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The Lumipulse G B-Amyloid Ratio (1-42/1-40) is an in vitro cerebral spinal fluid (CSF) test that combines the results of Lumipulse G B-Amyloid 1-42 and Lumipulse & B-Amyloid 1-40 assays into a ratio of ß-amyloid 1-42 to ß-amyloid 1-40 concentrations using the LUMIPULSE G 1200 System. The Lumipulse G B-Amyloid Ratio (1-42/1-40) is intended to be used in adult patients, aged 55 years and older, presenting with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive decline.

A test result ≥ 0.073 is a negative result which is consistent with a negative amyloid positron emission tomography (PET) scan result. A negative result reduces the likelihood that a patient's cognitive impairment is due to AD.

A test result ≤ 0.058 is a positive result which is consistent with a positive amyloid PET scan result. A positive result does not establish a diagnosis of AD or other cognitive disorder.

A test result between 0.059 and 0.072 is considered as a likely positive result as it is more likely consistent with a positive amyloid PET scan result. A likely positive result does not establish a diagnosis of AD or other cognitive disorders and has increased uncertainty in regard to amyloid PET positivity.

The Lumipulse G B-Amyloid Ratio (1-42/1-40) results must be interpreted in conjunction with other patient clinical information .

This test is not intended as a screening or stand-alone diagnostic test.

The Lumipulse G B-Amyloid Ratio (1-42/1-40) is an in vitro cerebral spinal fluid (CSF) test that calculates the ratio of two analytes, Lumipulse G ß-Amyloid 1-42 and Lumipulse & ß-Amyloid 1-40 assays to generate a numeric value between 0.001 to 1.000.

The test system consists of two component assays, Lumipulse & ß-Amyloid 1-42 and the Lumipulse G B-Amyloid 1-40 assay, running on LUMIPULSE G1200 system, and Lumipulse G B-Amyloid Ratio (1-42/1-40) Calculator Tool to calculate the Lumipulse G B-Amyloid Ratio (1-42/1-40). Lumipulse G B-Amyloid 1-42 and the Lumipulse G B-Amyloid 1-40 assays are packed individually. Results of individual assays have not been assessed to support the intended use except for determination of the Lumipulse G ß-Amyloid Ratio (1-42/1-40).

Acceptance Criteria and Device Performance for Lumipulse G ß-Amyloid Ratio (1-42/1-40)

This document describes the acceptance criteria and the study demonstrating the performance of the Lumipulse G ß-Amyloid Ratio (1-42/1-40) device.

1. Acceptance Criteria and Reported Device Performance

The core of the device's utility lies in its ability to predict amyloid PET scan results. The acceptance criteria and reported performance relate to the predictive values of the test for classifying patients as PET positive, likely positive, or negative.

Note on "Predictive Value for Negative Result (Ratio ≥ 0.073) for PET positivity": The table in the provided text for "Clinical Performance" presents the "Predictive Value %" as (Positive (n) / N), where N is the total for that Lumipulse G B-Amyloid Ratio category. Therefore, for the "Negative" category, "16.1% (15/93)" means that out of 93 patients with a negative Lumipulse G B-Amyloid Ratio, 15 (16.1%) were actually PET positive. This implicitly means that 93 - 15 = 78 (83.9%) were indeed PET negative when the Lumipulse test was negative.

2. Sample Size for Test Set and Data Provenance

• Sample Size for Test Set: 292 patients.
• Data Provenance: The data for the clinical performance study (test set) was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) sample bank.
  • Country of Origin: Not explicitly stated, but ADNI is a large-scale North American-based research study.
  • Retrospective or Prospective: The study utilized "banked CSF samples," indicating a retrospective approach to sample collection for the purpose of this device's validation. However, the PET evaluation was conducted, and the time interval between CSF sampling and PET evaluation was analyzed, suggesting that while samples were banked, their correlation to PET was part of the study design.

