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510(k) Data Aggregation
(105 days)
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
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Analytical Sensitivity (Detection Limit) | 1.3 ng/mL |
| Linearity/Assay Range | 90 – 897 ng/mL |
| Intra-assay Precision (n=80) | 4.3 %CV (throughout assay range) |
| Inter-assay Precision (n=20) | 6.3 %CV to 8.7 %CV (throughout assay range) |
| Interfering Substances | No appreciable interference from: - 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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(155 days)
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.
| Characteristic | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Analytical Performance | ||
| Analytical Sensitivity (Detection Limit) | A low detection limit suitable for intended use. | 1.2 ng/mL |
| Linearity (Dilution) | Percent recovery close to 100%. | Average recovery of 104% (range 133-1310 ng/mL) |
| Linearity (Dilution) | Percent recovery close to 100%. | Average recovery of 104% (range 79-982 ng/mL) |
| Antigen Recovery | Mean recovery close to 100% (with an acceptable range). | Mean recovery of 109% (range 97-119%) |
| Interfering Substances | No appreciable interference from common endogenous substances. | No appreciable interference for hemoglobin, triglycerides, cholesterol, bilirubin, and albumin at specified levels. |
| Precision (Intra-assay) | Low Coefficient of Variation (CV). | < 7% CV (n=80) |
| Precision (Inter-assay) | Low Coefficient of Variation (CV). | < 9% CV (n=20) |
| Clinical Performance | ||
| Prediction of CHD Risk | Statistically significant predictor of CHD risk. | Hazard Ratios (95% CI) demonstrated significance (e.g., Model 3: 1.71 (p=0.029) and 2.12 (p=0.003) for intermediate and highest levels respectively). |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size: 1348 banked EDTA-plasma samples.
- 608 from CHD cases
- 740 from participants free of CHD (controls)
- Data Provenance:
- Country of Origin: Not explicitly stated, but the "Atherosclerosis Risk In Communities (ARIC) Study" sponsored by the National Institutes of Health (NIH) strongly suggests USA.
- Retrospective or Prospective: The study is described as a "case-cohort study" where participants "free of CHD were enrolled and followed for the development of CHD for up to nine years." This indicates a prospective design for patient enrollment and follow-up data collection, with the Lp-PLA2 levels being measured retrospectively on banked samples from this cohort.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not specify the number of experts or their qualifications for establishing the ground truth (CHD diagnosis) for the test set. It states that the clinical data was collected "following a well-designed protocol conducted by qualified experts in a CLIA-certified laboratory" within the ARIC Study. This implies that the diagnosis of CHD and the determination of "free of CHD" were established through the standard clinical protocols and expert medical judgment within the large epidemiological study, rather than a specific expert panel convened solely for this device's ground truth adjudication.
4. Adjudication Method for the Test Set
The document describes the origin of the "ground truth" (CHD cases vs. controls) as being derived from the ARIC Study's follow-up data. It does not mention a specific adjudication method (like 2+1 or 3+1) for the diagnostic outcomes used as ground truth for this device study. The implication is that the diagnoses from the ARIC study are considered the established ground truth.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) test measuring a biomarker (Lp-PLA2) in plasma, not an imaging device or AI algorithm that human readers would interact with. Therefore, there is no "human readers improve with AI vs without AI assistance" component.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, the study presents the standalone performance of the diaDexus PLAC™ Test. The device measures Lp-PLA2 levels in plasma samples, and these levels are then used in statistical models (Cox regression) to predict the risk of CHD. This is an algorithm-only performance in the sense that the test results are generated by the assay (the device) independently, and then interpreted statistically. There is no human-in-the-loop interaction with the device's measurement process.
7. The Type of Ground Truth Used
The ground truth used was outcomes data, specifically the development of Coronary Heart Disease (CHD) over a nine-year follow-up period in participants from the ARIC Study.
8. The Sample Size for the Training Set
The document does not explicitly state a separate training set size for the device's development or the clinical study. The 1348 samples from the ARIC study are used for the clinical validation. It is possible that the assay itself (e.g., antibody selection, assay parameters) was developed using internal samples, but details on a formal training set for the prediction model are not provided. The cut-points (310 and 420 ng/mL) used in the Cox regression analysis were "generated from the ARIC data set," which implies they were derived from the same 1348 samples, suggesting this dataset served as both a development and validation set, or that these cut-points were post-hoc derived from the same studied population based on disease prevalence.
9. How the Ground Truth for the Training Set Was Established
As noted above, a distinct "training set" with separate ground truth establishment is not described. If the ARIC data was used for both deriving cut-points and demonstrating performance, then the ground truth (CHD outcomes) for this dataset was established through the follow-up of participants in the ARIC study for up to nine years, where clinical diagnosis of CHD was determined by "qualified experts in a CLIA-certified laboratory" as part of that large epidemiology study.
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