Identification of pediatric septic shock subclasses based on genome-wide expression profiling

Wong, Hector R.; Cvijanovich, Natalie Z.; Lin, Richard J.; Allen, Geoffrey L.; Thomas, Neal J.; Willson, Douglas F.; Freishtat, Robert J.; Anas, Nick; Meyer, Keith; Checchia, Paul A.; Monaco, Marie; Odom, Kelli; Shanley, Thomas P.

doi:10.1186/1741-7015-7-34

Cited by 244 publications

(274 citation statements)

References 44 publications

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“…The study is ongoing and our intent is to analyze mortality in a separate manuscript. Importantly, whole blood-based expression profiling clearly yields biologically relevant information (11,12,(42)(43)(44). These findings can be rapidly translated to the bedside to facilitate novel diagnostic and prognostic testing.…”

Section: Discussionmentioning

confidence: 98%

Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis

Wynn

Guthrie

Wong

et al. 2015

Mol Med

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Neonates manifest a unique host response to sepsis even among other children. Preterm neonates may experience sepsis soon after birth or during often-protracted birth hospitalizations as they attain physiologic maturity. We examined the transcriptome using genome-wide expression profiling on prospectively collected peripheral blood samples from infants evaluated for sepsis within 24 h after clinical presentation. Simultaneous plasma samples were examined for alterations in inflammatory mediators. Group designation (sepsis or uninfected) was determined retrospectively on the basis of clinical exam and laboratory results over the next 72 h from the time of evaluation. Unsupervised analysis showed the major node of separation between groups was timing of sepsis episode relative to birth (early, <3 d, or late, ≥3 d). Principal component analyses revealed significant differences between patients with early or late sepsis despite the presence of similar key immunologic pathway aberrations in both groups. Unique to neonates, the uninfected state and host response to sepsis is significantly affected by timing relative to birth. Future therapeutic approaches may need to be tailored to the timing of the infectious event based on postnatal age.

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Section: Discussionmentioning

confidence: 98%

Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis

Wynn

Guthrie

Wong

et al. 2015

Mol Med

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“…Recently, there has been an attempt to identify septic shock subclasses in children based on genome-wide expression profiling [11]. Complete microarray data from a large cohort of children with septic shock, representing the first 24 hours of admission, were used to identify septic shock subclasses.…”

Section: Gene-expression-based Identification Of Septic Shock Subclassesmentioning

confidence: 99%

Clinical review: Sepsis and septic shock - the potential of gene arrays

Wong

2012

Critical Care

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Over the past decade several investigators have applied microarray technology and related bioinformatic approaches to clinical sepsis and septic shock, thus allowing for an assessment of how, or if, this branch of genomic medicine has meaningfully impacted the field of sepsis research. The ability to simultaneously and efficiently measure the steady-state mRNA abundance of thousands of transcripts from a given tissue source (that is, 'transcriptomics') has provided an unprecedented opportunity to gain a broader, genome-level 'picture' of complex and heterogeneous clinical syndromes such as sepsis. A trancriptomic approach to sepsis and septic shock is technically challenging on multiple levels, but nonetheless modest, tangible advances are being realized. These include a genome-level understanding of the complexity of sepsis and septic shock, identification of novel candidate pathways and targets for potential intervention, discovery of novel, candidate diagnostic and stratification biomarkers, and the ability to stratify patients into clinically relevant, expression-based subclasses. The challenges moving forward include robust validation studies, standardization of technical approaches, standardization and further development of analytical algorithms, and large-scale collaborations.

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“…In one example of this approach, Wong and colleagues identified subclasses of pediatric septic shock based on genomewide expression profiles in an observational cohort of children (45,46). The study used an unsupervised learning approach, meaning that patients with similar geneexpression profiles were aggregated without foreknowledge of patients' outcomes.…”

Section: Identifying Biomarkers To Use For Predictive Enrichmentmentioning

confidence: 99%

Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design

Prescott

Calfee

Thompson

et al. 2016

Am J Respir Crit Care Med

272

237

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Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice.

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Identification of pediatric septic shock subclasses based on genome-wide expression profiling

Cited by 244 publications

References 44 publications

Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis

Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis

Clinical review: Sepsis and septic shock - the potential of gene arrays

Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design

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