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Immunoassay for the in vitro quantitative determination of tacrolimus in EDTA human whole blood. The assay is used as an aid in the management of liver and kidney transplant patients receiving tacrolimus therapy.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

Device Description

The Elecsys Tacrolimus immunoassay uses the principle of electrochemiluminescence for detection and measurement. Before testing with the Elecsys Tacrolimus assay, the specimen, calibrators and controls are pretreated with the Elecsys ISD Pretreatment Reagent. The reagent lyses the cells, extracts Tacrolimus and precipitates virtually all of the blood proteins. The pretreated samples are centrifuged, and an aliquot of the resulting supernatant containing Tacrolimus is then assayed using the Elecsys Tacrolimus assay.

Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode.

AI/ML Overview

This document describes the Elecsys Tacrolimus immunoassay, an in vitro quantitative determination of tacrolimus in EDTA human whole blood. The assay is used as an aid in the management of liver and kidney transplant patients receiving tacrolimus therapy. It is intended for use on Elecsys and cobas e immunoassay analyzers.

Here's a breakdown of the acceptance criteria and study information:

1. Table of Acceptance Criteria and Reported Device Performance

Performance Characteristic	Acceptance Criteria	Reported Device Performance
Precision	Repeatability:	cobas e 411 (Intermediate precision):
(cobas e 411)	LoQ – 3.5 ng/mL: SD ≤ 0.25 ng/mL	HSP 1 (1.28 ng/mL): SD=0.182, CV=14.2% (for reference, this is an intermediate precision pool)
	> 3.5 – 12 ng/mL: CV ≤ 5 %	HSP 2 (9.14 ng/mL): SD=0.513, CV=5.6%
	> 12 – 30 ng/mL: CV ≤ 6 %	HSP 3 (18.5 ng/mL): SD=0.600, CV=3.3%
	Intermediate Precision:	HSP 4 (27.07 ng/mL): SD=0.882, CV=3.3%
	LoQ – 3.5 ng/mL: SD ≤ 0.35 ng/mL	PC ISD1 (2.49 ng/mL): SD=0.213, CV=8.6%
	> 3.5 – 12 ng/mL: CV ≤ 6 %	PC ISD2 (10.2 ng/mL): SD=0.383, CV=3.7%
	> 12 – 30 ng/mL: CV ≤ 7 %	PC ISD 3 (19.6 ng/mL): SD=0.571, CV=2.9%
	Clinical Reproducibility:	All results met pre-defined acceptance criteria for repeatability and intermediate precision.
	UCL of SD (1-sided 95%) and % CV values are provided across different components (repeatability, between day, between lot, between site, system reproducibility) for various sample pools and controls. Specific criteria not explicitly stated in one place but values are provided.	See Table 2 on page 19 for detailed reproducibility results.
Analytical Sensitivity:	Limit of Blank (LoB): ≤ 0.3 ng/mL	LoB: 0.3 ng/mL
	Limit of Detection (LoD): ≤ 0.5 ng/mL	LoD: 0.5 ng/mL
	Limit of Quantitation (LoQ): 25% total error at LoQ ≤ 0.75 ng/mL	LoQ: 0.75 ng/mL
Recovery (Accuracy)	≤ ± 0.3 ng/mL for samples LoQ to 3 ng/mL	Recovery (accuracy) meets the specifications.
	± 10 % for samples > 3 ng/mL
Linearity	2 ng/mL
Analytical Specificity	Not explicitly stated but implied by cross-reactivity testing.	Provides cross-reactivity percentages for various metabolites (M I-M VIII). See Table on page 9.
Endogenous Interferences	LoQ to 3 to 30 ng/mL must be ≤ ± 10 % recovery to the reference
Exogenous Interferences (Drugs)	Recovery within ± 10 % of initial value.	All drugs met the criterion except Itraconazole at 10 ug/mL (114% recovery).
Biotin Interference	≤ 10% bias in results for biotin concentrations up to 100 ng/mL	At 100 ng/mL biotin, bias was +5.1% (for 2.28 ng/mL tacrolimus) and +1.8% (for 18.1 ng/mL tacrolimus). Higher concentrations showed significantly higher bias.
Reagent Stability	Shelf Life Stability:	All results met acceptance criteria.
	PreciControl ISD 1: 75 – 125% recovery of reference value
	PreciControl ISD 2 and 3: 80 – 120% recovery of reference value
Sample Stability	Percent recovery calculated based on reference T0 (fresh sample) values.	Data collected in-house supported short stability claims. Literature supported 1-month stability claim.
Method Comparison	vs. Abbott ARCHITECT Tacrolimus: Combined slope (95% CI) and correlation (r) provided.	Combined: Slope = 0.99 (0.98, 1.01), Intercept = 0.06 (-0.07, 0.18), r = 0.99
	vs. LC-MS/MS: Combined slope (95% CI) and correlation (r) provided.	Combined: Slope = 0.92 (0.90, 0.95), Intercept = -0.01(-0.16, 0.14), r = 0.96

