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The Alere NT-proBNP for Alinity i assay is a chemiluminescent microparticle immunoassay (CMIA) used for the in vitro quantitative determination of N-terminal pro B-type natriuretic peptide (NT-proBNP) in human serum and plasma on the Alinity i system.

In the emergency department, measurements of NT-proBNP are used as an aid in the diagnosis of heart failure (HF) in patients with clinical suspicion of new onset or worsening HF.

The Alere NT-proBNP for Alinity i assay is an automated, two-step immunoassay for the in vitro quantitative determination of NT-proBNP in human serum and plasma using chemiluminescent microparticle immunoassay (CMIA) technology. Sample and anti-NT-proBNP coated paramagnetic microparticles are combined and incubated. The NT-proBNP present in the sample binds to the anti-NT-proBNP coated microparticles. The mixture is washed. Anti-NT-proBNP acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle, Pre-Trigger and Trigger Solutions are added. The resulting chemiluminescent reaction is measured as a relative light unit (RLU). There is a direct relationship between the amount of NT-proBNP in the sample and the RLU detected by the system optics.

Despite the request for acceptance criteria and study proving the device meets said criteria, the provided document is a 510(k) summary for a diagnostic test (Alere NT-proBNP for Alinity i Reagent Kit). This type of document focuses on demonstrating substantial equivalence to a predicate device, and thus does not explicitly list "acceptance criteria" for performance in the same way one might find for a new medical device claiming superiority or non-inferiority.

Instead, the document details various performance characteristics of the device, comparing them to relevant standards (CLSI guidelines) and providing statistical data. It aims to show that the new device performs acceptably and similarly to a previously cleared device.

Therefore, I cannot extract a table of "acceptance criteria" as such a table is not explicitly presented. However, I can infer the implied acceptance criteria from the reported performance, specifically from the "No Significant Interference" and "within acceptable performance" statements in the nonclinical performance section, and the effectiveness of the cutoffs for diagnosis in the clinical performance. The "reported device performance" will be the actual numbers provided in the document.

Here's a summary of the available information, structured to address your points as much as possible given the document type:

Implied Acceptance Criteria and Reported Device Performance

As this is a 510(k) submission, explicit quantitative acceptance criteria are not stated in a dedicated table format. Instead, the device's performance characteristics are presented as evidence of substantial equivalence to a predicate device and adherence to recognized standards. The implied acceptance criteria are that the device demonstrates acceptable accuracy, precision, and clinical utility for its stated indications for use.

Here's a table summarizing key performance indicators that would implicitly serve as acceptance criteria given standard diagnostic device requirements:

Study Details:

1. Sample sizes used for the test set and the data provenance:

   • Clinical Performance Study (test set): 2127 Emergency Department (ED) subjects.
     • Provenance: Multi-center prospective study across 17 collection sites in the US.
     • Demographics: 1030 (48.4%) female, 1097 (51.6%) male, age 19-97 years. Predominantly White (53.1%) and Black/African American (39.5%). 90.9% non-Hispanic/Latino.
   • Nonclinical Performance (examples):
     • Within-Laboratory Precision: 240 replicates (controls/panels).
     • Reproducibility: 360 replicates (controls/panels) per assay (across 3 sites).
     • Lower Limits of Measurement: n ≥ 60 replicates for LoB, LoD, LoQ.
     • Analytical Specificity/Interference: Each substance tested at 2 analyte levels (approximately 125 pg/mL and 2000 pg/mL).

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

   • The ground truth for the clinical study was an "adjudicated diagnosis" determined by a panel of board-certified cardiologists. The exact number of cardiologists on the panel is not specified in the provided text.

3. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

   • The document states "An adjudicated diagnosis was determined by a panel of board-certified cardiologists." It does not specify the exact adjudication method (e.g., majority vote, sequential review, etc.).

4. 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:

   • No, this document describes the validation of a quantitative in vitro diagnostic (IVD) reagent kit for measuring NT-proBNP levels using an automated chemiluminescent immunoassay (CMIA) system. It is not an AI-assisted diagnostic imaging device, so an MRMC study is not relevant to this submission. The "readers" are the automated analyzers and laboratory personnel interpreting numerical results.

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

   • This device is a standalone diagnostic test in the sense that it provides a quantitative NT-proBNP result. The assay itself is a fully automated process on the Alinity i system. The performance data presented (precision, linearity, limits, specificity, clinical performance tables) represent the performance of the device "standalone" in generating these quantitative results, which are then used by clinicians as an "aid in diagnosis." There isn't a "human-in-the-loop" component to the measurement itself, though medical professionals interpret the results in a clinical context.

6. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

   • For the clinical performance study, the ground truth for Heart Failure (HF) diagnosis was established by expert consensus (adjudicated diagnosis by a panel of board-certified cardiologists).

7. The sample size for the training set:

   • This document describes a 510(k) submission for an in vitro diagnostic reagent kit. Unlike AI/ML software, such devices typically undergo analytical and clinical validation studies with defined test sets but do not have a "training set" in the sense of machine learning algorithms. The development and optimization of the assay would have involved various internal samples and experiments, but these are not explicitly termed "training sets" and their size is not reported in this context.

8. How the ground truth for the training set was established:

   • As explained above, the concept of a "training set" with established ground truth, as typically applied to machine learning or AI models, does not directly apply to the regulatory submission type for this diagnostic reagent kit. The assay is based on chemical and biological principles (CMIA) rather than learned algorithms from large datasets.

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The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated DxI Access Immunoassay Analyzers to aid in the following:

1. diagnosis of patients suspected of having acute heart failure in the Emergency Department
2. assessment of heart failure severity
3. risk stratification of patients with heart failure
4. risk stratification of patients with acute coronary syndrome

The Access NT-proBNP assay is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of N-terminal pro B-type natriuretic peptide levels in human serum and plasma using the automated Dxl 9000 Access Immunoassay Analyzers to aid in the following: 1) diagnosis of patients suspected of acute heart failure in the Emergency Department, 2) assessment of heart failure severity, 3) risk stratification of patients with heart failure, 4) risk stratification of patients with acute coronary syndrome.

The Access NT-proBNP is a two-site immunoenzymatic (sandwich) assay. Paramagnetic particles coated with monoclonal anti-NT-proBNP antibody and monoclonal anti-NTproBNP antibody conjugated to alkaline phosphatase are added to a reaction vessel along with a surfactant-containing buffer and serum or plasma sample. The human NTproBNP binds to the anti-NT-proBNP antibody on the solid phase, while the anti-NTproBNP antibody-alkaline phosphatase conjugate reacts with a different antigenic site on the NT-proBNP molecule. After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then the chemiluminescent substrate is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of analyte in the sample. Analyte concentration is automatically determined from a stored calibration.

