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The MAGLUMI X3 Fully-auto chemiluminescence immunoassay analyzer is an automated, immunoassay analyzer designed to perform in vitro diagnostic tests on clinical specimens.

The MAGLUMI 25-OH Vitamin D is an in vitro chemiluminescence immunoassay for the quantitative determination of 25-OH Vitamin D (25-OH VD) in human serum and plasma using the MAGLUMI series Fully-auto chemiluminescence immunoassay analyzer, and the assay is used for an aid in assessment of vitamin D sufficiency.

MAGLUMI X3 Fully-auto chemiluminescence immunoassay analyzer:

The MAGLUMI X3 Fully-auto chemiluminescence immunoassay analyzer is a fully automated instrument system designed to perform in vitro diagnostic tests on clinical specimens. The system utilizes chemiluminescent technology and uses pre-packaged reagent packs for qualitative or quantitative analysis of the analytes in human samples. The analyzer performs automatic sample pipetting, reagent loading, incubation, washing, measurements, and result calculations.

MAGLUMI 25-OH Vitamin D assay:

MAGLUMI 25-OH Vitamin D kit consists of the following reagents:

Magnetic Microbeads- coated with anti-25-OH VD antibody in PBS buffer, NaN3 (<0.1%). Calibrator Low- A low concentration of 25-OH VD antigen in Carbonate buffer, NaN3 (<0.1%). Calibrator High- A high concentration of 25-OH VD antigen in Carbonate buffer, NaN3 (<0.1%). Buffer- Acidic buffer ABEI Label- ABEI labeled with anti-25-OH VD antibody (~0.500 ug/mL) in PBS buffer, NaN3 (<0.1%). Control 1- A low concentration of 25-OH VD antigen in Carbonate buffer, NaN3 (<0.1%). Control 2- A high concentration of 25-OH VD antigen in Carbonate buffer, NaN3 (<0.1%).

The provided text describes the performance characteristics of the MAGLUMI 25-OH Vitamin D assay and MAGLUMI X3 Fully-auto chemiluminescence immunoassay analyzer as part of a 510(k) summary for FDA clearance. The information focuses on analytical performance rather than clinical validation with human-in-the-loop studies.

Here's a breakdown of the requested information based on the provided text:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly present a table of predefined acceptance criteria. Instead, it reports the analytical performance of the device, which implicitly demonstrates that the device meets some internal or expected performance metrics for an in vitro diagnostic device. The performance data is presented in the "11. Performance Characteristics" section.

Here's an approximation of an acceptance criteria table based on the reported performance, assuming the reported values are the achieved performance that meets internal criteria for release:

2. Sample sizes used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Precision Study:

  • Sample Size: 240 measurements per material (two controls, two calibrators, one spiked patient serum pool, three native patient sample pools) across three instruments. Each measurement was taken in duplicate, with 2 runs per day over 20 days.
  • Data Provenance: Not explicitly stated, but common practice for IVD analytical studies focuses on sample types and analytical conditions, not patient demographics or geo-location beyond what's relevant to endogenous interferents. The samples include "patient serum pool" and "native serum pool," implying human biological samples.

• Linearity Study:

  • Sample Size: Eleven linearity samples, each measured in quadruplicate on 3 lots of reagent.
  • Data Provenance: Samples prepared by blending "a low serum sample pool and a high serum sample pool," implying human serum. No country of origin specified.

• Detection Limit Study:

  • LOB: 60 measurements of 25-OH Vitamin D depleted serum samples using 3 different lots of reagents over 3 days.
  • LOD: Four levels of low samples, each measured in 60 replicates over 3 days per sample using 3 lots of reagents.
  • LOQ: Six low serum samples, in five replicates per run, one run per day, over 3 days, using 3 lots of reagents.
  • Data Provenance: "Serum samples," "low serum samples," implying human serum. No country of origin specified.

• Interference Study:

  • Sample Size: Three base serum samples (10, 50, 100 ng/mL 25-OH VD) for endogenous substances and common drugs; human serum samples for HAMA, RF, total protein.
  • Data Provenance: "Human serum pools" and "human serum samples." No country of origin specified.

• Method Comparison Study:

  • Sample Size: 329 native, single donor patient serum samples (121 male, 208 female, age 7 to 98 years).
  • Data Provenance: "Human serum samples." No country of origin specified explicitly, but this is typically retrospective collection of de-identified clinical samples.

• Reference Range Study:

  • Sample Size: 312 serum samples from normal, apparently healthy adult (21 years and older) individuals (181 males, 131 females).
  • Data Provenance: Samples collected from three regions (Central, Southeast and Northeast) in the US. This specifies the country of origin (USA) and regional distribution. This would be considered retrospective.

• Matrix Comparison Study:

  • Sample Size: 78 serum/plasma pairs from the same donor.
  • Data Provenance: "Samples drawn into serum and plasma collection tubes," "from the same donor." No country of origin specified.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This document describes an In Vitro Diagnostic (IVD) device, specifically a quantitative immunoassay. For such devices, "ground truth" is typically established by:

• Reference methods (e.g., LC-MS/MS for Vitamin D, which is considered a gold standard).
• Master Lot/Calibrator values.
• Comparison to a legally marketed predicate device (as done in the "Comparison Studies" section).

There is no mention of human experts (like radiologists) establishing ground truth for individual samples in this context. The "ground truth" in this analytical study is the quantitative concentration of 25-OH Vitamin D as determined by reference materials, calibrators, or the established predicate method.

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

Not applicable. Adjudication methods like 2+1 or 3+1 are typically used in clinical studies involving qualitative or semi-quantitative assessments (e.g., image-based diagnosis) where multiple human readers interpret data, and discrepancies need to be resolved. This document pertains to the analytical performance of a quantitative immunoassay analyzer, where the output is a numerical concentration.

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 device is an automated immunoassay analyzer for a quantitative biomarker (25-OH Vitamin D). It is not an AI-assisted diagnostic tool that aids human readers in interpreting complex data like medical images. Therefore, an MRMC study or AI assistance is not relevant to its stated purpose or performance evaluation.

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

The device is inherently a "standalone" system in an analytical sense. The MAGLUMI X3 analyzer and the MAGLUMI 25-OH Vitamin D assay perform the quantitative determination automatically. The performance characteristics (precision, linearity, detection limit, interference, method comparison) are all tests of the algorithm's performance (i.e., the instrument and reagent system) without human interpretation affecting the result generation process itself. Clinical interpretation of the numerical results (e.g., patient has vitamin D deficiency based on the number) happens downstream by a clinician, but the device performance itself is standalone.

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

For the analytical performance:

• Precision, Linearity, Detection Limit, Interference: Ground truth is established by the known concentrations of controls, calibrators, spiked samples, and highly characterized depleted/low concentration samples. The "truth" is the intended/expected concentration as determined by a highly accurate measurement or formulation.
• Method Comparison: The predicate device, MAGLUMI 2000 25-OH Vitamin D assay manufactured by SNIBE, served as the comparative "truth" or reference. The study measures agreement between the new device and the predicate. It states "Comparison of the MAGLUMI 25-OH Vitamin D assay (y) with the predicate device, MAGLUMI 2000 25-OH Vitamin D assay (x)."
• Reference Range: Established from empirically tested healthy individuals.

8. The sample size for the training set

This document describes the validation of an immunoassay kit and analyzer, not a machine learning or AI model that requires a "training set" in the computational sense. The "training" for such a system refers to the development and optimization of the chemical reagents, assay protocol, and instrument calibration algorithms by the manufacturer during product development, prior to the validation studies described here. The document does not provide details on the sample sizes or data used during this internal "training" or development phase.

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

As noted above, "training set" is not applicable in the context of a traditional immunoassay system validation as described here. The "ground truth" for the development and optimization of the assay would typically involve:

• Certified Reference Materials (CRMs): Substances with accurately known concentrations of the analyte, often traceable to international standards.
• Internal Reference Materials: Carefully prepared and validated in-house samples.
• Established Reference Methods: Highly accurate and precise methods (e.g., LC-MS/MS) used to characterize samples during development.
• Cross-validation with existing, well-characterized methods/platforms.

These elements guide the chemical formulation, antibody selection, and instrument parameter setting during the development phase.

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ALFIS Vitamin D in conjunction with ALFIS-3 Analyzer is an enzyme-linked fluorescence immunoassay intended for in vitro diagnostic use at clinical laboratories for the quantitative measurement of Total 25-hydroxy Vitamin D (25-OH Vitamin D) in human serum, lithium heparin plasma and sodium heparin plasma.

ALFIS Vitamin D is indicated to be used as an aid in the determination of Vitamin D sufficiency in adults.

ALFIS-3 Analyzer is a fluorescence-scanning instrument using magnetic beads and alkaline phosphatase enzyme system for in vitro diagnostic use in conjunction with various ALFIS immunoassays intended for measuring the concentration of designated analytes in human blood and other specimens.

