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The Cytovale IntelliSep test is a semi-quantitative test that assesses cellular host response via deformability cytometry of leukocyte biophysical properties and is intended for use in conjunction with clinical assessments and laboratory findings to aid in the early detection of sepsis with organ dysfunction manifesting within the first 3 days after testing. It is indicated for use in adult patients with signs and symptoms of infection who present to the Emergency Department. The test is performed on an EDTA anticoagulated whole blood sample.

The IntelliSep test generates an IntelliSep Index value that falls within one of three discrete interpretation bands based on the probability of sepsis with organ dysfunction manifesting within the first three days after testing. The IntelliSep test represents the probability of the clinical syndrome of sepsis and is intended to be used alongside other clinical information and clinical judgement. It does not identify the causative agent of infection and should not be used as the sole basis to determine the presence of sepsis. The IntelliSep test is intended for in vitro diagnostic use.

The Cytovale IntelliSep test is a short turn-around time (STAT) test, producing results in 10 minutes or less, to aid in the early identification of patients at risk for having or developing sepsis within three (3) days of testing. It assesses the state of immune activation in patients with clinical suspicion of infection who present in the Emergency Department (ED).

The IntelliSep test is run on the Cytovale System, a laboratory benchtop analyzer depicted in Figure 1. The Cytovale System is a closed system benchtop analyzer, comprised of three modules: Sample Preparation Module, Cell Imaging Module, and Imaging Analysis Module.

To run a test, the laboratory operator transfers 100 µL of whole blood into the sample preparation tube which is then placed into the Cytovale System. The system automatically lyses red blood cells, and washes the purified leukocytes in a diluent, producing a total volume of approximately 1mL of prepared sample, which the operator then transfers to the IntelliSep cartridge for analysis on the Cytovale System.

A microfluidic deformability cytometry technique is used to measure the biophysical properties of thousands of individual leukocytes in rapid succession. These properties have been shown to differ in quiescent white blood cell populations when compared to those in septic patients, enabling for rapid assessment of the host response and the likelihood of having or developing sepsis. Based on these measurements, the test provides a single score, the IntelliSep Index (ISI), ranging from 0.1-10.0, stratified into three discrete interpretation bands (Band 1, Band 2, Band 3) of sepsis likelihood.

Here's a breakdown of the acceptance criteria and study details for the Cytovale IntelliSep test, based on the provided document:

Acceptance Criteria and Device Performance

The document does not explicitly state pre-defined quantitative acceptance criteria in a pass/fail format for clinical performance endpoints (e.g., a specific PPV or likelihood ratio threshold). Instead, it focuses on demonstrating a clear relationship between the IntelliSep Index (ISI) and the likelihood of sepsis, and the statistical distinctness of the interpretation bands. For analytical performance, criteria are generally established for standard deviations within precision studies and confidence intervals for reproducibility and carry-over.

Here's a table summarizing the reported device performance, categorized by the relevant studies:

Clinical Performance

Implicit Acceptance Criterion: A clear relationship between ISI and the increasing likelihood of sepsis, and statistically distinct interpretation bands (non-overlapping 80% confidence intervals between bands).

Note: The clinical study explicitly states: "It is important to note that the algorithm for calculating the ISI ranges for the interpretation bands were defined based on prior sepsis-focused studies. No information from patients in this study influenced the calculations or interpretation bands of the ISI." and "Irrespective of the comparator scheme chosen, the probability of sepsis in the three ISI IntelliSep test Interpretation Bands was statistically distinct, defined as non-overlapping 80% confidence intervals between the bands." This suggests the demonstration of statistically distinct bands with appropriate clinical trends was the primary clinical performance criterion.

Analytical Performance

Study Details

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

   • Test Set Sample Size: 572 evaluable subjects were included in the primary analyses for clinical performance.
   • Data Provenance: The study was a "blinded, prospective, observational, multicenter cohort study" conducted at five hospitals at four geographically dispersed sites in the United States. The subjects were "representative of the adult population (≥ 18 years of age) typical of those presenting to EDs across the United States."

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

   • Number of Experts: A multi-tiered adjudication process was used:
     • Initially, two independent adjudicators reviewed each case.
     • If there was disagreement, a third adjudicator was involved in a consensus meeting.
   • Qualifications of Experts: Physicians with board certification in Medical or Surgical Critical Care (CC), Infectious Diseases (ID), Emergency Medicine (EM), or Internal Medicine (IM) or related fields, from different institutions. They were not participating as an Investigator in the Study.

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

   • The adjudication method was 2+1 (two independent adjudicators, with a third used for arbitration in case of disagreement).
   • Outcomes were categorized as 'unanimous' (both initial adjudicators agreed), 'consensus' (third adjudicator facilitated agreement), or 'forced' (majority two out of three if consensus couldn't be reached). The performance data is presented for all three schemes (forced, consensus, unanimous).

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, an MRMC comparative effectiveness study was not explicitly stated or performed. The study evaluated the IntelliSep test as an aid in conjunction with clinical assessments and laboratory findings, but it did not directly compare human reader performance with and without AI assistance (i.e., IntelliSep test results). The test provides a quantitative index and interpretation bands, not an image for interpretation by human readers.

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

   • Yes, a standalone performance evaluation was done. The IntelliSep test generates an "IntelliSep Index" (ISI) automatically from the measured biophysical properties of leukocytes. The clinical performance section directly assesses the predictive values and likelihood ratios of this automatically generated ISI, independent of real-time human interpretation during the study (treating physicians were unaware of study enrollment and IntelliSep test results). The test is intended for use in conjunction with clinical assessments, but its performance metrics are derived from the algorithm's output itself.

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

   • The ground truth was established through retrospective physician adjudication based on consensus definitions for Sepsis-2 and Sepsis-3. This involved a multi-tiered process by qualified physicians:
     • Collection of detailed patient information (demographics, labs, vitals, medical history, hospital encounter, infectious disease, medications, discharge disposition, SOFA scores, clinical impression).
     • Compilation into a Case Report Summary (CRS).
     • Review by independent adjudicators with arbitration for discordant results.
   • It's a form of expert consensus based on clinical data.

7. The sample size for the training set:

   • The document states: "It is important to note that the algorithm for calculating the ISI ranges for the interpretation bands were defined based on prior sepsis-focused studies. No information from patients in this study influenced the calculations or interpretation bands of the ISI."
   • This implies the training of the algorithm and definition of interpretation bands occurred prior to and separate from this specific clinical validation study. The sample size for the training set is not provided in this document.

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

   • Similar to the point above, the document only mentions that the ISI algorithm and interpretation bands were "defined based on prior sepsis-focused studies."
   • The method for establishing ground truth for those prior training studies is not detailed in this document.

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