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Lumipulse G 25-0H Vitamin D For in vitro diagnostic use.

Lumipulse G 25-0H Vitamin D is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of 25-hydroxyvitamin D (25-0H vitamin D) and other hydroxylated vitamin D metabolites in human serum and plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMIPULSE G System.

Lumipulse G 25-0H Vitamin D is to be used as an aid in the assessment of vitamin D sufficiency. Assay results should be used in conjunction with other clinical or laboratory data to assist the clinician in making individual patient management decisions.

Lumipulse G 25-0H Vitamin D Calibrators Lumipulse G 25-0H Vitamin D Calibrators are for in vitro diagnostic use in the calibration of Lumipulse G 25-0H Vitamin D on the LUMIPULSE G System.

Lumipulse G 25-OH Vitamin D is an assay system, including a set of immunoassay reagents, for the quantitative measurement of 25-OH Vitamin D in specimens based on CLEIA technology by a two-step sandwich immunoassay method on the LUMIPULSE G System. 25-OH Vitamin D Calibrator or specimen is initially auto-diluted with Specimen Diluent 1 in the system. 25-OH vitamin D in specimens is separated from vitamin D binding protein by the extraction agent and specifically bound to anti-25-OH vitamin D monoclonal antibody (sheep) on the particles, and antigen-antibody immunocomplexes are formed. The particles are washed and rinsed to remove unbound materials. Alkaline phosphatase (ALP: calf)-labeled anti-(25-OH vitamin D/anti- 25-OH vitamin D monoclonal antibody immunocomplexes) recombinant chicken monoclonal antibody specifically binds to 25-OH vitamin D immunocomplexes on the particles, and additional immunocomplexes are formed The particles are washed and rinsed to remove unbound materials. Substrate Solution is added and mixed with the particles. AMPPD contained in the Substrate Solution is dephosphorylated by the catalysis of ALP indirectly conjugated to particles. Luminescence (at a maximum wavelength of 477 nm) is generated by the cleavage reaction of dephosphorylated AMPPD. The luminescent signal reflects the amount of 25-OH vitamin D.

Here's an analysis of the acceptance criteria and study data for the Lumipulse G 25-OH Vitamin D device, based on the provided text:

Acceptance Criteria and Device Performance (Lumipulse G 25-OH Vitamin D)

