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The diaDexus PLAC® test is an enzyme immunoassay for the quantitative determination of Lp-PLA2 (lipoprotein-associated phospholipase A2) in human plasma and serum, to be used in conjunction with clinical evaluation and patient risk assessment as an aid in predicting risk for coronary heart disease, and ischemic stroke associated with atherosclerosis.

The diaDexus PLAC® test kit contains Lp-PLA2 calibrators, monoclonal anti-Lp-PLA2 (4B4) antibody conjugated to horseradish peroxidase, monoclonal anti-Lp-PLA2 (2C10) antibody-coated microwell strips with a stripwell frame, various buffers and related reagents, and a package insert. Each stripwell can be used for performing only one set of tests (i.e. single use). One plate may accommodate up to 40 clinical samples when assayed in duplicate. The kit expiration date and storage conditions are indicated on the package.

The diaDexus PLAC® test is based on the standard principle of a sandwich enzyme immunoassay using two specific monoclonal antibodies. A set of LD-PLA2 calibrators is used to plot a standard curve of absorbance (y-axis) versus Lp-PLA2 concentration in ng/mL (x-axis) from which the Lp-PLA2 concentration in the test sample can be determined. The concentration of Lp-PLA2 in each sample and control is then interpolated from the standard curve using a point-to-point curve fit with appropriate calibration curve fitting software.

Here's an analysis of the provided text, focusing on the acceptance criteria and the study proving the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance:

• Total Albumin ~6500 mg/dL
• Bilirubin 20 mg/dL
• Cholesterol 500 mg/dL
• Hemoglobin 1250 mg/dL
• Triglycerides 3000 mg/dL |
  | Intra-assay Precision (n=80) | Low percentage of coefficient of variation (%CV) for within-assay consistency | 4.3 %CV to 6.3 %CV |
  | Total Precision (n=80) | Low percentage of coefficient of variation (%CV) for overall consistency | 5.7 %CV to 11.0 %CV |
  | Correlation with Cleared PLAC Test (r value) | High correlation (r value close to 1) with the predicate device | 0.91 |
  | Correlation with Cleared PLAC Test (slope) | Slope close to 1 for close agreement with the predicate device | 1.02 |

Explanation of "Implied by reported value": The document explicitly states the "Reported Device Performance" but does not set a separate, distinct "Acceptance Criteria" for each analytical metric. Instead, the reported values are presented as the device's performance, implying that these values met the internal and regulatory expectations for the assay's function. For instance, the detection limit of 2.4 ng/mL is the accepted performance for this characteristic. The correlation values of 0.91 for r and 1.02 for slope demonstrate good correlation, implicitly meeting the acceptance criteria for equivalence.

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

• Sample Size for Analytical Performance Tests:
  • Analytical Sensitivity (Detection Limit): 16 replicates of the 0 ng/mL Lp-PLA2 calibrator were used.
  • Precision (Intra-assay and Total): n=80 for each precision study.
  • Interfering Substances: The exact number of samples for each interfering substance test is not explicitly stated, but the tested concentrations are provided.
• Sample Size for Correlation Study: Not explicitly stated, though it refers to "the modified PLAC test compared to the cleared PLAC test."
• Data Provenance: The document does not specify the country of origin for the data. The data appears to be prospective for the analytical studies (precision, sensitivity, linearity, interference) as these are part of the device's original characterization. For the correlation study, it compares the current (modified) device to a previously cleared device, suggesting the data for the modified device was prospectively generated for this comparison.

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

• Not Applicable. This document describes an in vitro diagnostic (IVD) assay for quantitative determination of a biomarker (Lp-PLA2). The "ground truth" for such devices is established by the accuracy of the assay's measurement against known concentrations (calibrators, controls) and its performance characteristics (precision, linearity, sensitivity, interference). It does not involve expert readers establishing ground truth for diagnostic interpretation of images or clinical cases using the device.

4. Adjudication Method (for the test set):

• Not Applicable. As this is an IVD assay measuring a biomarker, there is no expert adjudication method for the analytical performance tests. The "ground truth" for analytical performance relies on accurate measurement technologies, calibrated standards, and statistical methods such as calculating %CV or correlation coefficients.

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 an IVD device, not an AI-assisted diagnostic tool that aids human readers in interpreting clinical cases. Therefore, no MRMC study, human reader improvement analysis, or AI assistance effect size is relevant or presented.

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

• Yes, a standalone performance study was done. The entire "Performance Characteristics - Analytical" section describes the standalone performance of the diaDexus PLAC® test. This includes analytical sensitivity, linearity/assay range, interfering substances, and precision. The "Correlation" section also compares the standalone performance of the modified PLAC test to the cleared PLAC test. The device's function is to quantitatively determine Lp-PLA2 levels, which is a standalone measurement without human-in-the-loop diagnostic interpretation in the assay process itself.