3. Number of Experts and Qualifications for Ground Truth

• Number of Experts: A minimum of three trained independent readers.
• Qualifications of Experts: The experts were "trained independent readers" who were blinded to all other clinical data. Their specific professional qualifications (e.g., radiologist, neurologist) or years of experience are not explicitly stated in the provided text.

4. Adjudication Method for the Test Set

• Adjudication Method: 2+1 adjudication method. The amyloid PET status for each patient was determined by a minimum of three trained independent readers. If the first two readers disagreed, an adjudicator's reading was used.

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

• Was an MRMC comparative effectiveness study done? No, the provided text does not describe an MRMC comparative effectiveness study comparing human readers with AI assistance versus human readers without AI assistance (i.e., the effect size of how much human readers improve with AI vs without AI assistance). The device is an in-vitro diagnostic (IVD) assay that produces a numerical ratio result, not an AI assisting human image interpretation.

6. Standalone Performance Study

• Was a standalone (algorithm only without human-in-the loop performance) done? Yes, the clinical performance study evaluates the performance of the Lumipulse G B-Amyloid Ratio (1-42/1-40) device in isolation against the ground truth (visual amyloid PET read). The device generates a numerical ratio which is then categorized (positive, likely positive, negative) and compared directly to the PET results, without direct human intervention in interpreting the device's output or integrating it into a diagnostic workflow with human readers.

7. Type of Ground Truth Used

• Type of Ground Truth: The ground truth used was visual amyloid PET scan results. This was determined by "Florbetapir (18F) PET evaluation," with images analyzed by visual read and scored as either amyloid PET positive or amyloid PET negative by trained independent readers with adjudication.

8. Sample Size for the Training Set

• Sample Size for Training Set: 235 patients were used to determine the assay cutoff. This group was from the Amsterdam Dementia Cohort (ADC). It is important to note that this was explicitly stated as "distinct from the subjects ... evaluated in the pivotal clinical validation study (test set)."

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

• How Ground Truth for Training Set was Established: For the 235 patients from the Amsterdam Dementia Cohort (ADC) used to determine the assay cutoff, the ground truth was visual amyloid PET scan status.
  • PET Tracers Used: Florbetaben (18F), Florbetapir (18F), and Flutemetamol (18F).
  • Interpretation: Images were analyzed by visual read and scored as either amyloid PET positive or amyloid PET negative.
  • Protocol: CSF collection, processing, and handling were conducted according to a "standardized ADC protocol." A "pre-analytical bridging study was conducted using fresh prospectively collected individual CSF samples" to account for variations between ADC and ADNI protocols.

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Lumipulse® G Risk of Ovarian Malignancy Algorithm (ROMA®) is a qualitative serum and plasma (lithium heparin or dipotassium EDTA) test that combines the results of Lumipulse G CA 1251 and menopausal status into a numerical score.

Lumipulse G ROMA is intended to aid in assessing whether a premenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy on surgery. Lumipulse G ROMA is indicated for women who meet the following criteria: over age 18; ovarian adnexal mass present for which surgery is planned, and not yet referred to an oncologist. Lumipulse G ROMA must be interpreted in conjunction with an independent clinical and radiological assessment. The test is not intended as a screening or stand-alone diagnostic assay.

PRECAUTION: Lumipulse G ROMA should not be used without an independent clinical /radiological evaluation and is not intended to be a screening test or to determine whether a patient should proceed to surgery. Incorrect use of Lumipulse G ROMA carries the risk of unnecessary testing, surgery, and/or delayed diagnosis.

Lumipulse GROMA is a qualitative serum and plasma test that combines the results of 2 analytes, HE4 (Lumipulse G HE4) and CA125 (Lumipulse G CA 125 II) and menopausal status into a numerical score between 0.00 and 10.00. The premenopausal status must be based on ovarian function determined with information available from clinical evaluation and medical history.

The test system consists of Lumipulse G HE4, Lumipulse G CA 125 II, the Lumipulse G ROMA Calculator Tool and the LUMIPULSE G1200 System. The LUMIPULSE G1200 System is not capable of calculating the ROMA score. The immunoassays are performed according to the directions detailed in each product insert.

