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<!DOCTYPE html>
<html lang="" xml:lang="">
<head>
<title>Designing Microbiome Trials: Gut Microbiota for Health World Summit 2022</title>
<meta charset="utf-8" />
<meta name="author" content="Brendan J. Kelly, MD, MS" />
<meta name="date" content="2022-03-12" />
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<body>
<textarea id="source">
exclude: true
---
class: top left hide-count
background-image: url(img/cdc-QEU-QgIOJKA-unsplash_darkest.jpg)
background-size: cover
.move-top20[
.title-text[<span style='font-size:0.75em'>Designing Microbiome Trials</span>]
.title-subtext[<span style='font-size:1.2em'>Unique Challenges & Considerations</span>]
]
.callout-url-leftcorner[
.title-nametext[
Brendan J. Kelly, MD, MS
Infectious Diseases, Microbiology & Epidemiology
University of Pennsylvania
GMFH World Summit
12 March 2022
]
]
.footnote-right[<span style='color: white'>photo: CDC @unsplash</span>]
---
## Disclosures
.pad-left[
- No conflicts of interest.
- Research supported by:
- NIAID K23 AI121485
- CDC BAA 200-2016-91964
- CDC BAA 200-2016-91937
- CDC BAA 200-2018-02919
- CDC BAA 200-2021-10986
]
---
class: full-screen hide-count
<div class="grid-3-1">
<div class="extension-tile gridset-a animated flipInY"><div>How Randomized Trials Go Wrong</div></div>
</div>
---
layout: false
class: full-screen hide-count
<div class="grid-3-1">
<div class="extension-tile gridset-a"><div>How Randomized Trials Go Wrong</div></div>
<div class="extension-tile gridset-b animated flipInX"><div>RCTs of FMT</div></div>
</div>
---
layout: false
class: full-screen hide-count
<div class="grid-3-1">
<div class="extension-tile gridset-a"><div>How Randomized Trials Go Wrong</div></div>
<div class="extension-tile gridset-b"><div>RCTs of FMT</div></div>
<div class="extension-tile gridset-c animated bounceInDown"><div>Strategies for<br>the LBP Era</div></div>
</div>
---
layout: false
class: full-screen hide-count
<div class="grid-3-1">
<div class="extension-tile gridset-a"><div>How Randomized Trials Go Wrong</div></div>
<div class="extension-tile gridset-grey"><div>RCTs of FMT</div></div>
<div class="extension-tile gridset-grey"><div>Strategies for<br>the LBP Era</div></div>
</div>
---
## "Understanding and Misunderstanding RCTs"
.pad-left[
- Randomized clinical trials = gold standard for clinical research:
- balance known & unknown confounders
- powerful tool to measure causal effects
- RCTs can still mislead:
- selection bias (subjects ≠ population)
- "trial interventions are interactions" resulting in heterogenous effects
(subject features modify effect of trial intervention)
- "subjects aren't even fully representative of themselves"
(<u>time-varying features</u> also interact with trial intervention)
]
.footnote-left[Deaton & Cartwright _Social Science & Medicine_ 2018; Andrew Gelman]
---
## Time-Varying Gut Microbiota
<img src="./img/kelly_bioinf_2016.png" width="110%" style="display: block; margin: auto;" />
.footnote-left[Kelly et al _Bioinformatics_ 2015]
---
## Time-Varying Gut Microbiota
.pad-left[
- Dietary changes and antibiotics exert large effects...
... larger effects when followed by colonization from healthcare environment
- Gut microbiota at time of intervention ≠ microbiota at time of enrollment:
- misclassification of inclusion criteria kills randomized trials
- "the medicine doesn't work if the patient isn't sick"
- microbiome trials run a **high risk of eligibility misclassification**
]
.footnote-left[Kelly et al _ICHE_ 2021]
---
## How Microbiota Trials Go <u>Right</u>
.pad-left[
- RCTs can overcome effect modification by changing gut microbiota if:
- very precise disease phenotype (less likely time-varying gut microbiota)
- precision medicine: tailor treatment to near-real-time measures of gut microbiota
- interventions with huge effects (antibiotic conditioning prior to FMT)
]
---
layout: false
class: full-screen hide-count
<div class="grid-3-1">
<div class="extension-tile gridset-grey"><div>How Randomized Trials Go Wrong</div></div>
<div class="extension-tile gridset-b"><div>RCTs of FMT</div></div>
<div class="extension-tile gridset-grey"><div>Strategies for<br>the LBP Era</div></div>
</div>
---
## Fecal Microbiota Transplant (FMT) Trials
.pad-left[
- FMT in Infectious Diseases @ the University of Pennsylvania:
- FMT dose finding for recurrent _C. difficile_ infection (NCT03973697)
- serial FMT for severe _C. difficile_ infection (NCT03970200)
- FMT for MDRO colonization (CDC sponsored)
- Successful applications of FMT:
- recurrent & severe _C. difficile_, inflammatory bowel diseases, potentiation of anti-PD1 immunotherapy, MDRO colonization, food allergy mitigation
- heterogeneity of gut microbiota community composition?
