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Innovative Microbial Outcomes in Randomized Control Trials

  • Author(s): Ray, Kathryn
  • Advisor(s): Lietman, Thomas M
  • et al.

Randomized Control Trials (RCTs) in infectious disease can use a clinical outcome or a microbiological surrogate outcome. While caregivers are more interested in the clinical outcome, the microbiological outcome may be far more sensitive. Here I consider uncommon microbial outcomes to assess impacts of interventions in 4 different RCTs, ranging from presence of organism to microbiome diversity.

In chapter one, I design and analyze an experiment to compare community microbiome diversity estimates derived from 16s rRNA sequencing of 1) individually sequenced specimens versus 2) pooled specimens collected from a community. I then compare the gamma-estimates using Pearson’s correlation as well as conducting Bland & Altman agreement analysis. In chapter 2, I assess whether dominant genera of microbiome samples are associated with treatment or clinical outcomes in a probiotic RCT performed in cystic fibrosis pediatric patients. In chapters 3 and 4 I determine if results from a repeated fungal culture are predictive of clinical outcomes in two separate corneal ulcer RCTs.

The estimates of community level microbiome diversity from pooled samples correlated well with estimates from individual samples. Additionally, all pooled samples fell within the 95% limits of agreement. Pooling microbiome samples to estimate community level diversity as a microbiological surrogate outcome is a viable method and measure to consider in population-level association research studies. Distinct gut microbiota compositions, dominated by a particular genera, were associated with clinical outcomes in cystic fibrosis patients. These findings add to the growing body of scientific evidence that distinct gut microbiota states are associated with severity of clinical outcomes. Repeat culture positivity was strongly associated with primary clinical outcomes in two separate fungal corneal ulcer trials. Not only was repeated culture shown to be a possible surrogate outcome for corneal ulcer trials, but it also established a new standard of a care for some clinicians managing patients with fungal keratitis.

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