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The Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay is an in vitro diagnostic test for the quantitative measurement of procalcitonin in human serum and plasma (lithium heparin, K2EDTA, and K3EDTA) using the Dimension® EXL™ integrated chemistry system with LOCI® Module.

The Dimension EXL LOCI® BRAHMS PCT assay is intended for use in conjunction with other laboratory findings and clinical assessments, as an aid in:

· The risk assessment of critically ill patients on their first day of Intensive Care Unit (ICU) admission for progression to severe sepsis and septic shock.

• Assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission using percentage change in PCT levels over time.

· Decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.

· Decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

The Dimension EXL LOCI BRAHMS PCT assay is a homogeneous sandwich chemiluminescent immunoassay based on LOCI technology. The LOCI reagents include two synthetic bead reagents and one biotinylated anti-procalcitonin (anti-PCT) monoclonal antibody. The first bead reagent (Sensibeads) is coated with streptavidin and contains photosensitizer dye. The second bead reagent (Chemibeads) is coated with two anti-PCT monoclonal antibodies and contains chemiluminescent dye. Sample is incubated with biotinylated antibody and Chemibeads to form bead-PCT-biotinylated antibody sandwiches. Sensibeads are added and bind to the biotin to form bead-pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direct function of the procalcitonin (PCT) concentration in the sample.

The provided document describes the performance characteristics of the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay and its equivalence to a predicate device.

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

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample sizes for the test set and data provenance:

• Precision Studies: 80 replicates for each sample (QC and serum/plasma pools) for each lot (total 2 lots tested).
• Reproducibility Study: 225 replicates per sample ID (5 replicates/day x 5 days x 3 instruments x 3 reagent lots).
• Detection Capability: No specific sample size mentioned, CLSI EP17-A2 was referenced.
• Linearity: 16 samples.
• Dilution Recovery: 10 native serum specimens.
• Interference and Cross-Reactivity: Human serum pools, specifically "approximately 0.25 ng/mL and 2.00 ng/mL PCT". The exact number of individual samples is not explicitly stated.
• Hook Effect: Testing for PCT concentrations up to 2000.00 ng/mL. Number of samples not explicitly stated.
• Sample Carryover: 11 separate runs, each testing a pattern of high and low samples (21 tests per run).
• Method Comparison: 595 native human serum samples within the concentration range of 0.05-1000.00 ng/mL.
• Matrix Comparison: 76 matched sets (Serum, Lithium Heparin plasma, Sodium Heparin plasma, K2EDTA plasma, and K3EDTA plasma - except RST with 75 matched sets).
• Reference Interval Verification: Serum and plasma specimens from 33 apparently healthy individuals.

Data Provenance: The studies used human serum and plasma samples, as indicated by terms like "native human serum samples" and "patient-sourced internal standards." The document does not specify the country of origin, but it mentions Siemens Healthcare Diagnostics, Inc. in Newark, Delaware, USA, as the applicant. The nature of the studies (e.g., method comparison, stability) suggests these are retrospective analyses of collected samples or controlled laboratory experiments. It does not explicitly state prospective or retrospective data collection for all studies, but method comparison using "native human serum samples" implies existing clinical samples from a test set.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

This device is an in vitro diagnostic (IVD) test for quantitative measurement of procalcitonin (PCT). The "ground truth" here is not established by human readers/experts in the same way as, for example, a diagnostic imaging AI. Instead, the ground truth for this type of device is based on:

• Reference Method/Predicate Device: For method comparison, the predicate device (B·R·A·H·M·S PCT sensitive KRYPTOR) serves as the reference for comparison.
• Analytical Standards: For studies like linearity, detection capability, and precision, the "ground truth" or true value of PCT is established using known concentrations in control materials, calibrators, or by spiking samples with recombinant PCT. These are typically prepared and validated by qualified laboratory professionals following established analytical chemistry principles and CLSI guidelines.
• Defined Clinical Cut-offs: While the device aids in decision-making, the clinical cut-offs (e.g., 0.10 ng/mL, 0.25 ng/mL) are established within medical guidelines and clinical practice, not by individual experts for the purpose of validating this specific device's performance.

Therefore, the concept of "number of experts and their qualifications for establishing ground truth" as it applies to image interpretation AI is not directly applicable here. The "experts" would be the scientists and laboratorians who designed and executed the analytical validation studies according to CLSI guidelines and robust quality control practices.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

Adjudication methods like 2+1 or 3+1 are typically used in studies involving human readers interpreting diagnostic images or clinical cases where disagreement needs to be resolved by a tie-breaker. This is an in vitro diagnostic assay with quantitative results. Therefore, adjudication in that sense is not applicable or done. The performance is assessed against quantitative metrics, reference methods, or predicate devices.

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:

An MRMC comparative effectiveness study is not applicable for this device. This is a standalone in vitro diagnostic assay that provides a quantitative measurement of a biomarker (PCT) in clinical specimens. It does not involve human readers interpreting cases with or without AI assistance, nor does it involve improving human reader performance.

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

Yes, the studies presented are all standalone performance studies for the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay. The device measures PCT levels directly from patient samples, and its performance characteristics (precision, linearity, detection capability, interference, method comparison, etc.) are evaluated intrinsically without direct human interpretation influencing the measurement outcome. The role of the human is in operating the instrument, collecting samples, and interpreting the numerical results in a clinical context.

7. The type of ground truth used (expert concensus, pathology, outcomes data, etc):

The ground truth used for this quantitative in vitro diagnostic device is primarily based on:

• Assigned Values of Calibrators and Control Materials: For accuracy, precision, and linearity studies, known concentrations of PCT in calibrators and quality control materials serve as the ground truth. These values are established through rigorous analytical methods and traceability chains.
• Reference Method/Predicate Device Results: In the method comparison study, the results from the legally marketed predicate device (B·R·A·H·M·S PCT sensitive KRYPTOR) are used as the reference against which the candidate device's performance is compared to establish substantial equivalence.
• Spiking with Recombinant Procalcitonin: For studies like dilution recovery, interference, and cross-reactivity, samples are often "spiked" with known concentrations of highly purified recombinant procalcitonin (or interfering substances) to create samples with a known "true" concentration of the analyte for testing the assay's behavior.

8. The sample size for the training set:

This document describes the validation of an in vitro diagnostic assay, not a machine learning or AI algorithm in the context of typical "training" and "test" sets. Therefore, there isn't a "training set" in the sense of data used to train a predictive model. The development of such assays involves extensive R&D and analytical optimization, but a specific "training set sample size" as asked in the context of AI is not applicable.

9. How the ground truth for the training set was established:

As mentioned above, there is no "training set" in the AI/ML context. The development and optimization of an IVD assay like this involve:

• Immunoassay Design: Selection of specific antibodies (monoclonal anti-PCT antibodies) that bind to the analyte.
• Reagent Formulation: Optimizing concentrations of reagents (sensibeads, chemibeads, biotinylated antibody, assay buffer) and reaction conditions to achieve desired sensitivity, specificity, and dynamic range.
• Analytical Verification Studies: These studies (like those described in the document, e.g., precision, linearity, detection capability) are used iteratively during development to ensure the assay performs as intended. The "ground truth" during this phase would be known concentrations of purified analyte, reference materials, and comparison to established methods or predicate devices.

The "ground truth" is thus established through fundamental analytical chemistry principles, quantitative measurements, and comparison to internationally recognized standards or well-characterized reference materials and methods.

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