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The CORA System is intended for in vitro diagnostic use to provide semi-quantitative indications of the hemostasis state of a venous blood sample. The CORA System records the kinetic changes in a venous sample of 3.2% cirrated whole blood as the sample clots, and retracts in real time. The system output consists of a table of numerical values for parameters R, K, Angle, MA, and FLEV.

The CORA System provides specific blood modifiers, in the form of reagents dried-in-place within CORA Cartridges.

Results from the CORA analysis should not be the sole basis for a patient diagnosis, but should be evaluated together with the patient's medical history, the clinical picture and, if necessary, further hemostasis tests.

The indication for CORA System use is with adult patients where an evaluation of their blood hemostasis properties is desired. Hemostasis evaluations are commonly used to assess clinical conditions in cardiology procedures to assess hemorrhage or thrombosis conditions before, during and following the procedure.

The CORA System consists of a four-channel diagnostic analyzer with integrated computer module, system reagents (CK, CRT, CKH, and CFF), and Abnormal Quality Control material and microfluidic test cartridges.

To perform a test, a disposable CORA Cartridge is inserted into the analyzer. Blood or WQC material is added to an entry port on the cartridge and drawn into the cartridge under analyzer control. The amount of the sample drawn into the cartridge is automatically determined by the volume of the blood chambers in the cartridge. Once in the disposable, the sample is metered into as many as four separate analysis channels, depending upon the assays being performed. Reconstitution of reagents dried within the cartridge is accomplished by moving the sample back and forth through reagent chambers, under the control of microfluidic valves and bellows (pumps) within the cartridge. After each sample has been mixed with reagent, it is delivered to a test cell where it is monitored for visco-elastic changes due to coagulation. Excess sample material is moved under microfluidic control into an enclosed waste chamber within the cartridge.

The CORA technology is based on a disposable containing up to four independent measurement cells. Each cell consists of a short vertically-oriented injection molded tube (ring) with a diameter of 2.5mm and a length of 4.5mm. Detection of clotting in the CORA System is performed optically. Under control of the analyzer, approximately 20ul of prepared sample is delivered to the tube, where a meniscus naturally forms at each end of the tube. The tube is positioned so that the lower meniscus partially blocks light traveling from a collimated source toward a photodiode.

During testing, a piezoelectric actuator drives the measurement cell(s) through a motion profile composed of summed sinusoids at different frequencies. The profile has a maximum amplitude of under 10um and contains frequencies from 10-500Hz. Some, but not all, of the measurement cell motion will induce motion in the sample meniscus, which will be detected by the photodiode. The resulting motion of the meniscus is monitored optically and recorded by the analyzer to calculate the resonant frequency and modulus of elasticity (stiffness) of the sample. By performing a Fast Fourier Transform (FFT) on meniscus motion data, it is possible to determine the frequencies of input motion that caused the greatest deflection of the sample (these are called the resonant frequencies).

Here's an analysis of the acceptance criteria and study details for the CORA® (Coagulation Resonance Analysis) System, based on the provided text:

Important Note: The provided text is a 510(k) summary, which focuses on demonstrating substantial equivalence to a predicate device. It typically does not contain explicit "acceptance criteria" for performance in the same way a clinical trial protocol would. Instead, it demonstrates performance that aligns with a predicate device and adheres to established analytical performance guidelines (like CLSI standards). The "acceptance criteria" as presented below are inferred from the demonstrated performance and the context of regulatory submission for a device of this type.

1. Table of Acceptance Criteria and Reported Device Performance

Given the nature of the submission (510(k) summary), the "acceptance criteria" are implied by the precision limits set and met, and the acceptable agreement with the predicate device.