ALFIS Vitamin D Test Cartridge is a plastic structure molded in the form of a disposable, self-contained, unitized device which houses the 'magnetic bead', 'antibody-alkaline phosphatase-conjugator (Ab-ALP)', 'sample diluent', 'diethanolamine (DEA)', '4-Methylumbelliferyl phosphate (MUP)', 'washing buffer'; all of which are integral components of ALFIS Vitamin D test.

ALFIS Vitamin D test cartridge is an elongated structure having 150.8 mm length, 17 mm width and 16 mm height.

'ALFIS Vitamin D Test ID Chip' is a flat, rectangular device with its main body measuring 23 mm × 27 mm. Half of the portion along the breadth of the main body is 5 mm thick while remaining half is 3 mm in thickness. Another rectangular portion measuring 12 mm × 10 mm × 2 mm protrudes out from the breadth of apical side of the 3 mm-thick portion of the main body.

ALFIS Vitamin D Test ID Chip is an electronic memory device fitted into a plastic matrix. Lot-specific 'ALFIS Vitamin D Test ID Chip' is an integral component of ALFIS Vitamin D test system.

ALFIS-3 analyzer is a compact, bench-top, automated, fluorometric analyzer measuring 422 mm (L) x 270 mm (W) x 292 mm (H). ALFIS-3 weighs 13.0 kg.

ALFIS-3 analyzer is a fluorometer instrument of closed-system analyzer type.

'ALFIS Vitamin D Calibrators' needs to be tested by user laboratories for periodic calibration of ALFIS Vitamin D test system.

'ALFIS Vitamin D Controls' needs to be tested by user laboratories periodically for monitoring the performance of ALFIS Vitamin D test system.

The provided text describes the performance evaluation studies for the ALFIS Vitamin D and ALFIS-3 Analyzer system, which is an in vitro diagnostic device for quantitative measurement of Total 25-hydroxy Vitamin D.

Here's a breakdown of the requested information based on the provided document:

Acceptance Criteria and Device Performance

The document doesn't explicitly state "acceptance criteria" in a tabular format with specific numerical targets for each parameter (e.g., "LoD < X ng/mL"). Instead, it describes how each performance characteristic was evaluated and the resulting performance data, often concluding that the results are "acceptable" or "insignificant interference." However, we can infer the acceptance for some parameters from the reported findings. For instance, for linearity, the high R² value (0.9998) demonstrates acceptable linearity. For precision (repeatability and reproducibility), the CV < 10% is explicitly stated as indicating acceptability. For LoQ, the target of CV ≤ 20% is mentioned.

Here's a table summarizing the reported device performance, with inferred acceptance criteria where explicit values are not provided as a target but rather indirectly through the statement of acceptability:

Study Details

Here's the detailed information regarding the studies:

1. A table of acceptance criteria and the reported device performance: (Refer to the table above).

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

   • Limit of Blank (LoB): 72 blank replicates per lot/analyzer pair (total 3 lots, 3 analyzers) tested across 3 days. This implies 72 * 3 = 216 replicates in total.
   • Limit of Detection (LoD): 15 replicates per lot/analyzer pair (total 3 lots, 3 analyzers) for each of 4 low 25-hydroxyvitamin D-spiked serum samples. Total 45 * 4 = 180 replicates for samples (plus an unstated number for blanks).
   • Limit of Quantitation (LoQ): 12 replicates per lot/analyzer pair (total 3 lots, 3 analyzers) for each of 5 low 25-hydroxyvitamin D serum samples. Total 36 * 5 = 180 replicates for samples.
   • Linearity: 19 25-hydroxyvitamin D-spiked serum samples, tested in triplicate. Total 19 * 3 = 57 measurements.
   • High-dose Hook Effect: A series of spiked samples (10 concentrations from 12.5 ng/mL to 1000 ng/mL), tested in triplicate. Total 10 * 3 = 30 measurements.
   • Analytical Specificity (Interference): The specific number of samples for each interferent is not explicitly stated (e.g., "Performance... not been found to be significantly affected when the endogenous and exogenous substances were tested at specified highest concentrations").
   • Analytical Specificity (Cross-reactivity): The specific number of samples for each cross-reactant is not explicitly stated.
   • In-house repeatability and reproducibility:
     • Repeatability: 3 spiked serum samples, tested in duplicate daily for 20 successive days. Total 3 * 2 * 20 = 120 measurements.
     • Reproducibility: 3 spiked serum samples, tested in quintuplicate daily for 5 successive days (with 3 cartridge lots/analyzer/operator pairs). Total 3 * 5 * 5 = 75 measurements per lot/analyzer/operator pair for reproducibility (75 * 3 = 225 total).
   • External site-to-site reproducibility: 3 spiked serum samples, tested in quintuplicate daily for 5 successive days (across 3 sites/cartridge lots/analyzer-operators). Total 3 * 5 * 5 = 75 measurements per site, so 75 * 3 = 225 in total.
   • Matrix Comparison: 45 matching clinical serum, lithium heparin plasma, and sodium heparin plasma samples, plus an additional 5 spiked samples. Total 45 + 5 = 50 samples per matrix type.
   • Reference Interval: Serum samples collected from 299 apparently healthy adults in the United States. Data provenance is specified as US (central, northern, southern states), collected from external clinical sample repositories.
   • Method Comparison Study: 120 CDC VDSCP verification samples. Provenance of these samples is implied as US (CDC samples). The study was carried out at the "in-house laboratory."

   Data Provenance (Retrospective/Prospective): The document does not explicitly state whether the samples were collected retrospectively or prospectively for most studies. However, for the "Reference Interval" study, it mentions "samples collected from 299 apparently healthy adults in the United States," and "sample sets procured... met the following criteria: ...Collected after June 2021", which suggests recent, potentially prospective, collection or procurement for the study. For the method comparison, CDC VDSCP verification samples are typically existing, well-characterized samples, suggesting a retrospective use of these samples for the study.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: This information is not provided. For this type of IVD device (quantitative measurement of a biomarker), "ground truth" is typically established by certified reference methods, not human expert interpretation in the way it would be for an imaging AI device.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set: Not applicable for this type of quantitative IVD device. Ground truth is established by analytical methods or reference measurement procedures (RMP).

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 device is an automated immunoassay system, not an AI-assisted diagnostic tool requiring human reader studies or MRMC.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: The device itself is an automated, standalone system (ALFIS-3 Analyzer in conjunction with ALFIS Vitamin D cartridges) designed to measure 25-OH Vitamin D quantitatively without direct human interpretation of a visual output. The device results are numerical values. The performance studies (LoB, LoD, LoQ, Linearity, Precision, Analytical Specificity, Matrix Comparison, Method Comparison) all represent the "standalone" performance of the system.

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

   • For LoB, LoD, LoQ, Linearity, High-dose Hook, Analytical Specificity, Repeatability, Reproducibility, Matrix Comparison: Ground truth is based on the known concentrations of spiked samples or reference materials, or properties of the substances themselves.
   • For Method Comparison: Ground truth for the samples was established by the Reference Measurement Procedure (RMP) of 25-hydroxyvitamin D, i.e., ID-LC-MS/MS at a CDC certified laboratory with NIST standard reference material 2972. This is a highly robust and accepted method for establishing ground truth in clinical chemistry.

8. The sample size for the training set: Not applicable for this type of immunoassay device. The device operates based on a pre-defined enzyme-linked fluorescence immunoassay protocol, not a machine learning algorithm that requires a "training set" in the computational sense. The "training" for the device would involve calibration using provided calibrators.

9. How the ground truth for the training set was established: Not applicable. The "training set" concept doesn't apply here. However, for calibration, the instructions state that "ALFIS Vitamin D Calibrators" are used, with approximate assigned 25-OH Vitamin D levels (10 ng/mL and 40 ng/mL), and that a "Lot-specific master calibration curve/equation is encoded in the 'Lot-specific ALFIS Vitamin D Test ID Chip'." This implies that the calibrators' "ground truth" levels (or reference values) are pre-established by the manufacturer, likely traceable to a recognized standard such as the CDC RMP.

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The Access 25(OH) Vitamin D Total assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of total 25-hydroxyvitamin D [25(OH) vitamin D] levels in human serum and plasma using the DxI Access Immunoassay Analyzers. Results are to be used as an aid in the assessment of vitamin D sufficiency.

The Access 25(OH) Vitamin D Total assay is a competitive binding immunoenzymatic assay. The Access 25(OH) Vitamin D Total assay consists of the reagent pack and calibrators. Other items needed to run the assay include substrate and wash buffer. The Access 25(OH) Vitamin D Total assay reagent pack, Access 25(OH) Vitamin D Total assay calibrators, along with the UniCel Dxl Wash Buffer II are designed for use with the Dxl 9000 Access Immunoassav Analyzer in a clinical laboratory setting.

