Biomarker-enhanced Artificial Intelligence Based Pediatric Sepsis Screening Tool

Study Overview
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Brief Summary
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The overall objective of this proposed research is the derivation of a biomarker-enhanced artificial intelligence (AI)-based pediatric sepsis screening tool (PSCT) (software) that can be used in combination with the hospital's electronic health record (EHR) system to monitor and assess real-time emergency department (ED) electronic health record (EHR) data towards the enhancement of early pediatric sepsis recognition and the initiation of timely, aggressive personalized sepsis therapy known to improve patient outcomes. It is hypothesized that the screening performance (e.g., positive predictive value) of the envisioned screening tool will be significantly enhanced by the inclusion of a biomarker panel test results (PERSEVERE) that have been shown to be effective in prediction of clinical deterioration in non-critically ill immunocompromised pediatric patients evaluated for infection. It is also hypothesized that enhanced phenotypes can be derived by clustering PERSEVERE biomarkers combined with routinely collected EHR data towards improved personalized medicine.

Detailed Description
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Background and Rationale Existing automated pediatric sepsis screening tools (PSCT) based on consensus criteria currently used in emergency departments do not improve early recognition and/or inform personalized therapeutic decisions leading to improved outcomes. The Improving Pediatric Sepsis Outcomes (IPSO) initiative found that by including patients that receive treatment, the extended criteria captured not only patients who developed sepsis with organ dysfunction (OD), but also those in whom early sepsis was treated with OD potentially averted. The objective of the proposed effort is to derive and retrospectively validate a biomarker-enhanced AI-based pediatric sepsis screening tool that can be used to screen ED EHR data to improve early recognition, severity stratification, and the timely initiation of personalized sepsis therapy. CTA and its 6 institutional partners jointly propose to establish two de-identified patient registries: 1) the EHR-data only cohort (N = 2000) and 2) the EHR + biomarker data cohort (N = 400) in support of this objective. Encounter data elements to be abstracted from EHRs for inclusion in these registries include both structured (e.g., time-stamped physiological measurements, treatments, procedures, outcomes) as well as free text notes. Data Analysis and biases All study data, including physiological data extracted from patient EHR and results of biomarker assays will be analyzed using a variety of machine learning algorithms and techniques towards producing a high precision sepsis screening predictive model. Analytic methods involve standard descriptive statistical analysis of predictive classification performance (e.g., AUC, sensitivity/specificity, PPV, etc.).

Official Title
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Biomarker-enhanced Artificial Intelligence Based Pediatric Sepsis Screening Tool Towards Early Recognition and Personalized Therapeutics

Conditions
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Sepsis

Intervention / Treatment
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* Diagnostic Test: Pediatric sepsis screening tool (either algorithmic or manual)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 3 months -17 years of age, inclusive Diagnosed with sepsis by a clinician or trigger a sepsis alert and a blood culture is ordered. Controls will be false positive patients. For those patients that will be prospectively enrolled for blood sample collection: will require a venipuncture or intravenous line placement. Exclusion Criteria: Patients participating in an investigational program with interventions outside of routine clinical practice Patients with parents or LARs that don't speak English or Spanish Pregnancy

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Retrospective EHR-data only group<br>Members of this group are pediatric patients between the ages of 3 months to 17 years inclusive, that presented to one of the six participating institution's emergency department between the years 2016-2021 and screened positive for suspicion of sepsis using the institution's existing pediatric sepsis screening protocol and receive a blood culture order. Current pediatric screening/alerting tools are known to be highly sensitive but poorly specific. Cases in this cohort will be comprised of those that are ultimately diagnosed with sepsis and/or receive protocolized sepsis treatment. Controls in this cohort will be those with a false positive alert, i.e., are not diagnosed with sepsis and do not receive protocolized sepsis treatment. | Diagnostic Test: Pediatric sepsis screening tool (either algorithmic or manual)<br>* All participating institutions employ either an algorithmic, manual, or combined algorithmic/manual pediatric sepsis screening protocol for patients that present with fever and/or a concern for infection. While the specific parameters tested in screening tools differ, they generally consist of tests for a systemic inflammatory response (e.g. SIRS) and/or organ dysfunction (e.g. SOFA) and/or high susceptibility (e.g. immunocompromised) factors.<br>|
| Prospective EHR and Biomarker data group<br>Members of this group are pediatric patients between the ages of 3 months to 17 years inclusive, that presented to one of the six participating institution's emergency department during the study enrollment period, screen positive for suspicion of sepsis using the institution's existing pediatric sepsis screening protocol, receive a blood culture order and provide informed consent/assent for the collection of a 1-5 mL blood sample to be used to measure PERSEVERE biomarkers. Members of this cohort will have also consented to the reuse of their medical record data for the research. Current pediatric screening/alerting tools are known to be highly sensitive but poorly specific. Cases in this cohort will be comprised of those that are ultimately diagnosed with sepsis and/or receive protocolized sepsis treatment. Controls in this cohort will be those with a false positive alert, i.e., are not diagnosed with sepsis and do not receive protocolized sepsis treatment. | Diagnostic Test: Pediatric sepsis screening tool (either algorithmic or manual)<br>* All participating institutions employ either an algorithmic, manual, or combined algorithmic/manual pediatric sepsis screening protocol for patients that present with fever and/or a concern for infection. While the specific parameters tested in screening tools differ, they generally consist of tests for a systemic inflammatory response (e.g. SIRS) and/or organ dysfunction (e.g. SOFA) and/or high susceptibility (e.g. immunocompromised) factors.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effective Expert System-based Pediatric Sepsis Screening Tool (PSCT) | Over a usability test period, by emulation of the logic of experts in a screening tool that cam be continuously improved with experience, achieve a high level of ED workflow usability towards improved early recognition of IPSO sepsis, as perceived by practicing ED clinicians engaged in usability testing. | Final 3 months of study period. | 
| High performance Expert System-based Pediatric Sepsis Screening Tool (PSCT) | To derive a high performing (e.g., sensitivity/specificity > 90%, PPV > 40%) PSCT to identify patients in the ED meeting IPSO sepsis criteria using early encounter data (e.g. upon receipt of biomarker data within 1st 1-3 hours of presentation). | Using early data following presentation to ED, e.g., upon receipt of biomarker data within 1st 3 hours of presentation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effective sepsis phenotyping for personalized treatment | To show that combined PERSEVERE biomarker and EHR data as clustering features (e.g. using latent class analysis) enhances the detection of clinically useful prognostic phenotypes. | Features based on 1st 6 hours following presentation in patients diagnosed with sepsis and treatment protocol initiated. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric sepsis