| Acceptance Criteria Category | Specific Criteria | Reported Device Performance and Study Details |
|------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Analytical Performance | Precision/Reproducibility: Requires a total (within-laboratory) CV of ≤ 10%. | Precision: Lumipulse G 25-OH Vitamin D demonstrated precision ≤ 5.2% (total %CV), meeting the criteria.
Study: A study was run according to CLSI guideline EP5-A3. Five human serum-based samples (specimen pools) and three controls were assayed in replicates of two at two separate times of the day for 20 days (total 80 replicates for each sample) using one LUMIPULSE G1200 System. |
| | Linearity/Assay Reportable Range: Needs to demonstrate linearity throughout the assay range. | Linearity: Linearity was found in the range of 6.9 to 150.0 ng/mL for serum and plasma. The device correlated with expected concentrations: Serum: y = 1.0382(x) + 1.251 (R-squared: 0.9978); Plasma: y = 1.0151(x) + 6.7669 (R-squared: 0.9936).
Study: Consistent with CLSI Guideline EP6-A. Two human serum specimen pools and two K2EDTA plasma specimen pools with high 25-Hydroxyvitamin D2 and 25-Hydroxyvtiamin D3 levels were diluted with one human serum specimen pool and one dipotassium EDTA plasma specimen pool with low 25-Hydroxyvitamin D2 and 25-Hydroxyvtiamin D3 levels. |
| | High Dose Hook Effect: No high dose hook effect should be observed. | High Dose Hook: No high dose hook effect was observed for samples up to 3,000 ng/mL of 25-Hydroxyvitamin D2 and 25-Hydroxyvitamin D3. |
| | Detection Limit: LoB, LoD, and LoQ of ≤ 4.0 ng/mL. | Detection Limit:
LoB: 0.0 ng/mL
LoD: 0.28 ng/mL
LoQ: 3.33 ng/mL
All are ≤ 4.0 ng/mL, meeting the criteria.
Study: LoD and LoQ determined consistent with CLSI guideline EP17-A2. For LoD, seven low-level specimens were tested over 3 days using two LUMIPULSE G1200 Systems and two Lumipulse G 25-OH Vitamin D lots (120 determinations per panel). LoQ is the analyte level at which the CV is 10%. |
| | Analytical Specificity (Interferences): Average interference of ≤ 10% for each compound. | Interferences: Demonstrated average interference of ≤ 10% for a range of endogenous and therapeutic compounds (e.g., Bilirubin, Triglycerides, Hemoglobin, Acetaminophen, Ibuprofen, etc.). This meets the criteria.
Study: Consistent with CLSI guideline EP7-A2. Human serum specimens with 25-OH vitamin D concentrations of approximately 20, 40, and 100 ng/mL were supplemented with potentially interfering compounds. |
| | Analytical Specificity (Cross-Reactivity): Cross-reactivity should be evaluated for similar substances. | Cross-Reactivity: Cross-reactivity was evaluated for various vitamin D metabolites and related compounds. Some compounds showed notable cross-reactivity (e.g., 1,25(OH)2 vitamin D2 at 143% at 10 ng/mL, 1,25(OH)2 vitamin D3 at 39% at 100 ng/mL, 24,25(OH)2 vitamin D3 at 21% at 100 ng/mL). The acceptance criteria for cross-reactivity are not explicitly stated as a percentage here, but the data is provided for evaluation against potential clinical impact.
Study: Consistent with CLSI Protocol EP7-A2. Human serum specimens with 25-OH vitamin D concentrations of approximately 20, 40, and 100 ng/mL were supplemented with potentially cross-reacting compounds. |
| Method Comparison | Substantial Equivalence to Predicate Device: Acceptable correlation and bias compared to a legally marketed predicate device (LIAISON® 25 OH Vitamin D TOTAL Assay). | Comparison vs. Predicate (Liaison):
n=137
Correlation Coefficient (r): 0.9476
Intercept: -3.073 (95% CI: -4.357 – -1.790)
Slope: 1.09 (95% CI: 1.04 – 1.13)
Average Bias: 0.423 ng/mL.
This performance is presented to demonstrate substantial equivalence, implying it meets the necessary correlation and bias thresholds.
Study: Consistent with CLSI guideline EP9-A3. Weighted Deming regression used.
Range of samples: 4.0 to 107.3 ng/mL (Lumipulse G); 5.45 to 91.5 ng/mL (Liaison). |
| | Accuracy vs. Reference Method: Acceptable correlation and bias compared to a recognized reference measurement procedure (ID-HPLC-MS/MS). | Accuracy vs. ID-HPLC-MS/MS (CDC Reference Method):
n=117
Correlation Coefficient (r): 0.9986
Intercept: -2.788 (95% CI: -3.225 – -2.351)
Slope: 0.97 (95% CI: 0.96 – 0.99)
Average Bias: -3.826 ng/mL.
The high correlation and slope close to 1, with a small bias, indicate good accuracy.
Study: Consistent with CLSI guideline EP9-A3. Weighted Deming regression used.
Range of samples: 7.2 to 149.0 ng/mL (Lumipulse G); 8.65 to 153 ng/mL (ID-HPLC-MS/MS). |
| | Matrix Equivalency: Results should demonstrate equivalency between different sample matrices (serum, plasma types). | Matrix Equivalency: Demonstrated equivalency between serum (SST vs Red Top), K2EDTA plasma vs Red Top, Lithium Heparin vs Red Top, and Sodium Heparin vs Red Top. Correlation coefficients (r) ranged from 0.9964 to 0.9983, and slopes were close to 1.
Study: Fifty (50) matched sets of serum (red top and serum separator tubes (SST)) and plasma (sodium heparin, lithium heparin, K2EDTA) samples were evaluated. |
| Expected/Reference Values | Establish expected values for apparently healthy adults. | Expected Values: Observed range for 25(OH) vitamin D concentrations in 287 apparently healthy adults was 7.6 to 47.6 ng/mL (2.5th to 97.5th percentile), with a mean of 22.9 ng/mL and median of 22.2 ng/mL.
Study: Based on 322 samples from apparently healthy adults in the US (diverse regions, seasons, and skin types). Individuals with conditions or medications affecting vitamin D levels were excluded. Established according to CLSI Protocol EP28-A3c. |

Additional Information on the Studies:

