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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.

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Elecsys ß-Amyloid (1-42) CSF II and Elecsys Total-Tau CSF are in vitro electrochemiluminescence immunoassays for the measurement of the ß-Amyloid (1-42) (Abeta42) and Total-Tau (tTau) concentrations in cerebrospinal fluid (CSF) from adult patients aged 55 years and older being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment to generate a tTau/Abeta42 ratio value.

A negative result, defined as tTau/Abeta42 ratio value below cut-off or an Abeta42 value above the measuring range, is consistent with a negative amyloid position emission tomography (PET) scan result. A negative result reduces the likelihood that a patient's cognitive impairment is due to AD. A postive result, defined as tTau/Abeta42 ratio value above cut-off, is consistent with a positive amyloid PET scan result does not establish a diagnosis of AD or other cognitive disorder. The tTau/Abeta42 ratio result is used as an adjunct to other clinical diagnostic evaluations.

Limitations of Use

The performance of the tTau/Abeta42 ratio has not been established for:

· Predicting development of dementia or other neurologic conditions
· Monitoring responses to therapies

The Elecsys ß-Amyloid (1-42) II immunoassay makes use of a two-step, double antigen sandwich principle using a biotinylated monoclonal β-Amyloid (1-42)-specific and monoclonal ß-Amyloid (1-42) antibodies labeled with a ruthenium complex. The Elecsys ß-Amyloid (1-42) II immunoassay is intended for the in vitro quantitative determination of ß-Amyloid (1-42) in human CSF.

Similarly, the Elecsys Total-Tau immunoassay makes use of a two-step, double antigen sandwich principle using two biotinylated monoclonal Tau-specific antibodies (5.28.464 and 4.35.411) and a monoclonal Tau-specific (PC1P6) antibody labeled with a ruthenium complex. The Elecsys Total-Tau immunoassay is intended for the in vitro quantitative determination of Total-Tau in human CSF.

The assays are indicated for use with adult subjects being evaluated for Alzheimer's disease and other causes of cognitive impairment.

The results of the measurement of a CSF sample for each analyte in pg/mL is used in a ratio (tTau/Abeta42). The assays manually calculated ratio result is compared to a cutoff to determine if the test result indicates an amyloid PET positive or negative result. The result does not establish a diagnosis of AD or other cognitive disorders. Additionally, the result does not predict development of dementia or other neurologic disorders, nor does the result monitor responses to therapies. Both assays are intended for use on the cobas e 601 immunoassay analyzer.

Results for each assay are determined by an analyte specific calibration curve generated by 2point calibration and a master curve provided via the reagent barcode or e-barcode.

Here's an analysis of the provided text to extract information about the acceptance criteria and the study proving the device meets them:

Device: Elecsys B-Amyloid (1-42) CSF II and Elecsys Total-Tau CSF (used to generate a tTau/Abeta42 ratio value).

Intended Use: In vitro electrochemiluminescence immunoassays for the measurement of Abeta42 and tTau concentrations in CSF from adult patients aged 55 years and older being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment. The ratio result is used as an adjunct to other clinical diagnostic evaluations, consistent with amyloid PET scan results.

1. Table of Acceptance Criteria and Reported Device Performance

The document describes two separate phases of evaluation for the tTau/Abeta42 ratio: a BioFINDER cutoff setting cohort (using first-generation assays) and a clinical validation in an ADNI cohort (using a specific version of the assays, either first or second generation, with adjustments). The acceptance criteria are implicitly derived from the reported performance in the ADNI validation study which is stated to have "met the acceptance criteria."

Acceptance Criteria and Reported Device Performance (Clinical Validation in ADNI cohort):

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

• Test Set (Clinical Validation in ADNI cohort):

  • Sample Size: 646 participants.
  • Data Provenance: Retrospectively collected CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI-GO and ADNI2) studies.
  • Country of Origin: The ADNI study is primarily based in the United States and Canada.
  • Subject Characteristics: Patients with significant memory concerns (SMC, N = 94), early MCI (N = 272), late MCI (N = 152), and Alzheimer's Disease (AD, N = 128). Average age 72 years (range 55-91), 46% female / 54% male, 50% ApoE4 carriers / 50% non-carriers.

• BioFINDER Cohort (for initial cutoff setting):

  • Sample Size: 277 participants with mild cognitive symptoms.
  • Data Provenance: Retrospective samples from the Swedish BioFINDER1 study.
  • Country of Origin: Sweden.
  • Subject Characteristics: 120 subjective cognitive decline (SCD), 153 mild cognitive impairment (MCI), 4 not assigned.