Other items required to use the assay include calibrators, Lumi-Phos PRO, and wash buffer. The Access NT-proBNP reagent packs. Access NT-proBNP calibrators, along with the Access wash buffer, and Lumi-Phos PRO are designed for use on the Dxl 9000 Access Immunoassay Analyzers in a clinical laboratory setting.

Here's a breakdown of the acceptance criteria and study details for the Beckman Coulter Access NT-proBNP device, based on the provided text:

Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the clinical and non-clinical studies conducted, with the device performance needing to meet expected ranges and exhibit substantial equivalence to predicate devices. Specific quantitative acceptance criteria are given for imprecision, LoB/LoD/LoQ, and linearity.

Study Details

1. Sample Size and Data Provenance:

   • Test Set (Clinical Study for AHF Diagnosis): 2,384 patients presenting to the Emergency Department with clinical suspicion of acute heart failure.
     • Provenance: This was a "multicenter prospective study." While specific countries are not mentioned, regulatory submissions to the FDA typically involve studies conducted in the US or other regions following ICH GCP guidelines. The study type is explicitly prospective.
   • Test Set (Reference Interval Study): 675 apparently healthy adults for the overall ULN, broken down into 306 males and 369 females.
     • Provenance: This was a "multicenter prospective reference interval study." Again, specific countries are not mentioned but it was prospective.
   • Test Set (Imprecision): Number of runs (minimum 20 days) and replicates (duplicate) are specified for samples 1-7, with N ranging from 83 to 86 tests per sample.
   • Test Set (LoB, LoD, LoQ): Multiple reagents lots and 3 instruments over 3-5 days.
   • Test Set (Linearity): Native patient samples.
   • Test Set (Matrix Comparison): Sixty-eight (68) matched serum, lithium heparin, and EDTA plasma samples.
   • Test Set (Interfering Substances/Cross Reactivity): Lithium heparin plasma samples (concentrations approx. 125 ng/L and 1,800 ng/L) spiked with various substances. Number of individual samples not specified, but the number of substances tested is large.

2. Number of Experts and Qualifications for Ground Truth:

   • For the clinical sensitivity study (AHF diagnosis), "Final diagnoses were adjudicated by an independent committee of medical doctors."
   • Number of Experts: Not explicitly stated (e.g., "3 independent physicians"). It mentions "an independent committee," which implies more than one.
   • Qualifications: "Medical doctors." No specific specialties (e.g., cardiologists, emergency physicians) or years of experience are listed in the provided text.
   • For risk stratification, the basis for effectiveness comes from "an objective and systematic analysis of recent peer-reviewed literature and clinical practice guidelines," implying consensus from the broader medical community rather than a specific set of experts for this particular study.

3. Adjudication Method for the Test Set:

   • For the AHF diagnosis study, the text states: "Final diagnoses were adjudicated by an independent committee of medical doctors who decided on presence of acute heart failure. Adjudicators were blinded to the Access NT-proBNP assay results."
   • The specific method (e.g., 2+1, 3+1) is not explicitly detailed. It simply states "adjudicated by an independent committee," which could imply consensus, majority vote, or a specific tie-breaking rule, but the exact mechanism is not provided.

4. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

   • No, this device is an in-vitro diagnostic (IVD) assay, not an AI/imaging device. Therefore, an MRMC study and human reader improvement with AI assistance are not applicable. The comparison made is against another IVD assay (Elecsys proBNP II) as a standalone algorithm/test.

5. Standalone Performance:

   • Yes, the primary performance shown is standalone (algorithm only/test only) performance. The Access NT-proBNP assay is a quantitative determination of NT-proBNP levels. Its performance (e.g., analytical performance, diagnostic accuracy via ROC curves) is measured and reported as the output of the assay itself. The clinical performance section directly presents the assay's ability to diagnose AHF and correlates its results with NYHA classification and risk stratification, without human interpretation of the assay's output as an input to a further AI system.

6. Type of Ground Truth Used:

   • Clinical Diagnosis (Expert Consensus/Adjudication): For the acute heart failure diagnosis study, the ground truth was established by an "independent committee of medical doctors" adjudicating the final diagnoses. This falls under expert consensus based on clinical information.
   • Clinical Outcomes/Literature Review: For risk stratification, the ground truth is based on the correlation of NT-proBNP with "increased incidence of cardiovascular events, mortality and composite outcomes" as established in existing peer-reviewed literature and clinical practice guidelines.
   • Reference Intervals for Healthy Population: Established by recruiting "apparently healthy adults" based on defined exclusion criteria and screening with additional biomarkers (eGFR, hsTnl) to ensure the health status.

7. Sample Size for the Training Set:

   • The provided document describes the validation studies (test set) for the Access NT-proBNP device. It does not mention a separate "training set" in the context of an AI/machine learning model. This is an IVD assay, not an AI device trained on data. The development process for such an assay involves R&D, optimization, and internal verification stages, but the term "training set" doesn't directly apply in the same way it would for AI products.

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

   • As this is not an AI/machine learning device, the concept of a "training set" with established ground truth as per AI/ML typically doesn't apply. The development of the assay itself would involve internal studies and optimization based on known reference materials and clinical samples, but these are part of the assay's design and analytical verification, not a training phase for a learning algorithm.

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The ADVIA Centaur® NT-proBNPII (PBNPII) assay is for in vitro diagnostic use in the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in human serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP system.

In the Emergency Department (ED) and Outpatient (OP) populations, measurements of NT-proBNP are used as an aid in the diagnosis of heart failure (HF) in patients with clinical suspicion of new onset or worsening HF.

The ADVIA Centaur® NT-proBNPII (PBNPII) assay kit includes the Primary Reagent ReadyPack and the Calibrator. The Primary Reagent ReadyPack contains Lite Reagent, Solid Phase Reagent, and Ancillary Well Reagent. The Calibrator includes Low and High Calibrators which are lyophilized.

The provided document discusses the ADVIA Centaur® NT-proBNPII (PBNPII) assay, an in vitro diagnostic device for measuring N-terminal pro-brain natriuretic peptide (NT-proBNP) to aid in the diagnosis of heart failure in Emergency Department (ED) and Outpatient (OP) populations. The submission aims to demonstrate substantial equivalence to the predicate device, the Roche Elecsys proBNP II assay (K072437).

Here's an analysis of the acceptance criteria and the studies that support them:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" as a single, consolidated table with pass/fail values for all performance characteristics. Instead, it presents various performance studies with their results. Based on the "Comparison of Technological Characteristics with the Predicate Device" and the "Performance Characteristics" sections, we can infer some criteria and compare the device's performance.

Note: The "Acceptable Criteria" values for precision were primarily taken directly from comments in the tables (indicated by "<" followed by a number), which appear to be the applicant's internal criteria rather than directly from the predicate. The predicate's precision data is shown for comparison purposes in the "Comparison of Technological Characteristics."

