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For in vitro diagnostic use with the IMMULITE® 1000 Analyzers - for the quantitative measurement of CA125 antigen in serum, as an aid in monitoring the response to therapy for patients with epithelian ovarian cancer, and in detecting residual ovarian cancer in patients who have undergone first-line therapy and would be considered for diagnostic second look procedures.

For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers - for the quantitative measurement of CA125 antigen in serum, as an aid in monitoring the response to therapy for patients with epithelian ovarian cancer, and in detecting residual ovarian cancer in patients who have undergone first-line therapy and would be considered for diagnostic second-look procedures.

The IMMULITE®/IMMULITE 1000 OM-MA Assay is comprised of OM-MA Test Units (beads coated with murine monoclonal anti-CA125 antibody), OM-MA Cycle 1 Reagent Wedge (alkaline phosphatase conjugated to rabbit polyclonal anti-CA125 antibody in buffer), OM-MA Cycle 2 Reagent Wedge (buffer), and OM-MA Adjustors (Low and High, CA125 in a nonhuman protein/buffer matrix).

The IMMULITE® 2000 OM-MA Assay is a newer generation instrument that dispenses an individual bead from a pack into a separate reaction tube. It is comprised of OM-MA Bead Pack (beads coated with murine monoclonal anti-CA125 antibody), OM-MA Reagent Wedge (Well 1: alkaline phosphatase conjugated to rabbit polyclonal anti-CA125 antibody in buffer; Well 2: buffer), and OM-MA Adjustors (Low and High, CA125 in a nonhuman protein/buffer matrix).

Both assays are solid-phase, two-site chemiluminescent immunometric assays that measure CA125 antigen quantitatively in serum.

The Siemens Healthcare Diagnostics Products Ltd IMMULITE/IMMULITE 1000 OM-MA and IMMULITE 2000 OM-MA assays are intended for the quantitative measurement of CA125 antigen in serum. The devices aid in monitoring the response to therapy for patients with epithelial ovarian cancer and in detecting residual ovarian cancer in patients who have undergone first-line therapy.

Here's an analysis of the acceptance criteria and study proving device meets these criteria:

1. Table of Acceptance Criteria and Reported Device Performance

For IMMULITE/IMMULITE 1000 OM-MA Assay (modified):

For IMMULITE 2000 OM-MA Assay (modified):

2. Sample Size and Data Provenance

• Method Comparison Test Set: A total of 253 patient samples were used for method comparison studies for both the IMMULITE 1000 and IMMULITE 2000 assays. The documentation does not specify the country of origin of the data or whether it was retrospective or prospective.
• Precision Test Set: Five serum samples were tested for each assay (IMMULITE 1000 and IMMULITE 2000). The samples were tested in duplicate over 20 days, two runs per day, for a total of 80 replicates per sample level.
• Reproducibility Test Set: Five serum samples were tested for each assay (IMMULITE 1000 and IMMULITE 2000) using a 5x5x3 experimental design (5 days, 5 replicates, 3 reagent lots).
• Recovery Test Set: 19 samples were used for spike and recovery studies.
• Reference Range Verification Test Set: For each assay (IMMULITE 1000 and IMMULITE 2000), "apparently healthy female samples" were used. Specifically, for IMMULITE 1000, n=50 for Lot 1 and Lot 2, and n=45 for Lot 3. For IMMULITE 2000, n=50 for all three lots. The provenance is not explicitly stated beyond "healthy female samples."
• Stability Test Set: Native patient samples were used for accelerated stability studies, but the exact number of unique samples is not specified.

3. Number of Experts and Qualifications for Ground Truth

This device is an in vitro diagnostic (IVD) assay for quantitative measurement of a biomarker (CA125). The performance claims are based on analytical performance characteristics, not on interpretation of images or clinical outcomes by experts in the typical sense of a diagnostic imaging AI device. Therefore, the concept of "experts" to establish a ground truth for a test set, like radiologists or pathologists, is not directly applicable here. The "ground truth" for analytical performance studies is established by the assay's ability to accurately and precisely measure the analyte concentrations.

4. Adjudication Method for the Test Set

Not applicable. As an IVD assay measuring an analyte concentration, there is no adjudication process similar to that for subjective diagnostic interpretations. Performance is assessed through statistical analysis of quantitative results against established analytical methods and specifications.

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

No. An MRMC study is relevant for diagnostic imaging devices where multiple human readers interpret cases. This document describes an in vitro diagnostic assay that quantitatively measures a biomarker, not a device requiring human interpretation for diagnosis. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" does not apply.

6. Standalone Performance Measurement

Yes, the studies described are essentially standalone performance studies of the IMMULITE/IMMULITE 1000 OM-MA and IMMULITE 2000 OM-MA assays. The device (the assay) itself generates the quantitative measurement. The "human-in-the-loop" aspect, for this type of device, would be the clinician interpreting the numerical results in the context of a patient's treatment and disease status, a step downstream from the device's analytical performance. The studies focus on the analytical accuracy, precision, linearity, and interference of the assay itself.

7. Type of Ground Truth Used

The ground truth used for these analytical studies is primarily:

• Quantitative Reference Values / Expected Values:
  • For Detection Limits (LoB, LoD, LoQ), ground truth is based on the statistical determination of the lowest measurable concentrations.
  • For Linearity, ground truth is established by preparing samples with known, serially diluted concentrations (expected values).
  • For Method Comparison, the predicate device's results are used as the comparative "ground truth" (or reference method) to assess equivalence.
  • For Precision and Reproducibility, the ground truth is the inherent variability of the measurements around a mean dose.
  • For Spike Recovery, ground truth is the "expected" concentration after spiking known amounts of analyte into samples.
  • For Specificity (Cross-reactivity), ground truth is the known concentration of potentially cross-reacting substances.
  • For Interference, ground truth is the known concentration of potentially interfering substances.
  • For Reference Range, ground truth is derived from the established reference interval for healthy individuals (≤ 21 U/mL).

8. Sample Size for the Training Set

This document does not specify a separate "training set" or its size in the context of artificial intelligence or machine learning. The studies described are analytical performance validations for an in vitro diagnostic assay, which typically involve testing samples to verify performance against pre-defined specifications rather than training a machine learning model.

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

As there is no mention of a "training set" in the context of AI/ML for this device, information on how its ground truth was established is not provided or applicable. The ground truth for the performance validation studies, as described in point 7, is based on established analytical methods and known concentrations.

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For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of thyrotropin (TSH) in serum. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of non-protein-bound thyroxine (free T4) in serum and heparinized plasma. Measurements of free thyroxine are used in the diagnosis and treatment of thyroid disease.

Not Found

The provided text describes a 510(k) submission for the IMMULITE 2000 Third Generation TSH and IMMULITE 2000 Free T4 assays. The submission primarily focuses on adding pediatric reference intervals to the device's labeling and asserts that no modifications to the device's design or manufacturing processes are required, thus the predicate devices and subject devices are the same. This means that no new device performance studies were conducted for this specific submission, as the changes are limited to labeling updates based on existing assay capabilities and establishing new reference intervals for a specific population.

Therefore, the requested information regarding acceptance criteria and device performance for a new device study is largely not applicable in the context of this 510(k) summary, as it explicitly states that additional analytical performance data is not needed. The document emphasizes that existing performance characteristics continue to apply.

However, I can extract information related to the establishment of the pediatric reference intervals, which is a form of study performed to define normative values for a specific population for the device.

1. Table of Acceptance Criteria and Reported Device Performance

Since this submission is about establishing new reference intervals for an already approved device and not evaluating the device's analytical performance against new acceptance criteria, the "acceptance criteria" here refer to the statistical methodology used for defining these reference intervals. The "reported device performance" is the established reference interval.

Note: The primary "acceptance criteria" for this submission are that the methods used for establishing the reference intervals conform to CLSI EP28-A3c guidance and that the established pediatric reference intervals fall within the existing analytical measuring capability of the assay.