7. The Type of Ground Truth Used:

• The ground truth used for the analytical performance studies (sensitivity, linearity, precision) is based on calibrated standards and controls with known concentrations of Lp-PLA2.
  • For analytical sensitivity, the ground truth is the 0 ng/mL Lp-PLA2 calibrator.
  • For linearity/assay range, the ground truth is established by the known concentrations of calibrators used to plot the standard curve.
  • For interfering substances, the ground truth is the known concentration of Lp-PLA2 in samples spiked with interfering substances compared to control samples.
  • For precision, the ground truth is the expected value of the control samples or patient samples being repeatedly measured.
  • For correlation, the ground truth for comparison is the performance of the legally cleared predicate device (K050523).

8. The Sample Size for the Training Set:

• Not explicitly stated; likely not applicable in the conventional sense of machine learning training sets. This document describes a traditional enzyme immunoassay (EIA), not a machine learning or AI-based diagnostic algorithm that requires a "training set" of data to learn patterns. The "training" in this context refers to the development and refinement of the assay's reagents and protocol to accurately measure Lp-PLA2. The calibrators and controls are used for routine calibration and quality control, not as a training set for an algorithm.

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

• Not Applicable in the conventional sense. As explained above, this is not an AI/ML device. The "ground truth" for developing and validating the assay relies on:
  • Purified recombinant Lp-PLA2 (DDX-RA) characterized for consistency with literature (molecular weight, etc.). This serves as the "true" antigen.
  • Monoclonal anti-Lp-PLA2 antibodies characterized for purity and reactivity to quantitatively and specifically bind the Lp-PLA2 antigen.
  • Known concentrations of Lp-PLA2 calibrators prepared to establish the standard curve.
  • Quality control materials with defined concentrations to monitor assay performance.

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The diaDexus PLAC™ test is an enzyme immunoassay for the quantitative determination of Lp-PLA2 (lipoprotein-associated phospholipase A2) in human plasma, to be used in conjunction with clinical evaluation and patient risk assessment as an aid in predicting risk for coronary heart disease, and ischemic stroke associated with atherosclerosis.

The diaDexus PLAC™ test kit contains Lp-PLA2 calibrators, monoclonal anti-Lp-PLA2 (4B4) antibody conjugated to horseradish peroxidase, monoclonal anti-Lp-PLA2 (2C10) antibodycoated microwell strips with a stripwell frame, various buffers and related reagents, and a package insert. Each stripwell can be used for performing only one set of tests (i.e. single use). One plate may accommodate up to 40 clinical samples when assayed in duplicate. The kit expiration date and storage conditions are indicated on the package.

The diaDexus PLAC™ test is based on the standard principle of a sandwich enzyme immunoassay using two specific monoclonal antibodies. A set of Lp-PLA2 calibrators is used to plot a standard curve of absorbance (y-axis) versus Lp-PLA2 concentration in ng/mL (x-axis) from which the Lp-PLA2 concentration in the test sample can be determined. The concentration of Lp-PLA2 in each sample and control is then interpolated from the standard curve using a point-to-point curve fit with appropriate calibration curve fitting software.

Here's a breakdown of the acceptance criteria and the study details for the diaDexus PLAC™ Test, based on the provided text:

Acceptance Criteria and Device Performance

• Hemoglobin (500 mg/dL)
• Triglycerides (3,000 mg/dL)
• Cholesterol (500 mg/dL)
• Bilirubin (20 mg/dL)
• Albumin (6.2 g/dL)
• Aspirin (50 mg/dL)
• Tylenol® (20 mg/dL)
• Vitamin C (50 mg/dL)
• Benadryl® (50 mg/dL)
• Orinase (100 mg/dL)
• Pravachol® (446 µg/dL) |

Study Information

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

• Test Set Sample Size: 956 banked EDTA-plasma samples.
  • 194 cases (subsequently suffered an ischemic stroke)
  • 762 controls (stroke-free at time of censor)
• Data Provenance:
  • Country of Origin: United States.
  • Type: Retrospective (banked samples from a large, multi-center, observational epidemiology study sponsored by the National Institutes of Health's National Heart, Lung, and Blood Institute - the ARIC study).

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

• The document states that "stroke... was defined by the ARIC investigators." It does not specify the number of experts or their specific qualifications beyond "qualified experts" generally overseeing the study.

4. Adjudication Method for the Test Set:

• The document does not specify a formal adjudication method (e.g., 2+1, 3+1). The ground truth for stroke events was "defined by the ARIC investigators," implying established diagnostic criteria within that study.