Both Lumipulse G HE4 and Lumipulse G CA 125 Il are previously 510(k) cleared Class II devices (K151378 and K142895 respectively). The Lumipulse G HE4 assay is a chemiluminescent enzyme immunoassay (CLEIA) for the quantitative determination of HE4 antigen 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 assay values should be used in conjunction with other clinical methods used for monitoring ovarian cancer. Lumipulse G CA 125 II assay is a chemiluminescent enzyme immunoassay (CLEIA) for the quantitative determination of CA125 in human serum and plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMPULSE G System. The assay is to be used as an aid in monitoring recurrence or progressive disease in patients with ovarian cancer. Serial testing for patient CA125 assay values should be used in conjunction with other clinical methods used for monitoring ovarian cancer.

Lumipulse G ROMA scores (numerical score from 0.00 -10.00) for both premenopausal and postmenopausal women are calculated using the Lumipulse G ROMA Calculator Tool to indicate a low likelihood or high likelihood for finding malignancy on surgery using the value of the 2 immunoassays (Lumipulse G HE4 and Lumipulse G CA125II).

Here’s a summary of the acceptance criteria and the study proving the device meets them, based on the provided FDA 510(k) submission for Lumipulse G ROMA:

1. Table of Acceptance Criteria and Reported Device Performance

The submission does not explicitly state "acceptance criteria" in a quantitative manner for clinical performance in the way usually seen for AI/ML devices (e.g., minimum sensitivity or specificity targets). Instead, it demonstrates substantial equivalence to a predicate device and provides performance metrics (sensitivity, specificity, PPV, NPV) for direct disease detection and adjunctive use with Initial Cancer Risk Assessment (ICRA).

Given that the purpose of the submission is to demonstrate "substantial equivalence" to a predicate device, the implied acceptance criterion for clinical performance is that the Lumipulse G ROMA's performance should be comparable or non-inferior to the predicate device and demonstrate utility for its intended use. For analytical performance, the acceptance criteria are typically met by demonstrating acceptable precision, linearity, analytical specificity, and method comparison to the predicate. The clinical study results presented are the "reported device performance."

Adjunctive Use with ICRA (All Malignancies & LMP):
Combined Premenopausal & Postmenopausal: Sensitivity 88.1%, Specificity 67.5%, PPV 38.3%, NPV 96.1%
(Statistically significant improvement in NPV from 93.1% (ICRA alone) to 96.1% (Adjunctive)). |
| Method Comparison | Strong correlation with the predicate device for both premenopausal and postmenopausal women. | Premenopausal Women (n=53): Correlation Coefficient (r) = 0.9977, Intercept (-0.004), Slope (1.005)
Postmenopausal Women (n=115): Correlation Coefficient (r) = 0.9953, Intercept (-0.103), Slope (0.999) |
| Matrix Comparison | Equivalence between serum and K2 EDTA plasma samples. | Premenopausal (n=86): y= 1.001(x) - 0.072; r=0.9983
Postmenopausal (n=86): y= 1.004(x) - 0.058; r=0.9988 |
| Precision (Lot-to-Lot)| Acceptable %CV for ROMA scores across different lots. | Overall Total %CV for Premenopausal ROMA: 4.6% (Panel 1) to 0.0% (Panel 6)
Overall Total %CV for Postmenopausal ROMA: 2.4% (Panel 1) to 0.1% (Panel 6) |
| Reproducibility (Site-to-Site) | Acceptable %CV for ROMA scores across different sites. | Overall Total %CV for Premenopausal ROMA: 8.1% (Panel 1) to 0.1% (Panel 6)
Overall Total %CV for Postmenopausal ROMA: 5.2% (Panel 1) to 0.2% (Panel 6) |
| Analytical Specificity| Minimal interference from common endogenous interferents. | Mean Percent (%) Difference for all tested interferents (Free Bilirubin, Conjugated Bilirubin, Triglycerides, Hemoglobin, Total Protein, Immunoglobulin G, Biotin, HAMA, Rheumatoid Factor) was within a range of -2% to +1% for both pre- and post-menopausal ROMA scores. |

2. Sample Sizes and Data Provenance for Test Set (Clinical Study)

• Sample Size: A total of 450 women were evaluable in the clinical study test set.
  • Premenopausal: 244
  • Postmenopausal: 206
• Data Provenance: The study was described as a prospective, multi-center, blinded clinical trial. The specific country of origin is not mentioned in the provided text.