Here's a breakdown of the acceptance criteria and study details for the Access 25(OH) Vitamin D Total assay, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Method Comparison: 150 serum samples. The provenance of these samples (country of origin, retrospective/prospective) is not specified in the provided text.
• Precision: Multiple serum samples were tested in duplicate. The exact number of distinct serum samples beyond Sample 1-6 (which represent different concentration levels) is not specified, but each of the 6 samples was tested with N=80 replicates. The provenance is not specified.
• Limit of Blank (LoB): 120 replicates of a zero-analyte sample. The provenance is not specified.
• Limit of Detection (LoD): 8 to 11 serum samples containing low levels of Vitamin D analyte. These samples were tested over five days with one run per day and nine replicates per run for each pack lot, resulting in ≥ 40 replicates minimally required for LoD estimation for each sample on each pack lot tested. The provenance is not specified.
• Limit of Quantitation (LoQ): 10-13 serum samples containing low levels of Vitamin D analyte. Samples were tested in replicates of nine per run with one run per day and five total days on each pack lot and instrument, resulting in a minimum of 40 replicates for each sample on each pack lot. The provenance is not specified.

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

This device is an in vitro diagnostic (IVD) assay for quantitative determination of a biomarker (25-hydroxyvitamin D). The ground truth for such assays is established through analytical methods and reference standards, not typically by human expert consensus or pathology review in the way a diagnostic imaging AI might be evaluated.

Therefore:

• Number of experts: Not applicable.
• Qualifications of experts: Not applicable.

The assay is traceable to NIST-Ghent ID-LC-MS/MS, which serves as a highly accurate reference method for establishing the true concentration of Vitamin D in samples.

4. Adjudication Method for the Test Set

Not applicable for this type of IVD assay. The performance is assessed by comparing results directly to reference methods or statistical metrics, not through expert adjudication of qualitative or semi-quantitative interpretations.

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

Not applicable. This is an automated in vitro diagnostic assay, not an AI-assisted diagnostic imaging tool that would involve human readers.

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

Yes, the studies described (Method Comparison, Precision, Linearity, LoB, LoD, LoQ) evaluate the performance of the device (assay on the analyzer) in a standalone fashion, without human interpretation or intervention beyond running the tests according to protocol.

7. The Type of Ground Truth Used

• Method Comparison: The predicate device (Access 25(OH) Vitamin D Total assay run on the Access 2 Immunoassay System, K142373) serves as the comparator or "reference" for this study. While not an absolute ground truth, it's the established method against which the new device on the new instrument is compared for substantial equivalence.
• Precision, Linearity, LoB, LoD, LoQ: These studies rely on the inherent properties of the assay and statistical methodologies (e.g., CLSI guidelines) to characterize the device's analytical performance. The reference standard for traceability for the analyte itself is NIST-Ghent ID-LC-MS/MS. Low-level and zero-analyte samples are used to establish limits.

8. The Sample Size for the Training Set

This document describes the validation studies for a new IVD assay and instrument combination. It does not mention a "training set" in the context of machine learning, as this is a chemical immunoassay, not an AI/ML-based device. The term "training set" is not relevant here.

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

Not applicable, as there is no "training set" for this type of device.

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Binding assay for the in vitro quantitative determination of total 25-hydroxyvitamin D in human serum and plasma. This assay is to be used as an aid in the assessment of vitamin D sufficiency in adults.

The electrochemiluminescence binding assay is intended for use on cobas e immunoassay analyzers.

Elecsys Vitamin D total III is a binding assay for the in vitro quantitative determination of total 25-hydroxyvitamin D in human serum and plasma. The assay is to be used as an aid in the assessment of vitamin D sufficiency in adults. The assay is intended for use on the cobas e immunassay analyzers. The cobas e family of analyzers employ the electrochemiluminescence "ECLIA" technology.

Elecsys Vitamin D total III utilizes a competition test principle and has a total test duration of 27 minutes:

• 1st incubation: By incubating the sample (15 µL ) with pretreatment reagent 1 and 2, bound 25-hydroxyvitamin D is released from the vitamin D binding protein (VDBP).
• 2nd incubation: By incubating the pretreated sample with the ruthenium labeled VDBP, a complex between the 25-hydroxyvitamin D and the ruthenylated VDBP is formed. A specific unlabeled antibody binds to 24,25-dihydroxyvitamin D present in the sample and inhibits cross-reactivity to this vitamin D metabolite.
• 3rd incubation: After addition of streptavidin-coated microparticles and 25-hydroxyvitamin D labeled with biotin, unbound ruthenylated labeled VDBP become occupied. A complex consisting of the ruthenylated VDBP and the biotinylated 25-hydroxyvitamin D is formed and becomes bound to the solid phase via interaction of biotin and streptavidin.
• The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell/ProCell M. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier.

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

The reagent working solutions include the reagent rackpack (M, R1, R2) and the pretreatment reagents (PT1, PT2);

PT1 Pretreatment reagent 1 (white cap), 1 bottle, 4 mL: Dithiothreitol 1 g/L, pH 5.5
PT2 Pretreatment reagent 2 (gray cap), 1 bottle, 4 mL: Sodium hydroxide 57.5 g/L
M Streptavidin-coated microparticles (transparent cap), 1 bottle, 6.5 mL: Streptavidin-coated microparticles 0.72 mg/ml; preservative
R1 Vitamin D binding protein-Ru/(bpy) (gray cap), 1 bottle, 9 mL: Ruthenium labeled vitamin D binding protein 150 µg/L; bis-tris propane buffer 200 mmol/L; albumin (human) 25 g/L; pH 7.5; preservative
R2 25-hydroxyvitamin Dbiotin (black cap), 1 bottle, 8 5 mL: Biotinylated 25-hydroxyvitamin D 20 µg/L; bis-tris propane buffer 200 mmol/L; pH 8.6; preservative

This document describes the Elecsys Vitamin D total III assay, a binding assay for the in vitro quantitative determination of total 25-hydroxyvitamin D in human serum and plasma. It is intended to aid in the assessment of vitamin D sufficiency in adults and is designed for use on cobas e immunoassay analyzers.

1. Acceptance Criteria and Reported Device Performance

The provided text details several performance characteristics and the testing conducted to meet acceptance criteria. While explicit "acceptance criteria" values are not listed in a separate table for all tests, the document states that "All predefined acceptance criteria was met" for various studies. The reported performance for each study is summarized below:

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

• Precision Measurements: Sample size not specified, but conducted with multiple measurements over 21 days according to CLSI guideline EP05-A3. Data provenance is implied to be internal testing by Roche Diagnostics.
• Lot-to-Lot Reproducibility: Sample size not specified, but performed using three reagent lots. Data provenance is implied to be internal testing by Roche Diagnostics.
• Limit of Blank (LoB), Limit of Detection (LoD), Limit of Quantitation (LoQ): Sample size not specified; determined according to CLSI EP17-A2. Data provenance is implied to be internal testing by Roche Diagnostics.
• Linearity: Sample size not specified, but evaluated on one cobas e 601 analyzer. Data provenance is implied to be internal testing by Roche Diagnostics.
• High-Dose Hook Effect (HDHE): Two-fold determination with two samples on one cobas e 601 analyzer. Data provenance is implied to be internal testing by Roche Diagnostics.
• HAMA Interference: Sample size not specified, assessed on one cobas e 601 analyzer. Data provenance is implied to be internal testing by Roche Diagnostics.
• Endogenous Interference: 10 endogenous substances evaluated. Sample size not specified for each substance. Data provenance is implied to be internal testing by Roche Diagnostics.
• Cross-Reactivity: Cross-reactivity with various vitamin D metabolites and related compounds. Sample size not specified for each compound. Data provenance is implied to be internal testing by Roche Diagnostics.
• Exogenous Interference: 17 commonly and 3 specially used pharmaceutical compounds evaluated. Sample size not specified for each compound. Data provenance is implied to be internal testing by Roche Diagnostics.
• Method Comparison (LC-MS/MS): 157 single donor serum samples. Data provenance: CDC Verification Samples provided by the Vitamin D Standardization and Certification Program, with assigned values by the candidate Reference Method Procedure: ID-LCMS/MS at the CDC Vitamin D Reference Laboratory. This indicates a prospective and externally validated dataset.
• Method Comparison (Predicate Device): 151 human serum samples. Data provenance is implied to be internal testing by Roche Diagnostics, comparing with their own predicate device (Elecsys Vitamin D total II).
• Anticoagulant Effects: Single-donor samples (number not specified) drawn into serum, SST, Li-Heparin, K2-EDTA plasma primary tubes. Data provenance is implied to be internal testing by Roche Diagnostics.
• Plasma Separation Tubes (PSTs) Effects: Single-donor samples (number not specified) drawn into PSTs from 3 separate manufacturers. Data provenance is implied to be internal testing by Roche Diagnostics.
• Reagent Stability: Tested on one cobas e 601 analyzer. Data provenance is implied to be internal testing by Roche Diagnostics.
• On-board Reagent Stability: Tested on one cobas e 601 analyzer. Data provenance is implied to be internal testing by Roche Diagnostics.
• Lot Calibration Frequency: Tested on one cobas e 601 analyzer. Data provenance is implied to be internal testing by Roche Diagnostics.
• On-board Calibration Frequency: Tested on one cobas e 601 analyzer. Data provenance is implied to be internal testing by Roche Diagnostics.
• Reference Range Study: A total of 827 subjects enrolled; 463 eligible subjects included in the final determination after exclusions. Data provenance: Serum samples collected from adult subjects during summer and winter months from three geographically diverse locations in the U.S. (Northern regions). One clinical laboratory was contracted to measure samples. This indicates prospective, multi-site clinical data.