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

• Analytical Precision:

  • Normal Donors (original study): Blood draws from 3 donors (1 Hypo, 1 Normal, 1 Hyper) across 5 non-consecutive days, by 2 operators, using 3 reagent lots and 12 analyzers. Each test had 2 replicates. This results in 120 measurements for each parameter per level (Hypo, Normal, Hyper).
  • Spiked Samples (supplemental study): 3 donors for each reagent-parameter and spiking type (hypocoagulable, hypercoagulable). For each donor-reagent-parameter-hypo/hyper type, there were 12 outcomes (combinations of 3 operators, 3 reagent lots, 12 instruments, 2 replicates per instrument).
  • Anticoagulant Patients (supplemental study): 4 Dabigatran patients and 2 Warfarin patients for each reagent-parameter. 12 outcomes for each patient-reagent-parameter.
  • Data Provenance: Not explicitly stated, but performed in Coramed's laboratory. Given it's a US company, it's likely US-derived. This is a retrospective analysis of laboratory test samples.

• Reference Ranges:

  • Sample Size: Up to 55 normal volunteer subjects from each of three sites, totaling 157 samples. At least 151 valid results for every parameter for all reagents.
  • Data Provenance: Three clinical sites. Subjects chosen to represent demographic populations of these three areas (age, race, gender). This is a prospective study from normal volunteers.

• Method Comparison:

  • Sample Size: Not explicitly stated as a single number but conducted at three clinical sites on patient samples. Up to 10% contrived samples were added to broaden the comparison range.
  • Data Provenance: Three clinical sites: Mayo Clinic, University of Pittsburgh Medical Center, and Sinai Hospital, Baltimore. Subjects were patients undergoing cardiovascular surgery or cardiology procedures, with blood samples drawn pre- and post-surgery and in the ICU. This is a prospective study from clinical patients, with some contrived samples.

• Reader Study:

  • Sample Size: 30 test outcomes compared for each reagent test category (e.g., CK, CKH, CRT, CFF).
  • Data Provenance: Three sites.

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

• Analytical Precision, Linearity, Sensitivity & Specificity, Heparin Neutralization: The ground truth for these analytical studies is based on the known concentrations/conditions of the samples (e.g., spiked samples, known interferents) and laboratory measurements. No human "experts" established ground truth in the interpretative sense.

• Reference Ranges: Ground truth is established by obtaining samples from "normal volunteer subjects" and excluding outliers based on standard criteria. There is no mention of "experts" establishing a ground truth for individual samples.

• Method Comparison: Ground truth is the results obtained from the predicate TEG 5000 device.

• Reader Study:

  • Number of Experts: Nine readers (three experienced TEG 5000 doctors at each of the three sites).
  • Qualifications: "Experienced TEG 5000 doctors." Specific years of experience or board certification are not detailed.

4. Adjudication Method for the Test Set

• Analytical Precision, Linearity, Sensitivity & Specificity, Heparin Neutralization, Reference Ranges, Method Comparison: No adjudication method is described as these are quantitative analytical studies or comparisons to a predicate device. Ground truth is either inherent in the sample preparation or derived from the predicate device's measurements.

• Reader Study: No explicit adjudication method (e.g., 2+1, 3+1) is described. The study assessed "agreement between the two devices" based on the doctors' readings of both device outputs. It implies that the TEG 5000 reading was considered the reference for comparison, but not necessarily an adjudicated ground truth in the sense of multiple experts independently labeling cases and resolving discrepancies.

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

• Was an MRMC study done? Yes, a "Reader Study" was conducted, which has elements of an MRMC study in that it involved multiple readers and multiple cases.

• Effect Size of Human Readers Improve with AI vs. Without AI Assistance: This information is not applicable and not provided in the document. The CORA System is a diagnostic instrument that provides "semi-quantitative indications of the hemostasis state," similar to the predicate TEG 5000. It does not incorporate AI nor does it aim to "assist" human readers in interpreting complex images or deriving diagnoses. It measures parameters directly; the "Reader Study" was about comparing the readings of the outputs from the CORA System to the predicate TEG 5000, not about human performance with/without AI assistance.