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

• Number of Experts: 3 trained readers.
• Qualifications of Experts: They were "trained readers." No specific professional qualifications (e.g., "radiologist with 10 years of experience") are provided beyond being "trained." They were blinded to clinical information, diagnosis, and CSF biomarker measurements.

4. Adjudication Method for the Test Set

• Adjudication Method (for Amyloid PET scans): Majority voting was used to classify each image as amyloid positive or negative.

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

• No, a "multi-reader multi-case (MRMC) comparative effectiveness study" involving human readers improving with AI vs. without AI assistance was not done or described. This study focuses on the diagnostic performance of the device (a blood test generating a ratio) against an established ground truth (amyloid PET scan results). The "trained readers" mentioned were establishing the ground truth (PET read), not evaluating the device's impact on their own performance.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

• Yes, this study primarily represents a standalone performance evaluation of the device. The device (Elecsys B-Amyloid (1-42) CSF II and Elecsys Total-Tau CSF assay system) produces a tTau/Abeta42 ratio. This ratio is then compared directly to the amyloid PET scan status. There is no human-in-the-loop component for the device's interpretation; it provides a direct output (ratio) that is then compared to a cut-off to determine a positive or negative amyloid status.

7. The Type of Ground Truth Used

• The primary ground truth used for the clinical validation of the tTau/Abeta42 ratio was amyloid Positron Emission Tomography (PET) scan results, classified as amyloid positive or negative via visual read and majority voting by 3 trained readers.
• For the initial cutoff setting (BioFINDER cohort), the ground truth was also amyloid PET scan results ([18F]-Flutemetamol PET) by visual read.

8. The Sample Size for the Training Set

The document does not explicitly describe a separate "training set" for an AI algorithm in the traditional sense. It describes:

• Initial Cutoff Setting Cohort (BioFINDER): This cohort of 277 participants was used to define the initial ratio cutoff (0.26) based on agreement with amyloid PET status. While not a "training set" for an ML model, it served a similar purpose in establishing initial parameters for the assay's interpretation.
• Bridging Studies: Two bridging studies were conducted (N=20/17 and N=25/24) to adjust the cutoff based on pre-analytical differences and assay updates. These are not typical "training sets" for an algorithm, but rather calibration/normalization studies for the assay system.

Therefore, there isn't a "training set" for an AI model in this context, as the device is an in-vitro diagnostic immunoassay system, not an AI algorithm learning from data. The cut-off and the adjustments resemble empirical derivation from study data ("training" the cut-off, not an AI).

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

As noted above, there isn't a "training set" for an AI algorithm. However, for the data used to establish the cutoff for the assay:

• BioFINDER Cohort: The ground truth was established by amyloid PET scan results via visual read. The specifics of how many readers or their adjudication for this initial phase are not detailed, but it's implied to be based on clinical interpretation of PET scans.
• Conversion Factors/Bridging Studies: The ground truth for these studies involved paired CSF samples handled under different pre-analytical protocols or measured with different assay generations. The "ground truth" here is the comparative measurement of samples under controlled conditions to determine conversion factors.

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Elecsys ß-Amyloid (1-42) CSF II and Elecsys Phospho-Tau (181P) CSF are in vitro electrochemiluminescence immunoassays for the measurement of the ß-Amyloid (1-42) (Abeta42) and Phospho-Tau (181P) (pTau181) protein concentrations in cerebrospinal fluid (CSF) from adult patients aged 55 years and older being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment to generate a pTau181/Abeta42 ratio value. A negative result, defined as pTaul 81/Abeta42 ratio value below cut-off or an Abeta42 value above the measuring range. is consistent with a negative amyloid position tomography (PET) scan result. A negative result reduces the likelihood that a patient's cognitive impairment is due to AD. A positive result, defined as pTaul 81/Abeta42 ratio value above cut-off, is consistent with a positive amyloid PET scan result does not establish a diagnosis of AD or other cognitive disorder. The pTaul 81/Abeta42 ratio result is used as an adjunct to other clinical diagnostic evaluations.

The Elecsys ß-Amyloid (1-42) II immunoassay makes use of a two-step, double antigen sandwich principle using a biotinylated monoclonal β-Amyloid (1-42)-specific and monoclonal ß-Amyloid (1-42) antibodies labeled with a ruthenium complex. The Elecsys ß-Amyloid (1-42) II immunoassay is intended for the in vitro quantitative determination of ß-Amyloid (1-42) (Abeta42) in human CSF.