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

• Precision and Reproducibility:
  • Precision: Assayed in duplicate in 2 runs per day for 20 days. Number of samples not explicitly stated but implied to be multiple levels of serum and QCs (6 serum, 3 QC samples listed).
  • Reproducibility: N=90 samples assayed in duplicate in 2 runs per day for 5 days at 3 sites.
• Linearity: Not specified.
• Detection Limit (LoB, LoD, LoQ): Not specified.
• Interference (HIL & Other Substances): Not specified.
• Cross-Reactivity: Not specified.
• Specimen Equivalency: N=50 samples for each tube type comparison to serum.
• Expected Values (Reference Study Group): 723 apparently healthy subjects (362 females, 361 males).
• Clinical Performance (ED Population): 3128 subjects with signs and symptoms of acute HF who presented to the ED. 1148 adjudicated as acute HF, 1980 as without HF.
• Clinical Performance (OP Population): 1033 OP subjects with signs and symptoms of new onset HF. 185 adjudicated as new onset HF, 848 as without HF.

Data Provenance: The document does not explicitly state the country of origin for the clinical study data or if it was retrospective or prospective. However, the term "prospectively enrolled" is used for both the ED and OP clinical performance studies, indicating these were prospective studies.

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

• Clinical Performance (ED Population): An "independent central adjudication panel of expert clinicians (Cardiologists)" determined the diagnosis and severity of HF. The exact number of experts is not stated, nor are their specific qualifications (e.g., number of years of experience).
• Clinical Performance (OP Population): An "independent central adjudication panel of expert clinicians (Cardiologists)" determined the diagnosis of new onset HF. Similar to the ED population, the exact number and specific qualifications are not detailed.

4. Adjudication Method (for the test set)

The adjudication method used by the "independent central adjudication panel of expert clinicians (Cardiologists)" is not explicitly described (e.g., 2+1, 3+1, none). It only states they "determined" the diagnosis.

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

No MRMC comparative effectiveness study was done. This device is an in vitro diagnostic assay (laboratory test), not an imaging or interpretive device that typically involves human readers in the same way an MRMC study would apply. Therefore, there is no effect size reported for human readers improving with or without AI assistance.

6. Standalone Performance Study

Yes, a standalone (algorithm only) performance study was performed for the assay. The entire "Performance Characteristics" section (9.1 through 9.12) describes the analytical and clinical performance of the ADVIA Centaur PBNPII assay in isolation, without human interpretation of the assay results in the context of the study design. The clinical utility is assessed by how accurately the assay's quantitative results correlate with the adjudicated clinical diagnosis.

7. Type of Ground Truth Used

• Clinical Performance (ED and OP Populations): Clinical diagnosis adjudicated by an "independent central adjudication panel of expert clinicians (Cardiologists)." This falls under expert consensus clinical diagnosis.
• Analytical Performance (Precision, Linearity, Detection Limits, Interference, Cross-Reactivity, Specimen Equivalency): These are quantitative measurements against established reference methods, standards, or known concentrations, serving as the ground truth for analytical validity.

8. Sample Size for the Training Set

The document describes an in vitro diagnostic assay for measuring biomarkers. These types of assays typically do not have a "training set" in the same sense as machine learning algorithms, which require labeled data for model development. Instead, they involve method development and validation experiments. The document describes studies for:

• Establishing expected values (reference study group, N=723).
• Establishing disease study groups for statistical analysis of correlation (ED population N=1148, OP population N=185).
• Various analytical validation studies such as precision, linearity, and detection limits.

Therefore, the concept of a "training set" for the assay, in the context of algorithm development, is not directly applicable or discussed. The studies mentioned above contribute to the overall validation and characterization of the assay's performance.

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

As mentioned above, the concept of a "training set" for an assay like this is not directly applicable. If we consider the data used to characterize the assay's performance as analogous to "training data" (i.e., the data used to define the assay's characteristics and clinical cut-offs), then:

• Clinical Cut-offs: The clinical cut-offs for the ED and OP populations were established based on the measured NT-proBNP values in patient populations (ED and OP disease study groups) where the diagnosis of heart failure was determined by an "independent central adjudication panel of expert clinicians (Cardiologists)." This expert consensus clinical diagnosis serves as the ground truth for establishing the clinical utility of the various cut-off values.
• Reference Intervals: The reference interval was established using 723 apparently healthy subjects. The "healthy" status would have been determined through standard medical screening and criteria, serving as the ground truth for defining the normal range.
• Analytical Studies: Ground truth for analytical studies (e.g., linearity, detection limit) is established through reference materials, spiked samples with known concentrations, and comparison to established methods or gold standard instrumentation.

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Immunoassay for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide in human serum and plasma. This assay is used as an aid in the diagnosis of individuals suspected of having heart failure. It can be used as an aid in the diagnosis of acute decompensated heart failure (ADHF) in patients presenting with signs and symptoms of ADHF to the emergency department (ED). The test is further indicated for the risk stratification of patients with acute coronary syndrome and heart failure. The test may also serve as an aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease.

Elecsys proBNP II and proBNP II STAT are second-generation assays by Roche Diagnostics for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide (NT-proBNP) in human serum and plasma. The STAT and the 18 Minute assays are intended for use on the cobas e 601. The cobas e family of analyzers employs the electrochemiluminescence immunoassay "ECLIA" technology. The assays are sandwich principle methods using two monoclonal antibodies which are specifically directed against NT-proBNP. For the neutralization of free biotin in serum and plasma, Roche developed an antibody, which binds to free biotin. The antibodies are specific for free biotin and do not bind to or interact with the biotin-linker conjugates.

The provided document describes the Elecsys proBNP II and Elecsys proBNP II STAT assays, which are in vitro quantitative determination tests for N-terminal pro-Brain natriuretic peptide (NT-proBNP) used as an aid in the diagnosis of heart failure, specifically acute decompensated heart failure (ADHF). The document details the analytical and clinical performance evaluations of these devices.

Since the device is an in vitro diagnostic (IVD) test and not an AI-powered medical device for image analysis or similar, the acceptance criteria and study that proves the device meets them are focused on analytical performance (precision, sensitivity, linearity, interference) and clinical performance (diagnostic accuracy based on cut-points), rather than typical AI/ML metrics like AUC, sensitivity, specificity for image interpretation, or MRMC studies.

Therefore, many of the requested AI/ML specific information points (e.g., number of experts to establish ground truth for test set, adjudication method, MRMC study, sample size for training set, how ground truth for training set was established) are not directly applicable in the context of this IVD device's evaluation as described.

Here's an analysis based on the available information:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly present a single table of "acceptance criteria" alongside "reported device performance" for the clinical diagnostic accuracy in a pass/fail format. Instead, it provides detailed analytical performance results and clinical likelihood ratios for various patient subgroups. However, for analytical performance, conclusions are stated:

Analytical Performance Acceptance Criteria and Results:

Clinical Performance:
For clinical performance, the criterion is generally that the device provides "adequate performance when aiding in the diagnosis of acutely decompensated heart failure" and supports a "substantial equivalent decision" to the predicate. This is demonstrated through likelihood ratios (LR+ and LR-) for the various age and gender groups. While no explicit "acceptance criteria" for these LR values are given (e.g., LR+ > X and LR- < Y), the presentation of these values, along with post-test probabilities, is intended to show clinical utility and substantial equivalence.

