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The SeptiCyte RAPID test is a gene expression assay using reverse transcription polymerase chain reaction to quantify the relative expression levels of host response genes isolated from whole blood collected in PAXgene Blood RNA Tubes, K2-EDTA blood tubes, or K3-EDTA blood tubes. The SeptiCyte RAPID test is used in conjunction with clinical assessments and other laboratory findings as an aid to differentiate infection-positive (sepsis) from infection-negative systemic inflammation in patients suspected of sepsis on their first day of ICU admission. The SeptiCyte RAPID test generates a score (SeptiScore) that falls within one of four discrete Interpretation Bands based on the increasing likelihood of infection-positive systemic inflammation. SeptiCyte RAPID is intended for in-vitro diagnostic use on the Biocartis Idylla System.

The SeptiCyte RAPID test is a gene expression assay using reverse transcription polymerase chain reaction to quantify the relative expression levels of host response genes isolated from whole blood collected in PAXgene Blood RNA Tubes, K2-EDTA blood tubes, or K3-EDTA blood tubes. The SeptiCyte RAPID test is used in conjunction with clinical assessments and other laboratory findings as an aid to differentiate infection-positive (sepsis) from infection-negative systemic inflammation in patients suspected of sepsis on their first day of ICU admission. The SeptiCyte RAPID test generates a score (SeptiScore) that falls within one of four discrete Interpretation Bands based on the increasing likelihood of infection-positive systemic inflammation. SeptiCyte RAPID is intended for in-vitro diagnostic use on the Biocartis Idylla System.

The provided document is a 510(k) clearance letter for the SeptiCyte RAPID device, but it does not contain the detailed acceptance criteria, study design, or performance data that would typically be found in a summary of safety and effectiveness or a clinical study report. Therefore, I cannot fully answer your request based only on the provided text.

However, I can extract information about the device's intended use and general context, and explain what kind of information would be needed to answer your questions if it were present.

Based on the provided text:

The document concerns the SeptiCyte RAPID device, a gene expression assay using reverse transcription polymerase chain reaction.

Intended Use: The SeptiCyte RAPID test is used:

• In conjunction with clinical assessments and other laboratory findings.
• As an aid to differentiate infection-positive (sepsis) from infection-negative systemic inflammation.
• In patients suspected of sepsis on their first day of ICU admission.
• It generates a "SeptiScore" with four discrete Interpretation Bands indicating the increasing likelihood of infection-positive systemic inflammation.
• It's for in-vitro diagnostic use on the Biocartis Idylla System.

To answer your specific questions, the following information would be required from a more detailed submission document (e.g., 510(k) Summary of Safety and Effectiveness):

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

• This would typically include metrics like Sensitivity, Specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), and possibly AUC, along with the predefined acceptance thresholds for these metrics. The provided document does not include this table.

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• The document does not specify the sample size for the test set or its provenance (country/retrospective/prospective).

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

• The document does not provide details on ground truth establishment, expert number, or qualifications.

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

• The document does not describe an adjudication method.

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

• The SeptiCyte RAPID is described as a "gene expression assay" and not explicitly as an AI/CADe/CADx device that assists human readers. Therefore, an MRMC study comparing human readers with and without AI assistance is unlikely for this type of device, unless it has a human interpretation component, which is not evident here. The document does not mention an MRMC study or effect size.

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

• The SeptiCyte RAPID operates by quantifying gene expression to generate a "SeptiScore." This implies a standalone algorithmic assessment based on biological markers. The device is intended to be used "in conjunction with clinical assessments and other laboratory findings," suggesting it provides data for clinicians to interpret, rather than replacing clinical judgment. However, the performance of the device itself (its ability to differentiate sepsis) would be evaluated in a standalone manner. The document does not explicitly state a standalone study was done, but given the nature of the device, its core performance would be standalone.

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

• The document does not specify the type of ground truth used to establish reference for sepsis diagnosis in the study. For sepsis, ground truth is often clinical diagnosis based on a combination of criteria (e.g., Sepsis-3 definitions, physician review, culture results, organ dysfunction).

8. The sample size for the training set

• The document does not mention any details about a training set size.

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

• The document does not mention any details about how the ground truth for a training set was established.

In summary: The provided FDA clearance letter is a regulatory approval notice and lacks the detailed technical and clinical study information required to answer most of your questions. This detailed information would typically be found in the 510(k) "Summary of Safety and Effectiveness" document submitted by the manufacturer to the FDA.

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The SeptiCyte ® RAPID test is a gene expression assay using reverse transcription polymerase chain reaction to quantify the relative expression levels of host response genes isolated from whole blood collected in the PAXgene ® Blood RNA Tube. The SeptiCyte ® RAPID test is used in conjunction with clinical assessments and other laboratory findings as an aid to differentiate infection-positive (sepsis) from infectionnegative systemic inflammation in patients suspected of sepsis on their first day of ICU admission. The SeptiCyte ® RAPID test generates a score (SeptiScore®) that falls within one of four discrete Interpretation Bands based on the increasing likelihood of infectionpositive systemic inflammation. SeptiCyte ® RAPID is intended for in-vitro diagnostic use on the Biocartis IdyllaTM System.