Note: For internal testing studies (precision, linearity, interference, stability), the data provenance is implied to be prospective testing conducted by Roche Diagnostics in a controlled laboratory setting.

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

The document does not describe the use of "experts" to establish ground truth in the traditional sense of medical image analysis or diagnostic interpretation by physicians.

For the Method Comparison (LC-MS/MS), the "ground truth" (or reference values) for the 157 samples was established by the CDC Verification Samples with assigned values by the candidate Reference Method Procedure: ID-LCMS/MS at the CDC Vitamin D Reference Laboratory. This implies a highly standardized and validated reference method for quantifying vitamin D, rather than expert clinical judgment.

For the Reference Range Study, "characterization testing" was used to determine whether samples met stated inclusion/exclusion criteria. This involved a variety of characterization assays on cobas e 601 or cobas c 501 analyzers, not human expert adjudication.

4. Adjudication Method

Not applicable, as the studies described primarily involve analytical performance testing using quantitative measurements against reference methods or predefined criteria, rather than qualitative assessments requiring human adjudication.

5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study

Not applicable. The Elecsys Vitamin D total III is an in vitro diagnostic assay, not an AI-powered image analysis or diagnostic tool that assists human readers. Therefore, an MRMC study and the concept of "human readers improve with AI vs without AI assistance" are not relevant to this device's evaluation.

6. Standalone Performance Study

Yes, a standalone study of the algorithm (in this case, the assay system's performance) was done. All the non-clinical and clinical tests described, such as precision, accuracy (method comparison), linearity, limits of detection, interference, and stability, demonstrate the standalone performance of the Elecsys Vitamin D total III assay system. The device performs the quantitative analysis without human intervention in the measurement process itself, once the sample is loaded and the assay initiated.

7. Type of Ground Truth Used

The primary ground truth used for performance evaluation, particularly for accuracy, was:

• Reference Method/Standard: For the method comparison study, the CDC Verification Samples with values assigned by the ID-LCMS/MS (Isotope Dilution Liquid Chromatography-Mass Spectrometry/Mass Spectrometry) at the CDC Vitamin D Reference Laboratory served as the reference method or "ground truth" for 25-hydroxyvitamin D concentration. This is a highly accurate and precise analytical method.
• Predicate Device Comparison: The predicate device, Elecsys Vitamin D total II, also served as a reference for comparison, indicating substantial equivalence.
• Analytical Standards/Controls: For other analytical performance tests (e.g., precision, linearity, limits), ground truth is established through the use of certified reference materials, calibrators, and specified spiked samples with known concentrations.

8. Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning or AI algorithm development. The Elecsys Vitamin D total III is a binding assay with a defined chemical and immunological principle, not a machine learning algorithm that is "trained" on a dataset in the conventional sense. Therefore, the concept of a training set size for an AI model is not directly applicable here.

However, the assay's development and optimization would have involved extensive testing and "training" by researchers and developers in a broader, non-AI sense to establish reagent formulations, reaction conditions, and calibration parameters before formal validation studies. This is not detailed in the provided regulatory document.

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

As explained in point 8, the concept of a "training set" for AI is not directly applicable to this device. Therefore, the method for establishing ground truth for such a set is also not discussed. The assay's fundamental performance characteristics (e.g., binding kinetics, signal generation) are based on established biochemical principles and extensive internal research and development, which would have leveraged known concentrations of 25-hydroxyvitamin D and its metabolites in control samples and reference materials.

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The ADVIA Centaur® Vitamin D Total (VitD) assay is for in vitro diagnostic use in the quantitative determination of total 25(OH)vitamin D in human serum and plasma (EDTA, lithium heparin, sodium heparin) using the ADVIA Centaur® systems. The ADVIA Centaur® VitD assay is intended as an aid in the determination of vitamin D sufficiency.

The ADVIA Centaur® Vitamin D reagent kit comes in two configurations (100 or 500 test kit) and each kit contains the following:

• ReadyPack® primary reagent pack containing ADVIA Centaur VitD Lite Reagent, Solid . Phase Reagent, and Ancillary Well Reagent
• ReadyPack ancillary pack containing ADVIA Centaur VitD Ancillary Reagent .
• . ADVIA Centaur VitD Low Calibrator
• . ADVIA Centaur VitD High Calibrator
• ADVIA Centaur systems VitD Master Curve card ●
• ADVIA Centaur systems VitD Calibrator Assigned Value Card ●

The VitD Reagents consists of the following:
Lite Reagent 5.0 mL/reagent pack:
The reagent contains anti-VitD (monoclonal mouse) antibody labeled with acridinium ester (~0.8 µg/mL) in buffer with bovine serum albumin, mouse IgG, and sodium azide (< 0.1%)
Solid Phase Reagent 10.0 mL/reagent pack:
The Solid Phase Reagent contains anti-fluorescein (monoclonal mouse)-coated paramagnetic particles (PMP) (~0.60 mg/mL) in buffer with bovine serum albumin, surfactant, and sodium azide (< 0.1%)
Ancillary Well Reagent 5.0 mL/reagent pack:
The Ancillary Well Reagent contains vitamin D-analog conjugated to fluorescein (~0.2 µg/mL) and 1-anilinonaphthalene-8-sulfonic acid in buffer with bovine serum albumin and sodium azide (< 0.1%)
Ancillary Reagent Pack 25.0 mL/reagent pack:
The Ancillary Reagent Pack contains releasing agent in buffered saline with sodium azide (<0.1%) and stabilizers
The VitD Calibrators 2 x 2.0 mL/vial:
After reconstitution, low or high levels of 25(OH)vitamin D in buffered, defibrinated human plasma with bovine serum albumin, cholesterol, preservatives, and sodium azide (<0.1%).

Material Required but Not Provided

• ADVIA Centaur Wash 1 .
  Optional Materials
• ADVIA Centaur VitD Quality Control Material
• . ADVIA Centaur VitD Diluent
• . ADVIA Centaur VitD Master Curve Material (MCM)

The provided text describes the performance characteristics of the ADVIA Centaur® Vitamin D Total (VitD) assay and compares it to a predicate device. It primarily focuses on the analytical performance of the device and does not involve AI or human readers in the context of diagnostic interpretation.

Here's the breakdown of the information requested, based on the provided text:

1. A table of acceptance criteria and the reported device performance

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Precision: 6 samples, each assayed twice a day in replicates of 2, over 20 days (n=80 replicates per sample). Data provenance not specified.
• Method Comparison: 126 samples (118 native, 8 contrived). Data provenance not specified.
• Specimen Equivalence: 66 native and 8 contrived matched set samples (total 74 matched sets) for serum, SST, Lithium Heparin, Sodium Heparin, K2 EDTA, K3 EDTA. Data provenance not specified.
• Dilution Recovery: 5 serum samples. Data provenance not specified.
• Reference Interval:
  • Adult population: 291 apparently healthy male and female subjects of light and dark skin types, aged 21-93 years.
  • Pediatric population: 237 male and female subjects of light and dark skin types; 32 subjects (1-3 years), 114 subjects (3-12 years), 91 subjects (12-21 years).
  • Data Provenance: Samples collected in different seasons and from different geographical regions of the United States. This indicates prospective recruitment for this specific study, though the general term "established" could imply previous work.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This report describes an in vitro diagnostic (IVD) assay for quantitative measurement, not an AI diagnostic imaging device that requires expert interpretation. Therefore, the concept of "experts used to establish the ground truth" in the way it applies to diagnostic imaging is not relevant here. The ground truth for this device is chemically and analytically determined concentrations of Vitamin D.

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

Not applicable. This is an analytical performance study of an IVD assay, not a study involving human interpretation of diagnostic data needing 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 document describes an IVD assay, not AI software for diagnostic interpretation.

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

Yes, the studies described are standalone performance evaluations of the ADVIA Centaur® Vitamin D Total (VitD) assay. The device measures Vitamin D levels, and its performance is assessed analytically (precision, linearity, detection limits, method comparison) without human intervention in the result determination process.

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

The ground truth for the analytical performance studies (precision, linearity, limit of detection/quantitation, method comparison) is based on:

• Known concentrations: For studies like linearity, samples are prepared with known relative concentrations.
• Established reference methods: For method comparison, the device's results are compared against a "comparable assay" (which likely serves as a reference or a well-characterized method). For traceability, it mentions "ID-LC-MS/MS 25(OH)vitamin D (RMP)," indicating a highly accurate reference method.
• Statistical definitions: LoD and LoQ are defined statistically (e.g., 95% probability of detection, 20% total CV).
• Clinical populations: For establishing reference intervals, samples are drawn from defined healthy adult and pediatric populations, and inclusion criteria (normal values for PTH, calcium, TSH, no high-dose vitamin D supplements) are used to define the reference population.

