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Immunoassays for the in vitro quantitative determination of the soluble fms like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio in human serum.

The sFlt-1/PlGF ratio is indicated as an aid in the risk assessment of pregnant women, with a singleton pregnancy (23+0 to 34+6/7 weeks' gestation) hospitalized for hypertensive disorders of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia, or gestational hypertension), to develop preeclampsia with severe features within two weeks from testing. The sFit-1/PlGF ratio should be used in conjunction with clinical assessment and routine laboratory testing.

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

Device Description

The Elecsys sFlt-1 and Elecsys PlGF assays employ a sandwich principle using electrochemiluminescence immunoassay "ECLIA" technology. The total duration of each assay is 18 minutes. Samples are incubated with biotinylated and ruthenium-labeled monoclonal antibodies specific to sFlt-1 or PlGF, forming a sandwich complex. Streptavidin-coated microparticles are added, binding the complex to the solid phase. The microparticles are magnetically captured, unbound substances are removed, and a voltage is applied to induce chemiluminescent emission, which is measured by a photomultiplier. Results are determined via a calibration curve generated by 2-point calibration and a master curve provided via the reagent barcode. The reagents for each assay are combined in a "rackpack".

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the Elecsys sFlt-1 and Elecsys PlGF assays, based on the provided document.

Acceptance Criteria and Device Performance

Acceptance Criteria Category	Specific Criteria	Reported Device Performance
Clinical Performance	Risk Assessment for Preeclampsia with Severe Features within two weeks from testing (Cutoff: >38): high Negative Predictive Value (NPV) and acceptable Positive Predictive Value (PPV) for pregnant women with singleton pregnancy (23+0 to 34+6/7 weeks' gestation) hospitalized for hypertensive disorders of pregnancy.	Overall Intended Use Population (N=556):- Sensitivity: 91.40% (95% CI: 86.41, 95.00)- Specificity: 77.30% (95% CI: 72.68, 81.47)- NPV (ratio ≤ 38): 94.70% (95% CI: 91.54, 96.94)- PPV (ratio > 38): 66.93% (95% CI: 60.77, 72.68)
Non-Clinical Performance	Precision: Low coefficients of variation (CV) for repeatability (within-run) and intermediate precision (within-laboratory).	Elecsys PlGF (N=84 per sample type):- Repeatability CV: 1.0% - 5.7%- Intermediate precision CV: 1.4% - 9.9%Elecsys sFlt-1 (N=84 per sample type):- Repeatability CV: 0.9% - 2.4%- Intermediate precision CV: 1.7% - 3.7%Ratio (N=84 per sample type):- Repeatability CV: 1.1% - 4.9%- Intermediate precision CV: 1.4% - 7.0%
	Linearity/Assay Reportable Range: Measurements are linear across the claimed measuring range.	- Elecsys sFlt-1: 80-85000 pg/mL (claimed range)- Elecsys PlGF: 10-5400 pg/mL (claimed range)(Study concludes measurements are linear across these ranges)
	Limit of Blank (LoB): ≤ 2 pg/mL for PlGF and < 6 pg/mL for sFlt-1. (Highest observed measurement values for samples free of analyte).	- PlGF: 0.482 - 0.946 pg/mL across 3 lots (meets ≤ 2 pg/mL)- sFlt-1: 2.92 - 4.00 pg/mL across 3 lots (meets < 6 pg/mL)
	Limit of Detection (LoD): < 3 pg/mL for PlGF and < 10 pg/mL for sFlt-1. (Lowest amount of analyte detectable with 95% probability).	- PlGF: 1.65 - 2.19 pg/mL across 3 lots (meets < 3 pg/mL)- sFlt-1: 4.44 - 6.03 pg/mL across 3 lots (meets < 10 pg/mL)
	Limit of Quantitation (LoQ): < 10 pg/mL for PlGF and < 15 pg/mL for sFlt-1. (Lowest concentration quantifiable with stated accuracy and intermediate precision CV of no more than 20%).	- PlGF: 7.48 - 8.97 pg/mL across 3 lots (meets < 10 pg/mL)- sFlt-1: 10.2 - 12.6 pg/mL across 3 lots (meets < 15 pg/mL)
	High-Dose Hook Effect: No significant hook effect at high concentrations of analytes.	- No high-dose hook effect at sFlt-1 concentrations up to 200,000 pg/mL.- No high-dose hook effect at PlGF concentrations up to 100,000 pg/mL.
	HAMA Interference: Minimal to no interference by Human Anti-Mouse Antibodies (HAMA).	- No HAMA interference for Elecsys PlGF up to 81 ug/L HAMA concentration.- For sFlt-1 concentrations ≤ 2,190 pg/mL, HAMA showed interference resulting in ≥10% positive bias in sFlt-1/PlGF ratios.
	Other Interferences (Bilirubin, Hemoglobin, Intralipid, Rheumatoid Factors, Biotin, Pharmaceuticals): Minimal to no significant interference.	- Bilirubin: >26.4 mg/dL can cause up to 10% decrease in ratio.- Hemoglobin, Intralipid, Rheumatoid Factors, Biotin (up to 1200 ng/mL): No significant interference reported (implies within acceptable limits though quantitative data not listed).- Common Drugs (15 tested): No interference.- Additional Substances (13 tested): No interference.- Heparin: Interference with Elecsys PlGF for concentrations > 500 U/L.
	Analytical Specificity/Cross-Reactivity: Highly specific for sFlt-1 and PlGF, with minimal cross-reactivity with related substances.	- sFlt-1 cross-reactivity: <0.01% with VEGFR2/VEGFR3, <2.1% with VEGF-B.- PlGF cross-reactivity: <0.1% with VEGF-B, <0.2% with VEGF 165, <0.9% with VEGF/PlGF-1. Recombinant PlGF-2 protein shows up to 42% cross-reactivity.