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

IMMULITE 2000 Free T4:

• Sample Size: A total of 426 patients were analyzed:
  • Infants (01 – 23 months): 81
  • Children (02 – 12 years): 197
  • Adolescents (13 – 20 years): 148
• Data Provenance: The document does not specify the country of origin of the data. It is prospective testing, as it states "Data from a total of [N] patients... tested with the IMMULITE 2000 Free T4 assay were analyzed to establish the reference intervals."

IMMULITE 2000 Third Generation TSH:

• Sample Size: A total of 433 patients were analyzed:
  • Infants (01 – 23 months): 90
  • Children (02 – 12 years): 195
  • Adolescents (13 – 20 years): 148
• Data Provenance: The document does not specify the country of origin of the data. Similar to Free T4, this appears to be prospective testing based on the phrasing "Data from a total of [N] patients... tested with the IMMULITE 2000 Third Generation TSH assay were analyzed to establish the reference intervals."

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

For reference interval studies, the "ground truth" is typically defined by statistical methods applied to a population defined as "healthy" or "normal" for the analyte in question, rather than through expert consensus on individual cases. The document states that the reference intervals were established per the CLSI EP28-A3c guideline: "Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory." This guideline outlines statistical procedures for determining reference intervals. Therefore, independent experts for case-by-case ground truth establishment are not typically involved in this type of study. The expertise lies in the clinical chemists or statisticians who apply the CLSI guideline.

4. Adjudication method for the test set

Not applicable. Reference interval studies do not typically involve adjudication of individual cases in the way diagnostic accuracy studies do. The process involves identifying a healthy reference population and then statistically determining the range of values for that population.

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 submission is for an in-vitro diagnostic (IVD) assay (a lab test), not an AI-based diagnostic imaging or interpretive device that would involve human readers or AI assistance in that context.

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

Not applicable. This is an IVD assay, which generates quantitative results. The device itself is the "standalone" component in the sense that it performs the measurement. The establishment of reference intervals is for interpreting these quantitative results within a specific population.

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

The "ground truth" for the pediatric reference interval studies relies on the selection of a "healthy" pediatric population (presumably free from known thyroid or pituitary disorders) from whom samples were collected and tested. The reference intervals are then statistically derived from the measurements of these healthy individuals, following CLSI EP28-A3c guidelines. This is a statistical definition of "normal range" within a defined population rather than a case-specific ground truth like pathology or expert consensus for individual diagnoses. The assumption is that the participants in these groups represented a healthy pediatric population for thyroid function.

8. The sample size for the training set

Not applicable in the typical sense of machine learning. The data described (426 for Free T4, 433 for TSH) is used to establish the reference intervals (similar to a development/validation set in traditional statistics), rather than "training" an algorithm that would then be separately tested. The entire dataset is used to directly calculate the intervals.

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

Not applicable as a "training set." The "ground truth" for the reference interval establishment relies on the statistical methodology (Robust Symmetric, Non-Parametric) applied to a population described as healthy, as per CLSI EP28-A3c. The selection criteria for this "healthy" pediatric population are implied to be part of the study design to appropriately define the "normal" range.

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The IMMULITE® 2000 TSI (thyroid-stimulating immunoglobulins) Assay is an in vitro diagnostic immunoassay for the semi-quantitative determination of thyroid stimulating autoantibodies specific to thyroid stimulating hormone receptors (TSHR) in human serum (including Serum Separator tubes) or plasma (K2-EDTA or lithium heparin). The IMMULITE® 2000 TSI Assay is for use on the IMMULITE® 2000 system. The measurement of thyroid stimulating autoantibodies, in conjunction with other clinical and laboratory findings, is used as an aid in the diagnosis of patients suspected of having Graves' disease.

The IMMULITE® TSI Calibration Verification Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE® TSI Assay on the IMMULITE® 2000 Systems.

The IMMULITE 2000 TSI assay kit consists of the following components:

• TSI bead pack coated with MAb (3D7) anti-TSHR anchor antibody and hTSHR Capture Chimera
• TSI reagent wedge containing hTSHR-Chimera alkaline phosphatase conjugate
• TSI adjustors: low and high, containing TSI negative heat-inactivated bovine serum and thyroid stimulating human MAb (M22)
• TSI controls: negative, low, and high, containing TSI negative human serum and thyroid stimulating MAb (M22)
• Multi-Diluent 2

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

The acceptance criteria are generally implied from the "Drift Specifications" for stability and the statistical measures for precision and method comparison. The device performance is the "reported performance".

• Repeatability %CV: Ranged from 3.5% to 7.0%.
• Within Lab %CV: Ranged from 5.0% to 8.3%. |
  | Linearity/Reportable Range | Linearity data for % Difference to be ± 15% or 0.50 IU/L (whichever is greater). | Linearity data for % Difference was shown to be ± 15% or 0.50 IU/L (whichever is greater) for most samples; tested within range 0.50 - 40.0 IU/L. |
  | Assay/Component Stability Drift | Reagents and Beads:
• Control 1 at ≤ -60°C: ≤ 15% from Day 0 mean
• Control 2 at ≤ -60°C: ≤ 10% from Day 0 mean
• CVM 1 at ≤ -60°C: ≤ 0.15 IU/L from Day 0 mean
• MDP 1: ≤ 20% from Day 0 mean
• MDP 4: ≤ 10% from Day 0 mean
• Cal J: ≤ 10% from Day 0 mean
  (Also, all Control results must be within QC established range to validate the run). | Stability Claims Achieved:
• Kit, unopened: 12 Months (2-8 °C)
• Bead Pack, open: 90 Days (2-8 °C)
• Reagent wedge, open and on-board: 90 Days (2-8 °C)
• Sample diluent, open: 30 Days (2-8 °C)
• Sample diluent, open frozen aliquotted: 6 Months (-20 °C)
• Adjustors open: 90 Days (2-8 °C)
• Adjustors frozen aliquotted: 4 Months (-20 °C)
• Controls open: 90 Days (2-8 °C)
• Controls frozen aliquotted: 6 Months (-20 °C)
• CVM, unopened: 12 Months (2-8 °C)
• CVM, opened and reconstituted: 30 Days (2-8 °C)
  Sample Stability: 24 hours at 20-25°C, 7 days at 2-8°C, and 12 months at -20°C for serum and plasma. |
  | Limit of Blank (LoB) | LoB should be low enough for clinical utility. | Highest LoB by lot was determined to be 0.03 IU/L. |
  | Limit of Detection (LoD) | LoD should be low enough for clinical utility. | Highest LoD by lot was determined to be 0.06 IU/L. |
  | Analytical Specificity (Interference) | No interference (≤ 10% different than control sample). | Interferents (Intralipid, Hemoglobin, Bilirubin, K2-EDTA): No interference (≤ 10% difference) except for hemoglobin (≥ 200mg/dL potentially affects recovery) and short draw K2-EDTA (may result in under-recovery).
  HAMA: Individual sample bias of 90% for positive, negative, and overall). | Positive Agreement: 95.8% (95% CI: 93.0 – 97.7)
  Negative Agreement: 87.7% (95% CI: 84.5 - 90.5)
  Overall Agreement: 91.0% (95% CI: 88.8 - 92.9) |
  | Matrix Comparison (Regression Coefficient) | Strong correlation (e.g., R-value > 0.95 or 0.98). | SST Serum: Slope 1.01, Intercept 0.00, Correlation Coefficient 0.99
  K2-EDTA Plasma: Slope 1.03, Intercept -0.01, Correlation Coefficient 0.99
  Lithium Heparin Plasma: Slope 0.99, Intercept -0.01, Correlation Coefficient 0.99 |
  | Clinical Sensitivity and Specificity (at 0.55 IU/L cut-off) | High clinical sensitivity and specificity (generally >95%). | Clinical Sensitivity: 98.6% (95% CI: 96.8 – 99.5)
  Clinical Specificity: 98.5% (95% CI: 96.8 – 99.5) |
  | Reference Range (97.5th percentile) | Clinically appropriate range. | 180 measurements). Data provenance not specified.