8. The sample size for the training set

This document describes the validation of an IVD assay, not a machine learning model. Therefore, there is no "training set" in the context of AI/ML. The device's operational parameters are presumably set during development and optimized based on various experiments, but these are not referred to as a "training set" in the sense of AI.

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/ML model for this IVD assay.

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MAGLUMI 2000 25-OH Vitamin D is an in vitro chemiluminescence immunoassay for the quantitative determination of 25-OH Vitamin D in human serum using Maglumi 2000 Fully-auto chemiluminescence immunoassay analyzer. The measurement of 25-OH Vitamin D is to be used as an aid in the assessment of vitamin D sufficiency.

MAGLUMI 2000 25-OH VITAMIN D kit consists of the following reagents: Magnetic Microbeads- coated with 25-OH Vitamin D monoclonal antibody, containing BSA, NaN3 (<0.1%) Calibrator Low-Containing BSA and 25-OH Vitamin D antigen, NaN3(<0.1%) Calibrator High- Containing BSA and 25-0H Vitamin D antigen, NaN3(<0.1%) Displacing Reagent- Acidic buffer ABEI Label- 25-OH Vitamin D antigen labeled with ABEI Control 1- Containing BSA and 25-OH Vitamin D antigen, NaN3 (<0.1%) Control 2- Containing BSA and 25-OH Vitamin D antigen, NaN3 (<0.1%)

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Study Details:

The provided document describes a series of analytical performance studies and a method comparison study to demonstrate the performance characteristics of the MAGLUMI 2000 25-OH Vitamin D assay.

2. Sample Sizes and Data Provenance

• Test Set (for specific performance characteristics):

  • Precision: 240 samples per level across 9 sample types (3 controls, 2 calibrators, 3 spiked serum pools, 3 native serum pools). Total N = 240 * 9 = 2160 individual measurements (though some are duplicates/runs, the total 'data points' are numerous).
  • Linearity: 11 levels of linearity samples, each measured in quadruplicate, on 3 lots of reagent.
  • Detection Limit:
    • LOB: 60 measurements of 25-OH VITAMIN D depleted serum samples using 3 different lots of reagents over 5 days.
    • LOD: 4 levels of low samples measured in 60 replicates over 5 days per sample using 3 lots of reagents.
    • LOQ: Six low serum samples, in six replicates per run, one run per day, over 5 days, using 3 lots of reagents.
  • Interference (Cross-reactivity): Used two base serum samples (30 ng/mL and 60 ng/mL total 25-OH VD) spiked with various cross-reactants, measured using 3 lots of reagents.
  • Interference (Endogenous Substances & Common Drugs): Three serum samples (20, 30, and 60 ng/mL 25-OH VITAMIN D) analyzed for each substance.
  • Interference (HAMA, RF, Total Protein): Human serum samples supplemented with potential interferents, tested using 3 lots of reagents.
  • Method Comparison: 241 human serum samples.

• Data Provenance: The document does not explicitly state the country of origin for the clinical samples. It uses "human serum samples" and "patient serum pools." The studies appear to be retrospective in nature, using collected serum samples.

3. Number of Experts and Qualifications for Ground Truth

• This device is an in vitro diagnostic immunoassay. The concept of "ground truth" established by experts (like radiologists for imaging) is not applicable in the same way. The ground truth for such assays is typically established by:

  • Known concentrations for controls and calibrators, often traceable to reference materials (e.g., NIST RMP 2972 for traceability as mentioned).
  • Spiking studies where a known amount of analyte is added to a sample.
  • Comparison to a legally marketed predicate device, which itself has an established ground truth.
  • Pathology/biochemical analysis where the exact concentration of the analyte is determined by highly accurate reference methods (e.g., ID-LC-MS/MS).

  Therefore, there were no human experts establishing the ground truth in the context of clinical interpretation, but rather a robust analytical process to define true concentrations.

4. Adjudication Method for the Test Set

• Not applicable for this type of in vitro diagnostic assay. Adjudication methods like 2+1 or 3+1 are typically used in clinical trial settings where human interpretation or consensus for a diagnosis is required.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• No, an MRMC comparative effectiveness study was not done. This type of study is relevant for devices (often imaging AI) where multiple human readers interpret cases and their performance is compared with and without AI assistance. The MAGLUMI 2000 25-OH Vitamin D is an automated immunoassay, not a device requiring human interpretation in this manner.

6. Standalone (Algorithm Only) Performance

• Yes, a standalone performance was done. The entire analytical performance section (Precision, Linearity, Stability, Detection Limit, Interference) directly assesses the algorithm's (the immunoassay's) performance without human intervention in the measurement process. The "MAGLUMI 2000 Fully-auto chemiluminescence immunoassay analyzer" is an automated system, meaning the results are generated directly by the device. The method comparison study is also a standalone assessment of the device's output against a predicate.

7. Type of Ground Truth Used

• The ground truth for the analytical validation aspects (e.g., calibrators, controls, linearity samples) is based on pre-defined concentrations, often traceable to reference methods like ID-LC-MS/MS (Isotope Dilution Liquid Chromatography-Mass Spectrometry/Mass Spectrometry) and reference materials such as NIST RMP 2972.
• For interference studies, the "ground truth" is inferred by the known addition of interferents and measuring the deviation from the expected value.

8. Sample Size for the Training Set

• The document does not mention a training set in the context of machine learning or AI. This device is an immunoassay, which functions based on established biochemical principles and reagents, not on a machine learning model that requires a separate training set. The "development" or "optimization" of the assay would involve various experiments, but not a formally defined "training set" like in AI/ML validation.

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

• Not applicable, as there is no mention of a training set for an AI/ML model for this immunoassay.

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The BioPlex 2200 25-OH Vitamin D Kit is a multiplex flow competitive immunoassay intended for the quantitative determination of 25-hydroxyvitamin D in human serum. The BioPlex 2200 25-OH Vitamin D assay is to be used as an aid in the assessment of vitamin D sufficiency.

The BioPlex 2200 25-OH Vitamin D kit is intended for use with the Bio-Rad BioPlex 2200 System.

BioPlex 2200 25-OH Vitamin D kit includes the following components:

• One (1) 10 mL vial of Bead Set containing dyed beads coated with anti-25-0H ● Vitamin D antibody (sheep), an Internal Standard bead (ISB), and a Serum Verification bead (SVB) in buffer with protein stabilizers (bovine). ProClin 950 (< 1.0%) and sodium azide (< 0.1%) as preservatives.
• One (1) 10 mL vial of Release Buffer containing 25-OH Vitamin D releasing reagents in citrate and tri sodium citrate acid buffer at pH 4.1 and ProClin 950 (<1.0%) as preservative.
• One (1) 5 mL vial of Conjugate 1 containing biotinylated 25-OH Vitamin D . conjugate and biotinylated anti-human FXIII antibody conjugate (murine) in buffer with protein stabilizers (bovine). ProClin 950 (< 1.0%) and 5-bromo-5nitro-1, 3-dioxane (<0.1%) as preservatives and chemical blockers.
• . One (1) 5 mL vial of Conjugate 2 containing phycoerythrin conjugated streptavidin (SA-PE) in a buffer comprising protein stabilizers (bovine). ProClin 950 (< 1.0%) and sodium azide (< 0.1%) as preservatives, chemical blockers and detergent (Tween 20).

Additional materials required but not supplied include BioPlex 2200 Sheath Fluid containing Phosphate Buffered Saline (PBS), ProClin 300 (0.03%) and sodium azide (<0.1%) as preservatives; and BioPlex 2200 Wash Solution containing Phosphate Buffered Saline (PBS) and Tween 20. ProClin 300 (0.03%) and sodium azide (<0.1%) as preservatives.

The BioPlex 2200 25-OH Vitamin D Kit is a multiplex flow competitive immunoassay intended for the quantitative determination of 25-hydroxyvitamin D in human serum, to be used as an aid in the assessment of vitamin D sufficiency. The device underwent a 510(k) submission, K180577, to demonstrate substantial equivalence to its predicate device, BioPlex 2200 25-OH Vitamin D Kit (K141114). The new kit has been modified by re-assigning calibrators and standardizing the assay in accordance with the Vitamin D Standardization Program (VDSP).

Here's an analysis of the acceptance criteria and the studies performed:

1. Table of Acceptance Criteria and Reported Device Performance:

The document primarily focuses on demonstrating substantial equivalence to a predicate device and adherence to CLSI guidelines for analytical performance. Therefore, "acceptance criteria" for specific performance metrics are often implied by the standards set forth in these guidelines and the performance of the predicate device, rather than explicit numerical targets stated as acceptance criteria in the summary. However, we can infer some criteria from the presented data.