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

• Clinical Performance Test Set (ADHF Diagnosis Study):

  • Sample Size: 1485 subjects.
  • Data Provenance: Multi-center trial performed in the United States (US subjects).
  • Retrospective/Prospective: The description "multi-center trial was performed" suggests a prospective study design. Patients were enrolled with suspected ADHF and their ADHF status was subsequently adjudicated.

• Analytical Performance Test Sets:

  • Precision: 8 serum samples and 2 controls (n=84 determinations for each sample/control).
  • LoB: 60 determinations of an analyte-free sample.
  • LoD: 5 low-level human serum samples, 60 determinations per reagent lot (total of three reagent lots tested).
  • LoQ: 10 native, unaltered serum samples, 5 replicates per sample, over 5 days (n=25 measured values per sample).
  • Linearity: 10 levels of diluted high analyte human native serum.
  • Endogenous Interferences: Three different analyte concentration levels for serum samples.

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

• Clinical Performance Test Set (ADHF Diagnosis Study):
  • Ground truth for ADHF diagnosis was established "based on adjudication by a clinical events committee."
  • The number of experts on this committee and their specific qualifications (e.g., radiologist with X years of experience) are not explicitly specified in the provided text.

4. Adjudication Method for the Test Set

• Clinical Performance Test Set:
  • Ground truth was based on "adjudication by a clinical events committee."
  • The specific adjudication method (e.g., 2+1, 3+1, majority vote, etc.) for this committee is not explicitly detailed in the document.

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

• No, this is not applicable. The device is an in vitro diagnostic (IVD) test (immunoassay), not an AI-powered diagnostic imaging tool. Therefore, an MRMC study and the concept of "human readers improving with AI assistance" are not relevant to this type of device and its evaluation as described. The clinical performance evaluation focuses on the assay's ability to aid in diagnosis using predefined cut-points.

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

• Yes, in essence. The "standalone performance" of the Elecsys proBNP II and Elecsys proBNP II STAT assays is demonstrated by their analytical performance metrics (precision, LoB, LoD, LoQ, linearity, interference) and their diagnostic performance (likelihood ratios) when applied to patient samples. There isn't an "algorithm" in the typical AI sense, but rather a direct measurement of NT-proBNP concentration against established cut-points. The interpretation relies on these quantitative measurements.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

• Clinical Performance Test Set (ADHF Diagnosis Study): The ground truth for Acute Decompensated Heart Failure (ADHF) status was established by adjudication of a clinical events committee. This implies a panel of medical experts reviewed patient data (e.g., symptoms, signs, other diagnostic tests, clinical course) to determine the true ADHF status. This falls under a form of expert consensus on clinical diagnosis.

8. The Sample Size for the Training Set

• Not Applicable in the AI/ML sense. This is an in vitro diagnostic immunoassay, not an AI/ML device that requires a separate "training set" to develop an algorithm. The assay's analytical characteristics and clinical utility are established through the studies mentioned (analytical and clinical performance evaluation). The "training" of the device is inherent in its chemical and biological design and manufacturing, not a machine learning process.

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

• Not Applicable. As explained in point 8, there isn't a "training set" for an AI/ML algorithm in the context of this immunoassay. The analytical performance is validated against known standards and controls, and clinical performance is validated against clinical diagnoses adjudicated by a committee.

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Immunoassay for the in vitro quantitative determination of N terminal pro Brain natriuretic peptide in human serum and plasma. This assay is used as an aid in the diagnosis of individuals suspected of having heart failure. The test is further indicated for the risk stratification of patients with acute coronary syndrome and heart failure. The test may also serve as an aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease.

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

Elecsys proBNP II (updated assay) is a second-generation assay by Roche Diagnostics for the in vitro quantitative determination of N-terminal pro-Brain natriuretic peptide (NT-proBNP) in human serum and plasma with increased biotin tolerance. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The cobas e family of analyzers employs the electrochemiluminescence immunoassay "ECLIA" technology. The assays are an 18-minute (Elecsys proBNP II) and 9 minute (Elecsys proBNP II STAT) application following a sandwich principle using two monoclonal antibodies which are specifically directed against NT-proBNP.

Acceptance Criteria and Device Performance Study for Elecsys proBNP II and Elecsys proBNP II STAT Assays

The document describes the analytical performance studies conducted for the Elecsys proBNP II and Elecsys proBNP II STAT assays, which are in vitro diagnostic devices. These assays are intended for the quantitative determination of N-terminal pro-Brain natriuretic peptide (NT-proBNP) in human serum and plasma, aiding in the diagnosis of heart failure, risk stratification, and assessment of cardiovascular event risk. The assays have been modified to include increased biotin tolerance.

The studies aim to demonstrate that the updated assays meet predetermined acceptance criteria for various analytical parameters, ensuring their safety and effectiveness and substantial equivalence to their predicate devices.

1. Table of Acceptance Criteria and Reported Device Performance

The provided document doesn't explicitly list "acceptance criteria" alongside "reported device performance" in a single, dedicated table for all parameters. However, the "Conclusion" sections for each analytical study implicitly state whether the acceptance criteria were met. Based on the provided text, a table can be constructed as follows:

2. Sample Sizes and Data Provenance

• Test Set Sample Sizes:

  • Precision (Repeatability & Intermediate): 8 human serum samples and 2 controls (n=10 total) for each assay, measured in 84 determinations over 21 operating days. The exact number of individual patient samples contained within the "8 human serum samples" is not specified but appears to be 8 distinct pools/matrices.
  • Precision (Inter-Instrument): 8 native human serum sample pools and 2 quality control levels (n=10 total) for each assay, with 75 determinations per sample/QC level (due to 5 days, 3 laboratories, 25 determinations/site, 5x5=25, 3 sites x 25 = 75 total reported).
  • Analytical Sensitivity (LoB): 60 determinations of an analyte-free sample.
  • Analytical Sensitivity (LoD): 5 low-level human serum samples, with 60 determinations per reagent lot.
  • Analytical Sensitivity (LoQ): 9 native, unaltered serum samples for Elecsys proBNP II and 10 native, unaltered serum samples for Elecsys proBNP II STAT, each tested with 25 measured values.
  • Linearity/Assay Reportable Range: One high analyte human, native serum sample diluted to 11 concentrations.
  • Endogenous Interference (Bilirubin, Hemoglobin, Lipemia, Biotin, Rheumatoid Factor, Albumin): Three different analyte concentration levels (low, medium, high) in human native serum samples. Specific number of samples at each level not explicitly stated but implied to be several.
  • Cross-Reactivity: Two human native serum samples (low and high analyte levels) spiked with potential cross-reactants.
  • Exogenous Interference (Drugs): Two human native serum samples (low and high analyte concentrations).
  • Matrix Comparisons: Single donor samples drawn into Serum (reference), Li-Heparin (98 pairs), and K2-EDTA plasma (111 pairs).
  • Method Comparison: 1928 subjects for Elecsys proBNP II STAT and 1940 subjects for Elecsys proBNP II.