• LoD: 5 TSI serum samples, tested in 4 replicates using 3 reagent kit lots for 3 days on 3 systems (total 36 observations per sample). Data provenance not specified.
• Analytical Specificity (Interference): Three serum pools (for endogenous interferents), HAMA positive serum, RF positive serum, and six potential biological interferent samples. Data provenance not specified.
• Method Comparison: 811 serum samples from patients with Graves' disease, other thyroid or autoantibody diseases. Specimens tested at two external sites and one internal site for the IMMULITE 2000 TSI assay, and at one external site for the Thyretain device. Data provenance not explicitly stated, but implies mixed sources (internal/external, likely retrospective patient samples).
• Matrix Comparison: Graves' Disease sets of matched serum and plasma samples (clot tube, lithium heparin, SST, K2-EDTA). Sample size not specified. Data provenance not specified.
• Clinical Sensitivity and Specificity: 361 treated and untreated hyperthyroid Graves' disease patients and 404 individuals with other thyroid or autoimmune diseases. Data provenance not specified (likely retrospective clinical samples).
• Reference Range: 842 serum samples from apparently healthy males (n=151), non-pregnant females (n=155), first trimester (n=169), second trimester (n=191), and third trimester (n=176) pregnant donors. Data provenance not 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)

The document does not specify the number or qualifications of experts used to establish the ground truth for any of the test sets. For example, for clinical sensitivity and specificity, it refers to "Graves' Disease Diagnosis" and "other thyroid or autoimmune diseases" but does not detail how these diagnoses were definitively established or by whom. Similarly, for the method comparison, it refers to patient samples for Graves' disease or other thyroid/autoantibody diseases without detailing expert adjudication of these conditions.

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

The document does not describe any specific adjudication method for establishing ground truth diagnoses for the patient samples used in the studies. The diagnoses are simply stated as existing, implying they were pre-determined or established through typical clinical practice, rather than through a separate expert adjudication process for the study.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This is an immunoassay device, not an imaging AI device that involves human readers interpreting cases. The comparison study was a "Method Comparison" between the new Immulite 2000 TSI assay and a predicate immunoassay device (Thyretain TSI Reporter BioAssay), analyzing patient samples.

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

Yes, the studies presented are all standalone validations of the Immulite 2000 TSI assay system. It is an automated immunoassay for in vitro diagnostic use, meaning it provides results directly from patient samples without human interpretation of images or other complex data requiring "human-in-the-loop" decision-making. The performance characteristics (precision, linearity, detection limits, clinical sensitivity/specificity, etc.) reflect the algorithm/device's performance alone.

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

The ground truth for the clinical studies (clinical sensitivity/specificity, method comparison) appears to be clinical diagnosis of Graves' disease or other thyroid/autoimmune diseases. For analytical performance studies (precision, linearity, LoB, LoD, interference), the ground truth is based on spiking known concentrations, using negative samples, or established reference standards like the NIBSC standard.

8. The sample size for the training set

The document does not explicitly mention a "training set" in the context of machine learning. This is a traditional immunoassay, not an AI device that typically involves distinct training and test sets in the same manner. The studies describe validation sets, not training sets for model development.

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

As there is no distinct "training set" in the context of an AI/machine learning model as understood in typical AI/ML submissions, this question is not directly applicable. For traditional assays, calibrators are used to establish the measurement and are themselves calibrated against reference materials (e.g., NIBSC standard 08/204 for the Immulite 2000 TSI assay).

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IMMULITE® 2000 Androstenedione Calibration Verification Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE Androstenedione assay on the IMMULITE 2000 systems
IMMULITE® 2000 Troponin I Calibration Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE Troponin I assay on the IMMULITE 2000 systems

The IMMULITE® 2000 Androstenedione Calibration Verification Material (CVM) contains one set of four vials each 2mL in liquid form. CVM1 contains processed human serum with preservatives. CVM2, CVM3 and CVM4 contain androstenedione in processed human serum matrix with preservative.
The IMMULITE® 2000 Troponin I Calibration Verification Material (CVM) contains one set of four vials, 2mL each after reconstitution. CVM1 contains equine serum with 0.88% sodium azide and preservative. CVM2, CVM3 and CVM4 contain human Troponin I and rabbit Troponin C in equine serum matrix with 0.88% sodium azide and preservative.

Here's a breakdown of the acceptance criteria and the studies for both the IMMULITE® 2000 Androstenedione Calibration Verification Material and the IMMULITE® 2000 Troponin I Calibration Verification Material, based on the provided document:

Device 1: IMMULITE® 2000 Androstenedione Calibration Verification Material (CVM) (K143636)

1. Table of Acceptance Criteria and Reported Device Performance

The provided document details the stability acceptance criteria. Performance data is presented within the context of demonstrating compliance with these stability criteria rather than as a separate "reported performance" table.

2. Sample Size for Test Set and Data Provenance

• Test Set Description: The "test set" in this context refers to the samples used in the stability studies and value assignment.
  • Stability Studies: Multiple samples of each CVM level (LAOCVM1, LAOCVM2, LAOCVM3, LAOCVM4) from lot 006 were tested.
  • Real-time Stability: Samples were tested in duplicate at Day 0, 15, 27, and 38 months (Table 2). The specific number of individual vials/runs for each time point beyond "duplicate (as a minimum)" isn't detailed.
  • Open Component Stability: CVM lot 006 was tested at 2-hourly intervals for up to 9 hours. The number of samples per interval is not explicitly stated beyond "in duplicate (as a minimum)".
  • Value Assignment Validation: 28 samples (10 normal female serum samples and 18 spiked samples) and four levels of commercially available controls were used.
  • Expected Values/Target Values/Reference Range: Each CVM level was tested for a total of 27 replicates (9 runs and 3 replicates per run) using 3 different reagent kit lots and 8 IMMULITE 2000 systems.
• Data Provenance: Not explicitly stated as "country of origin," but "internal material" and "gravimetrically prepared" suggest internal laboratory data. It is prospective testing designed to characterize the device's performance.

3. Number of Experts and Qualifications for Ground Truth

• Not Applicable. This device is an in vitro diagnostic reagent (calibration verification material) for laboratory instruments, not an AI or imaging device requiring expert interpretation for ground truth. Ground truth is established through metrological traceability and standard reference methods (gravimetric preparation, assigned reference calibrators).

4. Adjudication Method for Test Set

• Not Applicable. See point 3.

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

• Not Applicable. See point 3.

6. Standalone Performance (Algorithm Only)

• Yes, in essence. The performance testing described (stability, value assignment) evaluates the intrinsic performance of the CVM as a standalone device (material), independent of human interpretation. Its function is to verify instrument calibration, not to provide diagnostic interpretations.

7. Type of Ground Truth Used

• Metrological Traceability: The CVMs are traceable to an internal material that has been gravimetrically prepared. They are also value assigned using assigned reference calibrators, which themselves would have established traceability.
• Reference Calibrators: The CVMs are described as a subset of 7-level Androstenedione calibrators, and their dose values are generated using curves from these assigned reference calibrators. These calibrators serve as the "ground truth" reference for verifying the CVM values.

8. Sample Size for Training Set

• Not Applicable in the conventional sense of machine learning. This is not an AI/ML device. The "training" here refers to the process of establishing the reference values and behavior of the CVM and the associated assay. The value assignment process describes the materials and procedures used to characterize the CVMs, which inherently involves multiple measurements and statistical analysis rather than a distinct "training set" like in AI.

9. How Ground Truth for Training Set Was Established

• Not Applicable in the AI sense. For this device, "ground truth" (or more appropriately, reference values) for the CVMs are established through:
  • Gravimetric Preparation: The internal material to which the CVMs are traceable is gravimetrically prepared, a fundamental method for establishing concentration.
  • Assigned Reference Calibrators: The CVMs' dose values are derived from curves generated by assigned reference calibrators. These reference calibrators represent the established "ground truth" for the assay.
  • Validated Materials and Procedures: The CVMs are manufactured using qualified materials and measurement procedures, ensuring their accuracy relative to the established reference values.

Device 2: IMMULITE® 2000 Troponin I Calibration Verification Material (CVM) (K143636)

1. Table of Acceptance Criteria and Reported Device Performance

Similar to the Androstenedione CVM, the document specifies stability acceptance criteria and indicates successful performance without providing detailed numerical results for each time point beyond the initial dose.

