Developing a Clinically Feasible Personalized Medicine Approach to Pediatric Septic Shock

Wong, Hector R.; Cvijanovich, Natalie Z.; Anas, Nick; Allen, Geoffrey L.; Thomas, Neal J.; Bigham, Michael T.; Weiss, Scott L.; Fitzgerald, Julie C.; Checchia, Paul A.; Meyer, Keith; Shanley, Thomas P.; Quasney, Michael W.; Hall, Mark W.; Gedeit, Rainer; Freishtat, Robert J.; Nowak, Jeffrey; Shekhar, Raj S.; Gertz, Shira J.; Dawson, Emily; Howard, Kelli; Harmon, Kelli; Beckman, Eileen; Frank, Erin; Lindsell, Christopher J.

doi:10.1164/rccm.201410-1864oc

Cited by 246 publications

(247 citation statements)

References 28 publications

Supporting

Mentioning

229

Contrasting

Unclassified

Order By: Relevance

“…The future of sepsis therapy may yet lie with protocols that permit a more individualized approach that is based on a greater understanding of the complex interplay among host genetics, individual pathophysiological features, and the infective agent. [18][19][20] …”

Section: Discussionmentioning

confidence: 99%

Early, Goal-Directed Therapy for Septic Shock — A Patient-Level Meta-Analysis

et al. 2017

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Early, Goal-Directed Therapy for Septic Shock — A Patient-Level Meta-Analysis

et al. 2017

View full text Add to dashboard Cite

“…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%

“…The gene-expression profiles were then condensed to the 100 best subclass predictors, where the key distinguishing genes corresponded with glucocorticoid receptor signaling (47). In the subclass with suppressed glucocorticoid receptor signaling, corticosteroids were independently associated with greater mortality (46). This preliminary work provides a testable hypothesis of which patients with septic shock may benefit from corticosteroids, a therapy that remains controversial because of our current difficulty in identifying which patients will benefit (48).…”

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

View full text Add to dashboard Cite

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.

show abstract

“…We should re-evaluate such treatment 'failures' by using predictive or prognostic enrichment [69]. Treatment-responsive sub-phenotypes have been suggested for ARDS [70] and sepsis [71], and these need to be explored further. We need to identify patients in whom therapies should be avoided.…”

Section: Mediator Modulationmentioning

confidence: 99%