• Data Provenance: The document generally refers to "human serum samples" and "native human serum samples" without specifying the country of origin. The studies are described as internal (e.g., "one internal site" for precision). There is no explicit mention of the data being retrospective or prospective, but the nature of in vitro diagnostic device performance studies (analytical validation) typically involves prospective testing of samples under controlled laboratory conditions, simulating diagnostic use.

3. Number of Experts and Qualifications for Ground Truth

The document does not describe the use of human experts to establish "ground truth" for the test set in the context of diagnostic interpretation (e.g., radiologists, cardiologists). This document details the analytical performance of an in vitro diagnostic assay, not an AI/imaging diagnostic device that requires expert adjudication of images. The "ground truth" in this context refers to the true analytical concentration of NT-proBNP in the samples, established through well-defined laboratory methodologies and traceable standards, or comparison to a previously cleared predicate device.

4. Adjudication Method for the Test Set

Not applicable. As this is an analytical validation of an in vitro diagnostic assay, there is no "adjudication method" in the sense of multiple human readers or experts resolving discrepancies in diagnostic interpretation. The methods involve quantitative analytical measurements of biochemical markers.

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

Not applicable. This is not an imaging or AI-assisted diagnostic device that would typically undergo an MRMC study. The study focuses on the analytical performance of a laboratory immunoassay.

6. Standalone (Algorithm Only) Performance

Not applicable in the typical sense for medical imaging AI. The "algorithm" here is the chemical reaction and measurement process of the immunoassay itself. The analytical performance metrics (precision, sensitivity, linearity, interference, matrix comparison) are effectively the "standalone performance" of the device. The method comparison study directly compares the performance of the updated device against its predicate (older version) without human intervention in the result generation.

7. Type of Ground Truth Used

The ground truth used for these analytical studies is primarily measured analytical concentration, established through:

• Reference materials: Calibrators and controls with known concentrations.
• Spiking experiments: Adding known amounts of analyte or interfering substances to samples.
• Dilutions: Creating samples with predictable concentrations.
• Comparison to predicate device: The method comparison studies compare the new device's results against the results from the previously cleared Elecsys proBNP II and Elecsys proBNP II STAT (older versions) as the reference.
• Consensus laboratory methods/standards: Studies like LoB, LoD, LoQ, and precision follow CLSI (Clinical and Laboratory Standards Institute) guidelines, which are established consensus standards for analytical validation.

There is no mention of pathology, clinical outcomes data, or expert consensus interpretation of results as a primary ground truth in this analytical performance section.

8. Sample Size for the Training Set

Not applicable. This document describes the analytical validation of laboratory assays, not a machine learning model that requires a "training set" in the same sense. The assay works based on established biochemical principles (electrochemiluminescence immunoassay, ECLIA, utilizing specific antibodies) and wet-lab procedures, not on learned patterns from a large dataset. Reagent formulation and process optimization might involve internal development data, but it's not a "training set" in the AI/ML context.

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

Not applicable, as there is no "training set" for an AI/ML model in this context. The "ground truth" for the development of the assay itself would be based on fundamental analytical chemistry principles, extensive laboratory testing, control materials, and established reference methods for quantifying NT-proBNP.

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The Tosoh ST AIA-PACK BNP assay is designed for IN VITRO DIAGNOSTIC USE ONLY for the quantitative measurement of BNP in human (K2EDTA) plasma on Tosoh AIA System Analyzers. BNP is used as an aid in the diagnosis of heart failure (HF) in patients presenting to the emergency department (ED) with clinical suspicion of new onset HF, acutely decompensated or exacerbated HF.

The ST AIA-PACK BNP is a two-site immunoenzymometric assay which is performed entirely in the ST AIA-PACK BNP test cups. BNP present in the test sample is bound with monoclonal antibody immobilized on magnetic beads and enzyme-labeled monoclonal antibody. The magnetic beads are washed to remove unbound enzyme-labeled monoclonal antibody and are then incubated with a fluorogenic substrate, 4-methylumbelliferyl phosphate (4MUP). The amount of enzyme-labeled monoclonal antibody that binds to the beads is directly proportional to the BNP concentration in the test sample. A standard curve is constructed, and unknown sample concentrations are calculated using the curve.

The Tosoh ST AIA-PACK BNP Assay aims to extend its measuring interval beyond 2,000 pg/mL through manual and automated 1:5 and 1:10 dilutions. This is a special 510(k) submission, meaning it refers to a device that has already been cleared (K192380) and modifications were made to it that do not significantly alter its performance or safety (e.g., modified firmware, revised labeling, minor material changes, etc.). Since this is a Special 510(k) and not a de novo submission, this document is a justification for substantial equivalence to its predicate device (K192380), and does not contain detailed information for how the predicate device was evaluated.

Therefore, the study summary below only refers to the performance of the modified device compared to its predicate device, and not a full evaluation of the predicate device's performance.

1. Acceptance Criteria and Reported Device Performance

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

The document does not specify the sample sizes used for the manual and automated dilution studies, nor does it specify the country of origin or whether the data was retrospective or prospective.

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

Not applicable. The ground truth method does not involve human experts; it relies on direct measurement.

4. Adjudication method for the test set

Not applicable. The ground truth method does not involve human experts.

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 versus without AI assistance

Not applicable. This is not an AI-assisted diagnostic device, but an in vitro diagnostic assay.

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

Not applicable. This device is an in vitro diagnostic assay, not an algorithm.

7. The type of ground truth used

The ground truth used for both manual and automated dilution studies is the recovery value of the BNP concentration after dilution, indicating the accuracy of the dilution process. This is a direct measurement based on the expected concentration after dilution.

8. The sample size for the training set

Not applicable. This device is an in vitro diagnostic assay and does not involve machine learning or a training set.

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

Not applicable. This device is an in vitro diagnostic assay and does not involve machine learning or a training set.

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For in vitro diagnostic use only.

For the quantitative measurement of N-terminal pro Brain Natriuretic Peptide (NT-proBNP) in human serum and plasma (K2 EDTA or Lithium Heparin) using the VITROS 3600 Immunodiagnostic System to aid in the diagnosis of heart failure. The test can also be used in the assessment of heart failure severity in patients diagnosed with heart failure.

The VITROS NT-proBNP II test is performed using the VITROS VITROS NT-proBNP II Reagent Pack and the VITROS NT-proBNP II Calibrators on the VITROS Systems.