2. Sample Size for Test Set and Data Provenance

• Test Set Description:
  • Stability Studies: Multiple samples of each CVM level (LTICVM1, LTICVM2, LTICVM3, LTICVM4) from lot 010 were tested.
  • Real-time Stability: Samples were run in duplicate (as a minimum) at Day 0, 3, 9, and 10 months (Table 2). Specific counts beyond "duplicate" are not specified.
  • Open Component Stability: CVM lot 090 was tested at 2-hourly intervals for up to 9 hours. Specific counts not detailed.
  • Value Assignment Validation: Three levels of commercially available controls and 25 spiked samples were used.
  • Expected Values/Target Values/Reference Range: Tested on 15 replicates in total (5 runs and 3 replicates per run) using 4 IMMULITE 2000 systems and 2 different reagent kit lots.
• Data Provenance: Not explicitly stated as "country of origin," but "internal standard" and "gravimetrically prepared" suggest internal laboratory data. It is prospective testing.

3. Number of Experts and Qualifications for Ground Truth

• Not Applicable. See point 3 for Androstenedione CVM.

4. Adjudication Method for Test Set

• Not Applicable. See point 3 for Androstenedione CVM.

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

• Not Applicable. See point 3 for Androstenedione CVM.

6. Standalone Performance (Algorithm Only)

• Yes, in essence. Similar to the Androstenedione CVM, the performance testing described evaluates the intrinsic performance of the Troponin I CVM as a standalone material.

7. Type of Ground Truth Used

• Metrological Traceability: The CVMs are traceable to an internal standard that has been gravimetrically prepared.
• Reference Calibrators: The CVMs are described as a subset of 10-level Troponin I calibrators, and their dose values are generated using curves from these assigned reference calibrators, which serve as the "ground truth" reference.

8. Sample Size for Training Set

• Not Applicable in the conventional sense of machine learning. See point 8 for Androstenedione CVM.

9. How Ground Truth for Training Set Was Established

• Not Applicable in the AI sense. For this device, "ground truth" (reference values) are established through:
  • Gravimetric Preparation: The internal standard to which the CVMs are traceable is gravimetrically prepared.
  • Assigned Reference Calibrators: The CVMs' dose values are derived from curves generated by assigned reference calibrators, which represent the established "ground truth" for the assay.
  • Validated Materials and Procedures: The CVMs are manufactured using qualified materials and measurement procedures, ensuring their accuracy relative to the established reference values.

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The IMMULITE® CEA Calibration Verification Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE CEA assay on the IMMULITE 2000 systems.

The CEA Calibration Verification Material (CVM) contains one set of four vials each 1.0mL after reconstitution. CVM1 contains lyophilized processed human serum with preservatives. CVM2, CVM3 and CVM4 contain various levels of human CEA in a lyophilized processed human serum matrix with preservatives.

This document describes the IMMULITE® 2000 CEA Calibration Verification Material (CVM), an in vitro diagnostic device used to verify the calibration of the IMMULITE CEA assay on IMMULITE 2000 systems. The provided text, however, does not align with the standard format for reporting AI/ML device studies as it describes a calibration verification material, not an AI-based device. Therefore, many of the requested fields are not applicable.

Here's the information extracted and adapted where possible:

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

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

• Test Set Sample Size: For stability testing, three lots of CVMs (Lot 006, 007, and 090) were used. For value assignment and expected values, each CVM level was tested on 27 replicates in total, comprised of 9 runs, 3 replicates per run, using 9 IMMULITE 2000 systems and 5 different reagent kit lots.
• Data Provenance: Not specified, but generally, such studies are conducted at the manufacturer's facilities. The document does not indicate country of origin or whether the data was retrospective or prospective, though stability studies are inherently prospective.

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)

• Not applicable. This device is a calibration verification material for an in vitro diagnostic assay, not an AI/ML device relying on expert interpretation for ground truth. The "ground truth" for CVMs is based on internal reference standards and gravimetric preparations.

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

• Not applicable. This is not an AI/ML device requiring human adjudication of results.

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 calibration verification material, not an AI-assisted diagnostic tool for human readers.

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

• Not applicable. This is a physical control material.

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

• Ground Truth for CVMs: The IMMULITE CEA CVMs are traceable to an internal standard. The assigned reference calibrators are prepared using CEA antigen stock and are traceable to an internal standard which has been gravimetrically prepared.

8. The sample size for the training set

• Not applicable. This is not an AI/ML device with a training set. The "IMMULITE CEA kit lot 290" and "CEA CVM lot 090" mentioned in the stability protocol are parts of the experimental setup for assessing the CVM's performance, not a training set for an algorithm.

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

• Not applicable. This is not an AI/ML device with a training set.

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The IMMULITE® Albumin Calibration Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE Albumin assay on the IMMULITE 2000 systems

The IMMULITE® Myoglobin Calibration Verification Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE Myoglobin assay on the IMMULITE 2000 systems

The Albumin Calibration Verification Material (CVM) contains one set of four vials each 2.0 mL after reconstitution. CVM1 contains bovine protein with preservatives. CVM2, CVM3 and CVM4 contain various levels of human albumin in a bovine protein matrix with preservatives. The CVMs are supplied in lyophilized form.

IMMULITE® 2000 Myoglobin Calibration Verification Material (CVM) contains one set of four vials each 2.0mL after reconstitution. CVM1 contains bovine serum with preservatives. CVM2, CVM3 and CVM4 contain various levels of human cardiac myoglobin in bovine serum with preservatives. The CVMs are supplied in lyophilized form.

The provided documents describe the performance testing for two medical devices: the IMMULITE® 2000 Albumin Calibration Verification Material (CVM) and the IMMULITE® 2000 Myoglobin Calibration Verification Material (CVM).

IMMULITE® 2000 Albumin Calibration Verification Material (CVM)

1. Table of Acceptance Criteria and Reported Device Performance

The device performance is reported as meeting the acceptance criteria, as stated in the stability summaries. The studies aimed to demonstrate that the CVM maintains optimal product performance within the established shelves life before and after reconstitution.

Table: Acceptance Criteria and Reported Device Performance for IMMULITE® 2000 Albumin CVM

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The IMMULITE® Ferritin Calibration Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE Ferritin assay on the IMMULITE 2000 systems.

The IMMULITE® IGFBP-3 Calibration Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE IGFBP-3 assay on the IMMULITE 2000 systems

The Ferritin Calibration Verification Material (CVM) contains one set of four vials. CVM1 contains 5.0mL of human serum albumin with preservatives. CVM2, CVM3, and CVM4 contain 2.0mL/vial of various levels of human ferritin in a human serum albumin matrix with preservatives. The CVMs are supplied in liquid form.

IMMULITE® 2000 IGFBP-3 Calibration Verification Material (CVM) contains one set of four vials each 2.0mL/vial. CVM1 contains bovine protein buffer matrix with preservatives. CVM2, CVM3 and CVM4 contain various levels of processed human serum (source of IGFBP-3) in bovine protein buffer matrix with preservatives. The CVMs are supplied in liquid form.

The document describes the acceptance criteria and stability studies for two calibration verification materials: the IMMULITE® 2000 Ferritin Calibration Verification Material (CVM) and the IMMULITE® 2000 IGFBP-3 Calibration Verification Material (CVM).

Here's a breakdown of the requested information for each device:

IMMULITE® 2000 Ferritin Calibration Verification Material (CVM)

1. Table of acceptance criteria and reported device performance

Acceptance Criteria for Stability of IMMULITE 2000 Ferritin CVM (from Table 3):

Reported Device Performance (Stability Summary - Section 7.1 and 7.1.1):
The document states that the IMMULITE® 2000 Ferritin Calibration Verification Materials are stable for up to 18 months when stored at 2-8°C prior to opening, and for 8 hours at ambient or room temperature (15-25°C) after reconstitution. The stability study involved testing CVM levels at time points 0, 6, 12, and 18 months, with "dose value determined from the reference calibrator curve." For open component testing, results were determined at 2-hourly intervals for up to 9 hours and compared to time zero. The document implies that the device met these criteria, as it concludes: "Performance testing has been carried out to demonstrate that this device meets the performance specifications for its intended use." and "The substantial equivalence of the device is supported by the non-clinical testing...". However, specific numerical results of the stability study demonstrating adherence to each range are not explicitly provided in the excerpt.

