Sepsis Multiomic Analysis & Risk sTratification in China (China SMART-1)

Sepsis Multiomic Analysis & Risk sTratification in China (China SMART-1): A Prospective Observational Cohort Study

Objectives:

1. Perform Bulk RNA-seq transcriptome sequencing on enrolled samples to screen sepsis-specific mRNA diagnostic biomarkers and evaluate their diagnostic efficacy for early sepsis in the ICU; establish a molecular risk stratification system for sepsis based on mRNA expression profiles, and clarify the immunobiological characteristics, clinical manifestation differences, and prognostic risk levels of each stratification.
2. Integrate core indicators screened from transcriptome sequencing, open-source databases, and previous studies to establish and optimize an RT-LAMP rapid detection method for core sepsis targets, validate its diagnostic accuracy, specificity, and reproducibility, and construct a rapid sepsis diagnostic model adapted to bedside scenarios.
3. Integrate core indicators screened from open-source databases and previous studies to screen sepsis-specific diagnostic biomarkers in plasma and urine via PRM and metabolomics, complete protein/metabolic level validation using immunological methods (ELISA), construct a combined diagnostic model for sepsis, and complete internal validation and efficacy evaluation.

Study Overview

• Status: Recruiting
• Conditions: Sepsis

Detailed Description

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and is listed by the World Health Organization as one of the top 10 causes of death worldwide. According to the Global Burden of Disease Study (GBD 2017), there are approximately 48.9 million cases of sepsis globally each year, resulting in about 11 million deaths, with a case fatality rate as high as 20%-40%. In China, the incidence of sepsis is approximately 240 cases per 100,000 population, and the sepsis-related mortality rate in ICU patients reaches 35.5%, significantly higher than that in developed countries. Although international guidelines (such as the Surviving Sepsis Campaign) emphasize the "golden 6 hours" early intervention concept, clinical practice still faces two core problems: delayed diagnosis and insufficient biomarker efficacy. The current diagnostic criteria (Sepsis-3) rely on the SOFA score and evidence of infection, but the SOFA score depends on laboratory indicators (such as platelets and bilirubin), which are difficult to obtain quickly in emergency settings. Commonly used clinical biomarkers such as procalcitonin (PCT) and C-reactive protein (CRP) have significant limitations: although PCT has certain specificity for bacterial infections, its sensitivity is low (approximately 60%-70%) in local infections (such as abscesses) or infections caused by atypical pathogens (such as viruses and fungi); as an acute-phase reactant, CRP elevation lags behind the inflammatory response (6-12 hours after infection) and is interfered with by non-infectious factors such as surgery and trauma; lactate reflects tissue hypoperfusion, but its elevation mostly indicates that the patient has entered the stage of septic shock, missing the window for early intervention.

Studies have shown that each 1-hour delay in the diagnosis of sepsis increases patient mortality by 7.6%. Therefore, the development of highly sensitive and specific early diagnostic tools is a key breakthrough to improve prognosis.

Although microbial culture is the gold standard for sepsis diagnosis, it takes too long and may delay the diagnosis of sepsis. In addition, microbial culture tests may be negative in approximately 30-50% of sepsis patients. Current research indicates that in the intensive care process of sepsis patients, clinical electronic medical record data are increasingly being used to construct multivariate clinical early warning models. Mining these data may accelerate clinical monitoring of sepsis and provide new ideas for the early identification of post-traumatic sepsis.

Peripheral blood mRNA expression levels can directly reflect the host's gene regulatory response to infection and theoretically show detectable systemic changes within hours after infection, having higher early diagnostic potential than protein biomarkers. With the maturity of RNA sequencing technology and the significant reduction in costs, biomarker screening based on whole transcriptome data has become an important strategy for discovering novel sepsis diagnostic biomarkers. However, existing transcriptome studies are mostly based on small-scale cohorts with limited sample sizes and mainly focus on European and American populations, lacking large-sample prospective studies that systematically screen and validate mRNA diagnostic biomarkers in Chinese ICU populations. In addition to diagnostic dilemmas, sepsis patients show significant differences in response to standardized treatment regimens, suggesting the existence of internal molecular subtypes with different biological characteristics. Transcriptomic studies have confirmed the molecular basis of this heterogeneity: Scicluna et al. identified four genomic intrinsic subtypes (MARS classification) in a European multicenter cohort, with significant differences in immune characteristics and 28-day mortality among subtypes; Seymour et al. described two robust clinical phenotypes (α-type and β-type), with β-type characterized by immunosuppression and multiple organ injury. These studies have laid the theoretical foundation for the precise stratification of sepsis, but their samples are all from European and American populations, and there are systematic differences in genetic background, pathogen spectrum, and medical practice compared with Chinese patients, limiting the direct extrapolation applicability of the classification results. Currently, there are no large-sample transcriptome-based stratification studies of sepsis in Chinese ICU populations. Therefore, we propose Substudy 1: Screening of early diagnostic molecular biomarkers and molecular stratification biomarkers for sepsis based on Bulk RNA-seq transcriptome sequencing.

Reverse transcription loop-mediated isothermal amplification (RT-LAMP) has the characteristics of high sensitivity, high specificity, and fast detection speed, and has been widely used in clinical testing. In our previous work, we developed relevant detection methods. Therefore, we propose Substudy 2: Validate the diagnostic efficacy of RT-LAMP as an early rapid bedside diagnostic tool for ICU sepsis.

