(166 days)
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
| Metric | Acceptance Criteria (Implicit for Clinical Validation) | Reported Device Performance (Clinical Validation in ADNI Cohort) |
|---|---|---|
| Positive Percent Agreement (PPA) | Not explicitly stated but expected to be high for substantial equivalence. | 88.2% (95% CI: 84.4% - 91.2%) |
| Negative Percent Agreement (NPA) | Not explicitly stated but expected to be high for substantial equivalence. | 92.6% (95% CI: 89.1% - 95.1%) |
| Overall Percent Agreement (OPA) | Not explicitly stated but expected to be high for substantial equivalence. | 90.25% with visual amyloid PET assessments |
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."
N/A