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

• Test Set Sample Size: For stability testing, CVMs and reference CVMs were run in duplicate (as a minimum) at specified time points (0, 6, 12, 18 months). For open component testing, Ferritin CVM lot 016A was tested at 2-hourly intervals for up to 9 hours. For value assignment and expected values, each CVM level was tested on 4 different days, on 15 replicates in total, comprised of 5 runs, 3 replicates per run, 5 IMMULITE 2000 systems and 3 different reagent kit lots. Additionally, five levels of commercially available controls and 30 samples (15 spiked and 15 normal samples) were used to validate calibrator/CVM value assignments.

• Data Provenance: Not explicitly stated. The manufacturer is Siemens Healthcare Diagnostics Inc. in Tarrytown, NY, USA, suggesting a US-based or international company, but specific country of origin for the data is not mentioned, nor is it specified if the data is retrospective or prospective. Given it's a stability study, it would be prospective data collection.

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)

• Number of experts: Not applicable. This is a calibration verification material for an in vitro diagnostic assay, where "ground truth" (or assigned value) is established through a metrological traceability chain rather than expert consensus on medical images or clinical outcomes.
• Qualifications of experts: Not applicable.

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

• Adjudication method: Not applicable. The process involves direct measurement against reference calibrators and statistical analysis, not human adjudication of observations. The CVM values are calculated based on recovered values for each run on each instrument independently and then averaged across all systems.

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

• MRMC study: Not applicable. This device is a quality control material for an automated assay, not an AI-assisted diagnostic tool involving human readers.

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

• Standalone study: The performance evaluated here is inherently "standalone" in the sense that it's the performance of the calibration material itself when run on the IMMULITE 2000 systems. There isn't an "algorithm only" device for this type of product separate from its use with the instrument.

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

• Type of Ground Truth: The ground truth for the Ferritin CVMs is based on traceability to WHO 2nd IS 80/578 and internal value assignment using assigned reference calibrators. These reference calibrators are prepared using Ferritin antigen stock. This represents a form of metrological traceability to an international standard.

8. The sample size for the training set

• Training Set Sample Size: Not explicitly applicable in the conventional sense of machine learning algorithms. The concept of a "training set" doesn't directly apply here. However, the value assignment process, which determines the "target values" for the CVMs, involves extensive testing with multiple replicates, instruments, and reagent lots. It's the equivalent of establishing the expected performance characteristics based on a large internal dataset.

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

• Ground Truth for Training Set: The "ground truth" (i.e., assigned values) for the calibrators and CVMs are established by Siemens Healthcare Diagnostics Inc. using a process outlined in Section 7.3 "Value Assignment". It involves:
  • Traceability to WHO 2nd IS 80/578.
  • Using assigned reference calibrators prepared with Ferritin antigen stock.
  • Testing CVMs on 4 different days, 15 replicates in total (5 runs, 3 replicates per run), 5 IMMULITE 2000 systems, and 3 different reagent kit lots.
  • Generating CVM dose values from curves generated by assigned reference calibrators, with values calculated for each run/instrument independently and then averaged across all systems.
  • Quality control through recovery of patient samples and commercial controls using the assigned CVM values, which must fall within their target ranges.

IMMULITE® 2000 IGFBP-3 Calibration Verification Material (CVM)

1. Table of acceptance criteria and reported device performance

Acceptance Criteria for Stability of IMMULITE 2000 IGFBP-3 CVM (from Table 3):

Reported Device Performance (Stability Summary - Section 7.1 and 7.1.1):
The document states that the IMMULITE® 2000 IGFBP-3 Calibration Verification Materials are stable for up to 4 years when stored at -20°C. The stability study involved testing CVM levels at time points 0, 30, 36, and 48 months, with "dose value determined from the reference calibrator curve." Similar to the Ferritin CVM, the document implies that the device met these criteria, concluding: "Performance testing has been carried out to demonstrate that this device meets the performance specifications for its intended use." and "The substantial equivalence of the device is supported by the non-clinical testing...". Specific numerical results of the stability study demonstrating adherence to each range are not explicitly provided.

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

• Test Set Sample Size: For stability testing, CVMs and reference CVMs were run in duplicate (as a minimum) at specified time points (0, 30, 36, 48 months). For value assignment and expected values, each CVM level was tested on 3 different days, on 15 replicates in total, comprised of 5 runs, 3 replicates per run, 3 IMMULITE 2000 systems and 3 different reagent kit lots. Additionally, two levels of commercially available controls and 30 diluted normal samples were used to validate calibrator/CVM value assignments.

• Data Provenance: Not explicitly stated. The manufacturer is Siemens Healthcare Diagnostics Inc. in Tarrytown, NY, USA, suggesting a US-based or international company, but specific country of origin for the data is not mentioned, nor is it specified if the data is retrospective or prospective. Given it's a stability study, it would be prospective data collection.

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)

• Number of experts: Not applicable. This is a calibration verification material for an in vitro diagnostic assay, where "ground truth" (or assigned value) is established through a metrological traceability chain.
• Qualifications of experts: Not applicable.

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

• Adjudication method: Not applicable. The process involves direct measurement against reference calibrators and statistical analysis, not human adjudication of observations. The CVM values are calculated based on recovered values for each run on each instrument independently and then averaged across all systems.

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

• MRMC study: Not applicable. This device is a quality control material for an automated assay, not an AI-assisted diagnostic tool involving human readers.

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

• Standalone study: The performance evaluated here is inherently "standalone" in the sense that it's the performance of the calibration material itself when run on the IMMULITE 2000 systems. There isn't an "algorithm only" device for this type of product separate from its use with the instrument.

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

• Type of Ground Truth: The ground truth for the IGFBP-3 CVMs is based on traceability to WHO NIBSC Reagent 93/560 and internal value assignment using assigned reference calibrators. These reference calibrators are prepared using IGFBP-3 antigen stock. This represents a form of metrological traceability to an international standard.

8. The sample size for the training set

• Training Set Sample Size: Not explicitly applicable in the conventional sense of machine learning algorithms. However, the value assignment process, which determines the "target values" for the CVMs, involves extensive testing with multiple replicates, instruments, and reagent lots. It's the equivalent of establishing the expected performance characteristics based on a large internal dataset.

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

• Ground Truth for Training Set: The "ground truth" (i.e., assigned values) for the calibrators and CVMs are established by Siemens Healthcare Diagnostics Inc. using a process outlined in Section 7.3 "Value Assignment". It involves:
  • Traceability to WHO NIBSC Reagent 93/560.
  • Using assigned reference calibrators prepared with IGFBP-3 antigen stock.
  • Testing CVMs on 3 different days, 15 replicates in total (5 runs, 3 replicates per run), 3 IMMULITE 2000 systems, and 3 different reagent kit lots.
  • Generating CVM dose values from curves generated by assigned reference calibrators, with values calculated for each run/instrument independently and then averaged across all systems.
  • Quality control through recovery of patient samples, spiked patient samples, and commercial controls using the assigned CVM values, which must fall within their target ranges.

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IMMULITE® 2000 Beta-2 Microglobulin Calibration Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE Beta-2 Microglobulin assay on the IMMULITE 2000 systems
IMMULITE® 2000 High Sensitivity CRP Calibration Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE High Sensitivity CRP assay on the IMMULITE 2000 systems

The IMMULITE® 2000 Beta-2 Microglobulin Calibration Verification Material (CVM) contains one set of four vials each 3mL. CVM1 contains bovine protein buffer matrix with preservatives and CVM2, CVM3, and CVM4 contain various levels of human Beta-2 Microglobulin in a lyophilized bovine protein buffer matrix with preservatives.
The IMMULITE® 2000 High Sensitivity CRP Calibration Verification Material (CVM) contains one set of four vials, 2mL each. CVM1 contains a bovine protein/buffer with 0.098% sodium azide and preservative. CVM2, CVM3, and CVM4 contain various levels of human CRP in a bovine protein/buffer with 0.098% sodium azide and preservative.

