a Standalone (Algorithm Only) Performance Study was Done

• No. This is not an AI algorithm. The device is a calibrator for an in vitro diagnostic test system (LUMIPULSE G System). The performance studies presented are for the calibrator's stability and accuracy in establishing known concentrations for the assay.

7. The Type of Ground Truth Used

The ground truth for the Progesterone-N Calibrators is established through:

• Metrological Traceability: Directly linked to internationally recognized reference materials (ERM-DA347 and BCR-348R by IRMM).
• Gravimetric Preparation: The calibrators are prepared by precise weighing of progesterone, ≥ 99%, from SIGMA-ALDRICH, dissolved in ethanol and spiked into a buffer.
• Assigned Values: The values are assigned based on measurements on the LUMIPULSE G system, cross-referenced with gravimetrically prepared stock solutions and ensuring the "mean ratio" (of primary to original calibrators) falls within an acceptable range (0.95 - 1.05).

8. The Sample Size for the Training Set

• Not Applicable. This is not an AI/ML device that requires a training set. The performance data relates to the physical and chemical properties of the calibrator itself.

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

• Not Applicable. As there is no training set for an AI/ML algorithm, this question is not relevant.

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Lumipulse G FSH-N Calibrators are for in vitro diagnostic use in the calibration of Lumipulse G FSH-N on the LUMIPULSE G System.

Master calibration data are recorded in a two-dimensional bar code on the Lumipulse G FSH-N Immunoreaction Cartridge case. The calibration curve is created based on recorded master calibration data and the calibration data. The follicle-stimulating hormone (FSH) concentration of a specimen is automatically calculated from the calibration curve. The result of the calculation is reported in mIU/mL.

Lumipulse® G FSH-N Calibrators:

Lumipulse® G FSH-N Calibrators REF 230930 Each calibrator kit contains one bottle each of calibrators 1 - 2 and consists of the following:

CAL 1 0 mlU/mL FSH calibrator (1 x 1.5 mL) CAL 2 250 mlU/mL FSH calibrator (1 x 1.5 mL) *Contains follicle-stimulating hormone (FSH) in 0.15 M sodium chloride in Tris buffer with protein stabilizer (bovine). Preservative: sodium azide.

Here's a breakdown of the acceptance criteria and study information for the Lumipulse® G FSH-N Calibrators, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Long-Term Stability (Tokyo, Japan):

  • 3 Lots of Lumipulse G FSH Calibrators.
  • 3 Lots of Lumipulse G FSH Immunoreaction Cartridges.
  • FSH solutions of 0 and 2 mIU/mL were measured in replicates of 3 at each test point.
  • 3 serum samples (ranged 10.5 - 185.0 mIU/mL) were tested in replicates of 3 for accuracy and replicates of 6 for reproducibility.
  • Provenance: Fujirebio, Inc. (Tokyo, Japan); data stored at 10°C, measured at 0, 3, 7, and 13 months.

• Real-Time (Intended Storage) Stability (Malvern, PA):

  • 3 Lots of Lumipulse G FSH-N calibrators.
  • Tested in duplicate at Month 0, 6, 12, and 13.
  • Provenance: Fujirebio Diagnostics, Inc. (Malvern, PA); study ongoing.

• Open-Vial (in-use) Stability (Malvern, PA):

  • 3 Lots of Lumipulse G FSH-N calibrators.
  • Tested in duplicate at Month 0, 6, 12, and 13.
  • Provenance: Fujirebio Diagnostics, Inc. (Malvern, PA); study ongoing.

• Transport Simulation (Tokyo, Japan):

  • Not explicitly stated, but the study implies testing of the Lumipulse G FSH-N Calibrators.
  • Replicates: Luminescence ratio (FSH-N calibrator 2 / FSH-N calibrator 1) for sensitivity, and single measurements (n=1) for accuracy.
  • Provenance: Fujirebio, Inc. (Tokyo, Japan).

• Transport Simulation (Malvern, PA):

  • Lumipulse G FSH-N Calibrators and Lumipulse G FSH-N ICs.
  • Calibrators were tested in duplicate, controls in replicates of 1, and panels in replicates of 3.
  • Provenance: Fujirebio Diagnostics, Inc. (Malvern, PA); study ongoing.

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

This device is a calibrator, not a diagnostic device requiring human interpretation of results. Therefore, the concept of "experts establishing ground truth" in the clinical sense (e.g., radiologists interpreting images) is not applicable here. The "ground truth" or reference values are established through metrological traceability and value assignment protocols.

4. Adjudication Method for the Test Set

Not applicable, as this is related to human interpretation and not directly relevant for a calibrator's performance evaluation.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is relevant for diagnostic devices where human readers interpret results, and the AI's impact on their performance is being evaluated. This document describes performance of a calibrator.

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

Yes, the performance characteristics described (stability, traceability, value assignment, transport simulation) are all standalone performance evaluations of the calibrator product itself. The calibrator's ability to provide accurate and stable calibration values is assessed independently.

7. The Type of Ground Truth Used

The ground truth for the calibrators is established through a combination of:

• Metrological Traceability: Calibrators are traceable to the 1st International Standard, 1997 (code 92/510) provided by the National Institute for Biological Standards and Control (NIBSC).
• Gravimetric Preparation: Calibrators are prepared gravimetrically.
• Value Assignment Protocol: Involves provisional value assignment based on measurements using secondary calibrators, then rate-matching and adjusting tertiary calibrators to secondary calibrators.

8. The Sample Size for the Training Set

The concept of a "training set" in the context of an AI/machine learning algorithm is not applicable here. This device is a chemical calibrator for an immunoassay system, not an AI or algorithm that requires training data.

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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