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Lumipulse G HE4 Immunoreaction Cartridges:
For in vitro diagnostic use.
Lumipulse G HE4 is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of HE4 in human serum and plasma (lithium heparin or dipotassium EDTA) on the Lumipulse G System.
The assay is to be used as an aid in monitoring recurrence or progressive disease in patients with epithelial ovarian cancer. Serial testing for patient HE4 values should be used in conjunction with other clinical methods used for monitoring epithelial ovarian cancer.

Lumipulse G HE4 Calibrators:
Lumipulse G HE4 Calibrators are for use in the calibration of the Lumipulse G System for the quantitative measurement of HE4 in human serum and plasma (lithium heparin or dipotassium EDTA).

The Lumipulse G HE4 is an assay system, including a set of immunoassay reagents, for the quantitative measurement of HE4 in specimens based on CLEIA technology by a two-step sandwich immunoassay method on the LUMIPULSE G System.

The provided document describes the analytical and clinical performance of the Lumipulse G HE4 Immunoassay for monitoring recurrence or progressive disease in patients with epithelial ovarian cancer.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for this device are primarily demonstrated through its analytical performance, comparison to a predicate device, and clinical concordance in monitoring disease progression. While explicit "acceptance criteria" are not listed in a separate section, they are implicitly defined by the satisfactory results presented in the analytical and clinical studies.

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

• Test Set (Clinical Study):

  • Sample Size: 72 patients with epithelial ovarian cancer, providing a total of 330 pairs of observations (serial samples). The average number of observations per patient was 5.6.
  • Data Provenance: Not explicitly stated regarding country of origin or specific institutions. The nature of the study (monitoring recurrence/progression) implies a retrospective collection of serial samples from patients already diagnosed, or a prospective collection over time. Given the context of a 510(k) submission, it is common for such clinical performance studies to be retrospective using existing clinical samples.

• Test Set (Analytical Studies - Precision, Linearity, Detection Limits, Interference):

  • Precision (within-lab): 8 human serum-based samples (specimen pools) and 2 commercially available serum-based controls. Each assayed in replicates of two, twice a day for 20 days (n=80 for each sample).

  • Precision (external lab): Human serum-based samples (specimen pools) and 2 commercially available controls. Assayed in replicates of two, twice a day for 10 days at 3 external sites (n=40 for each sample per site, total n=120 per sample across sites).

  • Precision (lot-to-lot): Human serum-based samples (specimen pools) and 2 commercially available controls. Assayed in replicates of two, twice a day for 10 days with 3 lots of cartridges and calibrators (n=40 for each sample per lot, total n=120 per sample across lots).

  • Linearity/Recovery: Human serum and dipotassium EDTA plasma samples (pools). The document doesn't specify the exact number of unique "serum/plasma samples" but rather "specimen pools" and subsequent dilutions/additions. Tables show 3 serum and 3 plasma samples assessed for recovery, each with 6 target HE4 levels.

  • Detection Limits (LoB, LoD, LoQ): Seven low-level specimens were tested over 3 days using three LUMIPULSE G Systems and three Lumipulse G HE4 lots, yielding 180 determinations for each panel.

  • Analytical Specificity (Interference): Human serum specimens supplemented with potentially interfering compounds. The exact number of unique "specimens" is not given, but a long list of compounds tested.

  • Method Comparison: 143 samples for the common measuring range, and 168 samples including those requiring dilution.

  • Matrix Comparison: Not specified, but involved comparing SST, K2EDTA, and Lithium Heparin tube types against Red top serum.

  • Data Provenance (Analytical): Not explicitly stated, but typically these are laboratory-generated studies using human donor samples, commercial controls, or spiked samples. The CLSI guidelines followed (EP5-A3, EP6-A, EP7-A2, EP9-A3, EP17-A2) are standard for in vitro diagnostic device validation, implying controlled laboratory conditions.

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

• For the clinical study (monitoring disease status): The ground truth was defined by "changes in disease status," which is a clinical outcome. The document states: "A positive change in HE4 was defined as an increase in the value that was at least 18% greater than the previous value of the test. This level of change takes into account the variability of the assay. Forty-nine percent (49%) or 30/61 of the patient samples with a positive change correlated with the disease progression while eighty percent (80%) or 214/269 of the patient serial samples with no significant change in HE4 value correlated with no progression."
  • This implies that the "disease progression" ground truth was established by independent clinical assessments, likely by treating physicians or oncology teams using standard clinical methods (imaging, physician assessment, other biomarkers, symptoms).
  • The document does not specify the number of experts or their specific qualifications (e.g., "Radiologist with 10 years of experience"). This is typical for IVD submissions where the ground truth is derived from standard clinical practice rather than a specific expert consensus panel for the study.