6. Standalone Performance (Algorithm only without human-in-the-loop performance)

• Was a standalone performance study done? Yes, the entire set of analytical performance studies (Analytical Precision, Interference, Linearity, Sensitivity and Specificity, Heparin Neutralization) and the Method Comparison study effectively represent standalone (algorithm only) performance. The CORA System generates numerical outputs (R, K, Angle, MA, FLEV) directly. The human "reader" in the "Reader Study" is interpreting the output of the device, not interacting with an algorithm to refine a diagnosis. Therefore, the core function of the device is standalone.

7. Type of Ground Truth Used

• Analytical Precision, Interference, Linearity, Sensitivity and Specificity, Heparin Neutralization: Ground truth was established by known sample properties (e.g., spiked concentrations of substances, known degrees of hemodilution) or through controlled laboratory measurements.
• Reference Ranges: Ground truth was established by samples from "normal volunteer subjects", with outliers removed using standard statistical criteria.
• Method Comparison: Ground truth was the predicate device (TEG 5000) measurements. This is a common approach in 510(k) submissions to demonstrate equivalence.
• Reader Study: Ground truth was readings from the predicate device (TEG 5000) outcomes by experienced clinicians, to which the CORA System's outcomes were compared. It's essentially a comparison of the device outputs' interpretability.

8. Sample Size for the Training Set

The document does not explicitly describe a "training set" for an AI/algorithm in the conventional sense. The CORA System is a measurement device that senses physical changes and calculates parameters. The development of its algorithms (how it analyzes frequency data to provide parameters) would have involved extensive engineering and potentially iterative testing, but this is distinct from the "training set" concept often associated with machine learning.

The analytical studies (precision, linearity, etc.) and method comparison effectively validate the final algorithms/calculations after their development.

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

As noted above, the concept of a "training set" and its "ground truth" in the context of an AI/ML algorithm isn't directly applicable here. The device's parameters are derived from physical measurements and established formulas related to viscoelastic properties of blood. The underlying physics and physiology are the "ground truth" upon which the measurement technique is built. Any internal calibration or algorithm development would have relied on known samples or precisely measured physical responses, but these are not explicitly detailed as a "training set" in the submission.

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The CORA PlateletMapping System is intended for in vitro diagnostic use to provide qualitative assessment of platelet function. The CORA System records the kinetic changes in a sample of heparinized whole blood as the sample clots.

The CORA System PlateletMapping Assay Cartridge provides four channels of dried-in-place reagents, HKH (Kaolin with Heparinase), Activator F, AA and ADP (one reagent in each channel). In combination, MA parameter results from these four reagents are used to calculate the parameters platelet % Inhibition and % Aggregation for AA and ADP.

Results from the CORA analysis should not be the sole basis for a patient diagnosis, but should be evaluated together with the patient's medical history, the clinical picture and, if necessary, further hemostasis tests.

The CORA System with CORA PlateletMapping Assay Cartridge is indicated for use with adult patients where an evaluation of their blood hemostasis properties is desired. Hemostasis evaluation with the CORA PlateletMapping System is used to assess clinical conditions in cardiovascular surgery and cardiology procedures to assess hemorrhage or thrombosis conditions.

The CORA PlateletMappingSystem consists of a four-channel diagnostic analyzer with integrated computer module, system reagents (ActF, AA, ADP and HKH) and microfluidic test cartridge. Reagents are dried-in-place within the cartridges during manufacturing.

To perform a test, a disposable CORA PlateletMapping Assay Cartridge is inserted into the analyzer. Blood is added to an entry port on the cartridge and drawn into the cartridge under analyzer control. The amount of the sample drawn into the cartridge is automatically determined by the volume of the blood chambers in the cartridge. Once in the disposable, the sample is metered into as many as four separate analysis channels, depending upon the assay being performed. Reconstitution of reagents dried within the cartridge is accomplished by moving the sample back and forth through reagent chambers, under the control of microfluidic valves and bellows within the cartridge. After each sample has been mixed with reagent, it is delivered to a test cell where it is monitored for changes due to coagulation. Excess sample material is moved under microfluidic control into an enclosed waste chamber within the cartridge.