2. Sample size used for the test set and data provenance:

• Precision Studies (CLSI EP5-A3):
  • Sample Size: 6 human serum samples and 2 control levels. Each tested in duplicate per run, on two runs per day over 20 days (N=80 results per sample/control).
  • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective), but it was human serum from a "panel".
• Reproducibility Studies (CLSI EP15-A3):
  • Sample Size: 8 panel members (serum matrix and QC controls), tested in replicates of two on two runs per day over five days (20 replicates per panel member).
  • Data Provenance: Performed at "one (1) US testing facility." Not explicitly stated if retrospective or prospective, or specific origin of serum matrix.
• Linearity/Assay Reportable Range (CLSI EP06-A):
  • Sample Size: Five high patient serum samples initially, serially diluted. Each sample and dilution evaluated in replicates of four.
  • Data Provenance: Not explicitly stated.
• Detection Limits (LoB, LoD, LoQ) (CLSI EP17-A2):
  • LoB: Five blank samples, tested in 4 replicates per day for 5 days (100 data points per reagent lot).
  • LoD: Six human samples with low 25-OH vitamin D, tested in 10 replicates per day for five days (50 data points per sample per reagent lot).
  • Data Provenance: Not explicitly stated.
• Interfering Substances (CLSI EP07-A2):
  • Sample Size: Not explicitly stated for number of samples, but "human serum pools" were used.
  • Data Provenance: Not explicitly stated.
• Cross-Reactivity (CLSI EP17-A2):
  • Sample Size: 2 human serum pools. Nine cross-reactants were spiked into these pools. Spiked and non-spiked samples evaluated in replicates of five.
  • Data Provenance: Not explicitly stated.
• Method Comparison with Predicate Device (CLSI EP09-A3):
  • Sample Size: 201 human samples (182 unaltered, 19 spiked with 25-hydroxyvitamin D3).
  • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective).
• Method Comparison to Reference Method (VDSP):
  • Sample Size: 120 native single donor patient serum samples.
  • Data Provenance: "reference sample set provided by the Vitamin D Standardization and Certification Program with assigned values by the RMP at CDC, independent from the samples used for standardization." This indicates a high-quality, external reference set. The origin of the patient samples themselves is not specified beyond "native single donor patient serum samples".
• Bias at Vitamin D Medical Decision Levels:
  • Sample Size: 303 samples overall for bias analysis, with specific numbers at each decision range (e.g., 7 for 19-21 ng/mL, 20 for 29-31 ng/mL, 6 for 95-105 ng/mL).
  • Data Provenance: Presumably a subset or re-analysis of samples from the method comparison studies.
• Expected Values/Reference Range (CLSI EP28-A3c):
  • Sample Size: 288 samples from "apparently healthy donors" (161 males, 127 females).
  • Data Provenance: Samples collected from "three regions (Northern, Central, and Southern) in the US" in spring, summer, and winter. Included African Americans, Hispanics, and Caucasians. This is prospective collection for establishing a reference range.

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) quantitative assay for a biomarker (25-OH Vitamin D). The "ground truth" for such devices is established through highly accurate and standardized analytical methods.

• For the Method Comparison to Reference Method, the ground truth was established by the Vitamin D Standardization and Certification Program (VDSP) using an ID-LC/MS/MS Reference Method Procedure (RMP) at CDC. This RMP is traceable to the National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) 2972a. These are highly qualified and internationally recognized reference methods and institutions for chemical measurements, representing the gold standard in analytical chemistry. It is not about expert consensus on interpretations, but rather expert execution and certification of analytical accuracy.
• For other studies (precision, linearity, etc.), the "ground truth" is typically the measured value itself by the reference method or the assigned value of controls and calibrators, which are also traceable to established analytical standards.

4. Adjudication method for the test set:

Not applicable in the conventional sense involving multiple human readers and an adjudication process. This is a quantitative IVD device where sample values are measured against established reference methods and standards, not interpreted by experts in a clinical imaging or diagnostic context that would require 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 a laboratory diagnostic assay, not an AI-assisted diagnostic tool that involves human readers interpreting cases.

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

This device performs as a standalone automated multiplex flow competitive immunoassay on the Bio-Rad BioPlex 2200 System. Its performance characteristics (precision, linearity, LLoQ, etc.) were evaluated directly without human intervention in the measurement process, representing a "standalone" analytical performance assessment. However, it's not an "algorithm only" device in the sense of AI; it's a chemical assay. The output is a quantitative measure of 25-OH Vitamin D concentration.

7. The type of ground truth used:

• For method comparison, the ground truth for the 120 samples was assigned values by the RMP at CDC, provided by the Vitamin D Standardization and Certification Program (VDSP). This is a highly accurate and externally certified analytical ground truth.
• For other analytical validation studies, the ground truth is established through internal standards, traceable calibrators, and reference materials specified by CLSI guidelines and traceable to NIST SRM 2972a.

8. The sample size for the training set:

• This submission describes performance validation for a modified in vitro diagnostic kit. The "training set" concept (as used in machine learning) is not directly applicable here. The device itself (the BioPlex 2200 system and its reagents) has established methodologies.
• The document states that Bio-Rad "modified the kit by re-assigning the calibrators and standardizing the assay in accordance with the Vitamin D Standardization Program (VDSP)." This implies that Bio-Rad used samples and measurements to establish these new calibrator assignments and standardization. However, the specific size and nature of such internal development/calibration "training" sets are not detailed in this 510(k) summary. The summary focuses on the validation of the finalized device.

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

• Again, the concept of a "training set" for an IVD kit often refers to the samples used during development and calibration. For this device, the key aspect of this "ground truth" for the modified kit is its standardization in accordance with the Vitamin D Standardization Program (VDSP). This means that the calibrators and ultimately the assay's measurements are referenced to the same highly accurate ID-LC/MS/MS RMP and NIST SRM 2972a that were used to establish the ground truth for the external validation sample sets. This ensures analytical accuracy and comparability across different methods and laboratories. The actual process of selecting and assigning values to the new calibrators would involve measuring reference materials and/or highly characterized samples using the VDSP-traceable methods.

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The Diazyme EZ Vitamin D Assay is intended for use in clinical laboratories for the quantitative determination of 25hydroxyvitamin D (25-OH-D) in human serum and plasma on automated chemistry analyzers. Measurement of 25hydroxyvitamin D (25-OH-D) is for the assessment of vitamin D sufficiency. For in vitro diagnostic use only.

Not Found

The provided text is a 510(k) Premarket Notification letter from the FDA to Diazyme Laboratories for their Diazyme EZ Vitamin D Assay. This document is a regulatory approval letter for an in vitro diagnostic (IVD) device, specifically a chemical assay to measure Vitamin D levels.

The questions you've asked (1-9) are typical for the clinical validation of an AI/ML-based diagnostic device, especially those that process medical images. The information needed to answer these questions, such as "acceptance criteria" based on metrics like sensitivity, specificity, or AUC, "sample sizes for test sets," "number of experts," "adjudication methods," "MRMC studies," and "standalone performance," are not applicable or present in this document.

This document confirms the device's substantial equivalence to a predicate device and states its intended use, but it does not contain the detailed performance study results that would typically be required for an AI/ML diagnostic system. For an IVD assay like the Diazyme EZ Vitamin D Assay, acceptance criteria and performance data would typically be demonstrated through:

• Analytical Performance Studies: Accuracy (trueness/bias), precision (repeatability, reproducibility), linearity, analytical measuring range, limit of detection, limit of quantitation, interference, etc.
• Clinical Performance Studies: Correlation with a reference method, clinical utility, and potentially comparative studies with other assays.

Therefore, I cannot populate the table or answer questions 1-9 based on the provided text. The text is a regulatory approval letter, not a detailed clinical study report for an AI/ML device.

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The LOCI Vitamin D Total assay is an in vitro diagnostic test for the quantitative measurement of total 25(OH)yitamin D in human serum and plasma on the Dimension® EXL™ integrated chemistry system with LOCI® Module. Measurements of vitamin D are used in the assessment of vitamin D sufficiency.

The LOCI VITD CAL is an in vitro diagnostic product for the calibration of the Vitamin D (VITD) Total assay on the Dimension® EXL™ integrated chemistry system with LOCI® module.

LOCI Vitamin D Total assay:
The LOCI Vitamin D Total assay is a homogeneous competitive chemiluminescent immunoassay based on LOCI technology. The assay measures the total 25(OH)vitamin D concentration [comprising both 25(OH)vitamin D2 and 25(OH)vitamin D3] in both serum and plasma. LOCI Vitamin D Total reagents include a releasing reagent, biotinylated monoclonal antibody, and two synthetic bead reagents. Patient sample is incubated with the releasing reagent to release 25(OH)vitamin D molecules from the vitamin D-binding proteins. The reaction mixture is then incubated with biotinylated antibody to form a 25(OH)vitamin D/biotinylated antibody complex.

Chemibeads containing 25(OH)vitamin D3 analog and chemiluminescent dye are added to remove the excess free biotinylated antibody. Streptavidin-coated Sensibeads containing a photosensitive dye are added to bind the biotinylated antibody. Aqqregates of the Chemibead analog/biotinylated antibody/streptavidin Sensibeads are formed as a result. Illumination of the reaction mixture by light at 680 nm generates singlet oxygen from the Sensibeads, which diffuses into the Chemibeads and triagers a chemiluminescent reaction. The resulting chemiluminescent signal is measured at 612 nm and is inversely proportional to the concentration of total 25(OH)vitamin D in the sample.