4. Adjudication Method for the Test Set

• For the clinical study: Not explicitly stated as a formal adjudication process involving multiple independent reviewers in the sense of medical imaging reader studies. The ground truth for "disease progression" appears to be derived from the patient's overall clinical status as assessed by their primary care or oncology team. The "correlation" mentions comparing HE4 changes with observed disease progression/no progression. There's no indication of multiple independent adjudicators for the disease status itself within the context of this study.

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

• No, an MRMC comparative effectiveness study was not done. This is an in vitro diagnostic (IVD) device, specifically an immunoassay for measuring a biomarker (HE4). MRMC studies are typically performed for imaging devices (e.g., AI for radiology) where human readers (e.g., radiologists) interpret images with and without AI assistance to measure improvement in diagnostic performance. This submission focuses on the analytical and clinical performance of a quantitative laboratory test.

6. Standalone Performance

• Yes, standalone performance was done. The entire analytical performance section (Precision, Linearity, Detection Limits, Analytical Specificity) describes the performance of the Lumipulse G HE4 assay as a standalone system (Lumipulse G System + HE4 kit).
• The clinical study also reports the performance characteristics (sensitivity, specificity, concordance) of the HE4 assay itself in correlating with disease progression, essentially its standalone diagnostic aid performance. The indication for use clearly states it is an "aid in monitoring recurrence or progressive disease," implying its utility as a standalone test in this context, albeit "in conjunction with other clinical methods."

7. Type of Ground Truth Used

• Analytical Studies:
  • Known concentrations: For linearity, recovery, and detection limits, the ground truth is established by preparing samples with known concentrations of HE4.
  • Reference materials/specimen pools: For precision and interference, ground truth relies on the characteristics of the prepared specimen pools or commercial controls.
• Clinical Study:
  • Clinical Outcomes/Disease Status: The ground truth for the clinical study was the "change in disease status" (progression or no progression). This is derived from an unstated combination of "other clinical methods used for monitoring epithelial ovarian cancer" as applied by the treating clinicians. This likely includes imaging, physical exams, symptoms, and potentially other biomarker trends, but the document does not specify.

8. Sample Size for the Training Set

• The document describes a 510(k) submission for an in vitro diagnostic assay, not an AI/machine learning algorithm that requires a "training set" in the computational sense.
• For an immunoassay, the equivalent of "training" would be the initial development and optimization phase, which uses various characterized samples (e.g., patient samples, spiked solutions, controls) to establish the assay's operational parameters, calibrate it, and define its intended performance characteristics before formal validation studies. The exact sample sizes for this development phase are typically not detailed in a 510(k) summary. The studies presented are validation studies (test sets) for regulatory approval.

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

• As above, the concept of a computational "training set" ground truth doesn't directly apply here. For the development and initial calibration of the immunoassay:
  • Ground truth for calibrators is established via a hierarchical process traceable to an in-house reference preparation, which correlates to the predicate device (HE4 EIA). This is a metrological traceability chain, not an expert panel.
  • Ground truth for developing the assay's measurement range, precision, and specificity would involve using characterized human samples (e.g., samples from healthy individuals, individuals with known HE4 levels, and individuals with confounding conditions) and spiked samples (where known amounts of HE4 are added to a matrix). The "ground truth" (i.e., the target value) for such samples is determined by precise laboratory methods, often against a reference standard or by the known amount of analyte added.

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The Elecsys HE4 assay is an immunoassay for the quantitative determination of HE4 in human serum and plasma. The assay is used as an aid in monitoring the recurrence or progressive disease in patients with epithelial ovarian cancer. Serial testing for patient HE4 assay values should be used in conjunction with other clinical findings used for monitoring ovarian cancer.

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

The Elecsys HE4 assay is a sandwich immunoassay which includes a biotinylated monoclonal, murine HE4-specific IgG antibody as capture and a ruthenium labeled monoclonal, murine HE4-specific IgG antibody as signal.