This document describes two calibration verification materials (CVMs): IMMULITE® 2000 Beta-2 Microglobulin CVM and IMMULITE® 2000 High Sensitivity CRP CVM. Since they are distinct devices with separate studies and acceptance criteria, I will describe them separately.

IMMULITE® 2000 Beta-2 Microglobulin Calibration Verification Material

This device is a quality control material intended for in vitro diagnostic use in the verification of calibration of the IMMULITE Beta-2 Microglobulin assay on the IMMULITE 2000 systems.

1. Acceptance Criteria and Reported Device Performance

The device's performance is demonstrated through stability studies. The acceptance criteria for stability are divided into two parts:

• Part 1: Guideline Acceptance Criteria:
  • CVM Level 2: Dose value to fall within ±15% of the assigned dose.
  • CVM Level 3 and 4: Dose value to fall within ±20% of the assigned dose.
• Part 2: Review Limits Criteria: If Part 1 criteria are not met, the dose value of the controls must be within 2 Standard Deviations (SD) of the control target value when generated from the stability calibrator curve.

The document states that the stability study was conducted to validate real-time shelf life and open component (in-use or open vial) claims. It also reports:

• Real-time shelf life: Stable up to 9 years when stored at -20°C prior to opening. The study for lots 011 and 012 is ongoing until the 119-month time point.
• Open component (in-use) stability: 8 hours of stability at ambient or room temperature (15-25°C) after opening.

The document does not provide a direct table comparing the acceptance criteria to actual numerical results for each CVM level. Instead, it states that the testing demonstrated the device meets the performance specifications.

2. Sample Size and Data Provenance for Test Set

• Sample Size:
  • For stability testing, CVMs were run in duplicate (as a minimum) at specified time points. Three lots were used: Lot 010, Lot 011, and Lot 012. Each lot had 4 CVM levels.
  • For open component testing, CVM lot 012 was tested using IMMULITE 2000 Beta-2 Microglobulin (L2KBM) kit lot 247 at 2-hourly intervals for up to 9 hours.
  • For Expected Values/Target Values/Reference Range establishment: Each CVM level was tested for a total of 15 replicates (5 runs and 3 replicates per run) using 3 different reagent kit lots and 5 IMMULITE 2000 systems.
• Data Provenance: The information does not specify the country of origin of the data. The studies are described as "non-clinical performance testing," implying they are internal validation studies conducted by the manufacturer. The data is prospective as it involves stability testing over time.

3. Number of Experts and Qualifications for Ground Truth

• This device is a calibration verification material. The "ground truth" for CVMs is typically established through precise analytical methods and traceability to reference materials. The document doesn't mention the involvement of "experts" in establishing ground truth in the same way clinical diagnostic devices might have radiologists or pathologists.
• The CVMs are described as traceable to an internal material which has been gravimetrically prepared. Value assignment involves generating dose values using a curve generated by assigned reference calibrators, with values averaged across systems. Quality control is performed by calculating recovery of patient samples (40 samples: 20 spiked and diluted urine, 10 neat urine, 10 diluted serum) and controls.

4. Adjudication Method for Test Set

Not applicable for a calibration verification material's performance studies. The evaluation is based on quantitative measurements against established internal and traceable standards.

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

Not applicable. This is a calibration verification material, not a diagnostic imaging device typically evaluated with MRMC studies comparing human readers with and without AI assistance.

6. Standalone Performance Study

Yes, the studies described are standalone performance studies for the calibration verification material itself. Its performance is evaluated independently against its established criteria and traceability.

7. Type of Ground Truth Used

The ground truth or reference values for the CVMs are established through:

• Traceability: To an internal material gravimetrically prepared.
• Value Assignment: Using assigned reference calibrators and averaging recovered values across systems.
• Validation: Through recovery calculation of patient samples (spiked and diluted urine, neat urine, diluted serum) and controls.

8. Sample Size for the Training Set

Not applicable. This is a calibration verification material; it does not involve machine learning or a "training set" in the conventional sense. The "training" of the assay itself (which these materials verify) would involve its own calibration process, which is distinct from the CVM performance study.

9. How Ground Truth for the Training Set Was Established

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

IMMULITE® 2000 High Sensitivity CRP Calibration Verification Material

This device is a quality control material intended for in vitro diagnostic use in the verification of calibration of the IMMULITE High Sensitivity CRP assay on the IMMULITE 2000 systems.

1. Acceptance Criteria and Reported Device Performance

The device's performance is demonstrated through stability studies. The acceptance criteria for stability are divided into two parts:

• Part 1: Guideline Acceptance Criteria:
  • CVM Level 2: Dose value to fall within ±20% of the assigned dose.
  • CVM Level 3: Dose value to fall within ±6% of the assigned dose.
  • CVM Level 4: Dose value to fall within ±10% of the assigned dose.
• Part 2: Review Limits Criteria: If Part 1 criteria are not met, the dose value of the controls must be within 2 Standard Deviations (SD) of the control target value when generated from the stability calibrator curve.

The document states that the stability study was conducted to validate real-time shelf life and open component (in-use or open vial) claims. It also reports:

• Real-time shelf life: Stable up to 11 months when stored at 2-8°C prior to opening. The study for lots 025, 026, and 090 is ongoing (up to 23, 12, and 11 months respectively).
• Open component (in-use) stability: 8 hours of stability at ambient or room temperature (15-25°C) after opening.

The document does not provide a direct table comparing the acceptance criteria to actual numerical results for each CVM level. Instead, it states that the testing demonstrated the device meets the performance specifications.

2. Sample Size and Data Provenance for Test Set

• Sample Size:
  • For stability testing, CVMs were run in duplicate (as a minimum) at specified time points. Three lots were used: Lot 025, Lot 026, and Lot 090. Each lot had 4 CVM levels.
  • For Expected Values/Target Values/Reference Range establishment: CVMs were tested on 15 replicates in total (comprised of 5 runs and 3 replicates per run) on 4 IMMULITE 2000 systems and 3 different reagent kit lots.
• Data Provenance: The information does not specify the country of origin of the data. The studies are described as "non-clinical performance testing," implying they are internal validation studies conducted by the manufacturer. The data is prospective as it involves stability testing over time.

3. Number of Experts and Qualifications for Ground Truth

• Similar to the Beta-2 Microglobulin CVM, this device is a calibration verification material. The "ground truth" for CVMs is typically established through precise analytical methods and traceability to reference materials. The document doesn't mention the involvement of "experts" in establishing ground truth in the same way clinical diagnostic devices might have radiologists or pathologists.
• The CVMs are described as traceable to WHO 1st IS 85/506 and CRM 470. Value assignment involves generating dose values using a curve generated by assigned reference calibrators, with values averaged across systems. Quality control is performed by calculating recovery of patient samples (28 samples: 21 normal, 7 spiked) and controls.

4. Adjudication Method for Test Set

Not applicable for a calibration verification material's performance studies. The evaluation is based on quantitative measurements against established internal and traceable standards.

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

Not applicable. This is a calibration verification material, not a diagnostic imaging device typically evaluated with MRMC studies comparing human readers with and without AI assistance.

6. Standalone Performance Study

Yes, the studies described are standalone performance studies for the calibration verification material itself. Its performance is evaluated independently against its established criteria and traceability.

7. Type of Ground Truth Used

The ground truth or reference values for the CVMs are established through:

• Traceability: To WHO 1st IS 85/506 and CRM 470.
• Value Assignment: Using assigned reference calibrators and averaging recovered values across systems.
• Validation: Through recovery calculation of patient samples (normal and spiked) and controls.

8. Sample Size for the Training Set

Not applicable. This is a calibration verification material; it does not involve machine learning or a "training set" in the conventional sense. The "training" of the assay itself (which these materials verify) would involve its own calibration process, which is distinct from the CVM performance study.

9. How 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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The IMMULITE® 2000 LH Calibration Verification Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE LH assay on the IMMULITE 2000 systems.