The VITROS NT-proBNP II test utilizes a one-step immunometric bridging assay design. A well is pushed from the pack and patient sample is dispensed into the antibody coated well. The assay reagent and the conjugate reagent are then dispensed into the well with the patient sample. NT-proBNP present in the sample binds with horseradish peroxidase (HRP)-labeled antibody conjugate which is captured by biotinylated anti-NT-proBNP capture antibody which is bound to Streptavidin coated microwells. The well is incubated for 8 minutes, before unbound materials are removed by washing.

The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrate (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the System. The amount of HRP conjugate bound is directly proportional to the concentration of NT-proBNP present.

The provided document describes the analytical and clinical performance of the VITROS Immunodiagnostic Products NT-proBNP II Reagent Pack, an in vitro diagnostic device used to aid in the diagnosis and assessment of heart failure.

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

1. Table of acceptance criteria and the reported device performance

The document does not explicitly present a "table of acceptance criteria" in terms of pre-defined thresholds for performance metrics that the device must meet for clearance. Instead, it describes the design goals and then reports the observed performance. For clarity, I will create a table summarizing the reported performance, which implicitly indicates the criteria were met or exceeded for FDA clearance.

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

• ED Setting (Diagnosis of Heart Failure):
  • Sample Size: 2200 subjects.
  • Data Provenance: Multi-center prospective study, 20 collection sites across the United States.
• Outpatient Setting (Diagnosis of Heart Failure):
  • Sample Size: 777 subjects.
  • Data Provenance: Multi-center prospective study, 10 collection sites across the United States.
• Correlation with NYHA Functional Classification:
  • Sample Size: 1143 subjects with heart failure.
  • Data Provenance: Not explicitly stated if this was a separate collection or a subset of the ED/outpatient studies, but given it's "subjects with heart failure," it likely derives from similar clinical populations.

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

• For both the ED and Outpatient settings: The final clinical diagnosis (ground truth) was adjudicated by independent cardiologists or ED physicians experienced in diagnosing HF.
• Number of Experts: Not specified. The document only mentions "independent cardiologists or ED physicians," implying more than one, but not a precise number.
• Qualifications: "Experienced in diagnosing HF." No specific number of years of experience or board certifications are mentioned.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

• The document states that the final clinical diagnosis was "adjudicated by independent cardiologists or ED physicians experienced in diagnosing HF." It does not specify a quantitative adjudication method like "2+1" or "3+1." This suggests that the adjudication process was qualitative and relied on the clinical expertise of the adjudicators to reach a consensus diagnosis for each patient, rather than a fixed number of readers and a tie-breaking rule.

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

• No, a MRMC comparative effectiveness study was not done. This document describes the performance validation of an in vitro diagnostic (IVD) immunoassay kit (VITROS NT-proBNP II Reagent Pack), which measures blood biomarkers. This is not an AI/imaging device where human readers would typically be assisted by AI. The product is a laboratory test, and its performance is evaluated based on its accuracy in measuring the biomarker and its diagnostic utility compared to clinical truth.

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

• Yes, this is effectively a standalone performance study. The VITROS NT-proBNP II Reagent Pack provides a quantitative measurement of NT-proBNP. Its performance is assessed purely on the analytical accuracy of the measurement and its direct correlation with clinical outcomes (diagnosis of HF, NYHA classification) as determined by the expert adjudicators, without human interpretation of the device's numerical output for diagnosis (i.e., it's a direct measurement, not an interpretative AI). The output values are then interpreted against established cutoffs to aid in diagnosis, but the device itself does not involve a human-in-the-loop for its direct performance.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

• The primary ground truth for heart failure diagnosis was expert clinical judgment/adjudication. For the diagnostic studies, "The final clinical diagnosis was adjudicated by independent cardiologists or ED physicians experienced in diagnosing HF."
• For the assessment of heart failure severity, the ground truth was New York Heart Association (NYHA) Functional Classification, which is a clinical classification based on patient symptoms and physical activity levels.

8. The sample size for the training set

• This document describes the validation of an in vitro diagnostic device (a reagent pack and system) for measuring a biomarker, not a machine learning or AI algorithm in the typical sense that would involve a "training set" for model development. The assays (immunoassays) are based on chemical reactions rather than statistical models trained on large datasets.
• The "training" of such a device primarily involves rigorous analytical development and characterization, ensuring the chemical processes are precise and accurate. Therefore, the concept of a separate "training set" with ground truth data, as used in AI/ML, is not directly applicable here. The document focuses on the performance validation of the developed assay.

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

• As noted above, the concept of a "training set" with ground truth for an AI/ML algorithm doesn't directly apply to this type of IVD immunoassay. The analytical methods and performance characteristics (precision, linearity, LoD, LoQ, analytical specificity, etc.) are established through laboratory experiments and characterization studies, not by training on a clinical dataset with ground truth in the AI/ML sense. Clinical performance is then validated against independently established clinical diagnoses (expert adjudication).

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The Tosoh ST AIA-PACK BNP assay is designed for IN VITRO DIAGNOSTIC USE ONLY for the quantitative measurement of BNP in human K2EDTA plasma on Tosoh AIA System analyzers. BNP is used as an aid in the diagnosis of heart failure (HF) in patients presenting to the emergency department (ED) with clinical suspicion of new onset HF, acutely decompensated or exacerbated HF.

The ST AIA-PACK BNP is a two-site immunoenzymometric assay which is performed entirely in the ST AIA-PACK BNP test cups. BNP present in the test sample is bound with monoclonal antibody immobilized on magnetic beads and enzyme-labeled monoclonal antibody. The magnetic beads are washed to remove unbound enzyme-labeled monoclonal antibody and are then incubated with a fluorogenic substrate, 4-methylumbelliferyl phosphate (4MUP). The amount of enzyme-labeled monoclonal antibody that binds to the beads is directly proportional to the BNP concentration in the test sample. A standard curve is constructed, and unknown sample concentrations are calculated using the curve.

The provided text describes the performance characteristics and clinical study results for the ST AIA-PACK BNP assay, an in vitro diagnostic device. This device is intended for the quantitative measurement of BNP in human K2EDTA plasma as an aid in the diagnosis of heart failure (HF).

Here's an analysis of the acceptance criteria and the study proving the device meets these criteria, based on the provided document:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly state "acceptance criteria" in a table format with pass/fail thresholds. Instead, it presents performance data from various analytical and clinical studies. We can infer performance parameters that would typically be subject to acceptance criteria in such a submission.