Here's a breakdown of the acceptance criteria and study information for the Elecsys HE4 Assay, based on the provided text.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the Elecsys HE4 Assay are primarily demonstrated through comparison with a predicate device (Abbott Architect HE4) and through its own labeled performance characteristics. The key performance metrics are listed below:

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

• Clinical Study for Sensitivity and Specificity:
  • Test Set Size: 81 sequential pairs from patients with disease progression (for sensitivity) and 332 sequential pairs from patients without disease progression (for specificity).
  • Data Provenance: The document does not explicitly state the country of origin. It notes "clinically characterized samples" and "subjects with ovarian cancer" but does not specify if the data is retrospective or prospective. Given the nature of monitoring recurrence, it is highly likely to be prospective data collected over time.

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

The document does not provide information on the number or qualifications of experts used to establish the ground truth for the clinical test set (i.e., whether patients had disease progression or not). The ground truth appears to be based on "clinically characterized samples" which would likely involve standard clinical assessments, possibly including imaging, biopsy results, and physician evaluations, but details are not given.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication method (e.g., 2+1, 3+1) for establishing the ground truth of disease progression or non-progression for the clinical test set. The term "clinically characterized samples" suggests that the disease status was determined through routine clinical diagnosis and monitoring processes.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done

No, an MRMC comparative effectiveness study involving human readers with and without AI assistance was not conducted. This device is an in-vitro diagnostic (IVD) assay that directly measures a biomarker, not an imaging or interpretive AI device where human reader improvement would be relevant.

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

Yes, the studies presented represent standalone performance of the Elecsys HE4 Assay (an algorithm/assay only) without human-in-the-loop performance. The device provides a quantitative measurement of HE4.

7. The Type of Ground Truth Used

The ground truth used for the clinical sensitivity and specificity evaluation appears to be clinical outcome data (disease progression vs. no disease progression) derived from "clinically characterized samples."

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning, as this is an immunoassay and not an AI/ML-based device that would typically have a separate training phase with a distinct training set. The data presented for performance characteristics (precision, linearity, sensitivity, specificity) are related to the assay's analytical and clinical validation.

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

As this is an immunoassay, the concept of a "training set" as understood in AI/ML is not directly applicable. The assay's development and optimization would rely on established biochemical and analytical methods, with calibration against known standards. The "standardization" of the Elecsys HE4 Assay against the HE4 EIA method from Fujirebio Diagnostics, Inc., serves a similar purpose to establishing a foundational "ground truth" for the assay's measurements.

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The HE4 EIA is an enzyme immunometric assay for the quantitative determination of HE4 in human serum. The assay is to be used as an aid in monitoring recurrence or progressive disease in patients with epithelial ovarian cancer. Serial testing for patient HE4 assay values should be used in conjunction with other clinical methods used for monitoring ovarian cancer.

For In Vitro Diagnostic Use Only.

Fujirebio Diagnostics Tumor Marker Control is intended for use as an assayed control serum to monitor the precision of laboratory testing procedures for the analytes listed in the lot specific assigned values sheet.

The Fujirebio Diagnostics Tumor Marker Controls are used for validation of each HE4 EIA assay series. The HE4 EIA results should be considered valid if the mean HE4 values of control duplicates are within the specified HE4 EIA ranges indicated on the Assigned Value Sheet provided with the Fujirebio Diagnostics Tumor Marker Controls.

This submission is for a control device (Fujirebio Diagnostics Tumor Marker Control) intended to replace existing controls for the HE4 EIA kit. Therefore, the "device" in question is the control material itself, not a diagnostic test that detects a medical condition. As such, concepts like "test set," "ground truth," "expert consensus," "MRMC study," and "standalone performance" are not applicable in their usual diagnostic sense. The study focuses on verifying the control's performance to ensure it effectively monitors the precision of the HE4 EIA assay.

Here's an analysis based on the provided document, addressing the closest equivalent concepts for a control device:

Acceptance Criteria and Device Performance Study for Fujirebio Diagnostics Tumor Marker Control

The purpose of this 510(k) submission is to replace the current HE4 EIA kit controls with the Fujirebio Diagnostics Tumor Marker Control. The study focuses on demonstrating that the new control material performs equivalently and reliably to the predicate controls for monitoring the precision of the HE4 EIA assay.

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria and reported performance relate to the value assignment process for the control materials. The key performance indicators are related to the precision and stability of the control material when assayed with the HE4 EIA kit.

Note: The document describes the methodology for establishing the assigned values and ranges for the new controls, rather than presenting a direct "results" table showing statistical verification of each acceptance criterion post-study. The implication is that the study was conducted to meet these criteria. The "Target HE4 Concentrations" for the new device (75 and 500 pM) are different from the predicate (50 and 400 pM), which is explicitly stated as acceptable since the HE4 EIA range is 15-900 pM.