Similarly, the Elecsys Phospho-Tau (181P) immunoassay makes use of a two-step, double antigen sandwich principle using a biotinylated monoclonal Phospho-Tau (181P)-specific and monoclonal Phospho-Tau (181P) antibodies labeled with a ruthenium complex. The Elecsys Phospho-Tau (181P) immunoassay is intended for the in vitro quantitative determination of Phospho-Tau (181P) (pTau181) in human CSF.

The assays are indicated for use with adult subjects being evaluated for Alzheimer's disease and other causes of cognitive impairment.

The results of the measurement of a CSF sample for each analyte in pg/mL is used in a ratio (pTau181/Abeta42). The assays manually calculated ratio result is compared to a cutoff to determine if the test result indicates an amyloid PET positive or negative result. The result does not establish a diagnosis of AD or other cognitive disorders. Additionally, the result does not predict development of dementia or other neurologic disorders, nor does the result monitor responses to therapies. Both assays are intended for use on the cobas e 601immunoassay analyzer.

Results for each assay are determined by an analyte specific calibration curve generated by 2point calibration and a master curve provided via the reagent barcode or e-barcode.

Here's an analysis of the provided text, focusing on the acceptance criteria and the study that proves the device meets those criteria, structured according to your request:

Device: Elecsys β-Amyloid (1-42) CSF II and Elecsys Phospho-Tau (181P) CSF (used to generate a pTau181/Abeta42 ratio)

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document states "The validation met the acceptance criteria" indicating that the reported PPA, NPA, and OPA were considered acceptable by the FDA, even though specific numerical targets for these metrics are not explicitly listed as "acceptance criteria" in the same way as, for example, precision limits. The initial cutoff setting cohort did have agreement rate percentages (PPA 90.9%, NPA 89.2%, OPA 89.9%) which can be inferred as a benchmark for acceptability.

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

• Test Set (Clinical Validation in ADNI cohort): 646 participants
• Data Provenance: Retrospectively collected CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) studies (ADNI-GO and ADNI2). The document also mentions a "BioFINDER cutoff setting cohort" from the Swedish BioFINDER1 study (277 participants, retrospective) used to initially define the cutoff, and subsequent "pre-analytical bridging studies" (N=19 for pTau181 and N=17 for Abeta42 for the first bridging study; N=25 for Abeta42 and N=22 for pTau181 for the second bridging study) primarily for adjusting the cutoff due to pre-analytical differences and assay updates, not as the primary clinical validation test set.

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

• Number of Experts: 3 trained readers
• Qualifications of Experts: They were "trained readers" who read and interpreted amyloid PET scans. No further specific qualifications (e.g., medical specialty, years of experience) are provided in the document.
• Blinding: The independent readers were blinded to any clinical information, including the patient's clinical status, diagnosis, and CSF biomarker measurements.

4. Adjudication Method for the Test Set

• Adjudication Method: Majority voting. If at least 2 out of 3 readers classified an image as amyloid positive, it was classified as positive, and vice versa for negative. This resulted in 347 (53.7%) positive and 299 (46.3%) negative amyloid PET reads.

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 with and without AI assistance was not conducted or reported in this document. This device is an in vitro diagnostic (IVD) immunoassay that measures biomarker concentrations in CSF, not an AI-powered image analysis tool for human readers.

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

Yes, the clinical validation study evaluates the performance of the immunoassay (the "algorithm only") in classifying amyloid status based on the pTau181/Abeta42 ratio, compared to the ground truth established by expert-read amyloid PET scans. This is a standalone performance assessment of the device.

7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)

The ground truth used was expert consensus on amyloid PET scan results.

8. The Sample Size for the Training Set

The document does not explicitly describe a separate "training set" for the clinical validation of the specific pTau181/Abeta42 ratio cutoff. Instead:

• The BioFINDER cutoff setting cohort (277 participants) appears to have functioned as the dataset for determining the initial cutoff value (0.022). While not a "training set" in the machine learning sense, it was used to establish an operational parameter for the device.
• Subsequent bridging studies (N=19/17 and N=25/22 samples respectively) were used to adjust this cutoff to 0.028 and then to 0.023, accounting for pre-analytical differences and assay updates.

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

For the BioFINDER cutoff setting cohort (which served a similar purpose to a training set for cutoff determination):

• Ground Truth: Amyloid PET scan results obtained with the tracer [18F]-Flutemetamol.
• Establishment: The document does not detail how the amyloid PET status was determined for the BioFINDER cohort, but it implies a visual read, similar to the ADNI cohort, as the cutoff was "calculated based on the agreement with amyloid PET status by visual read."

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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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