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

• Test Set Sample Size:
  • Analytical Performance:
    • Precision: 6 K2EDTA plasma samples tested, each at n=80 per lot across 3 lots (total n=240 for combined lot analysis).
    • Linearity: 14 samples ranging from 3.1 - 2271.5 pg/mL.
    • Detection/Quantitation Limit: 11 low-level samples tested in 10 replicates each (2 replicates over 5 days).
    • Interference: K2EDTA samples with known BNP concentrations spiked with various interferents/cross-reactants. Specific N for each interferent test not explicitly stated but implied multiple samples.
  • Clinical Performance:
    • Number of samples assayed: 825
    • Number of samples used for analysis (test set): 724 (101 excluded due to hemolysis, severe renal insufficiency, etc.)
• Data Provenance:
  • Country of Origin: Not explicitly stated for analytical samples. For clinical study: Samples were collected from patients presenting to Emergency Departments (EDs) at 8 clinical sites. The specific country is not mentioned, but given the FDA submission, it is likely the US or a region adhering to similar clinical trial standards.
  • Retrospective or Prospective:
    • Analytical performance: Appears to be prospective testing (e.g., precision study conducted at one site with specified reagents/analyzers, linearity study explicitly designed).
    • Clinical Performance: Prospective study, as it states "The prospective study enrolled male and female patients from 8 clinical sites comprised of Emergency Departments (ED)."

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

• Number of Experts: An independent central adjudication panel comprised of 4 expert cardiologists and 1 ER physician.
• Qualifications of Experts: Expert Cardiologists and an ER Physician. Their specific years of experience are not stated, but their designation as "expert" and the role in an adjudication panel for a clinical trial implies significant experience and qualifications in their respective fields related to heart failure diagnosis.

4. Adjudication method for the test set

• Adjudication Method: Diagnosis of HF or non-HF was determined by an independent central adjudication panel. The panel had access to patient CRFs and clinical information (including echocardiography, other cardiac/thoracic imaging, and standard of care BNP or NT-proBNP results if available). They were blinded to the attending physician's final diagnosis and NYHA classification. The document states that the adjudication was done "to ensure standardization and accuracy of diagnosis per 2013 ACCF/AHA Guidelines for Management of HF." This indicates a consensus-based approach based on comprehensive clinical data, supervised by multiple blinded experts.

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

• No, an MRMC comparative effectiveness study was not done. This submission is for an in vitro diagnostic (IVD) device (a blood test for BNP), not an AI-assisted diagnostic imaging device. Therefore, the concept of "human readers improving with AI vs without AI assistance" does not apply in this context. The study evaluates the performance of the assay itself compared to a ground truth established by clinical adjudication.

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

• Yes, a standalone performance was done. The clinical study evaluates the performance of the "ST AIA-PACK BNP assay" itself to quantitatively measure BNP and its ability to aid in the diagnosis of HF. The results (sensitivity, specificity, AUC) are presented as the performance of the device at the given cutoff, without human interpretation of the device's output influencing the performance metrics being reported. The human element (adjudication panel) was used to establish the ground truth for diagnosis, against which the device's measurements were compared.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

• Type of Ground Truth: The ground truth for the clinical study was established by expert consensus based on comprehensive clinical information and per established guidelines. Specifically, the "Diagnosis of HF or non- HF was determined by an independent central adjudication panel (comprised of 4 expert cardiologists and 1 ER physician) ... per 2013 ACCF/AHA Guidelines for Management of HF." They had access to patient CRFs, echocardiography, other cardiac/thoracic imaging, and standard of care BNP/NT-proBNP results. This represents a robust form of expert consensus based on extensive clinical data.

8. The sample size for the training set

• The document does not explicitly mention a separate "training set" for the device's development. The "Performance Characteristics" section details analytical and clinical validation studies. For a quantitative IVD like this, the "training" aspect is typically related to the assay's development, calibration, and optimization of reagents and protocols, rather than an explicit "training set" used in machine learning. The clinical study described is a validation study (test set).

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

• As a specific "training set" for algorithmic learning is not mentioned (as this is a biochemical assay), the concept of ground truth for a training set in that sense does not apply directly. However, the development of such an assay involves extensive work to ensure its accuracy and reliability across the dynamic range, linearity, precision, and minimizing interference. This often uses well-characterized, sometimes synthetic or spiked, samples with known concentrations to inform the assay's design and calibration. The "Traceability" section mentions that "The ST AIA-PACK BNP CALIBRATOR SET contains assigned concentrations of BNP. The assigned value is determined on a lot-by-lot basis and is designed to provide an assay calibration range of 4.0 to 2,000 pg/mL of BNP. The calibrators in this set are prepared gravimetrically and are compared to internal reference standards." This implies the "ground truth" for the internal calibration and ongoing quality control of the assay is established through gravimetric preparation and comparison to internal reference standards.

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Reagent Kit:

The ARCHITECT Galectin-3 assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of galectin-3 in human serum and EDTA plasma.

The ARCHITECT Galectin-3 assay may be used in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic heart failure (HF). The ARCHITECT Galectin-3 assay is used with the ARCHITECT i System with STAT protocol capability.

Calibrators:

The ARCHITECT Galectin-3 Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of galectin-3 in human serum and EDTA plasma.

Controls:

The ARCHITECT Galectin-3 Controls are for the verification of the ARCHITECT i System when used for the quantitative determination of galectin-3 in human serum and EDTA plasma.

The ARCHITECT Galectin-3 assay is a two-step immunoassay for the guantitative determination of galectin-3 in human serum or EDTA plasma using CMIA technology with flexible assay protocols, referred to as Chemiflex.

In the first step, sample and M3/38 anti-galectin-3 coated paramagnetic microparticles are combined. Galectin-3 present in the sample binds to the anti-galecin-3 coated microparticles. After washing, 87B5 anti-galectin-3 acridinium-labeled conjugate is added to create a reaction mixture in the second step. Following another wash cycle, pre-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 galectin-3 in the sample and the RLUs detected by the ARCHITECT i System optics. The kit is composed of the following:

ARCHITECT Galectin-3 Reagent Kit (5P03)
ARCHITECT Galectin-3 Calibrators (5P03-01)
ARCHITECT Galectin-3 Controls (5P03-10)

Here's the information about the acceptance criteria and the study that proves the device meets them, 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

• Precision (Analytical):

  • Test Set Description: 3 levels of controls and 5 levels of human serum and plasma panels.
  • Sample Size: Minimum of two replicates at two separate times per day for 20 different days (for one lot study) and for 10 different days (for two lots study), for a total of 40 replicates for each lot in the reproducibility study.
  • Data Provenance: Human serum and plasma samples. Retrospective (implied, as samples were collected and then tested for the study). Country of origin is not specified but implied to be US since the submission is to FDA.

• Linearity/Assay Reportable Range:

  • Test Set Description: Two serum samples (one low, one high) and two plasma samples (one low, one high).
  • Sample Size: Neat and diluted panels tested in replicates of three.
  • Data Provenance: Serum and plasma samples. Retrospective (implied). Country of origin not specified.

• Detection Limit:

  • Test Set Description: 7 normal human serum samples in ARCHITECT Galectin-3 Calibrator A, and Low Level Panel Set.
  • Sample Size: Replicates of five, twice per day over three days on two systems with two reagent lots (N= 120).
  • Data Provenance: Normal human serum samples. Retrospective (implied). Country of origin not specified.