LOCI VITD CAL:
The LOCI VITD CAL is a five level, liquid, single analyte, frozen product, which is stored at -15 ℃ to -25 ℃. The calibrator matrix consists of processed human serum with preservatives and stabilizers. Level 1 is a zero level, while levels 2 3, 4, and 5 contain approximately 12, 30, 75, and 165 ng/mL respectively. Each lot of calibrators will have lot specific assigned values assigned from master pool levels that are traceable by method correlation to Ghent University's ID-LC/MS/MS 25(OH)vitamin D Reference Method Procedure (RMP). The ID-LC/MS/MS RMP is traceable to the NIST SRM 2972.

Here's an analysis of the provided text regarding the LOCI Vitamin D Total Assay and LOCI VITD CAL, focusing on acceptance criteria and the supporting studies:

Summary of Acceptance Criteria and Device Performance for LOCI Vitamin D Total Assay

Unfortunately, the provided document does not explicitly state predetermined "acceptance criteria" for each performance characteristic in a table format, nor does it provide a direct statement "proving the device meets acceptance criteria."

Instead, the document describes the methods and presents the results of various performance studies. The implication is that these results demonstrate the device's acceptable performance for its intended use, based on generally accepted analytical performance standards in the medical device industry (e.g., CLSI guidelines).

However, I can extract the reported performance and infer what aspects would likely be critical for acceptance.

1. Table of Acceptance Criteria (Inferred) and Reported Device Performance

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

• Method Comparison:
  • Sample Size: 163 remnant de-identified human serum samples.
  • Data Provenance: Not explicitly stated, but "human serum samples" implies human origin. "Remnant de-identified" suggests retrospective data.
• Repeatability and Within Lab Precision:
  • Sample Size: Testing performed with Tri-Level Vitamin D Plus QC (3 levels) and 4 human serum/plasma samples (Serum 1, Serum 2, Serum 3, Plasma 2). Each sample/QC was analyzed as a single test from two independent cups, over 20 days with 2 runs per day.
  • Data Provenance: Not specified, but laboratory-controlled samples/QCs and potentially remnant human samples.
• Linearity:
  • Sample Size: One sample with high concentration serially diluted. Each dilution assayed in n=5 replicates.
  • Data Provenance: Laboratory prepared samples.
• Recovery:
  • Sample Size: Two separate serum samples (baseline 28.3 ng/mL and 54.7 ng/mL) were spiked.
  • Data Provenance: Human serum.
• Detection Capability (LoD, LoB):
  • Sample Size: 120 determinations (60 blank and 60 low-level replicates).
  • Data Provenance: Laboratory prepared blank and low-level samples.
• Interference Testing (HIL & Non-Interfering Substances):
  • Sample Size: Not explicitly stated per interferent, but tested at three levels of vitamin D concentrations (13.9-16.9 ng/mL, 28.4-32.0 ng/mL, 70.2-77.3 ng/mL).
  • Data Provenance: Laboratory prepared samples spiked with interferents.
• HAMA Interference:
  • Sample Size: 20 samples containing vitamin D (5.0 ng/mL to 87.5 ng/mL) with varying concentrations of HAMA (8 ng/mL to 161,000 ng/mL). Mean n=5 for bias calculations.
  • Data Provenance: Human samples containing HAMA.
• Serum Plasma Equivalency:
  • Sample Size: 70 matched lithium heparin plasma, K2 EDTA plasma, serum separator tube (SST), and red top serum samples. 8 were fresh native, 62 frozen (8 of these split and spiked).
  • Data Provenance: Human patient samples (U.S. geographical locations, potentially diverse, during different seasons). Indicated as remnant, de-identified and includes both fresh and frozen samples. This is a mix of prospective (freshly drawn) and retrospective (remnant, frozen) data from human patients in the US.
• Cross-Reactivity:
  • Sample Size: Not explicitly stated per cross-reactant, but tested at specified concentrations.
  • Data Provenance: Laboratory prepared samples spiked with cross-reactants.
• Apparently Healthy Population (Expected Values):
  • Sample Size: 252 adults (246 not taking supplements, 6 taking).
  • Data Provenance: Human serum samples collected from subjects residing in diverse U.S. geographical locations, during different seasons.

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

• Ground Truth for Method Comparison: The "ground truth" for the method comparison study was established by the ID-LC-MS/MS 25(OH) vitamin D Reference Measurement Procedure (RMP) from Ghent University, which is traceable to the NIST Standard SRM2972. This is a highly specialized analytical method, not typically performed by "experts" in the sense of a medical professional consensus. It's a gold-standard laboratory technique.
• Other Studies: For other performance characteristics, the ground truth is based on the known concentrations of controls, calibrators, spiked samples, or reference materials, which are established through rigorous analytical methodology rather than expert consensus on a clinical case.

4. Adjudication Method for the Test Set

This type of information (e.g., 2+1, 3+1 for clinical consensus) is not applicable to an in vitro diagnostic (IVD) assay product like the LOCI Vitamin D Total Assay. Adjudication methods are typically used in imaging studies or clinical trials where human interpretation of data (e.g., images, patient symptoms) is subject to variability and requires consensus among experts to establish a "ground truth" or clinical outcome. For IVD assays, the "ground truth" is largely analytical, based on reference methods or known concentrations.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Reader Improvement

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is primarily relevant for medical imaging AI devices where human readers interpret images, and the AI serves as an aid. The LOCI Vitamin D Total Assay is an automated in vitro diagnostic assay, where the output is a quantitative measurement, not an image requiring human interpretation or a "reader."

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

The entire set of performance characteristic studies for the LOCI Vitamin D Total Assay (e.g., precision, linearity, method comparison, interference) evaluates the standalone performance of the assay. It's an automated system (Dimension EXL integrated chemistry system with LOCI Module), and the results presented reflect the assay's output without direct human "in-the-loop" interpretation for each individual test result beyond the initial setup and quality control.

7. The Type of Ground Truth Used

The ground truth used for the critical method comparison study and calibrator traceability is traceability to a reference measurement procedure (RMP) and standard reference materials (SRM):

• For Method Comparison: Ghent University's ID-LC-MS/MS 25(OH) vitamin D Reference Measurement Procedure (RMP), traceable to NIST SRM 2972. This is considered a highly accurate and precise analytical "gold standard."
• For Calibrators (LOCI VITD CAL): Internal standards traceable by method correlation to Ghent University's ID-LC-MS/MS 25(OH) vitamin D RMP, which is traceable to NIST SRM 2972.
• For other studies (e.g., precision, linearity, recovery, detection capability, interference): Known concentrations of controls, calibrators, or prepared spiked samples.

8. The Sample Size for the Training Set

The document does not provide information about a "training set" because this is an in vitro diagnostic assay, not an AI/ML algorithm that requires an explicit training phase on a dataset of patient results. The development process for such assays involves extensive R&D, reagent formulation, and analytical validation but not "training" in the machine learning sense.

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

Since there is no explicit "training set" in the context of an AI/ML algorithm, this question is not applicable as per the understanding derived from the document. The "ground truth" for the analytical performance of the assay and its calibrators is established as described in point 7.

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The Elecsys Vitamin D total II assay is intended for the quantitative determination of total 25-hydroxyvitamin D in human serum and plasma. This assay is to be used as an aid in the assessment of vitamin D sufficiency in adults. The electrochemiluminescence binding assay is intended for use on the cobas e 411 immunoassay analyzer.

CalSet Vitamin D total II is used for calibrating the quantitative Elecsys Vitamin D total II assay on the cobas e 411 immunoassay analyzer.

PreciControl Vitamin D total II is used for quality control of the Elecsys Vitamin D total II assay on the cobas e 411 immunoassay analyzer.

This CalCheck set is an assayed control for use in calibration verification of the assay range established by the Elecsys Vitamin D total II reagent on the cobas e 411 immunoassay analyzer.

Elecsys Vitamin D total II is a second generation assay by Roche Diagnostics for the in vitro quantitative determination of 25-hydroxyvitamin D in human serum and plasma. It is intended for use on the cobas e 411 immunoassay analyzer. The cobas e family of analyzers employs the electrochemiluminescence "ECLIA" technology. The assay is a 27 minute assay utilizing a competition principle and a pretreatment step to release the bound 25-hydroxyvitamin D from the vitamin D binding protein.

Results are determined via a calibration curve which is instrument specifically generated by 2-point calibration against the master curve for that reagent lot.

The provided text describes the acceptance criteria and study proving the device meets those criteria for the Elecsys Vitamin D total II assay and its associated calibrators and controls.

Here's the breakdown of the information requested:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly present a "table of acceptance criteria" in terms of specific thresholds for performance metrics. Instead, it describes various studies conducted to demonstrate performance and states that the data supports substantial equivalence. The "reported device performance" is woven throughout Section 4, "Non-Clinical Performance Evaluation," and Section 5, "External (Clinical) Testing."