SeptiCyte RAPID is an in vitro diagnostic test for simultaneous amplification and detection of two RNA transcripts (PLA2G7 and PLAC8) using total RNA extracted from human blood. The test has been designed, manufactured, and validated for use on the Biocartis Idylla real-time PCR system. The SeptiCyte RAPID test is performed with an Idylla Cartridge, a single-use, disposable, multi-chambered fluidic cartridge that runs on the Biocartis Idylla System. In an automated fashion, all reaction steps take place within the cartridge, including sample extraction/purification, RT-qPCR for the detection and relative quantification of the two human mRNA targets PLAC8. PLA2G7. Test results (measured Cg values and calculated SeptiScore) are available in about 65 minutes.

The specimen used for the SeptiCyte RAPID is a sample of whole blood collected in a PAXgene blood RNA tube (FDA 510k number K042613). The cartridge contains all of the necessary reagents to perform RNA isolation from the sample.

SeptiCyte RAPID uses quantitative, real-time determination of the amount of each transcript in the sample based on the detection of fluorescence by the Biocartis Idylla qPCR instrument function. The cartridge includes the reagents for reverse transcription and PCR. Transcripts PLAC8 and PLA2G7 are amplified and quantified. These values are combined to produce the SeptiScore, which is interpreted and categorized into four discrete bands, which are associated with a sequentially higher likelihood of sepsis.

Here's a breakdown of the acceptance criteria and the study details for the Immunexpress, Inc. SeptiCyte RAPID device, based on the provided FDA 510(k) summary:

1. Acceptance Criteria and Reported Device Performance

The clinical studies for SeptiCyte RAPID had the following acceptance criteria for the primary endpoint:

1. A monotonic increase in the probability of sepsis across the four SeptiScore interpretation bands.
2. Non-overlapping 80% confidence intervals for the probability of sepsis between non-adjacent SeptiScore interpretation bands (i.e., between bands 1 and 3; and between bands 2 and 4).

Here's the performance reported using the Forced RPD Method (as it covers the full dataset and shows the trend across all bands):

Proof of Acceptance:
The reported device performance demonstrates:

1. Monotonic Increase: The observed probabilities of sepsis (0.12, 0.24, 0.48, 0.80) clearly increase monotonically across the four bands, meeting the first criterion.
2. Non-overlapping 80% Confidence Intervals:
   • Band 1 (0.08 - 0.18) vs. Band 3 (0.4 - 0.56): The intervals do not overlap.
   • Band 2 (0.18 - 0.3) vs. Band 4 (0.74 - 0.84): The intervals do not overlap.
     This meets the second criterion.

The analysis using Consensus and Unanimous RPD methods also showed similar results, fulfilling the acceptance criteria.

2. Sample Size and Data Provenance for the Test Set

• Sample Size: N = 386
  • N = 356 from retrospective studies
  • N = 30 from a prospective study
• Data Provenance:
  • Retrospective Study: Netherlands-based Molecular diagnosis And Risk Stratification of sepsis (MARS) clinical trial (NCT01905033)
  • Retrospective Study: USA-based Validation of septic gene Expression Using SeptiCyte (VENUS) clinical trial (NCT02127502)
  • Prospective Study: USA-based NEar PatienT MolecUlar TestiNg in Sepsis (NEPTUNE) clinical trial

3. Number of Experts and Qualifications for Ground Truth Establishment

• Number of Experts: Three-member expert panel.
• Qualifications of Experts: Not explicitly stated beyond "external three-member expert panel not involved in the care of the patients." It does not specify their medical specialty (e.g., critical care physicians, infectious disease specialists) or years of experience.

4. Adjudication Method for the Test Set

Three different methods of Retrospective Physician Diagnosis (RPD) were used:

• Consensus: Two or three RPD panelists agree that the patient is either sepsis or SIRS. Indeterminates are excluded.
• Unanimous: All three RPD panelists, as well as the consensus discharge evaluation of the site investigators, agree that the patient is either sepsis or SIRS.
• Forced: Applied to patients initially called "indeterminate" by RPD panelists. The panelists are then forced to make a consensus or unanimous call of sepsis or SIRS.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed. The device is an in vitro diagnostic (IVD) assay that provides a score to aid in diagnosis, not an imaging AI or a system designed to assist human readers in interpretation. Therefore, the question of human readers improving with AI vs. without AI assistance is not applicable in this context.

6. Standalone Performance Study

Yes, a standalone performance study was done. The entire clinical evaluation is based on the SeptiCyte RAPID test (algorithm only) generating a SeptiScore and its associated interpretation bands. The clinical studies aim to validate the device's ability to differentiate infection-positive (sepsis) from infection-negative systemic inflammation based solely on its output.

7. Type of Ground Truth Used

The ground truth used was expert consensus or retrospective physician diagnosis (RPD). This involved an external three-member expert panel reviewing clinical cases to determine whether a subject's clinical status was SIRS, sepsis, or indeterminate.

8. Sample Size for the Training Set

The document does not explicitly state a separate sample size for a training set. The clinical studies described (MARS, VENUS, NEPTUNE) were primarily for validation and 510(k) clearance of the already developed SeptiCyte RAPID test. It's common for gene expression assays to be developed using earlier research cohorts, but this document focuses on the validation of the specific device. The clinical studies might have been used for final validation and refinement of the SeptiScore cut-offs, but a distinct "training set" for the algorithm itself is not mentioned here.

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

As a distinct training set is not explicitly detailed, the method for establishing its ground truth is also not described. However, given that the clinical validation ground truth was established by expert consensus/RPD, it is highly probable that any development or training earlier in the product lifecycle would have used similar methodologies.

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