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

For value assignment of the Fujirebio Diagnostics Tumor Marker Control (K101809):

• Sample Size: 24 replicate analyses.
• Data Provenance: The replicates were collected in 4 independent runs, using "Different HE4 EIA kit reagent combinations in each run." The country of origin is not specified but implicitly Fujirebio Diagnostics, Inc. (Malvern, PA, USA is the submitter). The data is prospective as it was generated specifically for this submission.

For value assignment of the Predicate HE4 EIA kit controls (K072939):

• Sample Size: 26 replicate analyses.
• Data Provenance: Collected in 2 independent runs, using the "Same HE4 EIA kit reagent combination in each run." The country of origin is not specified.

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

This question is not applicable in the traditional sense for a control material. The "ground truth" for a control material is its assigned value, which is established through rigorous laboratory testing and statistical analysis, not expert interpretation of diagnostic images or clinical scenarios. The "experts" involved would be the laboratory scientists and statisticians who designed and executed the value assignment studies according to established protocols. Their specific number and qualifications are not detailed in this summary.

4. Adjudication method for the test set

This question is not applicable. Adjudication methods (like 2+1 or 3+1) are used to resolve discrepancies in expert interpretations (e.g., in medical image analysis). For a control material's value assignment, the "adjudication" is inherent in the statistical methods used to calculate the mean and standard deviation from replicate analyses, and the predefined criteria for acceptance (e.g., CV% limits, mean falling within ±2SD).

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

This question is not applicable. An MRMC comparative effectiveness study involving human readers and AI assistance is relevant for diagnostic devices that aid human interpretation. This submission is for a quality control material which does not involve human readers interpreting clinical cases or AI.

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

This question is not applicable. This is a control material, not a diagnostic algorithm. Its "performance" is in its ability to reliably produce expected results within defined ranges when tested with the HE4 EIA assay.

7. The type of ground truth used

For a control material, the "ground truth" is its assigned value and accepted range for HE4 concentration, established through a rigorous laboratory testing procedure outlined in item #2 and #9. This is not expert consensus, pathology, or outcomes data, but rather a derived value based on analytical measurements using a validated assay.

8. The sample size for the training set

This concept is not applicable for a control material. There is no "training set" in the context of machine learning or diagnostic algorithm development. The data described in section #2 for value assignment is analogous to characterization data for the control material itself.

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

This question is not applicable for a control material as there is no "training set." The "ground truth" (assigned values and ranges) for the control materials (both the new and predicate) was established through the following methods as described in the "Value Assignment comparisons" section:

• Fujirebio Diagnostics Tumor Marker Control (K101809):

  • 24 replicate analyses collected in 4 independent runs.
  • Different HE4 EIA kit reagent combinations were used in each run.
  • Criteria for value assignment: CV < 8% within run, and the mean value for each run had to be within ± 2SD for the other 3 runs.
  • Assigned range for Control Level 1: Total Mean ± 2SD, but not less than ± 30%.
  • Assigned range for Control Level 2: Total Mean ± 2SD, but not less than ± 25%.

• Predicate HE4 EIA kit controls (K072939):

  • 26 replicate analyses collected in 2 independent runs.
  • The same HE4 EIA kit reagent combination was used in each run.
  • Criteria for value assignment: Total CV% ≤ 5.
  • Assigned range for Control Level 1: Total Mean ± 30%.
  • Assigned range for Control Level 2: Total Mean ± 20%.

In summary, the study validates a laboratory control material, not a diagnostic algorithm. The "acceptance criteria" and "study" revolve around demonstrating the analytical performance and stability of the control material to ensure it accurately monitors the precision of the HE4 EIA assay.

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The ARCHITECT HE4 assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of HE4 antigen in human serum. The assay is to be used as an aid in monitoring recurrence or progressive disease in patients with epithelial ovarian cancer. Serial testing for patient HE4 assay values should be used in conjunction with other clinical methods used for monitoring ovarian cancer.

The ARCHITECT HE4 Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of HE4 antigen in human serum.

The ARCHITECT HE4 Controls are used for the verification of the accuracy and precision of the ARCHITECT i System when used for the quantitative determination of HE4 antigen in human serum.

The ARCHITECT HE4 assay is a two-step immunoassay for the quantitative determination of HE4 antigen in human serum using CMIA technology with flexible assay protocols, referred to as Chemiflex.