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 performed. This study focuses on the standalone performance of the diagnostic test (Lp-PLA2 levels) as a predictor.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:

• Yes, a standalone performance study was done. The clinical study evaluated the association of Lp-PLA2 levels (measured by the test) with the risk of ischemic stroke, independently of human interpretation of the test results for individual patient diagnosis. The test itself is an enzyme immunoassay, providing a quantitative value.

7. The Type of Ground Truth Used:

• Outcomes Data: The ground truth was based on documented clinical outcomes: whether participants subsequently suffered an ischemic stroke as defined by the ARIC investigators.

8. The Sample Size for the Training Set:

• The document does not specify a separate training set size for the clinical study. The 956 samples appear to be the "test set" used to evaluate the association between Lp-PLA2 levels and stroke outcomes. For the analytical characterization, various sample sizes (e.g., n=80 for intra-assay precision, n=20 for inter-assay precision) were used for establishing performance characteristics like precision, linearity, and sensitivity, but these are for analytical validation rather than a "training set" in the machine learning sense.

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

• As a distinct "training set" is not explicitly mentioned for the clinical validation of the predictive capability in the context of the provided text, information on how its ground truth was established is not available. The "ground truth" for the main clinical study (which could be considered a "test set" for the prediction model) was established by the ARIC investigators' definition of ischemic stroke as an outcome.

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The diaDexus PLAC™ test is an enzyme immunoassay for the quantitative determination of Lp-PLA2 (lipoprotein - associated phospholipase A2) in human plasma, to be used in conjunction with clinical evaluation and patient risk assessment as an aid in predicting risk for coronary heart disease.

Not Found

This is a 510(k) premarket notification for an in vitro diagnostic device, the diaDexus PLAC™ test, which is an enzyme immunoassay. The information provided in the document focuses on the regulatory aspects of the device's clearance and does not contain the details requested about acceptance criteria, study methodologies, sample sizes, ground truth establishment, or expert involvement for a clinical study proving device performance.

The document states that the FDA has determined the device is "substantially equivalent" to legally marketed predicate devices. This determination typically relies on demonstrating that the new device has the same intended use and technological characteristics as a predicate device, or if there are differences, that those differences do not raise new questions of safety and effectiveness.

Therefore, I cannot provide the requested information based on the provided text. The document is a regulatory clearance letter, not a clinical study report.

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The diaDexus PLAC™ test is an enzyme immunoassay for the quantitative determination of Lp-PLA2 (lipoprotein-associated phospholipase A2) in human plasma, to be used in conjunction with clinical evaluation and patient risk assessment as an aid in predicting risk for coronary heart disease.

The diaDexus PLAC™ test is based on the principle of a sandwich enzyme immunoassay using two specific monoclonal antibodies. The assay system utilizes monoclonal anti-Lo-PLA2 antibody (2C10) for solid phase immobilization on the microtiter stripwells. The test sample is first diluted with the sample diluent and incubated at 2-8°C for 60 minutes. The diluted test sample is then allowed to react with the immobilized monoclonal antibody at 2-8°C for 90 minutes. The wells are washed with distilled water to remove any unbound antigen. A second monoclonal anti-Lo-PLA2 antibody (4B4) labeled with the enzyme horseradish peroxidase (HRP) is then added and reacted with the immobilized antigen at 2-8℃ for 60 minutes, resulting in the Lp-PLA2 molecules being captured between the solid phase and the enzyme-labeled antibodies. The wells are washed with distilled water to remove unbound labeled antibodies. The substrate, tetramethylbenzidine (TMB). is then added and incubated at 2-8°C for 20 minutes resulting in the development of a blue color. Color development is stopped with the addition of Stop Solution (1N HCl), changing the color to yellow. The absorbance of the enzymatic turnover of the substrate is determined spectrophotometrically at 450 nm using a standard microplate reader and is directly proportional to the concentration of Lp-PLA2 present. A set of Lp-PLA2 calibrators is used to plot a standard curve of absorbance (v-axis) versus Lp-PLA2 concentration in ng/mL (x-axis) from which the Lp-PLA2 concentration in the test sample can be interpolated. The standard curve is constructed using a point-to-point curve fit manually or by using appropriate calibration curve fitting software.

Here's an analysis of the diaDexus PLAC™ Test based on the provided text, addressing your specific questions:

Acceptance Criteria and Device Performance Study for diaDexus PLAC™ Test

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for the analytical performance characteristics. Instead, it presents the results of these performance tests as factual observations. For the clinical performance, the acceptance criteria are implicitly defined by demonstrating a statistically significant association between Lp-PLA2 and CHD risk across different models.

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