]
---
### Microbial Heterogeneity in _C. difficile_
.pad-left[
- **Aim**: microbiome features that discriminate _C. difficile_ colonization / infection
- **Population**: 384 consecutive positive _C. difficile_ tests (in- & outpatient)
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<table class="gt_table">
<thead class="gt_col_headings">
<tr>
<th class="gt_col_heading gt_columns_bottom_border gt_left" rowspan="1" colspan="1"><i>C. difficile</i><br>Category</th>
<th class="gt_col_heading gt_columns_bottom_border gt_right" rowspan="1" colspan="1">Subject<br>Count</th>
<th class="gt_col_heading gt_columns_bottom_border gt_right" rowspan="1" colspan="1">Proportion</th>
</tr>
</thead>
<tbody class="gt_table_body">
<tr><td class="gt_row gt_left">GDH+ Toxin EIA- NAAT-</td>
<td class="gt_row gt_right">94</td>
<td class="gt_row gt_right">24.5%</td></tr>
<tr><td class="gt_row gt_left">GDH+ Toxin EIA- NAAT+</td>
<td class="gt_row gt_right">213</td>
<td class="gt_row gt_right">55.5%</td></tr>
<tr><td class="gt_row gt_left">GDH+ Toxin EIA+</td>
<td class="gt_row gt_right">77</td>
<td class="gt_row gt_right">20.1%</td></tr>
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</div>
- **Sampling**: stool 16S rRNA gene sequencing & 16S rRNA gene qPCR
- **Comparison**: toxin EIA+ (infection) versus NAAT+ only (colonization)
- **Outcome**: EIA+, with fecal lactoferrin as sensitivity analysis
]
.footnote-left[Tkatch et al _ASM World Microbiome Forum_ 2021]
---
background-image: url(figs/p_toxineia_clostridioides_boxplot_tp.png)
background-size: 65%
.footnote-left[Tkatch et al _ASM World Microbiome Forum_ 2021]
---
background-image: url(figs/p_cdi_cat_fecal_lacto_boxplot_tp.png)
background-size: 65%
.footnote-left[Tkatch et al _ASM World Microbiome Forum_ 2021]
---
## Phenotype Definitions & FMT Outcomes
.pad-left[
- The success of FMT depends on homogeneity of gut microbiota phenotype:
- moderate heterogeneity of _C. difficile_ infection
- large heterogeneity across IBD
- Pre-FMT antibiotic conditioning as a method to enforce homogeneity:
- which antibiotics are used?
- effects of other medications active on gut microbiota (e.g., PPIs)?
- FMT as part of a bundled intervention?
]
---
layout: false
class: full-screen hide-count
<div class="grid-3-1">
<div class="extension-tile gridset-grey"><div>How Randomized Trials Go Wrong</div></div>
<div class="extension-tile gridset-grey"><div>RCTs of FMT</div></div>
<div class="extension-tile gridset-c"><div>Strategies for<br>the LBP Era</div></div>
</div>
---
## Into the LBP Era
.pad-left[
- Live biotherapeutic products (LBPs) replacing FMT:
- Ferring, Seres, Vedanta, Finch...
- ensure greater homogeneity of intervention
- larger effects?
- Are bundled interventions still necessary?
- role for pre-LBP antibiotic conditioning?
- restrictions on medications that reshape gut microbial communities?
- role for precision medicine & pre-treatment microbiota profiles?
]
---
layout: false
class: full-screen hide-count
<div class="grid-3-1">
<div class="extension-tile gridset-a animated flipInY"><div>How Randomized Trials Go Wrong</div></div>
<div class="extension-tile gridset-b animated flipInX"><div>RCTs of FMT</div></div>
<div class="extension-tile gridset-c animated flipInY"><div>Strategies for<br>the LBP Era</div></div>
</div>
---
## Topics for Discussion
.pad-left[
- Every RCT intervention is an interaction:
- gut microbiota community composition varies over time
- account for changes in diet & medications, environment
- RCTs can overcome effect modification if:
- very precise disease phenotype (less likely time-varying gut microbiota)
- precision medicine: tailor treatment to near-real-time measures of gut microbiota
- interventions with huge effects (antibiotic conditioning prior to FMT)
- How to translate lessons from FMT trials to the LBP era?
]
---
exclude: true
## Acknowledgements
.pull-left[
- __ARES Group @ Penn__
Sean Loughrey, Laura Cowden, Laurel Glaser, Kyle Rodino,
Magda Wernovsky, Emily Reesey, Erik Clarke, Michael David,
Matt Ziegler, Lauren Dutcher, Ebbing Lautenbach, Jim Harrigan, Hatem Abdallah
- __Bushman Laboratory @ Penn__
Arwa Abbas, Aoife Roche, Andrew Marques,
Aubrey Bailey, Jacob Leiby,
Rick Bushman
- __PennCHOP Microbiome Program__
Lisa Mattei, Casey Hofstaedter, Huanjia Zhang, Kyle Bittinger
]
.pull-right[
- __Collman Laboratory @ Penn__
Ize Imai, Aurea Simon Soro, John McGinniss, Ron Collman
- __Division of ID @ Penn__
Ian Frank, Pablo Tebas, Robert Gross, Emily Blumberg
- __Rutgers University & Penn DBEI__
Jason Roy, Arman Oganisian
- __CDC Prevention Epicenters__
Clifford McDonald, Alison Laufer Halpin
- __Funding__
<u>CDC</u>: BAAs 200-2016-91964, 200-2018-02919, 200-2021-10986,
200-2021-10986 & <u>NIAID</u>: K23 AI121485
]
.center[
]
---
class: middle center hide-count
background-image: url(img/cdc-QEU-QgIOJKA-unsplash_darkest.jpg)
background-size: cover
.title-subtext[Questions?]
.callout-url-bottom[
.fade-in[<span style="font-size:0.5em; color:white">slides ↓ </span>]
<span style="link-color:white">[bjklab.org](http://www.bjklab.org)</span>
]
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