3. Number of Experts and Qualifications for Ground Truth (Clinical Study)

• Number of Experts: Not explicitly stated as a count of individual experts.
• Qualifications: "An initial cancer risk assessment (ICRA) was completed by a non-gynecological oncologist". The specific years of experience or board certifications are not provided.
• Ground Truth for Clinical Study: Histopathology reports collected after surgery were the definitive ground truth for malignancy.

4. Adjudication Method for the Test Set

• The text describes the clinical trial as "blinded," implying that those interpreting the Lumipulse G ROMA results were blinded to the initial cancer risk assessment (ICRA) and histopathology, and vice-versa for the ICRA.
• Adjudication Method: Not explicitly detailed beyond the "blinded" nature and the use of histopathology as the definitive truth. There is no mention of a 2+1 or 3+1 type of expert consensus for the initial clinical assessment.

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

• The study evaluated the adjunctive use of Lumipulse G ROMA with Initial Cancer Risk Assessment (ICRA). This is a form of comparative effectiveness study involving human readers (non-gynecological oncologists) with and without the device.
• Effect Size (Improvement with AI vs. without AI assistance):
  • The study showed a statistically significant improvement in the Negative Predictive Value (NPV) when Lumipulse G ROMA was used adjunctively with ICRA.
  • NPV for classifying benign patients into the low likelihood group increased from 93.1% (ICRA alone) to 96.1% (Adjunctive). This represents a 3% absolute increase in NPV.
  • Other metrics for adjunctive use compared to ICRA alone:
    • Sensitivity increased from 72.6% to 88.1%
    • Specificity decreased from 84.2% to 67.5%
    • PPV decreased from 51.3% to 38.3%

6. Standalone (Algorithm Only) Performance

• Yes, a standalone performance was done. The sections titled "Use of Lumipulse G ROMA for stratification into low likelihood and high likelihood groups for finding malignancy on surgery" and "The performance of Lumipulse G ROMA for stratification into low likelihood and high likelihood groups for premenopausal and postmenopausal women with epithelial ovarian cancer (EOC) only" directly present the performance of the Lumipulse G ROMA algorithm in isolation.
• The results are presented for premenopausal and postmenopausal women separately, and for all cancer and LMP tumors combined.

7. Type of Ground Truth Used

• For the clinical study, the definitive ground truth was histopathology reports collected after surgery. This is considered a high-quality, objective ground truth.

8. Sample Size for the Training Set

• The submission does not explicitly mention a separate training set for the Lumipulse G ROMA algorithm itself.
• The ROMA algorithm's equation (Predictive Index for premenopausal and postmenopausal women) and clinical cut-offs (1.31 and 2.77) are identical to the predicate device (ROMA (HE4 EIA + ARCHITECT CA 125 II) K103358). This suggests that the algorithm itself was likely developed and validated previously, and this submission focuses on the performance of the Lumipulse G HE4 and Lumipulse G CA125II assays within the established ROMA framework. The provided study serves as a clinical validation for the proposed device using these specific assays.

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

• Given that the algorithm and its cut-offs appear to be directly adopted from the predicate device and its previous development, the specific details of how the original training set for the ROMA algorithm's ground truth was established are not provided in this document.
• For the assays themselves (Lumipulse G HE4 and CA125II), which are previously cleared devices, their calibration and standardization would have been established against reference materials, but this isn't a "training set" for the algorithm.

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