Identification of Three Endotypes in Pediatric Acute Respiratory Distress Syndrome by Nasal Transcriptomic Profiling

  1. James Garrett Williams
  2. Rashika Joshi
  3. Rhonda Jones
  4. Toni Yunger
  5. Erin Stoneman
  6. Brian Varisco

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Abstract

1

Acute respiratory distress syndrome (ARDS) and pediatric ARDS (PARDS) can be triggered by multiple pulmonary and non-pulmonary insults and are the source of substantial morbidity and mortality. The nasal epithelium is similar to that of the lower conducting airways and nasal transcriptomic profiling identifies disease and endotypes in lung cancer, COPD, and asthma. We conducted a prospective trial of testing whether this technique could identify PARDS endotypes in 26 control and 25 PARDS subjects <18 admitted to the PICU extracting RNA from inferior turbinate brushings on days 1, 3, 7, and 14. Standard RNA processing and mRNA-seq yielded ~25% usable specimens and a modified, low-input RNA protocol yielded 95% usable specimens. Sixty-four low-input specimens from 10 control and 15 PARDS subjects were used for initial analysis. Control and some PARDS subjects clustered together in both by-day and combined analysis into Groups A while some day 1, 3, and 7 specimens from the same subjects clustered into Groups B and C with specimens from these subjects moving to Group A with PARDS resolution. In multivariate analysis, the only clinical variables predictive of Group B or C status was severity of lung injury or viral PARDS trigger. Compared to Group A, Group B had upregulation of innate immune processes and group C had upregulation of cilia-associated processes. Analysis of the 15 specimens processed and analyzed by standard techniques identified the same processes as differentiating Groups A, B, and C. Mortality appeared to be higher in group B (25%) and C subjects (28.6%) compared to A subject (5%, p=0.1). Our findings demonstrate three distinct PARDS endotypes which may be useful for prognostic and therapeutic enrichment. ClinicalTrials.gov Identifier NCT03539783

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    SciScore for 10.1101/2020.04.28.20083451: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Human Subjects Research: Studies were approved by the Cincinnati Children’s Hospital Institutional Review Board (IRB 2015-8514 & 2017-1345) and registered with ClinicalTrial.gov (NCT#03539783).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Clinical and biometric parameters at the times of enrollment and specimen collection were recorded in a RedCap database.
    RedCap
    suggested: (REDCap, RRID:SCR_003445)
    Statistical Analysis: Clusters were defined using Euclidean distance and principal component analysis in DESeq2 version 1.22.2. 22 For upstream analyses, ToppGene 23 and Ingenuity Pathway Analysis (v 20.0)24 were used with Bonferroni-corrected p-value (q-value) of less than 0.1 considered significant.
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    ToppGene
    suggested: ( ToppGene Suite , RRID:SCR_005726)
    Ingenuity Pathway Analysis
    suggested: (Ingenuity Pathway Analysis, RRID:SCR_008653)
    R-v3.5.3 was used for all statistical analyses using ggplot2 and finalfit v-1.0.0 25 with p-values of <0.05 considered significant using Fisher Exact test for nominal and ordinal data and Wilcoxon-Rank Sum and Kruskal-Wallis tests with Dunn’s post hoc text for continuous data.
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT03539783RecruitingIdentifying PARDS Endotypes

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.04.28.20083451v3 on medRxiv
  3. Version published to 10.1101/2020.04.28.20083451v2 on medRxiv
  4. Version published to 10.1101/2020.04.28.20083451v1 on medRxiv