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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.

Device Description

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.

AI/ML Overview

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.

Metric	Acceptance Criteria (Implicit from Clinical Study Results)	Reported Device Performance (Clinical Study)
Predictive Value for Positive Result (Ratio ≥ 0.00738)	High correlation with amyloid pathology (e.g., >90% PV)	91.8% (95% CI: 87.8%, 94.6%)
Predictive Value for Negative Result (Ratio ≤ 0.00370)	Low likelihood of amyloid pathology (e.g., <5% PV)	2.7% (95% CI: 1.2%, 6.1%)
Reproducibility/Precision (Total %CV)	≤ 10% (Common industry standard for similar assays)	≤ 10.2% on the Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio (for lowest concentration panel)
Linearity (R² correlation with expected concentrations)	High R² value (e.g., >0.99)	pTau 217: R²=0.9993, β-Amyloid 1-42-N: R²=0.9997
Interference (Change in result due to interferent)	Less than ±10% interference	Demonstrated less than ±10% for listed endogenous and exogenous interferents.
Cross-reactivity	Low percentage (e.g., <0.5%)	pTau 217: Max 0.090% (pTau 205); β-Amyloid 1-42-N: Max 0.200% (β-amyloid 1-43)
High Dose Hook Effect	No high dose hook effect observed within specified concentrations	No high dose hook effect observed up to 610 pg/mL for pTau 217 and 2,200 pg/mL for β-Amyloid 1-42.

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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