The CORA technology is based on a disposable containing up to four independent measurement cells. Each cell consists of a short vertically-oriented injection molded tube (ring) with a diameter of 2.5mm and a length of 4.5mm. Detection of clotting in the CORA System is performed optically. Under control of the analyzer, approximately 20uL of prepared sample is delivered to the tube, where a meniscus naturally forms at each end of the tube. The tube is positioned so that the lower meniscus partially blocks light traveling from a collimated source toward a photodiode.

During testing, a piezoelectric actuator drives the measurement cell(s) through a motion profile composed of summed sinusoids at different frequencies. The profile has a maximum amplitude of under 10um and contains frequencies from 10-500Hz. Some, but not all, of the measurement cell motion will induce motion in the sample meniscus, which will be detected by the photodiode. The resulting motion of the meniscus is monitored optically and analyzed by the analyzer to calculate the resonant frequency and modulus of elasticity (stiffness) of the sample. By performing a Fast Fourier Transform (FFT) on meniscus motion data, it is possible to determine the frequencies of input motion that caused the greatest deflection of the sample (these are called the resonant frequencies).

Resonance is the tendency of a material or structure to oscillate with greater amplitude at some frequencies than others. The exact frequencies at which resonance occurs will depend on the stiffness and mass of the sample. Stiffness, in turn, is a function of a material's modulus of elasticity and the boundary conditions to which the material is exposed, such as the geometry and materials of a test cell. By holding these boundary conditions and sample mass constant from run to run, the CORA System allows direct comparison of elasticity between samples.

In a typical test, blood that has been delivered to the measurement cell will not clot for several minutes. During this time the sample has no inherent stiffness except that provided by surface tension, and since this remains constant the measured resonant frequencies will not change. Once clotting begins, however, the elastic modulus and thus the resonant frequencies increase rapidly. In tests where clotting does not occur, the resonant frequency of the sample will not change. During coagulation, however, a clot will bind to the test tube (ring) and the resonant frequency will rise with increasing firmness of the clot. The CORA Analyzer collects meniscus motion data, tracks changing resonant frequencies and analyzes the frequency data to provide parameters describing the clot. Results are presented in a format identical to the TEG 5000.

The CORA System with PlateletMapping Assay is intended for in vitro diagnostic use to provide a qualitative assessment of platelet function. The system records kinetic changes in heparinized whole blood samples as they clot, calculating % Inhibition and % Aggregation for AA and ADP parameters.

Here's an analysis of the acceptance criteria and the study performance for the CORA System with PlateletMapping Assay:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for the clinical performance. Instead, it presents the device's sensitivity and specificity and compares them to the predicate device, the TEG 5000 Platelet Mapping Assay.

For analytical precision, the reported data indicates the variability (SD and %CV) across various factors (reagent lot, operator, analyzer, day, and repeatability) for MA parameters in HKH, and indicates that the percent positive and negative agreement for AA and ADP % aggregation inhibition at low and high level is 100%. However, no specific acceptance criteria for precision are provided.

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

• Reference Range Determination (Clinical Performance):

  • Sample Size: Up to 55 normal volunteer subjects were taken at each of the three clinical sites, totaling approximately 150 samples.
  • Data Provenance: Prospective, collected from normal volunteer subjects by three clinical sites representing demographic populations of the three areas regarding age, race, and gender.

• Method Comparison (Clinical Performance):

  • Sample Size: Not explicitly stated, but the study was conducted on "patient samples" from "surgical patients and normal donors (for CORA)." The sensitivity and specificity percentages are derived from these samples.
  • Data Provenance: The patients were undergoing heart surgery or PCI procedures, with blood samples drawn pre- and post-surgery and in the ICU. This indicates a prospective collection within a clinical setting. The study was conducted at three clinical sites.