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

   • Precision/Reproducibility: Five human serum-based samples and three controls, assayed in replicates of two at two separate times of the day for 20 days. This means 80 data points for each sample/control tested to derive the precision data. No specific country of origin is mentioned for these samples, but the general context is a US FDA submission. The nature of the study (analyzing manufactured controls and pooled human serum) suggests a prospective, controlled laboratory setting.
   • Linearity/Reportable Range: Two human serum specimen pools and two K2EDTA plasma specimen pools (high 25-OH vitamin D levels), diluted with one human serum specimen pool and one dipotassium EDTA plasma specimen pool (low 25-OH vitamin D levels). No specific number of individual samples is given, but it involves various dilutions of these pools.
   • Equimolar Recovery (D2/D3): Serum sample pool with low endogenous 25-OH vitamin D, supplemented to create 7 different ratios of D2 to D3. Each ratio was measured in n=3 replicates. Also, known concentrations of 25-OH vitamin D (D2 and D3) added to human serum and K2EDTA plasma samples (low endogenous levels). Measured in n=3 replicates for each spiked concentration across multiple serum/plasma samples.
   • Detection Limit (LoD): Seven low-level specimens, tested over 3 days using two LUMIPULSE G1200 Systems and two Lumipulse G 25-OH Vitamin D lots, resulting in 120 determinations for each panel.
   • Analytical Specificity (Interferences and Cross-Reactivity): Human serum specimens with 25-OH vitamin D concentrations of approximately 20, 40, and 100 ng/mL, supplemented with potentially interfering/cross-reacting compounds. The number of samples for each compound isn't specified but implies multiple measurements per compound at different 25-OHD levels.
   • Method Comparison (vs. Predicate): n=137 samples. Data provenance is not explicitly stated as retrospective or prospective, but clinical method comparison studies typically use prospectively collected patient samples or archived clinical samples. No country of origin is specified.
   • Method Comparison (vs. ID-HPLC-MS/MS): n=117 samples. Similar to the predicate comparison, data provenance is not explicitly stated, but it's a comparison to a CDC reference method.
   • Matrix Comparison: Fifty (50) matched sets of serum (red top and SST) and plasma (sodium heparin, lithium heparin, K2EDTA) samples.
   • Expected Values/Reference Range: 322 apparently healthy adults. These subjects were from two geographically diverse regions of the US (North: Northern California and New Jersey; South: Southern California and North Carolina) and sampled during spring/summer and fall/winter seasons. Specific exclusion criteria were applied. This data is prospectively collected for this purpose.

2. 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 assay for quantitative measurement, not an AI or imaging device requiring expert interpretation of results. Therefore, the concept of "experts establishing ground truth for a test set" with qualifications like "radiologist with 10 years of experience" is not directly applicable in the same way.
   • For the Method Comparison vs. ID-HPLC-MS/MS, the "ground truth" or reference measurement was established by the CDC reference method (ID-HPLC-MS/MS). The experts involved would be the analytical chemists and laboratory personnel operating and validating this highly accurate reference method. Their qualifications would involve extensive training and experience in mass spectrometry and laboratory diagnostics.

3. 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 subjective interpretation (e.g., radiology reads) where multiple human readers agree or a tie-breaker is needed.
   • For this in-vitro diagnostic device, which produces quantitative numerical results, such an adjudication method is not relevant. The device output is a concentration value directly. Any discrepancies in laboratory measurements would be resolved through standard laboratory quality control procedures, repeat testing, or by comparison to a reference method (as seen with the ID-HPLC-MS/MS comparison).

4. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

   • No, an MRMC comparative effectiveness study was not done. This device is an automated, quantitative immunoassay, not an AI-assisted diagnostic tool that aids human readers in interpreting images or other complex data. It provides a direct measurement of a biomarker.

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

   • Yes, the performance presented for the Lumipulse G 25-OH Vitamin D assay reflects its standalone performance as an automated, quantitative diagnostic system. It operates without human interpretive input for the final result. Human interaction is limited to sample loading, instrument operation, calibration, and review of results (which is standard for any lab test). The "algorithm" here refers to the immunoassay chemistry and the LUMIPULSE G System's processing of the chemiluminescent signal.

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

   • For Method Comparison vs. ID-HPLC-MS/MS: The ground truth was based on a validated isotope dilution high performance liquid chromatography tandem mass spectrometry (ID-HPLC-MS/MS) 25-OH Vitamin D method performed as a CDC reference method. This is considered a highly accurate and precise analytical reference method.
   • For Linearity and Equimolar Recovery: Ground truth was established by gravimetric preparation and known concentrations of analytes, confirmed by UV spectrophotometric analysis.
   • For Precision, Detection Limit, Analytical Specificity, Matrix Comparison, and Expected Values: The ground truth for these studies involves the intrinsic properties of the samples themselves (e.g., true concentration, absence/presence of interferents, matrix type) as measured by the device and compared against expected statistical behavior or comparative methods.

7. The sample size for the training set:

   • The document does not explicitly mention a "training set" in the context of machine learning. This device is an immunoassay, and its development involves optimizing reagents, assay conditions, and calibration curves through laboratory experimentation, rather than training an algorithm on a large dataset in the way AI models are trained.
   • However, the calibrator set itself can be considered analogous to "training data" for the instrument's internal curve fitting. The calibrator kit contains 6 concentrations (0, 10, 20, 50, 100, 150 ng/mL).

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

   • As interpreted from the context of an immunoassay (analogous to the "training set" being the calibrators), the ground truth for the calibrators was established by:
     • Gravimetric preparation: The calibrators were prepared by carefully weighing and diluting the pure analyte to achieve specific concentrations.
     • Traceability: They are traceable to internal reference calibrator concentrations determined by UV spectrophotometric analysis.
     • Verification: Further verified by a Reference Method Procedure (University of Ghent). This ensures high accuracy and reliability of the assigned values for the calibrators.

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