In the first step, sample and 2H5 anti-HE4 coated paramagnetic microparticles are combined. HE4 antigen present in the sample binds to the anti-HE4 coated microparticles. After washing, 3D8 anti-HE4 acridinium-labeled conjugate is added to create a reaction mixture in the second step. Following another wash cycle, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs).

A direct relationship exists between the amount of HE4 antigen in the sample and the RLUs detected by the ARCHITECT i System optics.

The ARCHITECT HE4 Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of HE4 antigen in human serum.

The ARCHITECT HE4 Controls are used for the verification of the accuracy and precision of the ARCHITECT i System when used for the quantitative determination of HE4 antigen in human serum.

Here's a summary of the acceptance criteria and the studies that demonstrate the ARCHITECT HE4 Assay meets those criteria, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Method Comparison: 193 serum specimens. Data provenance is not explicitly stated (e.g., country of origin) but implies a clinical laboratory setting for comparison with a commercially available EIA. The study compared the new device against an existing, commercially available HE4 EIA.
• Precision: Not explicitly an independent "test set" in the common sense, but involved assays of controls and panels. Performed at Fujirebio Diagnostics, Inc. and two external sites.
• Linearity: Samples prepared by mixing serum panels.
• Sensitivity (LoB, LoD, LoQ): One zero-level HE4 sample and four low-level HE4 samples.
• Specificity: Not explicitly a patient "test set". Tumor markers were prepared with ARCHITECT HE4 Calibrator A.
• Interference: Sera containing therapeutic agents and endogenous substances (concentration details provided), and clinical specimens positive for HAMA (6 specimens) and Rheumatoid Factor (6 specimens).
• Monitoring of Disease Status: 76 patients, resulting in 430 pairs of observations (serial samples, average 6.7 observations per patient). Data provenance is not explicitly stated (e.g., country of origin, retrospective/prospective). This appears to be a retrospective analysis of serial samples.

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

The document does not explicitly state the number or qualifications of experts used to establish ground truth for any of the studies, particularly for clinical disease progression. For the "Monitoring of Disease Status" study, "changes in disease status" are mentioned, implying a clinical assessment, but the method for determining disease progression or lack thereof (e.g., imaging, pathology, clinical criteria) and who made these assessments is not detailed.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method for establishing ground truth for any of the test sets. For the "Monitoring of Disease Status" study, while "changes in disease status" were used as a reference, the process by which this status was determined (e.g., consensus, single expert, independent review) is not provided.

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

There is no mention of a multi-reader multi-case (MRMC) comparative effectiveness study in the provided text. The device is an immunoassay for quantitative determination of a biomarker, not an imaging device or diagnostic tool that typically involves human interpretation. Therefore, a study comparing human readers with and without AI assistance is not applicable here.

6. Standalone Performance Study

The reported performance characteristics (Method Comparison, Precision, Linearity, Sensitivity, Specificity, Interference) are all standalone (algorithm only) performance studies of the ARCHITECT HE4 assay. These evaluate the analytical performance of the device without human interpretation in the loop, focusing on its ability to accurately measure HE4 antigen levels. The "Monitoring of Disease status" study also represents the standalone performance of the assay in classifying disease changes based on a defined threshold.

7. Type of Ground Truth Used

• Method Comparison: The ground truth was the results from a "commercially available HE4 EIA" (the predicate device, HE4 EIA K072939).
• Precision, Linearity, Sensitivity, Specificity, Interference: The ground truth was based on established analytical standards, spiked samples, or reference materials with known concentrations. For example, "zero-level HE4 sample," "four low-level HE4 samples," "tumor markers prepared with ARCHITECT HE4 Calibrator A," and "sera containing therapeutic agents and endogenous substances at indicated interferent concentrations."
• Monitoring of Disease Status: The ground truth was "changes in disease status" in patients with epithelial ovarian cancer. While not explicitly defined, this would typically involve a combination of clinical assessments, imaging (e.g., CT scans, MRI), and potentially other tumor markers or biopsy results, as determined by clinicians.

8. Sample Size for the Training Set

The document does not specify a training set for the ARCHITECT HE4 assay. This is typical for an immunoassay that operates based on a physically determined chemical reaction and a calibration curve, rather than a machine learning algorithm that requires a separate training phase. The device is calibrated using ARCHITECT HE4 Calibrators, which serve a similar function to a training set by defining the assay's response curve, but are distinct from data used to train a predictive algorithm.