However, we can infer some performance metrics and the studies that support them. The core of the device's acceptable performance is its substantial equivalence to a predicate device (Elecsys Vitamin D Assay K113546) and its traceability to a reference measurement procedure (ID-LC-MS/MS traceable to NIST SRM 2972).

Here's a table summarizing performance aspects:

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

The document describes various studies, each with its own sample size and provenance.

• Precision: 5 human serum samples (single donors, native and spiked).
• Analytical Sensitivity (LoB, LoD, LoQ):
  • LoB: 1 blank sample (Vitamin D depleted human serum pool), 60 determinations.
  • LoD: 5 low-level human serum sample pools (diluted), with replicates per run.
  • LoQ: At least 4 low-level samples of serum, Li-heparin, K2-EDTA, K3-EDTA plasma, 25 replicates/sample/reagent lot.
• Linearity/Assay Reportable Range: 1 high analyte serum and K3-EDTA plasma sample (single donors, spiked), diluted to at least 9 concentrations.
• High Dose Hook Effect: 1 human serum sample spiked to approx. 10,000 ng/mL, dilution series performed.
• Human Anti-Mouse Antibodies (HAMA): HAMA-serum (HAMA L2) and related basis serum (without interferent).
• Endogenous Interferences: For each interfering substance, three human serum samples (single donors, native as well as spiked) containing low, mid, and high concentrations of 25-OH Vitamin D.
• Exogenous Interferences (Drugs): Two human serum samples (single donors, native as well as spiked) with analyte concentrations approx. 30 and 70 ng/mL.
• Analytical Specificity/Cross-Reactivity: Native human sera with approximate 25-hydroxyvitamin D concentrations of 25, 40, and 60 ng/mL (spiked with cross-reactants).
• Sample Matrix Comparison: Minimum of 40 serum/plasma pairs per sample material (single donors - native, diluted, spiked).
• Method Comparison to Predicate: 105 serum samples (single donors, native).
• Method Comparison to Reference Method: 111 native single donor patient serum samples.
• Reagent Stability: 5 human serum (HS) samples and 2 controls for run qualification (for each stability study). Human serum samples were single donors (native as well as spiked).
• Calibrator Stability: "on-test" and "reference materials" (specific number of human serum samples not detailed for each study, but implied to be sufficient for analytical validation).
• PreciControl Vitamin D total II (Value Assignment): Native human serum sample panel (single donors).
• Calibration Stability: 5 human serum (HS) samples and 2 controls (PreciControl Vitamin D total II). Pools of human serum samples (native as well as spiked).
• CalCheck Vitamin D total II (Value Assignment): Not explicitly stated, but performed for each lot.
• External (Clinical) Testing (Reference Range): Approximately 600 study subjects. After exclusions, 421 subjects were used for the reference range calculation.

Data Provenance:

• Clinical Samples for Reference Range: Prospectively collected from three US sites (northern, midwest, southern) during summer and winter seasons.
• Method Comparison to Reference Method: Patient serum samples from the Vitamin D Standardization and Certification Program (VDSCP) with assigned values by the RMP (Reference Measurement Procedure) at CDC.
• Analytical Studies (Precision, Linearity, Interference, etc.): Predominantly used human serum and plasma samples, often from "single donors" (native as well as spiked). The document implies these were collected appropriately for laboratory studies, likely from a variety of sources but not specifically detailed by country of origin beyond the US sites for the reference range study. All analytical studies appear to be retrospective in the sense that samples were acquired for the purpose of the study rather than being prospectively collected specifically for patient outcomes.

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

The concept of "experts" as human readers establishing ground truth (common in imaging AI) is not directly applicable here. This device is an in vitro diagnostic (IVD) assay measuring a biomarker concentration.

• Ground Truth for Clinical Samples: For the Reference Range study (External/Clinical Testing), the "ground truth" is the measured Vitamin D total II concentration by the Elecsys Vitamin D total II assay itself, and the study then calculates the reference interval from this healthy population. The individuals themselves are not "experts" establishing a truth.
• Ground Truth for Analytical Studies:
  • Traceability and Standardization: The assay is traced to the ID-LC-MS/MS 25-hydroxyvitamin D Reference Measurement Procedure (RMP) at the University of Ghent, which is further traceable to the National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) 2972. This is the ultimate ground truth for Vitamin D concentration. These are established laboratory reference methods, not human expert consensus.
  • Value Assignment of Controls and Calibrators: Values are assigned for PreciControl Vitamin D total II and CalCheck Vitamin D total II based on measurements with the Elecsys Vitamin D total II assay, which is itself traceable to the RMP. The "ground truth" for these materials is their assigned concentration based on the reference standard.
  • Method Comparison: One comparison is against the ID-LC-MS/MS RMP at CDC, which serves as the independent reference standard (ground truth) for those 111 samples.
  • Sample Pools/Spiking: For many analytical studies (e.g., precision, linearity, interference), test samples were prepared by pooling or spiking human serum/plasma. The "true" concentration for these samples is derived from the known amounts of spiked analyte or the consensus value of the pool, assuming the measurement method for verification is accurate and traceable.

In summary, the "ground truth" is established through highly controlled, traceable analytical reference methods and materials, not by human expert interpretation.

4. Adjudication Method for the Test Set

Adjudication methods (like 2+1, 3+1) are typically used in studies where multiple human readers interpret images or clinical data and discrepancies need to be resolved. This is not directly relevant to an IVD assay where the output is a quantitative concentration.

For the analytical studies, the "adjudication" is inherent in the rigorous statistical analysis and adherence to established CLSI guidelines (e.g., EP5-A3 for precision, EP17-A2 for LoB/LoD, EP6-A for linearity, EP07-A2 for interference). Any outlying data points would be addressed through statistical methods or re-testing according to study protocols, not through human adjudication of differing interpretations. The method comparison studies (against predicate and RMP) use statistical regression analyses (Deming, Passing Bablok) to assess agreement, rather than adjudication of individual results.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not done. MRMC studies are specific to evaluating the impact of a medical device (often AI-powered) on the performance of human readers, commonly in imaging diagnostics. This device is an in vitro diagnostic (IVD) assay that directly measures a biomarker concentration. Its performance is evaluated analytically and against reference methods, not in how it assists human interpretation of complex cases.

Therefore, there is no effect size of how much human readers improve with AI vs. without AI assistance.

6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, the primary evaluation of the Elecsys Vitamin D total II assay is its standalone analytical performance. The entire "Non-Clinical Performance Evaluation" (Section 4) is dedicated to demonstrating the performance of the device itself (the assay on the cobas e 411 analyzer) across various metrics like precision, sensitivity, linearity, interference, specificity, and stability. The "Method Comparison to Reference Method" (4.11) particularly assesses its direct agreement with the gold standard RMP.

The "human-in-the-loop" component in this context is the laboratory technician operating the analyzer and interpreting the quantitative results within a clinical context (e.g., in aid of assessing vitamin D sufficiency). The performance evaluated here is solely that of the analytical system.

7. The Type of Ground Truth Used

The ground truth used for the device's validation is primarily external reference measurement procedures (RMPs) and reference materials.

• Primary Ground Truth: The ID-LC-MS/MS 25-hydroxyvitamin D Reference Measurement Procedure (RMP), specifically from the University of Ghent and CDC, traceable to the National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) 2972. This is the metrological traceability chain that provides the "true" value for vitamin D concentration.
• Secondary Ground Truth/Comparators:
  • Predicate Device: The Elecsys Vitamin D Assay (K113546) served as a comparator for demonstrating substantial equivalence.
  • Healthy Adult Population (for reference range): For establishing the clinical reference range, the ground truth is simply the distribution of measured values from a carefully selected cohort of healthy individuals. This is a form of outcomes data in the sense of a normal physiological range.
  • Known Spiked Concentrations: For many analytical studies (e.g., linearity, interference, specificity), samples were spiked with known amounts of analyte or interfering substances. The "true" concentration or the expected impact of the interferent serves as the ground truth for evaluating recovery or cross-reactivity.

8. The Sample Size for the Training Set

The document is a 510(k) summary for an IVD device, not an AI/ML device. Therefore, the concept of a "training set" for an algorithm in the machine learning sense is not applicable. The Elecsys Vitamin D total II assay is a chemical immunoassay, not a learning algorithm that undergoes a training phase with a dataset.

The parameters of the assay (reagent formulation, calibration curves) are established through developmental optimization and analytical validation, not through an iterative learning process with a "training set."

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

As noted above, there is no "training set" in the machine learning sense. The assay's performance characteristics and calibration are established through the use of:

• Reference materials (calibrators): CalSet Vitamin D total II, which is traceable to the ID-LC-MS/MS RMP. These calibrators are used to establish the instrument-specific calibration curve for each reagent lot, ensuring the assay's accuracy against a known standard.
• Quality controls (controls): PreciControl Vitamin D total II, used to monitor the assay's performance and ensure it stays within predefined limits. Their assigned values are derived from measurements against the master calibration curve, which is ultimately traceable to the RMP.

Therefore, the "ground truth" during the development and routine use of the assay is established via the metrological traceability chain to international reference standards and reference measurement procedures.

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