Study Details

Sample Size used for the Test Set and Data Provenance:
- Clinical Performance Study (PRAECIS): N=556 pregnant women.
- Data Provenance: The document does not explicitly state the country of origin for the PRAECIS study's clinical data, but it refers to the study as a "validation of the Roche sFlt-1/PlGF ratio cut-off." The reference range study (mentioned as a separate activity) collected samples from "$US" (United States) to establish normal reference ranges. Given the context, it's highly probable the PRAECIS clinical validation study also involved US patient data, though not explicitly stated for that specific study section.
- Retrospective or Prospective: The document describes the study as "Praecis 'Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification'" and states it included women "admitted to the hospital with (or develop while hospitalized) a hypertensive disorder." This strongly suggests a prospective design within the hospital setting, though "retrospective" is not explicitly excluded for patient inclusion/data collection aspects. However, the nature of "risk assessment...to develop preeclampsia with severe features within two weeks from testing" implies a prospective observation period.
Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications:
- The document does not specify the number of experts or their qualifications used to establish the ground truth for the clinical test set. The ground truth (preeclampsia with severe features within two weeks) would typically be established by clinicians based on diagnostic criteria, but further details are not provided.
Adjudication Method for the Test Set:
- The document does not specify an adjudication method (e.g., 2+1, 3+1, none) for establishing the clinical ground truth.
Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
- No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not mentioned or conducted in this submission. This device is an in-vitro diagnostic (IVD) immunoassay, not an imaging AI device that relies on human reader interpretation. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not directly applicable here.
Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study:
- Yes, the clinical performance evaluation (PRAECIS study) presents the standalone performance of the sFlt-1/PlGF ratio at a specified cutoff (38). It assesses the test's ability to predict clinical outcome (preeclampsia with severe features) directly. The "human-in-the-loop" aspect is that the results are "used in conjunction with clinical assessment and routine laboratory testing" by a physician, but the performance statistics presented (Sensitivity, Specificity, NPV, PPV) are for the assay's output itself.
Type of Ground Truth Used:
- Clinical Outcome Data: The ground truth used was the "development of preeclampsia with severe features within two weeks from testing," as defined by established medical guidelines (likely ACOG, given its mention for the predicate device). This is a clinical outcome.
Sample Size for the Training Set:
- The document does not explicitly describe a separate "training set" for an algorithm in the traditional sense, as these are immunoassays. The clinical validation study (PRAECIS) evaluates the performance of the established cutoff (38) for the sFlt-1/PlGF ratio. The cutoff itself might have been derived from earlier studies or internal research, which would implicitly act as a form of "training" or "development" data, but it's not detailed here with sample sizes. The reference range study for healthy pregnant women used 380 evaluable subjects to establish expected values.
How the Ground Truth for the Training Set Was Established:
- As there isn't an explicitly described "training set" for an algorithm to learn from, this question largely pertains to the development of the assay and its interpretive cutoffs. The cutoff of 38 for the sFlt-1/PlGF ratio is stated to be "validated" in the PRAECIS study. The process for initial establishment or derivation of this cutoff (38) is not detailed in this document. It's common for such cutoffs to be determined through prior multicenter clinical trials and statistical analysis to achieve optimal predictive performance targets.

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