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

As no explicit "training set" in the machine learning sense is described, this question is not directly applicable. For the calibrators (which functionally serve to "train" or calibrate the instrument), their values would be established through a rigorous process of manufacturing, characterization, and validation against reference standards by the manufacturer (Fujirebio Diagnostics, Inc.), ensuring accurate assignment of HE4 concentrations to each calibrator level.

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The HE4 EIA is an enzyme immunometric assay for the quantitative determination of HE4 in human serum. The assay is to be used as an aid in monitoring recurrence or progressive disease in patients with epithelial ovarian cancer. Serial testing for patient HE4 assay values should be used in conjunction with other clinical methods used for monitoring ovarian cancer.

The HE4 EIA is a solid-phase, non-competitive immunoassay based upon the direct sandwich technique based on two mouse monoclonal antibodies, 2H5 and 3D8, directed against two epitopes in the C-WFDC domain of HE4. Calibrators, controls and patient samples are incubated together with biotinylated Anti-HE4 monoclonal antibody (MAb) 2H5 in streptavidin coated microstrips. HE4 present in calibrators or samples is adsorbed to the streptavidin coated microstrips by the biotinylated Anti-HE4 MAb during the incubation. The strips are then washed and incubated with HRP labeled Anti-HE4 MAb 3D8. After washing, buffered Substrate/Chromogen reagent (hydrogen peroxide and 3, 3', 5' tetra-methyl-benzidine) is added to each well and the enzyme reaction is allowed to proceed. During the enzyme reaction a blue color will develop if antigen is present. The intensity of the color is proportionate to the amount of HE4 present in the samples. The color intensity is determined in a microplate spectrophotometer at 620 nm (or optionally at 405 nm after addition of Stop Solution). Calibration curves are constructed for each assay by plotting absorbance value versus the concentration for each calibrator. The HE4 concentrations of patient samples are then read from the calibration curve.

The provided text describes the HE4 EIA Kit, its intended use, and performance characteristics for monitoring epithelial ovarian cancer. Here's a breakdown of the information requested:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" for clinical performance. Instead, it presents the results of a study and lists sensitivity and specificity at various percent changes in HE4 concentration. The study aimed to demonstrate the device's effectiveness as an aid in monitoring recurrence or progressive disease. For the purpose of this table, I will present the reported performance at a 25% change in HE4 concentration, as this was the change used in the main 2x2 table and discussed in the text. Other performance characteristics are listed as "The HE4 EIA Kit precision is ≤ 15% total CV," etc. which can be considered performance goals or criteria.

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

• Sample Size for Test Set: 80 patients, contributing to a total of 354 pairs of observations (mean of 4.4 observations per patient).
• Data Provenance: Not explicitly stated (e.g., country of origin). The study appears to be retrospective based on "serial serum samples" from patients, but this is not explicitly confirmed as prospective or retrospective.

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

The document does not specify the number of experts used or their qualifications for establishing the ground truth ("change in disease status"). It simply refers to "disease status."

4. Adjudication Method for the Test Set

The document does not specify an adjudication method (e.g. 2+1, 3+1, none) for determining the ground truth for the test set.

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

This is an immunoassay device, not an imaging or diagnostic device involving human "readers" or AI assistance in the way an MRMC study would typically evaluate. Therefore, no MRMC comparative effectiveness study involving human readers with or without AI assistance was performed or is applicable here. The study compares the device's output to "disease status."

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

Yes, the performance characteristics and monitoring study described are for the device (HE4 EIA Kit) in a standalone capacity, i.e., without a human-in-the-loop performance evaluation in the context of its primary monitoring function. The "Intended Use" states it should be used "in conjunction with other clinical methods," implying it is an aid to a physician's overall assessment, but the performance data presented is for the assay itself.

7. The Type of Ground Truth Used

The ground truth used was "changes in disease status" for ovarian cancer patients. The method for determining "disease status" is not explicitly defined (e.g., pathology, clinical follow-up, imaging results, outcomes data), but it is implied to be a clinical assessment.

8. The Sample Size for the Training Set

The document does not specify a separate "training set" or sample size for training. This is an immunoassay kit, where "training" typically refers to the development and optimization of the assay itself (e.g., antibody selection, reagent concentrations), which is not detailed in terms of patient sample sizes. The performance studies described appear to be validation or verification studies.

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

As no explicit "training set" with associated ground truth is mentioned in the context of machine learning or algorithm development, this information is not applicable or provided. The ground truth for the performance studies (test set) was based on "changes in disease status," as described in point 7.

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