Redefining C.difficile patient outcomes through network medicine

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PROJECT SUMMARY From asymptomatic carriage to life-threatening diarrhea and colitis, C.difficile interacts with humans through a range of phenotypes. The mechanisms underlying this spectrum are incompletely understood. Despite progress in the understanding of the disease and the advent of newer therapies, patient outcomes such as failure to respond promptly to therapy (~20%), recurrence (~21%), death, colectomy or need for critical care (severe outcomes, ~3 %) remain common. As patient-centered outcomes (PCOs) take center stage in clinical research, C.difficile Infection (CDI) will not be an exception. This Career Development proposal is based on the central hypothesis that integrated analysis of immune, microbial and metabolic data (IMM/d) from new and existing cohorts of CDI patients and carriers, by identifying biological markers and pathways, can transform patient outcomes (especially PCOs) and re-categorize the CDI to colonization continuum (CDI/cc). Javier A. Villafuerte Gálvez [JVG], MD is an Instructor at Harvard Medical School (HMS) and a gastroenterologist subspecialized in immune-mediated digestive disease at Beth Israel Deaconess Medical Center (BIDMC). He has gained substantial experience in clinical and translational research during his post-doctoral and T32 fellowships while proving commitment to a patient centered research career. This Award will provide the applicant with the opportunity to develop quantitative analysis skill while taking full advantage of mentored research opportunities to address knowledge gaps in prediction, classification and pathobiology of CDI. Dr. Ciarán P. Kelly, an expert in CDI and bowel inflammation will serve as mentor, along with Dr. Yang-Yu Liu, an expert in bioinformatics studying the dynamics of the human gut microbiome who will be co-mentor. The Advisory Committee composed by CDI and methodological experts (Drs. Garey, Pollock, Gerszten and Dubberke) will confer regularly with the applicant to evaluate progress. The K23 award will aid JVG to establish an independent research program applying bioinformatics tools to unmet needs in immune-digestive disorders, with CDI as a first model. The backbone of the curriculum will be the Master in Biomedical Informatics at HMS. Grant writing training and support through Harvard Catalyst will be critical. The first aim of this project is to identify fecal IMM/d biological markers and pathways at the time of CDI diagnosis associated with severe outcomes, recurrence and disease trajectory. Informed by this, we will recruit a new CDI cohort to measure PCOs (symptoms, quality of life) while collecting biospecimens, in order to identify IMM/d biological markers and pathways predicting and underlying PCOs. Finally, with IMM/d as substrate to machine learning algorithms blinded to standard diagnostics, we will re-categorize patients in the CDI/cc in new functional disease groupings. This research will answer critical questions in CDI diagnostics, prognostication and pathobiology while placing PCOs at the forefront, generating foundational data for R-level proposals.