In addition, we previously used data-independent acquisition (DIA) proteomics and untargeted metabolomics to screen biomarkers with diagnostic potential for sepsis from plasma, such as AHSG, CLU, SERPINA4, etc. (see Appendix 3 for details). Some biomarkers have been validated in cohort studies. Urine has the same diagnostic value. Therefore, we propose Substudy 3: Validate the diagnostic efficacy of plasma protein/metabolic biomarkers as early diagnostic biomarkers for ICU sepsis. Substudy 4: Validate the diagnostic efficacy of urine protein/metabolic biomarkers as early diagnostic biomarkers for ICU sepsis.

This study intends to rely on the ICU of Yuebei People's Hospital to prospectively enroll 1400 subjects (1000 sepsis cases, 400 non-sepsis controls) and establish the largest comprehensive biobank for sepsis research in Chinese ICUs to date. Bulk RNA-seq, RT-LAMP, parallel reaction monitoring (PRM) proteomics, metabolomics, and ELISA-based immunological detection techniques will be used to detect and analyze whole blood, plasma, or urine samples from enrolled patients.

• Study Type: Observational
• Enrollment (Estimated): 1400

Contacts and Locations

• Study Contact: Name: Pingsen Zhao Principal Investigator, Dr.; Phone Number: 8613332876639; Email: zhaopingsen01@163.com

Study Locations

• China
  • Guangdong
    • Shaoguan, Guangdong, China, 512026
      • Recruiting
      • Yuebei People's Hospital
      • Contact: Pingsen Zhao Principal Investigator, Dr.; Phone Number: 8613332876639; Email: zhaopingsen01@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Critically ill adult patients admitted to the ICU of Yuebei People's Hospital, Shaoguan, Guangdong, China. The study population includes patients with confirmed sepsis (Sepsis-3 criteria) and non-sepsis controls admitted during the same period. All participants had blood samples (plasma and whole blood RNA) and urine samples collected within 24 hours of ICU admission and stored at -80°C.

Description

1. Inclusion Criteria for Sepsis Group Age > 18 years; Meet the Sepsis-3 diagnostic criteria for sepsis: confirmed or suspected infection with an increase in SOFA score (Sequential Organ Failure Assessment) of ≥ 2 points from baseline; Develop sepsis within 72 hours of ICU admission; Voluntarily sign the informed consent form (or signed by the legal representative).
2. Inclusion Criteria for Non-Sepsis Group Age > 18 years; Hospitalized in the ICU of our hospital during the same period, with no clear evidence of infection and not meeting the diagnostic criteria for sepsis; Expected ICU treatment time ≥ 24 hours; Voluntarily sign the informed consent form (or signed by the legal representative).
3. Exclusion Criteria Complicated with end-stage chronic organ failure (end-stage renal disease, decompensated liver cirrhosis (Child-Pugh Grade C), chronic heart failure NYHA Class IV), or malignant tumor; Immunocompromised or suffering from autoimmune diseases, or long-term use of glucocorticoids/immunosuppressants within the past 3 months; Pregnant and postpartum patients; Patients with incomplete data collection; Other conditions deemed unsuitable for participation in the study by the investigator (such as terminal state, refusal to cooperate with sample collection, or inability to cooperate with in-hospital and out-of-hospital follow-up).

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Sepsis group; Age > 18 years; Meet the Sepsis-3 diagnostic criteria for sepsis: confirmed or suspected infection with an increase in SOFA score (Sequential Organ Failure Assessment) of ≥ 2 points from baseline; Develop sepsis within 72 hours of ICU admission; Voluntarily sign the informed consent form (or signed by the legal representative).
Non-sepsis control group; Age > 18 years; Hospitalized in the ICU of our hospital during the same period, with no clear evidence of infection and not meeting the diagnostic criteria for sepsis; Expected ICU treatment time ≥ 24 hours; Voluntarily sign the informed consent form (or signed by the legal representative).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Whole-genome mRNA expression profiles of the sepsis group and the non-sepsis group, the list of core diagnostic biomarkers screened by multi-algorithm cross-validation (WGCNA + LASSO + SVM-RFE), and their diagnostic efficacy for early sepsis in the ICU.	Within 24 hours of ICU admission (baseline)
Results of sepsis molecular risk stratification, and differences in clinical characteristics, biological characteristics, and prognosis among different stratifications	At baseline (within 24 hours of ICU admission)
Methodological performance evaluation of the RT-LAMP rapid diagnostic method and its early diagnostic efficacy for sepsis, reporting AUC, sensitivity, specificity, positive/negative predictive values.	At baseline (within 24 hours of ICU admission)
Early diagnostic efficacy of protein/metabolic biomarkers in plasma/urine for sepsis, and AUC, sensitivity, specificity, positive/negative predictive values of the combined diagnostic model.	At baseline (within 24 hours of ICU admission

Secondary Outcome Measures

Outcome Measure	Time Frame
28-day all-cause mortality, ICU length of stay, and incidence of new organ dysfunction in patients.	28 days from baseline
Correlation between mRNA expression levels and protein expression levels of core biomarkers and 28-day all-cause mortality and SOFA score in patients	28 days from baseline
Comparison results of diagnostic efficacy between novel biomarkers/combined diagnostic models and traditional indicators PCT and CRP.	At baseline
Subgroup analysis of biomarkers (infection site, pathogen type, organ injury)	At baseline
Analysis of immune inflammatory pathway characteristics of different molecular stratifications of sepsis.	At baseline

Collaborators and Investigators

• Sponsor: Yuebei People's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2026
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): December 30, 2028

Study Registration Dates

• First Submitted: May 14, 2026
• First Submitted That Met QC Criteria: May 14, 2026
• First Posted (Actual): May 20, 2026

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 8, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Cohort study; ICU; Biomarkers; Sepsis; Early diagnosis; RT-LAMP; Bulk RNA-seq
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathological Conditions, Signs and Symptoms; Disease; Sepsis
• Other Study ID Numbers: China SMART-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No