The IMMULITE® 2000 Free T3 Calbration Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE Free T3 assay on the IMMULITE 2000 systems

The IMMULITE® 2000 Gastrin Calibration Verification Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE Gastrin assay on the IMMULITE 2000 systems

The IMMULITE 2000 LH Calibration Verification Material (CVM) contains one set of four vials each 3.0mL after reconstitution. CVM1 contains lyophilized bovine serum with preservatives. CVM2, CVM3 and CVM4 contain various levels of LH antigen from human pituitary glands in a lyophilized bovine serum matrix with preservatives.

IMMULITE® 2000 Free T3 Calibration Verification Material (CVM) contains one set of four vials. CVM1 contains 4.0 mL processed lyophilized human serum with preservatives after reconstitution. CVM2, CVM3 and CVM4 contain 2.0mL/vial of various levels of 3,31 Triiodo-L-Thyronine (Free Acid) in processed lyophilized human serum with preservatives after reconstitution.

The IMMULITE 2000 Gastrin Calibration Verification Material (CVM) contains one set of four vials, 2.0 mL each after reconstitution. CVM1 contains a lyophilized processed buffered human protein matrix with preservatives. CVM2, CVM3 and CVM4 contain various levels of synthetic-human gastrin in a lyophilized processed buffered human protein matrix with preservatives.

This document describes the acceptance criteria and performance testing for three In Vitro Diagnostic (IVD) calibration verification materials: IMMULITE® 2000 LH CVM, IMMULITE® 2000 Free T3 CVM, and IMMULITE® 2000 Gastrin CVM. The study proving the devices meet acceptance criteria is the Stability Study.

Due to the nature of these devices (Quality Control Materials), the typical AI/human comparative effectiveness studies, expert consensus for ground truth, or distinct training/test sets are not applicable as they are for diagnostic algorithms. Instead, the performance is evaluated by ensuring the material's dose values remain within specified acceptable ranges over time and under various conditions, determined by the instrument's calibrated reference curve.

The following information focuses on the LH CVM, Free T3 CVM, and Gastrin CVM separately, as each has its own specific acceptance criteria and performance data.

IMMULITE® 2000 LH Calibration Verification Material (CVM)

1. Table of Acceptance Criteria and Reported Device Performance

The stability study was conducted to validate real-time shelf life and open component (in-use or open vial) claim.

Note: The document states the tests were performed to demonstrate the device meets performance specifications, and concludes substantial equivalence, implying the acceptance criteria were met. Specific numerical results for each time point are not provided in this summary.

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

• Real-time shelf life stability: Not explicitly stated as a "test set" in the traditional sense, but the stability CVMs and reference CVMs were run in duplicate (as a minimum) at time points: 0, 72, 84, and 109 months.
• Open Component testing: LH CVM lot 090 was tested at 2-hourly intervals for up to 9 hours.
• Data Provenance: Not explicitly stated, but implied to be from internal laboratory testing at Siemens Healthcare Diagnostics Inc. (Tarrytown, NY, USA). This is a prospective test to determine the stability of newly manufactured CVMs.

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):

Not applicable in the context of IVD calibration verification materials. Ground truth for dose values is established through traceability to international reference standards (WHO 1st IRP 68/40 and 2nd IS 80/552) and internal reference calibrators.

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

Not applicable. Results are compared against pre-defined numerical acceptance ranges.

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 not an AI-assisted diagnostic device.

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

Not applicable. This is a chemical reagent product used in an automated analyzer. Its performance is inherent to its chemical stability and manufacturing consistency in relation to the instrument's operation.

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

The ground truth for the assigned dose values of the CVMs is established through traceability to WHO 1st IRP 68/40 and 2nd IS 80/552 via assigned reference calibrators. This falls under the category of reference standards.

8. The sample size for the training set:

Not applicable. This is a stability study for a calibration verification material, not a machine learning model.

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

Not applicable.

IMMULITE® 2000 Free T3 Calibration Verification Material (CVM) Summary

1. Table of Acceptance Criteria and Reported Device Performance

The stability study was conducted to validate shelf life claims.

Note: The document states the tests were performed to demonstrate the device meets performance specifications, and concludes substantial equivalence, implying the acceptance criteria were met. Specific numerical results for each time point are not provided in this summary.

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

• Real-time shelf life stability: Stability CVMs and reference CVMs were run in duplicate (as a minimum) at time points: 0, 6, 12, and 18 months.
• Data Provenance: Not explicitly stated, but implied to be from internal laboratory testing at Siemens Healthcare Diagnostics Inc. (Tarrytown, NY, USA). This is a prospective test to determine the stability of newly manufactured CVMs.

3-6. Not applicable (same reasons as for LH CVM).

7. The type of ground truth used:

The ground truth for the assigned dose values of the CVMs is established through traceability to an internal material which has been gravimetrically prepared. This acts as a reference standard.

8-9. Not applicable.

IMMULITE® 2000 Gastrin Calibration Verification Material (CVM) Summary

1. Table of Acceptance Criteria and Reported Device Performance

The stability study was conducted to validate real-time shelf life and open component (in-use or open vial) claim.

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The IMMULITE® Cortisol Calibration Material is for in vitro diagnostic use in the verification of calibration of the IMMULITE Cortisol assay on the IMMULITE 2000 systems.

The IMMULITE® Folic Acid Calibration Material is for in vitro diagnostic use in the verification of calibration of the IMMULITE Folic Acid assay on the IMMULITE 2000 systems.

The IMMULITE® Vitanin B12 Calibration Material is for in vitro diagnostic use in the verification of calibration of the IMMULITE Vitamin B12 assay on the IMMULITE 2000 systems.

The IMMULITE® 2000 Cortisol Calibration Verification Material (CVM) contains one set of four vials each 3mL. CVM1 contains human serum with preservatives and CVM2, CVM3, and CVM4 contain various levels of cortisol in human serum with preservatives.

The IMMULITE® 2000 Folic Acid Calibration Verification Material (CVM) contains one set of four vials, 3mL (CVM1) each. when reconstituted. CVM1 contains a lyophilized human albumin based matrix with preservatives. CVM2. CVM3. and CVM4 contain various levels of lyophilized folic acid in human albumin based matrix with preservatives.

IMMULITE® 2000 Vitamin B12 Calibration Verification Material (CVM) contains one set of four vials, 3 mL each, when reconstituted. CVM1 contains a lyophilized human albumin-based matrix with preservatives. CVM2, CVM3, and CVM4 contain various levels of lyophilized Vitamin B12 in human albumin-based matrix with preservatives.

The provided text describes three distinct devices: IMMULITE® 2000 Cortisol Calibration Verification Material, IMMULITE® 2000 Folic Acid Calibration Verification Material, and IMMULITE® 2000 Vitamin B12 Calibration Verification Material. Each device has its own acceptance criteria and associated study details.

Here's an analysis for each device as requested:

Device 1: IMMULITE® 2000 Cortisol Calibration Verification Material

1. Table of Acceptance Criteria and Reported Device Performance

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

• Sample Size (Test Set):
  • Stability Studies: CVM levels (LCOCVM1, LCOCVM2, LCOCVM3, LCOCVM4) run in duplicate (as a minimum) at specified time points (1, 182, 365, 425 days).
  • Open Component Testing: Lot 090 CVMs were tested at 2-hourly intervals for up to 9 hours.
  • Value Assignment Validation: Six levels of commercially available controls, 25 patient serum samples, 3 spiked normal serum samples, and 5 normal serum samples were used to validate calibrator/CVM value assignments.
  • Expected Values/Target Values/Reference Range Establishment: Each CVM level was tested for a total of 27 replicates (9 runs, 3 replicates per run) using 3 different reagent kit lots and 8 IMMULITE 2000 systems.
• Data Provenance: Not explicitly stated (e.g., country of origin). Appears to be based on internal laboratory studies ("Calibrators are not commercialized but are used internally during manufacture and release testing"). The studies are prospective in nature for stability testing.

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

• Not applicable in the context of this device. Ground truth is established through internal gravimetric preparation and reference calibrator curves, with values determined by multiple runs on multiple instruments. There's no mention of human expert interpretation for device performance evaluation.

4. Adjudication Method

• Not applicable. The performance is assessed against predefined numerical acceptance criteria and statistical ranges, not through an adjudication process involving human experts.