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

Precision (Non-clinical):
- Seven-member panel (four pooled patient and single donor spiked human whole blood samples, three controls).
- Measured in single determination in four separate aliquots (divided in two runs per day) for 21 operating days. The number of samples for the test set is not explicitly stated as a single number but implies repeated measurements over time.
- Data provenance: Not explicitly stated, but "pooled patient and single donor spiked human whole blood samples" suggests human biological samples.
Limit of Blank (LoB):
- Five analyte-free whole blood samples.
- 30 measuring points collected per instrument, for a total of 60 measured values (across two instruments).
Limit of Detection (LoD):
- Five spiked human whole blood samples with low analyte.
- 30 measuring points collected per instrument, for a total of 60 measured values (across two instruments).
Limit of Quantitation (LoQ):
- 14 spiked human whole blood samples each diluted to concentrations covering the range between LoB and 2x LoQ.
- 84 measuring points collected per instrument, for a total of 168 measured values per lot (across two instruments and three reagent lots).
Recovery (Accuracy):
- ISD-free human blood spiked with tacrolimus.
- Patient derived samples (from patients taking Tacrolimus) divided into at least four aliquots and spiked. The exact number of patient samples is not specified.
Linearity:
- Three dilution series prepared from three different spiked human whole blood samples.
- Each dilution series included 22 dilutions.
Dilution:
- Three ISD-free human whole blood samples spiked separately.
- Dilution series of nine respective dilutions.
Analytical Specificity (Cross-reactivity):
- Each cross-reactant compound spiked into two human whole blood samples (analyte-free and slightly elevated analyte level). Sample size for each cross-reactant is therefore 2 samples per compound.
Endogenous Interferences:
- Three spiked human whole blood samples (one low and one high concentration).
- Dilution series of 10 dilutions.
Exogenous Interferences (Drugs):
- 16 common and 25 additional pharmaceutical compounds spiked into two spiked human tacrolimus containing human whole blood samples (single donor samples spiked with 3 ng/mL and 10 ng/mL tacrolimus). So, 2 samples per drug.
Reagent Stability:
- Study 1 & 2: Five human whole blood samples (pooled patient samples and single donor samples spiked with tacrolimus) and three controls.
- Study 3: PreciControl ISD 1, 2, and 3.
Sample Stability:
- Not explicitly stated, but the studies mention "human EDTA blood" and "reference T0 (fresh sample) values."
Reproducibility (Clinical):
- Human sample pools (HSP 01-06) and PreciControl materials (PC ISD L1-L3).
- N=90 for each sample type. Data provenance: Human samples.
Method Comparison (Clinical):
- Abbott ARCHITECT Tacrolimus vs. Elecsys Tacrolimus: Combined 553 samples (346 Kidney, 207 Liver).
- Elecsys Tacrolimus vs. LC-MS/MS: Combined 554 samples (344 Kidney, 210 Liver).
- Data provenance: Clinical test results for enrolled subjects. No country of origin is specified.

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

This document describes the validation of an in vitro diagnostic assay for quantitative determination of tacrolimus. There is no mention of human experts (e.g., radiologists) establishing ground truth. The ground truth is established by reference methods or gravimetric preparation of known concentrations.

4. Adjudication Method (e.g., 2+1, 3+1, none) for the Test Set

Not applicable, as this is an in vitro diagnostic device and not a diagnostic imaging device requiring expert adjudication.

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

Not applicable. This is an in vitro diagnostic immunoassay, not an AI-driven imaging analysis system involving human readers.

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

The entire performance evaluation described is for the standalone device (Elecsys Tacrolimus immunoassay) without human-in-the-loop performance influencing the assay results. The device quantifies tacrolimus levels; human intervention is for sample preparation, loading, and interpretation of the quantitative result in a clinical context.

7. The Type of Ground Truth Used

The ground truth for the performance studies is established using:

Gravimetrically prepared reference material: For spiking studies (recovery, linearity, dilution, exogenous/endogenous interferences).
Reference Methods:
- Abbott ARCHITECT Tacrolimus (a legally marketed predicate device) for method comparison studies.
- LC-MS/MS (Liquid Chromatography-Mass Spectrometry/Mass Spectrometry) for method comparison studies, which is considered a gold standard for tacrolimus quantification.
Assigned values for controls: For stability and reproducibility studies (e.g., PreciControl ISD).
Analyte-free whole blood samples: For LoB determination.

8. The Sample Size for the Training Set

This document describes a premarket notification for an in vitro diagnostic device, not a machine learning or AI algorithm. Therefore, the concept of a "training set" in the context of AI models does not apply here. The document details studies designed to validate the assay's performance characteristics.

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

Not applicable, as there is no "training set" in the context of an AI algorithm for this in vitro diagnostic device.

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