• Analytical Specificity (Cross-Reactivity):

  • Test Set Description: Four serum and four plasma samples.
  • Sample Size: The 8 prepared samples were tested in replicates of three.
  • Data Provenance: Human serum and plasma samples. Retrospective (implied). Country of origin not specified.

• Analytical Specificity (Therapeutic Interference):

  • Test Set Description: Serum and plasma samples with various therapeutic agents spiked in.
  • Sample Size: Each galectin-3 sample pool was split into 2 equal aliquots for each therapeutic tested (test and control).
  • Data Provenance: Serum and plasma samples. Retrospective (implied). Country of origin not specified.

• Analytical Specificity (Endogenous Substance Interference):

  • Test Set Description: Serum and plasma samples with various endogenous substances spiked in.
  • Sample Size: Each galectin-3 sample was split into two aliquots for each endogenous substance tested (test and control).
  • Data Provenance: Serum and plasma samples. Retrospective (implied). Country of origin not specified.

• Clinical Study (Prognosis in HF):

  • Test Set Description: Specimens from a multicenter cohort of outpatients with chronic heart failure (HF).
  • Sample Size: 405 serum specimens.
  • Data Provenance: Human serum specimens from a multicenter cohort. Retrospective clinical study ("obtained at time of study entry"). Country of origin is not specified but the submission is to the US FDA.

• Expected Values/Reference Range:

  • Test Set Description: Plasma samples from apparently healthy subjects without known heart disease.
  • Sample Size: 274 plasma samples (133 females, 141 males).
  • Data Provenance: Plasma samples from an observational study. Retrospective (implied). Country of origin not specified.

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

• No information is provided about experts establishing ground truth for the analytical performance studies. These studies typically use pre-defined concentrations or reference materials.
• For the clinical study evaluating prognosis in HF: The ground truth (primary endpoint: hospitalization due to worsening HF, ventricular assist device placement, cardiac transplantation, or all-cause mortality) is based on outcome data. This would typically be recorded clinical events, not established by an adjudication panel of experts in the same way an imaging study would be. The clinical evaluation and diagnosis of heart failure, and classification of events, would be performed by treating physicians/specialists, but the specific process for confirming these outcomes for the study is not detailed as involving a separate panel of experts for ground truth establishment.

4. Adjudication Method for the Test Set

• Not applicable for the analytical performance studies as they rely on quantitative measurements against known standards or reference methods.
• For the clinical study, an explicit adjudication method (e.g., 2+1, 3+1) is not described for the primary endpoint events. The primary endpoint (hospitalization due to worsening HF, ventricular assist device placement, cardiac transplantation, or all-cause mortality) are events recorded during patient follow-up. While clinical judgments are involved in diagnosing and reporting these events, the document doesn't indicate a separate, independent adjudication panel for confirming these outcomes specifically for the study data.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size

• No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) assay that quantitatively measures galectin-3 from patient samples. MRMC studies are typically used for imaging devices or AI algorithms that assist human readers in interpreting complex images or data. The ARCHITECT Galectin-3 assay provides a numerical value, which is then used in conjunction with clinical evaluation, rather than assisting a human reader in a diagnostic task that involves pattern recognition.

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

• Yes, the ARCHITECT Galectin-3 assay operates as a standalone algorithm (device only). It produces a quantitative value (ng/mL) of galectin-3 from a patient sample. The performance characteristics described (precision, linearity, detection limit, analytical specificity) are all based on the device's ability to accurately and precisely provide this numerical output. The "human-in-the-loop" aspect comes during the interpretation of the result in conjunction with clinical evaluation, but the assay itself functions independently to generate the measurement. The clinical study demonstrates its effectiveness in its standalone capacity to provide a prognostic indicator.

7. The Type of Ground Truth Used

• Analytical Studies: The ground truth for analytical performance studies (precision, linearity, detection limit, analytical specificity) generally relies on reference materials, known concentrations, or established standard methods. For instance, precision is measured against the device's own reported values, linearity against expected dilutions, and detection limits against known low-concentration samples.
• Clinical Study: The ground truth for the clinical validation study was outcomes data. Specifically, the primary endpoint was a composite of hospitalization due to worsening HF, ventricular assist device placement, cardiac transplantation, or all-cause mortality. These are objective clinical events recorded during patient follow-up.

8. The Sample Size for the Training Set

• This is an in vitro diagnostic (IVD) assay, not typically an AI/ML algorithm that requires a distinct "training set" in the conventional sense of supervised machine learning.
• The "training" equivalent for an IVD kit would be the internal development and optimization work, including the choice of reagents, antibodies, and manufacturing processes. The document does not specify a "training set" size. The calibrators and controls (6 levels for calibrators, 3 levels for controls) are used for routine calibration and quality control of the instrument and assay, not a training set for an AI model.

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

• As explained above, there isn't a "training set" for an AI/ML model for this type of IVD device.
• The calibrators' concentrations (0.0 ng/mL to 114.0 ng/mL) and controls' target concentrations (9.1 ng/mL, 20.5 ng/mL, 74.1 ng/mL) are established. The text states that "The primary calibrators for the ARCHITECT Galectin-3 assay were manufactured gravimetrically and produced based on protein content." This means their concentrations are determined by a highly precise gravimetric (weighing) method and based on the amount of recombinant human galectin-3 protein added. This serves as the "ground truth" for calibrating the assay.

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The Critical Diagnostics Presage® ST2 Assay kit is an in vitro diagnostic device that quantitatively measures ST2 in serum or plasma by enzyme-linked immunosorbant assay (ELISA) in a microtiter plate format. The Presage® ST2 Assay is indicated to be used in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic heart failure.

The Presage® ST2 Assay Kit Controls, Level 1 and Level 2, are designed to be used for monitoring the performance of test procedures on the Critical Diagnostics Presage® ST2 Assay kit.

The Critical Diagnostics Presage® ST2 Assay kit is an in vitro diagnostic device that quantitatively measures ST2 in serum or plasma by enzyme-linked immunosorbant assay (ELISA) in a microtiter plate format.

The provided text is a 510(k) summary for the Presage® ST2 Assay. It focuses on the device's intended use, classification, and substantial equivalence to a predicate device. It does not contain information about acceptance criteria or the specific studies conducted to demonstrate that the device meets those criteria.

The document states: "The Critical Diagnostics Presage® ST2 Assay kit is an in vitro diagnostic device that quantitatively measures ST2 in serum or plasma by enzyme-linked immunosorbant assay (ELISA) in a microtiter plate format. The Presage® ST2 Assay is indicated to be used in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic heart failure."

Therefore, I cannot provide the requested table or detailed information about the study proving the device meets acceptance criteria, as that information is not present in the provided text.

To answer your request, I would need a different document that describes the performance studies (e.g., clinical trials, analytical validation) and the acceptance criteria established for the Presage® ST2 Assay.

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