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

• Not applicable. This is a calibration verification material, not a device for human interpretation or diagnosis.

6. Standalone Performance

• Yes, the performance testing described is for the device (IMMULITE® 2000 Cortisol CVM) in a standalone context, as it evaluates the material's stability and value assignment on the IMMULITE 2000 system. It's not an AI algorithm, but the "standalone performance" concept applies in that the material's performance is assessed intrinsically.

7. Type of Ground Truth Used

• Stability and Value Assignment: Traceable to an internal material which has been gravimetrically prepared. CVMs are manufactured using qualified materials and measurement procedures. Dose values are generated from a reference calibrator curve created by assigned reference calibrators, with values averaged across all systems.
• Expected Values/Target Ranges: Established based on the Target Mean and ± 2 Standard Deviation (SD) from extensive testing (27 replicates, 9 runs, 3 replicates/run, 3 kit lots, 8 IMMULITE 2000 systems).

8. Sample Size for the Training Set

• The term "training set" is not directly applicable to a calibration verification material. However, the data used to establish the reference calibrator curve (from which CVM dose values are generated) and the target values are analogous to a training dataset in that they define the expected performance.
• For the reference calibrator curve: Not specified in detail, but it's part of the internal manufacturing and release testing of Cortisol reagents and two-point adjustors.
• For CVM Target Values: Each CVM level was tested for a total of 27 replicates (9 runs, 3 replicates per run) using 3 different reagent kit lots and 8 IMMULITE 2000 systems to establish the target mean and SD.

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

• Reference Calibrator Curve: The CVMs are "value assigned using assigned reference calibrators." These calibrators are internally used during manufacture and release testing. The CVMs' dose values are generated using the curve established by these assigned reference calibrators. The underlying ground truth for these reference calibrators is based on gravimetric preparation and qualified measurement procedures.
• CVM Target Values: Established through extensive testing on multiple systems and reagent lots, calculating the mean and standard deviation from these empirical measurements, and then applying a 95% confidence interval ($\pm 2SD$).

Device 2: IMMULITE® 2000 Folic Acid Calibration Verification Material

1. Table of Acceptance Criteria and Reported Device Performance

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

• Sample Size (Test Set):
  • Stability Studies: CVM levels (LFOCVM1, LFOCVM2, LFOCVM3, LFOCVM4) run in duplicate (as a minimum) at specified time points (1, 912, 1095, 1280 days).
  • Open Component Testing: Lot 090B Folic Acid CVMs were tested at 2-hourly intervals for up to 9 hours.
  • Value Assignment Validation: Six levels of commercially available controls and 14 patient serum samples were used to validate calibrator/CVM value assignments.
  • Expected Values/Target Values/Reference Range Establishment: Folic Acid CVMs were tested on 27 replicates in total (9 runs, 3 replicates per run) on 6 IMMULITE 2000 systems and 3 different reagent kit lots.
• Data Provenance: Not explicitly stated (e.g., country of origin). Appears to be based on internal laboratory studies (calibrators used internally). The studies are prospective in nature for stability testing.

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

• Not applicable as this is a calibration verification material. Ground truth is established through internal gravimetric preparation, reference calibrator curves, and empirical measurements on multiple instruments. No human expert interpretation is involved in performance evaluation.

4. Adjudication Method

• Not applicable. Performance is assessed against numerical acceptance criteria and statistical ranges.

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

• Not applicable. This is a calibration verification material.

6. Standalone Performance

• Yes, performance testing is for the device in a standalone context, evaluating its stability and value assignment on the IMMULITE 2000 system.

7. Type of Ground Truth Used

• Stability and Value Assignment: Traceable to an internal material which has been gravimetrically prepared. CVMs are manufactured using qualified materials and measurement procedures. Dose values are generated from a reference calibrator curve created by assigned reference calibrators, with values averaged across all systems.
• Expected Values/Target Ranges: Established based on the Target Mean and ± 2 Standard Deviation (SD) from extensive testing (27 replicates, 9 runs, 3 replicates/run, 6 IMMULITE 2000 systems, 3 kit lots).

8. Sample Size for the Training Set

• Similar to the Cortisol CVM, the "training set" concept is not directly applicable.
• For the reference calibrator curve: Not specified in detail, but part of internal manufacturing and release testing of Folic Acid reagents and two-point adjustors.
• For CVM Target Values: The Folic Acid CVMs were tested on 27 replicates (9 runs, 3 replicates per run) on 6 IMMULITE 2000 systems and 3 different reagent kit lots to establish the target mean and SD.

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

• Reference Calibrator Curve: The CVMs are "value assigned using assigned reference calibrators." These calibrators are internally used during manufacture and release testing. The CVMs' dose values are generated using the curve established by these assigned reference calibrators. The underlying ground truth for these reference calibrators is based on gravimetric preparation and qualified measurement procedures.
• CVM Target Values: Established through extensive empirical testing (27 replicates on multiple systems and reagent lots) to calculate the mean and standard deviation, followed by defining a 95% confidence interval ($\pm 2SD$).

Device 3: IMMULITE® 2000 Vitamin B12 Calibration Verification Material

1. Table of Acceptance Criteria and Reported Device Performance

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

• Sample Size (Test Set):
  • Stability Studies: CVM levels (LVBCVM1, LVBCVM2, LVBCVM3, LVBCVM4) run in duplicate (at the minimum) at specified time points (0, 67, 68, 69 months).
  • Open Component Testing: Lot 108 Vitamin B12 CVMs were tested at 2-hourly intervals for up to 9 hours.
  • Value Assignment Validation: Eight levels of commercially available controls and 21 patient serum samples were used to validate CVM value assignments.
  • Expected Values/Target Values/Reference Range Establishment: Vitamin B12 CVMs were tested on 24 replicates in total (12 runs, 2 replicates per run) using 3 IMMULITE 2000 and 5 IMMULITE/IMMULITE 1000 systems, and 4 different reagent kit lots.
• Data Provenance: Not explicitly stated (e.g., country of origin). Appears to be based on internal laboratory studies (calibrators used internally). The studies are prospective in nature for stability testing.

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

• Not applicable as this is a calibration verification material. Ground truth is established through internal gravimetric preparation, internal reference standards, reference calibrator curves, and empirical measurements on multiple instruments. No human expert interpretation is involved in performance evaluation.

4. Adjudication Method

• Not applicable. Performance is assessed against numerical acceptance criteria and statistical ranges.

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

• Not applicable. This is a calibration verification material.

6. Standalone Performance

• Yes, performance testing is for the device in a standalone context, evaluating its stability and value assignment on the IMMULITE 2000 and IMMULITE/IMMULITE 1000 systems.

7. Type of Ground Truth Used

• Stability and Value Assignment: Traceable to an internal standard. CVMs are manufactured using qualified materials and measurement procedures. Dose values are generated from a reference calibrator curve created by assigned reference calibrators, with values averaged across all systems.
• Expected Values/Target Ranges: Established based on the Target Mean and ± 2 Standard Deviation (SD) from extensive testing (24 replicates, 12 runs, 2 replicates/run, 8 IMMULITE systems, 4 kit lots).

8. Sample Size for the Training Set

• The "training set" concept is not directly applicable.
• For the reference calibrator curve: Not specified in detail, but part of internal manufacturing and release testing of Vitamin B12 reagents and two-point adjustors.
• For CVM Target Values: The Vitamin B12 CVMs were tested on 24 replicates (12 runs, 2 replicates per run) using 3 IMMULITE 2000 and 5 IMMULITE/IMMULITE 1000 systems, and 4 different reagent kit lots to establish the target mean and SD.

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

• Reference Calibrator Curve: The CVMs are "value assigned reference calibrators." These calibrators are internally used during manufacture and release testing. The CVMs' dose values are generated using the curve established by these assigned reference calibrators. The underlying ground truth for these reference calibrators is based on internal standards and qualified measurement procedures.
• CVM Target Values: Established through extensive empirical testing (24 replicates on multiple systems and reagent lots) to calculate the mean and standard deviation, followed by defining a 95% confidence interval ($\pm 2SD$).

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