• Analytical Precision (Non-Clinical Performance):

  • Sample Size: For HKH, blood draws from 3 donors (Hypo, Normal, Hyper). For AA and ADP Percent Aggregation and Inhibition, blood draws from 2 donors (Normal, Abnormal). Each testing scenario involved 5 non-consecutive days, 2 operators, 3 reagent lots, 12 analyzers, and 2 replicates. This results in n=120 for each MA parameter level (Hypo, Hyper, Normal) for HKH.
  • Data Provenance: The testing was performed in Coramed's laboratory, suggesting internally generated data.

• Interference (Non-Clinical Performance):

  • Sample Size: Not explicitly stated.
  • Data Provenance: Performed in Coramed's laboratory.

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 use of experts to establish a "ground truth" in the traditional sense (e.g., radiologists interpreting images).

• For the Reference Ranges, the ground truth is established by selecting "normal volunteer subjects" and then deriving the range from their results. This is based on a statistical approach to define normalcy within the tested population.
• For the Method Comparison, the ground truth for determining disease status (e.g., platelet dysfunction) is implicitly established through clinical diagnosis of "surgical patients or PCI procedures" who are known to have conditions where blood hemostasis properties evaluation is desired. However, the exact method of confirming ground truth for individual results to calculate sensitivity and specificity (e.g., by another gold standard method, pathology, or expert clinical diagnosis) is not detailed. The comparison is made against the TEG 5000 as a predicate, which usually implies that the predicate serves as a reference, but a true independent ground truth for classification is not explicitly defined in the provided text.

4. Adjudication Method (for the test set)

No adjudication method involving experts is mentioned for clinical performance results. The sensitivity and specificity would be derived by comparing the CORA device's output against the "true" clinical status of the patients, or the predicate device's output, but the process of determining that "true" status is not elaborated in terms of an adjudication panel.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance

This is an in vitro diagnostic device for assessing platelet function, not an imaging device typically involving human readers interpreting results. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable and was not performed or described in this document.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, the studies presented appear to be standalone performance assessments of the CORA System. The "system" is an automated analyzer that generates quantitative results (MA, % Aggregation, % Inhibition). Its performance (precision, reference ranges, sensitivity, specificity) is evaluated directly, without explicitly describing a human-in-the-loop interaction in the context of the performance data. While the "results from the CORA analysis should not be the sole basis for a patient diagnosis, but should be evaluated together with the patient's medical history, the clinical picture and, if necessary, further hemostasis tests," this statement refers to the clinical application rather than the performance study design.

7. The Type of Ground Truth Used

• Reference Ranges: The ground truth is effectively derived from the measurements of a healthy reference population (normal volunteer subjects) to establish what is considered "normal."
• Method Comparison: The ground truth for calculating sensitivity and specificity is implicitly clinical diagnosis of patients undergoing cardiovascular procedures, where blood hemostasis evaluation is desired. However, the specific gold standard or method used to classify each patient's 'true' platelet function status (e.g., by another established assay, pathology, or expert clinical assessment) against which the CORA results are benchmarked is not explicitly defined. The comparison also heavily relies on the predicate device (TEG 5000), suggesting that the predicate might serve as a de facto reference for classification if an independent gold standard was not available or used. It states "studies were conducted... on patient samples following CLSI EP09-A3 Guideline," which typically involves comparison to a reference method.

8. The Sample Size for the Training Set

The document does not explicitly describe a "training set" in the context of an AI/machine learning model. The CORA System is an automated diagnostic device based on physical measurement techniques (e.g., resonance, optical detection), not typically an AI system that requires a training set. The descriptions of "precision testing" and "reference ranges" are for analytical and clinical validation, not algorithm training.

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

Since no "training set" for an AI/machine learning model is described, the question of how its ground truth was established is not applicable.

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